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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., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Elevated concentrations of cystatin C are associated with greater cardiovascular morbidity and mortality. We sought to determine whether elevated concentrations of cystatin C were associated with inducible ischemia in patients with coronary heart disease (CHD)., Methods: We measured serum cystatin C and performed exercise treadmill testing with stress echocardiography in a cross-sectional study of 899 outpatients with CHD., Results: Among the 241 participants in the highest quartile of cystatin C (>1.30 mg/L), 38% had inducible ischemia, compared with 13% of those in the lowest quartile of cystatin C < 0.92 mg/L; adjusted odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.2 to 3.8; p = 0.01). However, this association differed in participants with and without a history of coronary artery bypass graft (CABG), as well as in users and nonusers of beta-blockers and statins (p values for interaction < 0.1). Among participants without a history of CABG, 35% of those in the highest quartile and 9% of those in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 3.05; 95% CI: 1.3-6.9; p = 0.008). Among participants who were not using beta-blockers, 44% of those in the highest quartile and 7% in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 5.3; 95% CI: 1.8-15.5; p = 0.002). Among participants who were not using statins, 39% of participants in the highest quartile and 4% of those in the lowest quartile had inducible ischemia (adjusted OR: 10.3; 95% CI: 2.5-43.3; p = 0.001)., Conclusions: Elevated levels of cystatin C are independently associated with inducible ischemia among outpatients with stable coronary disease.

Aims: The predictive value of changes in global left ventricular (LV) size after exercise has not been studied. Left ventricular end-systolic volume (ESV) is a relatively load-independent echocardiographic marker of contractility that is easily measured. We investigated the role of the change in ESV at rest and after peak exercise on mortality among patients with stable coronary heart disease (CHD)., Methods and Results: We performed exercise treadmill testing with stress echocardiography in 934 ambulatory subjects with CHD. End-systolic volume was measured immediately before and after exercise using 2D echocardiography. We defined ESV reversal as an increase in ESV after exercise, and we examined the association of ESV reversal with all-cause mortality during a median follow-up of 3.92 years. Of the 934 participants, 199 (21%) had ESV reversal. At the end of follow-up, mortality was higher among participants with ESV reversal than those without (26 vs. 11%; P < 0.001). After adjustment for clinical covariates, ESV reversal remained predictive of all-cause mortality (HR 2.0; 95% CI 1.4-2.9; P = 0.001). The association of ESV reversal with mortality also persisted after adjustment for exercise-induced wall-motion abnormalities (HR 1.7; 95% CI 1.1-2.3, P = 0.006). To determine if the effect of ESV reversal was independent from other echocardiographic measurements, we created a separate model adjusting for resting LV ejection fraction, ESV, end-diastolic volume, and LV mass. End-systolic volume reversal was the only significant predictor of mortality in this model (HR 2.1, 95% CI 1.4-3.0, P < 0.001)., Conclusion: End-systolic volume reversal is a novel parameter that independently predicts mortality in patients with CHD undergoing exercise treadmill echocardiography, even after adjustment for a wide range of clinical, echocardiographic, and treadmill exercise variables. Because measurement of ESV is simple, reproducible, and requires no additional imaging views, identification of ESV reversal during exercise echocardiography can provide useful complementary information for risk stratification.

Background: B-type natriuretic peptide (BNP) is predictive of inducible ischemia in patients with coronary heart disease (CHD). Whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a comparable strength of association with ischemia is uncertain., Hypothesis: Resting NT-proBNP levels are associated with inducible ischemia in patients with stable CHD., Methods: We performed a cross-sectional study of 901 outpatients with stable CHD. NT-proBNP was measured in all patients prior to exercise treadmill testing and stress echocardiography. In addition, plasma BNP was measured in a subset of 355 participants. Logistic regression was used to examine the association of NT-proBNP and BNP quartiles with inducible ischemia., Results: Inducible ischemia was found in 216 (24%) patients. The proportion with inducible ischemia ranged from 42% (95/225) in the highest quartile of NT-proBNP levels (>410 pg/ml) to 9% (21/226) in the lowest quartile (0-72 pg/ml). The highest quartile had a 7-fold greater odds of inducible ischemia than the lowest quartile (odds ratio [OR]: 7.1, 95% confidence interval [CI]: 4.2-12; P < 0.0001). This association remained robust after adjustment for traditional cardiovascular risk factors, left ventricular ejection fraction, and diastolic dysfunction (OR: 3.6, 95% CI: 1.4-9.1; P = 0.009). In the subgroup with measurements of both NT-proBNP and BNP, both natriuretic peptides were predictive of ischemia. The multivariable-adjusted c-statistics for inducible ischemia were 0.71 for NT-proBNP and 0.62 for BNP (entered as continuous variables)., Conclusions: Resting NT-proBNP levels are independently associated with inducible ischemia in outpatients with stable CHD. Baseline elevations of natriuretic peptide may indicate subclinical inducible ischemia in high risk patients with CHD.

Background: High-sensitivity C-reactive protein (CRP) is an inflammatory marker that predicts coronary heart disease (CHD) and, in recent studies, incident heart failure (HF). Whether the association of inflammation with incident HF is explained by worse baseline left ventricular dysfunction or by underlying CHD is unknown., Methods and Results: Serum CRP was measured in a cohort of 985 outpatients with established CHD from the Heart and Soul Study. During 3 years of follow-up, 15% of the participants with elevated CRP levels (>3 mg/L) were hospitalised for HF, compared with 7% of those with CRP

Aims: Despite the prevalence of atrial fibrillation (AF) occurring after cardiac surgery, its pathophysiology is incompletely understood. Specifically, whether left atrial (LA) structural remodelling occurs, contributing to a decrement in atrial function and AF has not been previously determined. This study sought to determine the relationship between LA function and post-operative AF., Methods and Results: Three hundred patients undergoing elective coronary artery bypass graft surgery were monitored with intraoperative transoesophageal echocardiography to determine LA function and dimensions. Post-operative AF was monitored with continuous telemetry until hospital discharge. The relationship between clinical factors versus LA function and dimension was assessed using multi-variate logistic regression. By univariate analysis, patients who subsequently developed post-operative AF had a larger LA area and LA appendage area, and lower LA ejection fraction measured in the pre-bypass period compared to those without subsequent AF. By multivariable analysis, in addition to clinical data including age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.05-1.16, P<0.0001), body surface area (OR 13.31, 95% CI 1.87-94.5, P=0.0097) and white race, post-bypass atrial systolic function (atrial filling fraction 0.36, OR 2.51, 95% CI 1.03-6.13, P=0.04) and abnormal relaxation of the left ventricle (E duration 270 ms) (OR 2.89, 95% CI 1.34-6.24, P=0.0067) independently increased the risk of post-operative AF., Conclusion: These results demonstrate that some of the structural and functional changes in the atria common to chronic AF in the elderly population are also prevalent in surgical patients who develop post-operative AF, suggesting that post-operative and chronic AF may have similar pathophysiology.

Background: Elevated levels of C-reactive protein (CRP) are associated with an increased risk of coronary events, but whether inflammation is associated with inducible ischemia in patients with stable coronary disease is unknown., Methods and Results: We recruited patients with known coronary disease from 2 VA Medical Centers and 1 University-based medical center for the Heart and Soul Study. We measured CRP levels in 118 participants who had exercise-induced ischemia and in 111 who did not have inducible ischemia, as determined by stress echocardiography. We used logistic regression to examine the risk of exercise-induced ischemia associated with elevated CRP. We found that 75% (39/52) of participants in the highest CRP category (>0.38 mg/dL) had inducible ischemia, compared with 45% (79/177) in the lower 4 categories combined (adjusted odds ratio 4.2; 95% confidence interval 1.6 to 11; P=0.004). However, this association differed in users and nonusers of beta-blockers and statins. Among 89 participants who did not use beta-blockers, 93% in the highest CRP category had exercise-induced ischemia, compared with 42% in the lower 4 categories (P=0.03). Among 67 participants who did not use statins, 94% in the highest CRP category had exercise-induced ischemia, compared with 44% in the lower 4 categories (P=0.009). We did not observe a significant association between CRP and ischemia among participants who were treated with either of these medications., Conclusion: Elevated CRP levels are associated with inducible ischemia in patients with stable coronary disease, particularly among those not treated with beta-blockers or statins.

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined. [ABSTRACT FROM AUTHOR]

Objectives: We compared the predictive ability of tricuspid regurgitation (TR) and end-diastolic pulmonary regurgitation (EDPR) gradients in outpatients with coronary artery disease. Background: The TR and EDPR gradients, in conjunction with right atrial pressure, provide Doppler estimates of pulmonary artery systolic and diastolic pressures. We hypothesized that increases in TR or EDPR gradients in stable coronary artery disease would predict heart failure (HF) hospitalization or cardiovascular (CV) death. Methods: We measured TR and EDPR gradients in 717 adults with completed outcome adjudications who were recruited for the Heart and Soul Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for HF hospitalization, CV death, all-cause death, and the combined end point. Multivariate adjustments were made for age, gender, race, history of CV or pulmonary disease, functional class, and left ventricular ejection fraction. Results: There were 63 HF hospitalizations, 19 CV deaths, and 86 all-cause deaths at the 3-year follow-up. There were 466 measurable EDPR gradients and 573 measurable TR gradients. Age-adjusted ORs for EDPR >5 mm Hg predicted HF hospitalization (2.7, 95% CI 1.3 to 5.5, p = 0.006), all-cause death (2.5, 95% CI 1.4 to 4.4, p = 0.002), and HF hospitalization or CV death (2.7, 95% CI 1.4 to 5.2, p = 0.004). Age-adjusted OR for TR >30 mm Hg predicted HF hospitalization (3.4, 95% CI 1.9 to 6.2, p < 0.0001) and HF hospitalization or CV death (3.0, 95% CI 1.7 to 5.3, p = 0.0001). Multivariate adjusted OR per 5-mm Hg incremental increases in EDPR predicted HF hospitalization or CV death (1.9, 95% CI 1.01 to 3.6, p = 0.046) and all-cause death (1.7, 95% CI 1.05 to 2.8, p = 0.03). Multivariate adjusted OR per 10-mm Hg incremental increases in TR predicted HF hospitalization or CV death (1.6, 95% CI 1.1 to 2.4, p = 0.008). Conclusions: Increases in EDPR or TR gradients predict HF hospitalization or CV death among ambulatory adults with coronary artery disease. [Copyright &y& Elsevier]

Introduction: Serial increases in high-sensitivity cardiac troponin (hs-cTnT) have been associated with death in community-dwelling adults, but the association remains uninvestigated in those with ambulatory coronary artery disease (CAD). Hypothesis: An increase in hs-cTnT over 5 years predicts subsequent all-cause mortality in ambulatory CAD. Methods: We measured hs-cTnT at baseline and after 5 years in 635 participants with ambulatory CAD. We defined "undetectable" levels of hs-cTnT as < 5 pg/mL, "detectable" as between 5 and 14 pg/mL, and "elevated" as >14 pg/mL. We used an unadjusted and a multivariable-adjusted Cox proportional hazards model to evaluate the association between 5-year change in hs-cTnT and subsequent all-cause mortality. Results: There were 386 participants (61%) who had an increase in hs-cTnT levels between baseline and year 5 measurements (median increase 5.6 pg/mL, IQR 3.2-9.9 pg/mL). There were 182 deaths after a mean 4.2 years of follow-up after year 5. After adjusting for clinical variables, a > 50% increase in hs-cTnT between baseline and year 5 was associated with a nearly 2-fold increased risk of death from any cause (HR 1.7, 95% CI 1.1-2.7). Additional hazard ratios for death from any cause, categorized by levels of baseline and year 5 hs-cTnT, are displayed in the figure. Conclusion: In ambulatory CAD, serial increases in hs-cTnT predict death, suggesting that preventive strategies may be warranted in this setting. Figure: Hazard ratios for death from any cause, categorized by levels of baseline and year 5 high-sensitivity cardiac troponin (hs-cTnT), adjusted for clinical variables. Error bars represent 95% confidence intervals. Data for patients who had detectable baseline but undetectable year 5 levels, as well as patients with elevated baseline but undetectable year 5 levels are not displayed due to small numbers of deaths in these categories. [ABSTRACT FROM AUTHOR]

Introduction: C-reactive protein (CRP) level stratifies risk for events in coronary heart disease (CHD) and is independently associated with increased risk of heart failure (HF). It is unknown how CHD-associated risk of stroke, HF, and all-cause mortality is affected by CRP and if it is modifiable. Hypothesis: The risk associated with elevated CRP in patients with CHD can be modified by beta blocker and statin use. Methods: A cohort of outpatients with CHD from the Heart and Soul Study (N = 985) had serum CRP measured. Outcomes after 7.1 years ± 3.2 years including non-fatal MI, HF, stroke, cardiovascular death, and all-cause mortality were analyzed and modifying factors were compared using Kaplan Meier estimates. Results: Elevated CRP level > 3mg/L (CRPH) was associated with an increased risk of stroke (hazard ratio (HR) 2.4, p = 0.01), HF (HR 1.9, p = 0.001), and all-cause mortality (HR 1.4, p = 0.005), compared to low CRP level < 3mg/L (CRPL). CRPH patients not taking a statin had more HF events (HR 2.9, p = 0.001) and increased risk of all-cause mortality (HR 1.5, p = 0.045) compared to CRPL patients not taking a statin. CRPH patients not taking a beta blocker had more HF events (HR 2.5, p = 0.001) and increased risk of all-cause mortality (HR 1.7, p = 0.003) compared to CRPL patients not taking a beta-blocker. CRPH patients on neither beta blocker nor statin had more HF events (HR 2.7, p = 0.002) and increased risk of all-cause mortality (HR 2.0, p = 0.004) compared to CRPH patients on both medications. CRPL patients on both beta blocker and statin had reduced risk of all-cause mortality (HR 0.6, p = 0.04) compared to CRPL patients on neither medication. Conclusions: Among outpatients with CHD, CRPH is associated with an increased risk of adverse CHD outcomes including stroke, HF, and all-cause mortality. The risk of HF and all-cause mortality is considerable but modified by beta blockers and statins. Among those with CRPL, the use of beta blockers and statin reduces risk of all-cause mortality. [ABSTRACT FROM AUTHOR]