Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival

Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy

Ambulatory Blood Pressure Control and Subclinical Left Ventricular Dysfunction in Treated Hypertensive Subjects

Blood pressure (BP) control in hypertensive patients is crucial for reducing the risk of heart failure development and may be particularly important in elderly subjects, who have an especially high prevalence of hypertension and risk of heart failure (1). Left ventricular (LV) global longitudinal strain (GLS) is an echocardiographic measure of LV systolic function that can be an indicator of early subclinical cardiac dysfunction, even when LV ejection fraction is normal. The association of BP control with early subclinical LV dysfunction according to GLS has not been extensively studied, and it is also unknown whether assessing BP control with ambulatory blood pressure (ABP) monitoring is superior to using office BP measurements in this regard. Therefore, we investigated the association of BP control with GLS by using ABP and office BP criteria in a community-based, predominantly elderly cohort with normal LV ejection fraction

Relationship of Office and Ambulatory Blood Pressure With Left Ventricular Global Longitudinal Strain

BACKGROUND: Left ventricular (LV) global longitudinal strain (GLS) is an early indicator of subclinical cardiac dysfunction, even when LV ejection fraction (LVEF) is normal, and is an independent predictor of cardiovascular events. Ambulatory blood pressure (BP) is a better predictor of cardiovascular events, including heart failure, than office BP. We investigated the association of office and ambulatory BP measurements with subclinical LV systolic dysfunction in a community-based cohort with normal LVEF. METHODS: Two-dimensional speckle-tracking echocardiography and 24-hour ambulatory BP monitoring were performed in 577 participants (mean age 70±9 years; 60% women) with LVEF ≥50% from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. Univariable and multivariable linear regression analyses were used to assess the associations of BP measures with GLS. RESULTS: Higher ambulatory and office BP values were consistently associated with impaired GLS. After adjustment for pertinent covariates (age, sex, race/ethnicity, body mass index, diabetes mellitus, coronary artery disease, LV mass index, and antihypertensive medication), office diastolic BP and ambulatory systolic and diastolic BPs (24-hour, daytime and nighttime) were independently associated with GLS (P = 0.003 for office DBP, P ≤ 0.001 for all ambulatory BPs). When ambulatory and office BP values were included in the same model, all ambulatory BP measures remained significantly associated with GLS (all P < 0.01), whereas office BP values were not. CONCLUSIONS: Ambulatory BP values are significantly associated with impaired GLS and the association is stronger than for office BP. Ambulatory BP monitoring might have a role in the risk stratification of hypertensive patients for early LV dysfunction

Rapidly Progressive Heart Failure in a Female Carrier of Becker Muscular Dystrophy with No Skeletal Muscle Symptoms

Becker muscular dystrophy (BMD) carriers are at risk to developing cardiac dysfunction. The prevalence of female BMD carriers remains underestimated, and the disease progression varies. We herein report the case of a young female BMD carrier who developed dilated cardiomyopathy (DCM) and heart failure without any skeletal muscle signs. Her cardiac dysfunction progressed over a mere two months, resulting in the need for left ventricular assist device implantation. Her case demonstrates that progressive cardiomyopathy can be the only clinical manifestation in some BMD carriers, suggesting the need for a more aggressive implementation of genetic testing in female DCM patients

Left Ventricular Systolic Dysfunction by Longitudinal Strain Is an Independent Predictor of Incident Atrial Fibrillation

BACKGROUND: The increasing prevalence of atrial fibrillation (AF) represents a public health issue. Identifying new predictors of AF is therefore necessary to plan preventive strategies. We investigated whether left ventricular (LV) systolic dysfunction by global longitudinal strain (GLS), a predictor of cardiovascular events, may predict new-onset AF in a population setting. METHODS AND RESULTS: Participants (n=675, mean age 71±9 years, 60% women) in sinus rhythm from the population-based Northern Manhattan Study underwent two- and three-dimensional echocardiography as part of the Cardiac Abnormalities and Brain Lesions (CABL) study. LV systolic function was assessed by LV ejection fraction (LVEF) and speckle-tracking GLS. Over a mean follow-up of 63.6±18.7 months, 32 (4.7%) new confirmed cases of AF occurred. Lower GLS [adjusted hazard ratio (aHR)/unit decrease=1.22, 95% confidence interval (CI)=1.04-1.43, p=0.015] and increased left atrial volume index (LAVi) (aHR/unit increase=1.12, 95% CI=1.07-1.17, p<0.001) were significantly associated with incident AF, whereas LVEF was not (p=0.176). GLS>-14.7% was associated with risk of new-onset AF with an aHR=3.2 (95% CI=1.4-7.5, p=0.007). The coexistence of abnormal GLS/abnormal LAVi was associated with a 28.6% incidence of AF (aHR=12.1, 95% CI=3.3-44.8, p<0.001) compared to participants with normal GLS/normal LAVi (AF incidence=2.0%). AF incidence was intermediate in those with either abnormal GLS or abnormal LAVi (9.3% and 11.1%, respectively). GLS prognostic value for incident AF was incremental over risk factors and LAVi. CONCLUSIONS: LV systolic dysfunction by GLS was a powerful and independent predictor of incident AF. GLS assessment may improve AF risk stratification in addition to established parameters