Christine C. Welles

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.

The CHADS2 score predicts ischemic stroke in the absence of atrial fibrillation among subjects with coronary heart disease: data from the Heart and Soul Study.

BACKGROUND We sought to evaluate the prognostic performance of the CHADS(2) score for prediction of ischemic stroke/transient ischemic attack (TIA) in subjects with coronary heart disease (CHD) without atrial fibrillation (AF). METHODS In 916 nonanticoagulated outpatients with stable CHD and no AF by baseline electrocardiogram, we calculated CHADS(2) scores (congestive heart failure, hypertension, age ≥75 years, diabetes [1 point each], and prior stroke or TIA [2 points]). The primary outcome was time to ischemic stroke or TIA over a mean follow-up of 6.4 ± 2.3 years. RESULTS Over 5,821 person-years of follow-up, 40 subjects had an ischemic stroke/TIA (rate 0.69/100 person-years, 95% CI 0.50-0.94). Compared with subjects with low (0-1) CHADS(2) scores, those with intermediate (2-3) and high (4-6) CHADS(2) scores had an increased rate of stroke/TIA, even after adjustment for age, tobacco, antiplatelet therapy, statins, and angiotensin inhibitors (CHADS(2) score 2-3: HR 2.4, 95% CI 1.1-5.3, P = .03; CHADS(2) score 4-6: HR 4.0, 95% CI 1.5-10.6, P = .006). Model discrimination (c-statistic = 0.65) was comparable with CHADS(2) model fit in published AF-only cohorts. CONCLUSIONS The CHADS(2) score predicts ischemic stroke/TIA in subjects with stable CHD and no baseline AF. The event rate in non-AF subjects with high CHADS(2) scores (5-6) was comparable with published rates in AF patients with moderate CHADS(2) scores (1-2), a population known to derive benefit from stroke prevention therapies. These findings should inform efforts to determine whether stroke prevention therapies or screening for silent AF may benefit subjects with stable CHD and high CHADS(2) scores.

Vitamin D Deficiency and Cardiovascular Events in Patients With Coronary Heart Disease: Data From the Heart and Soul Study

A growing body of evidence supports an association between vitamin D and cardiovascular disease. However, the mechanisms underlying this association are unknown. From 2000 to 2002, we identified 946 participants with stable cardiovascular disease in San Francisco, California, and followed them prospectively for cardiovascular events (heart failure, myocardial infarction, stroke, or cardiovascular death). We then examined the extent to which the association was attenuated by adjustment for poor health behaviors, comorbid health conditions, and potential biological mediators. During a median follow-up period of 8.0 years (through August 24, 2012), 323 subjects (34.1%) experienced a cardiovascular event. Following adjustment for sociodemographic factors, season of blood measurement, health behaviors, and comorbid conditions, 25-hydroxyvitamin D levels under 20 ng/mL remained independently associated with cardiovascular events (hazard ratio = 1.30, 95% confidence interval: 1.01, 1.67). However, after further adjustment for potential biological mediators, the independent association was no longer present (hazard ratio = 1.11, 95% confidence interval: 0.85, 1.44). Parathyroid hormone, a potentially modifiable biological factor downstream from 25-hydroxyvitamin D, was responsible for the majority of this attenuation. These findings highlight the need for randomized controlled trials to determine whether vitamin D supplementation in persons with deficiency could be beneficial for the primary or secondary prevention of cardiovascular events.

Hemoglobinuria and Acute Kidney Injury Requiring Hemodialysis Following Intravenous Immunoglobulin Infusion

Intravenous immunoglobulin (IVIG), a product initially developed for patients with immunodeficiencies, now has multiple other indications and increasing off-label use. IVIG generally is well tolerated, with few adverse effects. Antibody-mediated (Coombs-positive) hemolysis is known to occur after IVIG infusion, but often is subclinical and previously has not been reported to lead to acute kidney injury (AKI). The predominantly known mechanism of AKI after IVIG infusion has been osmotic nephrosis, primarily associated with sucrose-containing formulations. We present a case of a bone marrow transplant recipient who was treated with a sucrose-free IVIG product and subsequently developed Coombs-positive hemolysis leading to AKI requiring hemodialysis, who ultimately died secondary to infectious complications. The severity of this case emphasizes the importance of identifying populations who may be at increased risk of pigment-mediated kidney injury before consideration of IVIG therapy.

Relation of Left Atrial Dysfunction to Ischemic Stroke in Patients With Coronary Heart Disease (from the Heart and Soul Study)

This study sought to determine whether left atrial (LA) dysfunction independently predicts ischemic stroke. Atrial fibrillation (AF) impairs LA function and is associated with ischemic stroke. However, ischemic stroke frequently occurs in patients without known AF. The direct relation between LA function and risk of ischemic stroke is unknown. We performed transthoracic echocardiography at rest in 983 subjects with stable coronary heart disease. To quantify LA dysfunction, we used the left atrial function index (LAFI), a validated formula incorporating LA volumes at end-atrial systole and diastole. Cox proportional hazards models were used to evaluate the association between LAFI and ischemic stroke or transient ischemic attack (TIA). Over a mean follow-up of 7.1 years, 58 study participants (5.9%) experienced an ischemic stroke or TIA. In patients without known baseline AF or warfarin therapy (n = 893), participants in the lowest quintile of LAFI had >3 times the risk of ischemic stroke or TIA (hazard ratio 3.3, 95% confidence interval 1.1 to 9.7, p = 0.03) compared with those in the highest quintile. For each standard deviation (18.8 U) decrease in LAFI, the hazard of ischemic stroke or TIA increased by 50% (hazard ratio 1.5, 95% confidence interval 1.0 to 2.1, p = 0.04). Among measured echocardiographic indexes of LA function, including LA volume, LAFI was the strongest predictor of ischemic stroke or TIA. In conclusion, LA dysfunction is an independent risk factor for stroke or TIA, even in patients without baseline AF.

Association of CHADS2, CHA2DS2-VASc, and R2CHADS2 Scores With Left Atrial Dysfunction in Patients With Coronary Heart Disease (from the Heart and Soul Study)

The predictive ability of the CHADS2 index to stratify stroke risk may be mechanistically linked to severity of left atrial (LA) dysfunction. This study investigated the association between the CHADS2 score and LA function. We performed resting transthoracic echocardiography in 970 patients with stable coronary heart disease and normal ejection fraction and calculated baseline LA functional index (LAFI) using a validated formula: (LA emptying fraction×left ventricular outflow tract velocity time integral)/LA end-systolic volume indexed to body surface area. We performed regression analyses to evaluate the association between risk scores and LAFI. Among 970 subjects, mean CHADS2 was 1.7±1.2. Mean LAFI decreased across tertiles of CHADS2 (42.8±18.1, 37.8±19.1, 36.7±19.4, p<0.001). After adjustment for age, sex, race, systolic blood pressure, hyperlipidemia, myocardial infarction, revascularization, body mass index, smoking, and alcohol use, high CHADS2 remained associated with the lowest quartile of LAFI (odds ratio 2.34, p=0.001). In multivariable analysis of component co-morbidities, heart failure, age, and creatinine clearance<60 ml/min were strongly associated with LA dysfunction. For every point increase in CHADS2, the LAFI decreased by 4.0%. Secondary analyses using CHA2DS2-VASc and R2CHADS2 scores replicated these results. Findings were consistent when excluding patients with baseline atrial fibrillation. In conclusion, CHADS2, CHA2DS2-VASc, and R2CHADS2 scores are associated with LA dysfunction, even in patients without baseline atrial fibrillation. These findings merit further study to determine the role of LA dysfunction in cardioembolic stroke and the value of LAFI for risk stratification.

Urine calcium excretion, cardiovascular events, and mortality in outpatients with stable coronary artery disease (from the Heart and Soul study).

We sought to evaluate the association of urine calcium excretion (UCaE), which reflects systemic calcium absorption, with cardiovascular (CV) events and mortality in outpatients with prevalent coronary heart disease (CHD). Calcium supplementation is associated with vascular calcification and adverse CV outcomes in patients with end-stage renal disease. Recent studies have raised concern that this phenomenon may also extend to the general population. However, previous studies have assessed oral calcium intake, which correlates poorly with systemic calcium absorption. We measured UCaE from 24-hour urine collections provided by 903 outpatients who were recruited from 2000 to 2002. We used Cox proportional hazard models to evaluate the association of baseline UCaE with a primary end point of any CV event (myocardial infarction [MI], heart failure, stroke, or CV mortality). During a mean follow-up of 6 ± 3 years, 287 subjects (32%) had a CV event. After multivariate adjustment for demographics, traditional CV risk factors, and kidney function, there was no association between UCaE and the primary end point of any CV event (per 10-mg/day greater UCaE, hazard ratio 1.00, 95% confidence interval 0.98 to 1.02). Evaluation of individual CV outcomes revealed a lower rate of MI with higher UCaE (hazard ratio 0.97, 95% confidence interval 0.94 to 1.00). In conclusion, greater UCaE is not associated with higher overall CV event rates or mortality in outpatients with stable CHD. On the contrary, greater UCaE is associated with a modestly lower rate of MI. These findings suggest that greater systemic calcium absorption does not confer CV harm in outpatients with prevalent CHD.