Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity.

Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data.

Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM.

This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

The contribution of neural feedback originating from exercising limb muscles to the cardiovascular response to exercise was first recognized nearly 100 years ago. Today, it is well established that this influence is initiated by the activation of group III and IV sensory neurons with terminal endings located within contracting skeletal muscle. During exercise, these sensory neurons project feedback related to intramuscular mechanical and metabolic perturbations to medullary neural circuits which reflexively evoke decreases in parasympathetic and increases in sympathetic nervous system activity with the purpose of optimizing central and peripheral hemodynamics. Considerable evidence from animal and human studies suggests that the function of this regulatory control system, known as the exercise pressor reflex (EPR), is abnormal in heart failure and exaggerates sympatho-excitation which impairs the hemodynamic response to exercise and contributes to the functional limitations characterizing these patients. This review briefly introduces the key determinants of EPR control in health and covers the impact of heart failure on the integrity of each of its components and overall function. These include the sensitivity of group III/IV muscle afferents, afferent signal transmission in the spinal cord, and the central integration and processing of sensory feedback within the brainstem. Importantly, although most data relevant for this review come from studies in HFrEF, the limited HFpEF-specific insights are included when available. While arguably not part of the EPR, we also discuss the impact of heart failure on the exercise-induced increase of intramuscular stimuli of group III/IV muscle afferents and end-organ responsiveness to sympathetic/neurochemical stimulation.

Limited studies show an association between elevated total homocysteine (tHcy) and heart failure (HF) risk, but no studies have assessed whether this association differs by HF subtype. This study examines the relationship between tHcy, HF overall, and HF subtype (HF with preserved ejection fraction [HFpEF] and HF with reduced ejection fraction) in the Multi-Ethnic Study of Atherosclerosis cohort.

Multi-Ethnic Study of Atherosclerosis participants with baseline tHcy and HF data were included (N=6765). Cox proportional hazards regression was used to calculate hazard ratios and 95% CI for tHcy and risk of HF. Models were stratified by impaired fasting glucose/type 2 diabetes status, and the combined impact of elevated tHcy and impaired fasting glucose/type 2 diabetes on HF incidence was examined.

Elevated tHcy (>12 μmol/L) was statistically significantly associated with HF overall and HFpEF, and conferred a higher risk for HF overall among individuals with dysglycemia impaired fasting glucose/type 2 diabetes compared with those with normoglycemia. Additionally, there was a statistically significant increased risk of HF overall and HF with reduced ejection fraction and a trend towards increased risk of HFpEF in individuals with both elevated tHcy and dysglycemia. tHcy appears to be a more significant contributor to HFpEF risk than dysglycemia, whereas dysglycemia seems to be more important in driving HF with reduced ejection fraction risk.

Our study confirms an association between hyperhomocysteinemia and HF risk in a large, multi-ethnic cohort. This is the first study to demonstrate that the impact of tHcy differs by HF subtype and appears to contribute more to HFpEF risk than HF with reduced ejection fraction risk.

Studies have shown an association of chronic kidney disease with heart failure (HF); however, this association has not been adequately examined in postmenopausal women, who are at heightened risk of both chronic kidney disease and HF. Additionally, association with HF subtypes is not well characterized.

Incident HF was defined as first hospitalization for acute decompensated HF, obtained by self-reported outcomes followed by physician adjudication through review of hospital records. Chronic kidney disease was defined using estimated glomerular filtration rate (eGFR). Restricted cubic splines tested the association of eGFR with incident overall HF, and HF with reduced ejection fraction (HFrEF) and preserved EF (HFpEF). Cox proportional hazards regression models evaluated the multivariable-adjusted association of eGFR categories with incident HF and its subtypes. The primary analysis included 23 309 women with 11 814 eGFR ≥90, 10 191 eGFR between 60 and 89, 1048 eGFR between 45 and 59 and 256 eGFR <45 mL/min per 1.73 m2. For overall HF, HFrEF and HFpEF, there was a stepwise increase in risk for incident HF with declining eGFR category. Associations were stronger for HFpEF (hazard ratio [HR], 2.80 [95% CI, 2.36-3.32]) than for HFrEF (HR, 2.18 [95% CI, 1.66-2.87]) for eGFR <45 as compared with eGFR ≥90. Heterogeneity of the HF subdistributions (HFpEF versus HFrEF) was significant (P=0.017).

Kidney dysfunction is associated with incident HF in postmenopausal women. Although lower eGFR is associated with both incident HFrEF and HFpEF, the association is stronger with HFpEF.

URL: https://clinicaltrials.gov; Unique Identifier: NCT00000611.

The therapeutic armamentarium for heart failure with preserved ejection fraction (HFpEF) remains notably constrained. A factor contributing to this problem could be the scarcity of in vitro models for HFpEF, which hinders progress in developing new therapeutic strategies. Here, we aimed at developing a novel, comorbidity-inspired, human, in vitro model for HFpEF.

Human induced pluripotent stem cells-derived cardiomyocytes were used to produce cardiac organoids. The generated organoids were then subjected to HFpEF-associated, comorbidity-inspired conditions, such as hypertension, diabetes, and obesity-related inflammation. To assess the development of HFpEF pathophysiological features, organoids were thoroughly evaluated for their structural, functional, electrophysiological, and metabolic properties.

Exposure to the combination of all comorbidity-mimicking conditions resulted in the largest cellular volume of 1692±52 versus 1346±84 µm3 in RPMI (Roswell Park Memorial Institute medium) control group (P=0.003), while lower in obesity, hypertension, and diabetes groups: 1059±40 µm3 (P=0.014), 1276±35 µm3 (P=0.940), and 1575±70 µm3 (P=0.146), respectively. Similarly, ultrastructural fibrosis was most significantly observed after exposure to the combination of all HFpEF-inducing conditions 14.6±1.2% compared with single condition exposure 5.2±1.3% (obesity), 6.7±3.5% (hypertension), and 9.0±1.1% (diabetes; P<0.001). Moreover, HFpEF-related conditions led to an increase in passive force compared with control (7.52±1.08 versus 2.33±0.46 mN/mm, P<0.001), whereas no significant alterations were noted in active contractile forces. Relaxation constant τ was significantly prolonged after exposure to HFpEF conditions showing a prolongation of 95.9 ms (36.4-106.4; P=0.028) compared with a shortening of 35.6 ms (43.3-67.3; P=0.80) in the control. Finally, organoid exposure to HFpEF conditions led to a significant increase in oxidative stress levels and a significant decline in oxygen consumption rate.

We established a novel, human, in vitro model for HFpEF, based on comorbidity-inspired conditions. The model faithfully recapitulated the structural, functional, and mechanistic features of HFpEF. This model holds the potential to provide mechanistic insights and facilitate the identification of novel therapeutic targets.

In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.

Heart failure with preserved ejection fraction (HFpEF) is a major healthcare problem with increasing prevalence. There has been a shift in HFpEF management towards early diagnosis and phenotype-specific targeted treatment. However, diagnosing HFpEF remains challenging due to a lack of universal criteria and patient heterogeneity. This review aims to provide a comprehensive assessment of the diagnostic workup of HFpEF, highlighting the role of echocardiography in HFpEF phenotyping.

Heart failure with preserved ejection fraction (HFpEF) poses a significant challenge in contemporary medicine, characterized by poor quality of life, high healthcare costs, and increased mortality. Despite advancements in medical research, treatment strategies for HFpEF remain elusive, with unclear guidance on the use of beta-blockers. While sympathetic overstimulation is common in HFpEF, beta-blockers, though potentially beneficial in reducing sympathetic activity, may exacerbate chronotropic incompetence and decrease exercise tolerance. Additionally, their impact on outcomes in HFpEF patients with concurrent atrial fibrillation is uncertain. Some studies suggest the potential benefits of beta-blockers on diastolic function, yet evidence on clinical endpoints remains inconclusive. Recent research indicates a potential reduction in all-cause mortality with beta-blocker use in HFpEF, although their effect on combined mortality or HF hospitalizations is less clear. Moreover, beta-blocker efficacy may vary depending on ejection fraction subgroups, with more favorable outcomes observed in HFmrEF compared to HFpEF. Current literature underscores the need for large-scale randomized clinical trials to clarify the role of beta-blockers in HFpEF management. Given the limitations of existing evidence, future research is essential to inform updated treatment guidelines and therapeutic protocols tailored to the contemporary clinical landscape.

There are several pharmacologic agents that have been touted as guideline-directed medical therapy for heart failure with preserved ejection fraction (HFpEF). However, it is important to recognize that older adults with HFpEF also contend with an increased risk for adverse effects from medications due to age-related changes in pharmacokinetics and pharmacodynamics of medications, as well as the concurrence of geriatric conditions such as polypharmacy and frailty. With this review, we discuss the underlying evidence for the benefits of various treatments in HFpEF and incorporate key considerations for older adults, a subpopulation that may be at higher risk for adverse drug events. Key considerations for older adults include: the use of loop diuretics, mineralocorticoid receptor antagonists (MRAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors for most; angiotensin receptor blockers/ angiotensin receptor-neprilysin inhibitors (ARB/ARNIs) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) as add-on therapies for some, though risk of geriatric conditions such as falls, malnutrition, and/or sarcopenia must be considered; and beta blockers for a smaller subset of patients (with consideration of deprescribing for some, though data are lacking on this approach). Naturally, when making clinical decisions for older adults with cardiovascular disease, it is critical to consider the complexity of their conditions, including cognitive and physical function and social and environmental factors, and ensure alignment of care plans with the patient's health goals and priorities.

Oral microenvironmental disorders are associated with an increased risk of heart failure with preserved ejection fraction (HFpEF). Hyperspectral imaging (HSI) technology enables the detection of substances that are visually indistinguishable to the human eye, providing a noninvasive approach with extensive applications in medical diagnostics.

The objective of this study is to develop and validate a digital, noninvasive oral diagnostic model for patients with HFpEF using HSI combined with various machine learning algorithms.

Between April 2023 and August 2023, a total of 140 patients were recruited from Renmin Hospital of Wuhan University to serve as the training and internal testing groups for this study. Subsequently, from August 2024 to September 2024, an additional 35 patients were enrolled from Three Gorges University and Yichang Central People's Hospital to constitute the external testing group. After preprocessing to ensure image quality, spectral and textural features were extracted from the images. We extracted 25 spectral bands from each patient image and obtained 8 corresponding texture features to evaluate the performance of 28 machine learning algorithms for their ability to distinguish control participants from participants with HFpEF. The model demonstrating the optimal performance in both internal and external testing groups was selected to construct the HFpEF diagnostic model. Hyperspectral bands significant for identifying participants with HFpEF were identified for further interpretative analysis. The Shapley Additive Explanations (SHAP) model was used to provide analytical insights into feature importance.

Participants were divided into a training group (n=105), internal testing group (n=35), and external testing group (n=35), with consistent baseline characteristics across groups. Among the 28 algorithms tested, the random forest algorithm demonstrated superior performance with an area under the receiver operating characteristic curve (AUC) of 0.884 and an accuracy of 82.9% in the internal testing group, as well as an AUC of 0.812 and an accuracy of 85.7% in the external testing group. For model interpretation, we used the top 25 features identified by the random forest algorithm. The SHAP analysis revealed discernible distinctions between control participants and participants with HFpEF, thereby validating the diagnostic model's capacity to accurately identify participants with HFpEF.

This noninvasive and efficient model facilitates the identification of individuals with HFpEF, thereby promoting early detection, diagnosis, and treatment. Our research presents a clinically advanced diagnostic framework for HFpEF, validated using independent data sets and demonstrating significant potential to enhance patient care.

China Clinical Trial Registry ChiCTR2300078855; https://www.chictr.org.cn/showproj.html?proj=207133.

Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear.

This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.

In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.

We determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1-133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.

PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.

Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF. Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function. Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.

The ratio of fibrinogen to albumin (FAR) is considered a new inflammatory biomarker and a predictor of cardiovascular disease risk. However, its prognostic value for patients with chronic heart failure (CHF) with different ejection fractions (EFs) remains unclear. A total of 916 hospitalized patients with CHF from January 2017 to October 2021 in the First Affiliated Hospital of Kunming Medical University were included in the study. Death occurred in 417 (45.5%) patients out of 916 patients during a median follow-up time of 750 days. Among these patients, 381 patients suffered from HFrEF (LVEF <40%) and 535 patients suffered from HFpEF or HFmrEF (HFpEF plus HFmrEF, LVEF ≥ 40%). Patients were categorized into high-level FAR (FAR-H) and low-level FAR (FAR-L) groups based on the optimal cut-off value of FAR (9.06) obtained from receiver operating characteristic (ROC) curve analysis. Upon analysing the Kaplan - Meier plots, the incidence of death was significantly higher in all patients with FAR-H and patients in both HF subgroups (p < 0.001). The multivariate Cox proportional hazard analyses indicated that the FAR was an independent predictor of all-cause mortality, regardless of heart failure subtype. (HR 1.115, 95% CI 1.089-1.142, p < 0.001; HFpEF plus HFmrEF, HR 1.109, 95% CI 1.074-1.146, p < 0.0001; HFrEF, HR 1.138, 95% CI 1.094-1.183, p < 0.0001) The optimal cut-off value of FAR in predicting all-cause mortality was 9.06 with an area under the curve value of 0.720 (95% CI: 0.687-0.753, p < 0.001), a sensitivity of 68.8% and a specificity of 65.6%. After adjusting for the traditional indicators (LVEF, Lg BNP, etc.), the new model with the FAR had better prediction ability in patients with CHF. Elevated FAR is an independent predictor of death in CHF and is not related to the HF subtype.

Left bundle branch block (LBBB) causes immediate electrical and mechanical dyssynchrony of the left ventricle (LV) and gradual structural damages in the Purkinje cells and myocardium. Mechanical dyssynchrony reduces the LV ejection fraction (EF) instantly, but only to ≈55% in an otherwise normal heart. Because of the heart's in-built functional redundancy, a patient with LBBB does not always notice the heart's reduced efficiency straightaway. After a variable period of time (which could be from days to decades), the patient may become symptomatic with heart failure (HF), which classifies as HF with preserved EF ≥50% (HFpEF). The LVEF drops further because of continuous adverse remodeling and inefficient cardiac contraction. The patient transits to HF with moderately reduced EF 35%-50% (HFmrEF) and then reduced EF ≤35% (HFrEF) over 5-21 years. Cardiac resynchronization therapy (CRT) is currently only indicated in guidelines for HFrEF and LBBB. LBBB shortens the median survival of patients with HFmrEF by 5.5 years. Randomized controlled trials have shown that CRT improves echocardiographic indices for HFmrEF with LBBB. CRT in HFpEF with LBBB is a promising but underexplored/underused therapy. There have been anecdotal reports that CRT produced symptom relief in patients debilitated by HFpEF with LBBB, who constitute ≈6% of all patients with HF and an adequate pool of potential randomized controlled trial participants. Conduction system pacing in the form of left bundle branch area pacing is an emerging pacing strategy that might reverse and forestall the deleterious effects of LBBB.

Heart failure with preserved ejection fraction (HFpEF) poses a significant clinical challenge, especially in older patients with HT. This study aimed to identify the factors influencing HFpEF occurrence in elderly patients with HT.

Elderly patients with HT were categorized into two groups: no HFpEF group and HFpEF group based on HFpEF diagnosis. Demographic, clinical, laboratory and echocardiographic data was conducted. Logistic regression analysis and joint prediction modeling were used to identify predictive factors for HFpEF.

Several factors were associated with HFpEF, including age, body mass index, duration of HT, atrial fibrillation (AF), chronic kidney disease (CKD), stroke, systolic blood pressure (SBP), serum creatinine (SCr), N-terminal pro brain natriuretic peptide (NT-proBNP), heart rate, serum sodium, low density lipoprotein cholesterol (LDL-c), triglyceride, left ventricular ejection fraction (LVEF), E/e' ratio, left atrial diameter, tricuspid regurgitation velocity, mitral regurgitation and C-reactive protein (CRP) levels. The joint prediction model shown high accuracy, with an area under the curve (AUC) of 0.840.

This study provided insights into the incidence rate and risk factors of HFpEF in elderly patients with HT. Key determinants included age, blood pressure, biomarkers, and echocardiographic parameters.

The very high energy demand of the heart is primarily met by adenosine triphosphate (ATP) production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure [including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), and diabetic cardiomyopathies] is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signalling and post-translational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.

A disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7) belongs to the family of metalloproteinases that contributes to tissue homeostasis during morphogenesis and reproduction. These metalloproteinases regulate various cell functions such as cell proliferation, are important regulators in tissue regeneration, and play a role in vascular remodelling, which is involved in atherosclerosis development. Despite the well-established association between ADAMTS-7 and atherosclerotic disease, data regarding the metalloproteinase's association with LV function remain scarce. The aim of this study was to investigate the association of ADAMTS-7 levels with diastolic dysfunction and various echocardiographic parameters in patients with type 2 diabetes mellitus. All patients underwent a clinical, vascular, and echocardiographic examination during their visit. Plasma ADAMTS-7 levels were measured in all patients. The results showed that diastolic dysfunction was strongly associated with age, but had no statistically significant association with ADAMTS-7. When individual echocardiographic parameters were examined, ADAMTS-7 levels showed a positive tendency only with deceleration time (DT), with the other echocardiographic parameters being positively associated only with age. The possible role of ADAMTS-7 in diastolic dysfunction and in the development and progression of heart failure in patients with type 2 diabetes mellitus deserves further investigation.

The relationship between serum glucose/potassium ratio (GPR) and the adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF) has not been completely clarified.

Patients were included from the American cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. The primary endpoint was the composite of cardiovascular mortality, aborted cardiac arrest, and hospitalization for HF. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) to examine the relationship between GPR and prognosis. Restricted cubic spline (RCS) curves were performed to explore the nonlinear relationship between GPR and the primary endpoint. Receiver Operating Characteristic (ROC) curves were constructed, and the areas under the curves (AUCs) for GPR and its components were compared using the DeLong test. Subgroup analysis and interaction effect were also explored.

A total of 1749 HFpEF patients were included. During the follow-up, 514 (29.4%) patients reached the primary outcome. An increase in GPR was independently associated with a higher risk in the primary endpoint [Tertile 3 vs. Tertile 1: HR (95% CI), 1.35 (1.07-1.70), P = 0.012] and HF hospitalization [Tertile 3 vs. Tertile 1: HR (95% CI), 1.57 (1.20-2.05), P = 0.001]. RCS curve showed a J-shape trend between GPR and primary endpoint (non-linear P = 0.002). The AUC for GPR was superior to that of the glucose and potassium (De long test P < 0.05). Additionally, the prognostic value of GPR was stronger in patients without diabetes and with less severe heart failure symptoms (P interaction < 0.05).

A J-shaped relationship was existed between GPR levels and the primary outcome in HFpEF patients. An increased GPR was an independent predictor of poor prognosis in HFpEF patients, especially in non-diabetic patients and those with less severe heart failure symptoms.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and advanced age is a main contributor to the prevalence of CVD. Cellular senescence is an irreversible state of cell cycle arrest that occurs in old age or after cells encounter various stresses. Senescent cells not only result in the reduction of cellular function, but also produce senescence-associated secretory phenotype (SASP) to affect surrounding cells and tissue microenvironment. There is increasing evidence that the gradual accumulation of senescent cardiomyocytes is causally involved in the decline of cardiovascular system function. To highlight the role of senescent cardiomyocytes in the pathophysiology of age-related CVD, we first introduced that senescent cardiomyoyctes can be identified by structural changes and several senescence-associated biomarkers. We subsequently provided a comprehensive summary of existing knowledge, outlining the compelling evidence on the relationship between senescent cardiomyocytes and age-related CVD phenotypes. In addition, we discussed that the significant therapeutic potential represented by the prevention of accelerated senescent cardiomyocytes, and the current status of some existing geroprotectors in the prevention and treatment of age-related CVD. Together, the review summarized the role of cardiomyocyte senescence in CVD, and explored the molecular knowledge of senescent cardiomyocytes and their potential clinical significance in developing senescent-based therapies, thereby providing important insights into their biology and potential therapeutic exploration.

Background: With modern diagnostic tools, incidence ischemia with no obstructive coronary atherosclerosis (INOCA) and heart failure with preserved ejection fraction (HFpEF) are found to be much higher than previously believed, and-as they lead to adverse cardiovascular outcomes-their causes and development are subjects of ongoing research. There is growing evidence that coronary microvascular dysfunction might be the underlying cause of both INOCA and HFpEF. Methods: In 65 patients with effort angina but no obstructive coronary artery disease, the index of microvascular resistance and coronary flow reserve were measured invasively in the LAD. The echocardiographic parameters, including left atrial strain, left ventricular strain, and indices of left ventricular diastolic dysfunction, were compared between two groups of patients: those with normal coronary microcirculation parameters and those with impaired coronary microvascular function. Results: Patients with coronary microvascular dysfunction had higher a E/E' index than those with normal microvessel reactivity. This finding was further confirmed by ROC analysis. The groups did not differ significantly in values of other echocardiographic parameters, including the left ventricular and left atrial strain. The prevalence of classical cardiovascular risk factors was similar in both groups. Conclusions: The coexistence of impaired coronary microvascular function with moderately elevated left ventricular filling pressures might correspond to the co-development of early stages of coronary microvascular dysfunction and HFpEF.

Despite the increasing prevalence and substantial burden of heart failure with preserved ejection fraction (HFpEF), which constitutes up to 50% of all heart failure cases, significant challenges persist in its diagnostic and therapeutic strategies. These difficulties arise primarily from the heterogeneous nature of the condition, the presence of various comorbidities and a wide range of phenotypic variations. Considering these challenges, current international guidelines endorse the utilization of invasive haemodynamic assessments, including resting and exercise haemodynamics, as the gold standard for enhancing diagnostic accuracy in cases where traditional diagnostic methods yield inconclusive results. These assessments are crucial not only for confirming the diagnosis but also for delineating the complex underlying pathophysiology, enabling the development of personalized treatment strategies, and facilitating the precise classification of HFpEF phenotypes. In this review, we summarize the haemodynamic changes observed in patients with HFpEF, comparing resting and exercise-induced parameters to those of normal subjects. Additionally, we discuss the current role of invasive haemodynamics in HFpEF assessment and highlight its utility beyond diagnosis, such as identifying HFpEF comorbidities, guiding phenotype-based personalized therapies and characterizing prognostication. Finally, we address the challenges associated with utilizing invasive haemodynamics and propose future directions, focusing on integrating these assessments into routine HFpEF care.

Renal denervation (RDN), a transcatheter renal sympathetic nerve ablation procedure, is a relatively novel established procedure for the treatment of hypertension, with it being recognized as a third option for hypertension management in the most recent European guidelines, together with pharmacotherapy, for achieving blood pressure targets. Given the relationship between both hypertension and sympathetic overdrive and the development of heart failure (HF), even studies at the dawn of research on RDN explored it as a treatment to overcome diuretic resistance in those patients. As it is now recognized that RDN does not only have organ-specific but also systemic effects, several investigators have aimed to delineate whether renal sympathetic denervation could alter the prognosis, symptoms, and adverse events of HF patients. Data are available in both HF patients with reduced and preserved ejection fraction. As the significance of neuromodulation is gaining grounds in the HF therapeutic arsenal, in this review, we aim to provide a rationale for using RDN in HF and an up-to-date overview of available data in both HF phenotypes, as well as discuss the future of neuromodulatory therapy in HF management.

Heart failure (HF) and renal dysfunction often coexist and interact in many complex and bidirectional pathways, leading to detrimental effects on patient outcomes. The treatment of HF patients with renal dysfunction presents a significant clinical challenge. Interestingly, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), may have beneficial effects on cardiac and renal outcomes in patients with HF with reduced ejection fraction, particularly by slowing the rate of decrease in the estimated glomerular filtration rate compared to a single angiotensin-converting enzyme inhibitor. Recently, more reports have emphasized the renal protection of sacubitril/valsartan in patients with HF. In HF patients with renal dysfunction, however, there is no strong evidence supporting the use of sacubitril/valsartan to reduce the absolute risk of hyperkalemia and worsening renal function; therefore, the administration of ARNI requires a careful balance between the benefits and risks. Furthermore, the lack of evidence-based management highlights the importance of an individualized approach based on published experience and multidisciplinary collaborations, as well as underlines the need for in-depth studies investigating the underlying mechanisms in cardiorenal interactions with a focus on treatments.

Heart failure with preserved ejection fraction (HFpEF) is associated with high hospitalization and mortality rates, representing a significant healthcare burden. This study aims to utilize various information including echocardiogram and phonocardiogram to construct and validate a nomogram, assisting in clinical decision-making.

This study analyzed 204 patients (68 HFpEF and 136 non-HFpEF) from the First Affiliated Hospital of Chongqing Medical University. A total of 49 features were integrated and used, including phonocardiogram, echocardiogram features, and clinical parameters. The least absolute shrinkage and selection operator (LASSO) regression was used to select the optimal matching factors, and a stepwise logistic regression was employed to determine independent risk factors and develop a nomogram. Model performance was evaluated by the area under receiver operating characteristic (ROC) curve (AUC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC).

The nomogram was constructed using five significant indicators, including NT-proBNP (OR = 4.689, p = 0.015), E/e' (OR = 1.219, p = 0.032), LAVI (OR = 1.088, p < 0.01), D/S (OR = 0.014, p < 0.01), and QM1 (OR = 1.058, p < 0.01), and showed a better AUC of 0.945 (95% CI = 0.908-0.982) in the training set and 0.933 (95% CI = 0.873-0.992) in the testing set compared to conventional nomogram without phonocardiogram features. The calibration curve and Hosmer-Lemeshow test demonstrated no statistical significance in the training and testing sets (p = 0.814 and p = 0.736), indicating the nomogram was well-calibrated. The DCA and CIC results confirmed favorable clinical usefulness.

The nomogram, integrating phonocardiogram and echocardiogram features, enhances HFpEF diagnostic efficiency, offering a valuable tool for clinical decision-making.

Acute coronary syndrome (ACS), heart failure (HF) and obstructive sleep apnea (OSA) often overlap and interact, the impact of OSA on ACS patients with HF remains unclear. The study sought to comprehensively evaluate the effects of the interaction between OSA and HF on long-term cardiovascular outcomes in ACS patients.

Between June 2015 and January 2020, patients hospitalized for ACS were prospectively enrolled and underwent portable sleep monitoring after clinically stabilization. OSA was defined as an apnea hypopnea index ≥15 events/h. HF was defined using medical records. The primary endpoint was major adverse cardiovascular and cerebrovascular event (MACCE), including death, myocardial infarction, stroke, ischemia-driven revascularization, and hospitalization for unstable angina.

Among all 1927 included patients, 214 (11.1 %) had HF, and 1014 (52.6 %) had OSA. For 2.9 years (1.5, 3.6 years) follow-up, OSA was independently associated with the risk of MACCE in HF patients (adjusted hazard ratio [HR], 2.11; 95%CI, 1.16-3.84; P = 0.014), but not in those without HF (adjusted HR, 1.15; 95%CI, 0.92-1.45; P = 0.228). Further analysis showed OSA exerted more prognostic effect in HF patients with preserved eject fraction (adjusted HR, 2.45; 95 % CI, 1.11-5.41; P = 0.027) than those with reduced eject fraction (adjusted HR, 1.62; 95 % CI, 0.63-4.20; P = 0.319).

In the settings of ACS, OSA was independently associated with poor prognosis in patients with concomitant HF especially those with persevered ejection fraction. Screening and treatment for OSA are highly recommended in ACS patients with HF.

URL: www.clinicaltrails.gov; Unique Identifier: NCT03362385.

This study investigates the prevalence and prognostic impact of diastolic dysfunction (DD) in patients hospitalized with heart failure (HF) with mildly reduced ejection fraction (HFmrEF) in sinus rhythm.

Data regarding the prognostic impact of DD in patients with HFmrEF is limited.

From 2016 to 2022, all patients hospitalized with HFmrEF (i.e., left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution. Patients with DD were compared to patients without (i.e., non-DD), further risk stratification was performed according to the severity of DD. The primary endpoint was all-cause mortality at 30 months (interquartile range (IQR) 15-61 months), key secondary endpoint was rehospitalization for worsening HF.

From a total of 1154 patients (median age 68 years, 68% males) hospitalized with HFmrEF, concomitant DD was present in 72% (grade I: 56%, grade II: 14%, grade III: 2%). Patients with DD were older (71 years vs. 65 years; p = 0.001) and presented with higher rates of cardiovascular comorbidities. The presence of DD was not associated with the risk of long-term all-cause mortality (adjusted HR = 0.815; 95% CI 0.612-1.085; p = 0.161) or HF-related rehospitalization (adjusted HR = 0.736; 95% CI 0.442-1.225; p = 0.238). Furthermore, the outcome did not differ in patients with more advanced stages of DD.

DD is commonly prevalent in patients with HFmrEF, but not associated with long-term prognosis.

Heart failure with preserved ejection fraction (HFpEF) accounts for 50 % of heart failure (HF) cases, making it the most common type of HF, and its prevalence continues to increase in the aging society. HFpEF is a systemic syndrome resulting from many risk factors, such as aging, metabolic syndrome, and hypertension, and its clinical features are highly heterogeneous in different populations. HFpEF syndrome involves the dysfunction of multiple organs, including the heart, lung, muscle, and vascular system. The heart shows dysfunction of various cells, including cardiomyocytes, endothelial cells, fibroblasts, adipocytes, and immune cells. The complex etiology and pathobiology limit experimental research on HFpEF in animal models, delaying a comprehensive understanding of the mechanisms and making treatment difficult. Recently, many scientists and cardiologists have attempted to improve the clinical outcomes of HFpEF. Recent advances in clinically related animal models and systemic pathology studies have improved our understanding of HFpEF, and clinical trials involving sodium-glucose cotransporter 2 inhibitors have significantly enhanced our confidence in treating HFpEF. This review provides an updated comprehensive discussion of the etiology and pathobiology, molecular and cellular mechanisms, preclinical animal models, and therapeutic trials in animals and patients to enhance our understanding of HFpEF and improve clinical outcomes.

Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research.

Heart failure with preserved ejection fraction (HFpEF) is a major healthcare problem that is raising in prevalence. There has been a shift in HpEF management towards early diagnosis and phenotype-specific targeted treatment. However, the diagnosis of HFpEF remains a challenge due to the lack of universal criteria and patient heterogeneity. This review aims to provide a comprehensive assessment of the diagnostic workup of HFpEF, highlighting the role of echocardiography in HFpEF phenotyping.

Patients who have heart failure with preserved ejection fraction (HFpEF) have signs and symptoms of heart failure, yet their ejection fraction remains greater than or equal to 50 percent. Understanding the underlying cause of HFpEF is crucial for accurate diagnosis and effective treatment. This condition can be caused by multiple factors, including ischemic or nonischemic myocardial diseases. HFpEF is often associated with diastolic dysfunction. Cardiac magnetic resonance (CMR) allows for a precise examination of the functional and structural alterations associated with HFpEF through the measurement of volumes and mass, the assessment of systolic and diastolic function, and the analysis of tissue characteristics. We will discuss CMR imaging indicators that are specific to patients with HFpEF and their relation to the disease. These markers can be acquired through both established and emerging methods.

This scoping review examines the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on health-related quality of life (HRQoL) and exercise capacity in heart failure patients with preserved ejection fraction (HFpEF). Five randomized controlled trials were analyzed, revealing consistent improvements in HRQoL metrics, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores and exercise capacity, measured by the six-minute walk distance (6MWD). The findings suggest that SGLT-2 inhibitors significantly enhance physical functioning and overall well-being in HFpEF patients. These benefits align with existing literature on SGLT-2 inhibitors' efficacy in heart failure with reduced ejection fraction (HFrEF), indicating broader applicability across heart failure phenotypes. However, the review highlights the need for long-term studies to confirm sustained benefits and further investigate the underlying mechanisms. Methodological improvements, such as standardized outcome measures, are also recommended to enhance future research robustness. Clinically, these findings advocate for incorporating SGLT-2 inhibitors into HFpEF management strategies, emphasizing their potential to improve patient outcomes and quality of life. Future research should focus on diverse patient populations and long-term effects to optimize the therapeutic use of SGLT-2 inhibitors in HFpEF.

Lately, a large number of stable ischemic patients, with no obstructed coronary arteries are being diagnosed. Despite this condition, which is being described as angina with no obstructive coronary arteries (ANOCA), was thought to be benign, recent evidence report that it is associated with increased risk for adverse cardiovascular outcomes. ANOCA is more frequent in women and, pathophysiologically, it is predominantly related with microvascular dysfunction, while other factors, such as endothelial dysfunction, inflammation and autonomic nervous system seem to also play a major role to its development, while other studies implicate ANOCA and microvascular dysfunction in the pathogenesis of heart failure with preserved ejection fraction. For establishing an ANOCA diagnosis, measurement including coronary flow reserve (CFR), microvascular resistance (IMR) and hyperemic microvascular resistance (HMR) are mostly used in clinical practice. In addition, new modalities, such as optical coherence tomography (OCT) are being tested and show promising results for future diagnostic use. Regarding management, pharmacotherapy consists of a wide selection of drugs, according to the respected pathophysiology of the disease (vasospastic angina or microvascular dysfunction), while research for new treatment options including interventional techniques, is currently ongoing. This review, therefore, aims to provide a comprehensive analysis of all aspects related to ANOCA, from pathophysiology to clinical managements, as well as clinical implications and suggestions for future research efforts, which will help advance our understanding of the syndrome and establish more, evidence-based, therapies.

Background: The role of epicardial adipose tissue (EAT) in heart failure with preserved ejection fraction (HFpEF) remains to be defined. Methods: A consecutive series of outpatients with chronic heart failure-heart failure with reduced ejection fraction (HFrEF) and HFpEF and/or diastolic dysfunction-had EAT assessed by echocardiographic measurement and related to indices of cardiac structure and function. Results: Epicardial fat thickness was significantly (p < 0.05) greater in HFpEF (N = 141) with a mean of 6.7 ± 1.6 mm compared with a mean of 5.1 ± 1.0 mm in HFrEF (n = 40). After adjusting for the relationship with BMI, in HFpEF, epicardial fat was significantly (p < 0.05) negatively correlated with left ventricular internal diameter end diastole (LVIDd), left ventricular internal diameter end systole (LVIDs), left ventricular (LV) end-diastolic volume (EDV) index, lateral e', septal e', right atrial (RA) volume index, and hemoglobin (Hgb). The association with Hgb was no longer significant after adjusting for the effect of age. HFpEF was associated with smaller LVIDd, LVIDs, LV EDV indexes, and left atrial (LA) and RA volume indexes. Conclusions: Epicardial fat is significantly (p < 0.05) greater in HFpEF than HFrEF. Epicardial fat is associated with smaller cardiac chamber sizes in HFpEF suggesting that epicardial fat acts as a constraint to cardiac dilation.

Heart failure (HF) is the predominant terminal stage and the leading cause of mortality in cardiac disease. Heart failure with preserved ejection fraction (HFpEF) affects roughly 50% of HF patients globally. Due to the global aging population, the prevalence, morbidity, and mortality of HFpEF have gradually increased. Epicardial adipose tissue (EAT), as a key visceral adipose tissue around the heart, affects cardiac diastolic function and exercise reserve capacity. EAT closely adheres to the myocardium and can produce inflammatory factors, neurotransmitters, and other factors through autocrine or paracrine mechanisms, affecting the heart function by inflammatory response, cardiac metabolism and energy supply, cardiomyocyte structure and electrical activity, and pericardial vascular function. Currently, research on the mechanism and treatment methods of HFpEF is constantly improving. EAT may play a multi-level impact on the occurrence and development of HFpEF. This review also summarizes the potential impact of EAT on the heart in HFpEF combined with other metabolism-related diseases such as obesity or diabetes over other obesity-related measures, such as body mass index (BMI) or other adipose tissue. Above all, this review comprehensively summarizes the potential mechanisms by which EAT may affect HFpEF. The objective is to enhance our comprehension and management of HFpEF. Future research should delve into the mechanistic relationship between EAT and HFpEF, and investigate interventions aimed at EAT to improve the prognosis of patients with HFpEF.

Methods to monitor cardiac functioning non-invasively can accelerate preclinical and clinical research into novel treatment options for heart failure. However, manual image analysis of cardiac substructures is resource-intensive and error-prone. While automated methods exist for clinical CT images, translating these to preclinical μCT data is challenging. We employed deep learning to automate the extraction of quantitative data from both CT and μCT images.

We collected a public dataset of cardiac CT images of human patients, as well as acquired μCT images of wild-type and accelerated aging mice. The left ventricle, myocardium, and right ventricle were manually segmented in the μCT training set. After template-based heart detection, two separate segmentation neural networks were trained using the nnU-Net framework.

The mean Dice score of the CT segmentation results (0.925 ± 0.019, n = 40) was superior to those achieved by state-of-the-art algorithms. Automated and manual segmentations of the μCT training set were nearly identical. The estimated median Dice score (0.940) of the test set results was comparable to existing methods. The automated volume metrics were similar to manual expert observations. In aging mice, ejection fractions had significantly decreased, and myocardial volume increased by age 24 weeks.

With further optimization, automated data extraction expands the application of (μ)CT imaging, while reducing subjectivity and workload. The proposed method efficiently measures the left and right ventricular ejection fraction and myocardial mass. With uniform translation between image types, cardiac functioning in diastolic and systolic phases can be monitored in both animals and humans.

Subclinical cardiovascular disease (Sub-CVD) is an early stage of cardiovascular disease and is often asymptomatic. Risk factors, including hypertension, diabetes, obesity, and lifestyle, significantly affect Sub-CVD. Progress in imaging technology has facilitated the timely identification of disease phenotypes and risk categorization. The critical function of dual-energy x-ray absorptiometry (DXA) in predicting Sub-CVD was the subject of this research. Initially used to evaluate bone mineral density, DXA has now evolved into an indispensable tool for assessing body composition, which is a pivotal determinant in estimating cardiovascular risk. DXA offers precise measurements of body fat, lean muscle mass, bone density, and abdominal aortic calcification, rendering it an essential tool for Sub-CVD evaluation. This study examined the efficacy of DXA in integrating various risk factors into a comprehensive assessment and how the application of machine learning could enhance the early discovery and control of cardiovascular risks. DXA exhibits distinct advantages and constraints compared to alternative imaging modalities such as ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography. This review advocates DXA incorporation into cardiovascular health assessments, emphasizing its crucial role in the early identification and management of Sub-CVD.

Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.

We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.

In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.

These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.