SMuRF-less ST-segment elevation myocardial infarction in contemporary Japanese practice: Clinical characteristics and prognostic implications from the Japan acute myocardial infarction registry

Abstract

Background

Standard modifiable cardiovascular risk factor (SMuRF)-less myocardial infarction, defined as the absence of diabetes, dyslipidemia, hypertension, and smoking, may have different clinical implications in East Asian patients because coronary pathophysiology and preventive treatment patterns differ from those in Western populations. We hypothesized that SMuRF-less ST-elevation myocardial infarction (STEMI) is associated with poorer outcomes despite contemporary primary percutaneous coronary intervention (PCI).

Methods

A total of 2310 STEMI patients (Male/Female: 1759/551; mean age: 67.2 years) from the Japan AMI Registry were stratified by SMuRF status and followed for one year. The primary endpoint was major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Results

Among eligible patients, 136 (5.9%) were SMuRF-less. Compared with SMuRF-positive patients, SMuRF-less patients were older, more often female, had lower body mass index, and a higher prevalence of atrial fibrillation. Despite similarly high primary PCI use, evidence-based secondary preventive therapies at discharge were less frequently prescribed in SMuRF-less patients. During a median follow-up of 358 days, MACE occurred more frequently in the SMuRF-less group (log-rank P < 0.01), and landmark analysis showed excess risk beyond the acute phase (log-rank P = 0.03). After adjustment for established prognostic factors, SMuRF-less status remained associated with unfavorable outcomes. A sex-stratified analysis suggested a more pronounced adverse association in men. An exploratory sex-stratified analysis suggested a more pronounced association in men.

Conclusions

In the contemporary primary PCI era, Japanese SMuRF-less STEMI patients represent a distinct high-risk phenotype characterized by lower implementation of secondary preventive therapies and poorer 1-year outcomes extending beyond the acute phase.

Highlights

• •SMuRF-less patients accounted for 5.9% of Japanese patients with STEMI.
• •Secondary prevention medications were less frequently prescribed in SMuRF-less patients.
• •SMuRF-less status was associated with unfavorable outcomes beyond the acute phase.
• •The absence of conventional risk factors should not imply low risk after STEMI.

1. Introduction

Prognosis for acute myocardial infarction (AMI) has improved substantially over recent decades owing to the widespread use of primary percutaneous coronary intervention (PCI) and advances in pharmacological therapy [1,2]. At the same time, prevention and risk stratification of AMI have been fundamentally based on standard modifiable cardiovascular risk factors (SMuRFs)—diabetes mellitus, dyslipidemia, hypertension, and smoking—which account for the majority of first myocardial infarction events and remain central therapeutic targets in contemporary cardiovascular medicine [3,4].

However, a clinically important subgroup of AMI patients presents without any of these conventional risk factors, referred to as SMuRF-less patients. This entity gained attention after large Western registries demonstrated that SMuRF-less patients may paradoxically experience worse short-term outcomes after first-presentation myocardial infarction despite the absence of established risk factors [5]. Subsequent studies from several countries extended these observations to broader coronary syndromes [6], although reported prognostic associations and sex-specific patterns remain inconsistent across registries.

Whether these findings are directly applicable to East Asian populations remains uncertain. Coronary pathophysiology, metabolic background, and preventive treatment patterns differ substantially between East Asian and Western populations, potentially modifying the clinical implications of SMuRF-less myocardial infarction. In addition, Japanese AMI populations include a relatively high proportion of older women, who often present with distinct clinical profiles and poorer outcomes than men, suggesting that sex-related prognostic implications of SMuRF-less STEMI may differ from those reported in Western cohorts. Prospective data evaluating long-term outcomes of SMuRF-less STEMI in contemporary East Asian practice remain limited.

Therefore, using the nationwide Japan AMI Registry (JAMIR), we sought to clarify the clinical characteristics and prognostic significance of SMuRF-less STEMI in Japanese patients treated in the contemporary primary PCI era, with particular attention to sex-related differences.

2. Methods

2.1. Study population

The JAMIR is a nationwide, multicenter, and prospective registry designed to enroll patients with AMI in Japan. The design of the JAMIR has been published previously [7]. In brief, consecutive patients presenting with spontaneous-onset AMI were recruited from 50 hospitals between December 2015 and May 2017. The diagnosis of AMI was based on the universal definition, with allowance for the MONICA criteria [8,9]. We excluded patients who were admitted to the hospital over 24 h after onset, with no recovery to spontaneous circulation on admission from out-of-hospital cardiopulmonary arrest, or who had AMI as a complication of PCI or coronary artery bypass grafting (CABG). Patient management, including the regimen of antiplatelet drugs, was at the treating physician's discretion. A follow-up study of patients was conducted 1 year after the onset of AMI based on the medical information available at each study site. Investigators, clinical research coordinators, or local data managers entered registration and follow-up data online. Finally, 3411 patients from 50 institutions in Japan were enrolled in the JAMIR study.

This study was conducted in accordance with the ethical guidelines for medical research on humans laid out in the Declaration of Helsinki. This research protocol was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center and local ethics committees or local institutional review board at each study site. Although informed consent was not obtained, because of the observational nature of this registry, details about the study were posted on a website and at the study sites (opt-out) to inform the subjects of the content and timeline of the study and to ensure that they had the opportunity to refuse inclusion in this registry. In addition, the research secretariat confirmed compliance with opt-out procedures at each study site. This study was registered with the Japanese UMIN Clinical Trials Registry (UMIN000019479).

2.2. Definitions of SMuRFs and their components

Patients with first-presentation ST-elevation myocardial infarction (STEMI), defined as no prior diagnosis or treatment for coronary artery disease, were classified according to the presence or absence of SMuRFs at baseline. SMuRFs were defined as hypertension, dyslipidemia, diabetes mellitus, or smoking based on clinical history, medication use, and established diagnostic criteria using admission measurements.

Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or current use of antihypertensive medication [10]. Dyslipidemia was defined as total cholesterol ≥220 mg/dL, low-density lipoprotein cholesterol ≥140 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, fasting triglycerides ≥150 mg/dL, or current use of lipid-lowering medication [11]. Diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL, random plasma glucose ≥200 mg/dL, HbA1c ≥ 6.5%, 2-h plasma glucose ≥200 mg/dL during a 75-g oral glucose tolerance test, or current use of antidiabetic medication [12]. Smoking was defined as current smoking or smoking within one year before registration. Patients without any of these four risk factors were classified as SMuRF-less. Laboratory-based definitions were based on admission measurements obtained before or during the index hospitalization.

Reduced LV function was defined as an LVEF <40%, based on echocardiographic assessment performed prior to hospital discharge.

2.3. Study endpoints

The primary endpoint of the present study was major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary endpoints were all-cause death within 1 year and major bleeding defined by Type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria [13].

2.4. Statistical analysis

Baseline continuous variables are presented as mean ± standard deviation (SD) or median and interquartile range (IQR) according to the distribution of the data. Categorical variables are presented as percentages of patients. T-test and the Mann-Whitney U test were used to compare continuous variables, and the χ 2 test was used to compare dichotomous variables. Both univariate and multivariate logistic regression models were utilized to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the identification of factors correlated with SMuRF-less STEMI. Through multivariate analysis, clinically relevant factors were selected as covariates and analyzed by the stepwise method. The cumulative incidence of the primary and secondary endpoints was evaluated using the Kaplan-Meier method, and differences were assessed using log-rank tests. We used landmark analysis to examine the impact of the presence or absence of SMuRF on the prognosis of STEMI patients in both the early phase (1-30 days) and the late phase (31-365 days). Hazard ratios (HRs) and 95% CIs for MACE were computed using both univariate and multivariate Cox proportional hazard models. Covariates in the multivariable models included SMuRF status, fundamental background variables and well-established prognostic factors for patients with AMI [14]. Multicollinearity among the covariates included in the multivariable model was assessed using the variance inflation factor (VIF). As a sensitivity analysis, 1:1 propensity score matching was performed to assess the robustness of the association between SMuRF status and clinical outcomes. As an additional sensitivity analysis, the association between SMuRF status and clinical outcomes was evaluated in patients who underwent primary PCI.

All statistical analyses were conducted using STATA software. Two-sided p-values < 0.05 were considered statistically significant.

3. Results

3.1. Clinical profile of patients with SMuRF-less STEMI

Among 2310 eligible patients with STEMI and no prior history of coronary artery disease, 136 (5.9%) were classified as SMuRF-less (Fig. S1). Baseline characteristics are summarized in Table 1. Compared with SMuRF-positive patients, those with SMuRF-less STEMI were older (72.2 ± 14.9 vs 66.9 ± 13.2 years, P < 0.01), more frequently female (37.5% vs 23.0%, P < 0.01), and had lower BMI (22.0 ± 3.8 vs 24.0 ± 3.9 kg/m², P < 0.01). They also more frequently presented with atrial fibrillation (11.0% vs 5.4%, P < 0.01) and symptomatic heart failure (Killip class II/III: 21.3% vs 13.2%, P < 0.01). Angiographic and procedural characteristics are shown in Table 1. SMuRF-less patients more frequently had no diseased vessel identified (3.8% vs 1.2%, P < 0.01) or an unidentified culprit lesion (2.2% vs 0.5%, P = 0.01). Although primary PCI was performed in most patients, its use tended to be lower in the SMuRF-less group (93.4% vs 97.4%), together with lower use of drug-eluting stents (83.9% vs 91.7%, P < 0.01). Patients classified as having zero diseased vessels did not undergo PCI. A total of 43 patients underwent CABG during the index hospitalization. Importantly, onset-to-device time was longer in SMuRF-less patients (342.0 ± 292 vs 323.1 ± 304 min, P = 0.04), and left ventricular rupture occurred more frequently (2.9% vs 1.0%, P = 0.04). At discharge, they were also less likely to receive guideline-directed medical therapies, including antiplatelet agents, renin–angiotensin system inhibitors, and statins.

Table 1.

Baseline patient characteristics.

	Over all (n = 2310)	SMuRF-less (n = 136)	SMuRF-positive (n = 2174)	P value
Age, years	67.2 ± 13.4	72.2 ± 14.9	66.9 ± 13.2	<0.01
Women, %	23.9	37.5	23.0	<0.01
BMI, kg/m2	23.9 ± 3.9	22.0 ± 3.8	24.0 ± 3.9	<0.01
Use of ambulance, %	86.9	83.1	87.1	0.18
Onset to Admission time, min	239.2 ± 280	244.5 ± 283	238.9 ± 280	0.32
Onset to device time, min (※)	324.1 ± 303	342.0 ± 292	323.1 ± 304	0.04
Killip I, %	76.4	66.9	77.0	<0.01
Killip II, %	8.4	14.0	8.0	0.02
Killip III, %	5.3	7.3	5.2	0.28
Killip IV, %	9.9	11.8	9.8	0.47
HTN, %	68.4	0	72.7	N.A
DM, %	31.8	0	33.8	N.A
DLP, %	67.4	0	71.6	N.A
Previous cerebrovascular disease, %	8.7	7.4	8.8	0.57
PAD, %	1.8	1.5	1.8	0.78
Malignancy, %	7.9	11.0	7.7	0.16
AF, %	5.8	11.0	5.4	<0.01
Smoking, %	42.1	0	44.7	N.A
Systolic blood pressure, mmHg	137.2 ± 32.2	128.2 ± 31.8	137.8 ± 32.2	<0.01
Heart rate, bpm	78.1 ± 21.3	75.0 ± 21.0	78.3 ± 21.3	0.09
eGFR, mL/min/1.73m2	66.6 ± 25.4	65.9 ± 26.0	66.6 ± 25.4	0.75
eGFR≦30 mL/min/1.73m2, %	6.5	5.9	6.5	0.77
Labo/TTE data
Hb, g/dL	13.9 ± 2.2	13.1 ± 2.2	14.0 ± 2.2	<0.01
LDL, mg/dL	123.5 ± 38.2	109.8 ± 28.7	124.3 ± 38.5	<0.01
CK, U/L	2916 ± 2911	2735 ± 2639	2927 ± 2928	0.46
CK ≧ 3,000, %	36.3	33.8	36.5	0.53
CK-MB, U/L	267.9 ± 266	266.3 ± 251	267.9 ± 267	0.95
EF, %	51.2 ± 12.1	50.1 ± 12.3	51.2 ± 12.1	0.36
EF ≦ 40%, %	15.2	16.9	15.1	0.57
Medication at discharge
Aspirin, %	97.9	91.2	98.3	<0.01
DAPT, %	95.4	86.0	96.0	<0.01
ACEI, %	54.8	48.5	55.2	0.13
ARB, %	25.0	17.7	25.4	0.04
ACEI/ARB, %	76.2	64.0	77.0	<0.01
βblocker, %	65.5	58.1	65.9	0.06
Statin, %	89.9	74.3	90.9	<0.01
OAC, %	12.6	17.7	12.3	0.07
The angiographic and interventional characteristics
Emergent CAG, %	98.8	97.8	98.9	0.25
Primary PCI, %	96.1	93.2	96.3	0.07
Thrombolysis, %	0.4	0.8	0.4	0.57
Concomitant PCI in no culprit lesion, %	5.3	4.5	5.3	0.69
DES, %	91.3	83.9	91.7	<0.01
Culprit lesion, %
LMT	1.5	2.2	1.5	0.50
LAD	49.8	47.1	50.0	0.51
LCx	10.9	11.8	10.8	0.73
RCA	38.9	38.2	38.9	0.88
Unknown	0.6	2.2	0.5	0.01
Final TIMI flow, %
0	2.1	2.3	2.1	0.86
1	1.7	0.7	1.7
2	6.3	6.8	6.3
3	89.9	90.2	89.9
Number of diseased vessel, %
0	1.3	3.8	1.2	0.04
1	58.4	60.9	58.2
2	25.1	19.5	25.4
3	15.2	15.8	15.2
Multivessel disease, %	40.3	35.3	40.6	0.23
IABP, %	13.6	14.7	13.6	0.71
PCPS, %	2.2	2.9	2.2	0.55
CABG, %	1.9	2.2	1.8	0.76
Complication, %
LV rupture (Blow out)	0.6	1.5	0.51	0.15
LV rupture (Oozing)	0.6	1.5	0.51	0.15
LV rupture (Total)	1.1	2.9	1.0	0.04
VSP	0.4	0	0.41	0.45

(※) This variable was analyzed only among patients who underwent primary PCI (Overall: n = 2,195, SMuRF-less: n = 124, SMuRF-positive: n = 2071).

ACEI = angiotensin-converting enzyme inhibitor, AF = Atrial Fibrillation, ARB = angiotensin II receptor blocker, BMI = body mass index, CAG = coronary artery angiography, CABG = coronary artery bypass grafting, CK = Creatin kinase, DAPT = dual antiplatelet therapy, DES = Drug-Eluting Stent, DLP = Dyslipidemia, DM = Diabetes Mellitus, EF = Ejection Fraction, eGFR = estimated Glomerular Filtration Rate, Hb = Hemogrobin, HTN = Hypertension, IABP = intra-aortic balloon pumping, LAD = Left Anterior Descending artery, LCx = Left Circumflex artery, LDL = Low-dense Lipoprotein Cholesterol, LMT = Left Main Trunk, OAC = Oral Anticoagulation drug, PAD = Peripheral Artery Disease, PCI = Percutaneous Coronary Intervention, PCPS = Percutaneous Cardiopulmonary Support, RCA = Right Coronary Artery, TIMI = Thrombolysis In Myocardial Infarction, TTE = Transthoracic echocardiography, VSP = Ventricular Septal Perforation.

In multivariable logistic regression analysis, female sex (OR 1.79, 95% CI 1.20–2.70), atrial fibrillation (OR 1.85, 95% CI 1.02–3.45), and lower BMI (OR 0.89, 95% CI 0.83–0.94) were independently associated with SMuRF-less STEMI (Table S1). A significant interaction by sex was observed for atrial fibrillation (P for interaction = 0.02).

3.2. Clinical outcomes of SMuRF-less STEMI

Clinical outcomes are summarized in Table 2. During a median follow-up of 358 days, SMuRF-less patients experienced higher incidences of MACE and all-cause death than SMuRF-positive patients (Fig. 1A and C).

Table 2.

In-hospital and one-year clinical outcomes.

	In-hospital outcomes			One-year outcomes
	SMuRF-less (n = 136)	SMuRF-positive (n = 2174)	P value	SMuRF-less (n = 136)	SMuRF-positive (n = 2174)	P value
MACE, n (%)	18 (13.2)	113 (5.2)	<0.01	23 (16.9)	161 (7.4)	<0.01
Non-fatal MI, n (%)	3 (2.2)	21 (1.0)	0.17	6 (4.4)	51 (2.4)	0.13
Stent thrombus, n (%)	0 (0)	14 (0.6)	0.35	1 (0.7)	19 (0.9)	0.87
All-cause death, n (%)	19 (14.0)	116 (5.3)	<0.01	26 (19.1)	161 (7.4)	<0.01
BARC 3/5, n (%)	9 (6.6)	80 (3.7)	0.08	9 (6.6)	114 (5.2)	0.49

BARC = Bleeding Academic Research Consortium.

Fig. 1.

Kaplan–Meier curves for 1-year clinical outcomes according to SMuRF status. Kaplan–Meier curves comparing 1-year clinical outcomes between patients with and without SMuRFs: (A) major adverse cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction, and ischemic stroke), (C) all-cause death. Thirty-day landmark analysis comparing clinical outcomes between patients with and without SMuRFs: (B) major adverse cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction, and ischemic stroke) and (D) all-cause death. BARC, Bleeding Academic Research Consortium; MACE, major adverse cardiovascular events; SMuRFs, standard modifiable cardiovascular risk factors.

To clarify the temporal pattern of excess risk, landmark analysis was performed by separating the acute (0–30 days) and late (31–365 days) phases after myocardial infarction. Within 30 days, MACE occurred more frequently in SMuRF-less patients than in SMuRF-positive patients (9.2% vs 4.1%, log-rank P < 0.01), and this difference persisted during days 31–365 (6.7% vs 2.6%, log-rank P < 0.05) (Fig. 1B). Similarly, all-cause death remained consistently higher in the SMuRF-less group during both the acute and late phases (both log-rank P ≤ 0.01) (Fig. 1D).

In multivariable Cox regression analysis, SMuRF-less status remained independently associated with MACE after adjustment for established prognostic factors, including age, reduced left ventricular function, peak CPK, renal dysfunction, and heart failure at admission (Table 3). All VIF values were <2, indicating no substantial multicollinearity among the covariates in the multivariable model.

Table 3.

Cox regression analysis for predictors of MACE.

Variable	Univariable adjusted HR[95%CI]	P value	Multivariable adjusted HR[95%CI]	P value
Overall
SMuRF-less	2.38[1.47 – 3.85]	<0.01	2.00[1.22 – 3.23]	<0.01
Age (≧Median: 68 years)	2.64[1.87 – 3.74]	<0.01	2.21[1.53 – 3.18]	<0.01
LVEF≦ 40%	2.76[1.97 – 3.86]	<0.01	1.59[1.11 – 2.26]	0.01
Max CK value ≧ 3000 U/L	1.72[1.26 – 2.35]	<0.01	1.50[1.09 – 2.08]	0.01
eGFR≦ 30 mL/kg/1.73m2	5.01[3.41 – 7.36]	<0.01	3.01[2.01 – 4.50]	<0.01
Killip≧2	4.54[3.32 – 6.21]	<0.01	2.94[2.09 – 4.13]	<0.01
AF	1.84[1.08 – 3.13]	0.03	1.14[0.66 – 1.96]	0.64
Sex (Female)	1.23[0.87 – 1.75]	0.25	0.90[0.62 – 1.30]	0.57
Male
SMuRF-less	3.03[1.75 – 5.26]	<0.01	2.44[1.35 – 4.35]	<0.01
Age (≧Median: 68 years)	2.78[1.88 – 4.09]	<0.01	2.25[1.51 – 3.35]	<0.01
LVEF≦ 40%	2.69[1.81 – 3.99]	<0.01	1.61[1.06 – 2.44]	0.03
Max CK value ≧ 3000 U/L	1.58[1.10 – 2.28]	0.01	1.39[0.95 – 2.02]	0.09
eGFR≦ 30 mL/kg/1.73m2	5.16[3.21 – 8.29]	<0.01	3.11[1.90 – 5.11]	<0.01
Killip≧2	4.30[2.98 – 6.20]	<0.01	2.82[1.90 – 4.20]	<0.01
Female
SMuRF-less	1.28[0.51 – 3.23]	0.59	1.27[0.49 – 3.33]	0.62
Age (≧Median: 68 years)	2.20[0.93 – 5.22]	0.07	1.91[0.79 – 4.61]	0.15
LVEF≦ 40%	3.07[1.60 – 5.90]	<0.01	1.59[0.80 – 3.16]	0.19
Max CK value ≧ 3000 U/L	2.55[1.40 – 4.67]	<0.01	1.94[1.04 – 3.62]	0.04
eGFR≦ 30 mL/kg/1.73m2	4.50[2.31 – 8.78]	<0.01	2.76[1.35 – 5.63]	<0.01
Killip≧2	5.19[2.79 – 9.64]	<0.01	3.21[1.63 – 6.34]	<0.01

In a sensitivity analysis using propensity score matching, 99 SMuRF-less patients were matched with 99 SMuRF-positive patients, with adequate covariate balance. Standard mean differences of covariates after propensity score matching were shown in Table S2. The risk of MACE was numerically higher in SMuRF-less patients, although the difference was not statistically significant (HR 1.49; 95% CI 0.64–3.48, P = 0.36). In the sensitivity analysis restricted to patients who underwent primary PCI, the association between SMuRF status and clinical outcomes was generally consistent with that observed in the overall cohort (Table S3).

3.3. Sex-specific prognostic impact of SMuRF-less status

Kaplan–Meier analysis stratified by sex demonstrated significant heterogeneity in prognosis. Among men, SMuRF-less status was associated with a significantly higher incidence of MACE (log-rank P < 0.01), whereas no significant difference was observed among women (log-rank P = 0.59) (Fig. S2A and S2B). Consistently, sex-stratified multivariable Cox analysis identified SMuRF-less status as an independent predictor of MACE only in men (Table 3).

4. Discussion

In this contemporary nationwide STEMI registry of JAMIR, the absence of SMuRFs identified a clinically distinct and prognostically vulnerable subgroup despite widespread use of guideline-based reperfusion therapy. SMuRF-less STEMI accounted for 5.9% of Japanese patients and was characterized by older age, lower BMI, more frequent atrial fibrillation, and a higher proportion of women. Importantly, excess mortality and cardiovascular events emerged early after STEMI and persisted during 1-year follow-up, with SMuRF-less status remaining independently associated with adverse outcomes after multivariable adjustment. Importantly, this prognostic disadvantage was predominantly observed in men, suggesting sex-specific heterogeneity in the clinical implications of SMuRF-less STEMI.

4.1. Prevalence and clinical significance of SMuRF-less STEMI in Japan

The present nationwide prospective registry demonstrates that SMuRF-less STEMI represents a relatively small but clinically important subgroup in contemporary Japanese practice, accounting for 5.9% of first-presentation STEMI cases in JAMIR. Although this prevalence is lower than that reported in international cohorts [5], it is consistent with previous Japanese registries, including the CREDO-Kyoto Registry and JCD-KiCS, in which the prevalence ranged from 3.2% to 6.8% [15], [16]. Importantly, unlike these earlier Japanese reports, the present study further shows that the prognostic disadvantage associated with SMuRF-less status persists beyond the acute phase and remains evident during 1-year follow-up.

Differences in patient selection and SMuRF definitions may partly explain discrepancies across studies. Because prior coronary artery disease was excluded and risk factors were assessed using contemporary diagnostic criteria in the present cohort, the current analysis may more specifically identify patients truly lacking recognized standard modifiable cardiovascular risk factors at first STEMI presentation. This methodological distinction strengthens the interpretation that SMuRF-less status represents a clinically distinct phenotype in contemporary Japanese practice.

4.2. Mechanisms underlying persistent excess risk in SMuRF-less STEMI

A major finding of the present study is that SMuRF-less STEMI was associated with excess adverse events not only during the acute phase but also throughout 1-year follow-up, despite contemporary primary PCI-based treatment. This indicates that the absence of conventional cardiovascular risk factors does not necessarily imply biological resilience once STEMI occurs.

The mechanisms underlying this persistent excess risk are likely multifactorial. In the acute phase, SMuRF-less patients presented with a clinically vulnerable profile characterized by older age, lower BMI, more frequent atrial fibrillation, and a higher prevalence of heart failure at admission. Although infarct-related angiographic findings and left ventricular systolic function were broadly comparable between groups, the higher incidence of left ventricular rupture suggests that reduced structural reserve or increased myocardial fragility may contribute to early mortality in this subgroup. Because left ventricular rupture remains strongly associated with advanced age and frailty after myocardial infarction [17], this complication may partly explain the disproportionate early hazard observed in SMuRF-less patients.

Beyond acute vulnerability, the present findings suggest that non-atherosclerotic mechanisms may also contribute to persistent excess risk in SMuRF-less STEMI. Atrial fibrillation was markedly more frequent in SMuRF-less patients, while culprit lesions were more often angiographically unclear and stent implantation less frequently required, together suggesting that embolic or non-plaque-mediated mechanisms may account for a subset of events. This interpretation is supported by prior evidence showing that atrial fibrillation independently increases myocardial infarction risk [18], and that coronary embolism is commonly associated with fewer conventional cardiovascular risk factors and worse clinical outcomes [19]. Although direct mechanistic confirmation was not available in the present registry, these observations support the possibility that heterogeneous pathophysiological substrates underlie part of the excess risk observed in SMuRF-less STEMI.

Secondary prevention after discharge may represent an important modifiable contributor to long-term prognosis. An additional consideration is the lower use of evidence-based secondary prevention therapies among SMuRF-less patients. Despite their higher subsequent risk, SMuRF-less patients were less likely to receive statins, antiplatelet agents, and renin–angiotensin system inhibitors at discharge. Previous studies have reported lower prescription rates and medication adherence among patients with myocardial infarction without conventional major coronary risk factors [20], raising the possibility that the absence of recognized risk factors may lead to underestimation of cardiovascular risk and less intensive secondary prevention. Although the present registry cannot determine whether such differences resulted from clinical inertia or other clinical considerations, the absence of SMuRFs should not be interpreted as an indication of low risk after STEMI.

4.3. Exploratory sex-stratified findings

An additional finding of interest was that the association between SMuRF-less status and adverse outcomes appeared more pronounced in men, despite women being more frequently represented in the SMuRF-less group. This observation differs from prior international reports in which worse outcomes were emphasized among SMuRF-less women [5]. However, the formal interaction between SMuRF status and sex was not statistically significant (P for interaction = 0.33) (Table S4). Therefore, given the limited number of SMuRF-less patients, particularly after stratification by sex, these findings should be interpreted as exploratory and hypothesis-generating rather than as definitive evidence of sex-specific effect modification.

4.4. Limitations

Several limitations of the present study should be acknowledged. First, because this was an observational registry analysis, causal relationships cannot be established, and residual confounding may remain despite multivariable adjustment. In particular, although major prognostic factors were adjusted for, differences related to age, frailty, and unmeasured comorbidities may have influenced the observed association between SMuRF-less status and outcomes. Second, misclassification of SMuRF status is possible. Smoking was defined as current smoking or smoking cessation within one year before registration; therefore, patients with more remote smoking exposure may have been classified as SMuRF-less. In addition, Detailed lipid profiles prior to the index STEMI were not available, and dyslipidemia was defined according to the criteria applicable at the time of registry enrollment, which may not fully correspond to current diagnostic standards. Furthermore, the absence of clinically recognized dyslipidemia at admission does not necessarily indicate the absence of lifetime exposure to atherogenic lipoproteins. Consequently, the classification of SMuRF-less status in the present study may not fully capture lifetime lipid-related cardiovascular risk. Some patients classified as SMuRF-less may have had prolonged, unrecognized exposure to elevated LDL-C levels, given the well-established association between cumulative cholesterol exposure and the development of coronary artery disease [21].Moreover,laboratory-based definitions of hypertension, dyslipidemia, and diabetes relied partly on admission measurements obtained during the acute phase of STEMI, which may have been influenced by the acute event itself. Third, the registry lacked detailed mechanistic information, including data on in-hospital arrhythmic burden, non-atherosclerotic causes of myocardial infarction, medication adherence after discharge, and inflammatory biomarkers such as high-sensitivity C-reactive protein. As a result, the proposed contributions of atrial fibrillation, coronary embolism, and treatment adherence to prognosis remain hypothesis-generating. Fourth, because the JAMIR registry was originally designed to evaluate antiplatelet therapy after PCI, patients in whom PCI was not attempted or considered unsuitable may have been underrepresented. This may have introduced selection bias, particularly among frail patients or those with severe complications. Fifth, the potential impact of differences in secondary prevention therapy should be considered. The lower use of evidence-based secondary prevention therapies may have contributed to the unfavorable long-term outcomes observed in SMuRF-less patients. Although under-recognition of cardiovascular risk and clinical inertia may be possible explanations, the present registry did not collect information on physicians’ risk perceptions, reasons for treatment decisions, or medication adherence after discharge. Therefore, the contribution of undertreatment to the observed adverse outcomes remains uncertain, and a causal relationship cannot be established. Finally, although the overall cohort was nationally representative, the number of SMuRF-less patients remained relatively small, which may have limited statistical power in subgroup analyses, particularly those stratified by sex. Therefore, the sex-stratified findings should be considered exploratory and hypothesis-generating and require confirmation in larger populations.

5. Conclusion

In this nationwide contemporary STEMI registry in Japan, SMuRF-less status identified a clinically vulnerable subgroup with persistent excess risk during both acute and late follow-up despite contemporary primary PCI-based management. These findings indicate that the absence of conventional cardiovascular risk factors should not be regarded as low risk after STEMI and support rigorous secondary prevention irrespective of baseline SMuRF status.

CRediT authorship contribution statement

Keima Wayama: Writing – original draft, Resources, Methodology, Investigation, Formal analysis, Data curation. Jun Takahashi: Writing – review & editing, Supervision, Methodology. Satoshi Honda: Supervision. Kensaku Nishihira: Supervision. Sunao Kojima: Supervision. Misa Takegami: Supervision, Data curation. Jun Yamashita: Supervision. Mike Saji: Supervision. Kohei Wakabayashi: Supervision. Kiyoshi Hibi: Supervision. Morimasa Takayama: Supervision. Tetsuya Sumiyoshi: Supervision. Hisao Ogawa: Supervision. Satoshi Yasuda: Writing – review & editing, Supervision, Project administration, Conceptualization.

Data availability

Data sharing is not applicable to this article because it could compromise the privacy of research participants.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Figure S1. Flow diagram of the study population. Patient selection for the present analysis from the JAMIR cohort. Of 3411 patients enrolled in JAMIR, 2310 patients with first-presentation STEMI were included after exclusion of patients with prior coronary artery disease and NSTEMI. Patients were subsequently stratified according to SMuRF status and sex. AMI, acute myocardial infarction; CAD, coronary artery disease; JAMIR, Japan Acute Myocardial Infarction Registry; NSTEMI, non-ST-segment elevation myocardial infarction; SMuRFs, standard modifiable cardiovascular risk factors; STEMI, ST-segment elevation myocardial infarction.

Figure S2. Kaplan–Meier curves for 1-year major adverse cardiovascular events according to sex and SMuRF status. Kaplan–Meier curves for 1-year major adverse cardiovascular events (MACE): (A) stratified by SMuRF status in men, and (B) stratified by SMuRF status in women. MACE, major adverse cardiovascular events; SMuRFs, standard modifiable cardiovascular risk factors Multimedia component 2