Correction: STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.

[This corrects the article DOI: 10.1371/journal.pone.0179835.].

Vitamin D3 induces mesenchymal-to-endothelial transition and promotes a proangiogenic niche through IGF-1 signaling.

Although vitamin D3 (VitD3) prevents angiogenesis in cancer, VitD3 deficiency is associated with greater incidence of cardiovascular events in patients. We examined the influence of VitD3 on the angiogenic potential of mesenchymal stem cells (MSCs). VitD3 treatment increased the expression of proangiogenic molecules in MSCs, which exhibited an endothelial cell-like phenotype and promoted vascularization in vitro and in vivo. VitD3 activated the IGF-1 promoter and boosted IGF-1 receptor (IGF-1R) signaling, which was essential for the mesenchymal-to-endothelial transition (MEndoT) of MSCs. VitD3-treated MSCs created a proangiogenic microenvironment for co-cultured arterial endothelial cells, as well as aortic rings. The induction of MEndoT and angiogenesis promotion by VitD3-stimulated MSCs was attenuated by IGF-1R inhibitor picropodophyllin. We conclude that VitD3 promotes MEndoT in MSCs, and VitD3-treated MSCs augment vascularization by producing a proangiogenic niche through continued IGF-1 secretion. These results suggest a potential therapeutic role of VitD3 toward enhancing MSC-induced angiogenesis.

Transplantation of Human Umbilical Cord Blood-Derived Cellular Fraction Improves Left Ventricular Function and Remodeling After Myocardial Ischemia/Reperfusion.

Rationale: Human umbilical cord blood (hUCB) contains diverse populations of stem/progenitor cells. Whether hUCB-derived nonhematopoietic cells would induce cardiac repair remains unknown. Objective: To examine whether intramyocardial transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular fraction after a reperfused myocardial infarction in nonimmunosuppressed rats would improve cardiac function and ameliorate ventricular remodeling. Methods and Results: Nonhematopoietic CD45-Lin- cells were isolated from hUCB. Flow cytometry and quantitative polymerase chain reaction were used to characterize this subpopulation. Age-matched male Fischer 344 rats underwent a 30-minute coronary occlusion followed by reperfusion and 48 hours later received intramyocardial injection of vehicle or hUCB CD45-Lin- cells. After 35 days, compared with vehicle-treated rats, CD45-Lin- cell-treated rats exhibited improved left ventricular function, blunted left ventricular hypertrophy, greater preservation of viable myocardium in the infarct zone, and superior left ventricular remodeling. Mechanistically, hUCB CD45-Lin- cell injection favorably modulated molecular pathways regulating myocardial fibrosis, cardiomyocyte apoptosis, angiogenesis, and inflammation in postinfarct ventricular myocardium. Rare persistent transplanted human cells could be detected at both 4 and 35 days after myocardial infarction. Conclusions: Transplantation of hUCB-derived CD45-Lin- nonhematopoietic cellular subfraction after a reperfused myocardial infarction in nonimmunosuppressed rats ameliorates left ventricular dysfunction and improves remodeling via favorable paracrine modulation of molecular pathways. These findings with human cells in a clinically relevant model of myocardial ischemia/reperfusion in immunocompetent animals may have significant translational implications.Visual Overview: An online visual overview is available for this article.

Separating Acute Rheumatic Fever from Nonrheumatic Streptococcal Myocarditis.

INTRODUCTION: Streptococcal pharyngitis has been historically complicated with systemic involvement manifesting as acute rheumatic fever, which is a serious condition that can lead to permanent damage to heart valves. A recent association between streptococcal pharyngitis and nonrheumatic heart disease is emerging in literature. We present a case of nonrheumatic streptococcal myocarditis diagnosed using cardiac MRI. CASE PRESENTATION: A 25-year-old male, presented with complaints of sore throat, nonproductive cough, fever, pleuritic chest pain, and progressive dyspnea for four days. The patient had elevated troponins at presentation of 0.47 (ng/L) that peaked at 4.0 (ng/L). ECG showed sinus rhythm and ST elevations in leads V2, V3, V4, and V5. NT-Pro-BNP was 1740. Transthoracic echocardiogram (TTE) showed reduced ejection fraction (EF) of 37% and global hypokinesis. The rapid strep test was positive for group A streptococcus and C-reactive protein was elevated at 161. Cardiac MRI demonstrated an EF of 53% and edema in the anterior wall without delayed gadolinium enhancement. Cardiac catheterization showed normal coronaries. DISCUSSION: According to modified Jones criteria, the patient did not meet the full major or minor criteria to be diagnosed with acute rheumatic fever. The course of the nonrheumatic myocarditis is favorable and includes a full recovery of cardiac function, no involvement of cardiac valves, or long-term use of antibiotics. CONCLUSION: It is crucial to make a separate distinction between acute rheumatic fever and nonrheumatic myocarditis because this will have huge implications on management and long-term use of antibiotics. Cardiac imaging modalities can aid in distinction between the two disease entities.

Mechanical function of the left atrium is improved with epicardial ligation of the left atrial appendage: Insights from the LAFIT-LARIAT Registry.

BACKGROUND: Left atrial (LA) strain (ε) and ε rate (SR) analysis by 2-dimensional speckle tracking echocardiography is a novel method for functional assessment of the LA. OBJECTIVE: The purpose of this study was to determine the impact of left atrial appendage (LAA) exclusion by Lariat epicardial ligation on mechanical function of the LA by performing ε and SR analysis before and after the procedure. METHODS: A total of 66 patients who underwent successful LAA exclusion were included in the study. Of these 66 patients, 32 had adequate paired data for ε and SR analysis. SR during ventricular systole (LA-SRs) represents LA reservoir function, and SR during early ventricular diastole (LA-SRe) represents LA conduit function. ε and SR were determined from apical 4- and 2-chamber views using the electrocardiographic QRS as a reference point. LA volume index as surrogate for LA remodeling was measured from apical views. RESULTS: Mean patient age was 70 ± 9.2 years. LAA ligation resulted in improved reservoir function (LA-SRs: pre 0.72, confidence interval [CI] 0.63-0.83 vs post 0.81, CI 0.73-0.98; P = .043) and conduit function (LA-SRe: pre 0.74, CI 0.67-0.99 vs post 0.89, CI 0.82-1.07; P = .025). LA volume index improved significantly with the Lariat (pre 35.4, CI 29.4-37.2 vs post 29.2, CI 28.2-35.9; P <.023). CONCLUSION: LAA exclusion seems to improve mechanical function of the LA and results in reverse LA remodeling.

Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs.

RATIONALE: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. OBJECTIVE: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. METHODS AND RESULTS: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV-treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. CONCLUSIONS: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.

Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and ß-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and ß-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling.

Adjunctive ablation strategies improve the efficacy of pulmonary vein isolation in non-paroxysmal atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Pulmonary vein (PV) isolation (PVI) has suboptimal outcomes in patients with non-paroxysmal atrial fibrillation (AF). Adjunctive strategies employed to ablate non-PV triggers have shown favorable outcomes. AIMS: To delineate the incremental benefit of adjunctive ablation in patients with non-paroxysmal AF through a meta-analysis. METHODS AND RESULTS: Database searches through August 2016 identified five non-randomized and seven randomized controlled trials (enrolling 1694 patients). The adjunctive strategies employed for non-PV ablation included focal impulse and rotor modulation; empirical linear lines, ablation of complex fractionated atrial electrograms and ganglionated plexi. The risk ratio (RR) for AF recurrence, calculated with random effects meta-analysis showed a 36% reduction of AF recurrence at a median follow up of 12 months (RR: 0.64, 95% Confidence interval: 0.48 to 0.85; p = 0.003). The benefits persisted during longer follow up when assessed in subgroup analysis. CONCLUSIONS: Addition of adjunctive ablation to PVI improves outcomes.

Bone marrow cells for heart repair: clinical evidence and perspectives.

More than 15 years ago, bone marrow cell (BMC) therapy for cardiac repair was hailed as a highly promising and revolutionary treatment approach that was poised to benefit countless patients with ischemic heart disease (IHD) and heart failure. The ensuing years have unfortunately witnessed endless controversy not only about the mechanisms of action of cardiac repair with cell therapy, but also regarding the efficacy of such approach. Somewhat discordant results from smaller clinical trials with diverse study designs, BMC types, routes of injection, timing after myocardial infarction (MI), and other key study variables have been less than conclusive. Because of this uncertainty regarding outcomes of BMC therapy, a large number of meta-analyses have been performed, also with dissimilar findings. Although the field continues to evolve with emergence of data from newer and larger clinical trials with more stringent design, the overall evidence does support efficacy of BMC injection in patients with IHD with regard to improvement in cardiac parameters as well as patient outcomes. Given the limitless potential of adult stem cell therapy in general, at this juncture, a careful appraisal of the cumulative evidence is critically necessary to appreciate the true impact of BMC therapy on injured heart. This review will discuss the clinical evidence and perspectives from trials and meta-analyses of BMC therapy in patients with IHD that have accumulated in published literature.

Continuous renal replacement therapy for haemodynamic collapse and rhabdomyolysis induced by pheochromocytoma crisis.

Pheochromocytoma associated with pregnancy is not common. Caesarean section may induce pheochromocytoma crisis, resulting in a lethal condition. The clinical picture of pheochromocytoma crisis is extremely variable. In this report, we describe a case of severe pheochromocytoma crisis induced by caesarean section presenting with hyperpyrexia, haemodynamic collapse, muscle weakness, heart failure, and acute kidney injury. Furthermore, we report that the muscle weakness was a manifestation of rhabdomyolysis, resulting from the pheochromocytoma crisis. Standard medical therapy failed to halt the patient's rapidly deteriorating condition. Continuous renal replacement therapy removed catecholamines from the circulation, resulting in improvement of haemodynamics and abrogation of rhabdomyolysis.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.

RATIONALE: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE: To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS: Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS: Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights From Randomized Controlled Trials.

RATIONALE: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.

Use of contact force sensing technology during radiofrequency ablation reduces recurrence of atrial fibrillation: A systematic review and meta-analysis.

The suboptimal outcomes of atrial fibrillation (AF) ablation have been attributed to lack of transmural lesions during pulmonary vein isolation. The advent of contact force (CF) sensing technology enables real-time assessment of the applied force at the catheter-tissue interface and increases the chances of transmural lesions. We sought to perform a meta-analysis of data from eligible studies to delineate the true impact of CF technology. Database searches through April 2015 identified 9 eligible studies (enrolling 1148 patients). The relative risk of AF recurrence at follow-up was used as the primary end point and assessed with random-effects meta-analysis. Radiofrequency (RF) duration, total procedure length, and fluoroscopy exposure were assessed as secondary outcomes using weighted mean difference with the random-effects model. Compared with standard technology, the use of CF technology showed a 37% reduction (relative risk 0.63; 95% confidence interval 0.44-0.91; P = .01) in AF recurrence at a median follow-up of 12 months and a 7.3-minute reduction (95% confidence interval -14.05 to -0.55; P = .03) in RF use during ablation. There was no significant difference in total procedure length and fluoroscopy exposure between the 2 groups. In conclusion, this meta-analysis shows that the use of CF technology decreases AF recurrence at a median follow-up of 12 months and also led to decreased use of RF during ablation. There was no difference in total procedure length and fluoroscopy exposure.