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 (<3 mm) and similar in the 2 groups. Within the MVP stroke group, NC-stroke had higher BMI, more hypertension and more atrial fibrillation compared to C-stroke. In the variables tested, patients with C-stroke did not differ from controls. CONCLUSIONS: MVP-related MR may be protective against stroke despite abnormal LA function. Risk of NC-stroke in MVP is related to common stroke risk factors rather than mitral valve leaflet thickness. The etiology of C-stroke in MVP warrants further studies.

Background

Many 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.

Methods

Unsupervised 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.

Results

The 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.

Conclusions

Transthoracic 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.

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: <5.6, 5.6 to <6.9, and ≧6.9. An elevated eSVR was defined as an eSVR in the third tertile (≧6.9). Follow-up eSVR was calculated at the fifth year of checkup. Cardiovascular outcomes included heart failure, major cardiovascular events, and all-cause death. Among the 984 participants (67±11 years old, 82% men), subjects with the highest baseline eSVR tertile were the oldest, with the highest systolic blood pressure and lowest left ventricular outflow tract velocity time integral. A higher eSVR was associated with increased risk of heart failure, major cardiovascular events, and death. The hazard ratio for major cardiovascular events was 1.38 (95% CI, 1.02-1.86, P=0.03) for subjects with the highest eSVR tertile compared with the lowest. In addition, those with a persistently elevated eSVR during follow-up had the most adverse outcomes. Conclusions An elevated eSVR, derived by the ratio of systolic blood pressure and left ventricular outflow tract velocity time integral, was more closely correlated with cardiovascular events than systolic blood pressure alone. Repeatedly elevated eSVR was associated with more adverse outcomes.

Background

The 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.

Methods

We 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.

Results

After 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<0.001). This was higher than what was seen with LAESVI (HR, 4.85; P<0.001). Similar associations were noted for the composite cardiovascular outcome (HR for LAEDVI, 2.97; P<0.001) and for all-cause mortality (HR for LAEDVI, 2.08; P<0.001). In adjusted models, LAEDVI demonstrated equal or better predictive power than LAESVI for HF hospitalization and the composite cardiovascular outcome.

Conclusions

LAEDVI is a strong predictor of cardiovascular events in ambulatory patients with stable coronary heart disease and may merit routine use.

Background

Aging is associated with higher incidence of heart failure and death following myocardial infarction (MI). The molecular and cellular changes that lead to these worse outcomes are not known.

Methods and results

Young and aging mice underwent induction of MI by LAD ligation. There was a significant increase in mortality in the aging mice. Neither the young nor aging hearts after MI had inducible ventricular tachycardia. Cardiomyocyte apoptosis increases early after MI in young and aging mice, but to a much greater degree in the aging mice. Caspase inhibition with Ac-DEVD-CHO resulted in a 61% reduction in activated caspase-3 and an 84% reduction in apoptosis in cardiomyocytes in young mice (P < 0.05), but not in aging mice. Gene pathway profiling demonstrated activation of both the caspase and Map3k1/Mapk10 pathways in aging mice following MI, which may contribute to their resistance to caspase inhibition.

Conclusions

Aging hearts activate distinct apoptotic pathways have more cardiomyocyte apoptosis and are resistant to antiapoptotic therapies following MI. Novel or combination approaches may be required to improve outcomes in aging patients following MI.

Objective

Bileaflet 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.

Methods

We 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.

Results

MVPs 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).

Conclusions

STE-derived mechanical dispersion may help identify MVP patients at higher arrhythmic risk.

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.

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.

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.

Background

The extracellular matrix plays an important role in tissue regeneration. We investigated whether extracellular matrix protein fragments could be targeted with antibodies to ischemically injured myocardium to promote angiogenesis and myocardial repair.

Methodology/principal findings

Four peptides, 2 derived from fibronectin and 2 derived from Type IV Collagen, were assessed for in vitro and in vivo tendencies for angiogenesis. Three of the four peptides--Hep I, Hep III, RGD--were identified and shown to increase endothelial cell attachment, proliferation, migration and cell activation in vitro. By chemically conjugating these peptides to an anti-myosin heavy chain antibody, the peptides could be administered intravenously and specifically targeted to the site of the myocardial infarction. When administered into Sprague-Dawley rats that underwent ischemia-reperfusion myocardial infarction, these peptides produced statistically significantly higher levels of angiogenesis and arteriogenesis 6 weeks post treatment.

Conclusions/significance

We demonstrated that antibody-targeted ECM-derived peptides alone can be used to sufficiently alter the extracellular matrix microenvironment to induce a dramatic angiogenic response in the myocardial infarct area. Our results indicate a potentially new non-invasive strategy for repairing damaged tissue, as well as a novel tool for investigating in vivo cell biology.