Person:

Everett, Brendan

Background: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. Methods: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan® probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. Results: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. Conclusion: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.

Aims Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown. Methods and results We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684–0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709–0.774); P = 0.001], the category-less net reclassification [0.490 (0.301–0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033–0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1–5, and 5+% [0.041 (−0.044–0.12); P = 0.33]. Conclusion: Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories.

Background— Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. Methods and Results— We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted hazard ratio [aHR], 2.19; 95% confidence interval, 1.56–3.06; P for trend <0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR, 1.94; 95% confidence interval, 1.41–2.68; P for trend <0.001). The risk of all-cause mortality was elevated for the highest versus the lowest tertiles of hsTnI (aHR, 2.61; 95% confidence interval, 1.81–3.78; P for trend <0.001) and BNP (aHR, 1.45; 95% confidence interval, 1.03–2.04; P for trend 0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range, 0.50–0.60) and BNP (aHR range, 0.42–0.67) with no statistically significant evidence of interaction (P for interaction=0.53 and 0.20, respectively). Conclusions— In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Background: Subclinical myocardial injury, as measured by high‐sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus. Methods and Results: We randomized, in a 2×2 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT‐proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1–Q3) plasma concentration was 35.4 (15.7–86.3) ng/L for NT‐proBNP and 6.7 (4.6–10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT‐proBNP concentration was 20.7% (7.9–35.0) in the insulin arm compared with 0.13% (−10.8 to 12.5) in the no‐insulin arm (P=0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT‐proBNP was 7.8% (−3.7 to 20.7) compared with 13.0% (0.72–26.8) in the no‐metformin arm (P=0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms. Conclusions: Insulin glargine was associated with a significant 20.7% increase in NT‐proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00366301.