Coronary microvascular dysfunction: from Cinderella to Princess

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. It is 250 years since Heberden’s description of angina pectoris.1 Recently a large body of evidence has convincingly shown that the mechanisms of angina are complex and to a large extent independent of epicardial stenoses. Coronary steal adds to this complexity.2–5 This Focus Issue on ischaemic heart disease contains the State of the Art Review entitled ‘Coronary steal: how many thieves are out there?’ by Alexandru Achim from the Kantonsspital Baselland in Switzerland, and colleagues.6 The authors point out that the colourful term ‘coronary steal’ arose in 1967 to parallel ‘subclavian steal’ coined in an anonymous 1961 editorial. In both instances, the word ‘steal’ described flow reversal in the setting of an interconnected but abnormal vascular network—in one case a left subclavian stenosis proximal to the origin of the vertebral artery and in the other case a coronary fistula. Over time, the term has morphed to include a larger set of pathophysiology without explicit flow reversal but rather with a decrease in stress flow due to other mechanisms. This review aims to shed light on this phenomenon from a clinical and a pathophysiological perspective, detailing the anatomical and physiological conditions that allow so-called steal to appear and offering treatment options for six distinct scenarios. Migraine and cardiovascular disease. Factors influencing the occurrence of migraine, the International Classification of Headache Disorders, 3rd edition, definition of migraine (in purple), cardiovascular diseases associated with migraine (in orange), and treatment options for migraine (in blue). Abbreviations: 5-HT, 5-hydroxytryptamine; ASD, atrial septal defect; CAD, coronary artery disease; CGRP, calcitonin gene-related peptide; CVD, cardiovascular disease; PFO, patent foramen ovale. Prevalence of migraine according to sex and age from Lancet Neurol 2008; 7:354–61. https://doi.org/10.1016/S1474-4422(08)70062-0.7 Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. In a State of the Art Review article entitled ‘Migraine and cardiovascular disease: what cardiologists should know’, Deborah Kalkman from Amsterdam UMC, University of Amsterdam in the Netherlands, and colleagues explain that people with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h.7 The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction (MI), and cardiovascular death compared with those without migraine. Ongoing studies investigate the relationship of migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale.8 Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiepileptics, antidepressants, some of the long-acting calcitonin gene-related peptide (CGRP) receptor antagonists, or monoclonal antibodies against CGRP or its receptor, or acute medication, such as triptans and CGRP receptor antagonists. However, these medications might raise concerns when migraine patients also have CVD due to possible (coronary) side effects. Specifically, knowledge gaps remain for the contraindication for newer treatments for migraine. All cardiologists will encounter patients with CVD and migraine. This state-of-the-art review outlines the basic pathophysiology of migraine and the associations between migraine and CVD, discusses current therapies, and proposes future directions for research (Figure 1). The pharmacological treatment of coronary microvascular dysfunction (CMD) remains an unmet need.9–11 In a Viewpoint article entitled ‘Novel therapy for ischaemia with no obstructive coronary arteries’, Andrew Morrow from the University of Glasgow in the UK and colleagues reiterate that myocardial ischaemia with no obstructive coronary arteries (INOCA) impairs quality of life and confers an increased likelihood of cardiovascular events and health resource utilization.12 Contemporary advances in non-invasive and invasive testing facilitate an accurate diagnosis and linked therapy. New guideline recommendations and patient advocacy are also relevant. This Viewpoint focuses on the emerging therapy for INOCA. The authors initially describe the pathophysiology and clinical endotypes of INOCA and then review novel therapeutic strategies, including ongoing clinical trials and future therapeutic possibilities. The treatment of left main coronary artery (LMCA) disease has recently been the target of an intense debate.13–18 In a Clinical Research article entitled ‘PCI or CABG for left main coronary artery disease: the SWEDEHEART registry’, Jonas Persson from Karolinska Institutet in Stockholm, Sweden, and colleagues have put together an observational nationwide all-comers prospective register study to analyse outcomes after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in unprotected LMCA disease.19 All patients undergoing coronary angiography in Sweden are registered in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Between 1 January 2005 and 31 December 2015, > 11 000 patients with LMCA disease underwent CABG (n = 9364) or PCI (n = 1773). Patients with previous CABG, ST-elevation myocardial infarction (STEMI), or cardiac shock were excluded. Death, MI, stroke, and new revascularization during follow-up until 31 December 2015 were identified using national registries. Cox regression with inverse probability weighting (IPW) and an instrumental variable (IV), namely administrative region, were used. Patients undergoing PCI were older and had higher prevalence of comorbidity but lower prevalence of three-vessel disease. PCI patients had higher mortality than CABG patients after adjustments for known cofounders with IPW analysis [hazard ratio (HR) 2.0] and known/unknown confounders with IV analysis (HR 1.5). PCI was associated with higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, or new revascularization) than CABG, with IV analysis (HR 2.8). There was a quantitative interaction for diabetic status regarding mortality (P = 0.014) translating into 3.6 years (95% CI 3.3–4.0) longer median survival time favouring CABG in patients with diabetes. The authors conclude that in this non-randomized study, CABG in patients with LMCA disease is associated with lower mortality and fewer MACCE compared with PCI after multivariable adjustment for known and unknown confounders. This manuscript is accompanied by an Editorial by Margaret McEntegart from the Columbia University Medical Center in New York, USA and Tommaso Gori from the University Medical Centre Mainz and DZHK Standort Rhein-Main in Germany.20 McEntegart and Gori conclude by highlighting that this study forces us to again reflect on the applicability of randomized trials to patients we encounter in routine clinical practice, while also highlighting the limitations of non-randomized comparisons of treatment strategies within observational registries. For the future, both patient selection in randomized trials and treatment selection in registries could be tackled by all-comer registry randomization, as was done effectively by this group in the iFR-SWEDEHEART study. The optimal utilization of troponins in patients with suspected acute coronary syndrome (ACS) remains debated.21–23 It is uncertain whether a single cardiac troponin measurement can safely rule out MI in patients presenting within a few hours of symptom onset. In a Clinical Research article entitled ‘Troponin in early presenters to rule out myocardial infarction’, Matthew Lowry from the University of Edinburgh in the UK, and colleagues assess the performance of troponin in early presenters.24 In patients with possible MI, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4–12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In >41 000 consecutive patients (mean age 60 years, 46% women), 31% presented within 3 h, and 9% had MI. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value (99.4% and 99.7%) compared with 5 ng/L (96.5% and 99.3%). In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% and 92.5%, respectively. Findings were consistent in an external validation cohort of >7000 patients. Lowry and colleagues conclude that in early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of MI. The 99th centile should not be used to rule out MI at presentation even in those presenting later following symptom onset. The contribution is accompanied by an Editorial by Hugo A. Katus and Evangelos Giannitsis from the University of Heidelberg in Germany.25 The authors note that given that comprehensive medical examination will be pursued and individualized care will be provided for all patients with suspected ACS, it is very reassuring that an undetectable cardiac troponin using a high sensitivity assay is an excellent indicator of a very low cardiac risk not only in presumably healthy populations but also—as shown here—in patients presenting early or late with suspected ACS in an emergency department. Diagnostic and prognostic value of the microvascular resistance reserve (MRR). The MRR is a novel index of the coronary vasodilatory capacity. The MMR is an index that corrects the assessment of the vasodilatory capacity for concomitant epicardial disease and the administration of vasodilatory indices. The MRR shows an excellent correlation with the coronary flow reserve (CFR), which decreases with decreasing fractional flow reserve (FFR) values. The MRR is an independent and significant predictor of both major adverse cardiac events (MACE) and target vessel failure (TVF) at 5-year follow-up.26 The microvascular resistance reserve (MRR) was introduced to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. In a Clinical Research article entitled ‘Microvascular resistance reserve: diagnostic and prognostic performance in the ILIAS registry’, Coen Boerhout from the Amsterdam UMC in the Netherlands and colleagues aimed to evaluate the diagnostic and prognostic performance of MRR.26 A total of ∼1500 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 and the overall relationship between MRR and CFR was good. The difference between CFR and MRR increased with decreasing FFR. A higher MRR was independently associated with major adverse cardiac events (MACE) (HR 0.78; P = 0.024) and target vessel failure (TVF) at 5-year follow-up (HR 0.83; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75) (Figure 2). The authors conclude that MRR is a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with haemodynamically significant epicardial coronary artery disease. The manuscript is accompanied by an Editorial by Stefano Rigattieri and Emanuele Barbato from Sant’Andrea University Hospital in Rome, Italy, and Colin Berry from the University of Glasgow, UK.27 The authors summarize that epicardial and microvascular disease represent a continuum. Currently, a comprehensive assessment of microvascular function is feasible and recommended in European and North American chest pain guidelines when INOCA is suspected. They also note that the authors of this study should be commended for having provided the first multicentre data on the clinical significance of MRR. Their study should pave the way for future studies in cardiovascular conditions where coronary microvascular dysfunction is implicated. Potentially, MRR may serve as a therapeutic target to guide therapy development for coronary microvascular disease. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.