Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH2-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3−/−) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3−/− mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3+/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3−/− TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3−/− TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

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 (<1.0%/y; score ≤17), intermediate (1.0-2.0%/y; score 18 to 21), and high risk (>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.

Background: The impact of comorbid disease states on the development of atrial and ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) remains unresolved.Objective: Evaluate the association of comorbidities linked to arrhythmias in other cardiovascular diseases (e.g., obesity, systemic hypertension, diabetes, obstructive sleep apnea, renal disorders, tobacco, and alcohol use) to atrial fibrillation (AF) and sudden cardiac death (SCD) events in a large cohort of HCM patients.Methods: A total of 2269 patients, 54 ± 15 years of age, 1392 males, were evaluated at the Tufts HCM Institute between 2004 and 2018 and followed for an average of 4 ± 3 years for new-onset clinical AF and SCD events (appropriate defibrillation for ventricular tachyarrhythmias, resuscitated cardiac arrest, or SCD).Results: One or more comorbidity was present in 75% of HCM patients, including 50% with ≥2 comorbidities, most commonly obesity (body mass index [BMI] ≥ 30 kg/m 2 ) in 43%. New-onset atrial fibrillation developed in 11% of our cohort (2.6%/year).On univariate analysis, obesity was associated with a 1.7-fold increased risk for AF (p = .03) with 12% of obese patients developing AF (3.3%/year) as compared to 7% of patients with BMI < 25 kg/m 2 (1.6%/year; p = .006). On multivariate analysis, age and LA transverse dimension emerged as the only variables predictive of AF. Comorbidities, including obesity, were not independently associated with AF development (p > .10 for each). SCD events occurred in 3.3% of patients (0.8%/year) and neither obesity nor other comorbidities were associated with increased risk for SCD (p > .10 for each).

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Background Accurate assessment of right atrial pressure (RAP) and pulmonary artery systolic pressure (PASP) is critical in the management of heart transplant recipients. The accuracy of echocardiography in estimating these pressures has been debated. Objective To assess the correlation and agreement between echocardiographic estimations of right heart pressures with those of respective invasive hemodynamic measurements by right heart catheterization (RHC) in adult heart transplant recipients. Methods This is a prospective evaluation of 84 unique measurements from heart transplant recipients who underwent RHC followed by standard echocardiographic evaluation within 159 ± 64 min with no intervening medication changes. The relationship between noninvasive pressure estimations and invasive hemodynamic measurements was examined. Results Mean RAP was 7 ± 5 mmHg and mean PASP was 33 ± 8 mmHg by RHC. There was no significant correlation between echocardiographic estimation of RAP and invasive RAP (Spearman's rho = −0.05, p = .7), and no significant agreement between these two variables (weighted kappa = −0.1). There was a modest correlation between echocardiographic estimation of PASP and invasive PASP ( r = .39, p = .002). Bland‐Altman analysis showed a mean bias of 2.1 ± 9 mmHg (limits of agreement = −15 to 20 mmHg). Conclusion In heart transplant recipients, there is no significant correlation or agreement between echocardiographic RAP estimation and invasively determined RAP. Noninvasive PASP estimation correlates significantly but modestly with invasively measured PASP. Further refinement of echocardiographic methods for assessment of RAP is warranted in this unique patient population.