Kari S. Kaikkonen

Family History and the Risk of Sudden Cardiac Death as a Manifestation of an Acute Coronary Event

Background— Observational studies have suggested that a parental history of sudden death increases one’s risk of dying suddenly. This study tested the hypothesis that a family history of sudden cardiac death (SCD) is a risk factor for SCD caused by an acute coronary event. Methods and Results— A retrospective case-control study included (1) consecutive victims of SCD (n=138) whose deaths were verified to be due to an acute coronary event without a history of prior myocardial infarction at medicolegal autopsy, (2) consecutive patients surviving an acute myocardial infarction (AMI; n=254), and (3) healthy control subjects (n=470). Family history of AMI and SCD among the first-degree relatives was ascertained in each study group. The incidence of SCD in the 1223 first-degree relatives of SCD victims was higher (5.2%) than that in the 2326 relatives of AMI survivors (3.3%; odds ration [OR] 1.6, 95% confidence interval [CI] 1.2 to 2.2, P<0.01) or the 3748 relatives of controls (OR 2.2; 95% CI 1.6 to 3.0, P<0.001). The history of SCD in 2 or more first-degree relatives was also higher (10.9%) among SCD victims than among AMI survivors (3.5%; OR 3.3, 95% CI 1.4 to 7.8, P<0.01) or controls (1.1%; OR 11.3, 95% CI 4.0 to 31.8, P<0.001). The family history of AMI did not differ between the SCD and AMI groups. Male gender and current smoking were the only coronary risk factors that were more prevalent among SCD victims than among AMI survivors (P<0.001 for both). Conclusions— Subjects with a family history of SCD have an increased risk of dying suddenly during an acute coronary event.

Cardiac Sarcoidosis: Epidemiology, Characteristics and Outcome over 25 Years in a Nationwide Study

Background— This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. Methods and Results— We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×105 adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×105. Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan–Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%. Conclusions— The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome.Background— This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. Methods and Results— We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×105 adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×105. Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan–Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P =0.0001) with a 10-year transplantation-free cardiac survival of only 53%. Conclusions— The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome. # CLINICAL PERSPECTIVE {#article-title-42}

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Causes of nonischemic sudden cardiac death in the current era

BACKGROUND Previous data have shown that various nonischemic cardiac diseases account for about 20% of sudden cardiac deaths (SCDs) and that dilated and hypertrophic cardiomyopathy (CM) are major causes of nonischemic SCD. OBJECTIVE The purpose of this study was to define the prevalence and causes of SCD due to nonischemic CM in the current era given the substantial change in the diagnosis and treatment of cardiac diseases and in lifestyle patterns. METHODS A total of 2661 consecutive victims of SCD from among a population of approximately 470,000 inhabitants in the Province of Oulu, Northern Finland, were included in the study. The causes of deaths were determined from the uniformly required autopsies of SCD victims in Finland, plus available medical records and standardized questionnaires. RESULTS Nonischemic cause of SCD was found in 579 victims (21.8% of all the SCDs). Mean age (± SD) was 55 (±12) years; 78% were males. After subgrouping the nonischemic SCDs into various categories, SCDs associated most closely with obesity (23.7%), followed by alcoholic CM (19.0%), hypertensive CM (15.5%), and fibrotic CM (13.6%). Fibrotic CM was the most common association with SCD in subjects younger than 40 years (28.3%), whereas alcoholic CM was the most common cause of death in subjects between 40 and 59 years of age (25.8%). CONCLUSION CM related to obesity, fibrotic CM, and alcoholic CM are commonly associated with nonischemic SCD in the current era. The association of SCD with fibrotic CM is notably frequent among victims younger than 40 years.

Psychotropic medications and the risk of sudden cardiac death during an acute coronary event

AIMS Psychotropic medication increases cardiac mortality, but the reasons for this association are not clear. We studied the role of psychotropic drugs as a triggering factor of sudden cardiac death (SCD) during an acute coronary event. METHODS AND RESULTS The use of medication was compared between victims of SCD and survivors of an acute coronary event in a case-control study including a consecutive series of victims of SCD (n= 1814, mean age 65 ± 11 years) verified to be due to an acute coronary event at medico-legal autopsy and consecutive series of patients surviving an acute myocardial infarction (AMI; n= 1171, mean age 66 ± 12 years). The medication history was obtained from autopsy/hospital records and interviews with relatives of SCD victims and AMI patients. The use of antipsychotics [9.7 vs. 2.4%, odds ratio (OR) 4.4, 95% confidence interval (CI) 2.9-6.6; P< 0.001] and antidepressants (8.6 vs. 5.5%, OR: 1.6, 95% CI: 1.2-2.2; P= 0.003) was more common in the SCD than AMI group, but the use of benzodiazepines did not differ between the groups (11.7 vs. 13.2%; P= 0.270). The use of antipsychotics remained as a significant risk factor for SCD after adjustment for confounding variables (OR: 3.4, 95% CI: 1.8-6.5; P< 0.001). Combined use of phenothiazines and any antidepressant was associated with a very high risk of SCD (OR: 18.3, 95% CI: 2.5-135.3; P< 0.001). CONCLUSION The use of psychotropic drugs, especially combined use of antipsychotic and antidepressant drugs, is strongly associated with an increased risk of SCD at the time of an acute coronary event.

Comparison of risk profiles between survivors and victims of sudden cardiac death from an acute coronary event

Aim. This study was designed to compare the risk profiles of sudden cardiac death (SCD) victims and survivors of an acute coronary event. Method. A case-control study included consecutive victims of SCD (n=425) verified to be due to an acute coronary event at medicolegal autopsy and consecutive patients surviving an acute myocardial infarction (AMI) (n=644). Results. Family history of SCD (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.0–2.2, P=0.03), male gender (OR 1.8, 95% CI 1.3–2.4, P<0.001), current smoking (OR 2.0, 95% CI 1.5–2.6, P<0.001), cardiac hypertrophy (OR 3.0, 95% CI 2.3–3.9, P<0.001) and three-vessel coronary artery disease (CAD) (OR 5.4, 95% CI 3.6–8.2, P<0.001) were more common among the victims of SCD as compared to survivors of AMI. There was a cumulative increase of risk of being a SCD victim versus AMI survivor when more than one risk factor was present, with the OR rising to 44.3 (95% CI 8.0–246.7) in a current male smoker with a family history of SCD and cardiac hypertrophy. Conclusions. There are specific features that differentiate the victims of SCD from survivors of an acute coronary event. Clustering of several variables, such as family history of SCD, smoking, cardiac hypertrophy and three-vessel CAD are alarm signals of a very high risk of SCD.

Temporal Trends in the Clinical and Pathological Characteristics of Victims of Sudden Cardiac Death in the Absence of Previously Identified Heart Disease

Background—Coronary artery disease is identified in ≈80% of victims of sudden cardiac death (SCD). Because the prevention strategies and public awareness have changed during the past decades, we studied the temporal trends in the pathogenesis of SCD. Methods and Results—FinGesture (n=4031) is a prospective study designed to classify the phenotype and genotype profiles of SCD in a consecutive series of victims of SCD in Northern Finland. On the basis of Finnish law, all subjects who die suddenly undergo autopsy. We analyzed the characteristics of SCD victims and autopsy findings in 1998 to 2002, 2003 to 2007, and 2008 to 2012. Among victims of SCD as a first cardiac event (n=2697), the proportion with coronary artery disease decreased during the 2008 to 2012 time period, compared with the 2 preceding 5-year periods: 74.0% in 1998 to 2002, 73.1% in 2003 to 2007, and 66.4% in 2008 to 2012 (P<0.001). Proportion of SCDs associated with hypertensive heart disease with left ventricular hypertrophy in the absence of coronary artery disease increased from 1.7% in 1998 to 2002 to 5.8% in 2003 to 2007 and 8.9% in 2008 to 2012 (P<0.001). Similarly, myocardial fibrosis in the absence of myocarditis or left ventricular hypertrophy, or other known pathogeneses, was 6.7% in the past 5-year period compared with 2 previous 5-year periods (3.7% and 4.0%; P<0.001 between 1998–2002 and 2008–2012 and between 2003–2007 and 2008–2012). Conclusions—The proportion of SCDs attributable to coronary artery disease, in the absence of a history of heart disease, has decreased, whereas the proportion associated with hypertensive heart disease and idiopathic fibrosis has increased during the past 15 years.

Usefulness of Cardiac Troponins as Markers of Early Treatment Response in Cardiac Sarcoidosis

Evaluation and treatment of cardiac sarcoidosis (CS) suffer from lack of sensitive and easily repeatable markers of disease activity. We studied measurements of high-sensitivity cardiac troponin T or troponin I (hs-cTnT/I) taken at presentation and during treatment in 62 patients with new-onset CS (48 women, mean age 49 years). Hs-cTnT was measured in 50 patients and was elevated (>13 ng/L) at presentation in 26 of them (52%). Hs-cTnI was measured in the remaining 12 patients and was elevated (>0.04 ng/mL) in 7 of them (58%). Left ventricular ejection fraction averaged 43 ± 14% in association with elevated hs-cTnT/I (n = 33) versus 53 ± 10% with normal hs-cTnT/I (n = 29; p = 0.001). Hs-cTnT/I was remeasured after 4 weeks of steroid therapy in 38 patients and was normalized in 16 of the 24 (67%) with an elevated pretreatment concentration and remained normal in the rest of the 14 patients (p <0.001). During follow-up (median, 17 months), cardiac death (n = 2), aborted sudden death (n = 5), sustained ventricular tachycardia (n = 8), or new complete atrioventricular block (n = 1) was recorded in 11 of 33 patients with elevated hs-cTnT/I versus in 5 of 29 with normal hs-cTnT/I (log-rank p = 0.068). Two-year event-free Kaplan-Meier cardiac survival estimate (95% confidence interval) was 67% (48% to 81%) with elevated hs-cTnT/I versus 93% (76% to 99%) with normal hs-cTnT/I. In CS, circulating hs-cTnT/I may help clinicians evaluate disease activity and treatment response. Their prognostic value remains tentative pending more follow-up data.

Association of the beta-1 adrenergic receptor carboxyl terminal variants with left ventricular hypertrophy among diabetic and non-diabetic survivors of acute myocardial infarction

BackgroundThe beta-1 adrenergic receptor (β1AR) plays a fundamental role in the regulation of cardiovascular functions. It carries a nonsynonymous single nucleotide polymorphism in its carboxyl terminal tail (Arg389Gly), which has been shown to associate with various echocardiographic parameters linked to left ventricular hypertrophy (LVH). Diabetes mellitus (DM), on the other hand, represents a risk factor for LVH. We investigated the possible association between the Arg389Gly polymorphism and LVH among non-diabetic and diabetic acute myocardial infarction (AMI) survivors.MethodsThe study population consisted of 452 AMI survivors, 20.6% of whom had diagnosed DM. Left ventricular parameters were measured with two-dimensional guided M-mode echocardiography 2-7 days after AMI, and the Arg389Gly polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism assay.ResultsThe Arg389 homozygotes in the whole study population had a significantly increased left ventricular mass index (LVMI) when compared to the Gly389 carriers (either Gly389 homozygotes or Arg389/Gly389 heterozygotes) [62.7 vs. 58.4, respectively (p = 0.023)]. In particular, the Arg389 homozygotes displayed thicker diastolic interventricular septal (IVSd) measures when compared to the Gly389 carriers [13.2 vs. 12.3 mm, respectively (p = 0.004)]. When the euglycemic and diabetic patients were analyzed separately, the latter had significantly increased LVMI and diastolic left ventricular posterior wall (LVPWd) values compared to the euglycemic patients [LVMI = 69.1 vs. 58.8 (p = 0.001) and LVPWd = 14.2 vs. 12.3 mm (p < 0.001), respectively]. Furthermore, among the euglycemic patients, the Arg389 homozygotes displayed increased LVMI and IVSd values compared to the Gly389 carriers [LVMI = 60.6 vs. 56.3, respectively (p = 0.028) and IVSd = 13.1 vs. 12.0 mm, respectively (p = 0.001)]. There was no difference in the LVMI and IVSd values between the diabetic Arg389 homozygotes and Gly389 carriers.ConclusionsThe data suggest an association between the β1AR Arg389Gly polymorphism and LVH, particularly the septal hypertrophy. The Arg389 variant appears to confer a higher risk of developing LVH than the corresponding Gly389 variant among patients who have suffered AMI. This association cannot be considered to be universal, however, since it does not appear to exist among diabetic AMI survivors.

Comparison of Family History of Sudden Cardiac Death in Nonischemic and Ischemic Heart Disease

Background— Recent studies have identified the presence of familial clustering of ischemic sudden cardiac death (SCD) as a clinical expression of coronary artery disease. The purpose of this study was to determine whether nonischemic SCD has a similar familial background, which would be evidence of a genetic predisposition. Methods and Results— The retrospective case-control study included (1) consecutive victims of nonischemic SCD (n=223), (2) consecutive victims of ischemic SCD (n=596), whose deaths and diagnosis were verified at medicolegal autopsy, and (3) control subjects without heart disease (n=475). In each study group, the family history of SCD among the first-degree relatives was determined and verified from death certificates. The prevalence of SCD in ≥1 first-degree relative was significantly higher in victims of ischemic (34.2%) than nonischemic SCD (13.4%; P<0.001) or controls (17.6%; P<0.001). The history of SCD in first-degree relatives did not differ from controls in nonischemic SCD victims (P=0.155). In a subgroup analysis of victims of ischemic SCD, the prevalence of family history of SCD in first-degree relatives did not differ between those with or without a prior infarct scar at autopsy (33.1% versus 29.9%, respectively; P=0.222). Conclusions— Ischemic SCD has a strong familial background both in cases with and without a prior myocardial infarction. The family history of SCD is not significantly increased in victims of nonischemic SCD, suggesting a larger role of sporadic occurrence than inherited traits as the cause of nonischemic SCD.