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1
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Gatterer C, Wollenweber T, Pichler V, Vraka C, Sunder-Plassmann G, Lenz M, Hengstenberg C, Hacker M, Loewe C, Graf S, Beitzke D. Detection of sympathetic denervation defects in Fabry disease by hybrid [ 11C]meta-hydroxyephedrine positron emission tomography and cardiac magnetic resonance. J Nucl Cardiol 2023; 30:1810-1821. [PMID: 36855009 PMCID: PMC10558396 DOI: 10.1007/s12350-023-03205-7] [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: 06/24/2022] [Accepted: 01/05/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Myocardial glycosphingolipid accumulation in patients with Fabry disease (FD) causes biochemical and structural changes. This study aimed to investigate sympathetic innervation in FD using hybrid cardiac positron emission tomography (PET)/magnetic resonance imaging (MRI). METHODS AND RESULTS Patients with different stages of Fabry disease were prospectively enrolled to undergo routine CMR at 1.5T, followed by 3T hybrid cardiac PET/MRI with [11C]meta-hydroxyephedrine ([11C]mHED). Fourteen patients with either no evidence of cardiac involvement (n = 5), evidence of left ventricular hypertrophy (LVH) (n = 3), or evidence of LVH and fibrosis via late gadolinium enhancement (LGE) (n = 6) were analyzed. Compared to patients without LVH, patients with LVH or LVH and LGE had lower median T1 relaxation times (ms) at 1.5 T (1007 vs. 889 vs. 941 ms, p = 0.003) and 3T (1290 vs. 1172 vs. 1184 p = .014). Myocardial denervation ([11C]mHED retention < 7%·min) was prevalent only in patients with fibrosis, where a total of 16 denervated segments was found in two patients. The respective area of denervation exceeded the area of LGE in both patients (24% vs. 36% and 4% vs. 32%). However, sympathetic innervation defects ([11C]mHED retention ≤ 9%·min) occurred in all study groups. Furthermore, a reduced sympathetic innervation correlated with an increased left ventricular mass (p = .034, rs = - 0.57) and a reduced global longitudinal strain (GLS) (p = 0.023, rs = - 0.6). CONCLUSION Hybrid cardiac PET/MR with [11C]mHED revealed sympathetic innervation defects, accompanied by impaired GLS, in early stages of Fabry disease. However, denervation is only present in patients with advanced stages of FD showing fibrosis on CMR.
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Affiliation(s)
- Constantin Gatterer
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Tim Wollenweber
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Verena Pichler
- Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria
| | - Chrysoula Vraka
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Gere Sunder-Plassmann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Max Lenz
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Christian Hengstenberg
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Marcus Hacker
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Christian Loewe
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Senta Graf
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Dietrich Beitzke
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Fasoula NA, Xie Y, Katsouli N, Reidl M, Kallmayer MA, Eckstein HH, Ntziachristos V, Hadjileontiadis L, Avgerinos DV, Briasoulis A, Siasos G, Hosseini K, Doulamis I, Kampaktsis PN, Karlas A. Clinical and Translational Imaging and Sensing of Diabetic Microangiopathy: A Narrative Review. J Cardiovasc Dev Dis 2023; 10:383. [PMID: 37754812 PMCID: PMC10531807 DOI: 10.3390/jcdd10090383] [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: 05/31/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/28/2023] Open
Abstract
Microvascular changes in diabetes affect the function of several critical organs, such as the kidneys, heart, brain, eye, and skin, among others. The possibility of detecting such changes early enough in order to take appropriate actions renders the development of appropriate tools and techniques an imperative need. To this end, several sensing and imaging techniques have been developed or employed in the assessment of microangiopathy in patients with diabetes. Herein, we present such techniques; we provide insights into their principles of operation while discussing the characteristics that make them appropriate for such use. Finally, apart from already established techniques, we present novel ones with great translational potential, such as optoacoustic technologies, which are expected to enter clinical practice in the foreseeable future.
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Affiliation(s)
- Nikolina-Alexia Fasoula
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Yi Xie
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Nikoletta Katsouli
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Mario Reidl
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Michael A. Kallmayer
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (M.A.K.); (H.-H.E.)
| | - Hans-Henning Eckstein
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (M.A.K.); (H.-H.E.)
| | - Vasilis Ntziachristos
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Leontios Hadjileontiadis
- Department of Biomedical Engineering, Healthcare Engineering Innovation Center (HEIC), Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates;
- Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | | | - Alexandros Briasoulis
- Aleksandra Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece;
| | - Gerasimos Siasos
- Sotiria Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece;
| | - Kaveh Hosseini
- Cardiac Primary Prevention Research Center, Cardiovascular Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713138, Iran;
| | - Ilias Doulamis
- Department of Surgery, The Johns Hopkins Hospital, School of Medicine, Baltimore, MD 21287, USA;
| | | | - Angelos Karlas
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany; (N.-A.F.); (Y.X.); (N.K.); (V.N.)
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany; (M.A.K.); (H.-H.E.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
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3
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Filipović N, Marinović Guić M, Košta V, Vukojević K. Cardiac innervations in diabetes mellitus-Anatomical evidence of neuropathy. Anat Rec (Hoboken) 2023; 306:2345-2365. [PMID: 36251628 DOI: 10.1002/ar.25090] [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: 06/07/2022] [Revised: 08/09/2022] [Accepted: 09/22/2022] [Indexed: 11/07/2022]
Abstract
The extensive innervations of the heart include a complex network of sympathetic, parasympathetic, and sensory nerves connected in loops that serve to regulate cardiac output. Metabolic dysfunction in diabetes affects many different organ systems, including the cardiovascular system; it causes cardiac arrhythmias, silent myocardial ischemia, and sudden cardiac death, among others. These conditions are associated with damage to the nerves that innervate the heart, cardiac autonomic neuropathy (CAN), which is caused by various pathophysiological mechanisms. In this review, the main facts about the anatomy of cardiac innervations and the current knowledge of CAN, its pathophysiological mechanisms, and its diagnostic approach are discussed. In addition, anatomical evidence for CAN from human and animal studies has been summarized.
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Affiliation(s)
- Natalija Filipović
- Department of Anatomy, Histology and Embryology, Laboratory for Experimental Neurocardiology, University of Split School of Medicine, Split, Croatia
| | - Maja Marinović Guić
- Department of Diagnostic and Interventional Radiology, University Hospital of Split, Split, Croatia
- University Department of Health Studies, University of Split, Split, Croatia
| | - Vana Košta
- Department of Neurology, University Hospital of Split, Split, Croatia
| | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, Laboratory for Experimental Neurocardiology, University of Split School of Medicine, Split, Croatia
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Adam CA, Marcu DTM, Mitu O, Roca M, Aursulesei Onofrei V, Zabara ML, Tribuș LC, Cumpăt C, Crișan Dabija R, Mitu F. Old and Novel Predictors for Cardiovascular Risk in Diabetic Foot Syndrome—A Narrative Review. APPLIED SCIENCES 2023; 13:5990. [DOI: 10.3390/app13105990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Diabetic foot syndrome (DFS) is a complication associated with diabetes that has a strong negative impact, both medically and socio-economically. Recent epidemiological data show that one in six patients with diabetes will develop an ulcer in their lifetime. Vascular complications associated with diabetic foot have multiple prognostic implications in addition to limiting functional status and leading to decreased quality of life for these patients. We searched the electronic databases of PubMed, MEDLINE and EMBASE for studies that evaluated the role of DFS as a cardiovascular risk factor through the pathophysiological mechanisms involved, in particular the inflammatory ones and the associated metabolic changes. In the era of evidence-based medicine, the management of these cases in multidisciplinary teams of “cardio-diabetologists” prevents the occurrence of long-term disabling complications and has prognostic value for cardiovascular morbidity and mortality among diabetic patients. Identifying artificial-intelligence-based cardiovascular risk prediction models or conducting extensive clinical trials on gene therapy or potential therapeutic targets promoted by in vitro studies represent future research directions with a modulating role on the risk of morbidity and mortality in patients with DFS.
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Affiliation(s)
- Cristina Andreea Adam
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, 700661 Iasi, Romania
| | - Dragos Traian Marius Marcu
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Clinical Hospital of Pneumophthisiology Iași, 700115 Iasi, Romania
| | - Ovidiu Mitu
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- “St. Spiridon” Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Mihai Roca
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, 700661 Iasi, Romania
| | - Viviana Aursulesei Onofrei
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- “St. Spiridon” Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Mihai Lucian Zabara
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laura Carina Tribuș
- Department of Internal Medicine, Faculty of Dentistry, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine, Ilfov County Emergency Hospital, 022104 Bucharest, Romania
| | - Carmen Cumpăt
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Management, “Alexandru Ioan Cuza” University, 700506 Iasi, Romania
| | - Radu Crișan Dabija
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Clinical Hospital of Pneumophthisiology Iași, 700115 Iasi, Romania
| | - Florin Mitu
- Department of Medical Specialties I and III and Department of Surgical Specialties, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Clinical Hospital of Pneumophthisiology Iași, 700115 Iasi, Romania
- Academy of Medical Sciences, 030167 Bucharest, Romania
- Academy of Romanian Scientists, 700050 Iasi, Romania
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Preda A, Liberale L, Montecucco F. Imaging techniques for the assessment of adverse cardiac remodeling in metabolic syndrome. Heart Fail Rev 2022; 27:1883-1897. [PMID: 34796433 DOI: 10.1007/s10741-021-10195-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/11/2021] [Indexed: 12/23/2022]
Abstract
Metabolic syndrome (MetS) includes different metabolic conditions (i.e. abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension) that concour in the development of cardiovascular disease and diabetes. MetS individuals often show adverse cardiac remodeling and myocardial dysfunction even in the absence of overt coronary artery disease or valvular affliction. Diastolic impairment and hypertrophy are hallmarks of MetS-related cardiac remodeling and represent the leading cause of heart failure with preserved ejection fraction (HFpEF). Altered cardiomyocyte function, increased neurohormonal tone, interstitial fibrosis, coronary microvascular dysfunction, and a myriad of metabolic abnormalities have all been implicated in the development and progression of adverse cardiac remodeling related to MetS. However, despite the enormous amount of literature produced on this argument, HF remains a leading cause of morbidity and mortality in such population. The early detection of initial adverse cardiac remodeling would enable the optimal implementation of effective therapies aiming at preventing the progression of the disease to the symptomatic phase. Beyond conventional imaging techniques, such as echocardiography, cardiac tomography, and magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this review, we summarize the pathophysiology of MetS-related cardiac remodeling and illustrate the relevance of state-of-the-art multimodality cardiac imaging to identify and quantify the degree of myocardial involvement, prognosticate long-term clinical outcome, and potentially guide therapeutic strategies.
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Affiliation(s)
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy.
- IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy.
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Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging. Nat Rev Cardiol 2020; 18:291-304. [PMID: 33188304 DOI: 10.1038/s41569-020-00465-5] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is an important public health issue. Projections estimate a sixfold increase in the number of adults with obesity in 40 years and an increase in the number of individuals with diabetes to 642 million by 2040. Increased adiposity is the strongest risk factor for developing diabetes. Early detection of the effects of diabesity on the cardiovascular system would enable the optimal implementation of effective therapies that prevent atherosclerosis progression, cardiac remodelling, and the resulting ischaemic heart disease and heart failure. Beyond conventional imaging techniques, such as echocardiography, CT and cardiac magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this Review, we summarize the effects of obesity and diabetes on myocardial structure and function and illustrate the use of state-of-the-art multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.
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7
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Nuclear Imaging of the Cardiac Sympathetic Nervous System. JACC Cardiovasc Imaging 2020; 13:1036-1054. [DOI: 10.1016/j.jcmg.2019.01.042] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 01/08/2023]
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8
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Yan P, Wan Q, Zhang Z, Xu Y, Miao Y, Chen P, Gao C. Association between Circulating B-Type Natriuretic Peptide and Diabetic Peripheral Neuropathy: A Cross-Sectional Study of a Chinese Type 2 Diabetic Population. J Diabetes Res 2020; 2020:3436549. [PMID: 33110921 PMCID: PMC7578714 DOI: 10.1155/2020/3436549] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/08/2020] [Accepted: 07/20/2020] [Indexed: 01/30/2023] Open
Abstract
Cardiovascular disease which is associated with cardiac dysfunction, usually measured with circulating levels of B-type natriuretic peptide (BNP), has been associated with incidence and progression of diabetic peripheral neuropathy (DPN). The potential relationship of circulating physiological levels of BNP with DPN, however, has not been reported. Circulating levels of BNP were measured in 258 patients with type 2 diabetes mellitus (T2DM), and participants were divided into a DPN group (n = 61) and no DPN group (n = 197). The relationship between circulating physiological levels of BNP and DPN and other parameters was analyzed. Circulating levels of BNP were significantly elevated in T2DM patients with DPN compared to those without (P = 0.001). Circulating levels of BNP were significantly and positively associated with systolic blood pressure (P = 0.035), neutrophil-to-lymphocyte ratio (P = 0.007), creatinine (P = 0.030), vibration perception threshold values (P = 0.021), and the prevalence of diabetic foot ulceration (P = 0.039), peripheral arterial disease (P = 0.013), DPN (P = 0.032), and diabetic nephropathy (P = 0.020) and negatively with lymphocyte count (P = 0.003) and ankle-brachial index (P = 0.038), irrespective of age, sex, and body mass index. Moreover, circulating levels of BNP was an independent decisive factor for the presence of DPN after multivariate adjustment (odds ratio, 1.044; 95% confidence interval, 1.006-1.084; P = 0.024). Additionally, the higher quartiles of circulating BNP were related significantly to an increased risk of DPN compared to the lowest quartile (P = 0.003). Last but most importantly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating levels of BNP to predict DPN was 15.18 pg/mL (sensitivity 78.7% and specificity 48.2%). These findings suggest that high circulating physiological levels of BNP may be associated with the development of DPN and may be a potential biomarker for DPN in patients with T2DM.
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Affiliation(s)
- Pijun Yan
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Qin Wan
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Zhihong Zhang
- Department of General Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yong Xu
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Ying Miao
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Pan Chen
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Chenlin Gao
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
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9
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Jungen C, Scherschel K, Flenner F, Jee H, Rajendran P, De Jong KA, Nikolaev V, Meyer C, Ardell JL, Tompkins JD. Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation. Am J Physiol Heart Circ Physiol 2019; 317:H1328-H1341. [PMID: 31625779 DOI: 10.1152/ajpheart.00249.2019] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.
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Affiliation(s)
- Christiane Jungen
- Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Katharina Scherschel
- Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Frederik Flenner
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Centre, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Haesung Jee
- University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California
| | - Pradeep Rajendran
- University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California
| | - Kirstie A De Jong
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, University of Hamburg, Germany
| | - Viacheslav Nikolaev
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, University of Hamburg, Germany
| | - Christian Meyer
- Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Jeffrey L Ardell
- University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California
| | - John D Tompkins
- University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California
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10
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Liu L, Li X, Dong L, Li Y, Yu H, Chen Q. A novel strategy for the preparation of the injectable PET/CT radiopharmaceutical (-)-[11C]-(1R,2S)-meta-hydroxyephedrine ((-)-[11C]HED. J Radioanal Nucl Chem 2019. [DOI: 10.1007/s10967-019-06534-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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11
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Beitzke D, Wielandner A, Wollenweber T, Vraka C, Pichler V, Uyanik-Uenal K, Zuckermann A, Greiser A, Hacker M, Loewe C. Assessment of sympathetic reinnervation after cardiac transplantation using hybrid cardiac PET/MRI: A pilot study. J Magn Reson Imaging 2019; 50:1326-1335. [PMID: 30892777 PMCID: PMC6766915 DOI: 10.1002/jmri.26722] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/01/2019] [Accepted: 03/02/2019] [Indexed: 12/12/2022] Open
Abstract
Background Sympathetic reinnervation after heart transplantation (HTX) is a known phenomenon, which has an impact on patient heart rate variability and exercise capacity. The impact of reinnervation on myocardial structure has not been evaluated yet. Propose To evaluate the feasibility of simultaneous imaging of cardiac reinnervation and cardiac structure using a hybrid PET/MRI system. Study type Prospective / pilot study. Subjects Ten patients, 4–21 years after cardiac transplantation. Field Strength/Sequence 3 T hybrid PET/MRI system. Cine SSFP, T1 mapping (modified Look–Locker inversion recovery sequence) pre/postcontrast as well as dynamic [11C]meta‐hydroxyephedrine ([11C]mHED) PET. Assessment All MRI and PET parameters were evaluated by experienced readers using dedicated postprocessing software packages for cardiac MRI and PET. For all parameters a 16‐segment model for the left ventricle was applied. Statistical Tests Mann–Whitney U‐test; Spearman correlations. Results Thirty‐six of 160 myocardial segments showed evidence of reinnervation by PET. On a segment‐based analysis, mean native T1 relaxation times were nonsignificantly altered in segments with evidence of reinnervation (1305 ± 151 msec vs. 1270 ± 112 msec; P = 0.1), whereas mean extracellular volume (ECV) was significantly higher in segments with evidence of reinnervation (35.8 ± 11% vs. 30.9 ± 7%; P = 0.019). There were no significant differences in wall motion (WM) and wall thickening (WT) between segments with or without reinnervation (mean WM: 7.6 ± 4 mm vs. group B: 9.3 ± 7 mm [P = 0.13]; WT: 79 ± 63% vs. 94 ± 74% [P = 0.27]) under resting conditions. Data Conclusion The assessment of cardiac reinnervation using a hybrid PET/MRI system is feasible. Segments with evidence of reinnervation by PET showed nonsignificantly higher T1 relaxation times and a significantly higher ECV, suggesting a higher percentage of diffuse fibrosis in these segments, without impairment of rest WM and WT. Level of Evidence: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1326–1335.
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Affiliation(s)
- Dietrich Beitzke
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Cardiovascular and Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Alice Wielandner
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Cardiovascular and Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Tim Wollenweber
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Chrysoula Vraka
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Verena Pichler
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Keziban Uyanik-Uenal
- Department of Surgery, Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Andreas Zuckermann
- Department of Surgery, Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Marcus Hacker
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Christian Loewe
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Cardiovascular and Interventional Radiology, Medical University of Vienna, Vienna, Austria
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Manabe O, Kikuchi T, Scholte AJHA, El Mahdiui M, Nishii R, Zhang MR, Suzuki E, Yoshinaga K. Radiopharmaceutical tracers for cardiac imaging. J Nucl Cardiol 2018; 25:1204-1236. [PMID: 29196910 PMCID: PMC6133155 DOI: 10.1007/s12350-017-1131-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 11/05/2017] [Indexed: 12/13/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of death and disease burden worldwide. Nuclear myocardial perfusion imaging with either single-photon emission computed tomography or positron emission tomography has been used extensively to perform diagnosis, monitor therapies, and predict cardiovascular events. Several radiopharmaceutical tracers have recently been developed to evaluate CVD by targeting myocardial perfusion, metabolism, innervation, and inflammation. This article reviews old and newer used in nuclear cardiac imaging.
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Affiliation(s)
- Osamu Manabe
- Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tatsuya Kikuchi
- Department of Radiopharmaceutical Development, National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, Chiba, Japan
| | - Arthur J H A Scholte
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Mohammed El Mahdiui
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ryuichi Nishii
- Diagnostic and Therapeutic Nuclear Medicine, National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-Ku, Chiba, 263-8555, Japan
| | - Ming-Rong Zhang
- Department of Radiopharmaceutical Development, National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, Chiba, Japan
| | - Eriko Suzuki
- Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Keiichiro Yoshinaga
- Diagnostic and Therapeutic Nuclear Medicine, National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-Ku, Chiba, 263-8555, Japan.
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Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes 2018; 9:1-24. [PMID: 29359025 PMCID: PMC5763036 DOI: 10.4239/wjd.v9.i1.1] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/09/2017] [Accepted: 12/29/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.
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Affiliation(s)
- Victoria A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
| | - Alexandr A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
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14
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Assessment of diabetic neuropathy with emission tomography and magnetic resonance spectroscopy. Nucl Med Commun 2017; 38:275-284. [DOI: 10.1097/mnm.0000000000000653] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Cardiovascular PET provides exquisite measurements of key aspects of the cardiovascular system and as a consequence it plays central role in cardiovascular investigation. Moreover, PET is now playing an ever increasing role in the management of the cardiac patient. Central to the success of PET is the development and use of novel radiotracers that permit measurements of key aspects of cardiovascular health such as myocardial perfusion, metabolism, and neuronal function. Moreover, the development of molecular imaging radiotracers is now permitting the interrogation of cellular and sub cellular processes. This article highlights these various radiotracers and their role in both cardiovascular research and potential clinical applications.
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Affiliation(s)
- Robert J Gropler
- Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO 63110, USA
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16
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Barsanti C, Lenzarini F, Kusmic C. Diagnostic and prognostic utility of non-invasive imaging in diabetes management. World J Diabetes 2015; 6:792-806. [PMID: 26131322 PMCID: PMC4478576 DOI: 10.4239/wjd.v6.i6.792] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/23/2014] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
Medical imaging technologies are acquiring an increasing relevance to assist clinicians in diagnosis and to guide management and therapeutic treatment of patients, thanks to their non invasive and high resolution properties. Computed tomography, magnetic resonance imaging, and ultrasonography are the most used imaging modalities to provide detailed morphological reconstructions of tissues and organs. In addition, the use of contrast dyes or radionuclide-labeled tracers permits to get functional and quantitative information about tissue physiology and metabolism in normal and disease state. In recent years, the development of multimodal and hydrid imaging techniques is coming to be the new frontier of medical imaging for the possibility to overcome limitations of single modalities and to obtain physiological and pathophysiological measurements within an accurate anatomical framework. Moreover, the employment of molecular probes, such as ligands or antibodies, allows a selective in vivo targeting of biomolecules involved in specific cellular processes, so expanding the potentialities of imaging techniques for clinical and research applications. This review is aimed to give a survey of characteristics of main diagnostic non-invasive imaging techniques. Current clinical appliances and future perspectives of imaging in the diagnostic and prognostic assessment of diabetic complications affecting different organ systems will be particularly addressed.
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Giorgetti A, Burchielli S, Positano V, Kovalski G, Quaranta A, Genovesi D, Tredici M, Duce V, Landini L, Trivella MG, Marzullo P. Dynamic 3D Analysis of Myocardial Sympathetic Innervation: An Experimental Study Using 123I-MIBG and a CZT Camera. J Nucl Med 2015; 56:464-9. [DOI: 10.2967/jnumed.114.143669] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Harms HJ, de Haan S, Knaapen P, Allaart CP, Rijnierse MT, Schuit RC, Windhorst AD, Lammertsma AA, Huisman MC, Lubberink M. Quantification of [(11)C]-meta-hydroxyephedrine uptake in human myocardium. EJNMMI Res 2014; 4:52. [PMID: 26116116 PMCID: PMC4452641 DOI: 10.1186/s13550-014-0052-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 09/08/2014] [Indexed: 12/02/2022] Open
Abstract
Background The aims of this study were to determine the optimal tracer kinetic model for [11C]-meta-hydroxyephedrine ([11C]HED) and to evaluate the performance of several simplified methods. Methods Thirty patients underwent dynamic 60-min [11C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (VT) data. Results The reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, VT derived using the single-tissue model correlated highly with that of the two-tissue model (r2 = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in VT. RI and SUV can provide misleading results because of non-linear relationships with VT. Conclusions Although the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with VT, and therefore, care has to be taken when using RI as a quantitative measure. Electronic supplementary material The online version of this article (doi:10.1186/s13550-014-0052-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hendrik J Harms
- Department of Radiology and Nuclear Medicine, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, the Netherlands,
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Cardiac sympathetic denervation in 6-OHDA-treated nonhuman primates. PLoS One 2014; 9:e104850. [PMID: 25133405 PMCID: PMC4136781 DOI: 10.1371/journal.pone.0104850] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/15/2014] [Indexed: 12/11/2022] Open
Abstract
Cardiac sympathetic neurodegeneration and dysautonomia affect patients with sporadic and familial Parkinson's disease (PD) and are currently proposed as prodromal signs of PD. We have recently developed a nonhuman primate model of cardiac dysautonomia by iv 6-hydroxydopamine (6-OHDA). Our in vivo findings included decreased cardiac uptake of a sympathetic radioligand and circulating catecholamines; here we report the postmortem characterization of the model. Ten adult rhesus monkeys (5–17 yrs old) were used in this study. Five animals received 6-OHDA (50 mg/kg iv) and five were age-matched controls. Three months post-neurotoxin the animals were euthanized; hearts and adrenal glands were processed for immunohistochemistry. Quantification of immunoreactivity (ir) of stainings was performed by an investigator blind to the treatment group using NIH ImageJ software (for cardiac bundles and adrenals, area above threshold and optical density) and MBF StereoInvestigator (for cardiac fibers, area fraction fractionator probe). Sympathetic cardiac nerve bundle analysis and fiber area density showed a significant reduction in global cardiac tyrosine hydroxylase-ir (TH; catecholaminergic marker) in 6-OHDA animals compared to controls. Quantification of protein gene protein 9.5 (pan-neuronal marker) positive cardiac fibers showed a significant deficit in 6-OHDA monkeys compared to controls and correlated with TH-ir fiber area. Semi-quantitative evaluation of human leukocyte antigen-ir (inflammatory marker) and nitrotyrosine-ir (oxidative stress marker) did not show significant changes 3 months post-neurotoxin. Cardiac nerve bundle α-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant α-synuclein (typical of PD pathology) was not observed. In the adrenal medulla, 6-OHDA monkeys had significantly reduced TH-ir and aminoacid decarboxylase-ir. Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection.
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Affiliation(s)
- Jens Jordan
- Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
| | - Jens Tank
- Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
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21
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Charnogursky GA, Emanuele NV, Emanuele MA. Neurologic Complications of Diabetes. Curr Neurol Neurosci Rep 2014; 14:457. [DOI: 10.1007/s11910-014-0457-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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22
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Magota K, Hattori N, Manabe O, Naya M, Oyama-Manabe N, Shiga T, Kuge Y, Yamada S, Sakakibara M, Yoshinaga K, Tamaki N. Electrocardiographically gated 11C-hydroxyephedrine PET for the simultaneous assessment of cardiac sympathetic and contractile functions. Ann Nucl Med 2013; 28:187-95. [DOI: 10.1007/s12149-013-0795-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 11/26/2013] [Indexed: 11/28/2022]
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Schnell O, Cappuccio F, Genovese S, Standl E, Valensi P, Ceriello A. Type 1 diabetes and cardiovascular disease. Cardiovasc Diabetol 2013; 12:156. [PMID: 24165454 PMCID: PMC3816572 DOI: 10.1186/1475-2840-12-156] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 10/08/2013] [Indexed: 12/16/2022] Open
Abstract
The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.
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Affiliation(s)
- Oliver Schnell
- Forschergruppe Diabetes e.V., Helmholtz Center Munich, Ingolstaedter Landstrasse 1, 85764 Munich-Neuherberg, Germany
| | | | - Stefano Genovese
- Department of Cardiovascular and Metabolic Diseases, Gruppo Multimedica, Sesto San Giovanni, Milan, Italy
| | - Eberhard Standl
- Forschergruppe Diabetes e.V., Helmholtz Center Munich, Ingolstaedter Landstrasse 1, 85764 Munich-Neuherberg, Germany
| | - Paul Valensi
- Service d’Endocrinologie-Diabétologie-Nutrition, Hôpital Jean Verdier, Bondy Cedex, France
| | - Antonio Ceriello
- Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Hospital Clínic Barcelona, Barcelona, Spain
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Abstract
Sympathetic neuroimaging provides an important supplement to physiological, neurochemical, and neuropharmacological approaches in the evaluation of patients with clinical autonomic disorders. Almost all sympathetic neuroimaging to date has involved visualization of noradrenergic innervation in the left ventricular myocardium. Single-photon emission computed tomography (SPECT) scanning after injection of the sympathomimetic amine (123)I-metaiodobenzylguanidine ((123)I-MIBG) constitutes by far the most commonly used means worldwide to assess cardiac sympathetic innervation. Based on heart:mediastinum ratios of (123)I-MIBG-derived radioactivity, decreased uptake, increased washout, or both have been reported in many disorders and relate to diagnosis and prognosis. Cardiac sympathetic neuroimaging and postmortem neuropathological findings have linked α-synucleinopathy with noradrenergic denervation in Lewy body diseases. Especially because of the utility of cardiac sympathetic neuroimaging in distinguishing Parkinson disease from multiple system atrophy in patients with clinical evidence of central neurodegeneration and orthostatic hypotension, sympathetic neuroimaging seems a valuable addition to physiological, neuropharmacological, and neurochemical approaches in the diagnostic evaluation of selected patients with autonomic and neurodegenerative disorders.
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25
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Bernardi L, Spallone V, Stevens M, Hilsted J, Frontoni S, Pop-Busui R, Ziegler D, Kempler P, Freeman R, Low P, Tesfaye S, Valensi P. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev 2011; 27:654-64. [PMID: 21695761 DOI: 10.1002/dmrr.1224] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 06/06/2011] [Indexed: 12/16/2022]
Abstract
This consensus document provides evidence-based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non-invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches.
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Affiliation(s)
- Luciano Bernardi
- Department of Internal Medicine, IRCCS S.Matteo and University of Pavia, Pavia, Italy.
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The role of cardiac PET in translating basic science into the clinical arena. J Cardiovasc Transl Res 2011; 4:425-36. [PMID: 21573964 DOI: 10.1007/s12265-011-9285-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 05/02/2011] [Indexed: 12/20/2022]
Abstract
Non-invasive imaging has become fundamental in translating findings from basic science research into clinical applications. In this aspect, positron-emission tomography (PET) offers important advantages over other common imaging modalities like single-photon emission computed tomography, computed tomography, and magnetic resonance imaging (MRI), since PET provides superior detection sensitivity in the evaluation of different cardiovascular targets and pathways at the cellular and subcellular level, and because it is a well-established technique for absolute image quantification. The development and the introduction of dedicated small animal PET systems have greatly facilitated and contributed to advancements in the translation of novel radio-labeled compounds from experimental to clinical practice. The scope of the present article is to review the most relevant and successful PET applications in cardiovascular translational research.
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Abstract
Diabetic heart disease is currently defined as left ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Its underlying etiology is likely to be multifactorial, acting synergistically together to cause myocardial dysfunction. Multimodality cardiac imaging, such as echocardiography, nuclear, computed tomography, and magnetic resonance imaging, can provide invaluable insight into different aspects of the disease process, from imaging at the cellular level for altered myocardial metabolism to microvascular and endothelial dysfunction, autonomic neuropathy, coronary atherosclerosis, and finally, interstitial fibrosis with scar formation. Furthermore, cardiac imaging is pivotal in diagnosing diabetic heart disease. Thus, the aim of the present review is to illustrate the role of multimodality cardiac imaging in elucidating the underlying pathophysiologic mechanisms of diabetic heart disease.
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Gerson MC, Caldwell JH, Ananthasubramaniam K, Clements IP, Henzlova MJ, Amanullah A, Jacobson AF. Influence of diabetes mellitus on prognostic utility of imaging of myocardial sympathetic innervation in heart failure patients. Circ Cardiovasc Imaging 2010; 4:87-93. [PMID: 21193691 DOI: 10.1161/circimaging.110.954784] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Patients with diabetes mellitus have accelerated progression of heart failure and often have impaired cardiac sympathetic innervation. The present study examines the implications for heart failure progression of cardiac sympathetic denervation, assessed by I-123 metaiodobenzylguanidine imaging, in diabetic compared with nondiabetic subjects. METHODS AND RESULTS We evaluated 343 diabetic and 618 nondiabetic subjects with New York Heart Association class II or III heart failure and a left ventricular ejection fraction ≤35% over a median follow-up of 17 months. A multivariable Cox proportional hazards model was used to examine the influence of clinical variables, b-type natriuretic peptide, plasma norepinephrine, left ventricular ejection fraction, and I-123 metaiodobenzylguanidine imaging parameters on time to a heart failure event. The late heart-to-mediastinum (H/M) ratio and the interaction term of diabetes mellitus with the prospectively selected late H/M ratio <1.6 were independent predictors of heart failure progression, providing incremental prognostic information beyond that available from all other variables. In diabetic subjects, late H/M ratio <1.6 was associated with a 2.99-fold greater 2-year rate of heart failure progression (33.5%) than late H/M ratio ≥1.6 (11.2% event rate). CONCLUSIONS The combination of diabetes mellitus and I-123 metaiodobenzylguanidine H/M ratio is an independent predictor of heart failure progression, confirming the high risk of diabetic subjects with impaired cardiac sympathetic nerve function.
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Affiliation(s)
- Myron C Gerson
- Division of Cardiology, Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
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Bax JJ, Kraft O, Buxton AE, Fjeld JG, Parízek P, Agostini D, Knuuti J, Flotats A, Arrighi J, Muxi A, Alibelli MJ, Banerjee G, Jacobson AF. 123 I-mIBG scintigraphy to predict inducibility of ventricular arrhythmias on cardiac electrophysiology testing: a prospective multicenter pilot study. Circ Cardiovasc Imaging 2008; 1:131-40. [PMID: 19808530 DOI: 10.1161/circimaging.108.782433] [Citation(s) in RCA: 128] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Disturbances of autonomic function after infarction are associated with both total mortality and sudden death. Although many imaging techniques for assessing the cardiac autonomic nervous system have been studied, the clinical usefulness of these techniques remains uncertain. This exploratory pilot study examined the relationship between abnormalities of ventricular sympathetic innervation delineated by scintigraphic imaging with (123)I-mIBG and inducible ventricular tachyarrhythmias in patients with left ventricular dysfunction and previous myocardial infarction. METHODS AND RESULTS Fifty patients underwent electrophysiological (EP) testing and 15-minute and 4-hour planar and single photon emission computed tomography (SPECT) imaging with (123)I-mIBG and SPECT imaging with (99m)Tc-tetrofosmin. The primary efficacy variables were the 4-hour heart:mediastinum ratio (H/M) and the (123)I-mIBG/(99m)Tc-tetrofosmin SPECT mismatch score. EP studies were categorized as positive (EP(+)) or negative (EP(-)) for inducibility of sustained (>30 seconds) ventricular tachyarrhythmias. Thirty patients were EP(+), and 20 were EP(-). There were no significant differences in the 4-hour H/M ratios or (123)I-mIBG/(99m)Tc-tetrofosmin SPECT mismatch scores between the two groups. In a multivariable analysis using all (123)I-mIBG and (99m)Tc-tetrofosmin SPECT measurements, the only variable that showed a significant difference between EP(+) and EP(-) patients was the 4-hour (123)I-mIBG SPECT defect score. A 4-hour (123)I-mIBG SPECT defect score of > or =37 yielded a sensitivity of 77% and specificity of 75% for predicting EP results. CONCLUSIONS The standard indices of (123)I-mIBG imaging (H/M and innervation-perfusion mismatch score) are not predictive of EP test results. The association of (123)I-mIBG SPECT defect severity with EP test inducibility in this exploratory study will require confirmation in a larger cohort of patients.
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Affiliation(s)
- Jeroen J Bax
- Leiden University Medical Centre, Albinusdreef 2, Leiden, The Netherlands.
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Henneman MM, Bengel FM, van der Wall EE, Knuuti J, Bax JJ. Cardiac neuronal imaging: application in the evaluation of cardiac disease. J Nucl Cardiol 2008; 15:442-55. [PMID: 18513651 DOI: 10.1016/j.nuclcard.2008.02.023] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Maureen M Henneman
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
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31
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Lautamäki R, Tipre D, Bengel FM. Cardiac sympathetic neuronal imaging using PET. Eur J Nucl Med Mol Imaging 2007; 34 Suppl 1:S74-85. [PMID: 17479262 DOI: 10.1007/s00259-007-0442-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases. PET AS AN IMAGING TOOL PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resolution of PET enables noninvasive quantification of neurophysiologic processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to determine involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia. REVIEW This review summarizes the recent findings in neurocardiological PET imaging. Experimental studies with several radioligands and clinical findings in cardiac dysautonomias are discussed.
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Affiliation(s)
- Riikka Lautamäki
- Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA
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Abstract
Heart failure and diabetes mellitus are frequently associated, with diabetes potentiating the development of heart failure after other myocardial insults. This review documents the evidence in support of a specific primary myocardial disease in diabetes. The strongest clinical evidence relates to the detection of otherwise unexplained diastolic dysfunction in apparently healthy diabetic subjects, but recent studies with sensitive echocardiographic markers have shown systolic disturbances as well. The mechanism of this myocardial disease is multifactorial, with contributions from metabolic effects on the myocyte, structural changes in the myocardium and interstitium, autonomic neuropathy, and perhaps coronary vascular disease. The common pathway appears to be related to glycemic control and new evidence suggests better metabolic control to be beneficial, as well as angiotensin-converting enzyme inhibition and cross-link breakers.
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Affiliation(s)
- Thomas H Marwick
- University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane, QLD 4102, Australia.
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33
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Chen GP, Tabibiazar R, Branch KR, Link JM, Caldwell JH. Cardiac receptor physiology and imaging: an update. J Nucl Cardiol 2006; 12:714-30. [PMID: 16344234 DOI: 10.1016/j.nuclcard.2005.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Grace P Chen
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA
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Valensi P, Pariès J, Lormeau B, Attia S, Attali JR. Influence of nutrients on cardiac autonomic function in nondiabetic overweight subjects. Metabolism 2005; 54:1290-6. [PMID: 16154426 DOI: 10.1016/j.metabol.2005.04.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2004] [Accepted: 04/28/2005] [Indexed: 11/22/2022]
Abstract
The current study sought to determine whether there is a link between cardiac autonomic dysfunction and food intake in overweight subjects. One hundred five nondiabetic overweight (body mass index >27 kg/m2) subjects were studied. Heart rate variations were analyzed during 3 bedside standard tests investigating mainly vagal control: deep breathing, lying-to-standing, and Valsalva tests. The resting metabolic rate and substrate oxidation rates were measured by indirect calorimetry. Dietary intake was estimated from a 3-day recall of food intake. Cardiac parasympathetic dysfunction (PSD) was found in 39 subjects. The sex ratio, age, anthropometric parameters, biochemical parameters and insulin resistance index, resting metabolic rate, and substrate oxidation rates did not differ in the subjects with or without PSD. The total 24-hour energy intake was similar, but the carbohydrate intake was significantly higher in the subjects with PSD (P = .006), and the fat and protein intakes were significantly lower (P = .026 and .045, respectively). In the logistic regression analyses, PSD correlated with carbohydrate and fat intake, independently of serum insulin levels. Glucose oxidation rate correlated negatively with fasting and postglucose serum insulin levels only in the subjects with PSD (P = .006 and .005, respectively). Cardiac parasympathetic dysfunction is associated with higher carbohydrate intake and lower fat and protein intakes in overweight subjects. A sympathetic override may contribute to reducing the glucose oxidation rate in subjects with PSD.
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Affiliation(s)
- Paul Valensi
- Department of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, AP-HP, Paris-Nord University, Bondy, France.
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35
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Link JM, Stratton JR, Levy W, Poole JE, Shoner SC, Stuetzle W, Caldwell JH. PET measures of pre- and post-synaptic cardiac beta adrenergic function. Nucl Med Biol 2004; 30:795-803. [PMID: 14698782 DOI: 10.1016/j.nucmedbio.2003.09.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Positron Emission Tomography was used to measure global and regional cardiac beta-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [(11)C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [(11)C]-CGP12177 was used to measure cell surface beta-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.
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Affiliation(s)
- Jeanne M Link
- Department of Radiology, Box 356004, University of Washington, Seattle, WA 98195, USA
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36
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Abstract
The autonomic nervous system plays a key role for regulation of cardiac performance, and the importance of alterations of innervation in the pathophysiology of various heart diseases has been increasingly emphasized. Nuclear imaging techniques have been established that allow for global and regional investigation of the myocardial nervous system. The guanethidine analog iodine 123 metaiodobenzylguanidine (MIBG) has been introduced for scintigraphic mapping of presynaptic sympathetic innervation and is available today for imaging on a broad clinical basis. Not much later than MIBG, positron emission tomography (PET) has also been established for characterizing the cardiac autonomic nervous system. Although PET is methodologically demanding and less widely available, it provides substantial advantages. High spatial and temporal resolution along with routinely available attenuation correction allows for detailed definition of tracer kinetics and makes noninvasive absolute quantification a reality. Furthermore, a series of different radiolabeled catecholamines, catecholamine analogs, and receptor ligands are available. Those are often more physiologic than MIBG and well understood with regard to their tracer physiologic properties. PET imaging of sympathetic neuronal function has been successfully applied to gain mechanistic insights into myocardial biology and pathology. Available tracers allow dissection of processes of presynaptic and postsynaptic innervation contributing to cardiovascular disease. This review summarizes characteristics of currently available PET tracers for cardiac neuroimaging along with the major findings derived from their application in health and disease.
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Affiliation(s)
- Frank M Bengel
- Nuklearmedizinische Klinik der Technischen Universität Müchen, 81675 Munich, Germany.
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Abstract
The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.
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Affiliation(s)
- Zhi You Fang
- University of Queensland, Brisbane, 4012, Australia
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38
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Laine H, Sundell J, Nuutila P, Raitakari OT, Luotolahti M, Rönnemaa T, Elomaa T, Koskinen P, Knuuti J. Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes. Heart 2004; 90:270-6. [PMID: 14966043 PMCID: PMC1768122 DOI: 10.1136/hrt.2003.013722] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To examine the role of the sympathetic nervous system in regulating insulin's action on coronary perfusion in uncomplicated type 1 diabetes by blocking centrally mediated sympathetic activity with dexamethasone. METHODS Positron emission tomography and oxygen 15 labelled water were used to quantify myocardial blood flow basally and during adenosine infusion with or without simultaneous euglycaemic physiological hyperinsulinaemia in nine non-smoking men with type 1 diabetes and 12 healthy non-diabetic men. Each patient was studied both with and without previous dexamethasone treatment for two days (2 mg/day). RESULTS Insulin increased coronary flow reserve in diabetic (from 4.3 (0.7) to 5.1 (0.6), p < 0.05) and non-diabetic (from 4.3 (0.3) to 5.4 (0.4), p < 0.05) patients. In contrast to non-diabetic patients dexamethasone pretreatment abolished the insulin induced increase in coronary flow reserve in diabetic patients (p < 0.05) leading to lower coronary flow reserve in diabetic than in non-diabetic patients (3.9 (0.6) v 7.1 (0.9), p < 0.05). CONCLUSIONS These results show that insulin's ability to modulate coronary perfusion is sustained in young patients with type 1 diabetes without microvascular complications or autonomic neuropathy. Dexamethasone treatment abolished the insulin induced increase in coronary flow reserve in diabetic patients but not in healthy study participants, suggesting that sympathetic activation plays an important part in regulating insulin's effects on myocardial perfusion in patients with type 1 diabetes.
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Affiliation(s)
- H Laine
- Turku PET Centre, Turku University Central Hospital, Turku, Finland
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39
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Hattori N, Rihl J, Bengel FM, Nekolla SG, Standl E, Schwaiger M, Schnell O. Cardiac autonomic dysinnervation and myocardial blood flow in long-term Type 1 diabetic patients. Diabet Med 2003; 20:375-81. [PMID: 12752486 DOI: 10.1046/j.1464-5491.2003.00939.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS The aim of the study was to assess scintigraphically the relationship between myocardial blood flow response and sympathetic dysinnervation in long-term Type 1 diabetic patients. Effects of the iron chelator deferoxamine on myocardial blood flow were studied and they were investigated according to the presence of cardiac sympathetic dysfunction. METHODS Myocardial blood flow (MBF) was assessed with N-13 ammonia positron emission tomography in 13 long-term Type 1 diabetic patients and 13 control subjects at rest and in response to sympathetic stimulation (cold pressor test (CPT)). In diabetic patients, the study was repeated after preinfusion with deferoxamine. Furthermore, 123I metaiodobenzylguanidine (MIBG) scintigraphy was applied to assess regional cardiac sympathetic dysinnervation (uptake score 1 = normal, homogeneous uptake em leader 6 = no uptake). RESULTS In diabetic patients, MBF increased in response to CPT from 78 +/- 18 ml/100 g/min to 84 +/- 26 ml/100 g (8%, P < 0.001). Control subjects demonstrated an increase from 63 +/- 17 ml/100 g to 84 +/- 26 ml/100 g (33%, P < 0.001), respectively. Resting MBF was higher in diabetic patients than in control subjects (P < 0.001). In diabetic patients, increase in MBF in response to CPT was significant in regions with a MIBG uptake score of <or= 3. Regions with a MIBG uptake score of > 3 did not exhibit a significant increase in MBF in response to CPT. After administration of deferoxamine, the increase in MBF in response to CPT was 23% and the magnitude of increase was related to the MIBG uptake score (r = 0.40, P < 0.0001). CONCLUSIONS Myocardial blood flow response to sympathetic stimulation is significantly impaired in long-term Type 1 diabetes. After preinfusion with deferoxamine the impairment is partially reversed and a relationship between myocardial blood flow and the extent of cardiac sympathetic dysfunction is observed.
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Affiliation(s)
- N Hattori
- Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, der Technischen Universität München, Germany
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40
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Foo K, Sekhri N, Deaner A, Knight C, Suliman A, Ranjadayalan K, Timmis AD. Effect of diabetes on serum potassium concentrations in acute coronary syndromes. Heart 2003; 89:31-5. [PMID: 12482786 PMCID: PMC1767495 DOI: 10.1136/heart.89.1.31] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES To compare serum potassium concentrations in diabetic and non-diabetic patients in the early phase of acute coronary syndromes. BACKGROUND Acute phase hypokalaemia occurs in response to adrenergic activation, which stimulates membrane bound sodium-potassium-ATPase and drives potassium into the cells. It is not known whether the hypokalaemia is attenuated in patients with diabetes because of the high prevalence of sympathetic nerve dysfunction. METHODS Prospective cohort study of 2428 patients presenting with acute coronary syndromes. Patients were stratified by duration of chest pain, diabetic status, and pretreatment with beta blockers. RESULTS The mean (SD) serum potassium concentration was significantly higher in diabetic than in non-diabetic patients (4.3 (0.5) v 4.1 (0.5) mmol/l, p < 0.0001). Multivariate analysis identified diabetes as an independent predictor of a serum potassium concentration in the upper half of the distribution (odds ratio 1.66, 95% confidence interval 1.38 to 2.00). In patients presenting within 6 hours of symptom onset, there was a progressive increase in plasma potassium concentrations from 4.08 (0.46) mmol/l in patients presenting within 2 hours, to 4.20 (0.47) mmol/l in patients presenting between 2-4 hours, to 4.24 (0.52) mmol/l in patients presenting between 4-6 hours (p = 0.0007). This pattern of increasing serum potassium concentration with duration of chest pain was attenuated in patients with diabetes, particularly those with unstable angina. Similar attenuation occurred in patients pretreated with beta blockers. CONCLUSION In acute coronary syndromes, patients with diabetes have significantly higher serum potassium concentrations and do not exhibit the early dip seen in non-diabetics. This may reflect sympathetic nerve dysfunction that commonly complicates diabetes.
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Affiliation(s)
- K Foo
- Department of Cardiology, Newham HealthCare NHS Trust, London, UK
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41
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Taskiran M, Fritz-Hansen T, Rasmussen V, Larsson HBW, Hilsted J. Decreased myocardial perfusion reserve in diabetic autonomic neuropathy. Diabetes 2002; 51:3306-10. [PMID: 12401723 DOI: 10.2337/diabetes.51.11.3306] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy are unknown. To investigate the effect of autonomic neuropathy on myocardial function, we performed dynamic contrast-enhanced magnetic resonance perfusion imaging during baseline conditions and after Dipyridamole-induced vasodilatation in nine type 1 diabetic patients with autonomic neuropathy (AN+), defined by cardiovascular tests, as well as in 10 type 1 diabetic patients without autonomic neuropathy (AN-) and 10 healthy control subjects. Baseline myocardial perfusion index (K(i)) was similar in the three groups (AN+ 88.6 +/- 8.7 ml. 100 g(-1). min(-1), AN- 82.6 +/- 7.2, control subjects 93.7 +/- 9.0) (means +/- SE). K(i) during Dipyridamole vasodilatation was significantly lower in the patients with autonomic neuropathy (P < 0.001) than in the other groups (AN+ 131.1 +/- 13.0 ml. 100 g(-1). min(-1), AN- 177.3 +/- 8.6, control subjects 197.2 +/- 8.9). Mean blood pressure was unchanged during Dipyridamole infusion in AN- and control subjects, whereas a significant blood pressure decrease was found in AN+ (15.6 +/- 2.6 mmHg, P < 0.025). There was a significant correlation between blood pressure response to Dipyridamole and myocardial perfusion reserve index. We conclude that type 1 diabetic patients with autonomic neuropathy have a decreased myocardial perfusion reserve capacity when challenged with a vasodilatator, a finding that may in part be the pathophysiological substrate for the increase in mortality in these patients. The underlying mechanism may be defective myocardial sympathetic vasodilatation, a lack of ability to maintain blood pressure during vasodilatation, or both.
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Affiliation(s)
- Mustafa Taskiran
- Department of Endocrinology, H:S Hvidovre University Hospital, Copenhagen, Denmark
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42
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Goldstein DS, Eisenhofer G. Sympathetic Nervous System Physiology and Pathophysiology in Coping with the Environment. Compr Physiol 2001. [DOI: 10.1002/cphy.cp070402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Eisenhofer G. The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 2001; 91:35-62. [PMID: 11707293 DOI: 10.1016/s0163-7258(01)00144-9] [Citation(s) in RCA: 232] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Catecholamines are translocated across plasma membranes by transporters that belong to two large families with mainly neuronal or extraneuronal locations. In mammals, neuronal uptake of catecholamines involves the dopamine transporter (DAT) at dopaminergic neurons and the norepinephrine transporter (NET) at noradrenergic neurons. Extraneuronal uptake of catecholamines is mediated by organic cation transporters (OCTs), including the classic corticosterone-sensitive extraneuronal monoamine transporter. Catecholamine transporters function as part of uptake and metabolizing systems primarily responsible for inactivation of transmitter released by neurons. Additionally, the neuronal catecholamine transporters, recycle catecholamines for rerelease, thereby reducing requirements for transmitter synthesis. In a broader sense, catecholamine transporters function as part of integrated systems where catecholamine synthesis, release, uptake, and metabolism are regulated in a coordinated fashion in response to the demands placed on the system. Location is also important to function. Neuronal transporters are essential for rapid termination of the signal in neuronal-effector organ transmission, whereas non-neuronal transporters are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. Besides their presynaptic locations, NET and DAT are also present at several extraneuronal locations, including syncytiotrophoblasts of the placenta and endothelial cells of the lung (NET), stomach and pancreas (DAT). The extraneuronal monoamine transporter shows a broad tissue distribution, whereas the other two non-neuronal catecholamine transporters (OCT1 and OCT2) are mainly localized to the liver, kidney, and intestine. Altered function of peripheral catecholamine transporters may be involved in disturbances of the autonomic nervous system, such as occurs in congestive heart failure and hypernoradrenergic hypertension. Peripheral catecholamine transporters provide important targets for clinical imaging of sympathetic nerves and diagnostic localization and treatment of neuroendocrine tumors, such as neuroblastomas and pheochromocytomas.
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Affiliation(s)
- G Eisenhofer
- Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Building 10, Room 6N 252, National Institutes of Health, 10 Center Drive, MSC 1620, Bethesda, MD 20892-1620, USA.
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44
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Raffel DM, Wieland DM. Assessment of cardiac sympathetic nerve integrity with positron emission tomography. Nucl Med Biol 2001; 28:541-59. [PMID: 11516699 DOI: 10.1016/s0969-8051(01)00210-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The autonomic nervous system plays a critical role in the regulation of cardiac function. Abnormalities of cardiac innervation have been implicated in the pathophysiology of many heart diseases, including sudden cardiac death and congestive heart failure. In an effort to provide clinicians with the ability to regionally map cardiac innervation, several radiotracers for imaging cardiac sympathetic neurons have been developed. This paper reviews the development of neuronal imaging agents and discusses their emerging role in the noninvasive assessment of cardiac sympathetic innervation.
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Affiliation(s)
- D M Raffel
- Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0552, USA.
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45
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Abstract
Cardiovascular autonomic neuropathy (CAN) is a common complication of diabetes, which results in disabling clinical manifestations and may predispose to sudden cardiac death. Recently, direct scintigraphic assessment of cardiac sympathetic integrity has become possible with the introduction of radiolabeled analogues of norepinephrine, which are actively taken up by the sympathetic nerve terminals of the heart. This article reviews how these techniques have been utilized to improve understanding of CAN complicating diabetes. Quantitative scintigraphic assessment of cardiac sympathetic innervation heart is possible with either [123I]-metaiodobenzylguanidine (MIBG) and single photon emission computed tomography (SPECT) or [11C]-hydroxyephedrine (HED) and positron emission tomography (PET). Studies in diabetic patients have explored the sensitivity of these techniques to detect CAN, characterize the effects of glycemic control on the progression of CAN and evaluate the effects of CAN on myocardial electrophysiology, blood flow regulation and function. Deficits of left ventricular (LV) [123I]-MIBG and [11C]-HED retention have been identified in diabetic subjects without abnormalities on cardiovascular reflex testing consistent with increased sensitivity to detect CAN. Poor glycemic control results in the progression of LV tracer deficits, which can be prevented or reversed by the institution of near-euglycemia. Deficits begin distally in the LV and may extend proximally. Paradoxically, however, absolute HED retention is increased in the proximal segments of the severe CAN subjects consistent with regional "hyperinnervation." These regions also exhibit abnormal blood flow regulation. Impaired myocardial MIBG uptake correlates with altered LV diastolic filling and myocardial electrophysiological deficits and is predictive of sudden death. Scintigraphic studies have provided unique insights into the effects of diabetes on cardiac sympathetic integrity and the pathophysiological consequences of LV sympathetic dysinnervation. Future studies using complementary neurotransmitter analogues will allow different aspects of regional dysfunction to be characterized with the aim of developing therapeutic strategies to prevent or reverse CAN.
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Affiliation(s)
- M J Stevens
- Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0678, USA.
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46
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Gaber AO, Wicks MN, Hathaway DK, Burlew BS. Sustained improvements in cardiac geometry and function following kidney-pancreas transplantation. Cell Transplant 2000; 9:913-8. [PMID: 11202578 DOI: 10.1177/096368970000900619] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Kidney-pancreas (KP) transplantation has been shown to improve left ventricular (LV) geometry and function 6-24 months after the procedure, yet whether these improvements are sustained in long-term survivors has not been demonstrated. This study examined whether early improvements in LV geometry and function were sustained 3-5 years after KP transplantation. Left ventricular function and geometry were prospectively evaluated prior to, and at 1, 2, and 3-5 years posttransplant using two-dimensional, M-mode, echocardiography with Doppler interrogation in the parasternal and apical views. The sample included 21 KP and a comparison group of 12 diabetic kidney-alone (KA) recipients. Long-term (3-5 years) data were obtained for KP recipients only. Although KA recipients had a longer duration of dialysis and worse diastolic function pretransplant, the groups were similar on other baseline measures. KA recipients experienced minimal improvements while KP recipients had significant improvements in cardiac function and geometry, both in terms of mean values and the percentage of KP recipients who experienced normalization posttransplant (p < 0.05). KP recipient improvements were also sustained at 3-5 years posttransplant on three of five measures, with 75% of long-term KP recipients achieving normal LV mass posttransplant compared with 31% pretransplant. Data indicate that significant impairments in cardiac geometry and function occur in diabetic KA and KP recipients. Though both groups experienced early improvements posttransplant, KP recipients achieved more dramatic and clinically significant improvements at 1, 2, and 3-5 years posttransplant. Additional studies are needed to examine the relevance of these findings with regard to the cardiac morbidity and mortality of these patients.
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Affiliation(s)
- A O Gaber
- College of Medicine, University of Tennessee Health Science Center, Memphis 38169, USA
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47
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Münch G, Nguyen NT, Nekolla S, Ziegler S, Muzik O, Chakraborty P, Wieland DM, Schwaiger M. Evaluation of sympathetic nerve terminals with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron emission tomography. Circulation 2000; 101:516-23. [PMID: 10662749 DOI: 10.1161/01.cir.101.5.516] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The goal of the present study was to directly compare the new radiopharmaceutical agent [(11)C]epinephrine (EPI) with [(11)C]hydroxyephedrine (HED) through the use of PET. METHODS AND RESULTS Seven healthy volunteers and 10 patients were investigated after heart transplantation. PET images of both tracers were of excellent quality in the volunteers. Values for radiolabeled metabolites (measured in percent of blood activity) at 5, 20, and 60 minutes after injection were approximately 35%, approximately 82%, and approximately 86% for EPI and approximately 13%, approximately 47%, and approximately 78% for HED, respectively. At 35 minutes, metabolite-corrected mean myocardial retention fraction of EPI (0. 235+/-0.022 min(-1)) was significantly greater (P<0.01) than that of HED (0.142+/-0.012 min(-1)). Corrected tracer retention fractions of both EPI and HED were significantly reduced in transplant recipients (0.055+/-0.004 min(-1), P<0.0001; and 0.050+/-0.006 min(-1), P<0. 0001, respectively) compared with volunteers. Normalization of retention fractions of patients with transplantation within 1 year to volunteers resulted in a value (ratio expressed in percent) of 20. 6+/-1.8% for EPI, significantly (P<0.03) smaller than 27.8+/-0.8% for HED. In patients with transplantation later than 1 year, the values were 26.0+/-2.9% for EPI compared with 44.2+/-5.6% for HED (P<0.014). CONCLUSIONS Both tracers showed high selectivity for neuronal uptake in the heart, with a significant reduction in tracer retention in transplant recipients compared with volunteers. Compared with HED, EPI showed greater retention in volunteers and a lower retention ratio in transplant recipients, suggesting that EPI may be the superior tracer with higher sensitivity to neuronal abnormalities. Because EPI reflects neuronal uptake, metabolism, and storage, it may be more suitable for the study of neuronal integrity than HED, which primarily traces uptake-1 capacity.
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Affiliation(s)
- G Münch
- Division of Nuclear Medicine, University of Michigan, Ann Arbor, MI, USA
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48
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Abstract
Methods for the direct chiral chromatographic separation of the four stereoisomers of meta-hydroxyphenylpropanolamine (MHPA) on an analytical and preparative scale are described. Separations were carried out on a Crownpak CR (+) chiral column with 113 mM aqueous perchloric acid as the mobile phase. Baseline resolution of the more retained (+)-stereoisomers (1S configuration) and partial resolution of the less retained (-)-stereoisomers (1R configuration) were obtained under these chromatographic conditions. Removal of the bulk of the (1R,2S)-stereoisomer (metaraminol) from the initial crude mixture by fractional crystallization as the (+)-bitartarate salt substantially improved the peak resolution factors (Rs) of the remaining three stereoisomers. Semipreparative chromatographic resolution of the latter isomeric mixture provided milligram quantities of each stereoisomer in >97% enantiomeric excess. Subsequent recrystallization of their bitartarate or fumarate salts gave enantiomeric purities >99%.
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Affiliation(s)
- M E Van Dort
- Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0552, USA.
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49
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Di Carli MF, Bianco-Batlles D, Landa ME, Kazmers A, Groehn H, Muzik O, Grunberger G. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999; 100:813-9. [PMID: 10458716 DOI: 10.1161/01.cir.100.8.813] [Citation(s) in RCA: 145] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND C ardiac sympathetic signals play an important role in the regulation of myocardial perfusion. We hypothesized that sympathetically mediated myocardial blood flow would be impaired in diabetics with autonomic neuropathy. METHODS AND RESULTS We studied 28 diabetics (43+/-7 years old) and 11 age-matched healthy volunteers. PET was used to delineate cardiac sympathetic innervation with [(11)C]hydroxyephedrine ([(11)C]HED) and to measure myocardial blood flow at rest, during hyperemia, and in response to sympathetic stimulation by cold pressor testing. The response to cardiac autonomic reflex tests was also evaluated. Using ultrasonography, we also measured brachial artery reactivity during reactive hyperemia (endothelium-dependent dilation) and after sublingual nitroglycerin (endothelium-independent dilation). Based on [(11)C]HED PET, 13 of 28 diabetics had sympathetic-nerve dysfunction (SND). Basal flow was regionally homogeneous and similar in the diabetic and normal subjects. During hyperemia, the increase in flow was greater in the normal subjects (284+/-88%) than in the diabetics with SND (187+/-80%, P=0.084) and without SND (177+/-72%, P=0.028). However, the increase in flow in response to cold was lower in the diabetics with SND (14+/-10%) than in those without SND (31+/-12%) (P=0.015) and the normal subjects (48+/-24%) (P<0.001). The flow response to cold was related to the myocardial uptake of [(11)C]HED (P<0.001). Flow-mediated brachial artery dilation was impaired in the diabetics compared with the normal subjects, but it was similar in the diabetics with and without SND. CONCLUSIONS Diabetic autonomic neuropathy is associated with an impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation, which is related to the degree of SND.
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Affiliation(s)
- M F Di Carli
- Department of Internal Medicine, Positron Emission Tomography Center Detroit, MI, USA.
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50
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Bengel FM, Ueberfuhr P, Ziegler SI, Nekolla S, Reichart B, Schwaiger M. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation. A longitudinal study using PET and C-11 hydroxyephedrine. Circulation 1999; 99:1866-71. [PMID: 10199884 DOI: 10.1161/01.cir.99.14.1866] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment. METHODS AND RESULTS In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0+/-0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9+/-9% of left ventricle for group A, P<0.05; 13+/-12% to 23+/-17% for group B, P<0.05; 21+/-21% to 37+/-23% for group C, P<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle. CONCLUSIONS The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.
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Affiliation(s)
- F M Bengel
- Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, Germany.
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