The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation. We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute’s Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3 , MYH7 , and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected. Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.

Background—: Re-endothelialization is delayed after drug-eluting stent (DES) implantation. In this setting, neointima is more prone to become lipid laden and develop neoatherosclerosis (NA), potentially increasing plaque vulnerability. Methods and Results—: Optical coherence tomography and near-infrared spectroscopy with intravascular ultrasound were used to characterize NA in 65 (51 DES and 14 bare-metal stents) consecutive symptomatic patients with in-stent restenosis. Median duration poststent implantation was 33 months. Optical coherence tomography–verified NA was observed in 40 stents with in-stent restenosis (62%), was more prevalent in DES than bare-metal stents (68% versus 36%; P =0.02), and demonstrated significantly higher prevalence of thin-cap neoatheroma (47% versus 7%; P =0.01) in DES. Near-infrared spectroscopy assessment demonstrated that the total lipid core burden index (34 [interquartile range, 12–92] versus 9 [interquartile range, 0–32]; P <0.001) and the density of lipid core burden index (lipid core burden index/4 mm, 144 [interquartile range, 60–285] versus 26 [interquartile range, 0–86]; P 70% in-stent restenosis. By logistic regression, prior DES was the only independent predictor of both NA (odds ratio, 7.0; 95% confidence interval, 1.7–27; P =0.006) and periprocedural myocardial infarction (odds ratio, 1.8; 95% confidence interval, 1.1–2.4; P =0.05). Conclusions—: In-stent thin-cap neoatheroma is more prevalent, is distributed more diffusely across the stented segment, and is associated with increased periprocedural myocardial infarction in DES compared with bare-metal stents. These findings support NA as a mechanism for late DES failure.