Hot topics in ischaemic heart disease: polygenic risk scores, coronary microvascular dysfunction, myocardial injury, and diagnostic role of imaging

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease contains a State of the Art Review article entitled ‘Polygenic risk scores for the prediction of cardiometabolic disease’. Jack O’Sullivan and Euan Ashley from the Stanford University School of Medicine in Stanford, CA, USA, and Perry Elliott from UCL Institute of Cardiovascular Science in London, UK reiterate that cardiometabolic diseases contribute more to global morbidity and mortality than any other group of disorders.1 Polygenic risk scores (PRSs), the weighted summation of individually small-effect genetic variants, represent an advance in our ability to predict the development and complications of several diseases, and of cardiometabolic diseases in particular. This article reviews the evidence supporting the use of PRSs in seven common cardiometabolic diseases: coronary artery disease (CAD), stroke, hypertension, heart failure and cardiomyopathies, obesity, atrial fibrillation (AF), and type 2 diabetes mellitus (T2DM). The data suggest that PRSs for CAD, AF, and T2DM consistently improve prediction when incorporated into existing clinical risk tools. In other areas such as ischaemic stroke and hypertension, clinical application appears premature, but emerging evidence suggests that the study of larger and more diverse populations coupled with more granular phenotyping will propel the translation of PRSs into practical clinical prediction tools. The use of biomarkers is undisputed in the diagnosis of primary myocardial infarction (MI). In contrast, their value for identifying MI is more controversial in other settings, including the post-operative phase following coronary artery bypass grafting (CABG).2–6 In a State of the Art Review article entitled ‘Cardiac troponin release following coronary artery bypass grafting: mechanisms and clinical implications’, Samuel Heuts from the Maastricht University Medical Center in the Netherlands, and colleagues note that to identify patients with peri-procedural MI (PMI), several conflicting definitions of PMI have been proposed, relying either on cardiac troponin (cTn) or on the MB isoenzyme of creatine kinase, with or without supporting evidence of ischaemia.7 However, CABG inherently induces the release of cardiac biomarkers, as reflected by significant cTn concentrations in patients with uncomplicated post-operative courses. Still, the underlying (patho)physiological release mechanisms of cTn are incompletely understood, complicating adequate interpretation of post-operative increases in cTn concentrations. Therefore, the aim of the current review was to present these potential underlying mechanisms of cTn release in general and following CABG in particular. Based on these mechanisms, dissimilarities in the release of cTnI and cTnT are discussed, with potentially important implications for clinical practice. Consequently, currently proposed cTn biomarker cut-offs by the prevailing definitions of PMI might warrant re-assessment, with differentiation in cut-offs for the separate available assays and surgical strategies. To resolve these issues, future prospective studies are warranted to determine the prognostic influence of biomarker release in general and PMI in particular. CFR, coronary flow reserve; FFR, fractional flow reserve; MMSE, Mini-Mental State Examination; ACE-III, Addenbrooke’s Cognitive Examination (attention domain); TMT-A, Trail Making Test A; MRI, magnetic resonance imaging; WMH, white-matter hyperintensity; FA, fractional anisotropy; MD, mean diffusivity; GM, grey matter.15 Coronary microvascular dysfunction (CMD) plays an important role in several cardiovascular diseases.8–14 It remains unknown, however, whether the presence of CMD correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). In a Fast Track Clinical Research article entitled ‘Coronary microvascular dysfunction is associated with impaired cognitive function: the cerebral–coronary connection study (C3 study)’, Hernan Mejia-Renteria from the Hospital Clinico San Carlos IdISSC in Madrid, Spain, and colleagues indicate that the C3 study, a prospective blinded study, investigated the prevalence of CMD in patients with CAD and its association with CSVD and cognitive function.15 Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were obtained in all patients. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR (<2.0) (55%) showed a higher burden of white-matter hyperintensities: 43.2 vs. 20.0% (P = 0.044). After statistical adjustment, low CFR was associated with lower grey matter volume (P = 0.024) and with parameters of white-matter microstructural damage in diffusion-tensor imaging (lower fractional anisotropy and higher mean diffusivity, P = 0.029 and P = 0.032, respectively). Low CFR was associated with higher resistive (P = 0.027) and pulsatility (P = 0.043) values on TCD, and worse neurocognitive test scores (lower Mini-Mental State Examination, P = 0.025, and slower Trail Making Test A, P = 0.034) (Figure 1). Mejia-Renteria and colleagues conclude that coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD. The contribution is accompanied by an Editorial by Carl Pepine from the University of Florida in Gainesville, FL, USA and C. Noel Bairey Merz from the Barbra Streisand Women’s Heart Center in Los Angeles, CA, USA.16 Pepine and Bairey Merz highlight that small vessel disease of the brain and heart have far-reaching clinical and economic implications. Pathophysiologically, both organs share common risk factors (e.g. hypertension, diabetes, dyslipidaemia, and ageing) and are likely to be affected similarly by systemic inflammation, atherosclerosis (ischaemia), vasospasm, microemboli, and neuroendocrine dysfunction. There is increasing awareness that sex differences modify interactions, yet it is unclear whether the phenotype of myocardial ischaemia resulting from CMD is linked with a similar brain condition, CSVD. They conclude by noting that as we seek treatment targets for both CVSD and CMD, at this time the best that we can conclude is ‘true’ = CMD is highly prevalent, and ‘true’ = CVSD is highly prevalent, but we have limited evidence to support the hypothesis that they are related, although the study by Hernan Mejia-Renteria makes one step forward in this direction. Inclisiran, a small interfering RNA (siRNA) administered twice yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. In a second Fast Track Clinical Research article entitled ‘Inclisiran and cardiovascular events: a patient-level analysis of Phase III trials’ Kausik Ray from Imperial College in London, UK, and colleagues note that it is not yet established if lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events.17 Patient-level, pooled analysis of ORION-9, -10, and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin therapy, randomized 1:1 to receive 284 mg of inclisiran or placebo on Days 1 and 90, and 6 monthly thereafter for 18 months. The pre-specified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal MI, and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 51% (P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE. Inclisiran significantly reduced composite MACE (odds ratio: 0.74). Ray et al. conclude that their analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger outcomes trials of longer duration. This manuscript is accompanied by an Editorial by Raul D. Santos and Viviane Z. Rocha from the University of Sao Paulo Medical School Hospital in Brazil.18 They note that these study results should only be considered as hypothesis-generating, as they were not designed to determine the impact of inclisiran on ASCVD outcomes. In addition, MACE were reported as adverse events, the events were not adjudicated, and follow-up was short. Despite the above limitations, these results trend similarly to the results of studies with proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal anti-bodies and are consistent with genetic studies supporting the clinical value of PCSK9 inhibition. The rates of events per year in the placebo group in the study of Ray et al. are high and occur despite the use of statins. These findings reinforce the need for additional therapies to reduce the so-called residual risk in similar populations. The risk may be driven by high atherosclerotic plaque burden, inflammation, comorbidities, and other risk factors such as diabetes, smoking, elevated lipoprotein(a) or triglyceride-rich lipoprotein remnants, genetic variants, and persistently elevated LDL-C. The authors conclude that the final chapter of the PCSK9 story book is not written yet, but the study of Ray et al. suggests a good draft. If the outcomes are positive, greater access to this novel agent will provide the readers with a happy ending. In the whole population of patients with chronic coronary syndromes (CCS) enrolled in the EURECA registry, 56% of patients were managed according to the 2019 European Society of Cardiology (ESC) Guidelines (GL) for the overall diagnostic process. The adoption of GL recommendations led to a lower proportion of invasive coronary angiograms (15% vs. 48%) and coronary revascularizations (8% vs. 19%). However, when invasive angiograms were performed adopting GL recommendations, 60% showed obstructive coronary artery disease (CAD) (>70% stenosis) and 54% led to revascularization as compared with 39% and 37%, respectively, when the diagnostic process did not adopt the GL recommendations.26 Imaging plays a key role in the assessment of ischemic heart disease.19–25 In a Clinical Research article entitled ‘Use of cardiac imaging in chronic coronary syndromes: the EURECA Imaging registry’, Danilo Neglia from the Fondazione Toscana G. Monasterio in Pisa, Italy, and colleagues note that the prospective, multicentre EURECA registry assessed the use of imaging and adoption of the European Society of Cardiology Guidelines (GL) in patients with chronic coronary syndromes (CCS).26 Between May 2019 and March 2020, 5156 patients were recruited in 73 centres from 24 ESC member countries. The adoption of GL recommendations was evaluated according to clinical presentation and pre-test probability (PTP) of obstructive CAD. The mean age of the population was 64 years, 60% of patients were males, 42% had PTP >15%, 27% had previous CAD, and ejection fraction was <50% in 5%. Exercise ECG was performed in 32% of patients, stress imaging as the first choice in 40%, and computed tomography coronary angiography (CTCA) in 22%. Invasive coronary angiography (ICA) was the first or downstream test in 17% and 11%, respectively. Obstructive CAD was documented in 24% of patients, inducible ischaemia in 19%, and 13% of patients underwent revascularization. In 44% of patients, the overall diagnostic process did not adopt the GL. In these patients, referral to stress imaging (21% vs. 58%; P < 0.001) or CTCA (17% vs. 30%; P < 0.001) was less frequent, while exercise ECG (43% vs. 22%; P < 0.001) and ICA (48% vs. 15%; P < 0.001) were more frequently performed. The adoption of GL was associated with fewer ICAs, a higher proportion of diagnosis of obstructive CAD (60% vs. 39%, P < 0.001) and revascularization (54% vs. 37%, P < 0.001), among those undergoing ICA, a higher quality of life, less additional testing, and longer times to late revascularization (Figure 2). Neglia et al. conclude that in patients with CCS, current clinical practice does not adopt GL recommendations on the use of diagnostic tests in a significant proportion of patients. When the diagnostic approach adopts GL recommendations, invasive procedures are less frequently used and the diagnostic yield and therapeutic utility are superior. The contribution is accompanied by an Editorial by Pieter van der Bijl, Jan Stassen, and Jeroen Baxs from Leiden University Medical Centre in the Netherlands.27 The authors highlight that the results from the EURECA registry expose the fact that there remains a fairly large gap between best practice, as recommended by the ESC guideline, and real-life clinical practice as far as cardiac imaging use for chronic coronary syndromes is concerned. The primary reasons for non-adherence include an over-reliance on exercise ECG and invasive coronary angiography, with underutilization of cardiac imaging. Use of invasive angiography as a first-line test appears to have been influenced by the perceived high risk constituted by being male, older, and having a family history of CAD, dyslipidaemia, and prior revascularization, while one can speculate that over-reliance on exercise ECG was probably due to historic trends or an overestimation of its diagnostic accuracy. Non-adherence to the guideline was not due to a lack of availability of multimodality imaging at the participating centres, and therefore strategies should be developed to improve adherence to the existing guideline. The information obtained from the EURECA registry will be useful as feedback to the ESC task force which compiled the guideline, when preparing the next iteration. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Cardiac troponin elevation after coronary artery bypass graft: improving risk stratification’, Matteo Armillotta, Alberto Foà, and Carmine Pizzi from the University of Bologna in Italy comment on the recent publication ‘High-sensitivity cardiac troponin I after coronary artery bypass grafting for post-operative decision-making’ by Hazem Omran from the Ruhr-Universität Bochum in Bad Oeynhausen, Germany.28,29 Omran et al. respond in a separate comment.30 Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.