Explore the vast range of titles available.

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R , IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management.

Background Fractional Flow Reserve (FFR) is a widely applied invasive physiological assessment, endorsed by major guidelines to aid in the decision to perform or defer revascularisation. While a threshold of  > 0.8 has been applied universally, clinical outcomes may be affected by numerous factors, including the presence of diabetes. This meta-analysis aims to investigate the outcomes of diabetic versus non-diabetic patients in whom revascularisation was deferred based on negative FFR. Methods We performed a meta-analysis investigating the outcomes of diabetic and non-diabetic patients in whom revascularisation was deferred based on negative FFR. A search was performed on MEDLINE, PubMed and EMBASE, and peer-reviewed studies that reported MACE for diabetic and non-diabetic patients with deferred revascularisation based on FFR  > 0.8 were included. The primary end point was MACE. Results The meta-analysis included 7 studies in which 4275 patients had revascularisation deferred based on FFR > 0.8 (1250 diabetic). Follow up occurred over a mean of 3.2 years. Diabetes was associated with a higher odds of MACE (OR = 1.66, 95% CI 1.35–2.04, p =  < 0.001), unplanned revascularisation (OR = 1.48, 95% CI 1.06–2.06, p = 0.02), all-cause mortality (OR = 1.74, 95% CI 1.20–2.52, p = 0.004) and cardiovascular mortality (OR = 2.08, 95% CI 1.07–4.05, p = 0.03). Conclusions For patients with stable coronary syndromes and deferred revascularisation based on FFR > 0.8, the presence of diabetes portends an increased long-term risk of MACE compared to non-diabetic patients. Trail registration URL:  https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42022367312.

Acute coronary collateralisation of an infarct-related arterial (IRA) territory may be identified during angiography for ST elevation myocardial infarction (STEMI). Whether the presence or absence of these collaterals affects outcomes remains uncertain. A search of EMBASE, MEDLINE and Cochrane Library, using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines was conducted to identify studies which reported on the association between coronary collaterals and in-hospital and longer term mortality, left ventricular ejection fraction (LVEF), risk of repeat acute myocardial infarction (AMI) and repeat revascularisation. Patients with Rentrop grade 0 or 1 were defined as poor collaterals whilst those with Rentrop grade two or three were defined as those with robust collaterals. Studies were eligible if they included patients ≥ 18 years of age who had immediate coronary angiography for STEMI. Included studies were observational which recorded the degree of collateral blood flow to the IRA. Two investigators reviewed all citations using a predefined protocol with final consensus for all studies, the data from which was then independently entered to ensure fidelity of results. Inverse variance random effects model for the meta-analysis along with risk of bias assessment was performed. 20 studies with a total of 14,608 patients were identified and included in the analysis. Patients with robust collaterals had lower mortality (OR 0.55, 95% CI 0.48–0.64), both in-hospital (OR 0.47, 95% CI 0.35–0.63) and longer term (OR 0.58, 95% CI 0.46–0.75). Patients with robust collaterals also had a higher mean LVEF (SMD 0.23, 95% CI 0.10–0.37). There was no difference in the rates of AMI or repeat revascularisation between patients with robust or poor collaterals. The presence of robust collaterals during STEMI is associated with reduced in-hospital and longer term mortality and improved left ventricular function. These findings have implications for prognostication and identifying patients who require close monitoring following STEMI.

Chronic total occlusions (CTO) are found commonly in patients with prior coronary artery bypass grafting (CABG). We sought to determine the effect of CABG on collateral robustness in patients with a CTO. Patients with a CTO diagnosed on coronary angiography between July 2010 and December 2019 were included in this study. Patients were classified as either CTO supplied by a functional graft, CTO supplied by collaterals from a non-grafted donor vessel (non-grafted) or a CTO supplied by collaterals from a grafted donor vessel (grafted). The degree of collateral robustness was determined by the Rentrop classification and collateral connection (CC) grade. Demographic, angiographic and clinical outcomes were recorded. A total of 2088 CTO lesions were identified, of which 878 (42.0%) were supplied by a functional graft, 994 (47.6%) CTOs were supplied by a non-grafted donor vessel and 216 (10.3%) CTOs were supplied by a grafted donor vessel. CTOs supplied by a grafted donor vessel had lower rates of robust collaterals (37.0% vs 83.0%, p < 0.0001) with less mature collaterals as determined by the Rentrop grade (p < 0.0001) and CC grade (p < 0.0001) as compared to CTOs supplied by a non-grafted donor vessel. In patients with a previous CABG, a grafted donor vessel results in less robust coronary collaterals with lower Rentrop and CC grade compared to an ungrafted donor vessel. This may be attributable to changes in coronary blood flow and shear stress, and may be a factor in the lower procedural success rates for CTO intervention in patients with prior CABG.

IntroductionAortic stenosis is the most common cardiac valve pathology worldwide and has a mortality rate of over 50% at 5 years if left untreated. Transcatheter aortic valve implantation (TAVI) is a minimally invasive and highly effective alternative treatment option to open-heart surgery. High-grade atrioventricular conduction block (HGAVB) is one of the most common complications after TAVI and requires a permanent pacemaker. Due to this, patients are typically monitored for 48 hours post TAVI, however up to 40% of HGAVB may delayed, and occur after discharge. Delayed HGAVB can cause syncope or sudden unexplained cardiac death in a vulnerable population, and no accurate methods currently exist to identify patients at risk.Methods and analysisThe prospective observational study on the accuracy of predictors of high-grade atrioventricular conduction block after transcatheter aortic valve implantation (CONDUCT-TAVI) trial is an Australian-led, multicentre, prospective observational study, aiming to improve the prediction of HGAVB, after TAVI. The primary objective of the trial is to assess whether published and novel invasive electrophysiology predictors performed immediately before and after TAVI can help predict HGAVB after TAVI. The secondary objective aims to further evaluate the accuracy of previously published predictors of HGAVB after TAVI, including CT measurements, 12-lead ECG, valve characteristics, percentage oversizing and implantation depth. Follow-up will be for 2 years, and detailed continuous heart rhythm monitoring will be obtained by inserting an implantable loop recorder in all participants.Ethics and disseminationEthics approval has been obtained for the two participating centres. Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numberACTRN12621001700820.

Purpose Obstructive sleep apnoea (OSA) which results in hypoxia may affect the ability to recruit coronary collaterals. The aim of this study was to determine whether the severity of OSA affects collateral recruitment in patients with total coronary occlusions. Methods Patients with total coronary artery occlusion were reviewed. Records from the sleep investigation laboratory were reviewed to identify those patients who had undergone diagnostic polysomnography. Robust coronary collaterals were those with Rentrop grade 2 or 3 collaterals. Results Sixty-four patients with a total coronary occlusion had polysomnography performed, of whom 60 patients had OSA. Thirty-two patients (53.3%) had poor collaterals, whilst 28 (46.7%) had robust collaterals. Twenty-four (40%) patients had mild OSA, 10 (16.7%) had moderate OSA and 26 (43.3%) had severe OSA. Patients with robust collaterals were more likely to be males (96.4% vs 74.3%, p  < 0.05) and have a history of hypercholesterolaemia (88.9% vs 51.6%, p  < 0.01). Patients with robust collaterals had a lower apnoea–hypopnoea index (13.6 vs 45.5, p  < 0.05), a higher MinS a O 2 (85.4% vs 79.8%, p  < 0.05), less time S a O 2  < 90% (0 min vs 30.4 min, p  < 0.05) and lower oxygen desaturation index (6.9 vs 26.8, p  < 0.05). Those with moderate OSA had a higher mean Rentrop grade (1.6 ± 0.3) than those with mild OSA (1.5 ± 1.1) and severe OSA (0.6 ± 0.2). Conclusion The presence of more severe OSA is associated with poorer coronary collateral recruitment in patients with total coronary artery occlusion. The effect of treatment of OSA on subsequent ability to recruit collaterals and other cardioprotective mechanisms requires further research.

The cardiovascular impact of cocaine use in otherwise healthy individuals who consider themselves 'social' users is not well established. Twenty regular cocaine users and 20 control subjects were recruited by word-of-mouth. Cardiovascular magnetic resonance was performed to assess cardiac and vascular structure and function. Cocaine users had higher systolic blood pressure compared to non-users (134±11 vs 126±11 mmHg, p = 0.036), a finding independent of age, body surface area, smoking and alcohol consumption. Cocaine use was associated with increased arterial stiffness - reflected by reduced aortic compliance (1.3±0.2 vs 1.7±0.5 cm2×10-2.mmHg-1, p = 0.004), decreased distensibility (3.8±0.9 vs 5.1±1.4 mmHg-1.10-3, p = 0.001), increased stiffness index (2.6±0.6 vs 2.1±0.6, p = 0.005), and higher pulse wave velocity (5.1±0.6 vs 4.4±0.6 m.s-1, p = 0.001). This change in aortic stiffness was independent of vessel wall thickness. Left ventricular mass was 18% higher in cocaine users (124±25 vs 105±16 g, p = 0.01), a finding that was independent of body surface area, and left atrial diameter was larger in the user group than controls (3.8±0.6 vs 3.5±0.3 cm, p = 0.04). The increased left ventricular mass, systolic blood pressure and vascular stiffness measures were all associated with duration and/or frequency of cocaine use. No late gadolinium enhancement or segmental wall motion abnormalities were seen in any of the subjects. Compared with the non-user control cohort, cocaine users had increased aortic stiffness and systolic blood pressure, associated with greater left ventricular mass. These measures are all well known risk factors for premature cardiovascular events, highlighting the dangers of cocaine use, even in a 'social' setting, and have important public health implications.

Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.

Invasive coronary physiology has been applied by interventional cardiologists to guide the management of coronary artery disease (CAD), with well-defined thresholds applied to determine whether CAD should be managed with optimal medical therapy (OMT) alone or OMT and percutaneous coronary intervention (PCI). There are multiple modalities in clinical use, including hyperaemic and non-hyperaemic indices. Despite endorsement in the major guidelines, there are various factors which impact and confound the readings of invasive coronary physiology, both within the coronary tree and beyond. This review article aims to summarise the mechanisms by which these factors impact invasive coronary physiology, and distinguish factors that contribute to ischaemia from confounding factors. The potential for mis-classification of ischaemic status is highlighted. Lastly, the authors identify targets for future research to improve the precision of physiology-guided management of CAD. The Complex Determinants of Invasive Coronary Physiology Created with BioRender.com [Display omitted]