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Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the myocardium which greatly hinders cellular function, survival, and recruitment, thus severely limits tissue regeneration. Here, we leverage biophysical microstructural cues made of hyaluronic acid (HA) loaded with the anti-fibrotic proteoglycan decorin to more robustly attenuate cardiac fibrosis after acute myocardial injury. Microrods showed decorin incorporation throughout the entirety of the hydrogel structures and exhibited first-order release kinetics in vitro. Intramyocardial injections of saline (n = 5), microrods (n = 7), decorin microrods (n = 10), and free decorin (n = 4) were performed in male rat models of ischemia-reperfusion MI to evaluate therapeutic effects on cardiac remodeling and function. Echocardiographic analysis demonstrated that rats treated with decorin microrods (5.21% ± 4.29%) exhibited significantly increased change in ejection fraction (EF) at 8 weeks post-MI compared to rats treated with saline (-4.18% ± 2.78%, p

BACKGROUND AND PURPOSE: Mitral valve prolapse (MVP) has been associated with an increased risk of ischemic stroke. Older age, thicker mitral leaflets, and significant mitral regurgitation (MR) leading to atrial fibrillation have been traditionally considered risk factors for ischemic stroke in MVP. However, specific risk factors for MVP-stroke subtypes are not well defined. The aim of this study is to evaluate clinical and echocardiographic parameters, including left atrial (LA) function, in MVP with cryptogenic (C) vs. non-cryptogenic (NC) stroke. METHODS: In this case-control matched study, MVPs were identified in consecutive echocardiograms obtained after a stroke from January 2013 to December2016 at the University of California, San Francisco. MVP was defined as leaflet displacement ≥2 mm in the parasternal long-axis view at end-systole. Age/gender matched MVPs without stroke and healthy controls without MVP were also identified. We analyzed LA end-systolic/diastolic volume index, emptying fraction (LAEF), function index (LAFI), and global longitudinal strain in all MVPs and controls. We also measured left ventricular (LV) volume indexes, mass index, ejection fraction (EF), degree of MR and leaflet thickness. RESULTS: We identified a total of 30 MVPs (age 70 ± 12, 50% females) with stroke (11 with C- and 19 with NC-stroke), 20 age/gender matched MVPs without a stroke and 16 controls. MVPs without stroke had lower BMI, less hypertension but more MR (≥moderate in 45% vs. 17%), more abnormal LA function (lower LAEF, LAFI) and larger LV volumes/mass (all p < 0.05) when compared to MVPs with stroke. Leaflet thickness was overall mild (

Background Systemic vascular resistance (SVR) is an integral component of the hemodynamic profile. Previous studies have demonstrated a close correlation between an estimated SVR analog (eSVR) based on echocardiographic methods and SVR by direct hemodynamic measurement. However, the prognostic impact of eSVR remains unestablished. Methods and Results Study participants with established coronary artery disease from the Heart and Soul Study formed this study cohort. We defined Doppler-derived eSVR as the ratio of systolic blood pressure to left ventricular outflow tract velocity time integral. Study participants were separated based on baseline eSVR tertile:

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drug-releasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.

BackgroundThe left atrial end-systolic volume index (LAESVI) is a predictor of cardiovascular outcomes and is the recommended measurement of left atrial size. The left atrial end-diastolic volume index (LAEDVI), representing the minimum or residual left atrial volume, has not been fully evaluated as a predictor of cardiovascular events. This study evaluated the predictive power of LAEDVI compared with LAESVI for heart failure (HF) hospitalizations, a composite of HF hospitalizations, myocardial infarction, stroke, and heart disease death, and all-cause mortality.MethodsWe measured LAESVI and LAEDVI in subjects without atrial fibrillation or flutter or significant mitral valve disease. Using Cox proportional-hazard models, the association of LAESVI and LAEDVI with the stated outcomes was examined.ResultsAfter a mean of 7.3±2.6 years of follow-up, there were 147 HF hospitalizations, 118 myocardial infarctions, 45 strokes, 96 heart disease deaths, and 351 deaths from all causes in 938 subjects. When comparing the highest and the lowest quartiles of LAEDVI, there was a near 6-fold increase in the hazard ratio (HR) for HF hospitalization (HR, 5.96; P

BackgroundMany individual echocardiographic variables have been associated with heart failure (HF) in patients with stable coronary artery disease (CAD), but their combined utility for prediction has not been well studied.MethodsUnsupervised model-based cluster analysis was performed by researchers blinded to the study outcome in 1,000 patients with stable CAD on 15 transthoracic echocardiographic variables. We evaluated associations of cluster membership with HF hospitalization using Cox proportional hazards regression analysis.ResultsThe echo-derived clusters partitioned subjects into four phenogroupings: phenogroup 1 (n = 85) had the highest levels, phenogroups 2 (n = 314) and 3 (n = 205) displayed intermediate levels, and phenogroup 4 (n = 396) had the lowest levels of cardiopulmonary structural and functional abnormalities. Over 7.1 ± 3.2 years of follow-up, there were 198 HF hospitalizations. After multivariable adjustment for traditional cardiovascular risk factors, phenogroup 1 was associated with a nearly fivefold increased risk (hazard ratio [HR] = 4.8; 95% CI, 2.4-9.5), phenogroup 2 was associated with a nearly threefold increased risk (HR = 2.7; 95% CI, 1.4-5.0), and phenogroup 3 was associated with a nearly twofold increased risk (HR = 1.9; 95% CI, 1.0-3.8) of HF hospitalization, relative to phenogroup 4.ConclusionsTransthoracic echocardiographic variables can be used to classify stable CAD patients into separate phenogroupings that differentiate cardiopulmonary structural and functional abnormalities and can predict HF hospitalization, independent of traditional cardiovascular risk factors.

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration.

ObjectiveBileaflet mitral valve prolapse (MVP) with either focal or diffuse myocardial fibrosis has been linked to ventricular arrhythmia and/or sudden cardiac arrest. Left ventricular (LV) mechanical dispersion by speckle-tracking echocardiography (STE) is a measure of heterogeneity of ventricular contraction previously associated with myocardial fibrosis. The aim of this study is to determine whether mechanical dispersion can identify MVP at higher arrhythmic risk.MethodsWe identified 32 consecutive arrhythmic MVPs (A-MVP) with a history of complex ventricular ectopy on Holter/event monitor (n=23) or defibrillator placement (n=9) along with 27 MVPs without arrhythmic complications (NA-MVP) and 39 controls. STE was performed to calculate global longitudinal strain (GLS) as the average peak longitudinal strain from an 18-segment LV model and mechanical dispersion as the SD of the time to peak strain of each segment.ResultsMVPs had significantly higher mechanical dispersion compared with controls (52 vs 42 ms, p=0.005) despite similar LV ejection fraction (62% vs 63%, p=0.42) and GLS (-19.7 vs -21, p=0.045). A-MVP and NA-MVP had similar demographics, LV ejection fraction and GLS (all p>0.05). A-MVP had more bileaflet prolapse (69% vs 44%, p=0.031) with a similar degree of mitral regurgitation (mostly trace or mild in both groups) (p>0.05). A-MVP exhibited greater mechanical dispersion when compared with NA-MVP (59 vs 43 ms, p=0.0002). Mechanical dispersion was the only significant predictor of arrhythmic risk on multivariate analysis (OR 1.1, 95% CI 1.02 to 1.11, p=0.006).ConclusionsSTE-derived mechanical dispersion may help identify MVP patients at higher arrhythmic risk.

Purpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI. Procedure: To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis. Results: The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates. Conclusions: Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI. [ABSTRACT FROM AUTHOR]

Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct.