Updates on MINOCA and INOCA through the 2022 publications in the International Journal of Cardiology

•Myocardial infarction with non-obstructed coronary arteries (MINOCA) is a ‘working diagnosis’.•A comprehensive diagnostic evaluation unravels the pathophysiology of MINOCA in the majority of cases.•Intravascular imaging and coronary physiology are needed in Myocardial ischemia with non-obstructed coronary arteries•Magnetic resonance, computed tomography and coagulation testing are fundamental diagnostic complements in MINOCA/INOCA. The syndromes of Myocardial Infarction or Ischemia with No Obstructive Coronary Artery Disease (aka as MINOCA and INOCA) have received increasing attention in recent years and several diagnostic uncertainties have been clarified [1Pasupathy S. Tavella R. Beltrame J.F. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management.Circulation. 2017; 135: 1490-1493Crossref PubMed Scopus (114) Google Scholar, 2Pelliccia F. Marzilli M. Boden W.E. Camici P.G. Why the term MINOCA does not provide conceptual clarity for actionable decision-making in patients with myocardial infarction with no obstructive coronary artery disease.J. Clin. Med. 2021; 10: 4630Crossref PubMed Google Scholar, 3Pelliccia F. Pepine C.J. Berry C. Camici P.G. The role of a comprehensive two-step diagnostic evaluation to unravel the pathophysiology of MINOCA: a review.Int. J. Cardiol. 2021; 336: 1-7Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 4Pelliccia F. Pasceri V. Tanzilli G. Speciale G. Camici P.G. Gaudio C. Malignancy in patients with myocardial infarction and non-obstructive coronary arteries: a systematic review and meta-regression.Eur. J. Intern. Med. 2020; 81: 38-43Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 5Pelliccia F. Pasceri V. Niccoli G. et al.Predictors of mortality in myocardial infarction and nonobstructed coronary arteries: a systematic review and meta-regression.Am. J. Med. 2020; 133: 73-83Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Contrary to what initially thought, there is now evidence that these patients suffer from major adverse cardiovascular events (MACE) that are not less serious than those in patients with obstructive coronary artery disease (CAD) [6Shimokawa H. Suda A. Takahashi J. et al.Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the coronary vasomotor disorders international study (COVADIS) group.Eur. Heart J. 2021; 42: 4592-4600Crossref PubMed Scopus (46) Google Scholar, 7Dias A. Núñez Gil I.J. Santoro F. et al.Takotsubo syndrome: state-of-the-art review by an expert panel - part 2.Cardiovasc. Revasc. Med. 2019; 20: 153-166Crossref PubMed Scopus (38) Google Scholar, 8Roncella A. Pristipino C. Cianfrocca C. et al.One-year results of the randomized, controlled, short-term psychotherapy in acute myocardial infarction (STEP-IN-AMI) trial.Int. J. Cardiol. 2013; 170: 132-139Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 9Marazzi G. Wajngarten M. Vitale C. et al.Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease.Int. J. Cardiol. 2007 Aug 9; 120: 79-84Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 10Pelliccia F. Pasceri V. Limongelli G. et al.Long-term outcome of nonobstructive versus obstructive hypertrophic cardiomyopathy: a systematic review and meta-analysis.Int. J. Cardiol. 2017 Sep 15; 243: 379-384Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 11Pelliccia F. Pasceri V. Marazzi G. Rosano G. Greco C. Gaudio C. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention.Am. Heart J. 2012; 163: 1019-1023Crossref PubMed Scopus (33) Google Scholar, 12Marazzi G. Campolongo G. Pelliccia F. et al.Usefulness of low-dose statin plus ezetimibe and/or nutraceuticals in patients with coronary artery disease intolerant to high-dose statin treatment.Am. J. Cardiol. 2019; 123: 233-238Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 13Pelliccia F. Patti G. Rosano G. Greco C. Gaudio C. Efficacy and safety of eplerenone in the management of mild to moderate arterial hypertension: systematic review and meta-analysis.Int. J. Cardiol. 2014; 177: 219-228Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 14Pelliccia F. Trani C. Biondi-Zoccai G.G. et al.Comparison of the feasibility and effectiveness of transradial coronary angiography via right versus left radial artery approaches (from the PREVAIL study).Am. J. Cardiol. 2012; 110: 771-775Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. A recent systematic review and meta-analysis of 82 studies in 8457 patients has shown that using a combination of noninvasive and invasive techniques it is possible to identify the pathogenetic mechanisms behind a diagnosis of MINOCA/INOCA in the majority of patients (Fig. 1) [[3]Pelliccia F. Pepine C.J. Berry C. Camici P.G. The role of a comprehensive two-step diagnostic evaluation to unravel the pathophysiology of MINOCA: a review.Int. J. Cardiol. 2021; 336: 1-7Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar], although, In clinical practice, their application remains limited. A number of articles published in the International Journal of Cardiology during 2022 have added several important pieces of information to the complex puzzle of MINOCA and INOCA. A new diagnostic hallmark has been identified by Graziani et al. who assessed and compared the prevalence and predictors of MINOCA in a large cohort of patients with hypertrophic cardiomyopathy and Fabry disease [[15]Graziani F. Lillo R. Biagini E. et al.Myocardial infarction with non-obstructive coronary arteries in hypertrophic cardiomyopathy vs Fabry disease.Int. J. Cardiol. 2022; 369: 29-32Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. The authors reported results of a multicenter, retrospective study which enrolled 2870 patients with hypertrophic cardiomyopathy and 267 with Fabry disease. During a mean follow-up of 4.5 years, MINOCA occurred in 16 patients with hypertrophic cardiomyopathy (0.5%) and 20 patients with Fabry disease (7.5%). Multivariate analysis disclosed that electrocardiographic criteria for left ventricular hypertrophy (p = 0.003) and maximal left ventricular wall thickness at echocardiography (p = 0.002) were independently associated with MINOCA. On the basis of these results, the authors concluded that MINOCA may be considered a red flag for Fabry disease contributing to the differential diagnosis with hypertrophic cardiomyopathy. Two important studies addressed the long-term outcome of MINOCA patients. Magnani et al. reviewed data of the “Italian Genetic Study on Early-onset Myocardial Infarction” which enrolled 2000 patients who experienced a first myocardial infarction before the age of 45 years and were then followed for almost 20 years [[16]Magnani G. Bricoli S. Ardissino M. et al.Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).Int. J. Cardiol. 2022; 354: 7-13Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Comparison of patients with MINOCA and those with obstructive CAD showed that cardiovascular death rate was lower in the MINOCA group (4.2% vs 8.4%, p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4), non-fatal ischemic stroke (9.5% vs 3.7%), and all-cause mortality (14.1% vs 20.7%) were not significantly different in the two groups. The authors concluded that MINOCA is frequent and that the long-term risk of MACE and overall mortality is not significantly compared to patients with obstructive CAD. Importantly, this study emphasized the fact that MINOCA is a heterogeneous condition whose exact causal mechanisms remain frequently unknown in individual patients. In case of suspected MINOCA, the routine use of cardiac magnetic resonance (CMR), and the selective use of adjunctive diagnostic tools (i.e., intracoronary imaging, provocative test for spasm) appear therefore essential to achieve a correct diagnosis and initiate targeted treatments [[17]Gragnano F. Cesaro A. Pelliccia F. Limongelli G. Early-onset MINOCA: prognostic implications and considerations for practice.Int. J. Cardiol. 2022; 354: 14-16Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Ananthakrishna et al. assessed the long-term outcome of 229 patients with a working diagnosis of MINOCA who underwent CMR at the time of the index event [[18]Ananthakrishna R. Liang Z. Raman B. et al.Long-term clinical outcomes in patients with a working diagnosis of myocardial infarction with non-obstructed coronary arteries (MINOCA) assessed by cardiovascular magnetic resonance imaging.Int. J. Cardiol. 2022; 349: 12-17Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Over a median follow-up of 7.1 years, 56 (24%) patients experienced MACE. In multivariate analysis, age (p < 0.001) and diagnosis of acute myocardial infarction at CMR (p = 0.001) were independent predictors of prognosis. Thus, the authors concluded that one in four patients suffers from a MACE during long-term clinical follow-up, and that CMR is pivotal to identify patients at higher risk. Noteworthy, this work provided further evidence that a comprehensive diagnostic work-up plays a crucial role for establishing a definitive diagnosis and more accurate prognosis [[19]Sammut E. Singhal A. Dastidar A.G. “MINOCA” the Pandora’s box.Int. J. Cardiol. 2022; 353: 1-2Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Two additional investigations focused on the sex differences in patients with MINOCA. Williams et al. evaluated the impact of sex on clinical presentation and outcome in 719 patients with suspected acute coronary syndrome and non-obstructed coronary arteries with a final diagnosis confirmed by CMR [[20]Williams M.G.L. Dastidar A. Liang K. et al.Sex differences in patients with acute coronary syndromes and non-obstructive coronary arteries: presentation and outcome.Int. J. Cardiol. 2022; 372 (S0167-5273(22)01719–3): 15-22Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. All-cause mortality was 9.5% over a median follow up of 4.9 years, with no significant difference between sexes (8.8% versus 10.1%). Men were more likely than women (55% v 41%, p < 0.001) to have MINOCA due to myocarditis, Takotsubo Syndrome or a cardiomyopathy. Age (p < 0.001) and left ventricular ejection fraction (p = 0.023) were independent predictors of mortality. Thus, the authors concluded that there is no difference in all-cause mortality between sexes in patients presenting with an acute coronary syndrome and non-obstructed coronary arteries. Similar findings were reported by Chaudhary et al. who performed a meta-analysis of 7 including 28,671 MINOCA patients (11,249 men and 17,422 women) with a mean follow-up of 2 years [[21]Chaudhary R. Bashline M. Novelli E.M. et al.Sex-related differences in clinical outcomes among patients with myocardial infarction with nonobstructive coronary artery disease: a systematic review and meta-analysis.Int. J. Cardiol. 2022; 369: 1-4Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Comparison of the two groups showed that only the incidence of stroke was significantly higher in women (3.5% vs. 2.2%, p = 0.04), whereas all-cause mortality, non-fatal myocardial infarction, and cardiovascular readmissions were not significantly different between men and women. Although these findings are of importance, the investigation should be considered hypothesis-generating due to the limitations intrinsic to any meta-analysis such as lack in robustness of the statistical model and publication bias [[22]Du L. Wang P. Chen H. Zhang Y. Ma J. Wen G. Among patients with MINOCA women versus men have the increased risks of MACE and stroke?.Int. J. Cardiol. 2023; 371: 82Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. In another contribution published in 2022, De Filippo et al. reported findings of a meta-analysis aimed at evaluating impact of medical therapies for secondary prevention on outcomes of patients suffering from MINOCA [[23]De Filippo O. Russo C. Manai R. et al.Impact of secondary prevention medical therapies on outcomes of patients suffering from myocardial infarction with NonObstructive coronary artery disease (MINOCA): a meta-analysis.Int. J. Cardiol. 2022; 368: 1-9Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Five adjusted observational studies including 10,546 patients were taken into consideration. During 24 months of follow up, statins were associated with a reduced risk of all-cause death (p 〈0,001), while ACE-inhibitors were not. Two studies indicated that beta-blockers and dual anti-platelet therapy were both associated with a significant reduction of all-cause death (p = 0.03). By contrast, in 4 other studies ACE-inhibitors entailed a reduced risk of MACE (p = 0.02) during a mean follow up of 36.5 months. Overall, the meta-analysis showed that beta-blockers, statins and dual antiplatelet therapy are associated with a survival benefit among MINOCA patients, ACE-inhibitors entail a reduced risk of MACE, while none of the investigated secondary prevention therapies were associated with a reduced risk of acute myocardial infarction. Most importantly, this study highlighted the fact that management of MINOCA remains challenging [[24]Scalone G. Di Vito L. Mariani L. et al.Which therapy for MINOCA patients? “dazed and confused for so long, it is not true”.Int. J. Cardiol. 2023; 371: 78-79Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Indeed, medical therapies represent a relevant and undetermined issue due to the uncertainties in the underlying pathophysiology. Physicians feel “dazed and confused’ about treatment of MINOCA and the results of multicenter randomized trials are much awaited in order to finally pave the way for a new pathophysiology-driven approach [[24]Scalone G. Di Vito L. Mariani L. et al.Which therapy for MINOCA patients? “dazed and confused for so long, it is not true”.Int. J. Cardiol. 2023; 371: 78-79Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. With regard to INOCA, Mehta et al. authored an elegant review [[25]Mehta P.K. Quesada O. Al-Badri A. et al.Ischemia and no obstructive coronary arteries in patients with stable ischemic heart disease.Int. J. Cardiol. 2022; 348: 1-8Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. They highlighted the fact that a large proportion of patients with suspected CAD have INOCA. Importantly, INOCA is associated with recurrent hospital admissions for episodes of severe chest pain, impaired functional capacity, reduced health-related quality of life, and high healthcare costs. Evidence of coronary microvascular dysfunction, through both endothelium-dependent and independent mechanisms, predicts adverse outcomes in INOCA. While non-invasive and invasive diagnostic testing has typically focused on identification of obstructive CAD in symptomatic patients, functional testing to detect coronary vasomotor disorders (i.e. endothelial dysfunction and both epicardial and microvascular spasm) should be considered in those patients with INOCA who have persistent angina [[26]Perera D. Berry C. Hoole S.P. et al.Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular dysfunction workstream of the British Heart Foundation/National Institute for Health Research Partnership.Heart. 2022; 109: 88-95PubMed Google Scholar]. In their article Mehta et al. reviewed current methods to diagnose coronary vasomotor disorders as well as the relative treatment strategies [[25]Mehta P.K. Quesada O. Al-Badri A. et al.Ischemia and no obstructive coronary arteries in patients with stable ischemic heart disease.Int. J. Cardiol. 2022; 348: 1-8Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. This information are of major importance due to the emerging evidence of the prognostic value of testing for coronary artery spasm in INOCA patients. In a subsequent narrative article, Seitz et al. provided a contemporary update on advances in the pathophysiology, diagnosis, treatment and prognosis of coronary artery spasm [[27]Seitz A. Martínez Pereyra V. Sechtem U. Ong P. Update on coronary artery spasm 2022 - a narrative review.Int. J. Cardiol. 2022; 359: 1-6Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. The authors performed a MEDLINE/PubMed search of articles published from 2010 to 2021 focusing on original randomized clinical trials, meta-analyses and systematic reviews dealing with diagnosis of epicardial and microvascular spasm in special conditions such as MINOCA, post-PCI angina or myocarditis. Particular attention was paid to more novel treatment approaches, such as nebivolol, endothelin-1-receptor antagonists and soluble guanylate cyclase stimulators. In the ‘Conclusions’, however, the authors acknowledged that, despite many recent advances, coronary artery spasm remains a complex and not fully understood condition and that more research is needed to better characterize and treat affected patients. Results of the Spanish ENDOCOR registry provided novel data regarding the factors predisposing to INOCA, showing that endothelial dysfunction is present in almost half of patients and is associated with worsening symptoms and a higher rate of adverse events [[28]Grigorian-Shamagian L. Oteo J.F. Gutiérrez-Barrios A. et al.Endothelial dysfunction in patients with angina and non-obstructed coronary arteries is associated with an increased risk of mayor cardiovascular events. Results of the Spanish ENDOCOR registry.Int. J. Cardiol. 2023; 370: 18-25Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Specifically, the prevalence of endothelial dysfunction and the clinical profile of patients with INOCA in Spain were assessed in 438 consecutive INOCA patients who underwent acetylcholine testing. Endothelial dysfunction was observed in 198 (45%) patients, while severe vasoconstriction was detected in 101 (23%). Multivariate analysis showed that endothelial dysfunction was predicted by the presence of exertional angina (p = 0.02), prior coronary disease (p < 0.01), and coronary intramyocardial bridging (p = 0.04). As compared with patients with normal endothelial function, those with endothelial dysfunction had worsening angina (25.6% vs. 12.8%) and increased levels of minimal effort angina (40% vs. 26.7%) more frequently during follow up. Endothelial dysfunction was also an independent predictor of myocardial infarction or unstable angina at 1-year (p = 0.03). Further findings emphasized the fact that increased patient awareness and physician recognition are needed to develop evidence-based guidelines for INOCA. Gulati et al. published the results of a patient self-report quality of life survey from INOCA international [[29]Gulati M. Khan N. George M. et al.Ischemia with no obstructive coronary artery disease (INOCA): a patient self-report quality of life survey from INOCA international.Int. J. Cardiol. 2023; 371: 28-39Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. The aim of the survey was to determine associations between INOCA and self-reported physical, social, and mental health. To this end, the authors performed a survey of all members (n = 1579) of the INOCA International patient support group. Most patients reported symptoms of chest pain, pressure, or discomfort. Overall, 34% were living with symptoms for ≥3 years before an INOCA diagnosis, and 77% were told their symptoms were not cardiac. Most respondents reported an adverse impact of symptoms on their home life (80%), social life (81%), mental health (70%), outlook on life (69%), sex life (55%), and partner/spouse relationship (53%), while approximately three-quarters reduced their work hours or stopped work completely, retired early, or applied for disability. On the basis of these results, the authors concluded that INOCA symptoms are associated with adverse physical, mental and social health quality of life. Finally, Morrone et al. provided an up-to-date guide for the choice and the interpretation of the currently available noninvasive anatomical and/or functional tests to be used in patients with suspected myocardial ischemia [[30]Morrone D. Gentile F. Aimo A. et al.Perspectives in noninvasive imaging for chronic coronary syndromes.Int. J. Cardiol. 2022; 365: 19-29Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. The authors emphasized that emerging techniques (e.g., coronary flow velocity reserve, stress-CMR, hybrid imaging, functional-coronary computed tomography angiography, etc.), will provide deeper pathophysiological insights to refine diagnostic and therapeutic pathways in the next future [[30]Morrone D. Gentile F. Aimo A. et al.Perspectives in noninvasive imaging for chronic coronary syndromes.Int. J. Cardiol. 2022; 365: 19-29Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar].