The MAP4 Projection Domain Accelerates Hypoxia-Induced Mitophagy Disruption through LIR Motif in Cardiomyocytes

Previously, we and other investigators have demonstrated that phosphorylated microtubule-associated protein 4 (p-MAP4) impacts myocardial hypertrophy and ischemic heart failure. However, the detailed mechanism behind this remains under elucidated. Published studies have suggested that impaired mitophagy contributes to hypoxia-induced myocardial damage, hence the involvement of p-MAP4 in mitophagy in cardiomyocytes was investigated. The results herein revealed that there was increased degradation of mitochondria, accumulated mitophagosomes and disrupted autophagic flux in both neonatal and adult ones of MAP4-knockin (KI) mice. This indicated that p-MAP4 persistently degraded mitochondria through activating mitophagy. Next, Tom70 was found as the importer of p-MAP4 in the context of mitochondrial translocation. And, the LC3-interacting region (LIR) motif (47–50aa) caused p-MAP4-induced mitochondrial engulfment, and the ubiquitin-interacting motif (UIM) domain determined the characteristics of p-MAP4-induced mitophagosomes, which were structure and membrane potential-independent. Moreover, p-MAP4 enhanced hypoxia-induced mitophagic flux impairment, and p-MAP4 LIR (47–50aa) mutation decreased hypoxia-induced autophagy both in MAP4 knockout and wildtype cardiomyocytes. Overall, this study identified that p-MAP4 as a novel mediator and cargo receptor in mitophagy, and that the degradation of the MAP4 PJ domain as a promising therapeutic target for improving the cardiac function of hypoxia-related heart failure or cardiac remodelling.

When Ischemic Heart Failure Complicated with Diabetes Mellitus

Diabetes and heart failure are mutually reinforcing factors. The treatment strategy and prognosis for patients with both diabetes and heart failure are inconclusive. This article reviews the current situation of ischemic heart failure complicated with diabetes, the pathophysiological relationship between diabetes and heart failure, and disease management. Especially, we highlight the latest result from CRISIS (Coronary Revascularization in Patients with Ischemic Heart Failure and Prevention of Sudden Cardiac Death) study, which finds that diabetes associates with greater ejection fraction improvement after revascularization in patients with reduced ejection fraction. This result implies the indication for revascularization in patients with heart failure who present with DM.

Derivation and Validation of Genome‐Wide Polygenic Score for Ischemic Heart Failure

Background Despite advances in cardiovascular disease and risk factor management, mortality from ischemic heart failure (HF) in patients with coronary artery disease (CAD) remains high. Given the partial role of genetics in HF and lack of reliable risk stratification tools, we developed and validated a polygenic risk score for HF in patients with CAD, which we term HF‐PRS. Methods and Results Using summary statistics from a recent genome‐wide association study for HF, we developed candidate PRSs in the Mount Sinai Bio Me CAD patient cohort (N=6274) by using the pruning and thresholding method and LDPred. We validated the best score in the Penn Medicine BioBank (N=7250) and performed a subgroup analysis in a high‐risk cohort who had undergone coronary catheterization. We observed a significant association between HF‐PRS score and ischemic HF even after adjusting for evidence of obstructive CAD in patients of European ancestry in both Bio Me (odds ratio [OR], 1.14 per SD; 95% CI, 1.05–1.24; P =0.003) and Penn Medicine BioBank (OR, 1.07 per SD; 95% CI, 1.01–1.13; P =0.016). In European patients with CAD in Penn Medicine BioBank who had undergone coronary catheterization, individuals in the top 10th percentile of PRS had a 2‐fold increased odds of ischemic HF (OR, 2.0; 95% CI, 1.1–3.7; P =0.02) compared with the bottom 10th percentile. Conclusions A PRS for HF enables risk stratification in patients with CAD. Future prospective studies aimed at demonstrating clinical utility are warranted for adoption in the patient setting.

Ischemic Heart Disease

All over the world ischemic heart disease remains as the leading cause of death, followed by stroke. Ischemic heart disease, also called coronary artery disease has a broad spectrum of clinical manifestations from the acute coronary syndromes which include, unstable angina pectoris and acute myocardial infarction with and without elevation of the ST segment and chronic coronary disease. In patients with diabetes mellitus the cardiovascular complications mainly ischemic heart disease, are the main cause of morbidity and mortality. However, in population-based studies, the risk of heart failure in patients with diabetes mellitus is significantly increased following adjustment for well-established heart failure risk factors such as hypertension or ischemic heart disease. Ischemic heart failure angiographically diagnosed is associated with a shorter survival than non-ischemic heart failure. Coronary artery disease is independently associated with higher mortality.

SnRNA sequencing defines signaling by RBC-derived extracellular vesicles in the murine heart

Extracellular vesicles (EVs) mediate intercellular signaling by transferring their cargo to recipient cells, but the functional consequences of signaling are not fully appreciated. RBC-derived EVs are abundant in circulation and have been implicated in regulating immune responses. Here, we use a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells to assess the role of this intercellular signaling mechanism in heart disease. Using fluorescent-based mapping, we detected an increase in RBC-EV–targeted cardiomyocytes in a murine model of ischemic heart failure. Single cell nuclear RNA sequencing of the heart revealed a complex landscape of cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in cell proliferation and stress signaling pathways compared with non-targeted cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently express cellular markers of DNA synthesis, suggesting the functional significance of EV-mediated signaling. In conclusion, our mouse model for mapping of EV-recipient cells reveals a complex cellular network of RBC-EV–mediated intercellular communication in ischemic heart failure and suggests a functional role for this mode of intercellular signaling.

The role of cytomegalovirus infection in ischemic heart failure progression

Objective To study an association between cytomegalovirus infection (CMV) and molecular biomarkers (NT-proBNP, tumor necrosis factor (TNF-α), Interleukin-1β) and evaluate prognostic role of CMV infection in ischemic heart failure (HF) progression during the 12-month follow-up period. Methods A total of 104 patients (61.5% men, median age of 59 [53; 62.5] years) with stable coronary artery disease and baseline left ventricular ejection fraction (LVEF) of 43% [36; 57]% were enrolled in the study. At baseline evaluation HF patients were of New York Heart Association (NYHA) class I (7.7%), class II (61.0%), and class III (31.3%). Sixty five percent of patients had prior myocardial infarction and 70.2% received prior myocardial revascularization (coronary artery bypass graft/stent). Cytomegalovirus DNA concentrations in EDTA whole-blood samples were measured using a polymerase chain reaction baseline and at 12 months of follow-up period. Serum levels of NT-proBNP, Interleukin-1β, TNF-α were measured baseline using an enzyme immunoassay. Two-dimensional transthoracic echocardiography was performed at baseline and at the 12 months. Results At baseline, all patients were divided into 2 groups: group A comprised CMV seropositive patients (n=52); group B comprised CMV seronegative patients (n=52). Plasma concentration of cytomegalovirus DNA was 1709.4 [615; 3176] copies/mL. The values of cytomegalovirus DNA significantly correlated with NT-proBNP (r=0.781), TNF-α (r=0.799) and Interleukin-1β (r=0.756). Levels of NT-proBNP were higher (p=0.0001) in group A by 36.6% than in group 2 (559 [364; 756] vs. 354.5 [279; 545.5] pg/mL, respectively). Levels of TNF-α were also higher (p<0,001) by 35.3% (8.5 [6.5; 10.9] vs. 5.5 [4.1; 7.3] ng/mL, respectively) and levels of Interleukin-1β (p<0,001) by 17.6% (19.3 [15.8; 23.75] vs. 15.9 [13.15; 18.7] ng/mL, respectively) in group A than in group B. During the 12-month follow-up period in group A the rate of HF progression was 51.6% cases, and in group B 26.9% (p=0.009). Based on ROC-analysis, baseline plasma concentration of cytomegalovirus DNA ≥2020 copies/mL (AUC=0.798; specificity 67%, sensitivity 82%; p<0.001) were identified as a cut-off values predicting development of HF progression during the 12-month follow-up period. 12-month levels of cytomegalovirus DNA did not differ (p=0,678) in comparison to baseline ones and were 1737.9 [321; 3384] copies /mL. In group A LVEF significantly increased by 18.8% from 50.5 [36.5; 56.0] to 41.0 [35.0; 50.0]%, end-systolic dimension significantly increased by 7.3%, end-diastolic dimension by 9.6% (p<0,0001), while in group B these parameters did not change. Conclusion Our data suggest that values of cytomegalovirus DNA are associated with NT-proBNP, TNF-α, Interleukin-1β levels, and may be considered as non-invasive biomarker for prediction of ischemic heart failure progression during the 12-month follow-up period. FUNDunding Acknowledgement Type of funding sources: None.