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Background: 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 coronary artery disease (CAD). Methods: We measured hs-cTnT at baseline and after 5 years in 635 ambulatory Heart and Soul Study patients with CAD. We also performed echocardiography at rest and after treadmill exercise at baseline and after 5 years. Participants were subsequently followed for the outcome of death. We used a multivariable-adjusted Cox proportional hazards model to evaluate the association between 5-year change in hs-cTnT and subsequent all-cause mortality. Results: Of the 635 subjects, 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-year follow-up after the year 5 visit. 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 (hazard ratio 1.7, 95% confidence interval 1.1–2.7). When addition of year 5 hs-cTnT was compared to a model including clinical variables and baseline hs-cTnT, there was a modest but statistically significant increase in C-statistic from 0.82 to 0.83 (p = 0.04). Conclusion: In ambulatory patients with CAD, serial increases in hs-cTnT over time are associated with an increased risk of death. [ABSTRACT FROM AUTHOR]

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]

Background 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. Methods Using echo-estimated LV end-diastolic volume index and diastolic function category, the relative position of the LV- EDPVR was defined in 901 participants with stable CAD as: (1) left-shifted, (2) right-shifted, or (3) intermediate. We then evaluated the association of LV- EDPVR position relative to the intermediate category with time to hospitalization for heart failure ( HF) or cardiovascular ( CV) death using Cox proportional hazards models. Results During 7.0 ± 3.1 years of follow-up, there were 207 admissions for HF or CV deaths. Both leftward and rightward shifts of LV- EDPVR were associated with a significantly higher risk of HF or CV death ( HR 1.73, 95% CI 1.15-2.62 and HR 6.75, 95% CI 4.02-11.31, respectively). In multivariable-adjusted models, these associations were attenuated but remained significant ( HR 1.66, 95% CI 1.08-2.55 for left-shifted and HR 4.19, 95% CI 2.32-7.55 for right-shifted). The association of LV- EDPVR with HF or CV death was no longer significant after inclusion of N-terminal pro-brain natriuretic peptide level as a covariate. Conclusions In stable CAD, echo-estimated leftward and rightward shifts in the LV- EDPVR are associated with HF and CV death. The loss of these associations after adjustment for N-terminal pro-brain natriuretic peptide level suggests that echo-estimated LV- EDPVR captures changes in LV filling pressure at any given LV end-diastolic volume. [ABSTRACT FROM AUTHOR]

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]