Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Role of myocardial strain imaging in surveillance and management of cancer therapeutics-related cardiac dysfunction: A systematic review.

Transthoracic echocardiography is the primary cardiac imaging modality for the detection of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD) through evaluation of serial changes in left ventricular ejection fraction (LVEF). However, LVEF assessment by standard methods including 3D Echo has important limitations including the fact that reduction in LVEF occurs late in the process of CTRCD. In contrast, by detecting early myocardial change, myocardial strain or deformation imaging has evolved to be a preferred parameter for detecting CTRCD. Peak systolic global longitudinal strain (GLS) by speckle-tracking echocardiography (STE) has become an important prechemotherapy parameter that can independently predict subsequent adverse cardiac events as these abnormalities typically precede reduction in LVEF. While an absolute GLS measurement may be informative, a 10%-15% early reduction in GLS by STE appears to be the most useful prognosticator for cardiotoxicity while on therapy. In this paper, we present a current systematic literature review of application of myocardial strain imaging in cancer patients performed following PRISMA guidelines using electronic databases from MEDLINE, Embase, and SCOPUS Library from their inception until June 11th 2020. This review demonstrates the incremental value of myocardial deformation imaging over traditional LVEF in detection and its clinical implication in management of CTRCD.

The association of non-alcoholic fatty liver disease and cardiac structure and function-Framingham Heart Study.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease confers increased risk for cardiovascular disease, including heart failure (HF), for reasons that remain unclear. Possible pathways could involve an association of liver fat with cardiac structural or functional abnormalities even after accounting for body size. METHODS: We analysed N = 2356 Framingham Heart Study participants (age 52 ± 12 years, 52% women) who underwent echocardiography and standardized computed tomography measures of liver fat. RESULTS: In cross-sectional multivariable regression models adjusted for age, gender, cohort and cardiovascular risk factors, liver fat was positively associated with left ventricular (LV) mass (ß = 1.45; 95% confidence interval (CI): 0.01, 2.88), LV wall thickness (ß = 0.01; 95% CI: 0.00, 0.02), mass volume ratio (ß = 0.02; 95% CI 0.01, 0.03), mitral peak velocity (E) (ß = 0.83; 95% CI 0.31, 1.36) and LV filling pressure (E/e' ratio) (ß = 0.16; 95% CI 0.09, 0.23); and inversely associated with global systolic longitudinal strain (ß = 0.20, 95% CI 0.07, 0.33), diastolic annular velocity (e') (ß = -0.12; 95% CI - 0.22, -0.03), and E/A ratio (ß = -0.01; 95% CI - 0.02, -0.00). After additional adjustment for body mass index (BMI), statistical significance was attenuated for all associations except for that of greater liver fat with increased LV filling pressure, a possible precursor to HF (ß = 0.11; 95% CI 0.03, 0.18). CONCLUSION: Increased liver fat was associated with multiple subclinical cardiac dysfunction measures, with most of associations mediated by obesity. Interestingly, the association of liver fat and LV filling pressure was only partially mediated by BMI, suggesting a possible direct effect of liver fat on LV filling pressure. Further confirmatory studies are needed.

Recurrent bioprosthetic mitral valve thrombosis treated with anticoagulation.

Bioprosthetic valve thrombosis (BPVT) is more common than previously thought and likely underreported. BPVT can be accurately diagnosed with cardiac imaging and treated successfully with anticoagulation, thus preventing reoperation. We hereby report a case of recurrent BPVT in the mitral position successfully treated with anticoagulation along with review of literature.

A spectrum of sinus of Valsalva aneurysm-From the young to the old.

Sinus of Valsalva aneurysm (SVA) is a rare but potentially serious condition. Proper and timely diagnosis is crucial to the outcome of patients, particularly when rupture has occurred. Echocardiography is often the initial diagnostic imaging modality of choice as it is ubiquitous, relatively inexpensive, and without need for radiation or iodinated contrast administration. There are several congenital abnormalities that can appear similar to SVA on echocardiography, making the diagnosis challenging especially if providers are unfamiliar with these conditions. Here, we present a case series of three patients with SVA, representing a wide spectrum ranging from a young man presenting with acute rupture and decompensated heart failure to an elderly asymptomatic male with an incidental unruptured aneurysm. We will also present a brief literature overview and our approach to differentiating SVA from other congenital abnormalities on echocardiography.

Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

The role of maximal inspiratory pressure on functional performance in adults with heart failure.

BACKGROUND: Exercise intolerance is common among adults with heart failure (HF) and is a strong prognostic indicator. We examined maximal inspiratory pressure (MIP) as an indicator of maximal and submaximal exercise capacity in older HF patients. METHODS: Fifty-one patients age ≥ 50 years with HF underwent MIP testing via the PrO2 device. Peak oxygen uptake (VO2), 6 min walk distance (6MWD), 30 s sit-to-stand test (STS), gait speed (GS), grip strength and lower extremity muscle strength [one-repetition maximum (1RM)] were measured. Correlation and exploratory multiple regression analyses investigated relationships between MIP, left ventricular ejection fraction (LVEF), age, body mass index (BMI) and physical function. MIP was then stratified by median (64 cm H2O), and endpoints were compared between median groups. RESULTS: The median age was 69 years [interquartile range (IQR): 66-73], and the median LVEF was 36.5% (IQR: 30%-45%). Regression identified MIP as an independent predictor for grip strength, 6MWD, 1RM weight and 30 s STS after adjustment for age, BMI and LVEF. MIP greater than the median (n = 25) independently predicted and reflected greater peak VO2 [14.2 (12.8-18.1) vs. 11.5 (9.7-13.0) mL/kg/min; P = 0.0007] as well as 6MWD, 1RM, 30 s STS and GS (all P < 0.05). CONCLUSION: The analysis demonstrates that MIP is a novel biometric for exercise tolerance in adults with HF. Assessments of MIP are safe and convenient, with the potential to enhance routine HF surveillance and provide novel biometrics to guide HF therapeutics.

Longitudinal tracking of left atrial diameter over the adult life course: Clinical correlates in the community.

BACKGROUND: Increased left atrial diameter (LAD) is associated with elevated risk of atrial fibrillation (AF) and cardiovascular disease. Information is limited regarding the short- or long-term correlates of LAD. METHODS AND RESULTS: We evaluated clinical correlates of LAD for a 16-year period in 4403 Framingham Study participants (mean age, 45 years; 52% women; median observations/participant=3) using multilevel modeling. We related age, sex, body mass index (BMI), systolic and diastolic blood pressure (BP), diabetes, and antihypertensive treatment to LAD. Sex-specific growth curves for LAD were estimated for individuals with low, intermediate, and high risk factor burden. We also related risk factors to changes in LAD during a 4-year period in 3365 participants. Age, male sex (3.83 mm compared to women), greater BMI, higher systolic BP (0.24 mm per 10 mm Hg increment), and antihypertensive treatment (0.54 mm) were associated positively with LAD (P<0.001). Men had a greater increase in LAD with BMI than women (2.02 versus 1.77 mm in women, per 5-unit increment), and individuals receiving antihypertensive treatment experienced a greater increase in LAD with age (0.95 versus 0.63 mm per 10-year age increment) when compared with those not receiving antihypertensive treatment. Overall, greater risk factor burden was positively associated with LAD. These risk factors were also associated positively with 4-year change in LAD (P<0.001). CONCLUSIONS: Our longitudinal study of a large community-based sample identified higher BP and greater BMI as key modifiable correlates of LAD, suggesting that maintaining optimal levels of these risk factors through the life course may prevent atrial remodeling and AF.

Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study.

BACKGROUND: The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited. METHODS AND RESULTS: Using multilevel modeling, we analyzed up to 4 serial echocardiographic observations obtained over a 16-year period in 4062 Framingham Heart Study participants (mean age 45 years, 54% women; 11 485 person-observations). We related left ventricular (LV) wall thickness, LV systolic and diastolic dimensions, and fractional shortening to age, sex, body mass index, blood pressure (including antihypertensive medication use), smoking, and diabetes mellitus (separate analyses for each echocardiographic measure). With advancing age, LV dimensions decreased, whereas fractional shortening and LV wall thickness increased concomitantly. Male sex, body mass index, and blood pressure indices/hypertension treatment were significantly related to both greater LV dimensions and LV wall thickness. The effect of age on cardiac remodeling was influenced by key covariates (P<0.05 for all interactions): Women and individuals with diabetes mellitus experienced greater age-associated increases in LV wall thickness; presence of diabetes or a higher blood pressure was associated with a lesser decrease in LV diastolic dimensions with increasing age; and antihypertensive medication use was a marker of an attenuated increase in fractional shortening with aging. CONCLUSIONS: Cardiac remodeling over the adult life course is characterized by a distinct pattern of increasing LV wall thickness, decreasing LV dimensions, and increasing fractional shortening with advancing age. Overall, female sex, greater blood pressure load, and presence of diabetes mellitus serve to attenuate this remodeling pattern. These observations suggest a mechanism for the preponderance of women with hypertension and individuals with diabetes among patients with diastolic heart failure.

Aortic root remodeling over the adult life course: longitudinal data from the Framingham Heart Study.

BACKGROUND: Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course. METHODS AND RESULTS: We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid to late adulthood and to determine its short-term (4 years; n=6099 observations in 3506 individuals) and long-term (16 years; n=14,628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size, and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P < or = 0.01). Aortic root diameter increased with age in both men and women but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m(2) increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10-mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size. CONCLUSIONS: These longitudinal community-based data show that aortic root remodeling occurs over mid to late adulthood and is principally associated with age, sex, body size, and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study.

Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.

Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.

Early Identification of Decompensated Aortic Regurgitation With Stress Echocardiography.

•Chronic severe AR progresses slowly with a long asymptomatic compensated phase.•Stress echocardiography (SE) has the ability to uncover subclinical LV dysfunction.•SE can identify patients with severe AR who may benefit from earlier intervention.

Longitudinal tracking of left ventricular mass over the adult life course: clinical correlates of short- and long-term change in the framingham offspring study.

BACKGROUND: Information is limited on the longitudinal tracking of left ventricular (LV) mass over the adult life course and the determinants of such change. METHODS AND RESULTS: We used multilevel modeling to evaluate the correlates of LV mass prospectively over a 16-year period in 4217 Framingham study participants (mean age 45 years, 53% women) using up to 4 serial routine echocardiographic observations on each individual (11 762 observations). Age, sex, body mass index, systolic blood pressure, antihypertensive treatment, smoking, and diabetes mellitus were related to longitudinal measures of LV mass. Women and participants with diabetes mellitus experienced a steeper increase in LV mass with advancing age (compared with men and those without diabetes mellitus; P for interactions <0.0001 and 0.0003, respectively). Women also displayed greater increments in LV mass with increasing body mass index (compared with men, P=0.04 for interaction). Participants with optimal values of these risk factors experienced lesser increases in LV mass over time. Analyses evaluating short-term (4-year) changes in LV mass (2605 unique individuals providing 4494 observations) identified the same key determinants that influenced its long-term trajectory (ie, body mass index, sex, systolic blood pressure, antihypertensive treatment, and smoking). CONCLUSIONS: Our longitudinal observations on a large community-based sample identified higher blood pressure, excess adiposity, smoking, and diabetes mellitus as fundamental determinants of LV mass tracking over the adult life course. These observations are consistent with the notion that maintenance of optimal levels of these risk factors in midlife will reduce the burden of LV hypertrophy, and possibly heart failure, in older age.

Prognostic Significance of Echocardiographic Measures of Cardiac Remodeling.

BACKGROUND: In recent decades, novel echocardiographic measures have constantly emerged. It is still unclear which echocardiographic measures have the most significant prognostic value in the general population. Accordingly, the aim of this study was to compare the prognostic value of a large panel of echocardiographic measures to identify the most promising measures. METHODS: A total of 1,497 Framingham study participants (mean age, 65 years; 55.4% women) who underwent echocardiographic measurements of left ventricular ejection fraction, left ventricular mass index, global longitudinal strain, global circumferential strain, mitral annular plane systolic excursion, mitral E/e' ratio, maximum and minimum left atrial (LA) volume index, LA emptying fraction, and left ventricular longitudinal synchrony were evaluated. These measures were related to the incidence of two composite outcomes: cardiovascular disease (CVD) or death and atrial fibrillation (AF) or congestive heart failure (CHF). RESULTS: On follow-up (mean, 8.3 years), there were 241 CVD events or deaths and 139 AF or CHF events. In multivariate-adjusted Cox models, higher LA emptying fraction was associated with a lower risk (hazard ratios per SD, 0.80 and 0.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) while higher minimum LA volume index (hazard ratios per SD, 1.32 and 1.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) and maximum LA volume index (hazard ratios per SD, 1.26 and 1.54 for CVD or death and AF or CHF, respectively; P ≤ .002 for both) were associated with a higher risk for both composite outcomes. CONCLUSIONS: In this community-based sample, LA volumes and function were the best echocardiographic predictors of clinical outcomes. Therefore, these values should be considered for inclusion in standard echocardiographic assessments for the purpose of risk stratification.

Relations of biomarkers representing distinct biological pathways to left ventricular geometry.

BACKGROUND: Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear. METHODS AND RESULTS: We evaluated 2119 Framingham Offspring Study participants (mean age, 57 years; 57% women) who underwent measurements of biomarkers of inflammation (C-reactive protein), hemostasis (fibrinogen and plasminogen activator inhibitor-1), neurohormonal activation (B-type natriuretic peptide), and renin-angiotensin-aldosterone system (aldosterone and renin modeled as a ratio [ARR]) and echocardiography at a routine examination. LV geometry was defined on the basis of sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT): normal (LVM and RWT <80th percentile), concentric remodeling (LVM <80th percentile but RWT >or=80th percentile), eccentric hypertrophy (LVM >or=80th percentile but RWT <80th percentile), and concentric hypertrophy (LVM and RWT >or=80th percentile). We related the biomarker panel to LV geometry using polytomous logistic regression adjusting for clinical covariates and used backwards elimination to identify a parsimonious set of biomarkers associated with LV geometry. Modeled individually, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1, and ARR were related to LV geometry (P<0.01). In multivariable analyses, the biomarker panel was significantly related to altered LV geometry (P<0.0001). On backwards elimination, logARR alone was significantly and positively associated with eccentric (odds ratio per SD increment, 1.20; 95% confidence interval, 1.05 to 1.37) and concentric LV hypertrophy (odds ratio per SD increment, 1.29; 95% confidence interval, 1.06 to 1.58). CONCLUSIONS: Our cross-sectional observations on a large community-based sample identified ARR as a key correlate of concentric and eccentric LV hypertrophy, consistent with a major role for the renin-angiotensin-aldosterone system in LV remodeling.

Prevalence, clinical correlates, and prognosis of discrete upper septal thickening on echocardiography: the Framingham Heart Study.

The upper interventricular septum may be prominent in elderly individuals, a finding referred to as discrete upper septal thickening (DUST). We examined the prevalence, clinical and echocardiographic correlates, and prognostic significance of DUST in a community-based sample. We evaluated Framingham Study participants who underwent routine echocardiography. In 3562 Framingham Study participants (mean age 58 years, 57% women), DUST was observed in 52 participants. The clinical correlates of DUST were increasing age (odds ratio [OR] per 10 year increment 2.59, 95% confidence intervals [CI] 1.64-4.08) and systolic blood pressure (OR per SD increment 1.55, 95% CI 1.15-2.09). DUST was positively associated with left ventricular (LV) fractional shortening and mitral annular calcification but inversely with LV diastolic dimensions (P < 0.02 for all). On follow-up (mean 15 years), 732 individuals died (33 with DUST) and 560 experienced a cardiovascular disease (CVD) event (18 with DUST). Adjusting for cardiovascular risk factors, DUST was not associated with CVD or mortality risk (P > 0.30 for both). The follow-up component of our study suggests that DUST is not independently associated with adverse prognosis.

Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Partial Atrioventricular Canal Defect With an Anomalous Left Circumflex Coronary Artery in an Elderly Veteran.

This study reports a case of partial atrioventricular canal defect with an anomalous left circumflex coronary artery in an elderly veteran presenting with unexplained dyspnea on exertion. This is a rare finding in this population and emphasizes the importance of a broad differential diagnosis and meticulous evaluation when more common conditions have been excluded. (Level of Difficulty: Intermediate.).