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Genetic Basis and Prognostic Value of Exercise QT Dynamics.

ABSTRACT: BACKGROUND:Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated. METHODS:QT dynamics during exercise and recovery were derived in 56?643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies were conducted to identify genetic variants and bioinformatics analyses were performed to prioritize candidate genes. The prognostic value of QT dynamics was evaluated for cardiovascular events (death or hospitalization) and all-cause mortality. RESULTS:Heritability of QT dynamics during exercise and recovery were 10.7% and 5.4%, respectively. Genome-wide association studies identified 20 loci, of which 4 loci included genes implicated in mendelian long-QT syndrome. Five loci did not overlap with previously reported resting QT interval loci; candidate genes included KCNQ4 and KIAA1755. Genetic risk scores were not associated with cardiovascular events in 357?882 unrelated individuals from UK Biobank. We also did not observe associations of QT dynamics during exercise and recovery with cardiovascular events. Increased QT dynamics during recovery was significantly associated with all-cause mortality in the univariate Cox regression analysis (hazard ratio, 1.09 [95% CI, 1.05-1.13], P=2.28×10-5), but the association was not significant after adjusting for clinical risk factors. CONCLUSIONS:QT interval dynamics during exercise and recovery are heritable markers but do not carry independent prognostic information for clinical outcomes in the UK Biobank, a population-based cohort. Their prognostic importance may relate to cardiovascular disease cohorts where structural heart disease or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.

SUBMITTER: van Duijvenboden S

PROVIDER: S-EPMC7439940 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genetic Basis and Prognostic Value of Exercise QT Dynamics.

van Duijvenboden Stefan S Ramírez Julia J Young William J WJ Mifsud Borbala B Orini Michele M Tinker Andrew A Munroe Patricia B PB Lambiase Pier D PD

Circulation. Genomic and precision medicine 20200611 4

<h4>Background</h4>Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated.<h4>Methods</h4>QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies were conducted to identify genetic variants and bioinformatics ana ...[more]

PMID: 32527199

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Project description:Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age- and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29-0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30-0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32-1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42-2.25], P=0.95). Conclusions Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

Project description:AimsThe study evaluated exercise left ventricular global longitudinal strain (LVGLS) and invasive haemodynamics for major adverse cardiac events (MACE) prediction in heart-transplanted (HTx) patients.Methods and resultsThe study comprised 74 stable consecutive HTx patients who were followed at the Department of Cardiology, Aarhus University Hospital, Denmark, from August 2013 to January 2017. All patients were transplanted a minimum of 12 months before study entry and were included at the time of their routine annual coronary angiography. A symptom-limited haemodynamic exercise test with simultaneous echocardiographic study was performed. The primary endpoint was MACE during follow-up defined as heart failure hospitalization, treated rejection episodes, coronary event, or cardiac death. The median time since transplant was 5 years [1:12] and the median follow-up was 1095 days [391;1506]. Thirty patients (41%) experienced MACE during follow-up. Patients who suffered MACE had an impaired resting and peak exercise systolic function in form of a lower LV ejection fraction (Rest: 56 ± 12% vs. 65 ± 7%, P < 0.001; Peak 64 ± 13% vs. 72 ± 6%, P < 0.01) and LVGLS (Rest: 13 ± 4% vs. 16 ± 2%, P < 0.01; Peak: 15 ± 6% vs. 20 ± 4%, P = 0.0001) than patients without MACE episodes. In contrast, resting diastolic filling patterns were comparable between patients suffering from MACE and patients without MACE. At rest, pulmonary capillary wedge pressure (mPCWP) and cardiac index did not predict MACE, whereas increased right atrial pressure (mRAP) was associated with increased MACE risk. Patients with peak exercise mPCWP >23 mmHg [hazard ratio (HR) 2.5, 95% confidence interval (CI): 1.2-5.4], cardiac index <5.9 L/min/m2 (HR 2.7, 95% CI: 1.0-6.3), or mRAP >13 mmHg (HR 2.7, 95% CI: 1.1-6.3) had increased MACE risk. Patients with exercise-induced LVGLS increase <3.5% and peak exercise cardiac index <5.9 L/min/m2 [HR 6.1 (95% CI: 2.2-17.1)] or mPCWP >23 mmHg [HR 6.1 (95% CI: 2.1-17.5)] or mRAP >13 mmHg [HR 7.5 (95% CI: 2.3-23.9)] had the highest MACE risk.ConclusionsResting haemodynamic parameters were poor MACE predictors in long-term HTx patients. In contrast, peak exercise mPCWP, mRAP, and CI were significant MACE predictors. LVGLS both at rest and during exercise were significant MACE predictors, and the combined model with peak exercise LVGLS and peak exercise mPCWP, mRAP, and CI clearly identified high-risk HTx patients in relation cardiovascular endpoints independently of time since HTx.

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Genetic Basis and Prognostic Value of Exercise QT Dynamics.

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Genetic Basis and Prognostic Value of Exercise QT Dynamics.

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