Ronald Mariani

Epidemiology of Sudden Cardiac Death: Clinical and Research Implications

The current annual incidence of sudden cardiac death in the United States is likely to be in the range of 180,000 to 250,000 per year. Coinciding with the decreased mortality from coronary artery disease, there is evidence pointing toward a significant decrease in rates of sudden cardiac death in the United States during the second half of the 20th century. However, the alarming rise in prevalence of obesity and diabetes in the first decade of the new millennium both in the United States and worldwide, would indicate that this favorable trend is unlikely to persist. We are likely to witness a resurgence of coronary artery disease and heart failure, as a result of which sudden cardiac death will have to be confronted as a shared and indiscriminate, worldwide public health problem. There is also increasing recognition of the fact that discovery of meaningful and relevant risk stratification and prevention methodologies will require careful prospective community-wide analyses, with access to large archives of DNA, serum, and tissue that link with well-phenotyped databases. The purpose of this review is to summarize current knowledge of sudden cardiac death epidemiology. We will discuss the significance and strengths of community-wide evaluations of sudden cardiac death, summarize recent observations from such studies, and finally highlight specific potential predictors that warrant further evaluation as determinants of sudden cardiac death in the general population.

Prolonged Tpeak-to-Tend Interval on the Resting ECG Is Associated With Increased Risk of Sudden Cardiac Death

Background— Early studies indicate that prolongation of the interval between the peak and the end of the T wave (Tpeak to Tend [TpTe]) on the 12-lead ECG is a marker of ventricular arrhythmogenesis. However, community-based studies have not been conducted. Methods and Results— TpTe and other ECG predictors were evaluated in the ongoing Oregon Sudden Unexpected Death Study based in the Portland, Oregon, metropolitan area using a case-control design. Cases of sudden cardiac death (SCD) (n=353; mean age, 66.6 years; 95% CI, 65.1 to 68.1 years; 67% men) were compared with living controls with coronary artery disease (n=342; mean age, 64.7 years; 95% CI, 63.4 to 66.0 years; 69% men) from the same region. Analysis of TpTe and selected ECG intervals was limited to sinus rhythm 12-lead ECGs. For cases, these were obtained before and unrelated to SCD. Independent-samples t tests and multiple logistic regression were used. Mean TpTe was significantly greater in cases (89.4 ms; 95% CI, 87.7 to 91.2 ms; P<0.0001) than in controls (76.1 ms; 95% CI, 74.8 to 77.4 ms). The other ECG intervals (corrected QT interval [QTc], QRS duration [QRSD], and TpTe/QT ratio) also were significantly prolonged among cases versus controls (P⩽0.01). TpTe remained a significant predictor of SCD after adjusting for age, sex, QTc, QRSD, and left ventricular function. Odds of SCD increased more with a 1-SD increase in TpTe (12 ms) among subjects with prolonged QRSD (odds ratio, 3.49; 95% CI, 2.06 to 5.91) than with a 1-SD increase in TpTe among subjects with normal QRSD (odds ratio, 1.96; 95% CI, 1.65 to 2.32). TpTe remained significantly associated with SCD in subjects with normal QTc. Conclusions— Prolongation of the TpTe interval measured in lead V5 was independently associated with SCD, with particular utility when the QTc was normal or not measurable because of prolonged QRSD.

Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease: The Oregon Sudden Unexpected Death Study

Background— In a recent cohort study, prolongation of the corrected QT interval (QTc) was associated with an independent increased risk of sudden cardiac death (SCD). We evaluated determinants of prolonged QTc and the relationship of prolonged QTc to SCD risk among patients with coronary artery disease in the general population. Methods and Results— A case-control design was used. Cases were SCD patients with coronary artery disease among a metropolitan area of 1 000 000 residents (2002 to 2006); controls were area residents with coronary artery disease but no history of SCD. All cases were required to have an ECG suitable for QTc analysis before and unrelated to the occurrence of SCD. A total of 373 cases and 309 controls met criteria for analysis. Mean QTc was significantly longer in cases than in controls (450±45 versus 433±37 ms; P<0.0001). In a multivariate model, gender, diabetes mellitus, and QTc-prolonging drugs were significant determinants of QTc prolongation in controls. In a logistic regression model predicting SCD, diabetes mellitus (odds ratio, 1.97; 95% confidence interval, 1.32 to 2.96) and use of QTc-prolonging drugs (odds ratio, 2.90; 95% confidence interval, 1.92 to 4.37) were significant predictors of SCD among subjects with normal or borderline QTc. However, abnormally prolonged QTc in the absence of diabetes and QT-prolonging medications was the strongest predictor of SCD (odds ratio, 5.53; 95% confidence interval, 3.20 to 9.57). Conclusions— Diabetes mellitus and QTc-affecting drugs determined QTc prolongation and were predictors of SCD in coronary artery disease. However, idiopathic abnormal QTc prolongation was associated with 5-fold increased odds of SCD. A continued search for novel determinants of QTc prolongation such as genomic factors is likely to enhance risk stratification for SCD in coronary artery disease.

Women Have a Lower Prevalence of Structural Heart Disease as a Precursor to Sudden Cardiac Arrest: The Ore-SUDS (Oregon Sudden Unexpected Death Study)

OBJECTIVES Our aim was to utilize a community-based approach to identify sex-related differences in risk factors for sudden cardiac arrest (SCA). BACKGROUND There are significant sex-based differences in prevalence and manifestation of SCA. Any differences related to predictors of SCA in women versus men are likely to have implications for risk stratification and prevention. METHODS The Ore-SUDS (Oregon Sudden Unexpected Death Study) is an ongoing prospective investigation of SCA in the Portland, Oregon, metropolitan area (population approximately 1 million). All cases meeting criteria for SCA were ascertained using multiple sources. Medical records were reviewed to identify clinical conditions that may contribute to SCA risk, and comparisons were made between male and female SCA cases using Pearsons chi-square tests for categorical variables, t tests for continuous variables, and multivariate logistic regression analysis. RESULTS During 2002 to 2007, 1,568 adult SCA cases were identified (women 36% vs. men 64%; p < 0.0001) and women were older (mean age 71 +/- 14 years vs. 65 +/- 14 years, p < 0.0001). There were no significant sex differences in prevalence of obesity, dyslipidemia, history of chronic obstructive pulmonary disease/asthma, left ventricular (LV) hypertrophy, or history of myocardial infarction. In multivariate analysis, women were significantly less likely to have severe LV dysfunction (odds ratio: 0.51; 95% confidence interval: 0.31 to 0.84) or previously recognized coronary artery disease (odds ratio: 0.34; 95% confidence interval: 0.20 to 0.60) compared with men. CONCLUSIONS Women were significantly less likely than men to have a diagnosis of structural heart disease (LV dysfunction or coronary artery disease) before SCA. These findings suggest that fewer women may be eligible for prophylactic implantable cardioverter-defibrillator placement based on current guidelines and therefore may not have equal opportunity for prevention. Enhancement of SCA risk stratification may have even higher importance for women.

Population-based analysis of sudden death in children: The Oregon Sudden Unexpected Death Study.

BACKGROUND There is a lack of prospective population-based data regarding sudden death in children. OBJECTIVE The purpose of this study was to assess the burden of sudden cardiac arrest (SCA) in the pediatric population in a 3-year community-wide study. METHODS During 2002-2005, all residents of Multnomah County, Oregon (population 660,486) who underwent SCA were ascertained from emergency medical services, the medical examiner, and emergency rooms of 16 area hospitals. A comprehensive evaluation was performed, including analysis of circumstances of death, medical records, and available autopsy data. Annual incidence rates were calculated for all residents age <18 years using the 2000 U.S. Census data. RESULTS A total of 33 children met the criteria for SCA (58% female, median age 0.37 years, range 0.03-12.3 years). The majority of SCAs (76%) occurred in children age <1 year. At least 90% of this subgroup also met the criteria for the sudden infant death syndrome (SIDS). Pediatric SCAs constituted 2.8% of all SCAs. The pediatric annual incidence rate per 100,000 population was 1.7 (95% confidence interval [CI] 1.1-2.3), compared with 60/100,000 for all ages. The pediatric annual incidence rate per 100,000 children was 7.5 (95% CI 5.1-10.5). The annual incidence rate of SIDS was 0.8/1000 live births. In contrast to an adult survival rate of 8%, none of the children survived to be discharged from the hospital. CONCLUSIONS The burden of pediatric sudden death was low (3% of all sudden deaths), but 90% occurred before the age of 1 year, and the majority were diagnosed as SIDS (70% of overall sudden deaths in children). Population education to prevent SIDS and enhanced postnatal diagnosis of occult heart disease are likely to have the greatest impact on the prevention of pediatric sudden death.

Factors Associated With Pulseless Electric Activity Versus Ventricular Fibrillation The Oregon Sudden Unexpected Death Study

Background— Corresponding with a continuing decline in the prevalence of sudden cardiac arrest cases presenting with ventricular fibrillation (VF), there has been a significant rise in the prevalence of pulseless electrical activity (PEA). Given significantly lower survival from PEA versus VF, we comprehensively investigated PEA correlates by incorporating first-responder data with lifetime clinical history information. Methods and Results— In the Portland, Ore, metropolitan area (population ≈1 million), cases of out-of-hospital sudden cardiac arrest who underwent attempted resuscitation were identified prospectively (2002–2007). Those presenting with PEA versus VF and asystole were compared with &khgr;2 tests, ANOVA, and logistic regression. A total of 1277 cases aged ≥18 years underwent resuscitation by first responders (mean age, 65±16 years; 67% male). Presenting arrhythmia was VF in 48%, PEA in 25%, and asystole/other in the remainder. Compared with VF cases, PEA cases were older (mean age, 68 versus 63 years; P=0.0002), more likely to be female (37% versus 26%; P=0.0008), and less likely to survive to hospital discharge (6% versus 25%; P<0.0001). A history of syncope was strongly associated with PEA (odds ratio, 2.6; confidence interval, 1.3 to 5.3) after adjustment for age, gender, response time, and arrest circumstances. Black race was also independently associated with PEA (odds ratio, 2.6; confidence interval, 1.3 to 5.4). Pulmonary disease and female gender were significant factors associated with PEA (P for interaction=0.04). In a subgroup analysis of resting ECGs (n=391), there were no differences in cardiac clinical history or prevalence of cardiac conduction system disease (PEA, 31.6% versus VF, 32.2%; P=0.48). Conclusions— PEA cases had a significantly higher prevalence of syncope in their lifetime, with other correlates, including black race, that were distinct from VF cases. Potential mechanistic links between syncope and future manifestation with PEA warrant further exploration.

Prolonged QRS duration on the resting ECG is associated with sudden death risk in coronary disease, independent of prolonged ventricular repolarization

BACKGROUND Abnormalities of ventricular repolarization as well as depolarization have been associated with increased risk of ventricular arrhythmias. OBJECTIVE To evaluate the relative contribution of these predictors to risk of sudden cardiac death (SCD) in patients with coronary artery disease (CAD). METHODS In the ongoing Oregon Sudden Unexpected Death Study, adult residents from the Portland, Oregon, metropolitan area (population ~1 million) who suffered SCD were identified prospectively (2002-2007). Of these, we analyzed the subgroup of SCDs that had a resting 12-lead ECG prior to SCD and also had associated CAD. Comparisons were conducted with a control group of subjects with known CAD but no history of SCD from the same geographic region. Corrected QT interval (QTc), JT interval (JTc), QRS duration (QRSd), and other parameters were measured from ECG prior and unrelated to SCD. Analysis of left ventricular function was limited to those subjects who had undergone echocardiography prior to and remote from SCD. RESULTS A total of 642 SCD cases (71 ± 13 years, 62% male) were compared to 450 controls (66 ± 12 years, 64% male). SCD cases had significantly longer QRSd (102 ± 25 ms vs 97 ± 20 ms, P = .0008) as well as JTc (348 ± 44 ms vs 339 ± 34 ms, P = .0006) vs controls. In cases with prolonged QRSd, 38% had severe left ventricular systolic dysfunction and 62% had normal, mild, or moderately decreased left ventricular systolic function. In a multivariable model, QRSd, JTc, age, and severe left ventricular systolic dysfunction were independent predictors. There was minimal overlap between prolonged QRSd and JTc in both case and control groups (3% and 4%, respectively). CONCLUSION Prolonged QRSd, JTc, and severe left ventricular systolic dysfunction had independent contributions to risk of SCD in coronary disease, in this community-based setting.

Physical activity as a trigger of sudden cardiac arrest: the Oregon Sudden Unexpected Death Study.

BACKGROUND Sudden cardiac arrest (SCA) is a significant public health problem and better understanding of triggers could enhance prevention. Vigorous physical activity has been suggested as a prominent trigger but has not been well-evaluated in the general population. We performed a community-based study to analyze the role of physical activity as a potential trigger of SCA. METHODS Medical records of 1180 subjects who sustained SCA during the ongoing Oregon Sudden Unexpected Death Study (Multnomah County, Oregon, USA; 2002-05) were reviewed. Analysis was limited to first responder and hospital records of patients who experienced witnessed SCA, with information available regarding physical activity immediately prior to SCA. An estimated metabolic equivalent (MET) score was used to classify levels of physical activity. RESULTS A total of 304 adults met criteria for analysis (mean age 69 years, 67% male). The majority (n=193, 63%) were performing light activities, 51 (17%) subjects were sleeping, 39 (13%) were performing moderate activities, 14 (5%) were performing heavy activities, and 7 (2%) were engaged in sexual activity. Light activities were associated with older age (72 years) and heavy activities with the youngest (51 years, p<0.001). Males were more likely to be involved in heavy activity (93% male) and the sexual activity group was exclusively male (p=0.04). CONCLUSION Vigorous physical activity was a potential trigger of SCA in a minority (5%). The vast majority (80%) of subjects were asleep or were performing light activities. The traditional view of SCA triggers may have to be re-visited, with renewed focus on factors such as emotional stress and sleep-related disorders.

Low rate of secondary prevention ICDs in the general population: multiple-year multiple-source surveillance of sudden cardiac death in the Oregon Sudden Unexpected Death Study.

Sudden Cardiac Death. Introduction: Sudden cardiac death (SCD) is a large public health problem that warrants on‐going evaluation in the general population. While single‐year community‐based studies have been performed there is a lack of studies that have extended evaluation to multiple years in the same community.

Distinctive profile of sudden cardiac arrest in middle-aged vs. older adults: A community-based study☆ , ☆☆

BACKGROUND While sudden cardiac arrest (SCA) rates increase with age, middle-aged adults (35-59 years) may comprise a significant proportion of SCA cases in the community (30-40%). However, there is a lack of studies evaluating SCA risk factors specifically associated with this age-group of the population. METHODS Using prospective multiple-source surveillance methodology we identified cases of SCA ≥35 years in the ongoing Oregon Sudden Unexpected Death Study (Portland, Oregon metropolitan area, population≈1,000,000). Out-of-hospital SCA cases, aged 35-59 years were compared to older SCA cases (≥60 years) in a comprehensive analysis of clinical profile of SCA. RESULTS The middle-aged (n=753) compared to older (n=1251) cases were more likely to be male, obese, have sleep apnea and seizure disorder (all p≤0.001); and were less likely to have a history of hypertension, diabetes mellitus, known coronary artery disease, congestive heart failure and syncope (all p<0.01). In multivariable analyses the middle-aged group had higher likelihood of male sex (O.R. 1.67, 95% C.I. 1.29-2.18), obesity (2.20, 1.52-3.19), sleep apnea (2.30, 1.44-3.68) and seizure disorder (2.69, 1.64-4.42); and lower rates of known coronary artery disease (0.57, 0.43-0.74) and congestive heart failure (0.35, 0.25-0.48). CONCLUSIONS SCA in the middle-aged adult was distinguishable from older subjects by higher rates of obesity, sleep apnea and seizure disorder; and lower prevalence of traditional clinical risk markers. With the growing epidemic of obesity, these findings have implications for SCA burden; and suggest the need for a clinical and investigational focus on SCA prediction and prevention in the middle-aged adult, that is distinct from older adults.