Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis.

BACKGROUND: Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2-sample Mendelian randomization approach. METHODS AND RESULTS: We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome-wide association study meta-analyses including 480 698 and 653 867 participants, respectively. We collected further genome-wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse-variance weighted was the primary analysis method, with weighted-median, weighted-mode, Mendelian randomization-Egger, and Mendelian randomization-Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85-1.04], P=0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97-1.12], P=0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations. CONCLUSIONS: The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis.

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 (IL1ß inhibitor) and colchicine (ß-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, IL1ß or ß-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.

Surface-Induced Hydrophobin Assemblies with Versatile Properties and Distinct Underlying Structures.

Hydrophobins are remarkable proteins due to their ability to self-assemble into amphipathic coatings that reverse surface wettability. Here, the versatility of the Class I hydrophobins EASΔ15 and DewY in diverse nanosuspension and coating applications is demonstrated. The hydrophobins are shown to coat or emulsify a range of substrates including oil, hydrophobic drugs, and nanodiamonds and alter their solution and surface behavior. Surprisingly, while the coatings confer new properties, only a subset is found to be resistant to hot detergent treatment, a feature previously thought to be characteristic of the functional amyloid form of Class I hydrophobins. These results demonstrate that substrate surface properties can influence the molecular structures and physiochemical properties of hydrophobin and possibly other functional amyloids. Functional amyloid assembly with different substrates and conditions may be analogous to the propagation of different polymorphs of disease-associated amyloid fibrils with distinct structures, stability, and clinical phenotypes. Given that amyloid formation is not required for Class I hydrophobins to serve diverse applications, our findings open up new opportunities for their use in applications requiring a range of chemical and physical properties. In hydrophobin nanotechnological applications where high stability of assemblies is required, simultaneous structural and functional characterization should be carried out. Finally, while results in this study pertain to synthetic substrates, they raise the possibility that at least some members of the pseudo-Class I and Class III hydrophobins, reported to form assemblies with noncanonical properties, may be Class I hydrophobins adopting alternative structures in response to environmental cues.

Lipids, Blood Pressure, and Diabetes Mellitus on Risk of Cardiovascular Diseases in East Asians: A Mendelian Randomization Study.

Elevated blood pressure, dyslipidemia, and impaired glycemic control are well-established cardiovascular risk factors in Europeans, but there are comparatively few studies focused on East Asian populations. This study evaluated the potential causal relations between traditional cardiovascular risk factors and disease risk in East Asians through a 2-sample Mendelian randomization approach. We collected summary statistics for blood pressure parameters, lipid subsets, and type 2 diabetes mellitus liability from large genome-wide association study meta-analyses conducted in East Asians and Europeans. These were paired with summary statistics for ischemic heart disease (IHD), ischemic stroke (IS), peripheral vascular disease, heart failure (HF) and atrial fibrillation (AF). We performed univariable Mendelian randomization analyses for each exposure-outcome pair, followed by multivariable analyses for the available lipid subsets. The genetically predicted risk factors associated with IHD and AF were similar between East Asians and Europeans. However, in East Asians only genetically predicted elevated blood pressure was significantly associated with IS (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001) and HF (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001), whereas nearly all genetically predicted risk factors were significantly associated with IS and HF in Europeans. In conclusion, this study provides supportive evidence for similar causal relations between traditional cardiovascular risk factors and IHD and AF in both East Asian and European ancestry populations. However, the identified risk factors for IS and HF differed between East Asians and Europeans, potentially highlighting distinct disease etiologies between these populations.

Influence of Obstructive Sleep Apnoea on Outcomes in Patients With ST Elevation Myocardial Infarction (STEMI): the Role of the Coronary Collateral Circulation.

BACKGROUND: Obstructive sleep apnoea (OSA) occurs frequently in patients with coronary artery disease, with associated intermittent hypoxia a possible stimulus for coronary collateral recruitment through ischaemic preconditioning. We sought to determine whether OSA affects recruitment of coronary collaterals and prognosis of patients presenting with ST elevation myocardial infarction (STEMI). METHODS: Patients with a STEMI undergoing percutaneous coronary intervention (PCI) from July 2010 to December 2019 were reviewed. Electronic medical records were accessed to determine documented patient history of OSA. Patients with robust collaterals were defined as Rentrop Grade 2 or 3. RESULTS: 1,863 patients were included, of which 143 (7.7%) patients had documented evidence of OSA in their health record. Patients with OSA had a higher body mass index (BMI) (30.2 kg/m2 vs 27 kg/m2, p<0.0001), greater rate of hypertension (61.1% vs 45.1%, p<0.0001), hypercholesterolaemia (47.4% vs 38.4%, p<0.05) and diabetes mellitus (22.6% vs 15.9%, p<0.05). Patients with OSA were more likely to have robust coronary collaterals (OR: 2.2 [95% CI: 1.5-3.2]) and a lower rate of left ventricular (LV) impairment (50.7% vs 63.1%, p<0.01), a higher LV ejection fraction (50.3% vs 46.7%, p<0.0001) and a lower peak troponin-I level (26,452 ng/L vs 39,469 ng/L, p<0.01). There were no differences in rates of in-hospital or longer term mortality, in patients with OSA compared to those without. CONCLUSIONS: Patients with documented OSA presenting with STEMI appear to have more robust coronary collaterals observed on angiography which likely mediates lower myocardial necrosis. Broader implications of this finding on treatment require further investigation.

Impact of coronary artery bypass grafting (CABG) on coronary collaterals in patients with a chronic total occlusion (CTO).

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.

Aortic Valve Disease and Associated Complex CAD: The Interventional Approach.

Coronary artery disease (CAD) is highly prevalent in patients with severe aortic stenosis (AS). The management of CAD is a central aspect of the work-up of patients undergoing transcatheter aortic valve implantation (TAVI), but few data are available on this field and the best percutaneous coronary intervention (PCI) practice is yet to be determined. A major challenge is the ability to elucidate the severity of bystander coronary stenosis independently of the severity of aortic valve stenosis and subsequent impact on blood flow. The prognostic role of CAD in patients undergoing TAVI is being still debated and the benefits and the best timing of PCI in this context are currently under evaluation. Additionally, PCI in the setting of advanced AS poses some technical challenges, due to the complex anatomy, risk of hemodynamic instability, and the increased risk of bleeding complications. This review aims to provide a comprehensive synthesis of the available literature on myocardial revascularization in patients with severe AS undergoing TAVI. This work can assist the Heart Team in individualizing decisions about myocardial revascularization, taking into account available diagnostic tools as well as the risks and benefits.

Novel device-based therapies to improve outcome in ST-segment elevation myocardial infarction.

Primary percutaneous coronary intervention (PPCI) has dramatically changed the outcome of patients with ST-elevation myocardial infarction (STEMI). However, despite improvements in interventional technology, registry data show little recent change in the prognosis of patients who survive STEMI, with a significant incidence of cardiogenic shock, heart failure, and cardiac death. Despite a technically successful PPCI procedure, a variable proportion of patients experience suboptimal myocardial reperfusion. Large infarct size and coronary microvascular injury, as the consequence of ischaemia-reperfusion injury and distal embolization of atherothrombotic debris, account for suboptimal long-term prognosis of STEMI patients. In order to address this unmet therapeutic need, a broad-range of device-based treatments has been developed. These device-based therapies can be categorized according to the pathophysiological pathways they target: (i) techniques to prevent distal atherothrombotic embolization, (ii) techniques to prevent or mitigate ischaemia/reperfusion injury, and (iii) techniques to enhance coronary microvascular function/integrity. This review is an overview of these novel technologies with a focus on their pathophysiological background, procedural details, available evidence, and with a critical perspective about their potential future implementation in the clinical care of STEMI patients.

No-reflow phenomenon in ST-segment elevation myocardial infarction: still the Achilles' heel of the interventionalist.

Improvements in systems, technology and pharmacotherapy have significantly changed the prognosis over recent decades in patients presenting with ST-segment elevation myocardial infarction. These clinical achievements have, however, begun to plateau and it is becoming increasingly necessary to consider novel strategies to further improve outcomes. Approximately a third of patients treated by primary percutaneous coronary intervention for ST-segment elevation myocardial infarction will suffer from coronary no-reflow (NR), a condition characterized by poor myocardial perfusion despite patent epicardial arteries. The presence of NR impacts significantly on clinical outcomes including left ventricular dysfunction, heart failure and death, yet conventional management algorithms neither assess the risk of NR nor treat NR. This review will provide a contemporary overview on the pathogenesis, diagnosis and treatment of NR.

Internet search volume for chest pain during the COVID-19 pandemic.

During the COVID-19 pandemic there has been a reduction in hospital admissions for acute myocardial infarction. This manuscript presents the analysis of Google Trends meta-data and shows a marked spike in search volume for chest pain that is strongly correlated with COVID-19 case numbers in the United States. This raises a concern that fear of contracting COVID-19 may be leading patients to self-triage using internet searches.

Effect of Recruitment of Acute Coronary Collaterals on In-Hospital Mortality and on Left Ventricular Function in Patients Presenting With ST Elevation Myocardial Infarction.

Recruitment of the coronary collateral circulation is frequently observed during ST elevation myocardial infarction (STEMI) and is of uncertain significance. The aim of this study was to identify and determine the predictors and prognostic implications of the presence of robust collaterals during STEMI. All patients presenting to a large tertiary centre with a STEMI undergoing percutaneous coronary intervention from 2010 to 2018 were reviewed. Patients with poor collateral recruitment were defined as those with Rentrop grade 0 or 1 collaterals, whilst patients with robust collateral recruitment were defined as Rentrop grade 2 or 3. A total of 1,625 patients were included in the study, with 1,280 (78.8%) patients having poor collateral recruitment and 345 patients (21.2%) having robust collateral recruitment. Patients with robust collaterals were younger (63.1 vs 65.1 years, p < 0.05), had a longer ischemic time (628.5 minutes vs 433.1 minutes, p < 0.0001), and more likely to have a chronic total occlusion of a noninfarct related artery (10.4% vs 5.3%, p < 0.001). The presence of robust collaterals was associated with higher rates of normal or mildly impaired left ventricular function (83.5% vs 63.2%, p < 0.0001) and lower in-hospital mortality (2.1% vs 7.6%, p < 0.0001). After correcting for left ventricular function, collateral recruitment was not an independent predictor of mortality. In conclusion, in patients presenting with STEMI, the presence of robust coronary collaterals appears to be associated with improved left ventricular function. Further research is required to identify mechanisms of collateral maturation and recruitment.

Transcatheter Aortic Valve Replacement Influence on Coronary Hemodynamics: A Quantitative Meta-Analysis and Proposed Decision-Making Algorithm.

BACKGROUND: As transcatheter aortic valve replacement (TAVR) expands to younger and lower-risk severe aortic stenosis patients, appropriate coronary artery disease treatment is key to reducing long-term adverse cardiovascular outcomes. Recently, studies have been exploring the role of coronary-physiology guided revascularization strategies. Our aim was to investigate whether TAVR influences coronary physiology measurements using quantitative meta-analytic methods. METHODS: We performed a Medline and Embase search for studies evaluating coronary physiology indices before and after TAVR. Double independent screening and extractions of baseline, procedural, angiographic, and echocardiographic data were performed. Risk of bias was assessed using the ACROBAT-NRSI tool. Pooled mean difference estimates of coronary hemodynamic indices before and after TAVR were derived using random-effects models with the inverse variance method (RevMan, Review Manager, version 5.3.5; Nordic Cochrane Centre). RESULTS: Five studies evaluating 250 coronary vessels in 169 severe aortic stenosis patients were quantitatively synthesized. Coronary flow reserve did not change immediately after TAVR in non-diseased vessels (n = 3; mean difference, 0.11; 95% confidence interval [CI], -0.10-0.32; P=.29; I²=0%; P=.68). Importantly, fractional flow reserve also did not vary significantly following TAVR in both non-diseased (n = 3; mean difference, -0.01; 95% CI, -0.04-0.03; P=.75; I²=41; P=.19) and diseased coronaries (n = 3; mean difference, -0.01; 95% CI, -0.03-0.01; P=.49; I²=0%; P=.46). Similarly, instantaneous wave-free ratio remained stable following TAVR (n = 2; mean difference, 0.00; 95% CI, -0.02-0.02; P>.99; I²=0; P>.99. CONCLUSIONS: Pooled coronary physiology measurements before and after TAVR are similar, but data on variation within individual lesions are limited.