Selective Contribution of Diabetes and Other Cardiovascular Risk Factors to Cardiac Autonomic Dysfunction in the General Population

Introduction

Risk factors for cardiovascular disease (CVD), including several components of the metabolic syndrome, represent a major cause of premature death ([Adult Treatment Panel III, 2002]; [Grundy et al., 2004]; [Malik et al., 2004]). The worldwide dramatic increase of obesity and diabetes causes an enormous burden to the persons affected, public health, and to national health budgets. The autonomic nervous system (ANS) plays a paramount role in affecting the cardiac milieu and promoting malignant ventricular activity ([Villareal et al., 2002]). Heart rate variability (HRV) is a noninvasive tool for assessing the status of the ANS in various diseases. Reduced HRV has been shown to predict increased mortality in the general population ([Dekker et al., 1997]) and in patients with CVD ([Villareal et al., 2002]). In diabetic patients, reduced HRV is regarded as a hallmark of cardiac autonomic neuropathy (CAN) which represents a serious complication ([Ziegler, 1999]) associated with an approximately 2-fold increased mortality ([Vinik et al., 2003]; [Maser et al., 2003]), sudden death ([Suarez et al., 2005]), and silent myocardial ischemia ([Vinik et al., 2003]; [Wackers et al., 2004]). Accumulating evidence suggests that reduced HRV may predict the development of CVD ([Valensi et al., 2001]) and stroke ([Toyry et al., 1996]).

The QT interval represents the period of global ventricular depolarization and subsequent repolarization. Prolongation of the QT interval corrected for heart rate (QTc) has been associated with an increased incidence of ventricular arrhythmias ([Chen and Kusumoto, 2004]). The QT dispersion (QTD), which has been defined as the difference between the longest and shortest QT intervals on a standard 12-lead ECG, is considered to reflect regional variation in ventricular recovery times. This spatial dispersion of repolarization could offer an electrophysiological substrate for malignant ventricular arrhythmias ([Chen and Kusumoto, 2004]; [Manttari et al., 1997]). Both prolonged QTc interval and increased QTD have been identified as predictors of increased cardiovascular and all-cause mortality in the general population ([Manttari et al., 1997]; [de Bruyne et al., 1998]; [de Bruyne et al., 1999]; [Karjalainen et al., 1997]) and in the diabetic population ([Okin et al., 2004]).

The significance of HRV, QTc, and QTD in the context of cardiovascular risk factors has not been addressed systematically in previous studies ([Whitsel et al., 2000]; [Festa et al., 2000]; [Brown et al., 2001]; [Carnethon et al., 2002]). Because reduced HRV, prolonged QTc, and increased QTD contribute to increased mortality, these risk markers were measured in the population-based MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg survey 1989/90 (S2), Germany, to elucidate to which extent such cardiac autonomic abnormalities are determined by major cardiovascular risk factors.

References

• 1 Antelmi I, de Paula R S, Shinzato A R, Peres C A, Mansur A J, Grupi C J. Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease.  Am J Cardiol. 2004;  93 381-385
• 2 Bazett H C. An analysis of the time-relations of electrocardiogram.  Heart. 1920;  7 353-370
• 3 Brown D W, Giles W H, Greenlund K J, Valdez R, Croft J B. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey.  J Cardiovasc Risk. 2001;  8 227-233
• 4 Carnethon M R, Golden S H, Folsom A R, Haskell W, Liao D. Prospective investigation of autonomic nervous system function and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study, 1987 - 1998.  Circul. 2003 a;  107 2190-2195
• 5 Carnethon M R, Jacobs Jr D R, Sidney S, Liu K. Influence of autonomic nervous system dysfunction on the development of type 2 diabetes: the CARDIA study.  Diabetes Care. 2003 b;  26 3035-3041
• 6 Carnethon M R, Liao D, Evans G W, Cascio W E, Chambless L E, Heiss G. Correlates of the shift in heart rate variability with an active postural change in a healthy population sample: the Atherosclerosis Risk in Communities Study.  Am Heart J. 2002;  143 808-813
• 7 Chen A, Kusumoto F M. QT dispersion: much ado about something?.  Chest. 2004;  125 1974-1977
• 8 de Bruyne M C, Hoes A W, Kors J A, Hofman A, van Bemmel J H, Grobbee D E. QTc dispersion predicts cardiac mortality in the elderly: the Rotterdam Study.  Circul. 1998;  97 467-472
• 9 de Bruyne M C, Hoes A W, Kors J A, Hofman A, van Bemmel J H, Grobbee D E. Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study.  Eur Heart J. 1999;  20 278-284
• 10 Dekker J M, Schouten E G, Klootwijk P, Pool J, Swenne C A, Kromhout D. Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study.  Am J Epidemiol. 1997;  145 899-908
• 11 Emdin M, Gastaldelli A, Muscelli E, Macerata A, Natali A, Camastra S, Ferrannini E. Hyperinsulinemia and autonomic nervous system dysfunction in obesity: effects of weight loss.  Circul. 2001;  103 513-519
• 12 Festa A, D'Agostino Jr R, Rautaharju P, Mykkanen L, Haffner S M. Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects.  Am J Cardiol. 2000;  86 1117-1122
• 13 Fontaine K R, Redden D T, Wang C, Westfall A O, Allison D B. Years of life lost due to obesity.  JAMA. 2003;  289 187-193
• 14 Fridericia L S. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken.  Acta Med Scand. 1920;  53 469-486
• 15 Grundy S M, Brewer Jr H B, Cleeman J I, Smith Jr S C, Lenfant C. American Heart Association . Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition.  Circul. 2004;  27 433-438
• 16 Hense H W, Filipiak B, Döring A. et al . Ten-year trends of cardiovascular risk factors in the MONICA Augsburg Region in Southern Germany: results from the 1984/85, 1989/90 and 1994/1995 surveys.  Cardiovasc Dis Prev. 1998;  1 318-327
• 17 Karjalainen J, Reunanen A, Ristola P, Viitasalo M. QT interval as a cardiac risk factor in a middle aged population.  Heart. 1997;  77 543-548
• 18 Keil U, Cairns V, Döring A. et al .MONICA-Project, Region Augsburg. Manual of Operations, Survey. GSF-Bericht 20. Munich; GSF-Forschungszentrum 1985
• 19 Kreier F, Yilmaz A, Kalsbeek A, Romijn J A, Sauerwein H P, Fliers E, Buijs R M. Hypothesis: shifting the equilibrium from activity to food leads to autonomic unbalance and the metabolic syndrome.  Diabetes. 2003;  52 2652-2656
• 20 Lemieux I, Lamarche B, Couillard C, Pascot A, Cantin B, Bergeron J, Dagenais G R, Despres J P. Total cholesterol/HDL cholesterol ratio vs. LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.  Arch Intern Med. 2001;  161 2685-2692
• 21 Liao D, Sloan R P, Cascio W E, Folsom A R, Liese A D, Evans G W, Cai J, Sharrett A R. Multiple metabolic syndrome is associated with lower heart rate variability. The Atherosclerosis Risk in Communities Study.  Diabetes Care. 1998;  21 2116-2122
• 22 Malik S, Wong N D, Franklin S S, Kamath T V, L'Italien G J, Pio J R, Williams G R. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.  Circul. 2004;  110 1245-1250
• 23 Manttari M, Oikarinen L, Manninen V, Viitasalo M. QT dispersion as a risk factor for sudden cardiac death and fatal myocardial infarction in a coronary risk population.  Heart. 1997;  78 268-272
• 24 Maser R E, Mitchell B D, Vinik A I, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis.  Diabetes Care. 2003;  26 1895-1901
• 25 Meisinger C, Thorand B, Schneider A. et al . Gender differences in risk factors for incident type 2 diabetes mellitus: the MONICA Augsburg Cohort Study.  Arch Intern Med. 2002;  162 82-89
• 26 Okin P M, Devereux R B, Lee E T, Galloway J M, Howard B V. Strong Heart Study. Electrocardiographic repolarization complexity and abnormality predict all-cause and cardiovascular mortality in diabetes: the Strong Heart Study.  Diabetes. 2004;  53 434-440
• 27 Perz S, Pöppl S J, Stieber J. ECG data management and analysis in the MONICA Survey Augsburg. Reichertz PL, Lindberg DAB Lecture Notes in Medical Informatics 25, Medical Informatics Europe 1985. Heidelberg; Springer 1985: 811
• 28 Pshenichnikov I, Shipilova T, Kaik J, Volozh O, Abina J, Lass J, Karai D. QT dispersion in relation to left ventricular geometry and hypertension in a population study.  Scand Cardiovasc J. 2003;  37 87-90
• 29 Quilliot D, Fluckiger L, Zannad F, Drouin P, Ziegler O. Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance.  Clin Auton Res. 2001;  11 79-86
• 30 Rabbia F, Silke B, Conterno A, Grosso T, De Vito B, Rabbone I, Chiandussi L, Veglio F. Assessment of cardiac autonomic modulation during adolescent obesity.  Obes Res. 2003;  11 541-548
• 31 Rana B S, Lim P O, Naas A A, Ogston S A, Newton R W, Jung R T, Morris A D, Struthers A D. QT interval abnormalities are often present at diagnosis in diabetes and are better predictors of cardiac death than ankle brachial pressure index and autonomic function tests.  Heart. 2005;  91 44-50
• 32 Sagie A, Larson M G, Goldberg R J, Bengtson J R, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study).  Am J Cardiol. 1992;  70 797-801
• 33 Salles G F, Deccache W, Cardoso C R. Usefulness of QT-interval parameters for cardiovascular risk stratification in type 2 diabetic patients with arterial hypertension.  J Hum Hypertens. 2005;  19 241-249
• 34 Schroeder E B, Chambless L E, Liao D, Prineas R J, Evans G W, Rosamond W D, Heiss G. Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) Study.  Diabetes Care. 2005;  28 668-674
• 35 Stevens J, Cai J, Juhaeri J, Thun M J, Williamson D F, Wood J L. Consequences of the use of different measures of effect to determine the impact of age on the association between obesity and mortality.  Am J Epidemiol. 1999;  150 399-407
• 36 Suarez G A, Clark V M, Norell J E, Kottke T E, Callahan M J, O'Brien P C, Low P A, Dyck P J. Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study.  J Neurol Neurosurg Psychiatry. 2005;  76 240-245
• 37 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology . Heart rate variability: standards of measurement, physiological interpretation and clinical use.  Circul. 1996;  93 1043-1065
• 38 Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report.  Circul. 2002;  106 3143-3421
• 39 Toyry J P, Niskanen L K, Lansimies E A, Partanen K P, Uusitupa M I. Autonomic neuropathy predicts the development of stroke in patients with non-insulin-dependent diabetes mellitus.  Stroke. 1996;  27 1316-1318
• 40 Valensi P, Paries J, Attali J R. French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications - the French Multicenter Study.  Metabolism. 2003;  52 815-820
• 41 Valensi P, Sachs R N, Harfouche B, Lormeau B, Paries J, Cosson E, Paycha F, Leutenegger M, Attali J R. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia.  Diabetes Care. 2001;  24 339-343
• 42 van Huysduynen B H, Swenne C A, Van Eck H J, Kors J A, Schoneveld A L, Van De Vooren H, Schiereck P, Schalij M J, Van Der Wall E E. Hypertensive stress increases dispersion of repolarization.  Pacing Clin Electrophysiol. 2004;  27 1603-1609
• 43 Villareal R P, Liu B C, Massumi A. Heart rate variability and cardiovascular mortality.  Curr Atheroscler Rep. 2002;  4 120-127
• 44 Vinik A I, Maser R E, Mitchell B D, Freeman R. Diabetic autonomic neuropathy.  Diabetes Care. 2003;  26 1553-1579
• 45 Wackers F J, Young L H, Inzucchi S E, Chyun D A, Davey J A, Barrett E J, Taillefer R, Wittlin S D, Heller G V, Filipchuk N, Engel S, Ratner R E, Iskandrian A E. Detection of ischemia in asymptomatic diabetics investigators. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study.  Diabetes Care. 2004;  27 1954-1961
• 46 Wang T D, Chen W J, Chien K L, Seh-Yi Su S S, Hsu H C, Chen M F, Liau C S, Lee Y T. Efficacy of cholesterol levels and ratios in predicting future coronary heart disease in a Chinese population.  Am J Cardiol. 2001;  88 737-743
• 47 Whitsel E A, Boyko E J, Siscovick D S. Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis.  Diabetes Care. 2000;  23 241-247
• 48 Tunstall-Pedoe H.. WHO MONICA Project Principal Investigators, prepared by . The World Health Organization MONICA Project (Monitoring of Trends and Determinants in Cardiovascular Disease): a major international collaboration.  J Clin Epidemiol. 1988;  34 105-114
• 49 Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement.  Diabetes Rev. 1999;  7 342-357