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The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by therapeutic cells injected into infarcted hearts can induce recovery through the delivery of cell-specific microRNAs. However, retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes (CMs) derived from induced pluripotent stem cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased CM apoptosis 24 h after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that EVs are enriched with cardiac-specific microRNAs known to modulate CM-specific processes. The extended delivery of EVs secreted from induced-pluripotent-stem-cell-derived CMs into the heart may help us to treat heart injury and to understand heart recovery. A hydrogel patch for the sustained delivery of extracellular vesicles from cardiomyocytes derived from induced pluripotent stem cells improves tissue regeneration in infarcted rat hearts.

Metabolic syndrome (MetS) predisposes to cardiovascular disease. Endothelial dysfunction is thought to be an important factor in the pathogenesis of atherosclerosis. We tested the hypothesis that both MetS and endothelial dysfunction are vascular risk factors and provide additive prognostic values in predicting cardiovascular events in a multiethnic community sample. The study population consisted of 819 subjects (467 female, mean age 66.5 ± 8.8 years, 66% Hispanic) enrolled in the NOMAS. Metabolic syndrome was defined using the revised Adult Treatment Panel III criteria. Brachial artery flow-mediated dilation (FMD) was measured using high-resolution ultrasound. Endothelial dysfunction was defined as FMD <8.44% (lower 3 quartiles). Cox proportional hazards models were used to assess the effect of MetS and endothelial dysfunction on risk of cardiovascular events. During 81 ± 21 months of follow-up, events occurred in 84 subjects. Metabolic syndrome was independently associated with cardiovascular events in a multivariate model, including cardiovascular risk factors (adjusted hazard ratio 2.08, 95% CI 1.27-3.40). Subjects with both MetS and endothelial dysfunction were at higher risk for cardiovascular events than those with either one of them alone (adjusted hazard ratio 2.60, 95% CI 1.14-5.92). Metabolic syndrome is associated with incident cardiovascular events. Combined use of MetS and FMD identifies those who are at higher risk of cardiovascular events. Metabolic syndrome and noninvasive FMD testing can be used concurrently for cardiovascular risk prediction.

[Display omitted] •Lower left atrial (LA) strain and LA strain rate were independently associated with new-onset atrial fibrillation (AF).•Lower LA strain and LA strain rate predicted AF even in participants with normal LA volume.•Reduced reservoir function predicted AF in participants with smaller LA volume.•Reduced pump function predicted AF in participants with larger LA volume. Atrial fibrillation (AF) is frequent in older adults and associated with left atrial (LA) dysfunction. LA strain (LAε) and LA strain rate (LASR) may detect subclinical LA disease. We investigated whether reduced LAε and LASR predict new-onset AF in older adults without history of AF or stroke. LAε and LASR were assessed by speckle-tracking echocardiography in 824 participants from the community-based Cardiovascular Abnormalities and Brain Lesions study. Positive longitudinal LAε and LASR during ventricular systole, LASR during early ventricular diastole, and LASR during LA contraction were measured. Cause-specific hazards regression model evaluated the association of LAε and LASR with incident AF, adjusting for pertinent covariates. The mean age was 71.1 ± 9.2 years (313 men, 511 women). During a mean follow-up of 10.9 years, new-onset AF occurred in 105 participants (12.7%). Lower LAε and LASR at baseline were observed in patients with new-onset AF (all p <0.01). In multivariable analysis, positive longitudinal LAε (adjusted hazard ratio [HR] per SD decrease 2.05, confidence interval [CI] 1.24 to 3.36) and LASR during LA contraction (HR per SD increase 2.24, CI 1.37 to 3.65) remained associated with new-onset AF, independently of LA volumes and left ventricular function. Along with positive longitudinal LAε, reduced LASR during ventricular systole predicted AF in participants with LA volume below the median value (HR 2.54, CI 1.10 to 6.09), whereas reduced LASR during LA contraction predicted AF in participants with larger LA (HR 2.35, CI 1.31 to 4.23). In conclusion, reduced positive longitudinal LAε and LASR predict new-onset AF in older adults regardless of LA size and may improve AF risk stratification.

ObjectiveLeft atrial (LA) maximum volume (LAVmax) is an indicator of left ventricular (LV) diastolic function. However, LAVmax is also influenced by systolic events, whereas the LA minimum volume (LAVmin) is directly exposed to LV pressure. The authors hypothesised that LAVmin may be a better correlate of LV diastolic function than LAVmax.DesignCross-sectional.SettingUniversity hospital.Patients357 participants from a community-based cohort study.MethodsLA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e'). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking.ResultsLAVmin significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAVmax was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAVmin and LAVmax were significant predictors of E/e', with higher parameter estimates for LAVmin. In multivariate models, LAVmin resulted strongly associated with E/e' (β=0.45, p<0.001), whereas LAVmax was not (β=−0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAVmax (β=−0.15, p=0.002), LAEV (β=−0.37, p<0.001) and LAEF (β=−0.28, p<0.001) but not with LAVmin.ConclusionsLAVmin is a better correlate of LV diastolic function than LAVmax. The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAVmax and LV diastolic function.

Volatiles from herbivore-infested plants function as a chemical warning of future herbivory for neighboring plants. ( Z )-3-Hexenol emitted from tomato plants infested by common cutworms is taken up by uninfested plants and converted to ( Z )-3-hexenyl β-vicianoside (HexVic). Here we show that a wild tomato species ( Solanum pennellii ) shows limited HexVic accumulation compared to a domesticated tomato species ( Solanum lycopersicum ) after ( Z )-3-hexenol exposure. Common cutworms grow better on an introgression line containing an S. pennellii chromosome 11 segment that impairs HexVic accumulation, suggesting that ( Z )-3-hexenol diglycosylation is involved in the defense of tomato against herbivory. We finally reveal that HexVic accumulation is genetically associated with a uridine diphosphate-glycosyltransferase (UGT) gene cluster that harbors UGT91R1 on chromosome 11. Biochemical and transgenic analyses of UGT91R1 show that it preferentially catalyzes ( Z )-3-hexenyl β- d -glucopyranoside arabinosylation to produce HexVic in planta . Volatiles from herbivore-infested plants can function as chemical warning signals to neighbouring plants. Here the authors show that a tomato UDP-glycosyltransferase can convert a volatile signal emitted by infested plants to promote plant defense.

Background Mitochondrial permeability transition pore (mPTP) closure triggers cardiomyocyte differentiation during development while pathological opening causes cell death during myocardial ischemia-reperfusion and heart failure. Ubiquinone modulates the mPTP; however, little is known about its mechanistic role in health and disease. We previously found excessive proton leak in newborn Fmr1 KO mouse forebrain caused by ubiquinone deficiency and increased open mPTP probability. Because of the physiological differences between the heart and brain during maturation, we hypothesized that developing Fmr1 KO cardiomyocyte mitochondria would demonstrate dissimilar features. Methods Newborn male Fmr1 KO mice and controls were assessed. Respiratory chain enzyme activity, ubiquinone content, proton leak, and oxygen consumption were measured in cardiomyocyte mitochondria. Cardiac function was evaluated via echocardiography. Results In contrast to controls, Fmr1 KO cardiomyocyte mitochondria demonstrated increased ubiquinone content and decreased proton leak. Leak was cyclosporine (CsA)-sensitive in controls and CsA-insensitive in Fmr1 KOs. There was no difference in absolute mitochondrial respiration or cardiac function between strains. Conclusion These findings establish the newborn Fmr1 KO mouse as a novel model of excess ubiquinone and closed mPTP in the developing heart. Such a model may help provide insight into the biology of cardiac development and pathophysiology of neonatal heart failure. Impact Ubiquinone is in excess and the mPTP is closed in the developing FXS heart. Strengthens evidence of open mPTP probability in the normally developing postnatal murine heart and provides new evidence for premature closure of the mPTP in Fmr1 mutants. Establishes a novel model of excess CoQ and a closed pore in the developing heart. Such a model will be a valuable tool used to better understand the role of ubiquinone and the mPTP in the neonatal heart in health and disease.

Control over cell engraftment, survival, and function remains critical for heart repair. We have established a tissue engineering platform for the delivery of human mesenchymal progenitor cells (MPCs) by a fully biological composite scaffold. Specifically, we developed a method for complete decellularization of human myocardium that leaves intact most elements of the extracellular matrix, as well as the underlying mechanical properties. A cell-matrix composite was constructed by applying fibrin hydrogel with suspended cells onto decellularized sheets of human myocardium. We then implanted this composite onto the infarct bed in a nude rat model of cardiac infarction. We next characterized the myogenic and vasculogenic potential of immunoselected human MPCs and demonstrated that in vitro conditioning with a low concentration of TGF-β promoted an arteriogenic profile of gene expression. When implanted by composite scaffold, preconditioned MPCs greatly enhanced vascular network formation in the infarct bed by mechanisms involving the secretion of paracrine factors, such as SDF-1, and the migration of MPCs into ischemic myocardium, but not normal myocardium. Echocardiography demonstrated the recovery of baseline levels of left ventricular systolic dimensions and contractility when MPCs were delivered via composite scaffold. This adaptable platform could be readily extended to the delivery of other reparative cells of interest and used in quantitative studies of heart repair.

Impaired cardiac function is considered a contraindication for lung transplantation (LT). Because right ventricular (RV) function is expected to improve after LT, poor left ventricular (LV) function is often the determinant for LT eligibility. However, the changes in cardiac function before and after LT have not yet been elucidated. Therefore, we reviewed echocardiograms obtained from 67 recipients before and after LT. In a subset of 49 patients, both RV and LV longitudinal strains based on 2-dimensional speckle tracking echocardiography were analyzed. The cardiopulmonary exercise tests were also reviewed. All patients showed significant improvements in their exercise capacity after LT. RV echo parameters improved in all patients after LT (RV fractional area change: 36.7 ± 5.6% to 41.5 ± 2.7%, RV strain: −15.5 ± 2.9% to −18.0 ± 2.1%, RV E/E′: 8.4 ± 1.8 to 7.7 ± 1.8; all p <0.05). Overall, the left ventricular ejection fraction (LVEF) did not change (58.7 ± 6.0% to 57.5 ± 9.7%, p = 0.385); however, 20 patients (30%) showed >10% decrease in LVEF after LT (61.5 ± 6.1% to 47.3 ± 4.2%, p <0.001) and an increase in LV E/E′ (11.8 ± 1.8 to 12.9 ± 2.2, p = 0.049). Multivariate logistic regression analysis revealed that pre-LT LV E/E′ was associated with decrease in LVEF after LT (odds ratio 1.381, 95% confidence interval 1.010 to 1.947, p = 0.043). Furthermore, patients with strain data showed that lower pre-LT LV strain was independently associated with LVEF decrease after LT (odds ratio 1.293, 95% confidence interval 1.088 to 1.614, p = 0.002). Although RV function improves after LT, LV systolic and diastolic functions deteriorate in a sizable proportion of patients. Impaired LV diastolic function before transplant appears to increase the risk of LVEF deterioration after LT.