Dataset Information

Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population.

ABSTRACT: BACKGROUND:Familial aggregation has been described for primary mitral regurgitation (MR) caused by mitral valve prolapse. We hypothesized that heritability of MR exists across different MR subtypes including nonprimary MR. METHODS AND RESULTS:Study participants were FHS (Framingham Heart Study) Generation 3 (Gen 3) and Gen 2 cohort participants and all adult Swedish siblings born after 1932 identified in 1997 and followed through 2010. MR was defined as ? mild regurgitation on color Doppler in FHS and from International Classification of Diseases codes in Sweden. We estimated the association of sibling MR with MR in Gen 2/Gen 3/Swedish siblings. We also estimated heritability of MR in 539 FHS pedigrees (7580 individuals). Among 5132 FHS Gen 2/Gen 3 participants with sibling information, 1062 had MR. Of siblings with sibling MR, 28% (500/1797) had MR compared with 17% (562/3335) without sibling MR (multivariable-adjusted odds ratio, 1.20; 95% confidence interval [CI], 1.01-1.43; P=0.04). When we combined parental and sibling data in FHS pedigrees, heritability of MR was estimated at 0.15 (95% CI, 0.07-0.23), 0.12 (95% CI, 0.04-0.20) excluding mitral valve prolapse, and 0.44 (95% CI, 0.15-0.73) for ? moderate MR only (all P<0.05). In Sweden, sibling MR was associated with a hazard ratio of 3.57 (95% CI, 2.21-5.76; P<0.001) for development of MR. CONCLUSIONS:Familial clustering of MR exists in the community, supporting a genetic susceptibility common to primary and nonprimary MR. Further studies are needed to elucidate the common regulatory pathways that may lead to MR irrespective of its cause.

SUBMITTER: Delling FN

PROVIDER: S-EPMC5679298 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population.

Delling Francesca N FN Li Xinjun X Li Shuo S Yang Qiong Q Xanthakis Vanessa V Martinsson Andreas A Andell Pontus P Lehman Birgitta T BT Osypiuk Ewa W EW Stantchev Plamen P Zöller Bengt B Benjamin Emelia J EJ Sundquist Kristina K Vasan Ramachandran S RS Smith J Gustav JG

Circulation. Cardiovascular genetics 20171001 5

<h4>Background</h4>Familial aggregation has been described for primary mitral regurgitation (MR) caused by mitral valve prolapse. We hypothesized that heritability of MR exists across different MR subtypes including nonprimary MR.<h4>Methods and results</h4>Study participants were FHS (Framingham Heart Study) Generation 3 (Gen 3) and Gen 2 cohort participants and all adult Swedish siblings born after 1932 identified in 1997 and followed through 2010. MR was defined as ≥ mild regurgitation on col ...[more]

PMID: 28993406

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Project description:ImportanceHeart failure (HF) aggregates in families, but the heritability of HF has not been determined. Discerning the genetic and environmental contributions to HF risk is important to further helping to identify individuals at risk. Adoption studies may establish the genetic contribution to HF.ObjectiveThis nationwide adoption study aimed to determine the heritability of HF.Design, setting, and participantsThis case-control study and cohort study design used logistic regression for calculating risks of HF in adoptees. Adoptees who were born in Sweden between 1942 and 1990 were linked to their adoptive parents and biological parents. The Swedish Multi-Generation Register was linked to the Swedish Patient Register for information on hospital inpatient and outpatient admissions and to the Swedish Cause of Death Register for the period 1964 through 2015. Heritability (h2 with a standard error) for HF was determined both with Falconer regression and with tetrachoric correlation. Data analysis was completed from July 2017 to April 2018.ExposuresHeart failure in biological parents and/or adoptive parents.Main outcomes and measuresHeritability; risk of HF, expressed as odds ratios.ResultsA total of 21 643 adoptees were included (of whom 10 626 [49.1%] were female), as well as 35 016 adoptive parents (14 872 [42.5%] female) and 43 286 biological parents (21 643 [50.0%] female). There were 194 cases of HF in adoptees, 3972 cases of HF in adoptive parents, and 3657 cases of HF in biological parents. The cohort study odds ratio (OR) for heart failure was 1.45 in adoptees (95% CI, 1.04-2.03) for biological parents with HF, compared with those without an affected biological parent. If cardiomyopathies were excluded, this OR was 1.58 (95% CI, 1.03-2.42). The corresponding OR associated with an affected adoptive parent were nonsignificant, both with cardiomyopathies included (OR, 0.83 [95% CI, 0.57-1.20]) and with cardiomyopathies excluded (OR, 0.79 [95% CI, 0.49-1.29]). The heritability of HF per Falconer regression (h2) was 26% (SE, 14%). With exclusion of cardiomyopathies the heritability using Falconer regression was 34% (SE, 18%).Conclusions and relevanceHeart failure in a biological parent is an HF risk factor that is worth clinical consideration. The increased heritability of HF suggests that genetic factors are important in HF pathogenesis.

Project description:Objectives: To assess the prevalence and impact of mitral regurgitation (MR) on survival in patients presenting to hospital in acute heart failure (AHF) using traditional echocardiographic assessment alongside more novel indices of proportionality. Background: It remains unclear if the severity of MR plays a significant role in determining outcomes in AHF. There is also uncertainty as to the clinical relevance of indexing MR to left ventricular volumes. This concept of disproportionality has not been assessed in AHF. Methods: A total of 418 consecutive patients presenting in AHF over 12 months were recruited and followed up for 2 years. MR was quantitatively assessed within 24 h of recruitment. Standard proximal isovelocity surface area (PISA) and a novel proportionality index of effective regurgitant orifice/left ventricular end-diastolic volume (ERO/LVEDV) >0.14 mm2/ml were used to identify severe and disproportionate MR. Results: Every patient had MR. About 331/418 (78.9%) patients were quantifiable by PISA. About 165/418 (39.5%) patients displayed significant MR. A larger cohort displayed disproportionate MR defined by either a proportionality index using ERO/LVEDV > 0.14 mm2/ml or regurgitant volumes/LVEDV > 0.2 [217/331 (65.6%) and 222/345 (64.3%), respectively]. The LVEDV was enlarged in significant MR-129.5 ± 58.95 vs. 100.0 ± 49.91 ml in mild, [p < 0.0001], but remained within the normal range. Significant MR was associated with a greater mortality at 2 years {44.2 vs. 34.8% in mild MR [hazard ratio (HR) 1.39; 95% CI: 1.01-1.92, p = 0.04]}, which persisted with adjustment for comorbid conditions (HR; 1.43; 95% CI: 1.04-1.97, p = 0.03). Disproportionate MR defined by ERO/LVEDV >0.14 mm2/ml was also associated with worse outcome [42.4 vs. 28.3% (HR 1.62; 95% CI 1.12-2.34, p = 0.01)]. Conclusions: MR was a universal feature in AHF and determines outcome in significant cases. Furthermore, disproportionate MR, defined either by effective regurgitant orifice (ERO) or volumetrically, is associated with a worse prognosis despite the absence of adverse left ventricular (LV) remodeling. These findings outline the importance of adjusting acute volume overload to LV volumes and call for a review of the current standards of MR assessment. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02728739, identifier NCT02728739.

Project description:OBJECTIVES:The Cardiothoracic Surgical Trials Network recently reported no difference in the primary end point of left ventricular end-systolic volume index at 1 year postsurgery in patients randomized to repair (n = 126) or replacement (n = 125) for severe ischemic mitral regurgitation. However, patients undergoing repair experienced significantly more recurrent mitral regurgitation than patients undergoing replacement (32.6% vs 2.3%). We examined whether baseline echocardiographic and clinical characteristics could identify those who will develop moderate/severe recurrent mitral regurgitation or die. METHODS:Our analysis includes 116 patients who were randomized to and received mitral valve repair. Logistic regression was used to estimate a model-based probability of recurrence or death from baseline factors. Receiver operating characteristic curves were constructed from these estimated probabilities to determine classification cut-points maximizing accuracy of prediction based on sensitivity and specificity. RESULTS:Of the 116 patients, 6 received a replacement before leaving the operating room; all other patients had mild or less mitral regurgitation on intraoperative echocardiogram after repair. During the 2-year follow-up period, 76 patients developed moderate/severe mitral regurgitation or died (53 mitral regurgitation recurrences, 13 mitral regurgitation recurrences and death, and 10 deaths). The mechanism for recurrent mitral regurgitation was largely mitral valve leaflet tethering. Our model (including age, body mass index, sex, race, effective regurgitant orifice area, basal aneurysm/dyskinesis, New York Heart Association class, history of coronary artery bypass grafting, percutaneous coronary intervention, or ventricular arrhythmias) yielded an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS:The model demonstrated good discrimination in identifying patients who will survive 2 years without recurrent mitral regurgitation after mitral valve repair. Although our results require validation, they offer a clinically relevant risk score for selection of surgical candidates for this procedure.

Project description:Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized.The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT) were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1) age, (2) age and body mass index (BMI), and (3) age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS) for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n=16), BMI (n=32), and waist-to-hip ratio (WHR, n=14), and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat.The heritability of renal sinus fat was 39% (p<0.0001); results were not materially different after adjustment for BMI (39%) or VAT (40%). No SNPs reached genome-wide significance in our GWAS. In our candidate gene analysis, we observed nominal, direction consistent associations with renal sinus fat for one SNP associated with renal function (p=0.01), two associated with BMI (p<0.03), and two associated with WHR (p<0.03); however, none remained significant after accounting for multiple testing. Finally, we observed that in aggregate, the 32 SNPs associated with BMI were nominally associated with renal sinus fat (multi-SNP genetic risk score p=0.03).Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.

Dataset Information

Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population.

Publications

Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population.

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