In NSTEMI, are patients without SMuRFs real?

This editorial refers to ‘Addressing disparities of care in non-ST-segment elevation myocardial infarction (NSTEMI) patients without standard modifiable risk factors: insights from a nationwide cohort study.’, by S.M. Moledina et al., pp. 1084–1092. Improvement in diagnosis and treatment of conventional cardiovascular (CV) risk factors (diabetes, hypertension, hypercholesterolaemia, and cigarette smoking) has led to better survival in acute coronary syndrome (ACS).1 Recent studies have reported a clinically significant proportion of patients presenting with ACS without any previous diagnosis of standard modifiable cardiovascular risk factors (SMuRFs).2–4 Contemporary data suggest that SMuRFless patients are increasing5 and may account for 11–27% of patients with ACS.2–4 In the present issue of the Journal, Moledina et al.6 compare the differences in clinical characteristics and outcomes in patients presenting with non-ST-elevation myocardial infarction (NSTEMI) with and without SMuRFs. This analysis was based on data from the prospective MINAP registry in the UK that included 230 medical centres. After excluding patients with previous coronary revascularization or known CAD, the analysis included 176 083 adult patients with NSTEMI between the years 2010 and 2017, among whom 40 860 (23%) were SMuRFless. They were older, with a higher frequency of male sex and White race. Furthermore, the study highlighted that SMuRFless patients were less likely to receive guideline-directed medical therapy [particularly the use of angiotensin-converting enzyme inhibitor (ACEi)], optimal pharmacotherapy (statins), and less frequently treated invasively, but they had lower in-hospital all-cause mortality [odds ratio (OR): 0.85, 95% confidence interval (CI): 0.77–0.93], cardiac mortality (OR: 0.85, 95% CI: 0.76–0.94), and major adverse cardiac events (MACE) (OR: 0.85, 95% CI: 0.77–0.93) than patients with SMuRFs. The present study reports a similar incidence of NSTEMI without SMuRFs compared with previous data on ST-elevation myocardial infarction (STEMI) patients without SMuRFs.2–4 The true incidence of SMuRFless ACS patients, however, remains unclear. Most of the data derived on SMuRFless status is based on registries. While some of the previous cohorts have shown high completeness of ascertainment and accuracy of classification of diagnoses,7 it remains a challenge with most of the observational data. Identification of SMuRF status is based on interrogation of medical records and is not independently validated with biochemical testing; thus, it may be susceptible to underdiagnosis. In the present analysis, former smoking, and family history of coronary artery disease (CAD) was not counted as risk factors, and information on established risk factors such as triglycerides (TG), HDL-c, and lipoprotein(a) were not available. Drug use, such as cocaine, amphetamines, or marijuana was not reported, nor was use of either prescription stimulants or supplements potentially containing those substances. Sex-specific risk factors for CV disease, such as premature menopause or complications of pregnancy, were not evaluated.8 Similarly, potentially emerging risk factors such as exposure to air pollution, vaping, clonal haematopoiesis of indeterminate potential, and polygenic risk scores were not available. In addition, information on socioeconomic or psychosocial risk factors and access to health care were not available. The proportion of SMuRFless patients presenting with subthreshold or borderline SMuRFs in the present cohort is not known. Most of the registries capture risk factors as categorical variables, and perhaps with changing cut-offs for optimal LDL-c or optimal blood pressure level over time, the true prevalence of SMuRF patients was underappreciated. Although previous data have shown that SMuRFless patients have lower body mass index, lower TG, and higher HDL-c concentrations,4 it is possible that in this study, a significant number of SMuRF patients are misclassified as SMuRFless due to lack of availability of detailed clinical phenotypes, underlying pathophysiology, biomarker data, and discharge diagnoses. Another important consideration related to the time frame of the registry is that the SMuRF-less group might have included patients who would have been differently categorized if they had been enrolled in a more contemporary period. An intriguing finding of the present study is lower cardiac and all-cause mortality in patients presenting with NSTEMI without SMuRFs. This is in contrast with the previous data showing increased all-cause mortality in SMuRFless STEMI patients.4 STEMI has higher in-hospital mortality rate than NSTEMI. Apart from pathophysiological differences in STEMI and NSTEMI, it is difficult to ascertain the underlying aetiology of NSTEMI from registry data, i.e. type I or type II myocardial infarction or other alternative aetiologies than plaque rupture such as spontaneous coronary artery dissection or myocardial infarction with non-obstructive coronary arteries (MINOCAs). Patients with MINOCA are known to have lower mortality compared with patients with obstructive CAD.9 However, it is important to note that in some of the previous cohorts of SMuRFless ACS patients, atherosclerotic mechanisms were confirmed in most of the patients by review of cardiac angiograms.4 One other explanation for the high proportion of SMuRFless status and lower mortality can be due to the continuum of SMuRF risk and perhaps milder subclinical forms of SMuRFs in these patients account for the lower mortality.10 The interesting findings of the present study should also give us pause on the completeness of present clinical risk score models based on SMuRFs. What defines risk in SMuRFless patients is not completely understood yet. Improved risk score models including genetic, metabolic, inflammatory, and imaging biomarkers of subclinical CV disease may be warranted. Coronary artery calcification (CAC) has been shown to predict CV events beyond traditional CV factors. Recently, one study suggested evidence of atherosclerosis in 50% patients without SMuRFs; another study had evidence of CAC in 32% of asymptomatic patients without SMuRFs, with 12% of patients having moderate or severe CAC (CAC score > 100 Agatston units).2 A prospective cohort study with a biobank that is currently ongoing may provide insight into subclinical atherosclerosis and biomarkers associated with it.3 In the present study, SMuRFless patients received less statin and ACEi. While it remains unclear if this is related to older age, comorbidities, or haemodynamics in these patients, an unresolved question that has not been well addressed to date is whether these patients with either preclinical or borderline or no SMuRFs can derive benefit from traditional preventive pharmacotherapy strategies at baseline. However, recent statistics, highlighted in the present cohort as well, show underusage of secondary prevention pharmacotherapy in these patients without SMuRFs.4 While many questions remain unanswered in ACS patients without SMuRFs at this point, the present study sheds new light on important findings in NSTEMI patients presenting without identified conventional risk factors. We hope that newer technology and research will accurately phenotype this population and identify underlying biological processes that are not yet completely understood. Ultimately, NSTEMI patients who appear not to have SMuRFs are in part due to underdiagnosis (and undertreatment) of conventional risk factors, but also due to emerging risk factors and yet undiscovered risk factors. Thus, patients without SMuRFs are indeed very real.