This study is the first to examine the prognostic outcomes of an often-overlooked subset of patients without standard modifiable risk factors, in a typically understudied Asian population presenting with ACS. It is also the first of such study to include both patients with NSTEMI and STEMI. The main findings of the study are: 1) The prevalence of SMuRF-less patients presenting with ACS in an Asian cohort was 8.6%, with its yearly prevalence relatively constant over the past decade; 2) SMuRF-less patients tend to present in a more critical state compared to SMuRF patients, with higher rates of ventricular arrhythmia, and requirement for inotropic and invasive ventilation support; 3) The adjusted risks of cardiovascular mortality, cardiogenic shock and stroke were significantly higher in the SMuRF-less patients compared to SMuRF patients; 4) The significantly higher cardiovascular mortality in SMuRF-less patients compared to SMuRF patients was apparent early from presentation and was sustained over the 30-day follow-up period. Such trend was observed in men and STEMI patients, but not in women or NSTEMI patients. Similar trend was also seen across all three Asian ethnicities.
Traditionally, both primary and secondary prevention of cardiovascular diseases have been focused on high risk individuals with cardiovascular risk factors18, 27. As a result, the subgroup of patients without SMuRFs remains understudied. Recent studies on both STEMI and NSTEMI have demonstrated an increasing prevalence of patients without traditional risk factors13, with the prevalence of SMuRF-less patients being 10.5% in the United States of America19, 14.5% in Canada15, 14.9% in Sweden11 and 19–25% in Australia13, 14. Notably, the population of SMuRF-less patients in our Asian cohort was much lower with a prevalence of only 8.6%. The stark difference in the proportion of SMuRF-less patients across the globe might be partly explained by the differences in risk factor identification28, genetic predisposition29, lifestyle factors such as smoking and physical activity30, 31, and individual country’s primary prevention programme28, 32. Even with the presence of traditional cardiovascular risk factors, their impacts might vary across different ethnic groups, with stroke being more common among hypertensive patients in Asia and chronic heart disease more prevalent in the West33. Despite relatively lower than that seen in the West, the prevalence of SMuRF-less patients in our Asian cohort remains sizeable and warrants further attention to address specific modifiable factors that might predispose Asians to various cardiovascular comorbidities.
Even though the SMuRF-less patients in our cohort were generally younger and had fewer baseline comorbidities, their cardiovascular mortality was higher than those with conventional risk factors. This is consistent with the findings from previous studies11, 14–16, 19 based in the West, and could be partly explained by multiple postulated reasons. Several cardiovascular risk factors, such as serum cholesterol or glycated haemoglobin A1c, have a linear relationship with the risk of cardiovascular morbidity and categorising the patients into binary groups using a standard diagnostic threshold can potentially introduce selection bias by missing out on patients with borderline measurements for certain risk factor that have not reached the diagnostic thresholds. As mentioned earlier, individuals with pre-disease state for various cardiovascular risk factors might also have a higher atherosclerotic cardiovascular risk. Moreover, the role of less well established risk factors such as body mass index, triglyceride concentrations, high-density lipoprotein concentration and sedentary lifestyle, which might also be the potential drivers of atherosclerosis but have not been concomitantly evaluated. Additionally, some recognised risk factors such as abdominal obesity, psychosocial factors, sedentary lifestyle, dietary factors and alcohol consumption are not easily quantified and hence their potential impact on the outcome of SMuRF-less patients is not well assessed34. Furthermore, as patients with known risk factors are more likely to be on treatment, the ACS severity may have been modified by evidence-based therapy used in primary intervention16 leading to better outcome among the SMuRF patients.
The pathogenesis of atherosclerosis, especially its genetic basis, is also not fully understood. A recent study reported as many as 55 genetic loci that are associated with coronary artery disease, with more than 66% of them not linked to the traditional risk factors35. Compared to the patients with SMuRF, more SMuRF-less patients in our study were of Indian ethnicity and had family history of premature coronary artery disease highly suggestive of a genetic predilection to develop atherosclerotic cardiovascular disease. It is plausible that these genetic factors might play a major role in the disease process among SMuRF-less patients leading to onset of disease at a younger age and more advanced disease at presentation with consequent worse prognosis. This raises the possibility that other unknown factors might be involved in the pathogenesis and presentation of ACS among the SMuRF-less patients.
Our study found an increased short-term cardiovascular mortality only in the male SMuRF-less patients, which is in contrary to the observation by Figtree et al11 which showed that SMuRF-less women with STEMI had an excess of short-term mortality over their men counterparts. Such discrepancy in observation could be partly attributed to constitutional differences in study population including ethnic background and the inclusion of full spectrum of ACS patients in our study as opposed to the subgroup of STEMI patients in Figtree et al’s study. Other possible factors include varying extent of delay in patient presentation36 and hormonal-mediated differences associated with atherosclerotic plaque characteristics37. However, our study was not granular enough to explain such differences and future studies are warranted.
Moreover, significant mortality difference between our SMuRF and SMuRF-less patients was only observed in the STEMI, but not NSTEMI patients. This is in contrast to a prior study that showed increased mortality in SMuRF-less as compared to SMuRF patients with NSTEMI19. One possible reason for this discrepancy is the difference in PCI rates between SMuRF and SMuRF-less patients as described by Roe et al, such that the lower use of invasive procedures in SMuRF-less patients might have contributed to their higher mortality19. Hence, similar PCI rates between SMuRF-less and SMuRF patients (53.2% versus 48.9% respectively, p = 0.321) might partly explain the similar mortality between the two groups of NSTEMI patients. Another possible reason is the significantly lower mortality events in NSTEMI as compared to STEMI patients (4.1% versus 8.3% respectively, p < 0.001) which might lead to less apparent difference seen between SMuRF and SMuRF-less patients among our NSTEMI patients38.
Similar to current literature11, 15, 16, we found that SMuRF-less patients were less likely to be treated with guideline-directed medication including beta-blockers, statins and/or ACE-I or ARBs when compared to the SMuRF patients. Figtree et al11 has shown that suboptimal prescription rate of ACE-I or ARBs and beta-blockers was directly correlated to a higher mortality among the SMuRF-less patients which is in line with other studies demonstrating the prognostic benefit of early initiation of beta-blocker and ACE-I in patients with ACS39–41. The reason SMuRF-less patients were less likely to be prescribed with prognostically important medication was unclear but could be related to the false perception that they were of lower cardiac risk. The worse clinical status at presentation, lack of pre-existing hypertension and higher incidence of stroke among the SMuRF-less patients might lead to a poorer hemodynamics which precluded the use of beta-blockers or ACE-I or ARBs. Increased awareness of the paradoxical unfavorable outcome in SMuRF-less patients presenting with ACS should be widely promoted and early initiation of guideline-directed medical therapy among ACS patients remains crucial regardless of the cardiovascular risk factor status.
Our findings raise concerns regarding the unfavourable outcome in SMuRF-less patients presenting with ACS among the Asian population. Such patients are not uncommon and may present in an even worse clinical state than those with one or more standard cardiovascular risk factors. These ameliorate the general sense of complacency that significant coronary artery disease is an unlikely health concern in individuals without cardiovascular risk factors. Clinicians need to be aware of this unexplained paradoxical phenomenon, and effective lifestyle and pharmacological intervention need to be optimised in all patients regardless of their SMuRF status. Although lower than that reported in the West, the proportion of SMuRF-less patients in our Asian population remains sizeable indicating that this is a global phenomenon that warrant its due attention by all healthcare systems. More efforts are needed to understand the underlying pathophysiology of atherosclerotic cardiovascular risk factors in SMuRF-less patients, from the onset of atherosclerosis through to its progression and the occurrence of ACS, in order to identify such individuals so that appropriate and timely preventative intervention can be given. Currently, most published studies were limited to short-term outcomes and hence further studies are also needed in order to understand the long-term outcome of SMuRF-less patients with ACS.
Strengths and Limitations
This study is the first to examine the prognosis of SMuRF-less patients presenting with ACS in a large Asian cohort over a 10-year period. However, this study has its limitations. Firstly, this is a single-centre retrospective observational study which might be affected by unknown confounders and bias. Therefore, causality cannot be deduced from our results. However, such potential bias was mitigated by adjusting for important covariates in the multivariable models and using mortality as the primary study outcome. Secondly, the current method of categorizing patients into SMuRF and SMuRF-less groups might not be ideal, but it is the universal method used by all published studies, and based on local or international diagnostic threshold for each of the SMuRFs. Such thresholds are generally derived based on clinical evidence or expert consensus, and usually form the thresholds for guideline-directed treatment. Thirdly, some recognized atherosclerotic cardiovascular risk factors other than those universally considered as SMuRF are also beyond the scope for evaluation in this study. The retrospective nature of the study did not allow further evaluation of SMuRF-less patients for non-atherosclerotic cause of ACS such as protein C and S deficiency.