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Sen I, Trzaskalski NA, Hsiao YT, Liu PP, Shimizu I, Derumeaux GA. Aging at the Crossroads of Organ Interactions: Implications for the Heart. Circ Res 2025; 136:1286-1305. [PMID: 40403108 DOI: 10.1161/circresaha.125.325637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 05/24/2025]
Abstract
Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.
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Affiliation(s)
- Ilke Sen
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
| | - Natasha A Trzaskalski
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Yung-Ting Hsiao
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
| | - Peter P Liu
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Ippei Shimizu
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (I. Shimizu)
| | - Geneviève A Derumeaux
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
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Agrawal N, Afzal M, Almalki WH, Ballal S, Sharma GC, Krithiga T, Panigrahi R, Saini S, Ali H, Goyal K, Rana M, Abida Khan. Longevity mechanisms in cardiac aging: exploring calcium dysregulation and senescence. Biogerontology 2025; 26:94. [PMID: 40259024 DOI: 10.1007/s10522-025-10229-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 03/20/2025] [Indexed: 04/23/2025]
Abstract
Cardiac aging is a multistep process that results in a loss of various structural and functional heart abilities, increasing the risk of heart disease. Since its remarkable discovery in the early 1800s, when limestone is heated, calcium's importance has been defined in numerous ways. It can help stiffen shells and bones, function as a reducing agent in chemical reactions, and play a central role in cellular signalling. The movement of calcium ions in and out of cells and between those is referred to as calcium signalling. It influences the binding of the ligand, enzyme activity, electrochemical gradients, and other cellular processes. Calcium signalling is critical for both contraction and relaxation under the sliding filament model of heart muscle. However, with age, the heart undergoes changes that lead to increases in cardiac dysfunction, such as myocardial fibrosis, decreased cardiomyocyte function, and noxious disturbances in calcium homeostasis. Additionally, when cardiac tissues age, cellular senescence, a state of irreversible cell cycle arrest, accumulates and begins to exacerbate tissue inflammation and fibrosis. This review explores the most recent discoveries regarding the role of senescent cell accumulation and calcium signalling perturbances in cardiac aging. Additionally, new treatment strategies are used to reduce aged-related heart dysfunction by targeting senescent cells and modulating calcium homeostasis.
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Affiliation(s)
- Neetu Agrawal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Girish Chandra Sharma
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - T Krithiga
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rajashree Panigrahi
- Department of Microbiology IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Abida Khan
- Center For Health Research, Northern Border University, Arar 73213, Saudi Arabia
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Kobak KA, Zarzycka W, King CJ, Borowik AK, Peelor FF, Baehr LM, Leutert M, Rodriguez-Mias RA, Villén J, Bodine SC, Kinter MT, Miller BF, Chiao YA. Proteostatic Imbalance Drives the Pathogenesis and Age-Related Exacerbation of Heart Failure With Preserved Ejection Fraction. JACC Basic Transl Sci 2025; 10:475-497. [PMID: 40306856 DOI: 10.1016/j.jacbts.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 05/02/2025]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a leading cause of hospitalization and mortality in older adults, yet the role of aging in its pathogenesis remains unclear. Old male mice subjected to chronic metabolic and hypertensive stress (2-hit) developed a more severe HFpEF phenotype compared with young counterparts. We identified that age-related disruptions in protein quality control (PQC) worsens proteostatic stress in HFpEF. Mammalian target of rapamycin complex 1 (mTORC1), a key regulator of PQC, is activated by both aging and 2-hit stress, and cardiac-specific mTORC1 inhibition protects against HFpEF. Our findings highlight the need to integrate aging into preclinical models of HFpEF and suggest targeting PQC as a therapeutic strategy.
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Affiliation(s)
- Kamil A Kobak
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Weronika Zarzycka
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Catherine J King
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Agnieszka K Borowik
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Frederick F Peelor
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Leslie M Baehr
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Mario Leutert
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | | | - Judit Villén
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | - Sue C Bodine
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
| | - Michael T Kinter
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
| | - Ying Ann Chiao
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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4
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Li J, Sun Y, Ren J, Wu Y, He Z. Machine Learning for In-hospital Mortality Prediction in Critically Ill Patients With Acute Heart Failure: A Retrospective Analysis Based on the MIMIC-IV Database. J Cardiothorac Vasc Anesth 2025; 39:666-674. [PMID: 39779429 DOI: 10.1053/j.jvca.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/03/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND The incidence, mortality, and readmission rates for acute heart failure (AHF) are high, and the in-hospital mortality for AHF patients in the intensive care unit (ICU) is higher. However, there is currently no method to accurately predict the mortality of AHF patients. METHODS The Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database was used to perform a retrospective study. Patients meeting the inclusion criteria were identified from the MIMIC-Ⅳ database and randomly divided into a training set (n = 3,580, 70%) and a validation set (n = 1,534, 30%). The variates collected include demographic data, vital signs, comorbidities, laboratory test results, and treatment information within 24 hours of ICU admission. By using the least absolute shrinkage and selection operator (LASSO) regression model in the training set, variates that affect the in-hospital mortality of AHF patients were screened. Subsequently, in the training set, five common machine learning (ML) algorithms were applied to construct models using variates selected by LASSO to predict the in-hospital mortality of AHF patients. The predictive ability of the models was evaluated for sensitivity, specificity, accuracy, the area under the curve of receiver operating characteristics, and clinical net benefit in the validation set. To obtain a model with the best predictive ability, the predictive ability of common scoring systems was compared with the best ML model. RESULTS Among the 5,114 patients, in-hospital mortality was 12.5%. Comparing the area under the curve, the XGBoost model had the best predictive ability among all ML models, and the XGBoost model was chosen as the final model for its higher net benefit. Its predictive ability was superior to common scoring systems. CONCLUSIONS The XGBoost model can effectively predict the in-hospital mortality of AHF patients admitted to the ICU, which may assist clinicians in precise management and early intervention for patients with AHF to reduce mortality.
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Affiliation(s)
- Jun Li
- Department of Anesthesiology, Dazhou Central Hospital, Dazhou, Sichuan, China
| | - Yiwu Sun
- Department of Anesthesiology, Dazhou Central Hospital, Dazhou, Sichuan, China
| | - Jie Ren
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Yifan Wu
- Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai, China
| | - Zhaoyi He
- Surgical Anesthesia Center, The First People's Hospital of Longquanyi District, Chengdu, China.
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5
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Balaraman AK, Altamimi ASA, Babu MA, Goyal K, PadmaPriya G, Bansal P, Rajotiya S, Kumar MR, Rajput P, Imran M, Gupta G, Thangavelu L. The interplay of senescence and MMPs in myocardial infarction: implications for cardiac aging and therapeutics. Biogerontology 2025; 26:46. [PMID: 39832057 DOI: 10.1007/s10522-025-10190-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/04/2025] [Indexed: 01/22/2025]
Abstract
Aging is associated with a marked increase in cardiovascular diseases, such as myocardial infarction (MI). Cellular senescence is also a crucial factor in the development of age-related MI. Matrix metalloproteinases (MMPs) interaction with cellular senescence is a critical determinant of MI development and outcomes, most notably in the aged heart. After experiencing a heart attack, senescent cells exhibit a Senescence-Associated Secretory Phenotype (SASP) and are involved in tissue regeneration and chronic inflammation. MMPs are necessary for extracellular matrix proteolysis and have a biphasic effect, promoting early heart healing and detrimental change if overexpressed shortly. This review analyses the complex connection between senescence and MMPs in MI and how it influences elderly cardiac performance. Critical findings suggest that increasing cellular senescence in aged hearts elevates MMP activity and aggravates extended ventricular remodeling and dysfunction. Additionally, we explore potential therapeutics that address MMPs and senescence to enhance old MI patient myocardial performance and regeneration.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari Cyber 11, Cyberjaya, Selangor, 63000, Malaysia
| | | | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Uttar Pradesh, Mathura, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - G PadmaPriya
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Pooja Bansal
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Sumit Rajotiya
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Pranchal Rajput
- Division of Research and Innovation, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
- Center for Health Research, Northern Border University, Arar, Saudi Arabia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Punjab, India
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Lakshmi Thangavelu
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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Kleynerman A, Rybova J, McKillop WM, Dlugi TA, Faber ML, Fuller M, O'Meara CC, Medin JA. Cardiac dysfunction and altered gene expression in acid ceramidase-deficient mice. Am J Physiol Heart Circ Physiol 2025; 328:H141-H156. [PMID: 39665198 DOI: 10.1152/ajpheart.00289.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 12/13/2024]
Abstract
Farber disease (FD) is an ultrarare, autosomal-recessive, lysosomal storage disorder attributed to ASAH1 gene mutations. FD is characterized by acid ceramidase (ACDase) deficiency and the accumulation of ceramide in various tissues. Classical FD patients typically manifest symptoms including lipogranulomatosis, respiratory complications, and neurological deficits, often leading to mortality during infancy. Cardiac abnormalities in several FD patients have been described; however, a detailed examination of cardiac pathology in FD has not been conducted. Here we report pronounced cardiac pathophysiology in a new P361R-FD mouse model of ACDase deficiency that we generated. P361R-FD mice displayed smaller hearts, altered cardiomyocyte architecture, disrupted tissue composition, and inclusion-containing macrophages. Echocardiography suggested ventricular atrophy, valve dysfunction, decreased cardiac output, and lowered stroke volumes. Troponin I was significantly elevated in P361R-FD mice. Hearts from P361R-FD mice were found to have increased ceramide, cholesterol, and other lipids. Histopathological analysis of heart tissue from neonatal P361R-FD mice revealed lysosomal disruption as early as postnatal day 1. Finally, we report cardiac conduction, striated muscle contraction, and sphingolipid homeostasis gene expression differences during cardiac development in P361R-FD mice. In summary, we investigated the heart in a mouse model of ACDase deficiency, demonstrating that ACDase deficiency induced lysosomal dysfunction, sphingolipid and cholesterol imbalances, tissue disruption, and significant inflammation, leading to impaired cardiac function in these animals.NEW & NOTEWORTHY This is the first characterization of cardiac function and histopathology in a mouse model of acid ceramidase deficiency. We report physiologic disruption suggestive of heart failure with preserved ejection fraction, progressive histopathology, and aberrant gene expression. We found significant lysosomal disruption at both neonatal and adult ages, suggesting a crucial role of acid ceramidase, and potentially ceramides, in cardiac development and function.
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Affiliation(s)
- Annie Kleynerman
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Jitka Rybova
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - William M McKillop
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Theresa A Dlugi
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Mary L Faber
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Maria Fuller
- Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, Adelaide Medical School and School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Caitlin C O'Meara
- Department of Physiology, Cardiovascular Center, and Genomics Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Jeffrey A Medin
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
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7
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Bahrami P, Aromolaran KA, Aromolaran AS. Mechanistic Relevance of Ventricular Arrhythmias in Heart Failure with Preserved Ejection Fraction. Int J Mol Sci 2024; 25:13423. [PMID: 39769189 PMCID: PMC11677834 DOI: 10.3390/ijms252413423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/05/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is increasing at an alarming rate worldwide, with limited effective therapeutic interventions in patients. Sudden cardiac death (SCD) and ventricular arrhythmias present substantial risks for the prognosis of these patients. Obesity is a risk factor for HFpEF and life-threatening arrhythmias. Obesity and its associated metabolic dysregulation, leading to metabolic syndrome, are an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese, leading to an enhanced risk of incidence and mortality due to cardiovascular disease (CVD). Obesity predisposes patients to atrial fibrillation and ventricular and supraventricular arrhythmias-conditions that are caused by dysfunction in the electrical activity of the heart. To date, current therapeutic options for the cardiomyopathy of obesity are limited, suggesting that there is considerable room for the development of therapeutic interventions with novel mechanisms of action that will help normalize sinus rhythms in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca-handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels and Ca-handling proteins remain incompletely understood. Obesity is marked by the accumulation of adipose tissue, which is associated with a variety of adverse adaptations, including dyslipidemia (or abnormal systemic levels of free fatty acids), increased secretion of proinflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, which cause electrical remodeling and, thus, predispose patients to arrhythmias. Furthermore, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which is marked by distinct signaling mechanisms. Thus, there may also be functional differences in the effects of the regional distribution of fat deposits on ion channel/Ca-handling protein expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge of the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. Nevertheless, substantial knowledge gaps remain regarding HFpEF treatment, requiring further investigations to identify potential therapeutic targets. The objective of this study is to review cardiac ion channel/Ca-handling protein remodeling in the predisposition to metabolic HFpEF and arrhythmias. This review further highlights interleukin-6 (IL-6) as a potential target, cardiac bridging integrator 1 (cBIN1) as a promising gene therapy agent, and leukotriene B4 (LTB4) as an underappreciated pathway in future HFpEF management.
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Affiliation(s)
- Pegah Bahrami
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, 95 S 2000 E, Salt Lake City, UT 84112, USA; (P.B.); (K.A.A.)
| | - Kelly A. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, 95 S 2000 E, Salt Lake City, UT 84112, USA; (P.B.); (K.A.A.)
| | - Ademuyiwa S. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, 95 S 2000 E, Salt Lake City, UT 84112, USA; (P.B.); (K.A.A.)
- Department of Surgery, Division of Cardiothoracic Surgery, Nutrition & Integrative Physiology, Biochemistry & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
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Arcuri G, Valente C, Romito G, Bonsembiante F, Mazzoldi C, Contiero B, Poser H, Guglielmini C. Evaluation of Galectin-3 in Dogs with Atrial Fibrillation. Animals (Basel) 2024; 14:2547. [PMID: 39272333 PMCID: PMC11394297 DOI: 10.3390/ani14172547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Galectin-3 (Gal-3) is a lectin associated with fibrosis and inflammation, and increased circulating concentrations are considered a risk factor for atrial fibrillation (AF) in humans. This retrospective study aimed to evaluate the serum concentration of Gal-3 in dogs with cardiac disease, both with and without AF. Dogs with AF associated with acquired heart diseases were selected, while cardiac healthy dogs and dogs with heart diseases but without AF served as controls. We statistically compared the serum concentration of Gal-3, which was assessed using a commercial canine-specific ELISA kit, among healthy dogs and dogs with heart disease with and without AF. Additionally, associations between Gal-3 and clinical and echocardiographic variables were evaluated. A total of 73 dogs were included, of which 17/73 (23.3%) were cardiac healthy and 56/73 (76.7%) had heart disease, with 26/56 (46.4%) having AF. No significant difference in Gal-3 concentration was found between cardiac healthy dogs (3.90 ± 1.65 ng/mL) and dogs with heart disease, either with or without AF (3.37 ± 1.04 ng/mL, p = 0.436 and 4.68 ± 1.80 ng/mL, p = 0.332, respectively). Gal-3 showed a significant positive correlation with age (r = 0.47, p < 0.001) and a negative correlation with body weight (r = -0.45, p < 0.001). The results of this study suggest that Gal-3 does not have an important role in the development of AF in dogs, but it is associated with advanced age.
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Affiliation(s)
- Giulia Arcuri
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
| | - Carlotta Valente
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
| | - Giovanni Romito
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, Italy
| | - Federico Bonsembiante
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
| | - Chiara Mazzoldi
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, Italy
| | - Barbara Contiero
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
| | - Helen Poser
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
| | - Carlo Guglielmini
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Padua, Italy
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9
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Sahu Y, Jamadade P, Ch Maharana K, Singh S. Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside. Mitochondrion 2024; 78:101923. [PMID: 38925493 DOI: 10.1016/j.mito.2024.101923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing.
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Affiliation(s)
- Yogita Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Pratiksha Jamadade
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Krushna Ch Maharana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India.
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10
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Shi Y, Zhao L, Wang J, Liu X, Bai Y, Cong H, Li X. Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis. Cardiovasc Diabetol 2024; 23:269. [PMID: 39044275 PMCID: PMC11267814 DOI: 10.1186/s12933-024-02366-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/16/2024] [Indexed: 07/25/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.
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Affiliation(s)
- Ying Shi
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Lili Zhao
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Jing Wang
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Xiankun Liu
- Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Yiming Bai
- Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China
| | - Hongliang Cong
- Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China.
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China.
- Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China.
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China.
| | - Ximing Li
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China.
- Chest Hospital, Tianjin University, Tianjin, 300072, China.
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China.
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11
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Lu J, Zhao Q, Wang L, Li J, Wang H, Lv L, Yuan M, Chen Q, Zhang Z, Luo D, Sheng S, Yuan K, Liu G, Liu M, Shi Y, Guo Y, Dong Z. MBNL2 promotes aging-related cardiac fibrosis via inhibited SUMOylation of Krüppel-like factor4. iScience 2024; 27:110163. [PMID: 38974966 PMCID: PMC11226984 DOI: 10.1016/j.isci.2024.110163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 02/06/2024] [Accepted: 05/29/2024] [Indexed: 07/09/2024] Open
Abstract
Aging-related cardiac fibrosis represents the principal pathological progression in cardiovascular aging. The Muscleblind-like splicing regulator 2 (MBNL2) has been unequivocally established as being associated with cardiovascular diseases. Nevertheless, its role in aging-related cardiac fibrosis remains unexplored. This investigation revealed an elevation of MBNL2 levels in the aged heart and senescent cardiac fibroblasts. Notably, the inhibition of MBNL2 demonstrated a capacity to mitigate H2O2-induced myofibroblast transformation and aging-related cardiac fibrosis. Further mechanistic exploration unveiled that aging heightened the expression of SENP1 and impeded the SUMO1 binding with KLF4, and SUMOylation of KLF4 effectively increased by the inhibition of MBNL2. Additionally, the inhibition of TGF-β1/SMAD3 signaling attenuated the impact of over-expression of MBNL2 in inducing senescence and cardiac fibrosis. MBNL2, by orchestrating SUMOylation of KLF4, upregulating the TGF-β1/SMAD3 signaling pathway, emerges as a significant promoter of aging-related cardiac fibrosis. This discovery identifies a novel regulatory target for managing aging-related cardiac fibrosis.
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Affiliation(s)
- Jing Lu
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Qi Zhao
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Lu Wang
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Jiahao Li
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Hongyan Wang
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Lin Lv
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Experimental Animal Center, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
| | - Meng Yuan
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Qiuyu Chen
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Zixin Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Health Care Road, Nangang District, Harbin 150081, China
| | - Dankun Luo
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
| | - Siqi Sheng
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Keying Yuan
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Guannan Liu
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Mingyu Liu
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Yuanqi Shi
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
| | - Yuanyuan Guo
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Department of Cardiology, Department of Geriatrics, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
| | - Zengxiang Dong
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
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Calvo-López M, Ortega-Paz L, Jimenez-Trinidad FR, Brugaletta S, Sabaté M, Dantas AP. Sex-associated differences in cardiac ageing: Clinical aspects and molecular mechanisms. Eur J Clin Invest 2024; 54:e14215. [PMID: 38624065 DOI: 10.1111/eci.14215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/17/2024]
Abstract
Despite the extensive clinical and scientific advances in prevention, diagnostics and treatment, cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality worldwide for people aged 65 and over. Of all ageing-related diseases, CVD are responsible for almost one-third of deaths in the elderly, being above all cancers combined. Age is an independent and unavoidable risk factor contributing to the impairment of heart and blood vessels. As the average age of the population in industrialized countries has doubled in the last century, and almost a fifth of the world's population is predicted to be over 65 in the next decade, we can assume that the burden of CVD will fall primarily on the elderly. Evidence from basic and clinical science has shown that sex significantly influences the onset and severity of CVD. In women, CVD usually develop later than in men and with atypical symptomatology. After menopause, however, the incidence and severity of CVD increase in women, reaching equality in both sexes. Although intrinsic sexual dimorphism in cardiovascular ageing may contribute to the sex differences in CVD progression, the molecular mechanisms associated with cardiovascular ageing and their clinical value are not known in detail. In this review, we discuss the scientific knowledge available, focusing on structural, hormonal, genetic/epigenetic and inflammatory pathways, seeking to transfer these findings to the cardiovascular clinic in terms of prevention, diagnosis, prognosis and management of these pathologies and proposing possible validation of target specifics.
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Affiliation(s)
- Margarita Calvo-López
- Clínic's Cardiovascular Institute (ICCV), Hospital Clinic of Barcelona, Barcelona, Spain
| | - Luis Ortega-Paz
- Department of Medicine, Division of Cardiology, UF Health Cardiovascular Center, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
| | - Francisco Rafael Jimenez-Trinidad
- Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Salvatore Brugaletta
- Clínic's Cardiovascular Institute (ICCV), Hospital Clinic of Barcelona, Barcelona, Spain
- Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Manel Sabaté
- Clínic's Cardiovascular Institute (ICCV), Hospital Clinic of Barcelona, Barcelona, Spain
- Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ana Paula Dantas
- Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
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13
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Stoicescu L, Crişan D, Morgovan C, Avram L, Ghibu S. Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach. Int J Mol Sci 2024; 25:794. [PMID: 38255869 PMCID: PMC10815792 DOI: 10.3390/ijms25020794] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/27/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is an increasingly frequent form and is estimated to be the dominant form of HF. On the other hand, HFpEF is a syndrome with systemic involvement, and it is characterized by multiple cardiac and extracardiac pathophysiological alterations. The increasing prevalence is currently reaching epidemic levels, thereby making HFpEF one of the greatest challenges facing cardiovascular medicine today. Compared to HF with reduced ejection fraction (HFrEF), the medical attitude in the case of HFpEF was a relaxed one towards the disease, despite the fact that it is much more complex, with many problems related to the identification of physiopathogenetic mechanisms and optimal methods of treatment. The current medical challenge is to develop effective therapeutic strategies, because patients suffering from HFpEF have symptoms and quality of life comparable to those with reduced ejection fraction, but the specific medication for HFrEF is ineffective in this situation; for this, we must first understand the pathological mechanisms in detail and correlate them with the clinical presentation. Another important aspect of HFpEF is the diversity of patients that can be identified under the umbrella of this syndrome. Thus, before being able to test and develop effective therapies, we must succeed in grouping patients into several categories, called phenotypes, depending on the pathological pathways and clinical features. This narrative review critiques issues related to the definition, etiology, clinical features, and pathophysiology of HFpEF. We tried to describe in as much detail as possible the clinical and biological phenotypes recognized in the literature in order to better understand the current therapeutic approach and the reason for the limited effectiveness. We have also highlighted possible pathological pathways that can be targeted by the latest research in this field.
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Affiliation(s)
- Laurențiu Stoicescu
- Internal Medicine Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (L.S.); or (D.C.); or (L.A.)
- Cardiology Department, Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Dana Crişan
- Internal Medicine Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (L.S.); or (D.C.); or (L.A.)
- Internal Medicine Department, Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania
| | - Lucreţia Avram
- Internal Medicine Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania; (L.S.); or (D.C.); or (L.A.)
- Internal Medicine Department, Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
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14
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Carvalho RA. The glycolytic pathway to heart failure. GLYCOLYSIS 2024:235-266. [DOI: 10.1016/b978-0-323-91704-9.00010-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Seropian IM, Cassaglia P, Miksztowicz V, González GE. Unraveling the role of galectin-3 in cardiac pathology and physiology. Front Physiol 2023; 14:1304735. [PMID: 38170009 PMCID: PMC10759241 DOI: 10.3389/fphys.2023.1304735] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.
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Affiliation(s)
- Ignacio M. Seropian
- Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Instituto de Investigaciones Biomédicas (UCA-CONICET), Facultad de Ciencias Médicas Universidad Católica Argentina, Buenos Aires, Argentina
- Servicio de Hemodinamia, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Pablo Cassaglia
- Departamento de Patología, Instituto de Salud Comunitaria, Universidad Nacional de Hurlingham, Buenos Aires, Argentina
| | - Verónica Miksztowicz
- Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Instituto de Investigaciones Biomédicas (UCA-CONICET), Facultad de Ciencias Médicas Universidad Católica Argentina, Buenos Aires, Argentina
| | - Germán E. González
- Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Instituto de Investigaciones Biomédicas (UCA-CONICET), Facultad de Ciencias Médicas Universidad Católica Argentina, Buenos Aires, Argentina
- Departamento de Patología, Instituto de Salud Comunitaria, Universidad Nacional de Hurlingham, Buenos Aires, Argentina
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Sivri F, Icen YK, Koca H, Coşkun M, Ardınç M, Deniz O, Arici FN, Koc M, Güngör H. Selvester QRS Score is a Predictor of Mortality in Heart Failure with Preserved Ejection Fraction. Arq Bras Cardiol 2023; 120:e20230235. [PMID: 37820175 PMCID: PMC10519357 DOI: 10.36660/abc.20230235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 06/15/2023] [Accepted: 07/17/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND The Selvester QRS (S-QRS) score on a 12-lead electrocardiogram (ECG) is associated with both the amount of myocardial scar and poor prognosis in myocardial infarction patients. However, its prognostic value in heart failure (HF) with preserved ejection fraction (HFpEF) is unknown. OBJECTIVE This study aims to investigate the predictive value of the S-QRS score for mortality in HFpEF. METHODS 359 patients were retrospectively enrolled in this study. Electrocardiographic, echocardiographic, and laboratory features of the patients were recorded. The simplified S-QRS score was measured and recorded. The mean follow-up time of the patients was 38.1±9.5 months. Statistical significance was set at p < 0.05. RESULTS Of 359 patients, 270 were in the survivor group, and 89 were in the deceased group. Age, Hs-CRP, troponin, pro-BNP, left atrial (LA) diameter, LA volume index, QRS duration, Tpe, and S-QRS score were statistically high in the deceased group. In multivariate logistic regression analysis, age, Hs-CRP, NT-proBNP, LA diameter, LA volume index, Tpe, and S-QRS score were shown to be independent risk factors for mortality. In the receiver-operating characteristic (ROC) analysis, the cut-off value of the S-QRS score was 5.5, the sensitivity was 80.8%, and the specificity was 77.2% (AUC:0.880, p:0.00). In Kaplan-Meier analysis, it was found that mortality was higher in the group with S-QRS score ≥ 5.5 than in the group with S-QRS score < 5.5. (Long-rank, p:0.00). CONCLUSIONS We think that the S-QRS score can be used as a prognostic indicator of long-term mortality in patients with HFpEF.
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Affiliation(s)
- Fatih Sivri
- Nazilli State HospitalDepartment of CardiologyAydinTurquiaNazilli State Hospital – Department of Cardiology, Aydin – Turquia
| | - Yahya Kemal Icen
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Hasan Koca
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Mükremin Coşkun
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Mustafa Ardınç
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Orshan Deniz
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Fatih Necip Arici
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Mevlüt Koc
- Adana Health Practice and Research CenterDepartment of CardiologyAdanaTurquiaAdana Health Practice and Research Center – Department of Cardiology, Adana – Turquia
| | - Hasan Güngör
- Adnan Menderes UniversityDepartment of CardiologyAydinTurquiaAdnan Menderes University – Department of Cardiology, Aydin – Turquia
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17
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Park K, Park TH. Comparative effects of nebivolol and carvedilol on left ventricular diastolic function in older patients with heart failure and preserved ejection fraction. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2023; 18:200201. [PMID: 37575339 PMCID: PMC10415684 DOI: 10.1016/j.ijcrp.2023.200201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 07/06/2023] [Accepted: 07/27/2023] [Indexed: 08/15/2023]
Abstract
Background Although many studies have compared carvedilol and nebivolol in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF), such comparative studies for the elderly have not been reported yet. Nebivolol is known to be effective for improving diastolic function of elderly patients with HF. Thus, this study aimed to determine whether nebivolol could improve LV diastolic function to a greater extent than carvedilol in older patients aged over 70 years. Methods This trial was a prospective, randomized, open-label, single-center, active-controlled study that enrolled 62 patients with class II or III HF over 70 years of age with an LVEF ≥40%. Patients were randomized into a carvedilol group or a nebivolol group. Transthoracic echocardiography was performed at baseline and 12 months by the same investigator who was blinded to clinical data. The primary endpoint was E/e' measured by echocardiographic evaluation 12 months after treatment. Results The median duration of follow-up was 24 months. Baseline clinical characteristics and echocardiographic parameters, such as LV diastolic function indices, did not differ significantly between carvedilol and nebivolol groups. Twelve-month follow-up echocardiography data showed no significant difference in E/e' or other LV diastolic function indices between the two groups. There were no significant changes in echocardiographic parameters over 12 months in either group. Conclusions There was no difference between carvedilol and nebivolol for improving diastolic function of elderly HF patients with LVEF ≥40%. This study showed no superiority of nebivolol over carvedilol in elderly patients with HF.
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Affiliation(s)
- Kyungil Park
- Regional Cardiocerebrovascular Center, Dong-A University Hospital; Division of Cardiology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Tae-Ho Park
- Regional Cardiocerebrovascular Center, Dong-A University Hospital; Division of Cardiology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
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18
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Ahmed F, Kahlon T, Mohamed TMA, Ghafghazi S, Settles D. Literature Review: Pathophysiology of Heart Failure with Preserved Ejection Fraction. Curr Probl Cardiol 2023; 48:101745. [PMID: 37087081 DOI: 10.1016/j.cpcardiol.2023.101745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 04/14/2023] [Indexed: 04/24/2023]
Abstract
Heart failure with preserved ejection fraction is a growing public health concern, a disease with poor health outcomes, and is showing increased prevalence globally. This review paper explores the literature with a focus on the pathophysiology and microbiology of preserved ejection fraction heart failure while drawing connections between preserved and reduced ejection fraction states. The discussion teases out the cellular level changes that affect the overall dysfunction of the cardiac tissue, including the clinical manifestations, microbiological changes (endothelial cells, fibroblasts, cardiomyocytes, and excitation-contraction coupling), and the burden of structural diastolic dysfunction. The goal of this review is to summarize the pathophysiological disease state of heart failure with preserved ejection fraction to enhance understanding, knowledge, current treatment models of this pathology.
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Affiliation(s)
- Faizan Ahmed
- Department of Anesthesiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
| | - Tani Kahlon
- Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Tamer M A Mohamed
- Department of Cardiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Shahab Ghafghazi
- Department of Cardiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Dana Settles
- Department of Cardiothoracic Anesthesia, University of Louisville School of Medicine, Louisville, Kentucky, USA
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19
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Fragasso G. The Concept of "Heart Failure with Preserved Ejection Fraction": Time for a Critical Reappraisal. Rev Cardiovasc Med 2023; 24:202. [PMID: 39076999 PMCID: PMC11266467 DOI: 10.31083/j.rcm2407202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 07/31/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is frequently observed in elderly physically deconditioned subjects, mainly women with hypertension, obesity, glucose intolerance/diabetes, atrial fibrillation, anaemia, coronary artery disease, chronic pulmonary disease, and chronic renal insufficiency. In practice, these conditions represent the majority of cardiac diseases we deal with in our daily clinical practice. For this reason, the HFpEF disease does not exist as a single entity and, as such, no specific unifying therapy could be found. New classification attempts still do not consider the multifaceted aspect of the HF syndrome and appear rather as an artefactual attempt to categorize a condition which is indeed not categorizable. The aim of the present article is to critically review the construction of the concept of the HFpEF syndrome and propose the return of a pathophysiological approach in the evaluation and treatment of patients. Considering the huge economic efforts employed up to date to run awfully expensive trials and research in this field, it is time to call action and redirect such resources towards more specific pathophysiological classifications and potential specific therapeutic targets.
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Affiliation(s)
- Gabriele Fragasso
- Heart Failure Clinic, Istituto Scientifico San Raffaele, 20132 Milano, Italy
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20
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Lira JR, Guymon AL, Yang L, Sternburg JO, Giri S, Wang X. The double-hit protocol induces HFpEF and impairs myocardial ubiquitin-proteasome system performance in FVB/N mice. Front Physiol 2023; 14:1208153. [PMID: 37362441 PMCID: PMC10285383 DOI: 10.3389/fphys.2023.1208153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a leading cause of death and disability, with its prevalence surpassing that of heart failure with reduced ejection fraction. Obesity and hypertension are often associated with HFpEF. HFpEF can be modeled through simultaneous metabolic and hypertensive stresses in male C57BL/6N mice provoked by a combination treatment of a high-fat diet (HFD) and constitutive nitric oxide synthase inhibition by Nω-nitro-L-arginine methyl-ester (L-NAME). Ubiquitin-proteasome system (UPS) dysfunction was detected in many forms of cardiomyopathy, but whether it occurs in HFpEF remains unknown. We report successful modeling of HFpEF in male FVB/N mice and, by taking advantage of a transgenic UPS reporter mouse, we have detected myocardial UPS functioning impairment during HFpEF, suggesting a pathogenic role for impaired protein degradation in the development and progression of HFpEF.
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21
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Jankauskas SS, Mone P, Avvisato R, Varzideh F, De Gennaro S, Salemme L, Macina G, Kansakar U, Cioppa A, Frullone S, Gambardella J, Di Mauro M, Tesorio T, Santulli G. miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction. Mech Ageing Dev 2023; 212:111818. [PMID: 37116731 DOI: 10.1016/j.mad.2023.111818] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 04/15/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Cardiac fibrosis represents a key feature in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), a condition highly prevalent amongst geriatric patients, especially if diabetic. The microRNA miR-181c has been shown to be associated with the response to exercise training in HFpEF patients and has been also linked to diabetic cardiovascular complications. However, the underlying mechanisms have not been fully elucidated. OBJECTIVE To measure circulating miR-181c in elderly patients with HFpEF and DM and identify gene targets pathophysiologically relevant in HFpEF. METHODS We quantified circulating miR-181c in frail older adults with a confirmed diagnosis of HFpEF and diabetes, and, as control, we enrolled age-matched subjects without HFpEF and without diabetes. We validated in human cardiac fibroblasts the molecular mechanisms linking miR-181c to a pro-fibrotic response. RESULTS 51 frail patients were included (34 patients with diabetes and HFpEF and 17 age-matched controls. We observed that miR-181c was significantly upregulated (p<0.0001) in HFpEF patients vs controls. We confirmed in vitro that miR-181c is targeting PRKN and SMAD7. CONCLUSIONS We demonstrate that miR-181c levels are significantly increased in frail elderly adults with diabetes and HFpEF and that miR-181c targets PRKN and SMAD7 in human cardiac fibroblasts.
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Affiliation(s)
- Stanislovas S Jankauskas
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA; ASL Avellino, Avellino, 83100, Italy
| | - Roberta Avvisato
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Fahimeh Varzideh
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | - Luigi Salemme
- Casa di Cura "Montevergine", Mercogliano (Avellino), 83013, Italy
| | | | - Urna Kansakar
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Angelo Cioppa
- Casa di Cura "Montevergine", Mercogliano (Avellino), 83013, Italy
| | | | - Jessica Gambardella
- Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | - Tullio Tesorio
- Casa di Cura "Montevergine", Mercogliano (Avellino), 83013, Italy
| | - Gaetano Santulli
- Department of Medicine, Einstein Institute for Aging Research, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA.
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Wahabi H, Esmaeil S, Zeidan R, Fayed A. Effects of Age, Metabolic and Socioeconomic Factors on Cardiovascular Risk among Saudi Women: A Subgroup Analysis from the Heart Health Promotion Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:623. [PMID: 36984624 PMCID: PMC10051484 DOI: 10.3390/medicina59030623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 06/18/2023]
Abstract
Background: Cardiovascular disease (CVD) remains the leading cause of death in women. Along with the effect of age on the risk of CVD, the reproductive profile of women can influence cardiac health among women. Objectives: The objective of this study is to investigate the influence of age and reproductive stages on the development and progression of cardiovascular disease risks in Saudi women. Methods: For this study, we included 1907 Saudi women from the Heart Health Promotion Study. The study cohort was divided into five age groups (less than 40 years, 40-45 years, 46-50 years, 51-55 years, and ≥56 years). The cohort stratification was meant to correspond to the social and hormonal changes in women's life, including reproductive, perimenopausal, menopausal, and postmenopausal age groups. The groups were compared with respect to the prevalence of metabolic, socioeconomic, and cardiac risks, and the age group of less than 40 years was considered as the reference group. The World Health Organization stepwise approach to chronic disease risk factor Surveillance-Instrument v2.1 was used in this study to collect the anthropometric and biochemical measurements and the Framingham Coronary Heart Risk Score was used to calculate the cardiovascular risk (CVR). Logistic regression analysis was conducted to assess the independent effect of age on CVD risks after adjustment of sociodemographic factors. Results: Metabolic and CVR increased progressively with the increase in age. There was a sharp increase in obesity, hypertension, diabetes, and metabolic syndrome, from the age group <40 years to 41-45 years and then again between the age groups of 46-50 and ≥56 years. A similar noticeable increase in metabolic risk factors (high cholesterol, high triglyceride, high Low-Density Lipoprotein) was observed between the age group <40 years and 41-45 years, but with a steady increase with the increase in age between the other age groups. The high and intermediate Framingham Coronary Heart Risk Scores showed a progressive increase in prevalence with the increase in age, where the proportion doubled from 9.4% at the age group 46-50 years, to 22% at the age group 51-55 years. It doubled again at the age group ≥56 years to 53%-these sharp inflections in the risk of CVD correspond to the women's reproductive lives. Conclusions: In Saudi women, CVR increases with the increase of age. The influence of pregnancy and menopause is apparent in the prevalence of increased risks for cardiovascular and metabolic diseases.
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Affiliation(s)
- Hayfaa Wahabi
- Research Chair for Evidence-Based Health Care and Knowledge Translation, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia
- Department of Family and Community Medicine, College of Medicine, King Saud University Medical City, P.O. Box 800, Riyadh 11421, Saudi Arabia
| | - Samia Esmaeil
- Research Chair for Evidence-Based Health Care and Knowledge Translation, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia
- Department of Family and Community Medicine, College of Medicine, King Saud University Medical City, P.O. Box 800, Riyadh 11421, Saudi Arabia
| | - Rasmieh Zeidan
- Cardiac Sciences Department, College of Medicine, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia
| | - Amel Fayed
- Clinical Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
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Kariya H, Yamaoka-Tojo M, Hamazaki N, Obara S, Kitasato L, Matsunaga A, Ako J. Association between instrumental activities of daily living frequency and clinical outcomes in older patients with cardiovascular disease. Eur J Cardiovasc Nurs 2023; 22:64-72. [PMID: 35670158 DOI: 10.1093/eurjcn/zvac043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 05/11/2022] [Accepted: 05/15/2022] [Indexed: 01/14/2023]
Abstract
AIMS Impairment in activities of daily living (ADL) is an independent predictor of poor prognosis in older patients. Nevertheless, the effects of instrumental ADL (IADL) frequency on prognosis in older patients with cardiovascular disease (CVD) are unclear. We investigate the associations between IADL frequency and all-cause mortality and hospital readmission due to cardiovascular events in older patients with CVD. METHODS AND RESULTS A total of 638 consecutive outpatients ≥65 years old with CVD were enrolled. A questionnaire, including Frenchay Activities Index (FAI) parameters, was used to determine IADL frequency at the start of the study as the baseline observation. The primary endpoint was all-cause mortality, and the secondary endpoint was readmission for cardiovascular events. We examined the relationship between IADL frequency and each endpoint. Among the 632 patients evaluated {median age 74.0 [interquartile range (IQR) 70.0-78.0] years; 439 males}, there were 39 deaths and 105 cardiovascular events during the median follow-up period of 4.0 (IQR, 2.3-4.0) years. After adjusting for clinical confounding factors, the hazard ratios for all-cause mortality and cardiovascular events in the FAI points were 0.957 [95% confidence interval (CI), 0.920-0.996] and 0.973 (95% CI, 0.950-0.997), respectively. CONCLUSION A higher IADL frequency was independently associated with better outcomes in older patients with CVD, suggesting that the preservation of instrumental activities should be focused on as the components of cardiovascular rehabilitation.
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Affiliation(s)
- Hidenori Kariya
- Department of Rehabilitation, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Minako Yamaoka-Tojo
- Kitasato University Regenerative Medicine and Cell Design Research Facility, Sagamihara, Japan.,Department of Rehabilitation, Kitasato University School of Allied Health Sciences, Sagamihara, Japan
| | - Nobuaki Hamazaki
- Department of Rehabilitation, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Shinichi Obara
- Department of Rehabilitation, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan
| | - Lisa Kitasato
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Atsuhiko Matsunaga
- Department of Rehabilitation, Kitasato University School of Allied Health Sciences, Sagamihara, Japan
| | - Junya Ako
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
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24
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Liu S, Wang T, Cheng Z, Liu J. N6-methyladenosine (m6A) RNA modification in the pathophysiology of heart failure: a narrative review. Cardiovasc Diagn Ther 2022; 12:908-925. [PMID: 36605077 PMCID: PMC9808110 DOI: 10.21037/cdt-22-277] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022]
Abstract
Background and Objective Heart failure is the end-stage of various cardiovascular diseases. Recent progress in molecular biology has facilitated the understanding of the mechanisms of heart failure development at the molecular level. N6-adenosine methylation (m6A) is a post-transcriptional modification of RNA. Recent research work reported that m6A regulates gene expression and subsequently affects the activation of cell signaling pathways related to heart failure. Moreover, m6A regulators like methyltransferase-like 3 (METTL3) were reported to participate in myocardium hypertrophy. However, the current research work related to the role of m6A participating in the occurrence of heart failure is rare in some aspects like immune cell infiltration and diabetic heart diseases. Thus, it is reasonable to review the current achievements and provide further study orientation. Methods We searched related literature using the keywords: m6A AND heart failure in PubMed, Web of Science and Medline. The language was confined to English. The published year of searched literature ranged from 2012 to 2022. The searched results were put into Endnote software for management. Two authors investigated the searching terms and reviewed the full text of selected terms. Key Content and Findings m6A and its regulators are involved in the metabolism of various types of RNAs. m6A modification can regulate various types of cell signaling pathways related to the heart failure via interaction with m6A regulators. m6A and its regulators broadly participate in the myocardium fibrosis, myocardium hypertrophy, myocardial cell apoptosis, and ischemic reperfusion injury. Specifically, m6A participates in the cell apoptosis via regulation of autophagy flux. However, the current research work does not have enough evidence to prove that m6A regulator played its specific effect on the target transcript via regulating the m6A level. Conclusions m6A and its regulators participates in the progression of heart failure via modifying the RNA level. Future investigation of m6A should focus on the interaction between the m6A regulators and targeted transcript. Besides, the regulation role of m6A in immune cell infiltration and diabetic heart diseases should also be focused.
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Affiliation(s)
- Sihan Liu
- Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Tongyu Wang
- Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Zeyi Cheng
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Liu
- Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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25
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Dong B, Yao Y, Xue R, Liang W, He J, Wei F, Dong Y, He X, Liu C. Distinct implications of body mass index in different subgroups of nonobese patients with heart failure with preserved ejection fraction: a latent class analysis of data from the TOPCAT trial. BMC Med 2022; 20:423. [PMID: 36324141 PMCID: PMC9632105 DOI: 10.1186/s12916-022-02626-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 10/24/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Obesity is a well-defined risk factor for heart failure with preserved ejection fraction (HFpEF), but it is associated with a better prognosis in patients with diagnosed HFpEF. The paradoxically poor prognosis in nonobese patients with HFpEF may be driven by a subset of high-risk patients, which suggests that the nonobese HFpEF subpopulation is heterogeneous. METHODS Latent class analysis (LCA) was adopted to identify the potential subgroups of 623 nonobese patients enrolled in the TOPCAT trial. The baseline characteristics of the identified nonobese subgroups were compared with each other and with the obese patients. The risks of all-cause, cardiovascular, and noncardiovascular mortality, and an HF composite outcome were also compared. RESULTS Two subgroups of nonobese patients with HFpEF (the physiological non-obesity and the pathological non-obesity) were identified. The obese patients were younger than both nonobese subgroups. The clinical profile of patients with pathological non-obesity was poorer than that of patients with physiological non-obesity. They had more comorbidities, more severe HF, poorer quality of life, and lower levels of physical activity. Patients with pathological non-obesity showed low serum hemoglobin and albumin levels. After 2 years of follow-up, more patients in the pathological group lost ≥ 10% of body weight compared with those in the physiological group (11.34% vs. 4.19%, P = 0.009). The prognostic implications of the two subgroups were opposite. Compared to patients with obesity, patients with physiological non-obesity had a 47% decrease in the risk of HF composite outcome (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.40-0.70, P<0.001) and a trend of decreased all-cause mortality risk (HR 0.75, 95% CI 0.55-1.01, P=0.06), while patients with pathological non-obesity had a 59% increase (HR 1.59, 95% CI 1.24-2.02, P<0.001) in all-cause mortality risk. CONCLUSIONS Two subgroups of nonobese patients with HFpEF with distinct clinical profiles and prognostic implications were identified. The low BMI was likely physiological in one group but pathological in the other group. Using a data-driven approach, our study provided an alternative explanation for the "obesity paradox" that the poor prognosis of nonobese patients with HFpEF was driven by a pathological subgroup.
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Affiliation(s)
- Bin Dong
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Yiling Yao
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Ruicong Xue
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Weihao Liang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Jiangui He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Fangfei Wei
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Yugang Dong
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China
| | - Xin He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China. .,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China. .,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China.
| | - Chen Liu
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China. .,NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China. .,National - Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, China. .,Department of Cardiology, the Affiliated Sanming First Hospital of Fujian Medical University, Sanming, China.
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26
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Iovanovici DC, Bungau SG, Vesa CM, Moisi M, Babes EE, Tit DM, Horvath T, Behl T, Rus M. Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure. Int J Mol Sci 2022; 23:11336. [PMID: 36232632 PMCID: PMC9570001 DOI: 10.3390/ijms231911336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/22/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment.
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Affiliation(s)
- Diana-Carina Iovanovici
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Madalina Moisi
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Elena Emilia Babes
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Delia Mirela Tit
- Doctoral School of Biomedical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Tunde Horvath
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun 248007, India
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
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Xu J, Wang J, Long F, Zhong W, Su H, Su Z, Liu X. Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction. Cell Biosci 2022; 12:134. [PMID: 35986422 PMCID: PMC9392317 DOI: 10.1186/s13578-022-00877-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Background Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has been demonstrated to play a role in transcriptional activation. However, the functions of Dot1L in the process of cardiac fibrosis still remain unknown. Results In the present study, we found that endogenous Dot1L is upregulated in cardiac fibroblasts (CFs) treated with angiotensin II (Ang II) or transforming growth factor (TGF)-β1, along with elevated extracellular matrix (ECM) such as fibronectin, collagen I and III. Silencing or inhibiting Dot1L mitigated Ang II-induced myofibroblast generation and fibrogenesis. We identified the transcription factor-forkhead box O (FoxO) 3a as a novel substrate of Dot1L, the transcriptional activating mark H3K79me3 level on the promoter of FoxO3a was increase in activated-CFs, and inhibition of Dot1L markedly decreased FoxO3a transcription accompanied by a significant decrease in the expression of fibrogenic gene. Knockdown of FoxO3a could alleviate ECM deposition induced by Ang II, on the contrary, overexpression FoxO3a resulting in CFs activation. Consistently, in vivo Dot1L ablation rescued myocardial ischemia-induced cardiac fibrosis and improved cardiac function. Conclusions Our findings conclude that upregulation of Dot1L results in activation of the cardiac fibroblasts to promote profibrotic gene, eventually causes cardiac fibrosis. Pharmacological targeting for Dot1L might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00877-5.
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Zhang M, Shu H, Chen C, He Z, Zhou Z, Wang DW. Epoxyeicosatrienoic acid: A potential therapeutic target of heart failure with preserved ejection fraction. Biomed Pharmacother 2022; 153:113326. [PMID: 35759865 DOI: 10.1016/j.biopha.2022.113326] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/15/2022] [Accepted: 06/22/2022] [Indexed: 11/02/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) reduces the quality of life, costs substantial medical resources, and has a high mortality. However, we lack an effective therapy for HFpEF due to our limited knowledge of its mechanism. Therefore, it is crucial to explore novel therapeutics, such as those with endogenous protective roles, and seek new targeted therapies. Epoxyeicosatrienoic acids (EETs) are endogenous bioactive metabolites of arachidonic acids produced by cytochrome P450 (CYP) epoxygenases. EETs can function as endogenous cardioprotective factors with potent inhibitory roles in inflammation, endothelial dysfunction, cardiac remodeling, and fibrosis, which are the fundamental mechanisms of HFpEF. This suggests that EETs have the potential function to protect against HFpEF. Therefore, we present an overview of the ever-expanding world of EETs and how they might help alleviate the pathophysiology underlying HFpEF to provide new insights for research in this field.
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Affiliation(s)
- Min Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Hongyang Shu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Zuowen He
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Zhou Zhou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.
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Chen X, Lin H, Xiong W, Pan J, Huang S, Xu S, He S, Lei M, Chang ACY, Zhang H. p53-Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc 2022; 11:e024582. [PMID: 35656994 PMCID: PMC9238719 DOI: 10.1161/jaha.121.024582] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.
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Affiliation(s)
- Xiaonan Chen
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Hao Lin
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Weiyao Xiong
- Shanghai Institute of Precision MedicineNinth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Jianan Pan
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Shuying Huang
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Shan Xu
- Shanghai Institute of Precision MedicineNinth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Shufang He
- Shanghai Institute of Precision MedicineNinth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Ming Lei
- Shanghai Institute of Precision MedicineNinth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Alex Chia Yu Chang
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China.,Shanghai Institute of Precision MedicineNinth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Huili Zhang
- Department of Cardiology Ninth People's HospitalShanghai Jiao Tong University School of Medicine Shanghai China
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30
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Buda V, Prelipcean A, Cozma D, Man DE, Negres S, Scurtu A, Suciu M, Andor M, Danciu C, Crisan S, Dehelean CA, Petrescu L, Rachieru C. An Up-to-Date Article Regarding Particularities of Drug Treatment in Patients with Chronic Heart Failure. J Clin Med 2022; 11:2020. [PMID: 35407628 PMCID: PMC8999552 DOI: 10.3390/jcm11072020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/24/2022] [Accepted: 04/01/2022] [Indexed: 11/17/2022] Open
Abstract
Since the prevalence of heart failure (HF) increases with age, HF is now one of the most common reasons for the hospitalization of elderly people. Although the treatment strategies and overall outcomes of HF patients have improved over time, hospitalization and mortality rates remain elevated, especially in developed countries where populations are aging. Therefore, this paper is intended to be a valuable multidisciplinary source of information for both doctors (cardiologists and general physicians) and pharmacists in order to decrease the morbidity and mortality of heart failure patients. We address several aspects regarding pharmacological treatment (including new approaches in HF treatment strategies [sacubitril/valsartan combination and sodium glucose co-transporter-2 inhibitors]), as well as the particularities of patients (age-induced changes and sex differences) and treatment (pharmacokinetic and pharmacodynamic changes in drugs; cardiorenal syndrome). The article also highlights several drugs and food supplements that may worsen the prognosis of HF patients and discusses some potential drug-drug interactions, their consequences and recommendations for health care providers, as well as the risks of adverse drug reactions and treatment discontinuation, as an interdisciplinary approach to treatment is essential for HF patients.
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Affiliation(s)
- Valentina Buda
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Andreea Prelipcean
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
| | - Dragos Cozma
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
- Institute of Cardiovascular Diseases Timisoara, 13A Gheorghe Adam Street, 300310 Timisoara, Romania
| | - Dana Emilia Man
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
- Institute of Cardiovascular Diseases Timisoara, 13A Gheorghe Adam Street, 300310 Timisoara, Romania
| | - Simona Negres
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania;
| | - Alexandra Scurtu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Maria Suciu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Minodora Andor
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
| | - Corina Danciu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Simina Crisan
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
- Institute of Cardiovascular Diseases Timisoara, 13A Gheorghe Adam Street, 300310 Timisoara, Romania
| | - Cristina Adriana Dehelean
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (V.B.); (A.P.); (A.S.); (M.S.); (C.D.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Lucian Petrescu
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
- Institute of Cardiovascular Diseases Timisoara, 13A Gheorghe Adam Street, 300310 Timisoara, Romania
| | - Ciprian Rachieru
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania; (D.E.M.); (M.A.); (S.C.); (L.P.); (C.R.)
- Center for Advanced Research in Cardiovascular Pathology and Hemostasis, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
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Peana D, Polo-Parada L, Domeier TL. Arrhythmogenesis in the aged heart following ischaemia-reperfusion: role of transient receptor potential vanilloid 4. Cardiovasc Res 2022; 118:1126-1137. [PMID: 33881517 PMCID: PMC9125801 DOI: 10.1093/cvr/cvab141] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 04/20/2021] [Indexed: 12/26/2022] Open
Abstract
AIMS Cardiomyocyte Ca2+ homoeostasis is altered with ageing and predisposes the heart to Ca2+ intolerance and arrhythmia. Transient receptor potential vanilloid 4 (TRPV4) is an osmotically activated cation channel with expression in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in Ca2+ handling and arrhythmogenesis following ischaemia-reperfusion (I/R), a pathological scenario associated with osmotic stress. METHODS AND RESULTS Cardiomyocyte membrane potential was monitored prior to and following I/R in Langendorff-perfused hearts of Aged (19-28 months) male and female C57BL/6 mice ± TRPV4 inhibition (1 μM HC067047, HC). Diastolic resting membrane potential was similar between Aged and Aged HC at baseline, but following I/R Aged exhibited depolarized diastolic membrane potential vs. Aged HC. The effects of TRPV4 on cardiomyocyte Ca2+ signalling following I/R were examined in isolated hearts of Aged cardiac-specific GCaMP6f mice (±HC) using high-speed confocal fluorescence microscopy, with cardiomyocytes of Aged exhibiting an increased incidence of pro-arrhythmic Ca2+ signalling vs. Aged HC. In the isolated cell environment, cardiomyocytes of Aged responded to sustained hypoosmotic stress (250mOsm) with an increase in Ca2+ transient amplitude (fluo-4) and higher incidence of pro-arrhythmic diastolic Ca2+ signals vs. Aged HC. Intracardiac electrocardiogram measurements in isolated hearts following I/R revealed an increased arrhythmia incidence, an accelerated time to ventricular arrhythmia, and increased arrhythmia score in Aged vs. Aged HC. Aged exhibited depolarized resting membrane potential, increased pro-arrhythmic diastolic Ca2+ signalling, and greater incidence of arrhythmia when compared with Young (3-5 months). CONCLUSION TRPV4 contributes to pro-arrhythmic cardiomyocyte Ca2+ signalling, electrophysiological abnormalities, and ventricular arrhythmia in the aged mouse heart.
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Affiliation(s)
- Deborah Peana
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
| | - Luis Polo-Parada
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, USA
| | - Timothy L Domeier
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
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Okamoto R, Hashizume R, Suzuki N, Ito R, Tokuhara T, Fujiwara H, Zhe Y, Ito H, Abe T, Dohi K. Serum-Induced Expression of Brain Natriuretic Peptide Contributes to Its Increase in Patients with HFpEF. Int J Mol Sci 2022; 23:ijms23062991. [PMID: 35328412 PMCID: PMC8955158 DOI: 10.3390/ijms23062991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 02/08/2023] Open
Abstract
Brain natriuretic peptide (BNP) levels are increased in both patients with heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), but the reasons for this remain unclear. Our purpose was to examine whether serum-induced BNP (iBNP) expression partly contributes to increased BNP in patients with HFpEF. BNP reporter cardiomyocytes from pBNP-luc-KI mice were stimulated with serum from patients with HFpEF or HFrEF (n = 114 and n = 82, respectively). Luciferase activity was examined as iBNP and the iBNP-to-BNP ratio was evaluated. Patient characteristics and clinical parameters were compared, and multivariate regression analysis was performed to determine independent predictors of the iBNP-to-BNP ratio. Female sex and frequencies of atrial fibrillation, hypertension and the use of a calcium channel blocker (CCB) were higher in HFpEF. The iBNP-to-BNP ratio was significantly higher in HFpEF (26.9) than in HFrEF (16.1, p < 0.001). Multivariate regression analysis identified the existence of HFpEF as an independent predictor of the iBNP-to-BNP ratio after adjusting for all other measurements (β = 0.154, p = 0.032). Age, hemoglobin, CCB usage and deceleration time were also independent predictors (β = 0.167, p = 0.025; β = 0.203, p = 0.006; β = 0.138, p = 0.049; and β = 0.143, p = 0.049, respectively). These results indicate that the elevated BNP in patients with HFpEF is partly due to iBNP from the heart.
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Affiliation(s)
- Ryuji Okamoto
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; (R.I.); (Y.Z.); (H.I.); (K.D.)
- Regional Medical Support Center, Mie University Hospital, Tsu 514-8507, Japan
- Correspondence: ; Tel.: +81-59-231-5015; Fax: +81-59-231-5201
| | - Ryotaro Hashizume
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan;
| | - Noboru Suzuki
- Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Tsu 514-8507, Japan;
| | - Rie Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; (R.I.); (Y.Z.); (H.I.); (K.D.)
| | - Tomoko Tokuhara
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; (T.T.); (T.A.)
| | - Hiroshi Fujiwara
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu 514-8507, Japan;
| | - Ye Zhe
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; (R.I.); (Y.Z.); (H.I.); (K.D.)
| | - Hiromasa Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; (R.I.); (Y.Z.); (H.I.); (K.D.)
| | - Takaya Abe
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; (T.T.); (T.A.)
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; (R.I.); (Y.Z.); (H.I.); (K.D.)
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Rocca A, van Heeswijk RB, Richiardi J, Meyer P, Hullin R. The Cardiomyocyte in Heart Failure with Preserved Ejection Fraction-Victim of Its Environment? Cells 2022; 11:867. [PMID: 35269489 PMCID: PMC8909081 DOI: 10.3390/cells11050867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/01/2022] [Indexed: 12/07/2022] Open
Abstract
Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) is becoming the predominant form of HF. However, medical therapy that improves cardiovascular outcome in HF patients with almost normal and normal systolic left ventricular function, but diastolic dysfunction is missing. The cause of this unmet need is incomplete understanding of HFpEF pathophysiology, the heterogeneity of the patient population, and poor matching of therapeutic mechanisms and primary pathophysiological processes. Recently, animal models improved understanding of the pathophysiological role of highly prevalent and often concomitantly presenting comorbidity in HFpEF patients. Evidence from these animal models provide first insight into cellular pathophysiology not considered so far in HFpEF disease, promising that improved understanding may provide new therapeutical targets. This review merges observation from animal models and human HFpEF disease with the intention to converge cardiomyocytes pathophysiological aspects and clinical knowledge.
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Affiliation(s)
- Angela Rocca
- Department of Cardiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland;
| | - Ruud B. van Heeswijk
- Department of Diagnostic and Interventional Radiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; (R.B.v.H.); (J.R.)
| | - Jonas Richiardi
- Department of Diagnostic and Interventional Radiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; (R.B.v.H.); (J.R.)
| | - Philippe Meyer
- Cardiology Service, Department of Medical Specialties, Faculty of Science, Geneva University Hospital, University of Geneva, 1205 Geneva, Switzerland;
| | - Roger Hullin
- Department of Cardiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland;
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Kobak KA, Zarzycka W, Chiao YA. Age and Sex Differences in Heart Failure With Preserved Ejection Fraction. FRONTIERS IN AGING 2022; 3:811436. [PMID: 35821846 PMCID: PMC9261310 DOI: 10.3389/fragi.2022.811436] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/13/2022] [Indexed: 11/29/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a multi-organ disorder that represents about 50% of total heart failure (HF) cases and is the most common form of HF in the elderly. Because of its increasing prevalence caused by the aging population, high mortality and morbidity, and very limited therapeutic options, HFpEF is considered as one of the greatest unmet medical needs in cardiovascular medicine. Despite its complex pathophysiology, numerous preclinical models have been established in rodents and in large animals to study HFpEF pathophysiology. Although age and sex differences are well described in HFpEF population, there are knowledge gaps in sex- and age-specific differences in established preclinical models. In this review, we summarize various strategies that have been used to develop HFpEF models and discuss the knowledge gaps in sex and age differences in HFpEF.
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35
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Rieger AC, Tompkins BA, Natsumeda M, Florea V, Banerjee MN, Rodriguez J, Rosado M, Porras V, Valasaki K, Takeuchi LM, Collon K, Desai S, Bellio MA, Khan A, Kashikar ND, Landin AM, Hardin DV, Rodriguez DA, Balkan W, Hare JM, Schulman IH. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:59-72. [PMID: 35641169 PMCID: PMC8895493 DOI: 10.1093/stcltm/szab004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/29/2021] [Indexed: 11/28/2022] Open
Abstract
Background Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF. Methods and Results Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness. Conclusions Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.
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Affiliation(s)
- Angela C Rieger
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Bryon A Tompkins
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Makoto Natsumeda
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Victoria Florea
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Monisha N Banerjee
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jose Rodriguez
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Marcos Rosado
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Valeria Porras
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Krystalenia Valasaki
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Lauro M Takeuchi
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kevin Collon
- Department of Orthopedic Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Sohil Desai
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michael A Bellio
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Ana Marie Landin
- Cell Therapy and Vaccine Lab, Moffitt Cancer Center, Tampa, FL, USA
| | - Darrell V Hardin
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel A Rodriguez
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ivonne Hernandez Schulman
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- Corresponding author: Ivonne H. Schulman, MD, Program Director, Translational and Clinical Studies of Acute Kidney Injury, Division of Kidney, Urologic and Hematologic Diseases (KUH), National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Two Democracy Plaza, Room #6077, 6707 Democracy Blvd, Bethesda, MD 20892-5458, USA. Tel: 301-435-3350; Mobile: 301-385-5744; Fax: 301-480-3510, ,
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Seki A, Fishbein MC. Age-related cardiovascular changes and diseases. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00004-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Choi RH, Tatum SM, Symons JD, Summers SA, Holland WL. Ceramides and other sphingolipids as drivers of cardiovascular disease. Nat Rev Cardiol 2021; 18:701-711. [PMID: 33772258 PMCID: PMC8978615 DOI: 10.1038/s41569-021-00536-1] [Citation(s) in RCA: 230] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/03/2023]
Abstract
Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.
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Affiliation(s)
- Ran Hee Choi
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Sean M Tatum
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - J David Symons
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
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Veteto AB, Peana D, Lambert MD, McDonald KS, Domeier TL. Transient receptor potential vanilloid-4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart. Cardiovasc Res 2021; 116:1887-1896. [PMID: 31693106 DOI: 10.1093/cvr/cvz287] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/29/2019] [Accepted: 11/04/2019] [Indexed: 01/06/2023] Open
Abstract
AIMS Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated transient receptor potential vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters Ca2+ handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch. METHODS AND RESULTS Left ventricular maximal pressure (PMax) was monitored in isolated working hearts of Aged (24-27 months) mice following preload elevation from 5 to 20mmHg, with and without TRPV4 antagonist HC067047 (HC, 1 µmol/L). In preload responsive hearts, PMax prior to and immediately following preload elevation (i.e. Frank-Starling response) was similar between Aged and Aged+HC. Within 1 min following preload elevation, Aged hearts demonstrated secondary PMax augmentation (Aged>Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 min at 20 mmHg Aged exhibited depressed PMax (Aged<Aged+HC) suggestive of TRPV4-dependent contractile dysfunction with sustained stretch. To examine stretch-induced Ca2+ homeostasis at the single-cell level, isolated cardiomyocytes were stretched 10-15% of slack length while measuring intracellular Ca2+ with fura-2. Uniaxial longitudinal stretch increased intracellular Ca2+ levels and triggered Ca2+ overload and terminal cellular contracture in Aged, but not Aged+HC. Preload elevation in hearts of young/middle-age (3-12 months) mice produced an initial PMax increase (Frank-Starling response) without secondary PMax augmentation, and cardiomyocyte stretch did not affect intracellular Ca2+ levels. Hearts of transgenic mice with cardiac-specific TRPV4 expression exhibited PMax similar to 3- to 12-month control mice prior to and immediately following preload elevation but displayed secondary PMax augmentation. Cardiomyocytes of mice with transgenic TRPV4 expression were highly sensitive to mechanical stimulation and exhibited elevated Ca2+ levels, Ca2+ overload, and terminal contracture upon cellular attachment and stretch. CONCLUSION TRPV4 contributes to a stretch-induced increase in cardiomyocyte Ca2+ and cardiac hypercontractility, yet sustained stretch leads to cardiomyocyte Ca2+ overload and contractile dysfunction in the aged heart.
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Affiliation(s)
- Adam B Veteto
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
| | - Deborah Peana
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
| | - Michelle D Lambert
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
| | - Kerry S McDonald
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
| | - Timothy L Domeier
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO 65212, USA
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Withaar C, Lam CSP, Schiattarella GG, de Boer RA, Meems LMG. Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models. Eur Heart J 2021; 42:4420-4430. [PMID: 34414416 PMCID: PMC8599003 DOI: 10.1093/eurheartj/ehab389] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/15/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.
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Affiliation(s)
- Coenraad Withaar
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - Carolyn S P Lam
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.,National University Heart Centre, Singapore and Duke-National University of Singapore
| | - Gabriele G Schiattarella
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.,Department of Cardiology, Center for Cardiovascular Research (CCR), Charité - Universitätsmedizin Berlin, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.,Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rudolf A de Boer
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - Laura M G Meems
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
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Esfahani NS, Wu Q, Kumar N, Ganesan LP, Lafuse WP, Rajaram MVS. Aging influences the cardiac macrophage phenotype and function during steady state and during inflammation. Aging Cell 2021; 20:e13438. [PMID: 34342127 PMCID: PMC8373275 DOI: 10.1111/acel.13438] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/14/2021] [Accepted: 07/03/2021] [Indexed: 12/16/2022] Open
Abstract
Aging‐mediated immune dysregulation affects the normal cardiac immune cell phenotypes and functions, resulting in cardiac distress. During cardiac inflammation, immune activation is critical for mounting the regenerative responses to maintain normal heart function. We investigated the impact of aging on myeloid cell phenotype and function during cardiac inflammation induced by a sub‐lethal dose of LPS. Our data show that hearts of old mice contain more myeloid cells than the hearts of young mice. However, while the number of monocytic‐derived suppressor cells did not differ between young and old mice, monocytic‐derived suppressor cells from old mice were less able to suppress T‐cell proliferation. Since cardiac resident macrophages (CRMs) are important for immune surveillance, clearance of dead cells, and tissue repair, we focused our studies on CRMs phenotype and function during steady state and LPS treatment. In the steady state, we observed significantly more MHC‐IIlow and MHC‐IIhigh CRMs in the hearts of old mice; however, these populations were decreased in both young and aged mice upon LPS treatment and the decrease in CRM populations correlated with defects in cardiac electrical activity. Notably, mice treated with a liver X receptor (LXR) agonist showed an increase in MerTK expression in CRMs of both young and old mice, which resulted in the reversal of cardiac electrical dysfunction caused by lipopolysaccharide (LPS). We conclude that aging alters the phenotype of CRMs, which contributes to the dysregulation of cardiac electrical dysfunction during infection in aged mice.
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Affiliation(s)
- Noushin Saljoughian Esfahani
- Department of Microbial Infection and Immunity/ College of Medicine The Ohio State University Wexner Medical Center Columbus OH USA
| | - Qian Wu
- Department of Microbial Infection and Immunity/ College of Medicine The Ohio State University Wexner Medical Center Columbus OH USA
| | - Naresh Kumar
- Department of Microbial Infection and Immunity/ College of Medicine The Ohio State University Wexner Medical Center Columbus OH USA
| | - Latha Prabha Ganesan
- Department of Internal Medicine College of Medicine The Ohio State UniversityWexner Medical Center Columbus OH USA
| | - William P. Lafuse
- Department of Microbial Infection and Immunity/ College of Medicine The Ohio State University Wexner Medical Center Columbus OH USA
| | - Murugesan V. S. Rajaram
- Department of Microbial Infection and Immunity/ College of Medicine The Ohio State University Wexner Medical Center Columbus OH USA
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Withaar C, Meems LMG, Markousis-Mavrogenis G, Boogerd CJ, Silljé HHW, Schouten EM, Dokter MM, Voors AA, Westenbrink BD, Lam CSP, de Boer RA. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction. Cardiovasc Res 2021; 117:2108-2124. [PMID: 32871009 PMCID: PMC8318109 DOI: 10.1093/cvr/cvaa256] [Citation(s) in RCA: 151] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/03/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
AIMS Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa). METHODS AND RESULTS Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype. CONCLUSIONS We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.
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MESH Headings
- Angiotensin II
- Animals
- Benzhydryl Compounds/pharmacology
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Diet, High-Fat
- Disease Models, Animal
- Female
- Fibrosis
- Gene Expression Regulation
- Glucagon-Like Peptide-1 Receptor/agonists
- Glucagon-Like Peptide-1 Receptor/metabolism
- Glucosides/pharmacology
- Heart Failure, Diastolic/drug therapy
- Heart Failure, Diastolic/metabolism
- Heart Failure, Diastolic/pathology
- Heart Failure, Diastolic/physiopathology
- Hypertrophy, Left Ventricular/drug therapy
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/physiopathology
- Incretins/pharmacology
- Liraglutide/pharmacology
- Mice, Inbred C57BL
- Myocardium/metabolism
- Myocardium/pathology
- Signal Transduction
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
- Mice
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Affiliation(s)
- Coenraad Withaar
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Laura M G Meems
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - George Markousis-Mavrogenis
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Cornelis J Boogerd
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands
| | - Herman H W Silljé
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Elisabeth M Schouten
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Martin M Dokter
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Adriaan A Voors
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - B Daan Westenbrink
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Carolyn S P Lam
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- National University Heart Centre, Singapore, Singapore
| | - Rudolf A de Boer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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Jaconiano E, Moreira-Gonçalves D. Unveiling the role of exercise training in targeting the inflammatory paradigm of heart failure with preserved ejection fraction: a narrative review. Heart Fail Rev 2021; 27:163-190. [PMID: 34244870 DOI: 10.1007/s10741-021-10138-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/01/2021] [Indexed: 12/30/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is currently lacking an effective pharmacological treatment with impact on major outcomes such as hospitalization and mortality. Exercise training (EXT) is recognized as an important nonpharmacological tool, capable of improving exercise capacity and quality of life, and has even been associated with a reduction in hospitalization and cardiovascular mortality risk. However, this positive impact largely lacks a physiological explanation. The aim of this narrative review was to provide an overview of the available data supporting the hypothesis that the beneficial role of EXT in HFpEF might be due to its effects on targeting the inflammatory paradigm described for this disease. A comprehensive literature search was conducted using the PubMed-NCBI database. We reviewed the effects of EXT throughout each step of the pathophysiological pathway leading to HFpEF and found clinical and/or preclinical evidence supporting the reduction of systemic inflammation, endothelial dysfunction, microvascular rarefaction, and myocardial stiffness. We also highlighted some gaps in the knowledge or topics that deserve further clarification in future studies. In conclusion, despite the scarcity of clinical studies in this population, there is compelling evidence suggesting that EXT modulates crucial aspects of the inflammatory pathway described for HFpEF and future investigation on cellular and molecular mechanisms are encouraged.
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Affiliation(s)
- Eliane Jaconiano
- Cardiovascular R&D Center (UnIC) and Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Daniel Moreira-Gonçalves
- Centre of Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, Porto, Portugal
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Del Campo A, Perez G, Castro PF, Parra V, Verdejo HE. Mitochondrial function, dynamics and quality control in the pathophysiology of HFpEF. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166208. [PMID: 34214606 DOI: 10.1016/j.bbadis.2021.166208] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/20/2022]
Abstract
Heart failure (HF) is one of the leading causes of hospitalization for the adult population and a major cause of mortality worldwide. The HF syndrome is characterized by the heart's inability to supply the cardiac output required to meet the body's metabolic requirements or only at the expense of elevated filling pressures. HF without overt impairment of left ventricular ejection fraction (LVEF) was initially labeled as "diastolic HF" until recognizing the coexistence of both systolic and diastolic abnormalities in most cases. Acknowledging these findings, the preferred nomenclature is HF with preserved EF (HFpEF). This syndrome primarily affects the elderly population and is associated with a heterogeneous overlapping of comorbidities that makes its diagnosis challenging. Despite extensive research, there is still no evidence-based therapy for HFpEF, reinforcing the need for a thorough understanding of the pathophysiology underlying its onset and progression. The role of mitochondrial dysfunction in developing the pathophysiological changes that accompany HFpEF onset and progression (low-grade systemic inflammation, oxidative stress, endothelial dysfunction, and myocardial remodeling) has just begun to be acknowledged. This review summarizes our current understanding of the participation of the mitochondrial network in the pathogenesis of HFpEF, with particular emphasis on the signaling pathways involved, which may provide future therapeutic targets.
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Affiliation(s)
- Andrea Del Campo
- Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gonzalo Perez
- División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo F Castro
- División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Chile
| | - Valentina Parra
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; Autophagy Research Center, Universidad de Chile, Santiago, Chile; Network for the Study of High-lethality Cardiopulmonary Diseases (REECPAL), Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Chile.
| | - Hugo E Verdejo
- División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Chile.
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G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence. Cell Death Dis 2021; 12:594. [PMID: 34103476 PMCID: PMC8187421 DOI: 10.1038/s41419-021-03874-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022]
Abstract
Aging is one of the most prominent risk factors for heart failure. Myeloid-derived suppressor cells (MDSCs) accumulate in aged tissue and have been confirmed to be associated with various aging-related diseases. However, the role of MDSCs in the aging heart remains unknown. Through RNA-seq and biochemical approaches, we found that granulocytic MDSCs (G-MDSCs) accumulated significantly in the aging heart compared with monocytic MDSCs (M-MDSCs). Therefore, we explored the effects of G-MDSCs on the aging heart. We found that the adoptive transfer of G-MDSCs of aging mice to young hearts resulted in cardiac diastolic dysfunction by inducing cardiac fibrosis, similar to that in aging hearts. S100A8/A9 derived from G-MDSCs induced inflammatory phenotypes and increased the osteopontin (OPN) level in fibroblasts. The upregulation of fibroblast growth factor 2 (FGF2) expression in fibroblasts mediated by G-MDSCs promoted antisenescence and antiapoptotic phenotypes of fibroblasts. SOX9 is the downstream gene of FGF2 and is required for FGF2-mediated and G-MDSC-mediated profibrotic effects. Interestingly, both FGF2 levels and SOX9 levels were upregulated in fibroblasts but not in G-MDSCs and were independent of S100A8/9. Therefore, a novel FGF2-SOX9 signaling axis that regulates fibroblast self-renewal and antiapoptotic phenotypes was identified. Our study revealed the mechanism by which G-MDSCs promote cardiac fibrosis via the secretion of S100A8/A9 and the regulation of FGF2-SOX9 signaling in fibroblasts during aging.
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Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart. NPJ Aging Mech Dis 2021; 7:16. [PMID: 34050186 PMCID: PMC8163749 DOI: 10.1038/s41514-021-00066-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/26/2021] [Indexed: 11/14/2022] Open
Abstract
It is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.
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Macrophage phenotype and function are dependent upon the composition and biomechanics of the local cardiac tissue microenvironment. Aging (Albany NY) 2021; 13:16938-16956. [PMID: 34292877 PMCID: PMC8312435 DOI: 10.18632/aging.203054] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/20/2021] [Indexed: 01/04/2023]
Abstract
Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.
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Daş T, Buğra A, Buğra AK. Evaluation of histopathological findings of cardiac deaths in forensic autopsies. Ir J Med Sci 2021; 191:937-944. [PMID: 33973126 DOI: 10.1007/s11845-021-02646-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/06/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND The vast majority of sudden and unexpected natural deaths are related to cardiovascular diseases, especially coronary artery diseases. AIMS In this study, we aimed to reveal the epidemiological differences between men and women and to investigate the most common pathologies that cause cardiac deaths. METHODS Five thousand seven hundred sixty-eight autopsy cases that were done in 2016 were reviewed for the autopsy information and histopathological findings. Of the 5768 autopsies performed, 866 were due to cardiac causes. Eight hundred thirty-two cases were reviewed due to lack of autopsy information in 34 cases. RESULTS One hundred sixteen (13.9%) were female, and 716 (86.1%) were male. Coronary artery disease was detected in 760 of 832 cases. There were findings of acute or previous myocardial infarction in 595 (71.5%), perivascular and interstitial fibrosis in 159 (19.1%), myocardial rupture and tamponade in 31 (%3.7), valvular disease in 6 (0.7%), cardiomyopathy in 4 (0.5%), and congenital heart disease in 3 (0.4%). In the study, it was observed that the mean age of death due to cardiac pathology other than coronary artery disease was significantly lower than deaths due to coronary artery disease (p < 0.05). The presence of coronary artery disease in men was found to be significantly higher than in women (p < 0.001). CONCLUSION In our study, it was found that deaths due to coronary artery disease are seen at an older age than cardiac deaths other than coronary artery disease. In addition, in line with current knowledge, it has been confirmed that the mortality rate of coronary artery disease is higher in men than in women.
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Affiliation(s)
- Taner Daş
- Morgue Department, Histopathology Unit, The Council of Forensic Medicine, Istanbul, Turkey.
| | - Aytül Buğra
- Morgue Department, Histopathology Unit, The Council of Forensic Medicine, Istanbul, Turkey
| | - Abdul Kerim Buğra
- Department of Cardiovascular Surgery, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training And Research Hospital, University Of Health Sciences, Istanbul, Turkey
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Tini G, Cannatà A, Canepa M, Masci PG, Pardini M, Giacca M, Sinagra G, Marchionni N, Del Monte F, Udelson JE, Olivotto I. Is heart failure with preserved ejection fraction a 'dementia' of the heart? Heart Fail Rev 2021; 27:587-594. [PMID: 33907929 DOI: 10.1007/s10741-021-10114-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2021] [Indexed: 01/09/2023]
Abstract
Heart failure with preserved ejection fraction (HFpEF) remains an elusive entity, due to its heterogeneous clinical profile and an arbitrarily defined nosology. Several pathophysiological mechanisms recognized as central for the development of HFpEF appear to be in common with the process of physiological aging of the heart. Both conditions are characterized by progressive impairment in cardiac function, accompanied by left ventricular hypertrophy, diastolic dysfunction, sarcomeric, and metabolic abnormalities. The neurological paradigm of dementia-intended as a progressive, multifactorial organ damage with decline of functional reserve, eventually leading to irreversible dysfunction-is well suited to represent HFpEF. In such perspective, certain phenotypes of HFpEF may be viewed as a maladaptive response to environmental modifiers, causing premature and pathological aging of the heart. We here propose that the 'HFpEF syndrome' may reflect the interplay of adverse structural remodelling and erosion of functional reserve, mirroring the processes leading to dementia in the brain. The resulting conceptual framework may help advance our understanding of HFpEF and unravel potential therapeutical targets.
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Affiliation(s)
- Giacomo Tini
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy. .,Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
| | - Antonio Cannatà
- Cardiothoracic Department, Azienda Sanitaria Universitaria Integrata Di Trieste, University of Trieste, Trieste, Italy
| | - Marco Canepa
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Pier Giorgio Masci
- Department of Cardiovascular Imaging, School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Matteo Pardini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Mauro Giacca
- School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre, London, UK
| | - Gianfranco Sinagra
- Cardiothoracic Department, Azienda Sanitaria Universitaria Integrata Di Trieste, University of Trieste, Trieste, Italy
| | - Niccolò Marchionni
- Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy
| | - Federica Del Monte
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - James E Udelson
- Division of Cardiology, Tufts Medical Center, Boston, MA, USA
| | - Iacopo Olivotto
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.,Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy
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Association between instrumental activities of daily living with the change in left ventricular function in older patients with cardiovascular disease. Heart Vessels 2021; 36:1298-1305. [PMID: 33683410 DOI: 10.1007/s00380-021-01812-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 02/19/2021] [Indexed: 01/09/2023]
Abstract
Left ventricular dysfunction is a pathophysiologic characteristic of heart failure. Impaired instrumental activities of daily living are associated with an elevated risk of mortality and heart failure in older adults. Nevertheless, the relationship between these activities and left ventricular function changes remains unclear. We determined whether instrumental activities of daily living are associated with subsequent left ventricular function changes in older cardiovascular disease patients. This retrospective cohort study included 383 outpatients with cardiovascular disease (74.5 ± 5.3 years, 273 males). Patients were divided according to the Frenchay activities index tertile and followed for six months after cardiovascular disease diagnosis. The left ventricular ejection fraction and annular early diastolic velocity (e') were measured for left ventricular systolic and diastolic function, respectively, at baseline and after one year. After adjusting for confounders, changes in the left ventricular ejection fraction were not significantly different. However, changes in the e' in the highest tertile group were significantly greater than in other groups. In the general linear model with multiple regression analysis, Frenchay activities index independently predicted the absolute change in the e'. In older cardiovascular disease patients, higher instrumental activities of daily living were associated with preserved left ventricular relaxation.
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