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Aims Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. Methods and results We found that direct cardiac release of cathepsin-L in STEMI patients (n  = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. Conclusion Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI. [ABSTRACT FROM AUTHOR]

Cessation of one component of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has been associated with increased risk of ischemic events but it is uncertain whether discontinuation of aspirin is preferable to discontinuation of the oral P2Y12 inhibitor. The GLOBAL LEADERS study compared two antiplatelet strategies following PCI, cessation of aspirin at 1 month with continued ticagrelor monotherapy for 23 months versus standard DAPT for 12 months followed by aspirin monotherapy for a further 12 months. We assessed recovery of platelet reactivity after withdrawal of either aspirin or ticagrelor at 1 month and 12 months, respectively, in this study. Platelet aggregation (PA) was assessed before cessation of DAPT ('baseline') and after 2, 7, and 14 days post-cessation using Multiplate whole-blood aggregometry with collagen, thrombin-receptor-activating peptide (TRAP), adenosine diphosphate (ADP) and arachidonic acid (AA) as agonists. Following cessation of aspirin at 1 month, there was marked recovery of PA induced by AA (baseline [mean ± SD]: 11.1 ± 7.4 U vs. 14 days: 64.9 ± 19.6 U, p <.0001) and collagen (37.4 ± 22.9 U vs. 79.8 ± 13.8 U, p <.0001), whereas PA induced by ADP (18.6 ± 6.6 vs. 69.1 ± 20.5, p <.0001) and collagen (34.4 ± 18.7 U vs. 43.0 ± 21.0, p =.0018) recovered following cessation of ticagrelor at 12 months. There were no significant changes in TRAP-induced PA in either group. In conclusion, cessation of either component of DAPT leads to substantial increase in platelet reactivity with differential effects on different pathways of platelet activation when aspirin or the P2Y12 inhibitor is stopped. Further work is required to determine which patients receive net benefit from long-term continuation of DAPT. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are considered to be at risk of progressive adverse cardiac remodelling which can lead to the development of heart failure and death. The early addition of a sodium–glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients.We performed a randomized, double‐blind, placebo‐controlled, multicentre trial using cardiovascular magnetic resonance imaging (MRI), in patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by MRI. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome was the change in left ventricular end‐systolic volume indexed to body surface area (LVESVI) from baseline to 24 weeks. Secondary outcomes included measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and high‐sensitivity troponin I (hs‐TnI) and N‐terminal prohormone of B‐type natriuretic peptide (NT‐proBNP) concentrations. From October 2022 to January 2024, 105 eligible patients were randomized. The mean age was 63 ± 11 years and 90 (87%) were male. The mean LVEF was 34.8 ± 6.0%. In the placebo group, LVESVI decreased by 7.8 ± 16.3 ml/m2, left ventricular end‐diastolic volume index (LVEDVI) did not change (−0.3 ± 18.7 ml/m2) and LVEF increased by 8.5 ± 7.4% at 24 weeks from baseline. Empagliflozin did not affect the change in LVESVI from baseline to 24 weeks (between‐group difference = 0.3 ml/m2, 95% confidence interval −5.2 to 5.8; p = 0.92). Compared with placebo, empagliflozin also had no effect on LVEDVI, LVEF, left atrial volume index, left ventricular mass index, NT‐proBNP, or hs‐TnI, but did increase haematocrit and reduced uric acid and weight.In patients with left ventricular systolic dysfunction after an acute MI receiving contemporary standard of care, treatment with empagliflozin had no effect on cardiac volumes or LVEF compared with placebo. Progressive adverse cardiac remodelling did not occur in the majority of patients. [ABSTRACT FROM AUTHOR]

Background: The relationship between atherosclerosis and endotypes of myocardial ischaemia with no obstructive coronary artery disease (INOCA) is unclear. We investigated potential associations between cumulative atherosclerotic plaque burden quantified using the Gensini score, novel invasive indices of coronary microvascular function (microvascular resistance reserve (MRR); resistive reserve ratio (RRR)) and related INOCA endotypes., Methods: Coronary angiography and invasive coronary function tests were simultaneously acquired in the CorMicA cohort. A comprehensive physiological assessment was performed using both a thermodilution-based diagnostic guidewire and intracoronary acetylcholine provocation testing. Angiograms were examined for luminal stenosis in each segment of the SYNTAX coronary model. Cumulative plaque burden was quantified using the Gensini score, which incorporated both the number of diseased coronary segments and stenosis severity. Results were compared with indices of microvascular function and INOCA endotypes. Angiographic analyses were performed blind to coronary physiology findings., Results: In 151 participants (median age 61 years; 73.5% female) without flow-limiting coronary artery disease, medical history included 41.7% smoking, 63.6% hypertension and 19.2% diabetes mellitus. The left anterior descending artery underwent diagnostic guidewire testing in 85.4%, and 55.0% of participants had abnormal coronary flow reserve (CFR) and/or Index of Microcirculatory Resistance (IMR). The median Gensini score was 6.0 (IQR 2.5-11.0). CFR (p=0.012), MRR (p=0.026) and RRR (p=0.026), but not IMR (p=0.445), were univariably associated with raised Gensini scores. These significant effects persisted in multivariable models controlling for potential confounders. Considering INOCA endotypes, Gensini scores differed among participants with microvascular angina (MVA) (7.0 (2.5-11.0)), vasospastic angina (VSA) (4.5 (2.0-10.0)), mixed MVA/VSA (9.0 (5.0-11.5)) and non-cardiac symptoms (3.5 (1.5-8.0)); Kruskal-Wallis p=0.030., Conclusions: Reduced CFR, MRR and RRR, and MVA were associated with increased coronary atherosclerotic plaque burden, as evidenced by higher Gensini scores. These novel findings provide a mechanistic link between INOCA and cardiovascular events, reinforcing the importance of antiatherosclerosis therapy in patients with MVA., Competing Interests: Competing interests: Dr TF received consulting fees from BioExcel; honoraria from Abbott, Boehringer, Novartis. Dr SW received honoraria from Abbott, AstraZeneca, Biosensors, Boston Scientific, Daiichi Sankyo, GE Healthcare and ShockWave Medical. Dr KR received honoraria from AstraZeneca and Abbott. Dr MM received consulting fees from Abbott, Boston Scientific and ShockWave Medical; honoraria from International Medical Device Solutions and Medtronic. Dr KGO received honoraria from Abbott, Biosensors International and Boston Scientific; full-time employee of Biosensors International since May 2020. Dr CB receives research funding from the British Heart Foundation grant (RE/18/6134217, PG/19/28/34310), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1) and Medical Research Council (MR/S018905/1). None of the declared interests regards the submitted work. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)