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Stefano Genovese Dipartimento Cardiovascolare e Metabolico

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.

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Stefano Genovese Dipartimento Cardiovascolare e Metabolico

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  1. MORTE IMPROVVISA NEI DIVERSI GRUPPI DI PAZIENTISUDDEN DEATH IN VARIOUS PATIENT POPULATIONSNel diabeteIn Diabetes Stefano Genovese Dipartimento Cardiovascolare e Metabolico

  2. Causes of death in the ACCORD Study ACCORD Study Group et al. NEJM 2008;358:2545-59

  3. Cardiovascular Disease Is Primary Cause of Death in Persons with Mental Illness* *Average data from 1996-2000. 40 30 Percentage of deaths 20 10 0 Oklahoma RhodeIsland Texas Utah Missouri Heart Disease Cerebrovascular Cancer 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

  4. 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 JCardiol 1986 57: 1410

  5. 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 KullerLet al. Medicine 1967; 46: 341

  6. Epidemiology of SCD - USA Zheng ZJ et al. Circulation. 2001;104:2158-2163

  7. Sudden cardiac deaths and diabetes mellitusThe Framingham cohort Fox CS et al. Circulation 2004; 110: 522

  8. Mechanisms of SCD in Diabetes • Silent ischemia • Autonomic dysfunction • QT interval prolongation • Autonomic neuropathy and QT interval • Hypoglycaemia • Hypercoaguable state • Diabetic cardiomyopathy • Impaired respiratory response

  9. 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

  10. Incidence of SCD after MI Junttila MJ et al. HeartRhythm 2010; 7:1396 –1403

  11. Incidence of SCD after MI Junttila MJ et al. HeartRhythm 2010; 7:1396 –1403

  12. 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. Autonomiccardiacdysfunction in diabetictransplantrecipientssuccumbingtosuddencardiacdeath. Transplantation, 1995; 59: 634–637 • RathmannWet al. Mortality in diabeticpatientswithcardiovascularautonomicneuropathy. DiabetMed, 1993; 10: 820–824 • Ewing DJ et al. Autonomicneuropathy, QT intervallengthening, and unexpecteddeaths in male diabeticpatients. Diabetologia, 1991; 34: 182–185 • Ewing DJ et al. The naturalhistoryofdiabeticautonomicneuropathy. QJ Med, 1980; 49: 95–108

  13. 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. JNeurolNeurosurgPsychiatry 2005;76:240–245

  14. 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 Ret al. DiabetMed, 1993; 10: 920–924 2. Veglio M, et al. JInternMed, 2002; 251: 317–324 3. Veglio M, et al. Diabetes Care, 2000; 23: 1381–1383

  15. QTc interval increases risk of SCD in diabetic patients Whitsel EA, et al. Diabetes Care, 2005; 28: 2045–2047

  16. 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. DiabetMed, 1997; 14: 648–654 Landstedt-HallinLet al. JInternMed, 1999; 246: 299–307 Robinson RT et al. Diabetes, 2003; 52: 1469–1474

  17. Intensive therapy and hypoglicaemia in the ACCORD and ADVANCE Study ACCORD1 ADVANCE2 Intensive therapy Standard therapy Terapia intensiva Terapia standard P < 0,001 P < 0,001 3,0 P < 0,001 2,5 2,0 Incidenza di ipoglicemia (%) Incidence of hypoglicaemia (%) 1,5 1,0 0,5 0,0 Request medical assistance Request medical assistance Severe hypoglycemia 1ACCORD Study Group N Engl J Med 2008; 358:2545-2559. 2ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-2572

  18. 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

  19. 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

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