Thomas Hucko

BACKGROUND: This study is the first to examine the effect of direct angiotensin II type 2 (AT(2)) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT(2) receptor agonist compound 21 (C21). METHODS AND RESULTS: Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1beta, and interleukin-2 expression, suggesting an antiinflammatory effect. CONCLUSIONS: Direct AT(2) receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.

Importance: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain. Objective: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. Design, Setting, and Participants: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. Exposures: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. Main Outcomes and Measures: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. Results: In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. Conclusions and Relevance: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.

Importance: Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. Objective: To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. Design, Setting, and Participants: The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. Interventions: Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. Main Outcomes and Measures: The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. Results: Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. Conclusions and Relevance: In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. Trial Registration: ClinicalTrials.gov Identifier: NCT02929329.