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.

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.

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.

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.

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.

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.

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.).

Left Ventricular Diastolic Dysfunction in the Community: Impact of Diagnostic Criteria on the Burden, Correlates, and Prognosis.

BACKGROUND: Left ventricular diastolic dysfunction (DD) is common, particularly in women and older individuals, and it is associated with adverse cardiovascular outcomes. We evaluated the impact of age- and sex-specific diagnostic criteria on the assessment of DD in the community-based Framingham Heart Study. METHODS AND RESULTS: We estimated age- and sex-specific reference limits for echocardiographic measures of DD in a healthy reference subsample (N=2355, mean age 44 years, 66% women). The prevalence, correlates, and association with future cardiovascular disease were compared for DD using age- and sex-specific versus single cut point reference limits in a broad sample (N=6102, mean age 50 years, 56% women). Using age- and sex-specific criteria, DD was present in ≈25% to 30% of individuals across age groups, and it was directly associated with a number of modifiable risk factors. In contrast, with single cut point criteria, age was the primary determinant of DD. During follow-up (mean 7.9±2.2 years), incident cardiovascular disease occurred in 213 of 5770 individuals. Using age- and sex-specific criteria, mild and moderate-severe DD were associated with 50% (95% confidence interval, 1.09-2.05) and 65% (95% confidence interval, 1.14-2.38) higher incidences of cardiovascular disease, respectively, in age- and sex-adjusted analyses. With single cut point criteria, moderate-severe DD (hazard ratio, 1.66; 95% confidence interval, 1.05-2.61), but not mild DD (hazard ratio, 0.94; 95% confidence interval, 0.63-1.40), was associated with incident cardiovascular disease. CONCLUSIONS: Age- and sex-specific reference limits may result in DD assessments that are less dependent on age, more robustly related to modifiable risk factors, and are more closely associated with incident cardiovascular disease.

Association of Left Atrial Function Index with Atrial Fibrillation and Cardiovascular Disease: The Framingham Offspring Study.

BACKGROUND: Left atrial (LA) size, a marker of atrial structural remodeling, is associated with increased risk for atrial fibrillation (AF) and cardiovascular disease (CVD). LA function may also relate to AF and CVD, irrespective of LA structure. We tested the hypothesis that LA function index (LAFI), an echocardiographic index of LA structure and function, may better characterize adverse LA remodeling and predict incident AF and CVD than existing measures. METHODS AND RESULTS: In 1786 Framingham Offspring Study eighth examination participants (mean age, 66±9 years; 53% women), we related LA diameter and LAFI (derived from the LA emptying fraction, left ventricular outflow tract velocity time integral, and indexed maximal LA volume) to incidence of AF and CVD on follow-up. Over a median follow-up of 8.3 years (range, 7.5-9.1 years), 145 participants developed AF and 139 developed CVD. Mean LAFI was 34.5±12.7. In adjusted Cox regression models, lower LAFI was associated with higher risk of incident AF (hazard ratio=3.83, 95% confidence interval=2.23-6.59, lowest [Q1] compared with highest [Q4] LAFI quartile) and over 2-fold higher risk of incident CVD (hazard ratio=2.20, 95% confidence interval=1.32-3.68, Q1 versus Q4). Addition of LAFI, indexed maximum LA volume, or LA diameter to prediction models for AF or CVD did not significantly improve model discrimination for either outcome. CONCLUSIONS: In our prospective investigation of a moderate-sized community-based sample, LAFI, a composite measure of LA size and function, was associated with incident AF and CVD. Addition of LAFI to the risk prediction models for AF or CVD, however, did not significantly improve their performance.

Comorbidities and Cardiometabolic Disease: Relationship With Longitudinal Changes in Diastolic Function.

OBJECTIVES: This study sought to evaluate the course, correlates, and prognosis of longitudinal changes in left ventricular (LV) diastolic dysfunction (DD) in the community-based Framingham Heart Study. BACKGROUND: Relationships of clinical risk factors to longitudinal progression of DD are incompletely understood. METHODS: Diastolic function was assessed by echocardiography performed at consecutive examinations (visits 1 and 2, mean interval 5.6 years) in 1,740 participants (64 ± 8 years of age at visit 1, 59% women) with normal LV systolic function and no atrial fibrillation. RESULTS: Of 1,615 individuals with normal-to-mild DD at visit 1, 198 (12%) progressed to ≥ moderate DD at visit 2. Progression was more likely in women and with advancing age (p < 0.0001). Of 125 individuals with ≥ moderate DD at visit 1, 25 (20%) regressed to normal-to-mild DD by visit 2. Regression of DD was associated with younger age (p < 0.03). In stepwise regression models, age, female sex, baseline and changes in systolic blood pressure, diastolic blood pressure, body mass index, serum triglycerides, and diabetes were positively associated with worsening diastolic function (all p < 0.05). Noncardiac comorbidity tracked with progressive DD. Cardiovascular disease (CVD) or death events occurred in 44 of 1,509 participants free of CVD at visit 2, during 2.7 ± 0.6 years of post-visit 2 follow-up. Presence of ≥ moderate DD was associated with higher risk (age- and sex-adjusted hazard ratio for CVD or death: 2.14; 95% confidence interval: 1.06 to 4.32; p = 0.03). CONCLUSIONS: In a community-based cohort of middle-aged to older adults, cardiometabolic risk factors and noncardiac comorbidities were associated with DD progression. Moderate or worse DD was associated with higher risk of CVD or death.

Prognosis of patients with secondary mitral regurgitation and reduced ejection fraction.

Objective: The impact of the severity of secondary mitral regurgitation (MR) on the risk of death and heart failure (HF) hospitalisations in patients with reduced left ventricular (LV) systolic function is poorly defined. The study sought to identify the incremental risk of secondary MR in patients with reduced LV systolic function. Methods: We studied 615 consecutive patients with LV ejection fraction ≤35% by transthoracic echocardiography at a single medical centre. Patients were divided into three groups of no MR, mild, or moderate to severe MR. The median follow-up was 2.9 years. The primary endpoint was a composite of death or HF hospitalisations. Results: Compared with patients with no MR, the risk of death or HF hospitalisations was higher for mild MR (HR 1.7, P=0.003) and moderate to severe MR (HR 2.7, P<0.001). The risk was also higher for the component endpoints of HF hospitalisations (mild MR: HR 2.3, P=0.001; moderate to severe MR: HR 3.5, P<0.001) and death (mild MR: HR 1.6, P=0.033; moderate to severe MR: HR 2.6, P<0.001). After adjustment for other covariates, MR was no longer significantly associated with death or HF hospitalisations, or death alone, but remained significantly associated with HF hospitalisations (mild MR: HR 1.7, P=0.028; moderate to severe MR: HR 2.2, P=0.002). Conclusions: In patients with reduced LV systolic function, secondary MR is associated with an increased risk of HF hospitalisations but not death.

Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades.

OBJECTIVES: The purpose of this study was to describe the temporal trends in prevalence of left ventricular systolic dysfunction (LVSD) in individuals without and with heart failure (HF) in the community over a 3-decade period of observation. BACKGROUND: Temporal trends in the prevalence and management of major risk factors may affect the epidemiology of HF. METHODS: We compared the frequency, correlates, and prognosis of LVSD (left ventricular ejection fraction [LVEF] <50%) among Framingham Study participants without and with clinical HF in 3 decades (1985 to 1994, 1995 to 2004, and 2005 to 2014). RESULTS: Among participants without HF (12,857 person-observations, mean age 53 years, 56% women), the prevalence of LVSD on echocardiography decreased (3.38% in 1985 to 1994 vs. 2.2% in 2005 to 2014; p < 0.0001), whereas mean LVEF increased (65% vs. 68%; p < 0.001). The elevated risk associated with LVSD (∼2- to 4-fold risk of HF or death) remained unchanged over time. Among participants with new-onset HF (n = 894, mean age 75 years, 52% women), the frequency of heart failure with preserved ejection fraction (HFpEF) increased (preserved LVEF ≥50%: 41.0% in 1985 to 1994 vs. 56.17% in 2005 to 2014; p < 0.001) and heart failure with reduced ejection fraction (HFrEF) decreased (reduced LVEF <40%: 44.10% vs. 31.06%; p = 0.002), whereas heart failure with midrange LVEF remained unchanged (LVEF 40% to <50%: 14.90% vs. 12.77%; p = 0.66). Cardiovascular mortality associated with HFrEF declined across decades (hazard ratio: 0.61; 95% confidence interval: 0.39 to 0.97), but remained unchanged for heart failure with midrange LVEF and HFpEF. Approximately 47% of the observed increase in LVEF among those without HF and 75% of the rising proportion of HFpEF across decades was attributable to trends in risk factors, especially a decline in the prevalence of coronary heart disease among those with HF. CONCLUSIONS: The profile of HF in the community has changed in recent decades, with a lower prevalence of LVSD and an increased frequency of HFpEF, presumably due to concomitant risk factor trends.

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.

Clinical and Echocardiographic Correlates of Left Atrial Function Index: The Framingham Offspring Study.

BACKGROUND: Left atrial (LA) remodeling is a predictor of cardiovascular disease (CVD). We performed measurement of the LA function index (LAFI), a composite measure of LA structure and function, in a community-based cohort and here report the distribution and cross-sectional correlates of LAFI. METHODS: In 1,719 Framingham Offspring Study participants (54% women, mean age 66 ± 9 years), we derived LAFI from the LA emptying fraction, left ventricular (LV) outflow tract velocity time integral, and indexed maximal LA volume. We used multivariable linear regression to assess the clinical and echocardiographic correlates of LAFI adjusting for age, sex, anthropometric measurements, and CVD risk factors. RESULTS: The average LAFI was 35.2 ± 12.1. Overall, LAFI declined with advancing age (ß = -0.27, P < .001). LAFI was significantly higher (37.5 ± 11.6) in a subgroup of participants free of CVD and CVD risk factors compared with those with either of these conditions (34.5 ± 12.2). In multivariable models, LAFI was inversely related to antihypertensive use (ß = -1.26, P = .038), prevalent atrial fibrillation (ß = -4.46, P = .001), heart failure (ß = -5.86, P = .008), and coronary artery disease (ß = -2.01, P = .046). In models adjusting for echocardiographic variables, LAFI was directly related to LV ejection fraction (ß = 14.84, P < .001) and inversely related to LV volume (ß = -7.03, P < .001). CONCLUSIONS: LAFI was inversely associated with antihypertensive use and prevalent CVD and was related to established echocardiographic traits of LV remodeling. Our results offer normative ranges for LAFI in a white community-based sample and suggest that LAFI represents a marker of pathological atrial remodeling.

Cardiometabolic Traits and Systolic Mechanics in the Community.

BACKGROUND: Obesity and cardiometabolic dysfunction are associated with increased risk of heart failure and other cardiovascular diseases. We sought to examine the association of cardiometabolic traits with left ventricular (LV) cardiac mechanics. We hypothesized that specific obesity-related phenotypes are associated with distinct aspects of LV strain. METHODS AND RESULTS: We evaluated the associations of obesity-related phenotypes, including central adiposity, diabetes mellitus, insulin resistance, and circulating adipokine concentrations with echocardiographic measures of LV mechanical function among participants of the Framingham Heart Study Offspring and Third Generation cohorts. Among 6231 participants, the mean age was 51±16 years, and 54% were women. Greater body mass index was associated with worse LV longitudinal strain, radial strain (apical view), and longitudinal synchrony (multivariable-adjusted P<0.0001). After accounting for body mass index, we found that central adiposity, as measured by waist circumference, was associated with worse global longitudinal strain and synchrony (P≤0.006). Measures of insulin resistance, dyslipidemia, and diabetes mellitus also were associated with distinct aspects of LV mechanical function. Circulating leptin concentrations were associated with global longitudinal and radial strain (apical view, P<0.0001), whereas no such association was found with leptin receptor, adiponectin, or C-reactive protein. CONCLUSIONS: Our findings highlight the association of central obesity and related cardiometabolic phenotypes above and beyond body mass index with subclinical measures of LV mechanical function. Interestingly, obesity-related traits were associated with distinct aspects of LV mechanics, underscoring potential differential effects along specific LV planes of deformation. These findings may shed light onto obesity-related cardiac remodeling and heart failure.

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.