Daily Cardiology Research Analysis
Analyzed 252 papers and selected 3 impactful papers.
Summary
A phase 1b/2a randomized trial in Lancet reports that AC01, a novel oral calcium-sensitizing ghrelin receptor agonist, was safe and well tolerated in HFrEF without pro-arrhythmic signals. A PROSPECT II substudy in ATVB links specific plasma lipid species to imaging-defined vulnerable coronary plaques and validates findings in SCAPIS, advancing biomarker-driven risk stratification. A mechanistic study in The Journal of Cell Biology reveals that tightly choreographed M-phase calcium transient dynamics governed by CDK1 and SERCA2a are essential for cardiomyocyte proliferation.
Research Themes
- Novel therapeutics for heart failure (oral inotropes/ghrelin agonism)
- Biomarker discovery linking lipidomics to vulnerable coronary plaque
- Cell-cycle calcium signaling mechanisms enabling cardiomyocyte proliferation
Selected Articles
1. Safety, pharmacokinetics, and exploratory efficacy of the oral ghrelin receptor agonist AC01 in heart failure with reduced ejection fraction (GOAL-HF1): a randomised, double-blind, placebo-controlled, phase 1b/2a study.
In a multicenter, randomized, double-blind, placebo-controlled phase 1b/2a study, oral AC01 demonstrated favorable safety and tolerability over up to 28 days in patients with HFrEF, without tachycardia, pro-arrhythmic signals, or biomarker evidence of myocardial injury. These data support dose selection and progression to efficacy-focused phase 2/3 studies.
Impact: This is the first randomized, double-blind clinical assessment of an oral calcium-sensitizing ghrelin receptor agonist in HFrEF, addressing a major therapeutic gap in safe outpatient inotropic support.
Clinical Implications: If efficacy is confirmed, AC01 could provide a safer, oral inotropic option to support contractility without the arrhythmic liabilities of traditional agents, potentially enabling outpatient optimization in HFrEF.
Key Findings
- AC01 was safe and well tolerated over 7–28 days with no AC01-related serious adverse events.
- No tachycardia, new-onset tachyarrhythmias, or ECG conduction abnormalities were observed.
- No apparent adverse signals on high-sensitivity troponin or NT-proBNP; safety profile comparable or favorable to placebo.
Methodological Strengths
- Randomized, double-blind, placebo-controlled design with multicenter enrollment
- Rigorous safety monitoring including continuous rhythm surveillance and biomarker assessment
Limitations
- Early-phase study with small sample size and safety-focused endpoints
- Implantable defibrillator requirement may limit generalizability to broader HFrEF populations
Future Directions: Proceed to phase 2/3 trials to evaluate efficacy (symptoms, function, remodeling, clinical events), dose–response, and longer-term safety in broader HFrEF cohorts.
BACKGROUND: The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF. METHODS: In this phase 1b/2a, randomised, double-blind, placebo-controlled study, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy. All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia. Other eligibility criteria included sinus rh
2. Linking Lipidomics to Vulnerable Coronary Plaques: A PROSPECT II Substudy.
In 877 post-MI patients profiled by NIRS–IVUS, multiple circulating lipid species associated with vulnerable plaque features; notably, sphingomyelins were negatively and 1‑palmitoyl‑2‑oleoyl‑GPE (16:0/18:1) positively associated with lipid-rich, high-burden plaques. These associations were validated in SCAPIS using CCTA-derived plaque metrics, supporting lipidomic biomarkers for coronary vulnerability.
Impact: This study integrates advanced intravascular imaging and mass spectrometry lipidomics with external validation, offering a path to noninvasive, biology-informed risk stratification of coronary vulnerability.
Clinical Implications: Specific lipid species may refine identification of patients at risk for plaque progression and events, informing surveillance and potentially targeted therapies as lipid pathways are elucidated.
Key Findings
- Circulating sphingomyelins were inversely associated with imaging-defined vulnerable plaque features.
- 1‑palmitoyl‑2‑oleoyl‑GPE (16:0/18:1) showed positive associations with lipid core burden and plaque burden.
- Findings were validated in SCAPIS using CCTA-based plaque metrics, strengthening generalizability.
Methodological Strengths
- Integration of NIRS–IVUS phenotyping with high-throughput mass spectrometry lipidomics
- Independent validation in a large population-based imaging cohort (SCAPIS)
Limitations
- Observational design limits causal inference; residual confounding possible
- Clinical utility thresholds and assay standardization for lipid species remain to be defined
Future Directions: Prospective studies to test lipidomic signatures for event prediction and to evaluate whether modifying implicated lipid pathways alters plaque biology and outcomes.
BACKGROUND: Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. METHODS: Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score. RESULTS: We identified 156 significant associations (
3. Sequential changes in calcium transients during M phase regulate cardiomyocyte proliferation.
Cardiomyocyte mitosis demands a temporally ordered tuning of calcium transients, with CDK1 driving dynein1‑dependent SERCA2a accumulation at spindle poles to locally lower Ca2+ and permit faithful division. Disrupting SERCA2a-mediated Ca2+ minima derails mitosis and yields binucleation, revealing a targetable axis for promoting proliferation without contractile failure.
Impact: This work uncovers a previously unrecognized, phase-specific Ca2+ signaling program that is necessary for cardiomyocyte cytokinesis, linking CDK1 to spatial SERCA2a control and defining actionable levers for cardiac regeneration.
Clinical Implications: While preclinical, the CDK1–SERCA2a–Ca2+ axis suggests strategies to induce proliferation of cardiomyocytes after injury while minimizing binucleation and dysfunction, informing regenerative therapeutics.
Key Findings
- Calcium transients follow a defined sequence through M phase: decline (prometaphase) → minimum (metaphase) → rise (anaphase) → reset in daughter cells.
- CDK1 activity mediates dynein1-dependent SERCA2a accumulation at spindle poles to locally reduce Ca2+.
- Blocking SERCA2a during prometaphase/metaphase raises cytosolic Ca2+, disrupts mitosis, and generates binucleated cardiomyocytes.
Methodological Strengths
- Multimodal mechanistic interrogation with live Ca2+ imaging and molecular perturbations (CDK1, SERCA2a, dynein1)
- Convergent evidence across cellular and in vivo cardiomyocyte models
Limitations
- Preclinical mechanistic work; human translational relevance requires validation
- Potential cell-type and species differences in mitotic Ca2+ control
Future Directions: Define druggable nodes to modulate the CDK1–SERCA2a pathway safely in adult hearts; test regenerative efficacy and arrhythmic safety in large-animal post-infarction models.
Heart muscle growth and regeneration require the proliferation of cardiomyocytes. Rapid pulsatile increases in cytosolic Ca2+ concentration, called calcium transients (CaTs), trigger cardiomyocyte contractions, but how cardiomyocytes adapt Ca2+ signaling during proliferation is largely unknown. Here, we show that cardiomyocyte proliferation requires changes in Ca2+ signaling. Cardiomyocytes undergo a sequence of CaT changes during M phase: CaT amplitudes begin to decline in prometaphase, reach a minimum in metaphase, rise during anaphase, and return to the original state in daughter cardiomyocytes. Spindle poles show decreased Ca2+ levels during prometaphase and metaphase. Localized reduction of Ca2+ levels at spindle poles is mediated by dynein 1-dependent SERCA2a accumulation. Active cyclin-dependent kinase 1 (CDK1) induces both the decrease in CaT amplitudes and the accumulation of SERCA2a at the spindle poles, whereas CDK1 inhibition reverses these effects. Forcing an increase in cytosolic Ca2+ levels by blocking SERCA2a during prometaphase and metaphase disrupts mitosis and produces binucleated cardiomyocytes, underscoring the essential role of Ca2+ signaling changes for cardiomyocyte proliferation.