Sonia Garg

Human Ventricular Unloading Induces Cardiomyocyte Proliferation

BACKGROUND The adult mammalian heart is incapable of meaningful regeneration after substantial cardiomyocyte loss, primarily due to the inability of adult cardiomyocytes to divide. Our group recently showed that mitochondria-mediated oxidative DNA damage is an important regulator of postnatal cardiomyocyte cell cycle arrest. However, it is not known whether mechanical load also plays a role in this process. We reasoned that the postnatal physiological increase in mechanical load contributes to the increase in mitochondrial content, with subsequent activation of DNA damage response (DDR) and permanent cell cycle arrest of cardiomyocytes. OBJECTIVES The purpose of this study was to test the effect of mechanical unloading on mitochondrial mass, DDR, and cardiomyocyte proliferation. METHODS We examined the effect of human ventricular unloading after implantation of left ventricular assist devices (LVADs) on mitochondrial content, DDR, and cardiomyocyte proliferation in 10 matched left ventricular samples collected at the time of LVAD implantation (pre-LVAD) and at the time of explantation (post-LVAD). RESULTS We found that post-LVAD hearts showed up to a 60% decrease in mitochondrial content and up to a 45% decrease in cardiomyocyte size compared with pre-LVAD hearts. Moreover, we quantified cardiomyocyte nuclear foci of phosphorylated ataxia telangiectasia mutated protein, an upstream regulator of the DDR pathway, and we found a significant decrease in the number of nuclear phosphorylated ataxia telangiectasia mutated foci in the post-LVAD hearts. Finally, we examined cardiomyocyte mitosis and cytokinesis and found a statistically significant increase in both phosphorylated histone H3-positive, and Aurora B-positive cardiomyocytes in the post-LVAD hearts. Importantly, these results were driven by statistical significance in hearts exposed to longer durations of mechanical unloading. CONCLUSIONS Prolonged mechanical unloading induces adult human cardiomyocyte proliferation, possibly through prevention of mitochondria-mediated activation of DDR.

Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension Systematic Review and Meta-Analysis

Background—Exercise training has been shown to improve cardiorespiratory fitness, physical capacity, and quality of life in patients with cardiopulmonary conditions, such as heart failure and chronic obstructive pulmonary disease. However, its role in management of pulmonary hypertension is not well defined. In this study, we aim to evaluate the efficacy and safety of exercise training in patients with pulmonary hypertension. Methods and Results—We included all prospective intervention studies that evaluated the efficacy and safety of exercise training in patients with pulmonary hypertension. Primary outcome of this meta-analysis was a change in 6-minute walk distance. We also assessed the effect of exercise on peak oxygen uptake, resting pulmonary arterial systolic pressure, peak exercise heart rate, and quality of life. A total of 469 exercise-training participants enrolled in 16 separate training studies were included. In the pooled analysis, exercise training was associated with significant improvement in 6-minute walk distance (weighted mean difference, 53.3 m; 95% confidence interval, 39.5–67.2), peak oxygen uptake (weighted mean difference, 1.8 mL/kg per minute; 95% confidence interval, 1.4–2.3), pulmonary arterial systolic pressure (weighted mean difference, −3.7 mm Hg; 95% confidence interval, −5.4 to −1.9), peak exercise heart rate (weighted mean difference, 10 beats per min; 95% confidence interval, 6–15), and quality of life as measured on SF-36 questionnaire subscale scores. Furthermore, exercise training was well tolerated with a low dropout rate, and no major adverse events were related to exercise training. Conclusions—Exercise training in patients with pulmonary hypertension appears safe and is associated with a significant improvement in exercise capacity, pulmonary arterial pressure, and quality of life.

Efficacy and Safety of Exercise Training in Chronic Pulmonary HypertensionCLINICAL PERSPECTIVE

Background—Exercise training has been shown to improve cardiorespiratory fitness, physical capacity, and quality of life in patients with cardiopulmonary conditions, such as heart failure and chronic obstructive pulmonary disease. However, its role in management of pulmonary hypertension is not well defined. In this study, we aim to evaluate the efficacy and safety of exercise training in patients with pulmonary hypertension. Methods and Results—We included all prospective intervention studies that evaluated the efficacy and safety of exercise training in patients with pulmonary hypertension. Primary outcome of this meta-analysis was a change in 6-minute walk distance. We also assessed the effect of exercise on peak oxygen uptake, resting pulmonary arterial systolic pressure, peak exercise heart rate, and quality of life. A total of 469 exercise-training participants enrolled in 16 separate training studies were included. In the pooled analysis, exercise training was associated with significant improvement in 6-minute walk distance (weighted mean difference, 53.3 m; 95% confidence interval, 39.5–67.2), peak oxygen uptake (weighted mean difference, 1.8 mL/kg per minute; 95% confidence interval, 1.4–2.3), pulmonary arterial systolic pressure (weighted mean difference, −3.7 mm Hg; 95% confidence interval, −5.4 to −1.9), peak exercise heart rate (weighted mean difference, 10 beats per min; 95% confidence interval, 6–15), and quality of life as measured on SF-36 questionnaire subscale scores. Furthermore, exercise training was well tolerated with a low dropout rate, and no major adverse events were related to exercise training. Conclusions—Exercise training in patients with pulmonary hypertension appears safe and is associated with a significant improvement in exercise capacity, pulmonary arterial pressure, and quality of life.

Refining the classification of left ventricular hypertrophy to provide new insights into the progression from hypertension to heart failure

Purpose of review Left ventricular hypertrophy (LVH), an important consequence of hypertension, is traditionally classified as either concentric or eccentric based on the presence or absence of increased relative wall thickness. In 2010, we proposed a novel four-tiered classification that accounted for LV dilatation in addition to LV wall thickness. The purpose of this review is to discuss the rationale for this revised classification and highlight subsequent studies that have assessed its utility. Recent findings A series of recent observational studies have tested whether the four-tiered classification identifies subphenotypes of LVH with differential risk of adverse outcomes, including incident heart failure. The majority have confirmed that eccentric hypertrophy can be subdivided into a high-risk and a low-risk group based on whether LV dilatation is present. Additional studies have shown that LV dilatation is an independent risk factor for the development of heart failure. Summary Incorporation of LV dilatation into the assessment of LVH identifies important subphenotypes within the standard two-tiered classification that have differential risk. Such refinements in the classification of LVH may yield new insights into how LVH progresses to heart failure, help identify risk factors for this transition, and improve therapeutic efforts to prevent its occurrence.

Predictors of depressed left ventricular function in patients presenting with ST-elevation myocardial infarction

Early in the course of ST-segment elevation myocardial infarction (STEMI), therapies that may harm patients who develop left ventricular (LV) dysfunction, such as β-blockers, are often administered. The investigators analyzed the ACTIVATE-SF database, a registry of consecutive STEMI activations presenting to 2 medical centers at the University of California, San Francisco. LV dysfunction was defined as an ejection fraction ≤40% on echocardiography. Of 211 patients included in the analysis, 66 (31%) had LV ejection fractions ≤40%. Patients with LV dysfunction were older (63 ± 15 vs 56 ± 13 years, p = 0.002). In multivariate regression models, decreased renal function (reference group, creatinine <1.0 mg/dl; adjusted odds ratio [AOR] creatinine >1.5 mg/dl 6.35, 95% confidence interval [CI] 1.66 to 24.31, p = 0.007), a history of coronary artery disease (AOR 3.12, 95% CI 1.26 to 7.71, p = 0.014), ST-segment elevation >2 mm on 12-lead electrocardiography (AOR 2.78, 95% CI 1.31 to 5.87, p = 0.008), and need for mechanical ventilation (AOR 3.98, 95% CI 1.41 to 11.19, p = 0.009) increased the odds of LV dysfunction. Inferior ST-segment elevations were associated with 88% decreased odds of LV dysfunction (AOR 0.12, 95% CI 0.06 to 0.35, p <0.001). A prediction score using these characteristics stratified patients into low-, intermediate-, and high-risk groups for LV dysfunction; positive likelihood ratios for LV dysfunction in these groups were 0.07, 1.14, and 4.93, respectively. In conclusion, 5 key predictors of in-hospital LV dysfunction after STEMI were identified; a risk score based on these predictors helps to quickly identify patients presenting with STEMI who are at the highest risk for developing significant LV dysfunction and could guide optimal therapeutic choices.

Dynamic Relation of Changes in Weight and Indices of Fat Distribution With Cardiac Structure and Function: The Dallas Heart Study

Background Obesity may increase heart failure risk through cardiac remodeling. Cross‐sectional associations between adiposity and cardiac structure and function have been elucidated, but the impact of longitudinal changes in adiposity on cardiac remodeling is less well understood. Methods and Results Participants in the Dallas Heart Study without cardiovascular disease or left ventricular dysfunction underwent assessment of body weight, anthropometrics, and cardiac magnetic resonance imaging at baseline and 7 years later. Associations between changes in indices of generalized and central adiposity with changes in left ventricular mass, volume, mass/volume ratio (concentricity), wall thickness, and ejection fraction were assessed using multivariable linear regression. The study cohort (n=1262) mean age was 44 years with 57% women, 44% black, and 36% obese participants. At follow‐up, 41% had ≥5% weight gain, and 15% had ≥5% weight loss. Greater weight gain was associated with younger age, lower risk factor burden, and lower body mass index at baseline. In multivariable models adjusting for age, sex, race, comorbid conditions at baseline and follow‐up, baseline adiposity, and cardiac measurement, increasing weight was associated with increases in left ventricular mass (β=0.10, P<0.0001), wall thickness (β=0.10, P<0.0001), and concentricity (β=0.06, P=0.002), with modest effects on end‐diastolic volume (β=0.04, P=0.044) and ejection fraction (β=0.05, P=0.046). Similar results were seen with other adiposity indices. Conclusions Concentric left ventricular remodeling is the predominant phenotype linked to increasing adiposity in middle age. Our findings support the importance of weight management to prevent secular changes in adiposity, concentric remodeling, and eventual heart failure over time.

Association of Concentric Left Ventricular Hypertrophy With Subsequent Change in Left Ventricular End-Diastolic Volume: The Dallas Heart Study

Background In the conventional paradigm of the progression of left ventricular hypertrophy, a thick-walled left ventricle (LV) ultimately transitions to a dilated cardiomyopathy. There are scant data in humans demonstrating whether this transition occurs commonly without an interval myocardial infarction. Methods and Results Participants (n=1282) from the Dallas Heart Study underwent serial cardiac magnetic resonance ≈7 years apart. Those with interval cardiovascular events and a dilated LV (increased LV end-diastolic volume [EDV] indexed to body surface area) at baseline were excluded. Multivariable linear regression models tested the association of concentric hypertrophy (increased LV mass and LV mass/volume0.67) with change in LVEDV. The study cohort had a median age of 44 years, 57% women, 43% black, and 11% (n=142) baseline concentric hypertrophy. The change in LVEDV in those with versus without concentric hypertrophy was 1 mL (−9 to 12) versus −2 mL (−11 to 7), respectively, P<0.01. In multivariable linear regression models, concentric hypertrophy was associated with larger follow-up LVEDV (P⩽0.01). The progression to a dilated LV was uncommon (2%, n=25). Conclusions In the absence of interval myocardial infarction, concentric hypertrophy was associated with a small, but significantly greater, increase in LVEDV after 7-year follow-up. However, the degree of LV enlargement was minimal, and few participants developed a dilated LV. These data suggest that if concentric hypertrophy does progress to a dilated cardiomyopathy, such a transition would occur over a much longer timeframe (eg, decades) and may be less common than previously thought. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00344903.

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation)

Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)‐seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off‐label use of letermovir for secondary prophylaxis of genotype‐confirmed ganciclovir‐resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities.

Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension: A Systematic Review and Meta-Analysis

Background—Exercise training has been shown to improve cardiorespiratory fitness, physical capacity, and quality of life in patients with cardiopulmonary conditions, such as heart failure and chronic obstructive pulmonary disease. However, its role in management of pulmonary hypertension is not well defined. In this study, we aim to evaluate the efficacy and safety of exercise training in patients with pulmonary hypertension. Methods and Results—We included all prospective intervention studies that evaluated the efficacy and safety of exercise training in patients with pulmonary hypertension. Primary outcome of this meta-analysis was a change in 6-minute walk distance. We also assessed the effect of exercise on peak oxygen uptake, resting pulmonary arterial systolic pressure, peak exercise heart rate, and quality of life. A total of 469 exercise-training participants enrolled in 16 separate training studies were included. In the pooled analysis, exercise training was associated with significant improvement in 6-minute walk distance (weighted mean difference, 53.3 m; 95% confidence interval, 39.5–67.2), peak oxygen uptake (weighted mean difference, 1.8 mL/kg per minute; 95% confidence interval, 1.4–2.3), pulmonary arterial systolic pressure (weighted mean difference, −3.7 mm Hg; 95% confidence interval, −5.4 to −1.9), peak exercise heart rate (weighted mean difference, 10 beats per min; 95% confidence interval, 6–15), and quality of life as measured on SF-36 questionnaire subscale scores. Furthermore, exercise training was well tolerated with a low dropout rate, and no major adverse events were related to exercise training. Conclusions—Exercise training in patients with pulmonary hypertension appears safe and is associated with a significant improvement in exercise capacity, pulmonary arterial pressure, and quality of life.

Predictors of Death in Adults With Duchenne Muscular Dystrophy–Associated Cardiomyopathy

Background Duchenne muscular dystrophy (DMD) is frequently complicated by development of a cardiomyopathy. Despite significant medical advances provided to DMD patients over the past 2 decades, there remains a group of DMD patients who die prematurely. The current study sought to identify a set of prognostic factors that portend a worse outcome among adult DMD patients. Methods and Results A retrospective cohort of 43 consecutive patients was followed in the adult UT Southwestern Neuromuscular Cardiomyopathy Clinic. Clinical data were abstracted from the electronic medical record to generate baseline characteristics. The population was stratified by survival to time of analysis and compared with characteristics associated with death. The DMD population was in the early 20s, with median follow‐up times over 2 years. All the patients had developed a cardiomyopathy, with the majority of the patients on angiotensin‐converting enzyme inhibitors (86%) and steroids (56%), but few other guideline‐directed heart failure medications. Comparison between the nonsurviving and surviving cohorts found several poor prognostic factors, including lower body mass index (17.3 [14.8–19.3] versus 25.8 [20.8–29.1] kg/m2, P<0.01), alanine aminotransferase levels (26 [18–42] versus 53 [37–81] units/L, P=0.001), maximum inspiratory pressures (13 [0–30] versus 33 [25–40] cmH2O, P=0.03), and elevated cardiac biomarkers (N‐terminal pro‐brain natriuretic peptide: 288 [72–1632] versus 35 [21–135] pg/mL, P=0.03]. Conclusions The findings demonstrate a DMD population with a high burden of cardiomyopathy. The nonsurviving cohort was comparatively underweight, and had worse respiratory profiles and elevated cardiac biomarkers. Collectively, these factors highlight a high‐risk cardiovascular population with a worse prognosis.