Association of cardiac autonomic neuropathy with subclinical myocardial dysfunction in type 2 diabetes.

OBJECTIVES The purpose of this study was to investigate the independent association between global cardiac autonomic neuropathy (CAN) and left ventricular (LV) dysfunction in addition to regional associations of LV dysinnervation and function, in patients with type 2 diabetes mellitus (T2DM). BACKGROUND CAN represents a potential mechanism in the etiology of nonischemic diabetic cardiomyopathy. METHODS Clinical measures of CAN based on total spectral power of heart rate variability and cardiac reflex testing and echocardiographic assessment of LV function were performed in 118 patients with type 2 diabetes mellitus. Systolic and diastolic function were defined at rest and peak exercise using peak systolic and peak early diastolic (Em) tissue velocities, calculated in 6 basal- and mid-segments using color tissue Doppler. Iodine 123-metaiodobenzylguanidine imaging was performed in 33 patients to directly quantify global (heart/mediastinum ratio) and regional LV sympathetic integrity. RESULTS Patients with CAN demonstrated higher resting heart rate, systolic and mean blood pressures, aortic stiffness, hemoglobin A(1c), and urine albumin/creatinine ratio, in addition to lower peak heart rate, chronotropic index, and exercise capacity. Diastolic function (Em) was associated with CAN, evidenced by total spectral power (r = 0.42, p < 0.001) and heart/mediastinum ratio (r = 0.41, p = 0.017). Diastolic function (Em) at rest and systolic function (peak systolic tissue velocity) at rest and exercise were significantly reduced in patients with CAN. Furthermore, total spectral power was associated with Em independent of age, hypertension, metabolic factors, and other relevant contributors to LV dysfunction (β = 0.20, p = 0.035). Relative regional tracer deficits indicative of local denervation were predominant in the anterior and lateral walls (p < 0.001). Associations with regional Em, independent of global iodine 123-metaiodobenzylguanidine uptake, were identified exclusively in mid-anterior (β = 0.45, p = 0.01) and mid-lateral walls (β = 0.34, p = 0.03). However, no association was found between regional denervation and systolic or diastolic dyssynchrony. CONCLUSIONS The diastolic dysfunction of type 2 diabetes mellitus shows associations with both regional markers of sympathetic integrity and clinical markers of autonomic neuropathy.

[1]  P Kligfield,et al.  Chronotropic response to exercise. Improved performance of ST-segment depression criteria after adjustment for heart rate reserve. , 1996, Circulation.

[2]  A. Vinik,et al.  Diabetic Cardiovascular Autonomic Neuropathy , 2007, Circulation.

[3]  Claudette Fortin,et al.  Preclinical diabetic cardiomyopathy: relation of left ventricular diastolic dysfunction to cardiac autonomic neuropathy in men with uncomplicated well-controlled type 2 diabetes. , 2003, Metabolism: clinical and experimental.

[4]  Steven W. Lee,et al.  Progression of Systolic Abnormalities in Patients With “Isolated” Diastolic Heart Failure and Diastolic Dysfunction , 2002, Circulation.

[5]  N Reichek,et al.  Echocardiographic Determination of Left Ventricular Mass in Man: Anatomic Validation of the Method , 1977, Circulation.

[6]  Braxton D Mitchell,et al.  The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. , 2003, Diabetes care.

[7]  M. Schwaiger,et al.  Cardiac sympathetic dysinnervation in diabetes: implications for enhanced cardiovascular risk. , 1998, Circulation.

[8]  P. Valensi,et al.  Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. , 2001, Diabetes care.

[9]  Arturo Evangelista,et al.  Recommendations for the evaluation of left ventricular diastolic function by echocardiography. , 2009, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[10]  T. Karamitsos,et al.  Impact of Autonomic Neuropathy on Left Ventricular Function in Normotensive Type 1 Diabetic Patients , 2008, Diabetes Care.

[11]  T. Marwick,et al.  Determinants of subclinical diabetic heart disease , 2005, Diabetologia.

[12]  A. Vinik,et al.  Abnormal cardiac function in diabetic patients with autonomic neuropathy in the absence of ischemic heart disease. , 1986, The Journal of clinical endocrinology and metabolism.

[13]  P. Monteagudo,et al.  Influence of autonomic neuropathy upon left ventricular dysfunction in insulin‐dependent diabetic patients , 2000, Clinical cardiology.

[14]  M. Spüler,et al.  Prevalence of Cardiovascular Autonomic Dysfunction Assessed by Spectral Analysis, Vector Analysis, and Standard Tests of Heart Rate Variation and Blood Pressure Responses at Various Stages of Diabetic Neuropathy , 1992, Diabetic medicine : a journal of the British Diabetic Association.

[15]  Thomas H Marwick,et al.  Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. , 2004, Endocrine reviews.

[16]  F. A. Gries,et al.  The Epidemiology of Diabetic Neuropathy , 1993 .

[17]  R. Freeman,et al.  Diabetic autonomic neuropathy. , 2003, Diabetes care.

[18]  T. Marwick,et al.  Echocardiographic detection of early diabetic myocardial disease. , 2003, Journal of the American College of Cardiology.

[19]  K. Fukuchi,et al.  Myocardial iodine-123-metaiodobenzylguanidine images and autonomic nerve activity in normal subjects. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[20]  J. Oh,et al.  Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiography , 2006, Heart.

[21]  M. Spüler,et al.  The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group. , 1992, Journal of diabetes and its complications.

[22]  Dan Ziegler,et al.  Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate , 2001, Clinical Autonomic Research.

[23]  P. Fasching,et al.  Myocardial m-[123I]Iodobenzylguanidine Scintigraphy for the Assessment of Adrenergic Cardiac Innervation in Patients With IDDM: Comparison With Cardiovascular Reflex Tests and Relationship to Left Ventricular Function , 1995, Diabetes.

[24]  R. Scognamiglio,et al.  Myocardial dysfunction and abnormal left ventricular exercise response in autonomic diabetic patients , 1995, Clinical cardiology.

[25]  R. Pop-Busui,et al.  Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. , 2004, Journal of the American College of Cardiology.

[26]  G. Arsos,et al.  Effect of quinapril or losartan alone and in combination on left ventricular systolic and diastolic functions in asymptomatic patients with diabetic autonomic neuropathy. , 2006, Journal of diabetes and its complications.

[27]  G. Jensen,et al.  Left ventricular dysfunction in normotensive Type 1 diabetic patients: the impact of autonomic neuropathy , 2004, Diabetic medicine : a journal of the British Diabetic Association.

[28]  G. Arsos,et al.  Left ventricular systolic and diastolic function in normotensive type 1 diabetic patients with or without autonomic neuropathy: a radionuclide ventriculography study. , 2003, Diabetes care.

[29]  A. Vinik,et al.  Radionuclide assessment of left ventricular diastolic filling in diabetes mellitus with and without cardiac autonomic neuropathy. , 1986, Journal of the American College of Cardiology.

[30]  Dan Ziegler,et al.  Assessment of Cardiovascular Autonomic Function: Age‐related Normal Ranges and Reproducibility of Spectral Analysis, Vector Analysis, and Standard Tests of Heart Rate Variation and Blood Pressure Responses , 1992, Diabetic medicine : a journal of the British Diabetic Association.