Shah, Ravi V.

Background: Mitral valve prolapse (MVP) is a common valvular abnormality. Observational studies demonstrate an association between MVP and increased risk of sudden cardiac death from ventricular arrhythmias, coined arrhythmogenic MVP. A genetic component has been postulated but remains under-investigated. Hypothesis: Predicted deleterious variants in Mendelian cardiomyopathy and arrhythmia genes are more frequent in arrhythmogenic MVP (aMVP) compared to non-arrhythmogenic MVP. Aims: To comprehensively phenotype and genotype a single-center aMVP cohort and compare to non-aMVP from two large population-based cohorts and investigate their clinical outcomes. Methods: The aMVP cohort included 46 prospectively enrolled patients from a regional referral center for inherited cardiovascular disease and had undergone multi-modality imaging and clinical gene panel testing. The non-aMVP comparator cohorts included 453 participants from the UK Biobank (UKBB), a prospective cohort of 500,000 UK residents, and 1,418 participants from the National Institutes of Health (NIH) All of Us (AoU), a prospective cohort of 450,000 USA participants. Gene variants were annotated in ANNOVAR. Participants with and without pathogenic/likely pathogenic (P/LP) variants reported on ClinVar with ≥2-star level of evidence were considered genotype positive (G+) and negative (G-) respectively. Results: The demographics for aMVP (age 61.2 ± 12.8 years, 56.5% female) and non-aMVP (UKBB: age 59.8 ± 7.3 years, 50.7% female and AoU: age 65.3 ± 13.4 years, 76.2% female) were comparable. G+ participants were more prevalent in the aMVP cohort 10/46 (21.7%) versus non-aMVP in the UKBB 8/453 (1.8%) and in the AoU 21/1418 (1.5%); p<0.001. The most frequently implicated gene in aMVP was TTN . Of 46 in aMVP cohort, 33 (71%) underwent CMR. G+ participants had a higher frequency of late gadolinium enhancement [6/6 (100%) vs. 14/27 (51.8%), p<0.001] and wall motion abnormalities [3/6 (50%) vs. 1/27 (3.7%), p<0.001] compared to G- participants. The aMVP cohort had significantly more implantable cardioverter defibrillator (ICD) implants compared to non-aMVP cohort [5/46 (10.9%) vs. 1/453 in UKBB (0.2%), p<0.001]. G+ aMVP cohort showed a trend for developing heart failure and ICD implants compared to G- aMVP . Conclusion: P/LP variants in cardiomyopathy and arrhythmia genes are more prevalent in aMVP participants compared to non-aMVP participants. This could be a hitherto unrecognized effect modifier predicting aMVP .

Introduction: Impaired left atrial (LA) function may limit optimal cardiac performance, reflecting both LA load and atrial dysfunction in HFpEF. The link between MRI-derived LA characteristics and exercise capacity in HFpEF has not been studied. Hypothesis: We hypothesized that total LA emptying fraction (LAEF) is reduced in HFpEF vs. healthy controls and LA functional impairment would be correlated with LV diastolic dysfunction, vascular dysfunction, and exercise intolerance. As LA hypertension may increase right ventricular load and limit increases in pulmonary perfusion with exercise, the correlation of LAEF with ventilatory efficiency (VE/VCO2 slope) was also examined. Methods: Baseline exercise, echo, and cardiac MRI data from RELAX (a study of sildenafil in HFpEF) in patients in sinus rhythm with a measureable LAEF by MRI (n=100) were utilized. Healthy volunteers (n=21) were included for comparison. LAV was measured by the biplane area-length method using 2-/4-chamber SSFP CMR. LAEF was defined as total (ΔLAVmax-min), passive/conduit (ΔLAVmax-before atrial contraction ), and active (ΔLAVbefore atrial contraction-min), each divided by maximal LAV. Results: As compared to controls, LAEF (particularly passive conduit function) was reduced in HFpEF (Table 1). In HFpEF, patients with lower LAEF had a larger LA, more echo diastolic dysfunction, higher PA systolic pressure and NT-proBNP, reduced aortic distensibility, worse exercise capacity, and ventilatory inefficiency (Table 2). Conclusions: LA function is impaired in HFpEF, may serve as a marker of chronic LA hypertension and may contribute to impaired exercise intolerance and ventilatory inefficiency.