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 (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

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually

Background: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. Aims: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. Methods: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. Results: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. Conclusion: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease

Anatomical, haemodynamic, biochemical and imaging characteristics of the coronary collateral circulation in acute and chronic atherosclerotic disease processes

Aim: Although frequently identified during coronary angiography, the mechanisms by which coronary collaterals develop, and their prognostic implications are, to date, unknown. This body of work aims to determine the prevalence and predictors of coronary collateral recruitment in the setting of ST elevation myocardial infarction (STEMI) and chronic total occlusion (CTO) and to determine their prognostic impact. Furthermore, to identify biochemical, cellular and haemodynamic processes by which collaterals are recruited and mature, and influence haemodynamics in the coronary circulation. Methods: Anatomical grading of collaterals using the Rentrop classification was performed in a large cohorts of patients with STEMI and CTO to determine predictors, reproducibility and prognostic implications of collaterals. Data linkage with other health parameters including a history of obstructive sleep apnoea (OSA) and prior coronary artery bypass grafting (CABG) was performed to determine impact of comorbidities and haemodynamic modulation on collateral recruitment. Subsequent systematic reviews and meta-analyses were performed. Invasive haemodynamic assessment of coronary blood flow and pressure in the presence and absence of collaterals was correlated with endothelial, haematological, biochemical and proteomic markers in both human and animal studies. Results: The important and novel findings are; - The presence of acutely recruited robust collaterals in the setting of STEMI are associated with a reduction in mortality and improved left ventricular function. - In the setting of a CTO, robust collaterals do not reduce mortality or risk of future ischaemic events, but do increase likelihood of successful percutaneous revascularisation. - Collateral maturation is driven by an elevation in shear stress, alterations in blood flow and tissue ischaemia. - The presence of collaterals results in a consistent increase in coronary blood flow in the donor vessel, with resultant effect on both pressure and flow derived indices of ischaemia assessment commonly used in clinical practice. - Recruitment and maturation of coronary collaterals are associated with upregulation of endothelial derived chemoattractant proteins, growth factors and transcription factors. - Coronary artery bypass grafting to a donor vessel, results in poorer collateral recruitment, likely driven by alterations in coronary blood flow and endothelial shear stress - The presence of OSA is associated with more robust coronary collaterals in both the setting of STEMI and CTO, however in more severe forms of OSA, characterised by severe and prolonged hypoxia, collateral recruitment is attenuated. Conclusions: Coronary collaterals impart significant prognostic implications in the setting of acute and chronic coronary artery disease, recruited as a result of alterations in coronary haemodynamics and tissue ischaemia with resultant downstream activation of growth factors, chemokines and transcription factors. Ongoing research is necessary to determine whether this prognostic advantage can be translated into meaningful therapeutic targets along with a greater understanding of clinical implications of collaterals

Cardiovascular Disease in the Post-COVID-19 Era - the Impending Tsunami?

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which causes coronavirus disease 2019 (COVID-19), has rapidly grown into a worldwide pandemic, ever since first being described in Wuhan, China at the end of 2019. At time of writing (10 April, 2020), the rapid spread of the virus throughout the world has resulted in over 1.6 million infections and over 95,000 deaths world-wide; in Australia, there have been 6,203 confirmed cases with 53 deaths, with a mortality rate of 0.85%, much less than the world average of around 6%. Given the ferocity and devastating effects on health care systems abroad, Australia has implemented a series of measures to reduce the rate of spread and prepare the health care system for the pandemic. This has included cancelling elective surgery, social distancing and a nation-wide shut down of non-essential service

Association between vessel-specific coronary Aggregated plaque burden, Agatston score and hemodynamic significance of coronary disease (The CAPTivAte study)

Background: CT coronary angiography (CTCA) is a guideline-endorsed assessment for patients with stable angina and suspected coronary disease. Although associated with excellent negative predictive value in ruling out obstructive coronary disease, there are limitations in the ability of CTCA to predict hemodynamically significant coronary disease. The CAPTivAte study aims to assess the utility of Aggregated Plaque Burden (APB) in predicting ischemia based on Fractional Flow Reserve (FFR). Methods: In this retrospective study, patients who had a CTCA and invasive FFR of the LAD were included. The entire length of the LAD was analyzed using semi-automated software which characterized total plaque burden and plaque morphological subtype (including Low Attenuation Plaque (LAP), Non-calcific plaque (NCP) and Calcific Plaque (CP). Aggregated Plaque Burden (APB) was calculated. Univariate and multivariate analysis were performed to assess the association between these CT-derived parameters and invasive FFR. Results: There were 145 patients included in this study. 84.8 % of patients were referred with stable angina. There was a significant linear association between APB and FFR in both univariate and multivariate analysis (Adjusted R-squared = 0.0469; p = 0.035). Mean Agatston scores are higher in FFR positive vessels compared to FFR negative vessels (371.6 (±443.8) vs 251.9 (±283.5, p = 0.0493). Conclusion: CTCA-derived APB is a reliable predictor of ischemia assessed using invasive FFR and may aid clinicians in rationalizing invasive vs non-invasive management strategies. Vessel-specific Agatston scores are significantly higher in FFR-positive vessels than in FFR-negative vessels. Associations between HU-derived plaque subtype and invasive FFR were inconclusive in this study

Outcomes of deferred revascularisation following negative fractional flow reserve in diabetic and non-diabetic patients: a meta-analysis

Abstract 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 =   0.8, 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

Immediate recruitment of dormant coronary collaterals can provide more than half of normal resting perfusion during coronary occlusion in patients with coronary artery disease

Background: Dormant coronary collaterals are highly prevalent and clinically beneficial in cases of coronary occlusion. However, the magnitude of myocardial perfusion provided by immediate coronary collateral recruitment during acute occlusion is unknown. We aimed to quantify collateral myocardial perfusion during balloon occlusion in patients with coronary artery disease (CAD). Methods: Patients without angiographically visible collaterals undergoing elective percutaneous transluminal coronary angioplasty (PTCA) to a single epicardial vessel underwent two scans with 99mTc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). All subjects underwent at least three minutes of angiographically verified complete balloon occlusion, at which time an intravenous injection of the radiotracer was administered, followed by SPECT imaging. A second radiotracer injection followed by SPECT imaging was performed 24 h after PTCA. Results: The study included 22 patients (median [interquartile range] age 68 [54-72] years. The perfusion defect extent was 19 [11-38] % of the LV, and the collateral perfusion at rest was 64 [58-67]% of normal. Conclusion: This is the first study to describe the magnitude of short-term changes in coronary microvascular collateral perfusion in patients with CAD. On average, despite coronary occlusion and an absence of angiographically visible collateral vessels, collaterals provided more than half of the normal perfusion