Daily Cardiology Research Analysis
Analyzed 252 papers and selected 3 impactful papers.
Summary
Analyzed 252 papers and selected 3 impactful articles.
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 58 HFrEF patients randomized to AC01 or placebo, AC01 over 7–28 days was safe and well tolerated without excess tachyarrhythmias, ischemic ECG changes, biomarker rises, or symptomatic hypotension. Treatment-emergent events were mostly mild/moderate; no AC01-related serious adverse events occurred, supporting further efficacy trials of this first-in-class oral inotrope.
Impact: Demonstrates early-phase safety of a novel, mechanistically distinct oral inotrope in HFrEF, addressing a long-standing therapeutic gap where prior inotropes increased risk.
Clinical Implications: No immediate change in practice, but supports advancing AC01 into larger efficacy trials as a potential safer inotrope option for symptomatic HFrEF.
Key Findings
- Across phase 1b/2a (n=58), AC01 had no treatment-related serious adverse events; most TEAEs were mild or moderate.
- Continuous rhythm and ECG monitoring revealed no excess tachyarrhythmias, ischemia, or conduction abnormalities with AC01.
- No apparent effects on high-sensitivity cardiac troponin I or NT-proBNP; no symptomatic hypotension was observed.
Methodological Strengths
- Randomised, double-blind, placebo-controlled multicentre design
- Continuous remote rhythm monitoring and prespecified safety endpoints
Limitations
- Small sample size and early-phase duration (7–28 days)
- Highly selected population with transvenous ICDs and backup pacing
Future Directions: Conduct larger phase 2/3 trials assessing clinical efficacy (symptoms, quality of life, exercise capacity) and safety over longer durations, with mechanistic biomarkers and arrhythmic risk profiling.
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 rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min. Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a. In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days. In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days. Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment. The primary outcome was safety and tolerability.
2. Sequential changes in calcium transients during M phase regulate cardiomyocyte proliferation.
This mechanistic study demonstrates that cardiomyocyte mitosis depends on phase-specific remodeling of calcium transients, including a dynein1-driven SERCA2a accumulation at spindle poles under CDK1 control. Experimentally elevating cytosolic Ca2+ during prometaphase/metaphase disrupts mitosis and yields binucleation, highlighting precise Ca2+ dynamics as essential for proliferative fidelity.
Impact: It uncovers a previously unrecognized, phase-resolved Ca2+ signaling program that is necessary for cardiomyocyte proliferation, providing concrete molecular levers (CDK1–SERCA2a–dynein1 axis) for regenerative strategies.
Clinical Implications: Targeting Ca2+ handling nodes (e.g., SERCA2a localization dynamics or CDK1-mediated control) could help design pro-proliferative yet mitotically faithful cardiac regeneration approaches while avoiding harmful binucleation.
Key Findings
- Calcium transient amplitudes decline in prometaphase, reach a minimum in metaphase, rise in anaphase, and normalize in daughter cardiomyocytes.
- Spindle poles exhibit locally reduced Ca2+ mediated by dynein 1–dependent SERCA2a accumulation.
- Active CDK1 drives both CaT amplitude reduction and SERCA2a accumulation; CDK1 inhibition reverses these effects.
- Blocking SERCA2a to force cytosolic Ca2+ elevation during prometaphase/metaphase disrupts mitosis and yields binucleated cardiomyocytes.
Methodological Strengths
- Multi-scale mechanistic interrogation combining live-cell Ca2+ imaging, molecular perturbations (CDK1 inhibition, SERCA2a manipulation), and spatial localization via dynein-1.
- Causal evidence linking precise Ca2+ dynamics to mitotic fidelity in cardiomyocytes.
Limitations
- Predominantly preclinical cellular models; in vivo regenerative relevance in adult mammalian myocardium remains to be established.
- Potential pro-arrhythmic risks of manipulating Ca2+ handling were not addressed.
Future Directions: Validate the CDK1–SERCA2a–dynein1 axis in vivo, define safe therapeutic windows for Ca2+ handling modulation, and explore combinatorial approaches with cell-cycle regulators to induce regenerative proliferation without binucleation.
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.
3. Whole-population trends in obesity across dimensions of inequality in England, 2019-25: a retrospective, longitudinal cohort study of 54 million adults.
Using individual-level EHR for 54.9 million adults (2019–2025), the study found nearly one in three adults in England are living with obesity, with 4.13 million first presentations (median age 43, 55.1% women). Disparities by socioeconomic position, age (notably younger and reproductive-age adults), ethnicity, and region widened after the pandemic, highlighting intersectional inequality.
Impact: Provides unprecedented whole-population, intersectional mapping of obesity burden post-pandemic, informing targeted primary prevention relevant to cardiovascular risk reduction.
Clinical Implications: Cardiovascular prevention should prioritize high-burden subgroups (e.g., socioeconomically deprived, younger/reproductive-age adults, and specific ethnic groups) with tailored interventions and resource allocation.
Key Findings
- Whole-population EHR analysis identified 54,892,390 adults; 4,131,555 had first presentation of obesity (median age 43 years; 55.1% women).
- Obesity affects nearly one in three adults, with widening disparities across socioeconomic, demographic, and regional strata post-pandemic.
- Ethnic composition among first obesity presentations: 75.2% White, 11.7% Asian/Asian British, 7.1% Black/Black British/Caribbean/African.
Methodological Strengths
- Whole-population, individual-level EHR with standardized incidence/prevalence estimation
- Intersectional stratification across multiple sociodemographic dimensions
Limitations
- Reliance on recorded BMI and healthcare encounters may introduce measurement and selection biases
- Observational design limits causal inference; pandemic-related healthcare disruptions may confound trends
Future Directions: Evaluate targeted, equity-focused interventions and assess longitudinal cardiometabolic outcomes; integrate environmental and policy exposures to explain regional heterogeneity.
BACKGROUND: Obesity is one of the 21st century's greatest public health challenges. Evidence on how inequalities intersect to shape the obesity burden is scarce, particularly since the COVID-19 pandemic. We aimed to investigate trends in the incidence and prevalence of obesity among adults in England, and to examine variation by age, sex, socioeconomic status, ethnicity, and geographical region. METHODS: In this retrospective, longitudinal cohort study, we analysed whole-population, individual-level, anonymised, electronic health records with life-course data on the entire population of adults aged 18-99 years in England, accessed via the National Health Service England Secure Data Environment. We estimated age- and sex-standardised incidence and prevalence rates of obesity (BMI ≥30·0 kg/m FINDINGS: Between Nov 1, 2019, and April 30, 2025, we identified 54 892 390 adults with records in the National Health Service England Secure Data Environment. 4 131 555 people had a first presentation of obesity during the study period, of whom 2 278 485 (55·1%) were women and 1 853 070 (44·9%) were men. 3 106 740 (75·2%) of individuals were White, 482 690 (11·7%) were Asian or Asian British, and 291 920 (7·1%) were Black, Black British, Caribbean, or African. The median age at first presentation of obesity was 43 years (IQR 31-58), and mean BMI was 33·4 kg/m