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Al Ward R, Waguespack SG, Varghese J, Lu Y, Jimenez C. Reply to the Letter to the Editor Concerning Metabolic and Pharma-cological Interactions of 131I-MIBG. Clin Nucl Med 2024:00003072-990000000-01338. [PMID: 39388315 DOI: 10.1097/rlu.0000000000005532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
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Patoulias D, Katsimardou A, Fragakis N, Papadopoulos C, Doumas M. Effect of SGLT-2 inhibitors on cardiac autonomic function in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Acta Diabetol 2023; 60:1-8. [PMID: 35986116 DOI: 10.1007/s00592-022-01958-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/09/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND Cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM). We sought to determine whether sodium-glucose co-transporter-2 (SGLT-2) inhibitors affect indices of CAN in patients with T2DM. METHODS We searched for parallel group or cross-over randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on CAN. PubMed, Cochrane Library and gray literature sources were searched. We set as primary efficacy outcome the change in the low-frequency-to-high-frequency (LF/HF) ratio. We set as secondary efficacy outcomes: first, the change in the standard deviation of all 5 min mean normal RR intervals and second, the change in the square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD). Protocol has not been registered at a publicly available repository. RESULTS We pooled data from four RCTs in a total of 247 subjects with T2DM. SGLT-2 inhibitor treatment did not have a significant effect on LF/HF ratio (MD = - 0.11, 95% CI - 0.35 to 0.12, I2 = 0%, p = 0.36). SGLT-2 inhibitor treatment did not have a significant impact either on SDNN (MD = - 2.83, 95% CI - 7.41 to 1.75, I2 = 31%, p = 0.23), or on r-MSSD (MD = - 0.14, 95% CI - 3.52 to 3.25, I2 = 46%, p = 0.94). Overall risk of bias was graded as low across the selected RCTs. CONCLUSION SGLT-2 inhibitor treatment in patients with T2DM does not seem to provide any significant beneficial effect on CAN indices.
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Affiliation(s)
- Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Konstantinoupoleos 49, 54642, Thessaloníki, Greece.
| | - Alexandra Katsimardou
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Konstantinoupoleos 49, 54642, Thessaloníki, Greece
| | - Nikolaos Fragakis
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital "Hippokration", Thessaloníki, Greece
| | - Christodoulos Papadopoulos
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital "Hippokration", Thessaloníki, Greece
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital "Hippokration", Konstantinoupoleos 49, 54642, Thessaloníki, Greece
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Heart diseases (autonomic dysfunctions)—Myocardial innervation imaging: 123I-MIBG planar scintigraphy and SPECT. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00057-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Quinaglia T, Oliveira DC, Matos-Souza JR, Sposito AC. Diabetic cardiomyopathy: factual or factoid? ACTA ACUST UNITED AC 2019; 65:61-69. [PMID: 30758422 DOI: 10.1590/1806-9282.65.1.69] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/26/2018] [Indexed: 02/08/2023]
Abstract
Although long ago described, there is no established consensus regarding the real existence of Diabetic Cardiomyopathy (CMPDM). Due to its complex pathophysiology, it has been difficult for clinical and experimental research to establish clear connections between diabetes mellitus (DM) and heart failure (HF), as well as to solve the mechanisms of the underlying myocardial disease. However, the epidemiological evidence of the relationship of these conditions is undisputed. The interest in understanding this disease has intensified due to the recent results of clinical trials evaluating new glucose-lowering drugs, such as sodium-glucose transporter inhibitors 2, which demonstrated favorable responses considering the prevention and treatment of HF in patients with DM. In this review we cover aspects of the epidemiology of CMPDM and its possible pathogenic mechanisms, as well as, present the main cardiac phenotypes of CMPDM (HF with preserved and reduced ejection fraction) and implications of the therapeutic management of this disease.
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Affiliation(s)
- Thiago Quinaglia
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - Daniela C Oliveira
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - José Roberto Matos-Souza
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
| | - Andrei C Sposito
- Subject of Cardiology, Faculty of Medical Sciences - State University of Campinas (Unicamp), Campinas, SP, Brasil
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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: 121] [Impact Index Per Article: 17.3] [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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6
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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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Khan AW, Corcoran SJ, Esler M, El-Osta A. Epigenomic changes associated with impaired norepinephrine transporter function in postural tachycardia syndrome. Neurosci Biobehav Rev 2016; 74:342-355. [PMID: 27345145 DOI: 10.1016/j.neubiorev.2016.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 06/05/2016] [Accepted: 06/15/2016] [Indexed: 01/20/2023]
Abstract
The postural tachycardia syndrome (POTS) is characterised clinically by symptoms of light-headedness, palpitations, fatigue and exercise intolerance occurring with standing and relieved by lying down. Symptoms occur in association with an inappropriate rise in heart rate in the absence of a fall in blood pressure with the assumption of standing. The pathophysiology of POTS is complicated and poorly understood. Plasma norepinephrine (NE) is often elevated in patients with POTS, resulting in consideration of dysfunction of the norepinephrine transporter (NET) encoded by SLC6A2 gene. Whilst some studies have implicated a defect in the SLC6A2 gene, the cause of reduced SLC6A2 expression and function remains unclear. The search to explain the molecular mechanism of NET dysfunction has focused on genetic variation in the SLC6A2 gene and remains inconclusive. More recent studies show epigenetic mechanisms implicated in the regulation of SLC6A2 expression. In this article, we discuss the epigenetic mechanisms involved in SLC6A2 repression and highlight the potential therapeutic application of targeting these mechanisms in POTS.
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Affiliation(s)
- Abdul Waheed Khan
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
| | - Susan J Corcoran
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
| | - Murray Esler
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
| | - Assam El-Osta
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia; Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.
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Asghar O, Arumugam P, Armstrong IS, Ray SG, Schmitt M, Malik RA. Individuals with impaired glucose tolerance demonstrate normal cardiac sympathetic innervation using I-123 mIBG scintigraphy. J Nucl Cardiol 2015; 22:1262-8. [PMID: 25698476 DOI: 10.1007/s12350-015-0070-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/16/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is associated with an increased risk of type 2 diabetes (T2DM) and cardiovascular disease. Some but not all studies have reported cardiac autonomic dysfunction in subjects with IGT and there is only one direct study of cardiac innervation in subjects with IGT. The purpose of this study was to assess global and regional cardiac sympathetic innervation and cardiac autonomic function in individuals with IGT. METHODS AND RESULTS We undertook (123)I-mIBG scintigraphy and cardiac autonomic function in 15 subjects with IGT and 15 age and sex-matched healthy controls. Early heart to mediastinum ratio (HMR) (1.71 ± 0.17 vs 1.67 ± 0.13, P = .49), late HMR (1.73 ± 0.18 vs 1.73 ± 0.16, P = .97) and washout rate (WR) (18.6 ± 4.2 vs 19.1 ± 7.6%, P = .84), did not differ between subjects with IGT and control subjects. More detailed regional analysis revealed reduced tracer uptake at the apex, base and inferior wall in all subjects and the anterior wall in a minority of subjects. There were no differences in total score (56.6 ± 4.0 vs 53.3 ± 8.4, P = .193), modified score (48.5 ± 3.3 vs 46.2 ± 6.0, P = .215), anterior wall score (10.2 ± 1.3 vs 10.1 ± 1.6, P = .898), inferior wall score (8.9 ± 1.9 vs 7.7 ± 2.6, P = .163), basal score (18.7 ± 1.9 vs 18.2 ± 3.3, P = .636) and tests of cardiac autonomic function between the groups. CONCLUSION Global and regional measures of MIBG uptake and washout as well as cardiac autonomic function did not differ between subjects with IGT and healthy controls.
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Affiliation(s)
- O Asghar
- Institute of Cardiovascular Sciences, University of Manchester & Manchester Heart Centre, Central Manchester Foundation Trust, Manchester, United Kingdom.
| | - P Arumugam
- Department of Nuclear Medicine, Central Manchester Foundation Trust, Manchester, United Kingdom
| | - I S Armstrong
- Department of Nuclear Medicine, Central Manchester Foundation Trust, Manchester, United Kingdom
| | - S G Ray
- North West Heart and Transplant Centre, University Hospital of South Manchester, Manchester, United Kingdom
| | - M Schmitt
- North West Heart and Transplant Centre, University Hospital of South Manchester, Manchester, United Kingdom
| | - R A Malik
- Centre for Endocrinology & Diabetes, Institute of Human Development, University of Manchester, Manchester, United Kingdom.
- Weill Cornell Medical College, Doha, Qatar.
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Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 2015; 36:1718-27, 1727a-1727c. [PMID: 25888006 DOI: 10.1093/eurheartj/ehv134] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 04/02/2015] [Indexed: 12/24/2022] Open
Abstract
Diabetes mellitus-related cardiomyopathy (DMCMP) was originally described as a dilated phenotype with eccentric left ventricular (LV) remodelling and systolic LV dysfunction. Recently however, clinical studies on DMCMP mainly describe a restrictive phenotype with concentric LV remodelling and diastolic LV dysfunction. Both phenotypes are not successive stages of DMCMP but evolve independently to respectively heart failure with preserved left ventricular ejection fraction (HFPEF) or reduced left ventricular ejection fraction (HFREF). Phenotype-specific pathophysiological mechanisms were recently proposed for LV remodelling and dysfunction in HFPEF and HFREF consisting of coronary microvascular endothelial dysfunction in HFPEF and cardiomyocyte cell death in HFREF. A similar preferential involvement of endothelial or cardiomyocyte cell compartments explains DMCMP development into distinct restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus (DM)-related metabolic derangements such as hyperglycaemia, lipotoxicity, and hyperinsulinaemia favour development of DMCMP with restrictive/HFPEF phenotype, which is more prevalent in obese type 2 DM patients. In contrast, autoimmunity predisposes to a dilated/HFREF phenotype, which manifests itself more in autoimmune-prone type 1 DM patients. Finally, coronary microvascular rarefaction and advanced glycation end-products deposition are relevant to both phenotypes. Diagnosis of DMCMP requires impaired glucose metabolism and exclusion of coronary, valvular, hypertensive, or congenital heart disease and of viral, toxic, familial, or infiltrative cardiomyopathy. In addition, diagnosis of DMCMP with restrictive/HFPEF phenotype requires normal systolic LV function and diastolic LV dysfunction, whereas diagnosis of DMCMP with dilated/HFREF phenotype requires systolic LV dysfunction. Treatment of DMCMP with restrictive/HFPEF phenotype is limited to diuretics and lifestyle modification, whereas DMCMP with dilated/HFREF phenotype is treated in accordance to HF guidelines.
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Affiliation(s)
| | - Walter J Paulus
- Institute for Cardiovascular Research VU (ICaR-VU), VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
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Balcıoğlu AS, Müderrisoğlu H. Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes 2015; 6:80-91. [PMID: 25685280 PMCID: PMC4317320 DOI: 10.4239/wjd.v6.i1.80] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/24/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN.
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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: 68] [Impact Index Per Article: 5.7] [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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Falcão-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev 2013; 17:325-44. [PMID: 21626163 DOI: 10.1007/s10741-011-9257-z] [Citation(s) in RCA: 267] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.
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Affiliation(s)
- Inês Falcão-Pires
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, University of Porto, Porto, Portugal
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Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. Dis Model Mech 2013; 6:1001-11. [PMID: 23580201 PMCID: PMC3701219 DOI: 10.1242/dmm.012203] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
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Affiliation(s)
- Jana K Shirey-Rice
- Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. J Neuropathol Exp Neurol 2013; 71:1000-8. [PMID: 23037327 DOI: 10.1097/nen.0b013e3182729fdc] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Skin biopsy has gained widespread use for the diagnosis of somatic small-fiber neuropathy, but it also provides information on sympathetic fiber morphology. We aimed to ascertain the diagnostic accuracy of skin biopsy in disclosing sympathetic nerve abnormalities in patients with autonomic neuropathy. Peripheral nerve fiber autonomic involvement was confirmed by routine autonomic laboratory test abnormalities. Punch skin biopsies were taken from the thigh and lower leg of 28 patients with various types of autonomic neuropathy for quantitative evaluation of skin autonomic innervation. Results were compared with scores obtained from 32 age-matched healthy controls and 25 patients with somatic neuropathy. The autonomic cutoff score was calculated using the receiver operating characteristic curve analysis. Skin biopsy disclosed a significant autonomic innervation decrease in autonomic neuropathy patients versus controls and somatic neuropathy patients. Autonomic innervation density was abnormal in 96% of patients in the lower leg and in 79% of patients in the thigh. The abnormal findings disclosed by routine autonomic tests ranged from 48% to 82%. These data indicate the high sensitivity and specificity of skin biopsy in detecting sympathetic abnormalities; this method should be useful for the diagnosis of autonomic neuropathy, together with currently available routine autonomic testing.
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Karayannis G, Giamouzis G, Cokkinos DV, Skoularigis J, Triposkiadis F. Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther 2013; 10:747-65. [PMID: 22894631 DOI: 10.1586/erc.12.53] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetic cardiovascular autonomic neuropathy (DCAN), the impairment of the autonomic balance of the cardiovascular system in the setting of diabetes mellitus (DM), is frequently observed in both Type 1 and 2 DM, has detrimental effects on the quality of life and portends increased mortality. Clinical manifestations include: resting heart rate disorders, exercise intolerance, intraoperative cardiovascular lability, orthostatic alterations in heart rate and blood pressure, QT-interval prolongation, abnormal diurnal and nocturnal blood pressure variation, silent myocardial ischemia and diabetic cardiomyopathy. Clinical tests for autonomic nervous system evaluation, heart rate variability analysis, autonomic innervation imaging techniques, microneurography and baroreflex analysis are the main diagnostic tools for DCAN detection. Aldose reductase inhibitors and antioxidants may be helpful in DCAN therapy, but a regular, more generalized and multifactorial approach should be adopted with inclusion of lifestyle modifications, strict glycemic control and treatment of concomitant traditional cardiovascular risk factors, in order to achieve the best therapeutic results. In the present review, the authors provide aspects of DCAN pathophysiology, clinical presentation, diagnosis and an algorithm regarding the evaluation and management of DCAN in DM patients.
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Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-78. [PMID: 22644723 DOI: 10.1007/s12265-012-9367-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 12/16/2022]
Abstract
Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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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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Moloney MA, Casey RG, O'Donnell DH, Fitzgerald P, Thompson C, Bouchier-Hayes DJ. Two weeks taurine supplementation reverses endothelial dysfunction in young male type 1 diabetics. Diab Vasc Dis Res 2010; 7:300-10. [PMID: 20667936 DOI: 10.1177/1479164110375971] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Type 1 diabetics have a well-recognised risk of accelerated cardiovascular disease. Even in the absence of clinical signs there are detectable abnormalities of conduit vessel function. Our group has previously reported reversal of endothelial dysfunction in diabetics with pravastatin. In young asymptomatic smokers, taurine supplementation has a beneficial impact on macrovascular function, assessed by FMD, and shows an up-regulation of nitric oxide from monocyte-endothelial cell interactions. We hypothesise that taurine supplementation reverses early endothelial abnormalities in young male type 1 diabetics, as assessed by applanation tonometry, brachial artery ultrasound and laser Doppler fluximetry. Asymptomatic, male diabetics (n=9) were scanned prior to treatment and then randomised in a double-blind cross-over fashion to receive either 2 weeks placebo or taurine. Control patients (n=10) underwent a baseline scan. Assessed diabetics had detectable, statistically significant abnormalities when compared with controls, in both arterial stiffness (augmentation index) and brachial artery reactivity (FMD). Both of these parameters were returned to control levels with 2 weeks taurine supplementation. In conclusion, 2 weeks taurine supplementation reverses early, detectable conduit vessel abnormalities in young male diabetics. This may have important implications in the long-term treatment of diabetic patients and their subsequent progression towards atherosclerotic disease.
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Scholte AJHA, Schuijf JD, Delgado V, Kok JA, Bus MTJ, Maan AC, Stokkel MP, Kharagitsingh AV, Dibbets-Schneider P, van der Wall EE, Bax JJ. Cardiac autonomic neuropathy in patients with diabetes and no symptoms of coronary artery disease: comparison of 123I-metaiodobenzylguanidine myocardial scintigraphy and heart rate variability. Eur J Nucl Med Mol Imaging 2010; 37:1698-705. [PMID: 20411258 PMCID: PMC2918794 DOI: 10.1007/s00259-010-1442-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Accepted: 03/08/2010] [Indexed: 12/16/2022]
Abstract
Purpose The purpose of this study was to evaluate the prevalence of cardiac autonomic neuropathy (CAN) in a cohort of patients with type 2 diabetes, truly asymptomatic for coronary artery disease (CAD), using heart rate variability (HRV) and 123I-metaiodobenzylguanidine (123I-mIBG) myocardial scintigraphy. Methods The study group comprised 88 patients with type 2 diabetes prospectively recruited from an outpatient diabetes clinic. In all patients myocardial perfusion scintigraphy, CAN by HRV and 123I-mIBG myocardial scintigraphy were performed. Two or more abnormal tests were defined as CAN-positive (ECG-based CAN) and one or fewer as CAN-negative. CAN assessed by 123I-mIBG scintigraphy was defined as abnormal if the heart-to-mediastinum ratio was <1.8, the washout rate was >25%, or the total defect score was >13. Results The prevalence of CAN in patients asymptomatic for CAD with type 2 diabetes and normal myocardial perfusion assessed by HRV and 123I-mIBG scintigraphy was respectively, 27% and 58%. Furthermore, in almost half of patients with normal HRV, 123I-mIBG scintigraphy showed CAN. Conclusion The current study revealed a high prevalence of CAN in patients with type 2 diabetes. Secondly, disagreement between HRV and 123I-mIBG scintigraphy for the assessment of CAN was observed.
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Affiliation(s)
- Arthur J H A Scholte
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
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Pop-Busui R, Roberts L, Pennathur S, Kretzler M, Brosius FC, Feldman EL. The management of diabetic neuropathy in CKD. Am J Kidney Dis 2010; 55:365-85. [PMID: 20042258 PMCID: PMC4007054 DOI: 10.1053/j.ajkd.2009.10.050] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 10/29/2009] [Indexed: 02/07/2023]
Abstract
A 64-year-old male with a 15-year history of poorly controlled type 2 diabetes and a 10-year history of hypertension and hyperlipidemia had developed multiple diabetes-related complications within the last 5 years. He first developed albuminuria 5 years ago, and over the next several years experienced fairly rapid decline in kidney function, with eGFR of 55 mL/min/1.73m2 noted 2 years ago. He was diagnosed with proliferative retinopathy 5 years ago and underwent laser photocoagulation. Four years ago, he noted symptoms of peripheral neuropathy manifested as shooting pain and numbness with loss of light touch, thermal and vibratory sensation in a stocking distribution. Last year he developed a non-healing ulcer on the plantar aspect of his left foot which was complicated with gangrene and resulted in a below-the-knee amputation of the left leg one year ago. He now reports a new onset of weakness, lightheadedness and dizziness on standing that affects his daily activities. He reports lancinating pain in his right lower extremity, worse in the evening. Medications include: neutral protamine Hagedorn insulin twice daily and regular insulin on a sliding scale, metoprolol 50 mg/d, lisinopril 40 mg/d, atorvastatin 80 mg/d, furosemide 40 mg/d and aspirin 81 mg/d. Blood pressure is 127/69 mm Hg with a pulse rate of 96 bpm while supine and 94/50 mmHg with a pulse rate of 102 bpm while standing. Strength is normal but with a complete loss of all sensory modalities to the knee in his remaining limb and up to the wrists in both upper extremities, and he is areflexic. Today's laboratory evaluations show a serum creatinine of 2.8 mg/dl, an estimated GFR (eGFR) of 24 ml/min/1.73m2, a hemoglobin A1c (HbA1c) of 7.9 % and 2.1 g of urine protein per gram of creatinine. What would be the most appropriate management for this patient?
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Affiliation(s)
- Rodica Pop-Busui
- University of Michigan Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes
| | | | | | - Mathias Kretzler
- University of Michigan Department of Internal Medicine, Division of Nephrology
| | - Frank C. Brosius
- University of Michigan Department of Internal Medicine, Division of Nephrology
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Affiliation(s)
- Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA.
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Korosoglou G, Humpert PM, Halbgewachs E, Bekeredjian R, Filusch A, Buss SJ, Morcos M, Bierhaus A, Katus HA, Nawroth PP, Kuecherer H. Evidence of left ventricular contractile asynchrony by echocardiographic phase imaging in patients with type 2 diabetes mellitus and without clinically evident heart disease. Am J Cardiol 2006; 98:1525-30. [PMID: 17126664 DOI: 10.1016/j.amjcard.2006.06.056] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2006] [Revised: 06/21/2006] [Accepted: 06/21/2006] [Indexed: 10/24/2022]
Abstract
Left ventricular electromechanical asynchrony has been shown to predict cardiac events in patients with heart failure. This study investigated whether left ventricular asynchrony is present in patients with type 2 diabetes mellitus (DM) with no clinically evident heart disease and normal QRS durations. Asynchrony was evaluated in 24 patients with DM, 15 nondiabetic control subjects, and 20 patients with left bundle branch block (LBBB) due to cardiomyopathy serving as positive controls by conventional tissue Doppler imaging and by a novel method, echocardiographic phase imaging. Asynchrony was significantly higher in patients with DM than in controls and significantly lower than in patients with LBBB. This was shown by tissue Doppler imaging: the SD of time to peak myocardial velocity was 13 +/- 10 ms in controls, compared with 30 +/- 19 ms in patients with DM (p <0.01) and 68 +/- 28 ms in those with LBBB (p <0.001). Similar data were obtained using echocardiographic phase imaging: the SD of phase degrees was 25 degrees +/- 8 degrees in controls, compared with 44 degrees +/- 21 degrees in patients with DM (p = 0.02) and 76 degrees +/- 25 degrees in those with LBBB (p <0.001). Tissue Doppler imaging correlated with echocardiographic phase imaging (r = 0.79, p <0.0001) but was more time consuming (15.5 +/- 4.5 vs 4.5 +/- 2.2 min/patient, p <0.05) and showed higher intraobserver variability (5.6% vs 3.2%, p <0.05). In conclusion, this is the first study showing increased left ventricular asynchrony in patients with DM and no clinical evidence of heart disease.
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van Gurp PJ, Willemsen JJ, Lenders JWM, Ross HA, Sweep CGJ, Smits P, Tack CJ. Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus. Eur J Clin Invest 2006; 36:674-81. [PMID: 16968462 DOI: 10.1111/j.1365-2362.2006.01707.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM). MATERIALS AND METHODS In 15 DM patients (DM duration 6.3 +/- 3.8 year; HbA1c 7.9 +/- 1.3%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis. Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test. Forearm blood flow was measured during forearm vascular alpha- and beta-adrenergic receptor blockade. RESULTS At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups. LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (DeltaFVR: 12 +/- 4 vs. 19 +/- 3 arbitrary units, P < 0.05). The responses of plasma NA and heart rate variability did not differ. CONCLUSIONS Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes. However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness.
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Affiliation(s)
- P J van Gurp
- Division of General Internal Medicine, Department of Medicine, Radboud University Nijmegen Medical Centre, the Netherlands.
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Abstract
Nuclear cardiology has made significant advances since the first reports of planar scintigraphy for the evaluation of left ventricular perfusion and function. While the current "state of the art" of gated myocardial perfusion single-photon emission computed tomographic (SPECT) imaging offers invaluable diagnostic and prognostic information for the evaluation of patients with suspected or known coronary artery disease (CAD), advances in the cellular and molecular biology of the cardiovascular system have helped to usher in a new modality in nuclear cardiology, namely, molecular imaging. In this review, we will discuss the current state of the art in nuclear cardiology, which includes SPECT and positron emission tomographic evaluation of myocardial perfusion, evaluation of left ventricular function by gated myocardial perfusion SPECT and gated blood pool SPECT, and the evaluation of myocardial viability with PET and SPECT methods. In addition, we will discuss the future of nuclear cardiology and the role that molecular imaging will play in the early detection of CAD at the level of the vulnerable plaque, the evaluation of cardiac remodeling, and monitoring of important new therapies including gene therapy and stem cell therapy.
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Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J, Larkin D, Yamada E, Raffel DM, Stevens MJ. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 2005; 44:2368-74. [PMID: 15607400 DOI: 10.1016/j.jacc.2004.09.033] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Revised: 07/02/2004] [Accepted: 09/14/2004] [Indexed: 12/15/2022]
Abstract
OBJECTIVES This study was designed to explore the relationships of early diabetic microangiopathy to alterations of cardiac sympathetic tone and myocardial blood flow (MBF) regulation in subjects with stable type 1 diabetes. BACKGROUND In diabetes, augmented cardiac sympathetic tone and abnormal MBF regulation may predispose to myocardial injury and enhanced cardiac risk. METHODS Subject groups comprised healthy controls (C) (n = 10), healthy diabetic subjects (DC) (n = 12), and diabetic subjects with very early diabetic microangiopathy (DMA+) (n = 16). [(11)C]meta-hydroxyephedrine ([(11)C]HED) and positron emission tomography (PET) were used to explore left ventricular (LV) sympathetic integrity and [(13)N]ammonia-PET to assess MBF regulation in response to cold pressor testing (CPT) and adenosine infusion. RESULTS Deficits of LV [(11)C]HED retention were extensive and global in the DMA+ subjects (36 +/- 31% vs. 1 +/- 1% in DC subjects; p < 0.01) despite preserved autonomic reflex tests. On CPT, plasma norepinephrine excursions were two-fold greater than in C and DC subjects (p < 0.05), and basal LV blood flow decreased (-12%, p < 0.05) in DMA+ but not in C or DC subjects (+45% and +51%, respectively). On adenosine infusion, compared with C subjects, MBF reserve decreased by approximately 45% (p < 0.05) in DMA+ subjects. Diastolic dysfunction was detected by two-dimensional echocardiography in 5 of 8 and 0 of 8 consecutively tested DMA+ and DC subjects, respectively. CONCLUSIONS Augmented cardiac sympathetic tone and responsiveness and impaired myocardial perfusion may contribute to myocardial injury in diabetes.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0678, USA
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van Gurp PJ, Rongen GA, Lenders JWM, Al Nabawy AKM, Timmers HJLM, Tack CJ. Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans. Eur J Appl Physiol 2004; 93:648-54. [PMID: 15778893 DOI: 10.1007/s00421-004-1247-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2004] [Indexed: 12/25/2022]
Abstract
An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l(-1) for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl(-1).min(-1) ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.
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Affiliation(s)
- P J van Gurp
- Division of General Internal Medicine, Department of Internal Medicine, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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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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Belfer I, Phillips G, Taubman J, Hipp H, Lipsky RH, Enoch MA, Max MB, Goldman D. Haplotype architecture of the norepinephrine transporter gene SLC6A2 in four populations. J Hum Genet 2004; 49:232-45. [PMID: 15362567 DOI: 10.1007/s10038-004-0140-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The norepinephrine transporter (NET) regulates levels of monoamine neurotransmitters integral to a variety of behaviors and autonomic functions. Two SLC6A2 polymorphisms have been used in genetic association studies, generating intriguing but nondefinitive results on traits such as hypertension and mood. One of these SLC6A2 variants is functional but rare. The other is common but not informative over the entire 48 kb SLC6A2 region and is insufficient to capture the functional diversity potentially contained within any SLC6A2 region. To elucidate SLC6A2 haplotype structure and define markers sufficient to capture haplotype diversity within detected haplotype blocks, 26 single-nucleotide polymorphisms (SNPs) were genotyped in 384 individuals evenly divided across Finnish Caucasian, US Caucasian, Plains American Indian, and African American populations. Three conserved blocks, 13.6, 12.5, and 25 kb in size and showing little evidence for historical recombination were observed in all populations. Haplotype diversity in block 1 and numbers of common haplotypes were highest in African Americans, among whom 5-6 optimal markers were sufficient to maximize diversity of each block. For other populations, 2-3 markers/block sufficed, but the optimal markers differed across populations. The SLC6A2 haplotype map and 25-marker panel (excluding the monomorphic one) is a comprehensive tool for genetic linkage studies on phenotypes related to NET function.
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Affiliation(s)
- Inna Belfer
- Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
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Kirpichnikov D, McFarlane SI, Sowers JR. Heart failure in diabetic patients: utility of beta-blockade. J Card Fail 2004; 9:333-44. [PMID: 13680555 DOI: 10.1054/jcaf.2003.36] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Congestive heart failure (CHF) occurs with increased frequency in patients with diabetes and carries a higher risk of morbidity and mortality compared with nondiabetic persons. Diabetic patients are more likely to suffer from CHF and its consequences because of hypertensive and ischemic heart disease and diabetic cardiomyopathy. METHODS Intensive combination therapy, directed at the different aspects of the pathophysiology of CHF in diabetes patients, results in improved outcomes. Improvement of glycemia, reduction of low-density lipoprotein cholesterol levels, tight control of blood pressure, and antiplatelet therapy have been all shown to decrease the morbidity and mortality associated with CHF in diabetic patients. beta-blockade added to angiotensin-converting enzyme (ACE) inhibition has become an increasingly integral component of CHF therapy. RESULTS Improved outcome with beta-blockade treatment is due to decreased incidence of both sudden death and pump failure and is of particular benefit to diabetic patients during and after myocardial infarctions complicated by systolic dysfunction. CONCLUSIONS Based on retrospective analysis, beta-blocking agents with vasodilating properties may provide additional benefits in diabetic patients because they may improve insulin sensitivity and vasorelaxation.
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Otter W, Kleybrink S, Doering W, Standl E, Schnell O. Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus. Diabet Med 2004; 21:183-7. [PMID: 14984455 DOI: 10.1111/j.1464-5491.2004.01114.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS To assess hospital mortality and morbidity in diabetic and non-diabetic patients with acute myocardial infarction and to compare the results between the two groups. METHODS All patients admitted in 1999 to the intensive care unit of the Schwabing City Hospital with diagnosis of acute myocardial infarction were assessed for hospital mortality and co-morbidity. RESULTS Three hundred and thirty patients with acute myocardial infarction were admitted. Of those, 126 (38%) were diabetic and 204 (62%) were non-diabetic patients. Mortality within 24 h after admission was 13.5% in diabetic patients and 5.4% in non-diabetic patients (P<0.01). Mortality during entire hospitalization was higher in diabetic than in non-diabetic patients (29.4% vs. 16.2%; P=0.004). Diabetic patients were resuscitated more frequently than non-diabetic patients (24% vs. 11%, P<0.01). In diabetic patients, heart rate at admission was increased (91 +/- 27 vs. 82 +/- 23/min; P<0.01) and presence of angina pectoris was reported less frequently (59% (n=72) vs. 82% (n=167); P<0.001). Preceding myocardial infarction, microalbuminuria, peripheral artery disease and arterial hypertension were more frequent in diabetic than in non-diabetic patients. Diabetic patients demonstrated higher C-reactive protein (CRP) levels than non-diabetic patients (91.4 +/- 78.2 mg/l vs. 45.2 +/- 62.4 mg/l; P<0.001). CONCLUSIONS In diabetic patients with acute myocardial infarction, early hospital mortality is increased and signs of cardiac autonomic dysfunction and microangiopathy are detected more frequently than in non-diabetic patients. The need for advanced treatment strategies early in the course of diabetic patients with myocardial infarction is emphasized.
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Affiliation(s)
- W Otter
- Department of Cardiology, Schwabing City Hospital and Diabetes Research Institute, Munich, Germany.
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A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. J Neurosci 2003. [PMID: 12805287 DOI: 10.1523/jneurosci.23-11-04470.2003] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The norepinephrine transporter (NET) mediates reuptake of norepinephrine released from neurons, and, as such, it is an important regulator of noradrenergic neurotransmission. Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). The presence of the hNET-A457P allele tracked with elevated heart rates and plasma NE levels in family members. hNET-A457P lacks >98% transport activity in several heterologous expression systems. In the present work, Western blot and biotinylation analyses performed in transiently transfected COS-7 cells revealed impairment in processing of hNET-A457P to the fully glycosylated form and a decrease in surface expression to approximately 30% of hNET-wild type (hNET-wt). Because the hNET-A457P mutation is carried on a single allele in OI subjects, we examined the influence of cotransfection of hNET-wt and hNET-A457P and found that hNET-A457P exerts a dominant-negative effect on hNET-wt uptake activity. Experiments to determine oligomerization as a potential mechanism of the dominant-negative effect demonstrated that hNET-A457P coimmunoprecipitates with, and diminishes surface expression of, hNET-wt. These results reveal that hNET-A457P causes a conformational disruption that interferes with transporter biosynthetic progression and trafficking of both the mutant transporter and hNET-wt. These results elucidate a molecular mechanism for the disrupted NE homeostasis and cardiovascular function evident in OI patients with the hNET-A457P mutation.
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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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Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, Kerényi Z, Tamás G, Ward JD, Fuller JH. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med 2002; 19:900-9. [PMID: 12421426 DOI: 10.1046/j.1464-5491.2002.00821.x] [Citation(s) in RCA: 113] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIMS To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study. METHODS The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests. RESULTS The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control. CONCLUSION Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.
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Affiliation(s)
- P Kempler
- Department of Medicine, Semmelweis University, Budapest, Hungary, Royal Hallamshire Hospital, Sheffield, London, UK
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Affiliation(s)
- Amar D Patel
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham 35294-0006, USA
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Russell RR, Chyun D, Song S, Sherwin RS, Tamborlane WV, Lee FA, Pfeifer MA, Rife F, Wackers FJ, Young LH. Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients. Am J Physiol Endocrinol Metab 2001; 281:E1029-36. [PMID: 11595660 DOI: 10.1152/ajpendo.2001.281.5.e1029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol. kg(-1). min(-1)) under either hypoglycemic (approximately 2.8 mmol/l) or euglycemic (approximately 5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects (n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (DeltaLVEF = 11 +/- 2%) and PFR [DeltaPFR = 0.88 +/- 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (DeltaLVEF = 13 +/- 2%; DeltaPFR = 0.79 +/- 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (DeltaLVEF = 7 +/- 1%) and nondiabetic (DeltaLVEF = 4 +/- 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study (P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.
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Affiliation(s)
- R R Russell
- Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut 06520, USA
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Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, Kerényi Z, Tamás G, Ward JD, Fuller JH. Blood pressure response to standing in the diagnosis of autonomic neuropathy: the EURODIAB IDDM Complications Study. Arch Physiol Biochem 2001; 109:215-22. [PMID: 11880924 DOI: 10.1076/apab.109.3.215.11589] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Autonomic neuropathy is associated with poor prognosis. Cardiovascular reflexes are essential for the diagnosis of autonomic nerve dysfunction. Blood pressure response to standing is the most simple test for the evaluation of sympathetic integrity, however it is still discussed which diagnostic criteria of abnormal response should be considered as optimal. The EURODIAB IDDM Complications Study involved the examination of randomly selected Type 1 diabetic patients from 31 centres in 16 European counties. Data from 3007 patients were available for the present evaluation. Two tests of autonomic function (response of heart rate /R-R ratio/ and blood pressure from lying to standing) just as the frequency of feeling faint on standing up were assessed. R-R ratio was abnormal in 24% of patients. According to different diagnostic criteria of abnormal BP response to standing (>30 mmHg, >20 mmHg, and >10 mmHg fall in systolic BP), the frequency of abnormal results was 5.9%, 18% and 32%, respectively (p < 0.001). The frequency of feeling faint on standing was 18%, thus, it was identical with the prevalence of abnormal blood pressure response to standing when >20 mmHg fall in systolic blood pressure was considered as abnormal. Feeling faint on standing correlated significantly with both autonomic test results (p < 0.001). A fall >20 mmHg in systolic blood pressure after standing up seems to be the most reliable criterion for the assessment of orthostatic hypotension in the diagnosis of autonomic neuropathy in patients with Type 1 diabetes mellitus.
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Affiliation(s)
- P Kempler
- First Department of Medicine, Semmelweis University, Budapest, Hungary
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Abstract
A key problem in ischemia-induced impairment of the vascular performance of the diabetic heart is the often-unrecognized cardiac sympathetic dysfunction. Advanced single-photon emission computed tomography (SPECT) and positron emission tomography (PET) using the radiopharmaceuticals, (123)I-metaiodobenzylguanidine ((123)I-MIBG) and (11)C-hydroxyephedrine ((11)C-HED), have shown that dysfunction of cardiac sympathetic nerves is present to a large extent in both type 1 and type 2 diabetes. The pattern of sympathetic disturbances is heterogeneous with a predominant effect in the posterior myocardial region. Furthermore, myocardial blood flow assessment with PET has shown that endothelial-dependent vasodilatation is reduced in proportion to the magnitude of cardiac sympathetic dysfunction. These mechanisms are currently proposed to lead from early changes to advanced impairment of cardiac function in diabetes.
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Affiliation(s)
- O Schnell
- Diabetes Reseach Institute, Kölner Platz 1, 80804 Munich, Germany.
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Takahashi N, Nakagawa M, Saikawa T, Ooie T, Yufu K, Shigematsu S, Hara M, Sakino H, Katsuragi I, Okeda T, Yoshimatsu H, Sakata T. Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients. J Am Coll Cardiol 2001; 38:232-7. [PMID: 11451280 DOI: 10.1016/s0735-1097(01)01363-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.
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Affiliation(s)
- N Takahashi
- Department of Internal Medicine I, School of Medicine, Oita Medical University, Japan.
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Turpeinen AK, Kuikka JT, Vanninen E, Yang J, Uusitupa MI. Long-term effect of acetyl-L-carnitine on myocardial 123I-MIBG uptake in patients with diabetes. Clin Auton Res 2000; 10:13-6. [PMID: 10750638 DOI: 10.1007/bf02291384] [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: 10/25/2022]
Abstract
Carnitine derivatives may have beneficial effects on cardiac and nerve function in patients with diabetes. The aim of this study was to investigate the effect of acetyl-L-carnitine (ALC) on myocardial sympathetic nervous function as measured with 123I-meta-iodobenzyl guanidine (MIBG) and single-photon emission tomography (SPET) in 19 patients with diabetes (placebo group, n = 6; ALC group, n = 13) at the beginning and at the end of a 1-year randomized, placebo-controlled, double-blind trial. The coefficient of variation for the MIBG analysis was 4%. In patients who were given a placebo, global myocardial MIBG uptake deteriorated during the study (MIBG uptake 1-year follow-up/baseline, 0.86 +/- 0.05, mean +/- standard error of mean), whereas in patients treated with ALC, MIBG uptake did not change significantly (1-year follow-up/baseline, 1.07 +/- 0.08; p = 0.03 between the groups). On the basis of these preliminary data, we conclude that long-term treatment with ALC may be of potential value in preventing the progressive loss of myocardial sympathetic nervous function in patients with diabetes. MIBG-SPET is a sensitive and thus valuable method in assessing the development of myocardial sympathetic nervous dysfunction.
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Affiliation(s)
- A K Turpeinen
- Department of Clinical Nutrition and Medicine, University of Kuopio, and Kuopio University Hospital, Finland.
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Togane Y. Evaluation of the cardiac autonomic nervous system in spontaneously non-insulin-dependent diabetic rats by 123I-metaiodobenzylguanidine imaging. Ann Nucl Med 1999; 13:19-26. [PMID: 10202944 DOI: 10.1007/bf03165423] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To evaluate the sensitivity of 123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy in detecting diabetic autonomic nervous system disorders. MATERIALS AND METHODS Thirty-one-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous non-insulin-dependent diabetes mellitus, were maintained for 8 weeks with or without 30% sucrose solution as a drinking water (n = 3 each). Long-Evans Tokushima Otsuka (LETO) rats (n = 3), served as controls. Plasma glucose and insulin levels were measured, and 123I-MIBG scintigraphy was performed with a gamma camera equipped with a pinhole collimator for animals. Plasma and cardiac tissue cathecolamine levels were also determined. RESULTS Plasma glucose levels of OLETF rats with and without sucrose loading (554+/-106 and 141+/-1.5 mg/dl respectively) were significantly higher than those of LETO rats (116+/-3.7 mg/dl). Norepinephrine concentrations in heart and plasma tended to be lower in diabetic rats. The washout rate of 123I-MIBG in diabetic rats was significantly higher than the rate in control rats. Cardiac uptake of 123I-MIBG, calculated as % dose/g of tissue, was significantly lower in diabetic rats than in control rats. CONCLUSION These results suggest that myocardial 123I-MIBG scintigraphy is suitable for assessing cardiac sympathetic activity noninvasively in diabetic states, even in the early stages.
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Affiliation(s)
- Y Togane
- First Department of Internal Medicine, Toho University School of Medicine, Japan.
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Stevens MJ, Raffel DM, Allman KC, Schwaiger M, Wieland DM. Regression and progression of cardiac sympathetic dysinnervation complicating diabetes: an assessment by C-11 hydroxyephedrine and positron emission tomography. Metabolism 1999; 48:92-101. [PMID: 9920151 DOI: 10.1016/s0026-0495(99)90016-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cardiovascular denervation complicating diabetes has been implicated in sudden cardiac death potentially by altering myocardial electrical stability and impairing myocardial blood flow. Scintigraphic evaluation of cardiac sympathetic integrity has frequently demonstrated deficits in distal left ventricular (LV) sympathetic innervation in asymptomatic diabetic subjects without abnormalities on cardiovascular reflex testing. However, the clinical significance and subsequent fate of these small regional defects is unknown. This study reports the results of a prospective observational study in which positron emission tomography (PET) with (-)-[11C]-meta-hydroxyephedrine ([11C]-HED) was used to evaluate the effects of glycemic control on the progression of small regional LV [11C]-HED retention deficits in 11 insulin-dependent diabetic subjects over a period of 3 years. The subjects were divided into two groups based on attained glycemic control during this period: group A contained six subjects with good glycemic control (individual mean HbA1c <8%), and group B contained five subjects with poor glycemic control (individual mean HbAlc > or =8%). Changes in regional [11C]-HED retention were compared with reference values obtained from 10 healthy aged-matched nondiabetic subjects. At baseline, abnormalities of [11C]-HED retention affected 7.3%+/-1.4% and 9.9%+/-6.6% of the LV in group A and B subjects, respectively, with maximal deficits of LV [ C]-HED retention involving the distal myocardial segments. At the final assessment in group A, the extent of the deficits in [11C]-HED retention decreased to involve only 1.7%+/-0.7% of LV (P<.05 v. baseline scan), with significant increases in [11C]-HED retention occurring in both the distal and proximal myocardial segments. In contrast, in group B with poor glycemic control, the extent of [11C]-HED deficits increased to involve 34%+/-3.5% of the LV (P<.01 v. baseline), with retention of [11C]-HED significantly decreasing in the distal segments ([11C]-HED retention index, 0.066+/-0.003 v. 0.057+/-0.002, P<.05, at baseline and final assessment, respectively). Poor glycemic control was associated with increased heterogeneity of LV [11C]-HED retention, since three of five group B subjects developed abnormally increased [11C]-HED retention in the proximal myocardial segments. In conclusion, defects in LV sympathetic innervation can regress or progress in diabetic subjects achieving good or poor glycemic control, respectively. In diabetic subjects with early cardiovascular denervation, institution of good glycemic control may prevent the development of myocardial sympathetic dysinnervation and enhanced cardiac risk.
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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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Affiliation(s)
- S Caprio
- Yale University School of Medicine, New Haven, Connecticut, USA
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