Efficacy and safety of CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: Rationale and design of the HF-REVERT trial.

AIM: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. METHODS: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period. CONCLUSION: The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.

Metabolic signatures in post-myocardial infarction heart failure, including insights into prediction, intervention, and prognosis.

Heart failure (HF) is a prevalent long-term complication of myocardial infarction (MI). The incidence of post-MI HF is high, and patients with the condition have a poor prognosis. Accurate identification of individuals at high risk for post-MI HF is crucial for implementation of a protective and ideally personalized strategy to prevent fatal events. Post-MI HF is characterized by adverse cardiac remodeling, which results from metabolic changes in response to long-term ischemia. Moreover, various risk factors, including genetics, diet, and obesity, can influence metabolic pathways in patients. This review focuses on the metabolic signatures of post-MI HF that could serve as non-invasive biomarkers for early identification in high-risk populations. We also explore how metabolism participates in the pathophysiology of post-MI HF. Furthermore, we discuss the potential of metabolites as novel targets for treatment of post-MI HF and as biomarkers for prognostic evaluation. It is expected to provide valuable suggestions for the clinical prevention and treatment of post-MI HF from a metabolic perspective.

Increased serum albumin corrected anion gap levels are associated with increased incidence of new-onset HF and poor prognosis in patients with acute myocardial infarction.

BACKGROUND: There is scant evidence on a relationship between metabolic acid load and acute myocardial infarction (AMI). We evaluated the relationship between serum albumin corrected anion gap (ACAG), a metabolic acid load biomarker, and post-myocardial infarction heart failure (post-MI HF) in patients with AMI. METHODS: This prospective, single-center study enrolled 3,889 patients with AMI. The primary endpoint was the incidence of post-MI HF. Serum ACAG levels were calculated with the following formula: ACAG = AG + (40 - [albuminemia in g/l]) × 0.25. RESULTS: After correction for multiple confounding factors, patients in the fourth quartile of ACAG (highest serum ACAG levels) showed 33.5% higher risk of out-of-hospital HF [hazard ratio (HR) = 1.335, 95% CI = 1.034-1.724, p = 0.027], and 60% higher risk of in-hospital HF [odds ratio (OR) = 1.600, 95% CI = 1.269-2.017, p < 0.001] than those in the first quartile of ACAG (lowest serum ACAG levels). Altered levels of eGFR mediated 31.07% and 37.39% of the association between serum ACAG levels with out-of-hospital HF and in-hospital HF, respectively. Furthermore, altered levels of hs-CRP mediated 20.85% and 18.91% of the association between serum ACAG levels with out-of-hospital and in-hospital HF, respectively. CONCLUSION: Our study showed that higher metabolic acid load was associated with increased incidences of post-MI HF in the AMI patients. Furthermore, deterioration of renal function and the hyperinflammatory state partially mediated the association between metabolic acid load and the incidence of post-MI HF.

Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3.

BACKGROUND: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). METHODS: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. FINDINGS: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK-/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. VALIDATION: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature. INTERPRETATION: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. FUNDING: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.