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Epidemiology of sudden cardiac death
News and Views
675
Parag Barwad, MD, DM; Nitish Naik, MD, DM
Department of Cardiology,All India Institute of Medical Sciences, New Delhi, India
Forthcoming Events
677
Abstract
Introduction
Sudden cardiac death (SCD) is an important cause of
cardiovascular morbidity and mortality in both developed and
developing countries. Coronary artery disease remains the
most important cause for SCD imajority of adults. Other
structural cardiac abnormalities including dilated
cardiomyopathy, hypertrophic cardiomyopathy and
arrhythmogenic right ventricular cardiomyopathy are
important diseases associated with SCD. Primary electrical
disorders including long QT Syndrome, Brugada syndrome,
short QT syndrome, etc are associated with significant risk
of SCD.
Sudden cardiac death (SCD) is a major cardiovascular
health problem which frequently occurs during prime years
of life. As coronary artery disease (CAD) is the dominant
cause for cardiovascular disease, CAD accounts for more
1–4
than half of deaths due to SCD. Furthermore, since the
south Asian population has a high prevalence of coronary
risk factors, and have CAD at earlier age compared to
developed countries, SCD proportionately occurs in
younger individuals.5,6 It has also been estimated that by the
end of present decade, 60% of world’s heart disease is
expected to occur in India7 and proportionately the
incidence and prevalence of SCD is expected to rise.
Key Words
•
Sudden cardiac death
•
Coronary artery disease
•
Primary electrical disorders
•
Ventricular tachycardia
Though there has been major advances in cardiopulmonary
resuscitation8 and post-resuscitation care, survival to
hospital discharge amongst patients of SCD even in the
best of centres remain poor.9 In the majority of developing
world including India, there does not exists a first
responder service of the kind to deliver advance cardiac life
support for sudden cardiac arrest patients as in developed
nations. Thus, a clear epidemiological picture of SCD in
developing nations is lacking.
Past few decades have witnessed a tremendous progress
towards understanding of SCD and in its prevention and
management. Applying this in clinical practice has led to a
huge surge in utilization of automated external defibrillator
(AED) and implantable cardioverter-defibrilator (ICD).
However, SCD still remains a major public health problem
as majority of death caused by SCD occurs in population
10,11
with no prior diagnosis of heart disease.
Also, risk
stratifying an individual based on criteria laid down by
clinical trials and cohort study lacks specificity.
Received: 26-02-14; Revised: 12-09-14; Accepted: 10-10-14
Disclosures: This article has not received any funding and has no vested commercial interest
Acknowledgements: None
Please send in your letters to the Editor at [email protected]
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
639
Naik N, et al
In 1940’s Dawber and his co-workers pioneered
epidemiological and population based approach to
investigate cardiovascular disease. Framingham heart
study and Seven countries study were the initial studies
which provided the community based data on incidence,
course and prognosis of cardiovascular disease and also
helped us understand the risk factors and pathogenesis of
disease.12 Since then the maximum knowledge on SCD
including the genetic origin has come from
epidemiological studies.
n
Definition and incidence
SCD is unexpected death that occurs within one hour from
the start of symptoms when death is witnessed, and within
24 hours of being seen alive and well when it is
unwitnessed.13 The majority of SCD’s are not witnessed
and if witnessed information is obtained, it is unreliable.
Furthermore, in many cases the records are unavailable,
autopsies are not performed, and the cause of death given
on the death certificate is speculative.2,10,14 The incidence of
SCD in the USA ranges from 180,000 to 450,000 cases
annually.15 These estimates vary according to the definition
applied and the surveillance method used to determine the
incidence.15,16 Majority of these estimates are based on
retrospective assessment and the assumption that all out of
hospital death for which CAD is suspected as a cause are
SCD. Such a strategy, though sensitive, lacks specificity
and leads to overestimation of the true incidence of SCD.
Conversely, restricting the definition of SCD to death
within 1 hour of symptom onset will lead to
underestimation of incidence.17–19 Thus multiple sources of
ascertainment are required to determine the true incidence
of SCD. Recent prospective studies from the United
States,20,21 Ireland22 and China23 have shown incidences of
SCD to range from 50 to 100 per 100,000 in general
population. Furthermore, SCD occurred in 6.8% of
patients in Framingham Heart Study and 4.4% of patients
in Paris Prospective Study.24–26 Prevalence study from
southern India shows10%–17% of total deaths to be caused
by SCD with CAD contributing to 75% of SCD’s.27
Although improvement in the primary and secondary
prevention strategies have resulted in significant reduction
in CAD related mortality28 in the developed nations, SCD
rate has not declined substantially.25,29–31 This is because in
hospital mortality has declined more rapidly than out of
hospital mortality. Therefore, SCD now accounts for >50%
of cardiovascular mortality.29 As no such declining trend in
CAD related mortality is seen in India, but on the contrary
shows a rising trend, SCD related deaths are projected to
rise in future.
640
n
Demographic features
The age distribution of SCD demonstrate peak during
infancy and after the age of 45 years. Age is the principal
determinant of incidence of SCD irrespective of sex and
race. This is because it mirrors the risk of CAD with
increasing age.11,21 For example, incidence for 50-year-old
men is 100 per 100000 when compared with 800 per
100000 for 75-year-old.32 In younger population (<30 years
of age), however, the common causes of SCD are
cardiomyopathies, coronary anomalies, arrhythmogenic
disorders, and drug abuse rather than CAD.33 At any age
women have a lesser incidence of SCD than men, even
after adjustment of CAD risk factors.34,35 This difference in
mortality decreases with increasing age, probably related
to post menopausal increase in CAD in women. The overall
decline in SCD rate in developed nation is less amongst
women, particularly in younger age group. This is probably
because of lower overall burden of CAD in women.36–38 In
addition, in survivors of SCD, women are found to have
more structurally normal heart.39,40
Racial difference in the incidence of SCD is not thoroughly
investigated. The available data from death certificate
suggest that, for both sexes, SCD is more among black
American population than white population.29,31 Black
patients suffering from SCD are less likely to survive after
hospital discharge post cardiopulmonary resuscitation
(CPR) compared to white population.41 Blacks are also
more likely to have unwitnessed arrest with unfavorable
rhythm such as pulseless electrical activity at the time of
arrest.32,37 This disparity in racial outcome is partly
contributed by socioeconomic influence and not purely
because of genetic predisposition.
Temporality and rhythm variation
Around 80% of all SCD’s occur at home and 60% of it is
unwitnessed.36,42–44 Subsequently, the proportion of patients
receiving CPR after a SCD is less as this is more likely to
occur in public. Studies have also shown that SCD’s are
predominantly seen on Monday and are concentrated
during early hours of day (05:00 a.m. to 09:00 a.m.).45–48
These variations are related to increased adrenergic drive
during the period.
Rhythm abnormality thought to cause SCD is
predominantly ventricular tachyarrhythmia. In a study
evaluating the rhythm abnormality in patients of SCD
found 70% of them having ventricular tachycardia or
fibrillation if detected within 3 min of cardiac arrest which
declines to 43% if detected later in the event.49 The other
rhythms found in patients are asystole in 18% and pulseless
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
Epidemiology of SCD
electrical activity in 11%. A recent study has shown a trend
towards reduction in the incidence of ventricular
tachyarrhythmias (contributing to 41% of SCD events).50
The reason for this change is conjectural and may be related
to aging of population with higher prevalence of death due
to heart failure and less due to SCD.
Pathophysiology of SCD
Pathophysiology of SCD is complex and involves an
interaction between the baseline substrate for SCD and the
inciting event. This leads to the electrical instability in the
myocardium culminating in final common pathway of
ventricular tachyarrhythmia and cardiovascular collapse. A
variety of risk factors are proposed with CAD contributing
upto 75% of SCD.36,51–53 Other disease contributing to SCD
are cardiomyopathies (dilated or hypertrophied),
arrhythmogenic right ventricular cardiomyopathy, primary
electrical disorder of heart (channelopathies).51 In around
5% of patients even after detailed evaluation and autopsy,
the cause and mechanism of SCD cannot be
ascertained.39,54,55 CAD predisposes to SCD by three
principal mechanisms: (1) acute myocardial infarction, (2)
ischemia of myocardium, (3) ventricular remodelling and
scar formation.
Mechanism of SCD in myocardial infarction
Acute ST elevation myocardial infarction (MI) is
associated with SCD. The risk of SCD in acute MI is
maximum during the first 30 days and this gradually
decreases with time.56–58 Among the survivors of MI who
have left ventricular dysfunction the risk of SCD is
reported to be 1.4% in the initial 30 days and declines to
0.14% per month after 2 years.57 In population based
studies, the risk of SCD after a MI is 1.2% in the first month
and exceeds the overall population risk markedly.56
Thereafter, the risk of SCD declines to 1.25% per year. This
decline is attributable to application of secondary
prevention strategies which are widely applied in
developed nations.
Arrhythmias occurring during the initial 24 hours of MI are
not considered predictor of SCD. But this concept has now
been challenged.59 A study demonstrated worse outcomes
in patients with both early and late ventricular arrhythmias.
Therefore, it is now recommended to assess for ventricular
function 6 weeks after MI to assess need for primary
prevention with an ICD. It has also been shown that
ventricular tachycardia induced during programmed
electrical stimulation after MI done for risk stratification
also predicts risk for SCD and these patients may benefit
from ICD implantation.60
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
Epidemiology of SCD in patients with MI has changed
significantly in the past few decades. The incidence of SCD
has decreased in parallel to decline in the CAD related
mortality. Study of 1980s have shown 10% of MI survivors
dying suddenly in the subsequent four years.61 This
proportion has declined to less than 1% per year in patients
receiving appropriate secondary prevention strategy and
revascularization procedure. Moreover, in earlier studies
40–50% of post MI deaths61,62 were because of SCD but the
proportion has declined to 20–30% in present
contemporary studies.56,63,64
Magnitude of risk for SCD changes over time in patients
after MI. The various determinants are LV remodeling,
anatomical and electrophysiological properties of
myocardial scar and progression of CAD.65 The risk of
SCD beyond the first 30 days after MI is markedly
increased by the presence of concomitant heart failure and
ischemic events.46,62,64,66,67
n
Risk factors of SCD
Clinical risk predictors
CAD contributes predominantly to the population of SCD.
In fact, in around 50% of patients with CAD, the first
clinical manifestation is a SCD.36 The risk factors for SCD
are also predictors of CAD-related death and all-cause
mortality.65 The various risk factors common to both CAD
and SCD are older age, male sex, cigarette smoking,
hypertension, diabetes mellitus, hypercholesterolemia,
obesity, and family history of CAD.10,67,68–70 These risk
factors are powerful predictors at a population level; they
are not specific enough to determine risk in an individual
patient because of relatively low event rates (i.e., low
absolute risk).
Additional risk factors, such as left ventricular
hypertrophy, left ventricular dysfunction, heart failure,
poor functional status, elevated heart rate, an abnormal
electrocardiogram, and abnormal autonomic markers, also
lack the specificity to discriminate SCD from other noncardiac death.3,10,71–74 Those who are high risk of arrhythmias
contribute to only a very small proportion of SCD.13 Thus
identification of an individual at high risk of SCD requires
multimarker strategy. A multivariable risk algorithm has
been proposed for risk stratifying individuals for SCD.71,72
The variable taken into consideration are age, history of
heart failure, LV ejection fraction, ventricular arrhythmias,
functional class, and presence of atrial fibrillation.
However, the performance of these algorithms for
predicting SCD has not been evaluated in any prospective
studies.
641
Naik N, et al
In 1940’s Dawber and his co-workers pioneered
epidemiological and population based approach to
investigate cardiovascular disease. Framingham heart
study and Seven countries study were the initial studies
which provided the community based data on incidence,
course and prognosis of cardiovascular disease and also
helped us understand the risk factors and pathogenesis of
disease.12 Since then the maximum knowledge on SCD
including the genetic origin has come from
epidemiological studies.
n
Definition and incidence
SCD is unexpected death that occurs within one hour from
the start of symptoms when death is witnessed, and within
24 hours of being seen alive and well when it is
unwitnessed.13 The majority of SCD’s are not witnessed
and if witnessed information is obtained, it is unreliable.
Furthermore, in many cases the records are unavailable,
autopsies are not performed, and the cause of death given
on the death certificate is speculative.2,10,14 The incidence of
SCD in the USA ranges from 180,000 to 450,000 cases
annually.15 These estimates vary according to the definition
applied and the surveillance method used to determine the
incidence.15,16 Majority of these estimates are based on
retrospective assessment and the assumption that all out of
hospital death for which CAD is suspected as a cause are
SCD. Such a strategy, though sensitive, lacks specificity
and leads to overestimation of the true incidence of SCD.
Conversely, restricting the definition of SCD to death
within 1 hour of symptom onset will lead to
underestimation of incidence.17–19 Thus multiple sources of
ascertainment are required to determine the true incidence
of SCD. Recent prospective studies from the United
States,20,21 Ireland22 and China23 have shown incidences of
SCD to range from 50 to 100 per 100,000 in general
population. Furthermore, SCD occurred in 6.8% of
patients in Framingham Heart Study and 4.4% of patients
in Paris Prospective Study.24–26 Prevalence study from
southern India shows10%–17% of total deaths to be caused
by SCD with CAD contributing to 75% of SCD’s.27
Although improvement in the primary and secondary
prevention strategies have resulted in significant reduction
in CAD related mortality28 in the developed nations, SCD
rate has not declined substantially.25,29–31 This is because in
hospital mortality has declined more rapidly than out of
hospital mortality. Therefore, SCD now accounts for >50%
of cardiovascular mortality.29 As no such declining trend in
CAD related mortality is seen in India, but on the contrary
shows a rising trend, SCD related deaths are projected to
rise in future.
640
n
Demographic features
The age distribution of SCD demonstrate peak during
infancy and after the age of 45 years. Age is the principal
determinant of incidence of SCD irrespective of sex and
race. This is because it mirrors the risk of CAD with
increasing age.11,21 For example, incidence for 50-year-old
men is 100 per 100000 when compared with 800 per
100000 for 75-year-old.32 In younger population (<30 years
of age), however, the common causes of SCD are
cardiomyopathies, coronary anomalies, arrhythmogenic
disorders, and drug abuse rather than CAD.33 At any age
women have a lesser incidence of SCD than men, even
after adjustment of CAD risk factors.34,35 This difference in
mortality decreases with increasing age, probably related
to post menopausal increase in CAD in women. The overall
decline in SCD rate in developed nation is less amongst
women, particularly in younger age group. This is probably
because of lower overall burden of CAD in women.36–38 In
addition, in survivors of SCD, women are found to have
more structurally normal heart.39,40
Racial difference in the incidence of SCD is not thoroughly
investigated. The available data from death certificate
suggest that, for both sexes, SCD is more among black
American population than white population.29,31 Black
patients suffering from SCD are less likely to survive after
hospital discharge post cardiopulmonary resuscitation
(CPR) compared to white population.41 Blacks are also
more likely to have unwitnessed arrest with unfavorable
rhythm such as pulseless electrical activity at the time of
arrest.32,37 This disparity in racial outcome is partly
contributed by socioeconomic influence and not purely
because of genetic predisposition.
Temporality and rhythm variation
Around 80% of all SCD’s occur at home and 60% of it is
unwitnessed.36,42–44 Subsequently, the proportion of patients
receiving CPR after a SCD is less as this is more likely to
occur in public. Studies have also shown that SCD’s are
predominantly seen on Monday and are concentrated
during early hours of day (05:00 a.m. to 09:00 a.m.).45–48
These variations are related to increased adrenergic drive
during the period.
Rhythm abnormality thought to cause SCD is
predominantly ventricular tachyarrhythmia. In a study
evaluating the rhythm abnormality in patients of SCD
found 70% of them having ventricular tachycardia or
fibrillation if detected within 3 min of cardiac arrest which
declines to 43% if detected later in the event.49 The other
rhythms found in patients are asystole in 18% and pulseless
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
Epidemiology of SCD
electrical activity in 11%. A recent study has shown a trend
towards reduction in the incidence of ventricular
tachyarrhythmias (contributing to 41% of SCD events).50
The reason for this change is conjectural and may be related
to aging of population with higher prevalence of death due
to heart failure and less due to SCD.
Pathophysiology of SCD
Pathophysiology of SCD is complex and involves an
interaction between the baseline substrate for SCD and the
inciting event. This leads to the electrical instability in the
myocardium culminating in final common pathway of
ventricular tachyarrhythmia and cardiovascular collapse. A
variety of risk factors are proposed with CAD contributing
upto 75% of SCD.36,51–53 Other disease contributing to SCD
are cardiomyopathies (dilated or hypertrophied),
arrhythmogenic right ventricular cardiomyopathy, primary
electrical disorder of heart (channelopathies).51 In around
5% of patients even after detailed evaluation and autopsy,
the cause and mechanism of SCD cannot be
ascertained.39,54,55 CAD predisposes to SCD by three
principal mechanisms: (1) acute myocardial infarction, (2)
ischemia of myocardium, (3) ventricular remodelling and
scar formation.
Mechanism of SCD in myocardial infarction
Acute ST elevation myocardial infarction (MI) is
associated with SCD. The risk of SCD in acute MI is
maximum during the first 30 days and this gradually
decreases with time.56–58 Among the survivors of MI who
have left ventricular dysfunction the risk of SCD is
reported to be 1.4% in the initial 30 days and declines to
0.14% per month after 2 years.57 In population based
studies, the risk of SCD after a MI is 1.2% in the first month
and exceeds the overall population risk markedly.56
Thereafter, the risk of SCD declines to 1.25% per year. This
decline is attributable to application of secondary
prevention strategies which are widely applied in
developed nations.
Arrhythmias occurring during the initial 24 hours of MI are
not considered predictor of SCD. But this concept has now
been challenged.59 A study demonstrated worse outcomes
in patients with both early and late ventricular arrhythmias.
Therefore, it is now recommended to assess for ventricular
function 6 weeks after MI to assess need for primary
prevention with an ICD. It has also been shown that
ventricular tachycardia induced during programmed
electrical stimulation after MI done for risk stratification
also predicts risk for SCD and these patients may benefit
from ICD implantation.60
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
Epidemiology of SCD in patients with MI has changed
significantly in the past few decades. The incidence of SCD
has decreased in parallel to decline in the CAD related
mortality. Study of 1980s have shown 10% of MI survivors
dying suddenly in the subsequent four years.61 This
proportion has declined to less than 1% per year in patients
receiving appropriate secondary prevention strategy and
revascularization procedure. Moreover, in earlier studies
40–50% of post MI deaths61,62 were because of SCD but the
proportion has declined to 20–30% in present
contemporary studies.56,63,64
Magnitude of risk for SCD changes over time in patients
after MI. The various determinants are LV remodeling,
anatomical and electrophysiological properties of
myocardial scar and progression of CAD.65 The risk of
SCD beyond the first 30 days after MI is markedly
increased by the presence of concomitant heart failure and
ischemic events.46,62,64,66,67
n
Risk factors of SCD
Clinical risk predictors
CAD contributes predominantly to the population of SCD.
In fact, in around 50% of patients with CAD, the first
clinical manifestation is a SCD.36 The risk factors for SCD
are also predictors of CAD-related death and all-cause
mortality.65 The various risk factors common to both CAD
and SCD are older age, male sex, cigarette smoking,
hypertension, diabetes mellitus, hypercholesterolemia,
obesity, and family history of CAD.10,67,68–70 These risk
factors are powerful predictors at a population level; they
are not specific enough to determine risk in an individual
patient because of relatively low event rates (i.e., low
absolute risk).
Additional risk factors, such as left ventricular
hypertrophy, left ventricular dysfunction, heart failure,
poor functional status, elevated heart rate, an abnormal
electrocardiogram, and abnormal autonomic markers, also
lack the specificity to discriminate SCD from other noncardiac death.3,10,71–74 Those who are high risk of arrhythmias
contribute to only a very small proportion of SCD.13 Thus
identification of an individual at high risk of SCD requires
multimarker strategy. A multivariable risk algorithm has
been proposed for risk stratifying individuals for SCD.71,72
The variable taken into consideration are age, history of
heart failure, LV ejection fraction, ventricular arrhythmias,
functional class, and presence of atrial fibrillation.
However, the performance of these algorithms for
predicting SCD has not been evaluated in any prospective
studies.
641
Naik N, et al
Post-mortem analyses in patients of SCD
Autopsy studies in patients with SCD have shown 80% of
patients having concomitant CAD.10,75 Predominant
findings are intracoronary complicated plaque (rupture
with or without thrombus formation) and myocardial
scar.75,76 These findings suggest an acute coronary event or a
previous MI causing scar as a substrate for
tachyarrhythmia and SCD. Other uncommon findings are
interstitial fibrosis, infiltration (amyloid deposition),
inflammation, and ventricular hypertrophy.77,78 However, in
5–10% of cases of SCD the cause cannot be determined
even after autopsy analysis.2,3,10
Heart failure
Overall, as the average survival age is increasing and
quality of medical care is improving, the proportion of
patients with advanced age with multiple comorbidities is
increasing. In the US, 5 million suffer from heart failure
with around 600,000 are added to the count every year.79
Progressive heart failure causes remodeling, leading to
structural and electrical changes in the myocardium and
neuro-hormonal activation. This causes inhomogeneity
and thus leading to substrate for arrhythmogenesis.80
Clinical heart failure increases the risk of SCD by 5 fold
and SCD accounts for 30–50% of all deaths in heart failure
patients.81 But, as the age advances, the proportion of
deaths by SCD decreases and patients dying of progressive
heart failure increases. It has been observed that 63% of
patients with mild heart failure die of SCD as opposed to
33% with advanced heart failure.13 Severe LV dysfunction,
irrespective of the cause is a major predictor of risk to
SCD.82 Thus, LV function <35% is an important criteria for
ICD implantation for primary prevention of SCD. It has
been observed that only 20–30% of ICD recipients receive
appropriate shocks during 4 years of prospective followup. While, in population studies >60% of patients suffering
SCD are found to have either normal LV function or mild
LV dysfunction.83,84 This decreases the overall predictive
efficacy of LV function as a risk marker of SCD.
Electrical predictors of SCD
Various abnormalities on 12 lead electrocardiogram have
been detected which can act as a marker of an underlying
heart disease and may help predict risk of SCD.
Pathological Q waves are a marker of underlying CAD and
dynamic ST, T changes suggest myocardium at high risk of
infarction. R wave amplitude and QRS duration is marker
of Left Ventricular hypertrophy (LVH) or an underlying
cardiomyopathy. Left bundle branch block and LVH are
associated with 1.5 times increased risk of SCD.73,85 Total
642
QRS duration and fragmented QRS are also found to be
associated with increased risk of SCD.86–88 Primary
arrhythmogenic disorders such as long and short QT
syndromes, Brugada syndrome, arhhythmogenic right
ventricular cardiomyoapathy (ARVC), catecholaminergic
polymorphic ventricular tachycardia (CPVT), WolfParkinson-White (WPW) are diagnosed primarily based on
their ECG features. These disorders are rare in the
community but recognizing them by a simple and noninvasive test has a large bearing at an individual level. QT
interval irrespective of the age, sex, heart rate, drug used,
and diagnosis of long or short QT syndromes is a marker of
SCD. The corrected QT interval >440 msec increases the
risk of SCD 2.3 times compared to those with corrected QT
interval <440 msec.89 And, in the absence of drugs causing
QT prolongation this risk increases by 5 folds.90 Other
markers of risk identified on ECG are late potentials on
signal averaged ECG, microvolt T wave alternans, reduced
heart rate variability on holter monitoring and abnormal
heart rate profile on exercise ECG.59,91,92 But these markers
lack specificity while assessing risk for SCD.
Socioeconomic and psychosocial risk predictors
The prevalence of cardiovascular diseases, CAD, and its
mortality is high in low socioeconomic countries.93 The
incidence of out-of-hospital cardiac arrest and SCD are
also higher in areas of socioeconomic deprivation than in
more affluent areas.2,94,95 Various factors influence the
association between low socioeconomic status and SCD.
These are probably related to lower access to health
facility, increased smoking, genetic influences to CAD,
and behavioral influences. Psychological factors
associated with SCD are lifestyle changes, increased stress
in life, and social isolation.9,96 Moreover, history of
psychiatric disease is also associated with increased risk
of SCD.97
Genetic risk predictors
Research in the recent years has seen major advancements
in the field of genetic determinants of SCD.26,98–100 Genetic
basis of primary arrhythmogenic disorders such as LQTs
has been recognized since long. But, application of
knowledge of recent research in genetics and genome wide
analysis (Human Genome Project) has provided the
foundation to identify novel genes and biological pathways
implicated in conduction system disease, cardiac
arrhythmias, and SCD. It has been shown that the risk of
SCD is twice higher in an individual with one of the parents
dying suddenly and it increases to nine-fold if both patients
had SCD.26 These effects are independent of the history of
MI in parents. To some extent it has been shown that SCD is
J. Preventive Cardiology Vol. 4
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Nov 2014
Epidemiology of SCD
an expression of underlying coronary heart disease,
hereditary factors that contribute to coronary heart disease
risk operate non-specifically for the SCD syndrome. But it
has also been shown that family history of SCD and the
cumulative ST deviation are the only two differences
between patients who had SCD with MI compared to those
who had SCD without MI.98 This suggests that the heritable
risk factors play an important role in determining the risk
for SCD irrespective of the CAD risk factors. Furthermore,
the strength of association to SCD increases with
increasing number of relatives affected by SCD. This is
because of the complex genetic architecture, in which
susceptibility alleles increase risk additively.101
In a recent review, Noteworthy et al. describes the genetic
contribution to SCD either by rare variants with strong
effects, rare variants with modest effects, or common
variants with modest effects.92 Rare variants with strong
effect are identified in genes associated with very
uncommon inherited cardiac disease but with very high
risk of ventricular tachyarrhythmia’s and SCD. These
include disease like long and short QT syndromes, Brugada
syndrome and catecholaminergic polymorphic VT.92
However, these mutations are subjected to inherent
negative selection, thus does not contribute significantly to
the burden of disease at population level.92,101
Rare variant with modest effect are less malignant variants
associated with disease like long QT syndrome. They
increase the susceptibility to arrhythmia in general
population. Mutation in gene KCNH2 (HERG) which
encodes for voltage gated potassium channel is found in
around 16% of patients suffering SCD.102 Similar result was
shown in another study where 30% of patients suffering
SCD were found to have mutation linked to LQTs and 14%
of patients having mutation related to Ryanodine receptor
gene (RYR2).103,104 Nurses’ health study also shows 10%
prevalence of SCN5A mutation in patients suffering
SCD.105 However, community based study shows a lower
prevalence of only 6% in SCN5A mutation in patients
suffering SCD. These data support the concept that rare
variants with modest effects might not produce an
identifiable clinical syndrome in isolation, but could
predispose the individual to acquired long QT syndrome
and SCD after exposure to a secondary risk factor, such as a
QT-interval-prolonging medication.92
The common variant with modest effect is most prevalent
in general population. This variant contributes increasingly
to the SCD risk at population level. As this variant remains
unaffected by negative selection and can reach relatively
high allele frequency in the population. For example the
S1102Y variant of the SCN5A was found in 57% of black
J. Preventive Cardiology Vol. 4
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Nov 2014
patients with a history of arrhythmia, syncope, and QT
prolongation versus on in 13% of healthy control
individuals.106 Common genetic variants in isolation are
unlikely to cause SCD, these variants contribute only
incrementally to the overall risk of SCD by reducing
“repolarization reserve” and predisposing some
individuals to SCD through interactions with other risk
factors such as ischemia, hypokalemia, or drug exposure.
As discussed above, genes for QT prolongation has been
consistently associated with risk of SCD in population.10,107
While QT interval adjusted for age, sex, and heart rate is
normally distributed in general population, 35% of its
interval variability is attributable to genetic factors.108 The
common variants such as KCNH2 and NOS1AP influences
QT interval duration. However, these variants have a
modest effect on QT interval at baseline (6 to 12 ms) and an
external influence is necessary to prolong the QT interval
to a degree where the SCD risk increases substantially.
Thus, inheritable factors are partly involved in the
pathogenesis of SCD and the genetic basis of these events
is multifactorial and potentially includes the genetics of
atherothrombosis and plaque stability, among other factors
significantly contributing to SCD.109,110
Triggers for SCD
Occurrence of SCD requires a complex interplay between
the substrate for SCD and its triggering factors which could
be an external or internal trigger. As the majority of SCD
are unwitnessed the possible triggers to the SCD are
difficult to identify, while abnormal substrate can be
determined in most by ante-mortem or post-mortem
analysis. In witnessed SCD the predominant symptoms
prior to SCD are angina, dyspnea, syncope, nausea,
vomiting, and sense of not feeling well.36,42 A study has
shown cigarette smoking and analgesic use as an important
trigger prior to SCD.111 Possible mechanism by which
cigarette smoking leads to SCD are increased platelet
aggregation, catecholamine surge, coronary spasm, plaque
rupture, and increased thrombogenic milieu.112,113 The uses
of analgesic and anti-inflammatory drugs prior to SCD are
probably linked to their sense of feeling unwell. Another
study has shown a lag period of almost 75 min between
symptom onset and SCD when the episodes have occurred
out of hospital.42 This underscores the importance of public
awareness of the cardiovascular disease and the warning
signs and symptoms of SCD, especially in patients with
structural heart disease.
n
Role of public access defibrillators
Time is the prime determinant of survival in patients
643
Naik N, et al
Post-mortem analyses in patients of SCD
Autopsy studies in patients with SCD have shown 80% of
patients having concomitant CAD.10,75 Predominant
findings are intracoronary complicated plaque (rupture
with or without thrombus formation) and myocardial
scar.75,76 These findings suggest an acute coronary event or a
previous MI causing scar as a substrate for
tachyarrhythmia and SCD. Other uncommon findings are
interstitial fibrosis, infiltration (amyloid deposition),
inflammation, and ventricular hypertrophy.77,78 However, in
5–10% of cases of SCD the cause cannot be determined
even after autopsy analysis.2,3,10
Heart failure
Overall, as the average survival age is increasing and
quality of medical care is improving, the proportion of
patients with advanced age with multiple comorbidities is
increasing. In the US, 5 million suffer from heart failure
with around 600,000 are added to the count every year.79
Progressive heart failure causes remodeling, leading to
structural and electrical changes in the myocardium and
neuro-hormonal activation. This causes inhomogeneity
and thus leading to substrate for arrhythmogenesis.80
Clinical heart failure increases the risk of SCD by 5 fold
and SCD accounts for 30–50% of all deaths in heart failure
patients.81 But, as the age advances, the proportion of
deaths by SCD decreases and patients dying of progressive
heart failure increases. It has been observed that 63% of
patients with mild heart failure die of SCD as opposed to
33% with advanced heart failure.13 Severe LV dysfunction,
irrespective of the cause is a major predictor of risk to
SCD.82 Thus, LV function <35% is an important criteria for
ICD implantation for primary prevention of SCD. It has
been observed that only 20–30% of ICD recipients receive
appropriate shocks during 4 years of prospective followup. While, in population studies >60% of patients suffering
SCD are found to have either normal LV function or mild
LV dysfunction.83,84 This decreases the overall predictive
efficacy of LV function as a risk marker of SCD.
Electrical predictors of SCD
Various abnormalities on 12 lead electrocardiogram have
been detected which can act as a marker of an underlying
heart disease and may help predict risk of SCD.
Pathological Q waves are a marker of underlying CAD and
dynamic ST, T changes suggest myocardium at high risk of
infarction. R wave amplitude and QRS duration is marker
of Left Ventricular hypertrophy (LVH) or an underlying
cardiomyopathy. Left bundle branch block and LVH are
associated with 1.5 times increased risk of SCD.73,85 Total
642
QRS duration and fragmented QRS are also found to be
associated with increased risk of SCD.86–88 Primary
arrhythmogenic disorders such as long and short QT
syndromes, Brugada syndrome, arhhythmogenic right
ventricular cardiomyoapathy (ARVC), catecholaminergic
polymorphic ventricular tachycardia (CPVT), WolfParkinson-White (WPW) are diagnosed primarily based on
their ECG features. These disorders are rare in the
community but recognizing them by a simple and noninvasive test has a large bearing at an individual level. QT
interval irrespective of the age, sex, heart rate, drug used,
and diagnosis of long or short QT syndromes is a marker of
SCD. The corrected QT interval >440 msec increases the
risk of SCD 2.3 times compared to those with corrected QT
interval <440 msec.89 And, in the absence of drugs causing
QT prolongation this risk increases by 5 folds.90 Other
markers of risk identified on ECG are late potentials on
signal averaged ECG, microvolt T wave alternans, reduced
heart rate variability on holter monitoring and abnormal
heart rate profile on exercise ECG.59,91,92 But these markers
lack specificity while assessing risk for SCD.
Socioeconomic and psychosocial risk predictors
The prevalence of cardiovascular diseases, CAD, and its
mortality is high in low socioeconomic countries.93 The
incidence of out-of-hospital cardiac arrest and SCD are
also higher in areas of socioeconomic deprivation than in
more affluent areas.2,94,95 Various factors influence the
association between low socioeconomic status and SCD.
These are probably related to lower access to health
facility, increased smoking, genetic influences to CAD,
and behavioral influences. Psychological factors
associated with SCD are lifestyle changes, increased stress
in life, and social isolation.9,96 Moreover, history of
psychiatric disease is also associated with increased risk
of SCD.97
Genetic risk predictors
Research in the recent years has seen major advancements
in the field of genetic determinants of SCD.26,98–100 Genetic
basis of primary arrhythmogenic disorders such as LQTs
has been recognized since long. But, application of
knowledge of recent research in genetics and genome wide
analysis (Human Genome Project) has provided the
foundation to identify novel genes and biological pathways
implicated in conduction system disease, cardiac
arrhythmias, and SCD. It has been shown that the risk of
SCD is twice higher in an individual with one of the parents
dying suddenly and it increases to nine-fold if both patients
had SCD.26 These effects are independent of the history of
MI in parents. To some extent it has been shown that SCD is
J. Preventive Cardiology Vol. 4
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Nov 2014
Epidemiology of SCD
an expression of underlying coronary heart disease,
hereditary factors that contribute to coronary heart disease
risk operate non-specifically for the SCD syndrome. But it
has also been shown that family history of SCD and the
cumulative ST deviation are the only two differences
between patients who had SCD with MI compared to those
who had SCD without MI.98 This suggests that the heritable
risk factors play an important role in determining the risk
for SCD irrespective of the CAD risk factors. Furthermore,
the strength of association to SCD increases with
increasing number of relatives affected by SCD. This is
because of the complex genetic architecture, in which
susceptibility alleles increase risk additively.101
In a recent review, Noteworthy et al. describes the genetic
contribution to SCD either by rare variants with strong
effects, rare variants with modest effects, or common
variants with modest effects.92 Rare variants with strong
effect are identified in genes associated with very
uncommon inherited cardiac disease but with very high
risk of ventricular tachyarrhythmia’s and SCD. These
include disease like long and short QT syndromes, Brugada
syndrome and catecholaminergic polymorphic VT.92
However, these mutations are subjected to inherent
negative selection, thus does not contribute significantly to
the burden of disease at population level.92,101
Rare variant with modest effect are less malignant variants
associated with disease like long QT syndrome. They
increase the susceptibility to arrhythmia in general
population. Mutation in gene KCNH2 (HERG) which
encodes for voltage gated potassium channel is found in
around 16% of patients suffering SCD.102 Similar result was
shown in another study where 30% of patients suffering
SCD were found to have mutation linked to LQTs and 14%
of patients having mutation related to Ryanodine receptor
gene (RYR2).103,104 Nurses’ health study also shows 10%
prevalence of SCN5A mutation in patients suffering
SCD.105 However, community based study shows a lower
prevalence of only 6% in SCN5A mutation in patients
suffering SCD. These data support the concept that rare
variants with modest effects might not produce an
identifiable clinical syndrome in isolation, but could
predispose the individual to acquired long QT syndrome
and SCD after exposure to a secondary risk factor, such as a
QT-interval-prolonging medication.92
The common variant with modest effect is most prevalent
in general population. This variant contributes increasingly
to the SCD risk at population level. As this variant remains
unaffected by negative selection and can reach relatively
high allele frequency in the population. For example the
S1102Y variant of the SCN5A was found in 57% of black
J. Preventive Cardiology Vol. 4
No. 2
Nov 2014
patients with a history of arrhythmia, syncope, and QT
prolongation versus on in 13% of healthy control
individuals.106 Common genetic variants in isolation are
unlikely to cause SCD, these variants contribute only
incrementally to the overall risk of SCD by reducing
“repolarization reserve” and predisposing some
individuals to SCD through interactions with other risk
factors such as ischemia, hypokalemia, or drug exposure.
As discussed above, genes for QT prolongation has been
consistently associated with risk of SCD in population.10,107
While QT interval adjusted for age, sex, and heart rate is
normally distributed in general population, 35% of its
interval variability is attributable to genetic factors.108 The
common variants such as KCNH2 and NOS1AP influences
QT interval duration. However, these variants have a
modest effect on QT interval at baseline (6 to 12 ms) and an
external influence is necessary to prolong the QT interval
to a degree where the SCD risk increases substantially.
Thus, inheritable factors are partly involved in the
pathogenesis of SCD and the genetic basis of these events
is multifactorial and potentially includes the genetics of
atherothrombosis and plaque stability, among other factors
significantly contributing to SCD.109,110
Triggers for SCD
Occurrence of SCD requires a complex interplay between
the substrate for SCD and its triggering factors which could
be an external or internal trigger. As the majority of SCD
are unwitnessed the possible triggers to the SCD are
difficult to identify, while abnormal substrate can be
determined in most by ante-mortem or post-mortem
analysis. In witnessed SCD the predominant symptoms
prior to SCD are angina, dyspnea, syncope, nausea,
vomiting, and sense of not feeling well.36,42 A study has
shown cigarette smoking and analgesic use as an important
trigger prior to SCD.111 Possible mechanism by which
cigarette smoking leads to SCD are increased platelet
aggregation, catecholamine surge, coronary spasm, plaque
rupture, and increased thrombogenic milieu.112,113 The uses
of analgesic and anti-inflammatory drugs prior to SCD are
probably linked to their sense of feeling unwell. Another
study has shown a lag period of almost 75 min between
symptom onset and SCD when the episodes have occurred
out of hospital.42 This underscores the importance of public
awareness of the cardiovascular disease and the warning
signs and symptoms of SCD, especially in patients with
structural heart disease.
n
Role of public access defibrillators
Time is the prime determinant of survival in patients
643
Naik N, et al
experiencing SCD. With every minute that passes between
the SCD and defibrillation the survival rate decreases by
3–4% in patients receiving CPR and 7–10% those with no
CPR.114 Thus, the overall survival in patients of SCD is
5–10 % in countries like USA where the average response
time for emergency medical service is 8–15 min. For
patients who are defibrillated within 10 min of SCD have a
survival rate up to 40% and long term survival equals age
and gender matched general population. Automated
external defibrillators (AED’s) are computerized devices
programmed to analyze the cardiac rhythm and deliver
shock in case of ventricular tachycardia and fibrillation.
These devises can be applied at public places and are easy
to operate even by an untrained layman.115,116 In Public
Access Defibrillation Trial, multiple volunteers from
public were trained in CPR or CPR with AED use. AEDs
were made available at various public sites like shopping
malls, apartment complex, entertainment complex, etc.
Individuals who suffered a SCD and received resuscitation
with CPR and AED were twice more likely to survive
compared to those resuscitated with only CPR.117 In
developed nation like US, AEDs are applied at all federal
building, airports and are also recommended at health and
fitness facilities and schools. No such law regulating the
use of AEDs in India is operational or is in pipeline.
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experiencing SCD. With every minute that passes between
the SCD and defibrillation the survival rate decreases by
3–4% in patients receiving CPR and 7–10% those with no
CPR.114 Thus, the overall survival in patients of SCD is
5–10 % in countries like USA where the average response
time for emergency medical service is 8–15 min. For
patients who are defibrillated within 10 min of SCD have a
survival rate up to 40% and long term survival equals age
and gender matched general population. Automated
external defibrillators (AED’s) are computerized devices
programmed to analyze the cardiac rhythm and deliver
shock in case of ventricular tachycardia and fibrillation.
These devises can be applied at public places and are easy
to operate even by an untrained layman.115,116 In Public
Access Defibrillation Trial, multiple volunteers from
public were trained in CPR or CPR with AED use. AEDs
were made available at various public sites like shopping
malls, apartment complex, entertainment complex, etc.
Individuals who suffered a SCD and received resuscitation
with CPR and AED were twice more likely to survive
compared to those resuscitated with only CPR.117 In
developed nation like US, AEDs are applied at all federal
building, airports and are also recommended at health and
fitness facilities and schools. No such law regulating the
use of AEDs in India is operational or is in pipeline.
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Address for correspondence
Dr. Nitish Naik: Email: [email protected]
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Address for correspondence
Dr. Nitish Naik: Email: [email protected]
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