Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10⁻¹⁰), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10⁻⁸ and P=1.8×10⁻⁸, respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Approximately 2 million people participate in long-distance running races in the United States annually. Reports of race-related cardiac arrests have generated concern about the safety of this activity.

Iron deficiency is the most common nutritional deficiency worldwide, affecting more than 15% of the global population as of 2010¹ and approximately one-half of patients with symptomatic heart failure.² The presence of iron deficiency in patients with heart failure, regardless of hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality.^2,3

Background—: Exercise capacity as measured by peak oxygen uptake (V o ₂ ) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of V o ₂ changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o ₂ extraction (arterio-mixed venous o ₂ content difference, [C(a-v)o ₂ ]) during exercise significantly contributes to impaired exercise capacity in HFpEF. Methods and Results—: We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak V o ₂ =13.9±0.5 mL kg ⁻¹ min ⁻¹ , mean±SEM, and HFrEF, n=56, peak V o ₂ =12.1±0.5 mL kg ⁻¹ min ⁻¹ ) and 24 control subjects (peak V o ₂ 27.0±1.7 mL kg ⁻¹ min ⁻¹ ). Peak exercise C(a-v)o ₂ was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P <0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Ca o ₂ , or cardiac filling pressures. Peak C(a-v)o ₂ and peak heart rate emerged as the leading predictors of peak V o ₂ in HFpEF. Impaired peripheral o ₂ extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise ( r =0.49, P =0.0005). Conclusions—: In the first study to directly measure C(a-v)o ₂ throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o ₂ was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o ₂ extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.