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Background: Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform., Methods: In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch., Results: The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival., Conclusions: We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity., (© 2017 American Heart Association, Inc.)

Background: Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function., Methods and Results: A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance., Conclusions: The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764., (© 2015 American Heart Association, Inc.)

Background: There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into ingenuity pathway analysis in patients with isolated MR., Methods and Results: Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared with 13 normal controls. Cine-MRI was performed in 31 patients before surgery to measure LV function and volume from serial short-axis summation. LV end-diastolic volume was 2-fold (P=0.005) higher in MR patients than in normal controls, and LV ejection fraction was 64±7% (50%-79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in β-adrenergic, cAMP, and G-protein-coupled signaling, whereas there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR versus control left ventricles. However, mRNA and protein levels of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold, respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal left ventricles and its marked upregulation in MR left ventricles., Conclusions: These results demonstrate alterations in multiple pathways associated with β-adrenergic signaling and sarcolipin in the left ventricles of patients with isolated MR and LV ejection fraction>50%, suggesting a beneficial role for β-adrenergic blockade in isolated MR.

Background: Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart., Methods and Results: Ninety-four patients (age, 54 ± 11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44 ± 14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (P<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61 ± 7% to 54 ± 8% (P<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (P<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery., Conclusions: Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.

Background: It is believed that increasing cardiac glucose metabolism in the setting of ischemia and reperfusion is protective because of the resulting decrease in fatty acid oxidation, which improves cardiac efficiency and increases glucose oxidation relative to glycolysis; however, these conclusions are based primarily on studies in which glucose is the only carbohydrate provided. The goal of this study was to examine the effect of stimulating myocardial carbohydrate use either by increasing glucose and insulin levels or by using dichloroacetate on the response to ischemia and reperfusion in hearts perfused with physiological concentrations of lactate and pyruvate plus glucose and fatty acids., Methods and Results: Metabolic fluxes were determined in hearts from male Sprague-Dawley rats perfused with 13C-labeled substrates using 13C/1H-NMR isotopomer analysis after 30 minutes of low-flow ischemia (0.3 mL/min) and 60 minutes of reperfusion. Measurements were made under control conditions: 5 mmol/L glucose, 1 mmol/L lactate, 0.1 mmol/L pyruvate, 0.3 mmol/L palmitate, and 50 microU/mL insulin plus dichloroacetate 5 mmol/L or glucose and insulin increased to 30 mmol/L and 1000 microU/mL, respectively. Dichloroacetate increased carbohydrate oxidation and the ratio of glucose oxidation to glycolysis but did not improve functional recovery or cardiac efficiency; however, elevated glucose and insulin levels improved functional recovery and cardiac efficiency but did not increase carbohydrate oxidation or the ratio of glucose oxidation to glycolysis., Conclusions: These data support the notion that increasing myocardial glucose use is beneficial in the setting of ischemia and reperfusion; however, the protective effect appears not to be mediated by shifting the balance between carbohydrate and fatty acid oxidation.