Plasma GAS6 predicts mortality risk in acute heart failure patients: insights from the DRAGON-HF trial.

BACKGROUND: Growth arrest-specific 6 (GAS6) is a vitamin K-dependent protein related to inflammation, fibrosis, as well as platelet function. Genetic ablation of GAS6 in mice protects against cardiac hypertrophy and dysfunction. Nonetheless, the association between plasma GAS6 levels and acute heart failure (AHF) patients is still unknown. METHODS: We measured plasma GAS6 concentrations in 1039 patients with AHF who were enrolled in the DRAGON-HF trial (NCT03727828). Mean follow-up of the study was 889 days. The primary endpoint is all-cause death. RESULTS: In total, there were 195 primary endpoints of all-cause death and 135 secondary endpoints of cardiovascular death during the mean follow-up duration of 889 days. The higher levels of GAS6 were associated with higher rates of all-cause and cardiovascular death (P < 0.05). Baseline plasma GAS6 levels were still strongly correlated with clinical outcomes in different models after adjustment for clinical factors and N-terminal pro-brain natriuretic peptide (NT-proBNP, P < 0.05). GAS6 could further distinguish the risks of clinical outcomes based on NT-proBNP measurement. CONCLUSION: Elevated plasma GAS6 levels were associated with an increased risk of all-cause and cardiovascular death in patients with AHF. Trial registration NCT03727828 (DRAGON-HF trial) clinicaltrials.gov.

PLK inhibitors identified by high content phenotypic screening promote maturation of human PSC-derived cardiomyocytes.

Human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) provide an unlimited source of human cardiomyocytes for disease modeling, cell therapies, and other biomedical applications. However, hPSC-CMs remain developmentally immature which limits their suitability in translational applications. High Content Screening (HCS) is a powerful tool for identifying novel molecules and pathways regulating complex biological processes, but no HCS assay for hPSC-CM maturation has yet been reported. PCM1, a centriole satellite protein, is specifically restricted on nuclear envelope in mature cardiomyocytes. We developed a High Content Screen (HCS) based on PCM1 subcellular localization in hPSC-CMs to identify novel molecules promoting cardiomyocyte maturation, which identified 93 from 1693 compounds that enhance maturation of hPSC-CMs, including multiple PLK inhibitors. Volasertib and Centrinone, two PLK inhibitors, can enhance binucleation, and promote metabolic and electrophysiological maturation in hPSC-CMs. Furthermore, PI3K-AKT signaling pathway was found to be suppressed by PLK inhibitors, and VO-Ohpic, a PTEN inhibitor that activates AKT pathway, blunted the effect of PLK inhibitors on hPSC-CM maturation. In summary, our HCS assay found that PLK inhibitors can promote maturation of hPSC-CMs through suppressing AKT signaling pathway.

Efficacy and Dosage Pattern of Sacubitril/Valsartan in Chinese Heart Failure with Reduced Ejection Fraction Patients.

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (> 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed.

Circulating miR-19b-3p as a Novel Prognostic Biomarker for Acute Heart Failure.

Background Circulating microRNAs are emerging biomarkers for heart failure (HF). Our study aimed to assess the prognostic value of microRNA signature that is differentially expressed in patients with acute HF. Methods and Results Our study comprised a screening cohort of 15 patients with AHF and 5 controls, a PCR-discovery cohort of 50 patients with AHF and 26 controls and a validation cohort of 564 patients with AHF from registered study DRAGON-HF (Diagnostic, Risk Stratification and Prognostic Value of Novel Biomarkers in Patients With Heart Failure). Through screening by RNA-sequencing and verification by reverse-transcription quantitative polymerase chain reaction, 9 differentially expressed microRNAs were verified (miR-939-5p, miR-1908-5p, miR-7706, miR-101-3p, miR-144-3p, miR-4732-3p, miR-3615, miR-484 and miR-19b-3p). Among them, miR-19b-3p was identified as the microRNA signature with the highest fold-change of 8.4 and the strongest prognostic potential (area under curve with 95% CI, 0.791, 0.654-0.927). To further validate its prognostic value, in the validation cohort, the baseline level of miR-19b-3p was measured. During a follow-up period of 19.1 (17.7, 20.7) months, primary end point comprising of all-cause mortality or readmission due to HF occurred in 48.9% patients, while patients in the highest quartile of miR-19b-3p level presented the worst survival (Log-rank P<0.001). Multivariate Cox model showed that the level of miR-19b-3p could independently predict the occurrence of primary end point (adjusted hazard ratio,1.39; 95% CI, 1.18-1.64). In addition, miR-19b-3p positively correlated with soluble suppression of tumorigenicity 2 and echocardiographic indexes of left ventricular hypertrophy. Conclusions Circulating miR-19b-3p could be a valuable prognostic biomarker for AHF. In addition, a high level of circulating miR-19b-3p might indicate ventricular hypertrophy in AHF subjects. Registration URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03727828.

Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy.

While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.

Predictive value of left atrial appendage lobes on left atrial thrombus or spontaneous echo contrast in patients with non-valvular atrial fibrillation.

BACKGROUND: Left atrial appendage morphology has been proved to be an important predictor of left atrial thrombus (LAT) and left atrial spontaneous echo contrast (LASEC) and stroke in patients with non-valvular atrial fibrillation (NVAF). However, the relation between left atrial appendage (LAA) lobes and LAT or LASEC is still unknown. The aim of this study is to investigate the correlation between the number of left atrial appendage lobes and LAT/LASEC in patients with NVAF. METHODS: This monocentric cross-sectional study enrolled 472 consecutive patients with non-valvular atrial fibrillation, who had transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) prior to cardioversion or left atrial appendage closure (LAAC) from July 2009 to August 2015 in department of cardiology of Shanghai Tenth People's Hospital. Patients who had significant mitral or aortic valve disease, previous cardiac valvular surgery and other complicated cardiac diseases were excluded. Individuals were divided into two groups:the LAT/LASEC group (16.95%), which comprised patients with LAT or LASEC, as confirmed by TEE; and a negative control group (83.05%).Baseline overall group characterization with demographic, clinical, laboratory data and echocardiographic parameters, alongside with information on medication was obtained for all patients. Subgroup analysis with line chart was applied for exploring the association between LAA lobes and LAT/LAESC. Receptor-operating curves (ROC) were used to test the value of LA anteroposterior diameter detected by different echocardiography methods predicting LAT or LASEC. Multivariable logistic regression analysis was used to investigate independent predictors of LAT/LASEC. RESULTS: Among 472 patients, 23 (4.87%) had LA/LAA thrombus and 57 (12.1%) had LA spontaneous echo contrast. Compared to the negative group, patients in LAT/LASEC group had higher CHA2DS2-VASc score (3.79 ± 1.75 vs 2.65 ± 1.76, p < 0.001), larger LAD (measured by TTE, 48.1 ± 7.7 vs 44.6 ± 6.5, P < 0.001; measured by TEE, 52.2 ± 6.2 vs 46.7 ± 7.1, P < 0.001), lower left upper pulmonary venous flow velocity (LUPVFV) (0.54 ± 0.17 m/s vs 0.67 ± 0.26 m/s, CI 95% 0.05-0.22, P = 0.003), more left atrial appendage lobes (1.67 ± 0.77 vs 1.25 ± 0.50, p < 0.001). There was a good discriminative capacity for LAD detected by TTE (area under the curve (AUC), 0.67, CI 95% 0.61-0.73, p < 0.001) and LAD detected by TEE (AUC, 0.73, CI 95% 0.67-0.79, p < 0.001). The subgroup analysis based on gender and different LAA lobes yielded similar results (male group: p < 0.001;female group: p = 0.004) that the number of LAA lobes were significantly associated with LA thrombus or SEC. In multivariable logistic regression analysis, both the number of LAA lobes (odds ratio: 2.37; CI 95% 1.37-4.09; p = 0.002) and the persistent AF (odds ratio: 3.57; CI 95% 1.68-7.57; p = 0.001) provided independent and incremental predictive value beyond CHA2DS2-VASc score. CONCLUSION: The number of LAA lobes is an independent risk factor and has a moderate predictive value for LAT/LASEC among NVAF patients in China.

Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy.

BACKGROUND: Translocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown. METHODS AND RESULTS: In the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss-of-function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild-type littermates. Moreover, we generated cardiomyocyte-specific TIM50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM50. Meanwhile, expression of the ASK1-JNK/P38 axis was increased in TIM50-deficient mice, and TIM50 overexpression decreased the activity of the ASK1-JNK/P38 axis. Finally, we treated mice with the antioxidant N-acetyl cysteine to reduce oxidative stress. After N-acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM50 deficiency were all remarkably reversed. CONCLUSIONS: These data indicated that TIM50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.

XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling.

BACKGROUND: Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation. METHODS: Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound-healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, ß-actin, JNK, phosphorylated JNK, Axin2 and ß-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of ß-catenin. RESULTS: XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway. CONCLUSIONS: XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.

Different ß-blockers and initiation time in patients undergoing noncardiac surgery: a meta-analysis.

The effects of differences among ß-blockers and initiation times in patients undergoing noncardiac surgery (NCS) remain unknown. On June 1, 2012, the authors searched PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to identify all trials of perioperative ß-blockers in patients undergoing NCS published between January 1960 and June 2012. The authors included only randomized, double-blind and placebo-controlled trials of perioperatively administered ß-blockers (ie, during the pre-, intra- and/or postoperative period) in patients with at least 1 risk factor for coronary artery disease undergoing NCS. The endpoints of these trials had to include all-cause mortality, myocardial infarction (MI) and/or stroke. The authors identified 8 English-language publications, involving 11,180 patients, which fulfilled our inclusion criteria. Perioperative ß-blocker therapy was associated with a significant decrease in patient risk of developing MI (relative risk [RR] = 0.73; 95% confidence interval [CI], 0.61-0.86) but a significant increase in risk of developing stroke (RR = 2.17; 95% CI, 1.35-3.50) versus placebo, resulting in a nonsignificant decrease in overall mortality (RR = 0.91; 95% CI, 0.60-1.36). Indirect comparisons demonstrated that perioperative atenolol therapy was associated with lower mortality and incidence of MI. ß-blocker therapy initiated >1 week before surgery was associated with improved postoperative mortality. Perioperative ß-blocker treatment of patients undergoing NCS increases the incidence of stroke but decreases the incidence of MI, leading to a nonsignificant decrease in mortality. The authors also observed that atenolol treatment or ß-blocker therapy initiated >1 week before NCS was associated with improved outcomes.