Mathilda Regan

Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts

AIMS Growth differentiation factor 11 and/or its homologue growth differentiation factor 8 (GDF11/8) reverses age-related cardiac hypertrophy and vascular ageing in mice. We investigated whether GDF11/8 associates with cardiovascular outcomes, left ventricular hypertrophy (LVH), or age in humans. METHODS AND RESULTS We measured plasma GDF11/8 levels in 928 participants with stable ischaemic heart disease in the Heart and Soul study. We adjudicated heart failure hospitalization, stroke, myocardial infarction, death, and their composite endpoint. Left ventricular hypertrophy was evaluated by echocardiography. We used multivariable Cox proportional hazards models to compare rates of cardiovascular events and death across GDF11/8 quartiles and logistic regression models to evaluate the association between GDF11/8 and LVH. Four hundred and fifty participants (48.5%) experienced a cardiovascular event or death during 8.9 years of follow-up. The adjusted risk of the composite endpoint was lower in the highest compared with the lowest GDF11/8 quartile [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.33-0.60; P < 0.001]. We replicated this relationship of GDF11/8 to adverse events in 971 participants in the HUNT3 cohort (adjusted HR, 0.34; 95% CI, 0.23-0.51; P < 0.001). Left ventricular hypertrophy was present in 368 participants (39.7%) at baseline. Participants in the highest quartile of GDF11/8 were less likely to have LVH than those in the lowest quartile (adjusted OR, 0.55; 95% CI, 0.35-0.86; P = 0.009). GDF11/8 levels were lower in older individuals (P < 0.001). CONCLUSION In patients with stable ischaemic heart disease, higher GDF11/8 levels are associated with lower risk of cardiovascular events and death. Our findings suggest that GDF11/8 has similar cardioprotective properties in humans to those demonstrated in mice.

B-type Natriuretic Peptides for the Prediction of Cardiovascular Events in Patients With Stable Coronary Heart Disease: The Heart and Soul Study

Background Brain‐type natriuretic peptide (BNP) and the amino‐terminal fragment of its prohormone (NT‐proBNP) are known predictors of cardiovascular outcomes in patients with coronary heart disease; however, the relative prognostic value of these 2 biomarkers for secondary events remains unclear. Methods and Results In 983 participants with stable coronary heart disease, we evaluated the association of BNP and NT‐proBNP with time to hospitalization for heart failure, nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and combined major adverse cardiovascular events (MACE). During an average follow‐up of 6.5±3.3 years, both BNP and NT‐proBNP were associated with increased risk of MACE in a multivariable‐adjusted model (hazard ratio per standard deviation of log BNP: 1.58; 95% CI: 1.32 to 1.89; hazard ratio per standard deviation of log NT‐proBNP: 1.84; 95% CI: 1.52 to 2.24). When added to traditional risk factors, NT‐proBNP predicted MACE better than BNP (C statistic: 0.76 versus 0.72, P<0.001). Similarly, the addition of NT‐proBNP resulted in a greater net reclassification improvement for predicting MACE than the addition of BNP (65% for NT‐proBNP, 56% for BNP). Conclusions Both BNP and NT‐proBNP were significant predictors of MACE in stable coronary heart disease; however, NT‐proBNP was superior to BNP for net risk reclassification for MACE.

Association between kidney function and telomere length: the Heart and Soul Study

Background: Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening. Methods: The Heart and Soul Study is a longitudinal study of patients with stable coronary heart disease. Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFRCKD-EPI), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (n = 954) and 5 years later (n = 608). Linear regression models were used to test the association of kidney function with (i) baseline telomere length and (ii) change in telomere length over 5 years. Results: At baseline, mean eGFRCKD-EPI was 72.6 (±21.5) ml/min/1.73 m2, eGFRcys was 71.0 (±23.1) ml/min/1.73 m2 and ACR was 8.6 (±12.3) mg/g. Only lower baseline eGFRCKD-EPI was associated with shorter baseline telomere length (9.1 (95% CI 1.2–16.9) fewer base pairs for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). Lower baseline eGFRCKD-EPI (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 (95% CI 4.3–17.3) decrease in base pairs over 5 years for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). After adjustment for age, these associations were no longer statistically significant. Conclusions: In patients with coronary heart disease, reduced kidney function is associated with (i) shorter baseline telomere length and (ii) more rapid telomere shortening over 5 years; however, these associations are entirely explained by older age.

Lifetime trauma exposure and prospective cardiovascular events and all-cause mortality: Findings from the Heart and Soul Study

Objective Little is known about the effect of cumulative psychological trauma on health outcomes in patients with cardiovascular disease. The objective of this study was to prospectively examine the association between lifetime trauma exposure and recurrent cardiovascular events or all-cause mortality in patients with existing cardiovascular disease. Methods A total of 1021 men and women with cardiovascular disease were recruited in 2000 to 2002 and followed annually. Trauma history and psychiatric comorbidities were assessed at baseline using the Computerized Diagnostic Interview Schedule for DSM-IV. Health behaviors were assessed using standardized questionnaires. Outcome data were collected annually, and all medical records were reviewed by two independent, blinded physician adjudicators. We used Cox proportional hazards models to evaluate the association between lifetime trauma exposure and the composite outcome of cardiovascular events and all-cause mortality. Results During an average of 7.5 years of follow-up, there were 503 cardiovascular events and deaths. Compared with the 251 participants in the lowest trauma exposure quartile, the 256 participants in the highest exposure quartile had a 38% greater risk of adverse outcomes (hazard ratio = 1.38, 95% confidence interval = 1.06–1.81), adjusted for age, sex, race, income, education, depression, posttraumatic stress disorder, generalized anxiety disorder, smoking, physical inactivity, and illicit drug abuse. Conclusions Cumulative exposure to psychological trauma was associated with an increased risk of recurrent cardiovascular events and mortality, independent of psychiatric comorbidities and health behaviors. These data add to a growing literature showing enduring effects of repeated trauma exposure on health that are independent of trauma-related psychiatric disorders such as depression and posttraumatic stress disorder.

Alcohol consumption and 5-year change in left atrial volume among patients with coronary heart disease: results from the Heart and Soul study.

BACKGROUND Heavy alcohol consumption is a risk factor for developing atrial fibrillation, but whether chronic alcohol use affects left atrial volume is unknown. We evaluated the association of self-reported alcohol consumption with 5-year change in left atrial volume among patients with coronary heart disease (CHD). METHODS We studied 601 participants with stable CHD who underwent 2-dimensional echocardiography at baseline (2000-2002) and after 5 years of follow-up (2005-2007). Alcohol consumption was determined at baseline with the use of the Alcohol Use Disorders Identification Test consumption questions (AUDIT-C), with a standard cutoff point of ≥3 used to define at-risk drinking. We used logistic regression to evaluate the association of baseline alcohol use with 5-year increase in left atrial end-systolic volume index (defined as being in the highest tertile of percent change). RESULTS After adjustment for covariates, each standard deviation (2.4-point) increase in AUDIT-C score was associated with a 24% greater odds of experiencing a 5-year increase in left atrial volume index (adjusted odds ratio [OR] 1.24, 95% confidence interval [CI] 1.04-1.48; P = .02). Compared with the 369 participants who had AUDIT-C scores of <3, the 171 participants with scores of 3-5 had a 51% greater odds (OR 1.51, 95% CI, 1.11-2.25) and the 61 participants with scores of >5 a 98% greater odds (OR 1.98, 95% CI, 1.10-3.56) of experiencing a 5-year increase in left atrial volume index. CONCLUSIONS In patients with CHD, heavier alcohol consumption is associated with a 5-year increase in left atrial volume. Whether greater left atrial volume contributes to the increased risk of atrial fibrillation associated with alcohol use deserves further study.

Effect of physical activity level on biomarkers of inflammation and insulin resistance over 5 years in outpatients with coronary heart disease (from the Heart and Soul Study).

Higher levels of physical activity are associated with lower rates of coronary heart disease (CHD). Previous studies have suggested that this is due partly to lower levels of inflammation and insulin resistance. The aim of this study was to determine whether physical activity level was associated with inflammation or insulin resistance during a 5-year period in outpatients with known CHD. A total of 656 participants from the Heart and Soul Study, a prospective cohort study of outpatients with documented CHD, were evaluated. Self-reported physical activity frequency was assessed at baseline and after 5 years of follow-up. Participants were classified as low versus high activity at each visit, yielding 4 physical activity groups: stable low activity, decreasing activity (high at baseline to low at year 5), increasing activity (low at baseline to high at year 5), and stable high activity. Year 5 markers of inflammation (C-reactive protein [CRP], interleukin-6, and fibrinogen) and insulin resistance (insulin, glucose, and glycated hemoglobin) were compared across the 4 activity groups. After 5 years of follow-up, higher activity was associated with lower mean levels of all biomarkers. In the fully adjusted regression models, CRP, interleukin-6, and glucose remained independently associated with physical activity frequency (log CRP, p for trend across activity groups = 0.03; log interleukin-6, p for trend = 0.01; log glucose, p for trend = 0.003). Subjects with stable high activity typically had the lowest levels of biomarkers. In conclusion, in this novel population of outpatients with known CHD followed for 5 years, higher physical activity frequency was independently associated with lower levels of CRP, interleukin-6, and glucose.

Hostility, health behaviors, and risk of recurrent events in patients with stable coronary heart disease: findings from the Heart and Soul Study.

Background Hostility is a significant predictor of mortality and cardiovascular events in patients with coronary heart disease (CHD), but the mechanisms that explain this association are not well understood. The purpose of this study was to evaluate potential mechanisms of association between hostility and adverse cardiovascular outcomes. Methods and Results We prospectively examined the association between self‐reported hostility and secondary events (myocardial infarction, heart failure, stroke, transient ischemic attack, and death) in 1022 outpatients with stable CHD from the Heart and Soul Study. Baseline hostility was assessed using the 8‐item Cynical Distrust scale. Cox proportional hazard models were used to determine the extent to which candidate biological and behavioral mediators changed the strength of association between hostility and secondary events. During an average follow‐up time of 7.4±2.7 years, the age‐adjusted annual rate of secondary events was 9.5% among subjects in the highest quartile of hostility and 5.7% among subjects in the lowest quartile (age‐adjusted hazard ratio [HR]: 1.68, 95% confidence interval [CI]: 1.30 to 2.17; P<0.0001). After adjustment for cardiovascular risk factors, participants with hostility scores in the highest quartile had a 58% greater risk of secondary events than those in the lowest quartile (HR: 1.58, 95% CI: 1.19 to 2.09; P=0.001). This association was mildly attenuated after adjustment for C‐reactive protein (HR: 1.41, 95% CI, 1.06 to 1.87; P=0.02) and no longer significant after further adjustment for smoking and physical inactivity (HR: 1.25, 95% CI: 0.94 to 1.67; P=0.13). Conclusions Hostility was a significant predictor of secondary events in this sample of outpatients with baseline stable CHD. Much of this association was moderated by poor health behaviors, specifically physical inactivity and smoking.

Soluble endothelial cell selective adhesion molecule and cardiovascular outcomes in patients with stable coronary disease: A report from the Heart and Soul Study

BACKGROUND AND AIMS Endothelial cell-selective adhesion molecule (ESAM) is selectively expressed on vascular endothelium and is postulated to play a role in atherogenesis. We investigated the association of serum soluble ESAM (sESAM) levels with subsequent cardiovascular outcomes in patients with stable ischemic heart disease. METHODS We measured sESAM levels in 981 patients with stable coronary disease enrolled between September 2000 and December 2002 in a prospective cohort study. Poisson regression models were used to define the relationship between baseline sESAM levels and cardiovascular outcomes, including myocardial infarction, heart failure hospitalization, and mortality. RESULTS There were 293 occurrences of the composite endpoint over a median follow-up of 8.9 years. After adjusting for demographic and clinical risk factors, participants in the highest sESAM quartile (compared to the lower three sESAM quartiles) had a higher rate of the composite endpoint (incident rate ratio (IRR) 1.52 (95% CI 1.16-1.99) as well as of its individual components: myocardial infarction (IRR 1.64 (1.06-2.55)), heart failure hospitalizations (IRR 1.96 (1.32-2.81)), and death (IRR 1.5 (1.2-1.89)). These associations were no longer significant after adjustment for estimated glomerular filtration rate. CONCLUSIONS sESAM levels associate with myocardial infarction, heart failure, and death after adjustment for demographic and clinical risk factors, but not after adjustment for kidney function. sESAM may be involved in the pathogenesis of concurrent kidney and cardiovascular disease.

The Prognostic Utility of Echo‐Estimated Left Ventricular End‐Diastolic Pressure–Volume Relationship in Stable Coronary Artery Disease: The Heart and Soul Study

While changes in the left ventricular end‐diastolic pressure–volume relationship (LV‐EDPVR) can be estimated using echocardiography, their prognostic utility in stable coronary artery disease (CAD) is unknown.

Association of Alcohol Use Biomarkers and Cognitive Performance in Veterans With Problematic Alcohol Use and Posttraumatic Stress Disorder: Data From the Mind Your Heart Study

The authors conducted a study of alcohol use biomarkers and cognitive performance among 85 veterans with problematic alcohol use and posttraumatic stress disorder (PTSD). All analyses were adjusted for demographics, depression, anxiety, and PTSD symptoms. Elevated levels of aspartate aminotransferase were associated with worse performance on the Trail Making Test Part A and Hopkins Verbal Learning Test. Two other biomarkers were not associated with any neurocognitive measures. Indirect alcohol use biomarkers (e.g., aspartate aminotransferase) may have a specific role in identifying veterans with problematic alcohol use and PTSD who show a change in psychomotor speed and immediate verbal memory performance.