AIMS:Adenosine, acting through A1 adenosine receptors (A1ARs), exerts anti-adrenergic effects by inhibiting β1-adrenergic receptor (β1AR)-mediated cyclic adenosine monophosphate (cAMP) production and contractility in the heart. While the functional interaction between A1ARs and β1ARs is well established in both atrial and ventricular myocytes, the subcellular compartmentalization of this crosstalk and how it is disrupted in heart failure (HF) remains incompletely understood. This study investigates the spatial confinement of A1AR-β1AR signalling within atrial microdomains and assesses how structural remodelling in HF alters this regulatory axis. METHODS AND RESULTS:Quantitative polymerase chain reaction (qPCR) analysis revealed that A1AR is the predominant adenosine receptor subtype in both rat and human atrial tissues. In healthy rat and mouse atrial myocytes, A1AR activation reduced β1AR-induced cAMP production and sarcomere shortening, with suppression of cAMP signals at sarcolemmal microdomains enriched in protein kinase A Type II. This was further supported by scanning ion conductance microscopy-guided scanning patch-clamp, which showed that A1AR suppressed β1AR-driven L-type Ca2+ channel activity at both T-tubule and crest membrane domains. In atrial myocytes isolated from failing rat and human hearts, A1AR-mediated inhibition of β1AR-induced cAMP production and contractility was impaired. Caveolar disruption by methyl-β-cyclodextrin in rat atrial myocytes or via cardiac-specific caveolin-3 (Cav3) knockout in mice abolished this A1AR-mediated inhibition. Notably, cholesterol repletion alone did not restore membrane cAMP regulation, whereas Cav3 overexpression rescued A1AR-dependent suppression, supporting a requirement for Cav3-dependent organization. In mouse atrial preparations isolated from failing hearts, high-resolution optical mapping showed that A1AR-mediated anti-adrenergic regulation of Ca2+ cycling was selectively lost in the intercaval region, correlating with the regional absence of T-tubule and downregulation of caveolae structures. CONCLUSION:A1ARs provide anti-adrenergic restraint of β1AR signalling through Cav3-dependent membrane organization. In HF, regional caveolar disorganization uncouples this protective pathway, contributing to spatially heterogeneous Ca2+ dysregulation in the atrium.

Therapies promoting microvascular flow and endothelial repair require effective identification of new targets in ischemic heart disease (IHD). The aim of this study was to unravel and functionally investigate circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) networks in endothelial cells in the context of IHD and type 2 diabetes mellitus (T2DM). We performed RNA sequencing on left ventricle biopsies from patients with IHD, IHD and T2DM, and non-IHD. Next, we created circRNA-miRNA-mRNA networks and mechanistically investigated the top circRNA-miRNA sponging interactions in endothelial cells. We found that circNPHP1 promotes angiogenesis via sponging of miR-221-3p and regulates its downstream target genes, VEGFA and BCL2, in IHD and T2DM.

ABSTRACT Background Coronary artery bypass grafting (CABG) to physiologically non-significant coronary artery stenosis may result in graft failure due to competitive native flow. We evaluated whether an instantaneous wave-free ratio (iFR)-guided revascularization strategy improves graft patency and clinical outcomes compared to conventional angiography-guided CABG. Methods In this prospective, randomized, single-blinded trial, patients with multivessel disease and at least one angiographically intermediate stenosis (50%–75%) were randomized to either CABG guided by angiography alone or angiography supplemented with iFR assessment groups. The primary endpoint was graft patency (occlusion or hypoperfusion of the graft) evaluated by coronary computed tomography angiography (CCTA) at 2, 12, and 36 months. Results At 36 months, 78% of the patients completed follow-up. Left internal mammary artery (LIMA)-to-left anterior descending (LAD) artery graft patency was significantly higher in the iFR-guided group than in the angiography-guided group (80.5% vs. 56.8%; absolute risk difference, 23.7% [95% CI , 3.7%–43.8%]; RR , 1.42 [95% CI , 1.03–1.95]; P = 0.03). Saphenous vein graft patency also improved with iFR guidance (90.2% vs. 70.3%; P = 0.046). Major adverse cardiac and cerebrovascular events (MACCE) were similar between groups (28% vs. 20%; RR , 1.40 [95% CI , 0.69–2.85]; P = 0.48). Conclusions iFR-guided CABG advocates significantly improved mid-term graft patency compared with angiography-guided CABG by optimizing surgical target selection and reducing competitive flow. CLINICAL PERSPECTIVE What Is New? This prospective randomized trial demonstrates that physiological guidance using instantaneous wave-free ratio (iFR) significantly improves both arterial and venous graft patency at 36 months follow up compared to angiography-guided coronary artery bypass grafting (CABG). A pre-operative iFR threshold of >0.875 in the target vessel was identified as a potent predictor of subsequent graft occlusion or hypoperfusion. The study provides longitudinal evidence that competitive flow, identified by iFR, remains a critical determinant of long-term conduit durability. What Are the Clinical Implications? Integrating routine iFR assessment into the surgical planning for multivessel coronary artery disease may identify fewer significant stenoses, reducing the need for CABG. Using physiological rather than purely anatomical criteria for revascularization may mitigate the risk of graft failure associated with competitive native flow. These results suggest that preoperative physiological assessment can refine surgical revascularization strategies and enhance long-term conduit durability.

Saphenous vein grafts (SVGs) remain widely used in coronary artery bypass grafting (CABG). This study examines the role of wall shear stress (WSS) and graft geometry on SVG patency and evaluates the potential of computational fluid dynamics (CFD) as an assessment tool post-CABG. A systematic search was conducted in PubMed, Cochrane Library, Scopus and EMBASE using the terms ‘wall shear stress’, ‘geometry’, ‘computational fluid dynamics’ and ‘saphenous vein graft patency’. From 374 articles, 82 met the inclusion criteria, focussing on WSS and/or graft geometry in relation to SVG patency in coronary disease. Studies limited to qualitative findings or animal models were excluded, narrowing the selection to 64 eligible articles. Adverse WSS conditions were linked to pronounced intimal hyperplasia, atherosclerosis and graft failure. Geometrical factors influencing SVG patency included graft diameter, target coronary diameter (> 2.0 mm), graft wall thickness (> 1.5 mm), curvature at the graft-host junction and anastomotic angles exceeding 15–20°. CFD-based evaluations of SVG patency aligned with existing literature findings. The interplay between SVG patency, WSS and graft geometry is well documented. CFD offers a promising modality for in-depth graft analysis by gauging geometry and flow dynamics. By delivering objective information, CFD can equip surgeons with the tools to optimise strategies and thereby enhance CABG patient outcomes.

Percutaneous left ventricular assist devices (LVADs) have become essential tools during coronary reperfusion in high-risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 min (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart–lung transplantation. The recipient’s heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p = 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6

AIMS:The left atrial appendage (LAA) produces natriuretic peptides and its removal or occlusion might increase the risk of heart failure (HF). We aimed to investigate the incidence of HF after LAA occlusion or removal (LAAO) in the Left Atrial Appendage Occlusion Study (LAAOS III). METHODS AND RESULTS:Patients (n = 4811) with atrial fibrillation (AF) and a CHA2DS2-VASc score ≥2, who were having cardiac surgery for another indication, were randomized to undergo surgical LAAO or not. We compared the composite outcome of HF-related hospitalizations and HF death between the two groups. HF assessment required clinical and radiographic evidence of HF. Analyses included a landmark analysis before and after 30 days and subgroups. Mean age was 71.2 years, 67.5% were male and 57.0% had prior HF. Over a mean follow-up of 3.8 years, 396 (8.3%) patients met the composite HF outcome: 209 (8.8%) with LAAO (n = 2379) and 187 (7.8%) without LAAO (n = 2391) (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.92-1.37, p = 0.25). There was no difference between the two groups in the first 30 days (1.6% vs. 1.1%; p = 0.12) and thereafter (7.6% vs. 7.1%; p = 0.57). Subgroups based on age, sex, body mass index, AF type, prior HF, cardiac rhythm or left ventricular ejection fraction showed consistent results. There was no difference in HF outcomes with LAAO between the cut-and-sew (HR 0.93, 95% CI 0.70-1.23, p = 0.62) versus other closure methods (HR 1.05, 95% CI 0.77-1.41, p = 0.77). CONCLUSIONS:Left atrial appendage occlusion or removal at the time of cardiac surgery does not appear to alter the risk of HF-related hospitalization or death. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT01561651.

INTRODUCTION:Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. METHODS AND ANALYSIS:The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). ETHICS AND DISSEMINATION:The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. TRIAL REGISTRATION:ISRCTN15255199. Registered in March 2019.

Coronary artery disease (CAD) is a major health issue. This study focused on pericardial macrophages and small extracellular vesicles (sEVs) in CAD. The macrophages in CAD patients showed reduced expression of protective markers and unchanged levels of proinflammatory receptors. Similar changes were observed in buffy-coat-derived macrophages when stimulated with CAD pericardial fluid-derived sEVs. The sEV contained miRNA-6516-5p, which inhibited CD36 and affected macrophage lipid uptake. These findings indicate that sEV-mediated miRNA actions contribute to the decrease in protective pericardial macrophages in CAD.

Myocardial revascularization in coronary artery disease via percutaneous coronary intervention or coronary artery bypass graft (CABG) surgery effectively relieves symptoms, significantly improves prognosis and quality of life when combined with guideline-directed medical therapy. Hybrid coronary revascularization is a promising alternative to percutaneous coronary intervention or CABG in selected patients and is defined as a planned and/or intended combination of consecutive CABG surgery using at least 1 internal mammary artery to the left anterior descending (LAD), and catheter-based coronary intervention to the non-LAD vessels for the treatment of multivessel disease. The main indications for hybrid coronary revascularization are (i) to achieve complete revascularization in patients who cannot undergo conventional CABG, (ii) to treat patients with acute coronary syndromes and multivessel disease with a non-LAD vessel as the culprit lesion that needs revascularization and (iii) in highly select patients with multivessel disease with complex LAD lesions and simple percutaneous coronary intervention targets for all other vessels. Hybrid coronary revascularization patients receive a left internal mammary artery graft to the LAD artery through a minimal incision along with percutaneous coronary intervention to the remaining diseased coronary vessels using latest generation drug-eluting stents. A collaborative environment with a dedicated heart team is the optimal platform to perform such interventions, which aim to improve the quality and outcome of myocardial revascularization. This position paper analyses the rationale of hybrid coronary revascularization and the currently available evidence on the various techniques and delves into the sequence of the interventions and pharmacological management during and after the procedure.