Introduction: Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. Methods: A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. Results: Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33 ± 0.02 vs. 0.92 ± 0.21, P < 0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9 ± 39.2 vs. 319.3 ± 13.8 ms, P < 0.005; and 671.0 ± 41.1 vs. 372.9 ± 14.2 ms, P < 0.005). ML277, a small molecule recently identified to selectively activate K_V7.1, reversed the decreased IKs and partially restored APDs in patient hiPSC-CMs. Conclusions: From a LQT1 patient carrying a novel heterozygous exon7 deletion mutation of KCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), associated with impaired quality of life, risk for embolic stroke, and unpredictable onset. We sought to create a predictive model to identify risk for AF development in HCM. Methods: A cohort of 1900 patients with HCM followed for newly diagnosed AF in the Tufts HCM center was used for model development. A cohort of 387 patients from Toronto General Hospital was used for external validation. Data in the development cohort generated the HCM-AF score, a point score to predict AF probability at 2 and 5 years: left atrial dimension (+2 points per 6 mm increase), age at clinical evaluation (+3 points per 10-year increase), age at initial HCM diagnosis (−2 points per 10-year increase), and heart failure symptoms (+3 points if symptomatic). Results: The HCM-AF score stratifies risk as low (2.0%/y; score ≥22) for AF development for individual patients. Concordance of the HCM-AF score was 0.70 in the development cohort and 0.68 in the external validation cohort. In the development cohort, 17.2% of high-risk patients developed AF (rate 3.4%/y), while only 3.3% of low-risk patients developed AF (rate 0.7%/y) at 5 years ( P <0.001). Similarly, in the external validation cohort, 13.3% of high-risk patients developed AF (rate 2.7%/y), whereas only 1.1% of low-risk patients developed AF (rate 0.2%/y). The HCM-AF score provided greater predictive power for future AF risk than left atrial dimension alone (concordance of 0.58) and outperformed other non–HCM risk models. Conclusions: The HCM-AF score is a novel externally validated predictive tool to identify AF risk in HCM. This score can reliably stratify patients with HCM to risk of newly diagnosed AF and offers the opportunity to inform expectations regarding future clinical course.

Diuretic responsiveness is associated with heart failure disease progression. Among patients with advanced heart failure, we hypothesized that decreased diuretic responsiveness and higher diuretic requirement are correlates of progressive right ventricular dysfunction and may help to risk stratify patients undergoing left ventricular assist device (LVAD) evaluation. We performed a single-center, retrospective analysis of 147 patients undergoing LVAD implantation between 2014 and 2018. The primary outcome was early right heart failure (RHF) or death during the index hospital stay. Patients were stratified by tertiles of preoperative 24-hour diuretic dose within 72 hours of surgery. The incidence of early RHF was higher in the highest-dose group (66.0%) compared to the medium- (41.3%) and low-dose groups (23.5%) (p < 0.001). Each 40 mg increase in intravenous furosemide dose was associated with a 6% increase in the risk of RHF, after adjusting for other known risk factors. The median ICU length of stay was 2 days longer for patients in the highest compared to low-dose group (7 vs 5 days, p = 0.02). Mortality within 14 days post-op was numerically higher although not significantly different between the highest-dose group and the low-dose group (12.0% vs 5.9%, p = 0.55). Six-month survival across diuretic dose tertiles was also not statistically different (p = 0.40). We concluded that higher preoperative diuretic dose is associated with risk of early RHF following LVAD surgery. These data furthermore support the role of progressive right ventricular dysfunction on the development of cardiorenal disease and diuretic resistance.

Paradoxical low-flow low-gradient aortic stenosis (P-LFLG AS) is a high-risk yet incompletely understood subset of severe AS, ¹ Hachicha Z. Dumesnil J.G. Bogaty P. Pibarot P. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation. 2007; 115 : 2856-2864 Google Scholar for which studies have not uniformly noted improved outcomes after aortic valve replacement. ² Eleid M.F. Sorajja P. Michelena H.I. Malouf J.F. Scott C.G. Pellikka P.A. Flow-gradient patterns in severe aortic stenosis with preserved ejection fraction. Circulation. 2013; 128 : 1781-1789 Google Scholar ^{, 3} Mohty D. Magne J. Deltreuil M. Aboyans V. Echahidi N. Cassat C. et al. Outcome and impact of surgery in paradoxical low-flow, low-gradient severe aortic stenosis and preserved left ventricular ejection fraction: a cardiac catheterization study. Circulation. 2013; 128 : S235-S242 Google Scholar Several vascular, valvular, and myocardial conditions contribute to low transvalvular flow (LF) across stenosed aortic valves. ⁴ Annabi M.S. Clisson M. Clavel M.A. Pibarot P. Workup and management of patients with paradoxical low-flow, low-gradient aortic stenosis. Curr Treat Options Cardiovasc Med. 2018; 20 : 49 Google Scholar The cumulative burden of LF conditions may affect hemodynamic improvement after transcatheter aortic valve replacement (TAVR) and explain the aforementioned varying survival benefits. In this cohort of P-LFLG AS patients who underwent TAVR, we assessed whether the cumulative burden of LF conditions present at the time of TAVR was associated with change in indexed stroke volume (SVi) post-TAVR.

Statins reduce coronary vasculopathy and mortality after heart transplantation (HT). However, it remains uncertain if intensified statins are tolerated and related to the preservation of cardiac function. We conducted a single-center, retrospective cohort study of all single-organ adult HT recipients between 2012 and 2021. Standard intensity statin was defined as pravastatin ≤20 mg or equivalent doses, while higher doses were defined as intensified statin. Overall, 277 patients met eligibility criteria. The incidence of intolerability was similar between patients on standard and intensified statin (7% vs . 3%; p = 0.56). Similarly, no differences were detected for intolerability with conventional classifications as low- (5%), moderate- (4%), or high-intensity (3%) statin users ( p = 0.58). At 1 year after HT, low-density lipoprotein (LDL) increased from 70 (49–88) mg/dl to 82 (66–99) mg/dl ( p = 0.01) in standard statin users but remained similar for those on intensified statin from 75 (56–97) mg/dl to 80 (59–97) mg/dl ( p = 0.67). Left ventricular global longitudinal strain (n = 53) from 1 to 3 years after HT was lower by −10% in those on standard compared with −2% on intensified statin ( p = 0.03). In conclusion, intensified statin is well tolerated after HT, leads to better LDL control, and is associated with greater preservation of myocardial function.