Different Impact of Immunosuppressive Therapy on Cardiac Outcomes in Systemic Versus Isolated Cardiac Sarcoidosis.

Isolated cardiac sarcoidosis (iCS) is increasingly recognized; however, its prognosis and the efficacy of immunosuppressive therapy remain undetermined. We aimed to compare the prognosis of iCS and systemic sarcoidosis including cardiac involvement (sCS) under immunosuppressive therapy.We retrospectively reviewed the clinical data of 42 patients with sCS and 30 patients with iCS diagnosed at Kyushu University Hospital from 2004 through 2022. We compared the characteristics and the rate of adverse cardiac events including cardiac death, fatal ventricular tachyarrhythmia, and heart failure hospitalization between the 2 groups. The median follow-up time was 1535 [interquartile range, 630-2555] days, without a significant difference between the groups. There were no significant differences in gender, NYHA class, or left ventricular ejection fraction. Immunosuppressive agents were administered in 86% of sCS and in 73% of iCS patients (P = 0.191). When analyzed only with patients receiving immunosuppressive therapy (sCS, n = 36; iCS, n = 21), the cardiac event-free survival was significantly lower in iCS than sCS (37% versus 79%, P = 0.002). Myocardial LGE content at the initial diagnosis was comparable in both groups. The disease activity was serially evaluated in 26 sCS and 16 iCS patients by quantitative measures of FDG-PET including cardiac metabolic volume and total lesion glycolysis, representing 3-dimensional distribution and intensity of inflammation in the entire heart. Although iCS patients had lower baseline disease activity than sCS patients, immunosuppressive therapy did not attenuate disease activity in iCS in contrast to sCS.iCS showed a poorer response to immunosuppressive therapy and a worse cardiac prognosis compared to sCS despite lower baseline disease activity.

Fatal Pulmonary Hemorrhagic Infarction Caused by Pulmonary Vein Thrombotic Occlusion During Venoarterial Extracorporeal Membrane Oxygenation.

A 20-year-old man with arrhythmogenic right ventricular cardiomyopathy (ARVC) was resuscitated from ventricular fibrillation. He was transferred to our hospital because of progressive multiorgan dysfunction despite mechanical circulatory support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pump (IABP). At admission to our hospital, chest X-ray showed bilateral complete lung opacification, and echocardiography revealed a massive thrombus occupying the left atrium (LA) and left ventricle (LV). Conversion to central ECMO with transapical LV venting and thrombectomy were performed. The huge LA thrombus occluded all pulmonary veins (PVs). Despite the surgery and intensive care, complete lung opacity remained, and he died of multiorgan failure associated with sepsis. Autopsy demonstrated bilateral pulmonary multiple red infarctions, and histopathology showed alveolar wall necrosis with extensive hemorrhage, confirming a diagnosis of pulmonary hemorrhagic infarction. Extensive pulmonary infarction was attributable to PV occlusion due to massive LA thrombus. PV thrombosis should be considered when refractory lung opacities are encountered during VA-ECMO and necessitates early intervention.

Impact of Hospital Practice Factors on Mortality in Patients Hospitalized for Heart Failure in Japan　- An Analysis of a Large Number of Health Records From a Nationwide Claims-Based Database, the JROAD-DPC.

BACKGROUND: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan.Methods and Results:We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: "Interventional cardiology", "Cardiovascular surgery", "Pediatric cardiology", "Electrophysiology" and "Cardiac rehabilitation". Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the "Pediatric cardiology" (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628-0.729, P<0.0001), "Electrophysiology" (OR 0.876, 95% CI: 0.832-0.923, P<0.0001), and "Cardiac rehabilitation" (OR 0.832, 95% CI: 0.792-0.873, P<0.0001) factors were associated with lower mortality. In contrast, "Interventional cardiology" (OR 1.167, 95% CI: 1.070-1.272, P<0.0001) was associated with higher mortality. CONCLUSIONS: Hospital factors, including various cardiovascular therapeutic practices, may be associated with the early death of HF patients.

Systemic-to-Pulmonary Collateral Flow Correlates with Clinical Condition Late After the Fontan Procedure.

In the Fontan circulation, there is a substantial degree of systemic-to-pulmonary collateral flow (SPCF), which can be measured by cardiac magnetic resonance (CMR). However, the correlation between the degree of SPCF and long-term outcomes is not fully understood. We retrospectively studied 321 patients who underwent the Fontan procedure and CMR at a single center. Using CMR, we calculated SPCF as pulmonary blood flow - systemic blood flow. %SPCF was defined as SPCF ÷ pulmonary blood flow. The mean age of patients at CMR was 14.3 ± 7.5 years. The average %SPCF was 13.0% ± 11.0%. With a multivariate analysis, %SPCF was significantly correlated with time (i.e., the longer the time period since the Fontan procedure, the lower the %SPCF) (p = 0.006), previous total anomalous pulmonary vein drainage (p = 0.007), a low pulmonary artery index (Nakata index) before the Fontan procedure (p = 0.04), and older age at the time of the Fontan procedure (p = 0.002). Regarding the findings after the Fontan procedure, %SPCF was significantly correlated with ventricular end-diastolic volume (p < 0.001), ventricular end-systolic volume (p < 0.001), central venous pressure (p < 0.001), plasma brain natriuretic peptide concentration (p < 0.001), hemoptysis (p = 0.009), and poor New York Heart Association functional class (p = 0.007). SPCF was correlated with clinical condition after the Fontan procedure. The importance of sufficient growth of the pulmonary vascular bed should be emphasized because the development of SPCF is believed to result from the poor condition of the pulmonary circulation.

Ivabradine for the Treatment of Cardiovascular Diseases.

Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the If current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of If inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.

Cilostazol Is Useful for the Treatment of Sinus Bradycardia and Associated Hemodynamic Deterioration Following Heart Transplantation.

Bradycardia is a common complication at the early postoperative period after heart transplantation (HT). The heart rate (HR) usually recovers within a few weeks; however, several patients need a temporary pacemaker or chronotropic agents to stabilize their hemodynamics. Here, we report the first case of transient bradycardia associated with hemodynamic deterioration following HT, which was successfully treated with cilostazol, a phosphodiesterase-3-inhibiting agent. A 59-year-old man received HT for advanced heart failure due to ischemic cardiomyopathy. General fatigue persisted even after the HT. His HR was around 60 beats per minute (bpm) with sinus rhythm. Echocardiography showed no abnormal findings. Right heart catheterization showed that the cardiac index (CI) was 1.9 L/minute/m2. Continuous intravenous infusion of isoproterenol (0.003 µg/kg/minute) increased the HR to 80 bpm and CI to 2.7 L/minute/m2 and improved his symptoms. Isoproterenol was switched to oral administration of cilostazol (100 mg, twice a day), which maintained the HR at around 80 bpm and CI of 2.5 L/minute/m2. The patient's HR gradually recovered and cilostazol could be discontinued three months after the HT. Oral administration of cilostazol can be a therapeutic option for patients with sinus bradycardia following HT, who need positive chronotropic support.

Flow Pattern of Outflow Graft is Useful for Detecting Pump Thrombosis in a Patient with Left Ventricular Assist Device.

Pump thrombosis (PT) is a serious complication after continuous-flow left ventricular assist device (LVAD) implantation. To detect PT, echocardiographic ramp test using left ventricular end-diastolic diameter (LVEDD) is known to be useful. However, this method has several limitations. In this study, we propose an alternative novel ramp test using the flow velocity of outflow graft (OG). A 46-year-old man underwent continuous-flow LVAD (HeartMate II, Abbott Laboratories, Lake Forest, IL, USA) implantation for advanced heart failure due to idiopathic dilated cardiomyopathy. About 2 years after implantation, he suffered from hemolysis and symptoms of heart failure, and PT was strongly suspected. The change in LVEDD was minimal with increase in pump speed (-0.06 cm/400 rotations per minute (rpm)), suggesting PT. The systolic to diastolic velocity (S/D) ratio of OG flow, which we proposed as a new indicator of PT, also showed minimal change (-0.07/400 rpm). His clinical symptoms improved with anticoagulation therapy, and the changing slope of the S/D ratio dramatically improved to -0.92/400 rpm. Although its consistency should be verified in many other cases, this novel method can be useful for detecting PT and evaluating its clinical course.

JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells.

OBJECTIVE: Jumonji C (JmjC) domain-containing proteins modify histone and nonhistone proteins thereby controlling cellular functions. However, the role of JmjC proteins in angiogenesis is largely unknown. Here, we characterize the expression of JmjC domain-containing proteins after inducing endothelial differentiation of murine embryonic stem cells and study the function of JmjC domain-only proteins in endothelial cell (EC) functions. APPROACH AND RESULTS: We identified a large number of JmjC domain-containing proteins regulated by endothelial differentiation of murine embryonic stem cells. Among the family of JmjC domain-only proteins, Jmjd8 was significantly upregulated on endothelial differentiation. Knockdown of Jmjd8 in ECs significantly decreased in vitro network formation and sprouting in the spheroid assay. JMJD8 is exclusively detectable in the cytoplasm, excluding a function as a histone-modifying enzyme. Mass spectrometry analysis revealed JMJD8-interacting proteins with known functions in cellular metabolism like pyruvate kinase M2. Accordingly, knockdown of pyruvate kinase M2 in human umbilical vein ECs decreased endothelial sprouting in the spheroid assay. Knockdown of JMJD8 caused a reduction of EC metabolism as measured by Seahorse Bioscience extracellular flux analysis. Conversely, overexpression of JMJD8 enhanced cellular oxygen consumption rate of ECs, reflecting an increased mitochondrial respiration. CONCLUSIONS: Jmjd8 is upregulated during endothelial differentiation and regulates endothelial sprouting and metabolism by interacting with pyruvate kinase M2.

Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells.

RATIONALE: The developmental role of the H3K27 demethylases Jmjd3, especially its epigenetic regulation at target genes in response to upstream developmental signaling, is unclear. OBJECTIVE: To determine the role of Jmjd3 during mesoderm and cardiovascular lineage commitment. METHODS AND RESULTS: Ablation of Jmjd3 in mouse embryonic stem cells does not affect the maintenance of pluripotency and self-renewal but compromised mesoderm and subsequent endothelial and cardiac differentiation. Jmjd3 reduces H3K27me3 marks at the Brachyury promoter and facilitates the recruitment of ß-catenin, which is critical for Wnt signal-induced mesoderm differentiation. CONCLUSIONS: These data demonstrate that Jmjd3 is required for mesoderm differentiation and cardiovascular lineage commitment.

Long-term outcomes after catheter ablation for idiopathic atypical atrial flutter.

BACKGROUND: Idiopathic atypical (non-cavotricuspid isthmus-dependent) atrial flutter (IAAFL) may be seen in patients without structural heart disease and without previous cardiac surgery or ablation. OBJECTIVE: This study sought to determine the patient characteristics, electrophysiologic and electroanatomic properties, and clinical outcomes after ablation in patients with IAAFL. METHODS: We retrospectively compared IAAFL patients with cavotricuspid isthmus-dependent AFL (C-AFL) patients undergoing catheter ablation. The primary outcome was a composite of death from cardiovascular causes, ischemic stroke, and hospitalization for worsening of heart failure. RESULTS: Of 180 patients who underwent catheter ablation for AFL, 89 were included in this study (22 IAAFL and 67 C-AFL). Electrophysiologic study showed significantly longer intra-atrial conduction time and lower atrial voltage during sinus rhythm in the IAAFL group compared with the C-AFL group. The atrial scar was observed in all 22 IAAFL patients, with the most common sites being the posterior or lateral wall of the right atrium in 10 (45.5%) and the anterior wall of the left atrium in 8 (36.4%). During 3.5 ± 2.8 years of follow-up, the composite primary end point occurred significantly more frequently in the IAAFL group (hazard ratio [HR], 3.45; 95% confidence interval [CI], 1.20-9.89; P = .015). In multivariable analysis, brain natriuretic peptide levels (HR, 1.01; 95% CI, 1.00-1.01, per 1 pg/mL; P = .01) and IAAFL (HR, 4.14; 95% CI, 1.21-14.07; P = .02) were independently associated with the primary outcome. CONCLUSION: IAAFL in patients had distinct electrophysiologic features suggestive of atrial cardiomyopathy. These patients are at risk for development of cardiovascular adverse events after ablation.

Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells.

RATIONALE: Proangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage are unclear. OBJECTIVE: To elucidate the epigenetic control of endothelial gene expression in proangiogenic cells and EPCs. METHODS AND RESULTS: Here we demonstrate that the endothelial nitric oxide synthase (eNOS) promoter is epigenetically silenced in proangiogenic cells (early EPCs), CD34(+) cells, and mesoangioblasts by DNA methylation and prominent repressive histone H3K27me3 marks. In order to reverse epigenetic silencing to facilitate endothelial commitment, we used 3-deazaneplanocin A, which inhibits the histone methyltransferase enhancer of zest homolog 2 and, thereby, reduces H3K27me3. 3-Deazaneplanocin A was not sufficient to increase eNOS expression, but the combination of 3-deazaneplanocin A and the histone deacetylase inhibitor Trichostatin A augmented eNOS expression, indicating that the concomitant inhibition of silencing histone modification and enhancement of activating histone modification facilitates eNOS expression. In ischemic tissue, hypoxia plays a role in recruiting progenitor cells. Therefore, we examined the effect of hypoxia on epigenetic modifications. Hypoxia modulated the balance of repressive to active histone marks and increased eNOS mRNA expression. The reduction of repressive H3K27me3 was associated with an increase of the histone demethylase Jmjd3. Silencing of Jmjd3 induced apoptosis and senescence in proangiogenic cells and inhibited hypoxia-mediated up-regulation of eNOS expression in mesoangioblasts. CONCLUSIONS: These findings provide evidence that histone modifications epigenetically control the eNOS promoter in proangiogenic cells.

Prognostic Value of Left Atrial Calcification After Catheter Ablation for Atrial Fibrillation.

BACKGROUND: Left atrial calcification (LAC) has occasionally been observed in patients who underwent catheter ablation for atrial fibrillation (AF) by chest computed tomography (CT). However, the evidence regarding the clinical impact of LAC in patients with AF is lacking. OBJECTIVES: This study aims to investigate the prevalence of LAC in AF patients and evaluate its clinical significance after AF ablation. METHODS: This observational registry included AF patients who received computed tomography and serial transthoracic echocardiography between January 2010 and November 2017. The primary composite outcome included cardiovascular death, hospitalization for worsening heart failure, and ischemic stroke. RESULTS: Among 534 patients (age 72 ± 13 years, 62.5% men) who met the inclusion criteria, 31 (5.8%) had LAC. In multivariable analysis, AF ablation was associated with an 11.8-fold (OR: 11.8; 95% CI: 2.03-227.65) increased risk of the development of LAC in AF patients. Among 218 patients with AF ablation, LAC was detected in 30 (13.8%) patients. Prior stroke (HR: 2.73; 95% CI: 1.08-6.93) and multiple ablation procedures (HR: 4.21; 95% CI: 1.63-10.87) were independently associated with the development of LAC in AF-ablation patients. During a median follow-up of 5.8 years, the primary composite outcome occurred in 11 patients in the LAC group (39.8 per 1,000 person-years) and 10 patients in the non-LAC group (8.9 per 1,000 person-years). The adjusted HR for the primary composite outcome in the LAC group, as compared with the non-LAC group, was 2.81 (95% CI: 1.16-6.84; P = 0.02). CONCLUSIONS: The presence of LAC was a significant and independent prognostic factor for identifying major adverse cardiovascular events after AF ablation.

Visibility of Pulmonary Valve and Pulmonary Regurgitation on Intracardiac Echocardiography in Adult Patients with Tetralogy of Fallot.

Pulmonary regurgitation (PR) is a risk factor for sudden cardiac death in adult patients with repaired tetralogy of Fallot (TOF). However, transthoracic echocardiography (TTE) cannot fully visualize the pulmonary valve (PV) and PR. We investigated whether intracardiac echocardiography (ICE) could visualize the PV and PR better than TTE. Thirty adult patients with TOF (mean age 33 ± 15 years) scheduled for cardiac catheterization underwent ICE. The visualization of PV and the severity of PR were classified into three grades. ICE depicted the PV better than TTE (ICE vs. TTE: not visualized, partially visualized, and fully visualized: n = 1 [3%], n = 13 [43%], and n = 16 [53%] vs. n = 14 [47%], n = 13 [43%], and n = 3 [10%], p < 0.001). Especially in patients after pulmonary valve replacement (PVR), the PV was more fully visualized by ICE. The assessment of PR by TTE underestimated the severity of PR in comparison to cardiac magnetic resonance imaging (MRI) (severe PR: 8 [28%] vs. 22 [76%], p = 0.004), while there was no discrepancy between the results of ICE and MRI (21 [72%] vs. 22 [76%], p = 1.000). In comparison to TTE, ICE can safely provide better visualization of the PV and PR in adults with TOF, especially in patients who have undergone PVR.

Role of the microRNA-17-92 cluster in the endothelial differentiation of stem cells.

MicroRNAs (miRs) are small non-coding RNAs that recently emerged as potent regulators of gene expression. The members of the miR-17-92 cluster have been shown to control endothelial cell functions and neovascularization; however, the regulation and function of the cluster in endothelial cell lineage commitment has not been explored. This project aimed to test the role of the miR-17-92 cluster during endothelial differentiation. We demonstrate that miR-17, miR-18, miR-19 and miR-20 are increased upon the induction of endothelial cell differentiation of murine embryonic stem cells or induced pluripotent stem cells. In contrast, miR-92a and the primary miR-17-92 transcript were downregulated. The inhibition of each individual miR of the cluster by cholesterol-modified antagomirs did not affect endothelial marker gene expression. Moreover, the combination of all antagomirs had no effect. These findings illustrate that although the miR-17-92 cluster regulates vascular integrity and angiogenesis, none of the members has a significant impact on the endothelial differentiation of pluripotent stem cells.

Sox2 transduction enhances cardiovascular repair capacity of blood-derived mesoangioblasts.

RATIONALE: Complementation of pluripotency genes may improve adult stem cell functions. OBJECTIVES: Here we show that clonally expandable, telomerase expressing progenitor cells can be isolated from peripheral blood of children. The surface marker profile of the clonally expanded cells is distinct from hematopoietic or mesenchymal stromal cells, and resembles that of embryonic multipotent mesoangioblasts. Cell numbers and proliferative capacity correlated with donor age. Isolated circulating mesoangioblasts (cMABs) express the pluripotency markers Klf4, c-Myc, as well as low levels of Oct3/4, but lack Sox2. Therefore, we tested whether overexpression of Sox2 enhances pluripotency and facilitates differentiation of cMABs in cardiovascular lineages. METHODS AND RESULTS: Lentiviral transduction of Sox2 (Sox-MABs) enhanced the capacity of cMABs to differentiate into endothelial cells and cardiomyocytes in vitro. Furthermore, the number of smooth muscle actin positive cells was higher in Sox-MABs. In addition, pluripotency of Sox-MABs was shown by demonstrating the generation of endodermal and ectodermal progenies. To test whether Sox-MABs may exhibit improved therapeutic potential, we injected Sox-MABs into nude mice after acute myocardial infarction. Four weeks after cell therapy with Sox-MABs, cardiac function was significantly improved compared to mice treated with control cMABs. Furthermore, cell therapy with Sox-MABs resulted in increased number of differentiated cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. CONCLUSIONS: The complementation of Sox2 in Oct3/4-, Klf4-, and c-Myc-expressing cMABs enhanced the differentiation into all 3 cardiovascular lineages and improved the functional recovery after acute myocardial infarction.

Hepatocyte growth factor mobilizes non-bone marrow-derived circulating mesoangioblasts.

AIMS: The identification of factors that mobilize subsets of endogenous progenitor cells may provide new therapeutic tools to enhance the repair of ischaemic tissue. We previously identified circulating mesenchymal cells that co-express endothelial markers (so-called circulating mesoangioblasts, cMABs) in children undergoing heart surgery with cardiopulmonary bypass (CPB). However, the mechanisms by which these cells are mobilized and their origin is unclear. METHODS AND RESULTS: Circulating CD73(+)CD45(-)KDR(+) cMABs were analysed in adults undergoing heart surgery with (n = 21) or without CPB (n = 8). During surgery with CPB, cMABs are mobilized with a maximal response at the end of the operation. In contrast, off-pump heart surgery does not stimulate cMAB mobilization, indicating that the stress mediated by CPB induces the mobilization of cMAB. Circulating mesoangioblasts were enriched in blood obtained from the coronary sinus. Histologically, CD73(+) cells were detected around vessels in the heart, indicating that the heart is one of the niches of cMABs. Consistently, studies in gender mismatched bone marrow transplanted patients demonstrated that cMABs did not originate from the bone marrow. Cytokine profiling of serum samples revealed that hepatocyte growth factor (HGF) was profoundly increased at the time point of maximal mobilization of cMABs. Hepatocyte growth factor stimulated the migration of cMABs. Importantly, injection of recombinant HGF increased cMABs in rats. CONCLUSIONS: Hepatocyte growth factor induces mobilization of non-haematopoietic progenitor cells with a cardiac repair capacity. This newly identified function together with the known pleiotrophic effects of HGF makes HGF an attractive therapeutic option for the treatment of ischaemic heart disease.

Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model.

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. METHODS: Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. RESULTS: The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-ß signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-ß-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. CONCLUSIONS: Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.

Control of cardiovascular differentiation by microRNAs.

MicroRNAs (miRs) are small non-coding RNAs, which control gene expression either by inducing mRNA degradation or by blocking translation, and play a crucial role in tissue homeostasis. In the cardiovascular system, miRs were shown to control cardiac hypertrophy, fibrosis and apoptosis, angiogenesis, and vessel remodeling. In addition, miRs regulate stem cell maintenance and some miRs induced cell fate decisions. This review summarizes the current insights into the control of stem cells and lineage commitment by miRs focusing specifically to the regulation of endothelial, smooth muscle, and cardiac lineage.