US Pharm. 2013;38(2):38-42.
ABSTRACT: Sudden cardiac death (SCD) has been associated with
diabetes, although it is unclear whether diabetes is a risk factor for
SCD. Diabetes is a risk factor for common preventable comorbidities
associated with SCD, including coronary artery disease (CAD), myocardial
infarction, and heart failure. Researchers are seeking ways to measure
susceptibility to SCD, but because of SCD’s multifactorial development,
most likely no single test will be able to identify at-risk individuals.
Until tests with proven predictive value are available, preventive
efforts should focus on slowing the progression or development of
cardiovascular diseases that frequently cause SCD. This can be
accomplished by promptly initiating ACE inhibitors, angiotensin receptor
blockers, beta-blockers, antiplatelet agents (aspirin), and possibly
statin therapy for CAD, hypertension, and/or hypercholesterolemia. SCD
prevention strategies for the general population are the same as those
for patients with diabetes.
Sudden cardiac death (SCD) is an event that can occur in asymptomatic
individuals, as well as in those with advanced cardiovascular (CV)
disease.1 SCD typically manifests as a structural abnormality
coupled with a disturbance in cardiac electrical activity that leads to
fatal arrhythmias.1,2 However, in 5% to 10% of SCD cases, no definable structural cardiac abnormality exists.3
Patients may either be asymptomatic or experience symptoms including
palpitations, chest pain or discomfort, dyspnea, fatigue, or syncope.3-5
Sudden cardiac arrest (SCA), in which an electrical malfunction causes
the heart to stop abruptly, may occur in these patients; if the heart is
not quickly shocked back into rhythm, SCD ensues. At least 90% to 95%
of SCA cases in the community setting end in death before the patient
receives medical assistance.3,6
In the United States, the annual number of SCDs is estimated to be
between 250,000 and 300,000, with a predominance in males and an
increased incidence with age for both genders.1,3,6,7 SCD is
the first cardiac event in approximately 55% of men and 68% of women,
while in other cases SCD follows multiple cardiac events.2,6
Unfortunately, the prevalence of SCD is difficult to determine since
there previously was no unified definition of the condition. In general,
SCD is defined as unexpected death occurring within a specific time
frame after initial onset of cardiac symptoms.8 Depending
upon the study being reviewed for SCD, the time frame between symptom
onset and death varies greatly, from less than 1 hour up to 24 hours.
The most common preventable comorbidities associated with SCD include
coronary artery disease (CAD), myocardial infarction (MI), and heart
failure (HF).1 Since diabetes is a risk factor for these
comorbidities, it has been deemed to have an association with SCD. The
association between diabetes and SCD may involve a combination of
macrovascular and microvascular complications that can affect the
electrical system controlling cardiac rhythm, thus increasing the
propensity for SCD.9,10 With the number of diabetes patients
growing in epidemic proportions (approximately 29.9 million in the
U.S.), there is an urgent need to determine whether having diabetes
increases one’s risk for SCD.11
Approximately 80% of SCD cases have underlying CAD; 90% of cases have arrhythmias which may be caused by CAD.5,8,12-14
CAD exhibits a direct role in SCD, although the exact mechanism
provoking the condition is unclear and may be multifactorial. The study
with perhaps the most insight into the relationship between SCD and
macrovascular disease is the Framingham Heart Study, in which long-term
trends in CAD and SCD were evaluated. A Framingham multivariate risk
index combined several CV risk factors (e.g., systolic blood pressure,
total cholesterol, relative weight) with other CAD risk factors (e.g.,
age, smoking, heart rate [HR], vital capacity, ECG abnormalities) to
predict SCD risk.9 The predicted risk of SCD increased with
the addition of each risk factor. However, at 15-year follow-up, the
number of SCDs was significantly lower than was predicted through the
risk index. Thus, the Framingham risk index may be an acceptable tool
overall for risk prediction in the general population, but perhaps less
useful for individual risk prediction until more specific predictors of
SCD are identified.3
Cardiac Autonomic Neuropathy (CAN): Chronic hyperglycemia contributes to progressive autonomic neural dysfunction.15 Patients with CAN typically experience resting tachycardia and less HR variability during exercise.10
CAN is characterized initially by an early increase of cardiac
sympathetic activity, which leads to apoptosis and myocardial injury.15
Patients with diabetes-related CAN have increased mortality compared
with patients with nondiabetes-related CAN, and they are more likely to
develop arrhythmias, cardiomyopathy, silent ischemia, and subsequent
SCD.9,10,15 Patients would benefit from learning how to
recognize less distinct signs of ischemia, such as dyspnea with or
without cough, extreme fatigue, and sudden onset of nausea and vomiting.
In the Diabetes Control and Complications Trial, intensive glycemic
control slowed CAN’s development and progression and reduced the
progression of atherosclerosis and microvascular disease in patients
with type 1 diabetes (T1DM).1,9,16 This has not been
demonstrated in type 2 diabetes (T2DM) patients, however. Additionally,
SCD was not directly assessed in this trial. Furthermore, it has since
been found that glycemic control that is too intensive may increase
mortality.17 Data are inconclusive regarding intensive
glycemic control and reduced risk of CAN in patients with T2DM. However,
if possible, intensive glycemic control should be recommended in T1DM
patients to reduce the risk of CAN.
Silent Ischemia: Silent ischemia is a painless
condition in which narrowed or blocked arteries prevent oxygen-rich
blood from reaching the heart. Diabetes patients, particularly those
with CAN, are at increased risk for developing silent ischemia, which
eventually may lead to SCD secondary to arrhythmias.8,10 However, no studies clearly demonstrate the risk of SCD due to silent ischemia in patients with diabetes.
QT-Interval Prolongation: The Rotterdam Heart
Study and the Oregon Sudden Unexpected Death Study provided evidence
that prolonged QT intervals heighten the risk of SCD in the general
population.1,4,5,18,19 QT-interval prolongation is common in
diabetes, particularly in CAN patients, although the mechanism behind
this association is unclear.8,19 QT-interval prolongation has
been indicated as an independent predictor of mortality and has been
associated with a suspected increase in risk of SCD in diabetes
patients; however, further research is necessary to determine the
association between QT prolongation and SCD in patients with diabetes.8,9
HF: Systolic dysfunction—particularly left
ventricular ejection fraction (LVEF) below 30% to 35%—increases the risk
of SCD in the general population, but little is known about the effect
of diastolic dysfunction on SCD risk.1,4,8 Patients with less
severe HF are more likely to die from SCD, whereas those with more
severe HF (i.e., New York Heart Association [NYHA] Class IV) are more
likely to die from pump failure.4,20 However, since the NYHA
classification can rapidly fluctuate between Class I and Class IV, this
approach only estimates functional consequences, so the usefulness of HF
classification as a marker for risk of SCD is minimal. In a post hoc
analysis of the Valsartan in Acute Myocardial Infarction Trial, LVEF was
a strong predictor of SCD, which increased by 21% with every 5%
reduction in ejection fraction.20,21 Left ventricular systolic dysfunction is established as a strong predictor of SCD.6,21
Microvascular disease caused by diabetes may result in autonomic
neuropathy, which may lead to QT-interval prolongation. Optimal glycemic
control reduces the incidence of microvascular disease, but at the risk
of increased hypoglycemic events.8,16,17,22 Frequent hypoglycemia has been indicated as a potential contributor to SCD.15
Intensive glycemic control may reduce the risk of diabetes complications, but it also increases the incidence of hypoglycemia.8,16,17,22 Even a single hypoglycemic event can impair hormonal and autonomic responses to subsequent events.8,17
Once hormonal and autonomic responses to hypoglycemia are impaired,
hypoglycemia unawareness or asymptomatic hypoglycemia may ensue. This
impaired response may induce transient QT prolongation and promote a
reduced threshold for arrhythmias and, subsequently, SCD.8,15
Based on autopsy reports, thrombus, plaque disruption, or both occur in more than 50% of SCD cases.14 When stable atherosclerotic plaques fissure, platelet activation and aggregation occur, resulting in thrombosis.14 Plaque rupture occurs more often in women, particularly those of advanced age.14
Distribution of coronary artery lesions does not appear to play a
substantial role in SCD development. However, acute thrombosis was
observed two to three times more often in smokers than in nonsmokers,
likely because of an increase in platelet adhesiveness.14 SCD
was much more likely to occur in current cigarette smokers,
underscoring the importance of tobacco cessation. The increased risk of
SCD development in diabetes patients through early coronary
atherosclerosis and thrombosis appears to be theoretical.9,10
Family history may be a significant risk factor for SCD, according to
the Paris Prospective Study I (PPSI), a 23-year analysis of CV outcomes
in 7,746 asymptomatic middle-aged men.23 In this study, diabetes and parental history of SCD were identified as independent risk factors for SCD.1,23,24
Multifactorial statistical analyses of PPSI indicated that the relative
risk (RR) for development of SCD in offspring was 1.8 if only one
parent experienced SCD; however, the RR rose to 9.4 if both parents had a
positive family history.4,13,23,24 Thus, it appears that the
risk of SCD is heightened in diabetes patients and in patients with a
family history of SCD. Currently, researchers are examining ways to
measure genetic susceptibility to SCD, but because of the multifactorial
development of SCD, it is likely that no single test will be able to
identify at-risk individuals.
It is understood that most patients with underlying CAD are at
greater risk for SCD, and most efforts to stratify SCD risks have
focused on patients with known CAD. However, there are no standardized
recommendations for predicting risk in patients who have no underlying
structural heart disease. Since SCD is multifactorial, prediction of
individual risk is more difficult.3 Researchers have reviewed
numerous markers for potential predictors of fatal arrhythmias,
including QT dispersion, HR variability, and inflammatory markers such
as C-reactive protein; however, they have not performed well as
predictors of SCD.3 Diabetes, while currently recognized as a clinical risk marker, is not used for risk stratification to predict SCD.6
Only left ventricular systolic dysfunction is an established clinical
risk predictor of SCD, but it is an effective predictor only in patients
with a substantial reduction in LVEF.6 In an effort to
elucidate the prevalence and risk of SCD, the National Heart, Lung, and
Blood Institute and the Heart Rhythm Society have developed a unified
definition for future studies (TABLE 1).6
Because of the sudden and unpredictable nature of SCD, risk
stratification continues to be an area of interest. The Framingham study
revealed a 49% decline in SCD between 1990 and 1999 versus between 1950
and 1969, possibly because of the increased use of preventive agents
and/or devices for CV morbidity and mortality.25 Automated external defibrillators, which became available in the 1970s, may have contributed to the decline in SCD prevalence.25
Implantable cardioverter defibrillators (ICDs), which were not
routinely used until the 1990s, are recommended to prevent SCD in
high-risk patients (e.g., prior MI, left ventricular dysfunction).1,4,9,26
Although the cost-effectiveness of ICDs as a population-based
prevention strategy has been questioned, these devices remain a mainstay
of SCD prevention.6
Theoretically, since the vast majority of deaths attributed to SCD
involve underlying CAD, controlling the risk factors should indirectly
reduce SCD incidence. In fact, many methods of SCD prevention have
focused on slowing the progression or development of CV diseases that
frequently cause SCD.6,26 Since patients with diabetes and
those who experience SCD share risk factors such as CAD,
hypercholesterolemia, and hypertension, controlling the comorbid
conditions associated with diabetes should, by default, lessen the risk
of SCD in diabetes patients. Pharmacologic agents believed to improve CV
longevity include ACE inhibitors, beta-blockers, and antiplatelet
agents (aspirin).9,26 Drugs that modulate the
renin-angiotensin-aldosterone system, such as ACE inhibitors and
angiotensin receptor blockers, are thought to have indirect
antiarrhythmic effects and therefore may be useful for preventing SCD.27 Beta-blockers—in particular, carvedilol—prevent SCD in CAD and HF.27
Statins may help reduce SCD incidence by slowing the progression of CV
disease; however, few data demonstrate an overall beneficial effect on
SCD prevention.1 Interestingly, Class 1 antiarrhythmics (TABLE 2)
are not recommended for SCD prevention, based on unexpected outcomes of
the Cardiac Arrhythmia Suppression Trial (CAST) and CAST II, in which
CAD patients using these agents had an increased risk of death.14,27 Class IV antiarrhythmics have limited use in preventing SCD, but Class III may be considered for this purpose.27
Nonpharmacologic prevention strategies include weight reduction,
dietary education, smoking cessation, stress management, physical
activity, and ICDs (in high-risk patients).1,4,6,9,14,26
It is difficult to ascertain whether diabetes is a direct risk factor
for SCD. The notion that diabetes results in enhanced susceptibility to
SCD is generally accepted, but is not evidence based. Therefore,
although diabetes is recognized as a clinical risk marker for SCD, it is
not currently used for risk stratification. If the incidence of SCD is
greater in patients with diabetes, the root cause remains unclear.
Overall, mortality remains high, most likely owing to the unexpectedness
of the event and failure to recognize warning symptoms in a timely
manner. Thus, it is critically important to develop prediction and
prevention strategies for SCD.
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