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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