Ivy A. Ku

Left Atrial Function Predicts Heart Failure Hospitalization in Subjects with Preserved Ejection Fraction and Coronary Heart Disease: Longitudinal Data from the Heart and Soul Study

OBJECTIVES This study sought to determine whether left atrial (LA) dysfunction predicts heart failure (HF) hospitalization in subjects with preserved baseline ejection fraction (EF). BACKGROUND Among patients with preserved EF, factors leading to HF are not fully understood. Cross-sectional studies have demonstrated LA dysfunction at the time of HF, but longitudinal data on antecedent atrial function are lacking. METHODS We performed resting transthoracic echocardiography in 855 subjects with coronary heart disease and EF ≥50%. Left atrial functional index (LAFI) was calculated as ([LA emptying fraction × left ventricular outflow tract-velocity time integral] / [indexed LA end-systolic volume]), where LA emptying fraction was defined as (LA end-systolic volume--LA end-diastolic volume) / LA end-systolic volume. We used Cox models to evaluate the association between LAFI and HF hospitalization. RESULTS Over a median follow-up of 7.9 years, 106 participants (12.4%) were hospitalized for HF. Rates of HF hospitalization were inversely proportional to quartile (Q) of LAFI: Q1, 47 per 1,000 person-years; Q2, 18.3; Q3, 9.6; and Q4, 5.3 (p < 0.001). Each standard deviation decrease in LAFI was associated with a 2.6-fold increased hazard of adverse cardiovascular outcomes (unadjusted hazard ratio: 2.6, 95% confidence interval: 2.1 to 3.3, p < 0.001), and the association persisted even after adjustment for clinical risk factors, N-terminal pro-B-type natriuretic peptide, and a wide range of echocardiographic parameters (adjusted hazard ratio: 1.5, 95% confidence interval: 1.0 to 2.1, p = 0.05). CONCLUSIONS Left atrial dysfunction independently predicts HF hospitalization in subjects with coronary heart disease and preserved baseline EF. The LAFI may be useful for HF risk stratification, and LA dysfunction may be a potential therapeutic target.

High-Sensitivity Cardiac Troponin T Levels and Secondary Events in Outpatients With Coronary Heart Disease From the Heart and Soul Study

IMPORTANCE Levels of high-sensitivity cardiac troponin T (hs-cTnT) predict secondary cardiovascular events in patients with stable coronary heart disease. OBJECTIVES To determine the association of hs-cTnT levels with structural and functional measures of heart disease and the extent to which these measures explain the relationship between hs-cTnT and secondary events. DESIGN We measured serum concentrations of hs-cTnT and performed exercise treadmill testing with stress echocardiography in a prospective cohort study of outpatients with coronary heart disease who were enrolled from September 11, 2000, through December 20, 2002, and followed up for a median of 8.2 years. SETTING Twelve outpatient clinics in the San Francisco Bay Area. PARTICIPANTS Nine hundred eighty-four patients with stable coronary heart disease. MAIN OUTCOMES AND MEASURES Cardiovascular events (myocardial infarction, heart failure, or cardiovascular death), determined by review of medical records and death certificates. RESULTS Of 984 participants, 794 (80.7%) had detectable hs-cTnT levels. At baseline, higher hs-cTnT levels were associated with greater inducible ischemia and worse left ventricular ejection fraction, left atrial function, diastolic function, left ventricular mass, and treadmill exercise capacity. During follow-up, 317 participants (32.2%) experienced a cardiovascular event. After adjustment for clinical risk factors, baseline cardiac structure and function, and other biomarkers (N-terminal portion of the prohormone of brain-type natriuretic peptide and C-reactive protein levels), each doubling in hs-cTnT level remained associated with a 37% higher rate of cardiovascular events (hazard ratio, 1.37 [95% CI, 1.14-1.65]; P = .001). CONCLUSIONS AND RELEVANCE In outpatients with stable coronary heart disease, higher hs-cTnT levels were associated with multiple abnormalities of cardiac structure and function but remained independently predictive of secondary events. These findings suggest that hs-cTnT levels may detect an element of risk that is not captured by existing measures of cardiac disease severity.

Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: data from the Heart and Soul Study.

OBJECTIVE Serum adiponectin protects against incident ischemic heart disease (IHD). However, in patients with existing IHD, higher adiponectin levels are paradoxically associated with worse outcomes. We investigated this paradox by evaluating the relationship between adiponectin and cardiovascular events in patients with existing IHD. METHODS We measured total serum adiponectin and cardiac disease severity by stress echocardiography in 981 outpatients with stable IHD who were recruited for the Heart and Soul Study between September 2000 and December 2002. Subsequent heart failure hospitalizations, myocardial infarction, and death were recorded. RESULTS During an average of 7.1 years of follow-up, patients with adiponectin levels in the highest quartile were more likely than those in the lowest quartile to be hospitalized for heart failure (23% vs. 13%; demographics-adjusted hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.04-2.56, p=0.03) or die (49% vs. 31%; HR 1.67, 95% CI 1.24-2.26, p<0.008), but not more likely to have a myocardial infarction (12% vs. 17%; HR 0.64, 95% CI 0.38-1.06, p=0.08). The combined outcome of myocardial infarction, heart failure, or death occurred in 56% (136/245) of participants in the highest quartile of adiponectin vs. 38% (94/246) of participants in the lowest quartile (HR 1.54, 95% CI 1.31-2.21, p<0.002). Adjustment for left ventricular ejection fraction, diastolic dysfunction, inducible ischemia, C-reactive protein, and NT-proBNP attenuated the association between higher adiponectin and increased risk of subsequent events (HR 1.43, 95% CI 0.98-2.09, p=0.06). CONCLUSIONS Higher concentrations of adiponectin were associated with heart failure and mortality among patients with existing IHD.

Association of low leptin with cardiovascular events and mortality in patients with stable coronary artery disease: The Heart and Soul Study

OBJECTIVE Leptin is an adipokine with both protective and harmful effects on the cardiovascular (CV) system. Prior studies evaluating the association between leptin and CV outcomes have yielded conflicting results. Thus, we sought to investigate the relationship between leptin and CV events and mortality in patients with chronic stable coronary artery disease (CAD). METHODS We performed a prospective cohort study of 981 outpatients with stable CAD. Leptin levels were measured in fasting venous samples at baseline. We used proportional hazards models to evaluate the association of baseline leptin with subsequent CV events (myocardial infarction, stroke, transient ischemic attack) and death. RESULTS During a mean follow-up of 6.2±2.1 years, there were 304 deaths, 112 myocardial infarctions, and 52 strokes/TIAs. In models adjusted for age, sex, and race, low leptin was associated with a 30% increased risk of the combined outcome (HR 1.30, CI 1.05-1.59, p=0.01). After further adjustment for obesity, traditional CV risk factors and biomarkers, low leptin remained associated with a 37% increased risk of events (HR 1.37, CI 1.06-1.76, p=0.02). CONCLUSIONS Low leptin is associated with increased CV events and mortality in patients with stable coronary artery disease. This association is independent of known factors affecting leptin levels, including gender and obesity.

Traditional Risk Factors Versus Biomarkers for Prediction of Secondary Events in Patients With Stable Coronary Heart Disease: From the Heart and Soul Study

Background Patients with stable coronary heart disease (CHD) have widely varying prognoses and treatment options. Validated models for risk stratification of patients with CHD are needed. We sought to evaluate traditional and novel risk factors as predictors of secondary cardiovascular (CV) events, and to develop a prediction model that could be used to risk stratify patients with stable CHD. Methods and Results We used independent derivation (912 participants in the Heart and Soul Study) and validation (2876 participants in the PEACE trial) cohorts of patients with stable CHD to develop a risk prediction model using Cox proportional hazards models. The outcome was CV events, defined as myocardial infarction, stroke, or CV death. The annual rate of CV events was 3.4% in the derivation cohort and 2.2% in the validation cohort. With the exception of smoking, traditional risk factors (including age, sex, body mass index, hypertension, dyslipidemia, and diabetes) did not emerge as the top predictors of secondary CV events. The top 4 predictors of secondary events were the following: N-terminal pro-type brain natriuretic peptide, high-sensitivity cardiac troponin T, urinary albumin:creatinine ratio, and current smoking. The 5-year C-index for this 4-predictor model was 0.73 in the derivation cohort and 0.65 in the validation cohort. As compared with variables in the Framingham secondary events model, the Heart and Soul risk model resulted in net reclassification improvement of 0.47 (95% CI 0.25 to 0.73) in the derivation cohort and 0.18 (95% CI 0.01 to 0.40) in the validation cohort. Conclusions Novel risk factors are superior to traditional risk factors for predicting 5-year risk of secondary events in patients with stable CHD.

Early statin therapy in acute coronary syndromes: the successful cycle of evidence, guidelines, and implementation.

That statins should be prescribed for patients before hospital discharge after an episode of acute coronary syndrome (ACS) is a Level of Evidence: 1A recommendation of the American College of Cardiology/American Heart Association Joint Task Force. This level of recommendation is based upon 2 clinical trials: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trials. In the MIRACL trial, 3,086 patients with unstable angina or non-Q-wave myocardial infarction were randomized within 4 days of the event to atorvastatin 80 mg/day or to placebo and followed for 16 weeks. The primary composite end point occurred in 14.8% of atorvastatin patients and 17.4% of placebo patients, a 16% relative risk reduction (p = 0.048). In the PROVE-IT trial, 4,162 patients hospitalized with an ACS within the preceding 10 days were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and were followed for a mean of 24 months. The primary event rate was 22.4% in the atorvastatin group and 26.3% in the pravastatin group, a 16% relative risk reduction (p = 0.005). A strong trend toward a reduction in total mortality was seen in the atorvastatin group (2.2% vs. 3.2%, p = 0.07). Using a composite end point of death, myocardial infarction, and rehospitalization for ACS, the difference between the treatment groups is already statistically significant at 30 days and remains so throughout the follow-up period. Comprehensive treatment programs in ACS patients that include initiation of statins before hospital discharge have been shown to improve outcomes such as recurrent myocardial infarction and total mortality at 1 year. Guidelines prove their utility when their implementation improves outcomes across a broad population at risk, such as in this instance.

Polycystic Ovary Syndrome Is Associated with Higher Left Ventricular Mass Index: The CARDIA Women's Study

OBJECTIVE The aim of the study was to determine whether young women with polycystic ovary syndrome (PCOS) have evidence of early structural changes in echocardiographic parameters as a measurement of cardiovascular risk. METHODS We investigated the association of PCOS and echocardiographic parameters in 984 black and white women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort followed prospectively for 20 yr. Women ages 34-46 (Year 16) completed questionnaires recalling symptoms of oligomenorrhea and hirsutism in their 20s and 30s. Serum androgens were obtained at Year 2. Women in their 20s and 30s were classified into four mutually exclusive groups: 1) PCOS; 2) isolated oligomenorrhea (IO); 3) isolated hyperandrogenism (IH); and 4) reference group. Outcome measures were defined as echocardiography data from Year 5. We used multivariable linear regression models to evaluate the association of PCOS and its components with left ventricular (LV) mass index, left atrial (LA) diameter, LV ejection fraction (LVEF), and mitral inflow early wave to late wave ratio. RESULTS Among 984 participants, 42 women (4.3%) were classified as PCOS, 67 (6.8%) as IO, and 178 (18.0%) as IH. In multivariable linear regression analyses, women with PCOS had a 3.14 g/m(2.7) (95% confidence interval, 0.48-5.81) higher LV mass index compared to the reference group (approximately 10% higher). PCOS women also had a 0.11 cm/m (95% confidence interval, 0.02-0.19) larger LA diameter, after adjustment for age and race. CONCLUSION PCOS, but not IO or IH, is associated with a higher LV mass index and larger LA diameter in young women, suggestive of early adverse cardiac remodeling. Additional longitudinal studies are needed to evaluate whether this difference persists over time.

Association of Gestational Diabetes Mellitus With Left Ventricular Structure and Function: The CARDIA Study

OBJECTIVE Gestational diabetes mellitus (GDM) predicts incident cardiovascular disease (CVD). However, mechanisms linking GDM to CVD beyond intervening incident diabetes are not well understood. We examined the relation of GDM with echocardiographic parameters of left ventricular (LV) structure and function, which are important predictors of future CVD risk. RESEARCH DESIGN AND METHODS We studied 609 women (43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who delivered one or more births during follow-up and had echocardiograms in 1990–1991 (mean age 28.8 years) and 2010–2011. RESULTS During the 20-year follow-up, 965 births were reported, with GDM developing in 64 women (10.5%). In linear regression models adjusted for sociodemographic factors, BMI, physical activity, parity, smoking, use of oral contraceptives, alcohol intake, family history of coronary heart disease, systolic blood pressure, and lipid levels, women with GDM had impaired longitudinal peak strain (−15.0 vs. −15.7%, P = 0.025), circumferential peak strain (−14.8 vs. −15.6%, P = 0.028), lateral e′ wave velocity (11.0 vs. 11.8 cm/s, P = 0.012), and septal e′ wave velocity (8.6 vs. 9.3 cm/s, P = 0.015) in 2010–2011 and a greater 20-year increase in LV mass indexed to body surface area (14.3 vs. 6.0 g/m2, P = 0.006) compared with women with non-GDM pregnancies. Further adjustment for incident type 2 diabetes after pregnancy did not attenuate these associations. CONCLUSIONS Pregnancy complicated by GDM is independently associated with increased LV mass and impaired LV relaxation and systolic function. Implementation of postpartum cardiovascular health interventions in women with a history of GDM may offer an additional opportunity to reduce future CVD risk.

Comparison of radionuclide angiographic synchrony analysis to echocardiography and magnetic resonance imaging for the diagnosis of arrhythmogenic right ventricular cardiomyopathy

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable arrhythmia syndrome entailing a high risk of sudden cardiac death. Discernment from benign arrhythmia disorders, particularly right ventricular outflow tract ventricular tachycardia (RVOT VT), may be challenging, providing an impetus to explore alternative modalities that may facilitate evaluation of patients with suspected ARVC. OBJECTIVE We evaluated the role of equilibrium radionuclide angiography (ERNA) as a diagnostic tool for ARVC. METHODS ERNA measures of ventricular synchrony-synchrony (S) and entropy (E)-were examined in patients with ARVC (n = 16), those with RVOT VT (n = 13), and healthy controls (n = 49). The sensitivity and specificity of ERNA parameters for ARVC diagnosis were compared with those of echocardiography (ECHO) and cardiovascular magnetic resonance (CMR). RESULTS ERNA right ventricular synchrony parameters in patients with ARVC (S = 0.91 ± 0.07; E = 0.61 ± 0.1) differed significantly from those in patients with RVOT VT (S = 0.99 ± 0.01 [P = .0015]; E = 0.46 ± 0.05 [P < .001]) and healthy controls (S = 0.97 ± 0.02 [P = .003]; E = 0.48 ± 0.07 [P = .001]). The sensitivity of ERNA synchrony parameters for ARVC diagnosis (81%) was higher than that for ECHO (38%; P = .033) and similar to that for CMR (69%; P = .162), while specificity was lower for ERNA (89%) than that for ECHO and CMR (both 100%; P = .008). CONCLUSION ERNA right ventricular synchrony parameters can distinguish patients with ARVC from controls with structurally normal hearts, and its performance is comparable to that of ECHO and CMR for ARVC diagnosis. These findings suggest that ERNA may serve as a valuable imaging tool in the diagnostic evaluation of patients with suspected ARVC.