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MORTE IMPROVVISA NEI DIVERSI GRUPPI DI PAZIENTI SUDDEN DEATH IN VARIOUS PATIENT POPULATIONS Nel diabete In Diabetes Stefano Genovese Dipartimento Cardiovascolare e Metabolico Causes of death in the ACCORD Study ACCORD Study Group et al. NEJM 2008;358:2545-59 Cardiovascular Disease Is Primary Cause of Death in Persons with Mental Illness* Percentage of deaths *Average data from 1996-2000. 40 30 20 10 0 Missouri Oklahoma Rhode Island Texas Utah Heart Disease Cancer Cerebrovascular Chronic Respiratory Accidents Diabetes Influenza/Pneumonia Suicide Colton CW, Manderscheid RW. Prev Chronic Dis [serial online] 2006 Apr [date cited]. Available at URL: http://www.cdc.gov/pcd/issues/2006/apr/05_0180.htm Definition of Sudden Cardiac Death (SCD) - WHO • Unexpected death occurring within a specific period of time after the onset of initial symptoms – Time frame ranges from less than one hour up to 24 hours after symptom onset Roberts WC Am J Cardiol 1986 57: 1410 Effects of lack of a single, accepted definition of SCD • Over 3,421 natural deaths – 12% were sudden if defined as <2 hours from the onset of symptoms, and 88% of these were from a cardiac aetiology – 32% of natural deaths were sudden and 75% from a cardiac aetiology, when the definition was extended to death within 24 hours of symptom onset Kuller L et al. Medicine 1967; 46: 341 Epidemiology of SCD - USA Zheng ZJ et al. Circulation. 2001;104:2158-2163 Sudden cardiac deaths and diabetes mellitus The Framingham cohort Fox CS et al. Circulation 2004; 110: 522 Mechanisms of SCD in Diabetes • • • • • Silent ischemia Autonomic dysfunction QT interval prolongation Autonomic neuropathy and QT interval Hypoglycaemia Silent ischemia • Silent ischemia ranges from 6-59% in patients with diabetes mellitus • In DIAD (Detection of Ischemia in Asymptomatic Diabetics) Study 15,9% of patients had abnormal myocardial perfusion • Silent ischemia is supposed to eventually lead to lethal arrhythmias and SCD in diabetic patients • There are no studies on attributable risk of SCD due to silent ischemia Incidence of SCD after MI Junttila MJ et al. Heart Rhythm 2010; 7:1396 –1403 Incidence of SCD after MI Junttila MJ et al. Heart Rhythm 2010; 7:1396 –1403 Autonomic dysfunction • Small observational studies suggested that CAN (Cardiac Autonomic Neuropathy) was independently associated with an increased risk of sudden cardiac death • Hathaway DK et al. Autonomic cardiac dysfunction in diabetic transplant recipients succumbing to sudden cardiac death. Transplantation, 1995; 59: 634–637 • Rathmann W et al. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med, 1993; 10: 820–824 • Ewing DJ et al. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia, 1991; 34: 182–185 • Ewing DJ et al. The natural history of diabetic autonomic neuropathy. QJ Med, 1980; 49: 95–108 SCD in Diabetes Mellitus: Risk factors in the Rochester Diabetic Neuropathy Study • Large prospective study: – 462 patients with DM were followed over 15 years, with 21 cases of SCD reported over this period. Subjects with CAN were found to have a hazard ratio of 1.52 (1.2–1.91) for SCD on univariate analysis, although this was not significant after multivariate analysis. • Conclusions: – Sudden cardiac death was correlated with atherosclerotic heart disease and nephropathy, and to a lesser degree with DAN (Diabetic Autonomic Neuropathy) and HDL cholesterol. Although DAN is associated with sudden cardiac death, it is unlikely to be its primary cause. Suarez JA et al. J Neurol Neurosurg Psychiatry 2005;76:240–245 QT interval prolongation • Is common in patients with diabetes mellitus: – 25.6% in Type 1 and 30.8% in Type 1 with DAN1 – 25.8% in Type 22 • Is a significant, indipendent and powerful predictor of mortality – In a study of Type 1 pts, QTc (>400 ms) was the only variable associated with increased mortality in multivariate analysis with an odd ratio of 24.6 (95% CI 6.51-92.85)3 1.Sivieri R et al. Diabet Med, 1993; 10: 920–924 2. Veglio M, et al. J Intern Med, 2002; 251: 317–324 3. Veglio M, et al. Diabetes Care, 2000; 23: 1381–1383 QTc interval increases risk of SCD in diabetic patients Whitsel EA, et al. Diabetes Care, 2005; 28: 2045–2047 Hypoglycemia • Experimentally induced hypoglycemia causes changes in ventricular repolarization both in Type 1 and Type 2 diabetic patients (QTc increase) • Beta-blockade nearly abolish the effects of hypoglycemia on QTc prolongation • QTc prolongation is driven by sympathoexitation during hypoglycemia • Dead in bed syndrome – Unexpected death in young (<50) Type 1 diabetics (lethal arrhythmia?) – Hypothesis: QTc prolongation for DAN + QTc prolongation from hypoglycemia + underlying genetic predisposition Marques JL et al. Diabet Med, 1997; 14: 648–654 Landstedt-Hallin L et al. J Intern Med, 1999; 246: 299–307 Robinson RT et al. Diabetes, 2003; 52: 1469–1474 Intensive therapy and hypoglicaemia in the ACCORD and ADVANCE Study ACCORD1 ADVANCE2 P < 0,001 P < 0,001 Request medical assistance Terapia intensiva Terapia standard 3,0 P < 0,001 Request medical assistance Incidenza di ipoglicemia (%) Incidence of hypoglicaemia (%) Intensive therapy Standard therapy 2,5 2,0 1,5 1,0 0,5 0,0 1ACCORD Severe hypoglycemia Study Group N Engl J Med 2008; 358:2545-2559. 2ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-2572 Results of the VADT study: predictors of mortality for CV causes Risk of death lower higher RR (Confidence limit) Hypoglycemia HbA1c HDL-C Age Previous event *P=0,01; **P=0,02; ***P<0,01 Abraira C. 68th Meeting of American Diabetes Association; 6-10 June 2008, San Francisco, USA Summary • Diabetes is associated with an increased risk of SCD, at least in part, from an increased presence and extent of coronary atherosclerosis (macrovascular disease). • Diabetes also is associated with microvascular disease and autonomic neuropathy; and, these non-coronary atherosclerotic pathophysiologic processes also have the potential to increase the risk of SCD • Atherosclerosis is a major contributor to the increased SCD risk associated with diabetes • Prediction of SCD in this “high” risk population is likely to remain a challenge • Recommendations for the prevention of SCD in the community, related to both lifestyle prescriptions and risk factor reduction, are likely to reduce mortality from SCD among patients with diabetes