Daily Cardiology Research Analysis
Analyzed 274 papers and selected 3 impactful papers.
Summary
A large multicenter randomized trial in NEJM shows that extending dual antiplatelet therapy to 24 months in event-free patients with multivessel coronary artery disease reduces cardiovascular death, nonfatal myocardial infarction, or stroke without increasing bleeding. A placebo-controlled phase 2 trial in the European Heart Journal reports that trientine reduces left ventricular mass in hypertrophic cardiomyopathy, suggesting copper modulation as a disease-targeting strategy. A Science Translational Medicine study demonstrates that a controlled-release mitochondrial protonophore attenuates early- and late-stage atherogenesis in dysmetabolic mice, highlighting bioenergetic targeting as a potential anti-atherosclerotic therapy.
Research Themes
- Antithrombotic therapy optimization after PCI
- Disease-modifying strategies in hypertrophic cardiomyopathy
- Mitochondrial bioenergetics as a target in atherosclerosis
Selected Articles
1. Extended Dual Antiplatelet Therapy for Multivessel Coronary Artery Disease.
In 8,250 event-free multivessel CAD patients 12 months after DES implantation, extending DAPT with clopidogrel plus aspirin for another 12 months reduced the composite of cardiovascular death, nonfatal MI, or nonfatal stroke versus continuing aspirin alone (HR 0.82) without increasing BARC ≥2 bleeding. Median follow-up was 34.3 months.
Impact: This large randomized trial provides high-level evidence that tailored DAPT extension in a high-risk anatomical subset reduces ischemic events without excess bleeding, likely informing future guideline refinements.
Clinical Implications: For event-free multivessel CAD patients 12 months post-DES, extending DAPT to 24 months can be considered to reduce ischemic events without increasing clinically relevant bleeding; patient-specific bleeding risk still requires careful assessment.
Key Findings
- Primary composite endpoint at 36 months: 5.8% with extended DAPT vs 6.8% with aspirin alone (HR 0.82, 95% CI 0.69–0.98, P=0.03).
- Clinically relevant or major bleeding (BARC ≥2): 1.4% vs 1.5% (HR 0.89, 95% CI 0.61–1.30, P=0.54).
- Randomized 8,250 patients across 97 centers; median follow-up 34.3 months.
Methodological Strengths
- Large multicenter randomized design with prespecified primary efficacy and safety endpoints.
- Prospectively registered (NCT04624854) with long median follow-up (34.3 months).
Limitations
- Open-label design may introduce performance or ascertainment bias.
- Generalizability beyond Chinese population and to other P2Y12 inhibitors requires caution.
Future Directions: Define optimal candidates for DAPT extension integrating bleeding-risk scores, intravascular imaging, and platelet function; evaluate alternative P2Y12 agents and de-escalation strategies in multivessel disease.
BACKGROUND: Patients with multivessel coronary artery disease often receive 12 months of dual antiplatelet therapy (DAPT) after stenting to reduce the risk of ischemic events. Whether extending DAPT beyond 12 months in event-free patients with multivessel disease provides a benefit is uncertain. METHODS: We conducted an open-label, randomized trial at 97 centers in China. Patients 18 to 75 years of age with multivessel coronary artery disease who had no major ischemic or bleeding events while receiving DAPT for 12 months after implantation of a drug-eluting stent were randomly assigned in a 1:1 ratio to receive an additional 12 months of DAPT (clopidogrel plus aspirin) or aspirin monotherapy. The primary efficacy end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary safety end point was clinically relevant or major bleeding (i.e., a bleeding event of Bleeding Academic Research Consortium [BARC] type ≥2; BARC types range from 0 to 5, with higher values indicating greater severity of bleeding). RESULTS: A total of 8250 patients were randomly assigned to receive extended DAPT (4125 patients) or aspirin monotherapy (4125 patients). The median follow-up was 34.3 months. A primary efficacy end-point event occurred in 222 patients in the DAPT group and in 266 patients in the aspirin-monotherapy group (36-month Kaplan-Meier cumulative incidence, 5.8% vs. 6.8%; hazard ratio, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03). Clinically relevant or major bleeding occurred in 51 patients in the DAPT group and in 57 patients in the aspirin-monotherapy group (36-month Kaplan-Meier cumulative incidence, 1.4% vs. 1.5%; hazard ratio, 0.89; 95% CI, 0.61 to 1.30; P = 0.54). CONCLUSIONS: Among patients with multivessel coronary artery disease who were in stable condition 12 months after implantation of a drug-eluting stent, extending DAPT with clopidogrel and aspirin for an additional 12 months led to a lower risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than continuing aspirin alone, without an increased risk of bleeding. (Funded by the National Natural Science Foundation of China and others; DAPT-MVD ClinicalTrials.gov number, NCT04624854.).
2. Trientine for hypertrophic cardiomyopathy: a phase 2 trial.
In a multicenter, placebo-controlled phase 2 RCT (n=154), trientine 400 mg twice daily for 52 weeks reduced LV mass index versus placebo (between-group difference −3.2 g/m2; P=0.009), with greater benefit at higher baseline LV mass and mediation via reduced myocardial cellular mass. Adverse event rates were similar between groups.
Impact: Introduces a copper-modulating therapy that reduces LV mass in HCM with mechanistic mediation, opening a plausible disease-modifying pathway beyond symptom control.
Clinical Implications: Trientine may emerge as a disease-modifying option for select HCM patients; confirmatory phase 3 trials with clinical outcomes and stratification by baseline LV mass are warranted before routine use.
Key Findings
- LV mass index decreased more with trientine than placebo over 52 weeks (between-group difference −3.2 g/m2; 95% CI −5.6 to −0.8; P=0.009).
- Treatment effect increased at higher baseline LV mass (interaction P=0.015).
- Causal mediation analysis indicated reduction in myocardial cellular mass (ACME −3.9 g/m2; 95% CI −6.8 to −0.9); adverse events were similar between groups.
Methodological Strengths
- Multicenter, placebo-controlled randomized design with standardized CMR endpoint.
- Prespecified mediation analysis linking imaging response to cellular mass changes.
Limitations
- Phase 2 trial with surrogate imaging endpoint; not powered for hard clinical outcomes.
- Follow-up limited to 52 weeks; long-term efficacy and safety remain unknown.
Future Directions: Conduct phase 3 outcomes trials, explore biomarkers for response prediction (e.g., baseline LV mass), and assess effects on arrhythmia burden, functional capacity, and fibrosis progression.
BACKGROUND AND AIMS: Pathophysiological features of hypertrophic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, and myocardial energy deficiency. Depletion of cardiomyocyte copper I ions leads to impaired mitochondrial function, a state associated with left ventricular hypertrophy. Unbound or loosely bound copper II ions activate profibrotic pathways. Trientine dihydrochloride improves intracellular copper I ion trafficking and availability, and chelates copper II ions. In preclinical studies, trientine improved myocardial mitochondrial function and reduced left ventricular hypertrophy and fibrosis. The efficacy and safety of trientine in persons with hypertrophic cardiomyopathy are unknown. METHODS: In this multicentre, placebo-controlled phase 2 trial, adults with hypertrophic cardiomyopathy, a left ventricular wall thickness of 15 mm or greater, and who were in New York Heart Association class I to III were randomly assigned to receive trientine 400 mg twice daily or placebo for 52 weeks. Patients with any left ventricular outflow tract (LVOT) gradient were eligible. The primary endpoint was the change in left ventricular mass indexed to body surface area measured using cardiovascular magnetic resonance. RESULTS: A total of 154 patients underwent randomization. The mean age was 53.4 years, median maximum left ventricular wall thickness was 20.0 mm, median maximum LVOT gradient was 6.0 mmHg, 18.6% of patients had a resting LVOT gradient ≥30 mmHg, and 61.7% were in New York Heart Association class I. At 52 weeks, the mean change in the left ventricular mass indexed to body surface area was -4.4 ± 7.7 g/m2 in the trientine group and -1.5 ± 6.1 g/m2 in the placebo group (between-group difference -3.2 g/m2; 95% confidence interval -5.6 to -0.8; P = .009). The efficacy of trientine increased at higher levels of baseline left ventricular mass (baseline left ventricular mass indexed to body surface area by treatment allocation interaction P = .015). The effect of trientine was mediated via a reduction in myocardial cellular mass (average causal mediated effect -3.9 g/m2; 95% confidence interval -6.8 to -0.9). The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among patients with hypertrophic cardiomyopathy, treatment with trientine resulted in a significantly greater reduction in left ventricular mass indexed to body surface area than placebo. (Funded by NIHR; TEMPEST ClinicalTrials.gov number, NCT04706429).
3. A controlled-release mitochondrial protonophore attenuates early- and late-stage atheroprogression in mice.
In dysmetabolic, HFCD-fed LDL receptor–deficient mice, controlled-release mitochondrial protonophore therapy attenuated both early and late atherosclerotic lesion progression. Prior work established metabolic benefits across species; this study extends efficacy to vascular disease, supporting mitochondrial bioenergetic targeting as a therapeutic strategy for ASCVD in insulin resistance.
Impact: Demonstrates disease-modifying anti-atherosclerotic effects of a bioenergetic therapy in a cardiometabolic model, bridging metabolic reprogramming to vascular outcomes and motivating translational development.
Clinical Implications: While preclinical, these findings support mitochondrial uncoupling as a potential therapeutic avenue for ASCVD in insulin-resistant states; careful human dose-finding and safety evaluation will be essential.
Key Findings
- Controlled-release mitochondrial protonophore (CRMP) attenuated early- and late-stage atherogenesis in HFCD-fed LDL receptor–deficient mice.
- Builds on prior cross-species evidence that CRMP reverses hypertriglyceridemia, hepatic steatosis, and insulin resistance.
- Supports mitochondrial bioenergetic modulation as a disease-modifying mechanism in atherogenesis.
Methodological Strengths
- Use of a dysmetabolic, LDL receptor–deficient murine model relevant to cardiometabolic syndrome.
- Therapeutic evaluation across both early and late atherosclerosis stages, extending prior metabolic efficacy data.
Limitations
- Preclinical mouse study limits direct translatability to humans.
- Long-term safety of mitochondrial uncoupling and dose translation require rigorous human studies.
Future Directions: Advance CRMP to first-in-human dose-escalation studies focusing on safety, metabolic and vascular biomarkers, and evaluate combinatorial strategies with lipid-lowering or anti-inflammatory agents.
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality in patients with insulin resistance, and new therapies are urgently needed. We previously developed an orally administered formulation of 2,4-dinitrophenol, here termed controlled-release mitochondrial protonophore (CRMP), and showed that it safely reversed hypertriglyceridemia, hepatic steatosis, and insulin resistance in dysmetabolic rodents and nonhuman primates. Here, we investigated the therapeutic utility of CRMP for treating atherogenesis in a murine model of cardiometabolic syndrome [high-fat cholesterol diet (HFCD)-fed low-density lipoprotein receptor-deficient (