Non-traditional risk factors for myocardial infarction in adults under forty: A systematic review of emerging trends

Table 1 Study characteristics and participant demographics

Ref.	Country	Study design	Sample size	Age range	Sex distribution	Comorbidities	MI classification
Krittanawong et al[18], 2020	United States	Retrospective cohort (NIS)	5764755 (< 55 years), 1149185 AMI	< 55 (mean 45.1 AMI)	66.6% men, 33.4% women (AMI)	Obesity, smoking, HTN, diabetes, HIV, SLE, OSA, RA	STEMI, NSTEMI
Zhu et al[19], 2024	United States	Prospective cohort (VIRGO)	2979	18-55 (median 48)	67.2% women, 32.8% men	HTN, diabetes, obesity, smoking, alcohol abuse, prior CVD, COPD	STEMI, NSTEMI, EF < 40%
Dreyer et al[20], 2021	United States	Prospective cohort (VIRGO)	2979	18-55 (mean 47.1)	67.4% women, 32.6% men	HTN, diabetes, obesity, smoking, prior AMI, COPD	STEMI, NSTEMI
Gupta et al[21], 2020	India	Case-control	154 (77 MI, 77 controls)	18-45 (mean 35.3 MI)	65 men/12 women (MI), 58 men/19 women (controls)	Excluded smokers, diabetics, BMI > 35	AWMI, IWMI, LWMI
Cho et al[22], 2019	South Korea	Population-based cohort	2705090	20 + (stratified)	Not split, large population	HTN, diabetes, hypercholesterolemia, SES, depression	AMI (ICD-10)
Fan et al[23], 2019	China	Prospective cohort	804	18-85 (mean 57.5)	82.6% men	HTN, diabetes, hyperlipidemia, prior MI/PCI, smoking	ACS (STEMI/NSTEMI/UA)
Smolderen et al[24], 2015	United States, Spain, Australia	Cohort (VIRGO)	3572	18-55 (median 48)	67.1% women, 32.9% men	HTN, diabetes, obesity, smoking, hypercholesterolemia, prior AMI, CHF	STEMI, NSTEMI
Turati et al[25], 2015	Italy	Case-control	760 cases, 682 controls	19-79 (median 61 MI)	76.3% men (MI)	HTN, diabetes, hyperlipidemia, BMI	Non-fatal AMI
Orth-Gomér et al[26], 1986	Sweden	Case-control	210 (89 MI, 121 controls)	18-45 (mean 39.5)	89 men (MI), 121 men (controls)	HTN, diabetes, hyperlipidemia, smoking	MI (survivors < 45)
Zhao et al[27], 2023	China	Cross-sectional	8103	18-99 (mean 50.3)	53.5% women, 46.5% men	HTN, diabetes, obesity	Not MI-specific
Head et al[28], 2019	United States	Cross-sectional autopsy (PDAY)	2651	15-34 (mean 24.8)	75% men, 25% women	Excluded major comorbidities	Subclinical atherosclerosis
Lu et al[29], 2022	United States	Case-control (VIRGO/NHANES)	2264 AMI, 2264 controls	18-55 (median 48)	68.9% women, 31.1% men	HTN, diabetes, hypercholesterolemia, obesity, depression, low income, family history	STEMI, NSTEMI, type 1
Jariwala et al[30], 2022	India	Retrospective, multicenter	3656 (< 45 years PCI)	< 45 (mean men 37.4, women 41.1)	69.2% men, 30.8% women	HTN, diabetes, overweight, dyslipidemia, family history, smoking, alcoholism	ACS (STEMI/NSTEMI/UA)

NIS: National inpatient sample; VIRGO: Variation in recovery: Role of gender on outcomes of young AMI patients (a major multinational study); PDAY: Pathobiological determinants of atherosclerosis in youth (study); NHANES: National Health and Nutrition Examination Survey; MI: Myocardial infarction; HTN: Hypertension; HIV: Human immunodeficiency virus; SLE: Systemic lupus erythematosus; OSA: Obstructive sleep apnea; RA: Rheumatoid arthritis; STEMI: ST-elevation myocardial infarction; NSTEMI: Non-ST-elevation myocardial infarction; CVD: Cardiovascular disease; COPD: Chronic obstructive pulmonary disease; EF: Ejection fraction; AMI: Acute myocardial infarction; BMI: Body mass index; AWMI: Anterior wall myocardial infarction; IWMI: Inferior wall myocardial infarction; LWMI: Lateral wall myocardial infarction; PCI: Percutaneous coronary intervention; ACS: Acute coronary syndrome; UA: Unstable angina.

Table 2 Exposure details and outcomes

Study ID	Non-traditional risk factors assessed	Measurement methods	Outcome measures	Effect estimates (OR/HR/RR with 95%CI)	Covariates adjusted for
1	HIV, SLE, OSA, RA	ICD-9 codes (NIS)	AMI risk	HIV: OR = 4.06 (3.48-4.71); SLE: OR = 2.12 (1.89-2.39); OSA: OR = 1.16 (1.12-1.20); RA: OR = 0.83 (0.76-0.89)	Age, sex, race, BMI, DM, HTN, HLD, CKD, smoking
2	Marital/partner status, depression, social support, stress	Structured interview, PHQ-9, Social Support Inventory, Perceived Stress Scale	1-year all-cause readmission	HR = 1.31 (1.15-1.49) unpartnered vs partnered; adjusted HRs for demo/SES/clinical/psychosocial	Age, sex, race, SES, clinical, psychosocial
3	Depression, social support, stress, SES	PHQ-9, Social Support Inventory, PSS, SES data	1-year all-cause readmission	HR = 1.28 (1.15-1.42) unpartnered vs partnered; adjusted HRs	Age, sex, race, MI severity, comorbidities, psychosocial
4	Telomere length (biological aging)	qPCR for telomere length	Telomere length in MI vs controls	Mean T/S ratio MI 0.115 vs controls 0.792 (P < 0.0001); shorter in MI	Age, gender, BMI
5	Socioeconomic status, depression	Insurance premium, ICD-10 codes	AMI incidence	HR low SES vs high 1.16 (1.14-1.19); HR depression vs none 126 (1.21-1.31)	Age, sex, comorbidities
6	OSA	Polygraphy (AHI ≥15)	MACCE, unstable angina	HR = 1.55 (0.94-2.57) MACCE; HR = 3.87 (1.20-12.46) MACCE after 1 years	Age, sex, BMI, HTN, diabetes, prior MI/PCI
7	Depression, psychosocial stress	PHQ-9, PSS, interview	Prevalence of depressive symptoms at AMI	Women: 39% PHQ-9 ≥ 10, men: 22%; adjusted OR for women 1.64 (1.36-1.98)	Age, sex, SES, comorbidities
8	Mediterranean diet adherence	Food Frequency Questionnaire, MDS	Non-fatal AMI	MDS ≥ 6: OR = 0.55 (0.40-0.75); per point: OR = 0.91 (0.85-0.98)	Age, sex, BMI, HTN, diabetes
9	Type A behavior, psychosocial work, education	Jenkins Activity Survey, work environment survey	MI risk, variance explained	Work monotony/poor discretion 5% variance; type A 2%; education NS	Age, sex, education
10	Sleep duration	Self-report, AHA CVH score	Ideal CVH, BP, glucose, cholesterol	≤ 6 hours sleep: OR = 1.38 (1.15-1.67) for non-ideal CVH	Age, sex, BMI, comorbidities
11	Unexplained (likely non-traditional) risk	Autopsy, lesion quantification	Subclinical atherosclerosis	OR high-growth group per year age: 1.125 (1.063-1.190)	Age, cholesterol, BMI, HbA1c, CRP
12	Depression, low income, family history	PHQ-9, interview, lab, SES	First AMI, PAFs	Women: Depression OR = 3.09 (2.37-4.04); low income OR = 1.79 (1.28-2.50)	Age, sex, SES, comorbidities
				Men: Depression OR = 1.77 (1.15-2.73)
13	Hypothyroidism, CTD, RHD, takayasu, SCAD, OCP use	Medical record, interview, labs	Prevalence, in-hospital outcomes	Non-traditional RFs rare; no adjusted effect estimates; in-hospital mortality 1.77%-2%	Age, sex

OR: Odds ratio; HR: Hazard ratio; RR: Relative risk; CI: Confidence interval; HIV: Human immunodeficiency virus; SLE: Systemic lupus erythematosus; OSA: Obstructive sleep apnea; RA: Rheumatoid arthritis; BMI: Body mass index; DM: Diabetes mellitus; HTN: Hypertension; PHQ-9: Patient Health Questionnaire-9; SES: Socioeconomic status; MACCE: Major adverse cardiovascular/cerebrovascular event; MDS: Mediterranean Diet Score; CVH: Cardiovascular health; CTD: Connective tissue disorder; RHD: Rheumatic heart disease; SCAD: Spontaneous coronary artery dissection; OCP: Oral contraceptive pill; PAF: Population attributable fraction; PSS: Perceived Stress Scale; HLD: Hyperlipidemia; CKD: Chronic kidney disease; MI: Myocardial infarction; qPCR: Quantitative polymerase chain reaction; ICD-10: International classification of diseases, 10^th revision; AMI: Acute myocardial infarction; PCI: Percutaneous coronary intervention; SES: Socioeconomic status; NS: Not significant; AHA: American Heart Association; BP: Blood pressure; HbA1c: Hemoglobin A1c; CRP: C-reactive protein; RFs: Risk factors.

Table 3 Summary table of evidence strength

Risk factor category	Number of studies	Direction of association	Effect estimates (range)	Strength of evidence
Depression/psychosocial	5	Positive (risk ↑)	OR = 1.64-3.09, HR = 1.28-1.31	Strong
Low socioeconomic status	3	Positive (risk ↑)	HR = 1.16-1.47	Moderate
Autoimmune (HIV, SLE)	2	Strong positive (risk ↑)	OR = 2.12-4.06	Strong
Rheumatoid arthritis	1	Negative (risk ↓)	OR = 0.83	Emerging
Telomere length	1	Positive (risk ↑, shorter TL)	T/S ratio 0.115 vs 0.792	Emerging
Obstructive sleep apnea	1	Positive (risk ↑)	HR = 1.55-3.87	Moderate
Mediterranean diet	1	Negative (risk ↓)	OR = 0.55	Moderate
Short sleep duration	1	Positive (risk ↑) (CV health)	OR = 1.38	Emerging
Occupational stress	1	Positive (risk ↑)	5% variance explained	Emerging

Strength of evidence: Strong factors show consistent findings in multiple large studies; moderate factors show consistent findings in ≥ 2 studies or 1 large study; emerging factors show single or small studies, or inconsistent results. OR: Odds ratio; HR: Hazard ratio; HIV: Human immunodeficiency virus; SLE: Systemic lupus erythematosus; TL: Telomere length; T/S: Telomere-to-single-copy gene ratio; CV: Cardiovascular.

Table 4 Subgroup and sensitivity analyses

Study ID	Subgroup (e.g., sex, age, region)	Effect estimates (OR/HR/RR with 95%CI)	Notes
1	Age (< 40 vs 40-55), sex	HIV: OR = 4.06 (3.48-4.71); SLE: OR = 2.12 (1.89-2.39); OSA: OR = 1.16 (1.12-1.20) for MI risk in young adults	No stratified data < 40; large administrative database; cross-sectional analysis of hospitalizations
2	Sex (women vs men), marital status (unpartnered vs partnered)	HR = 1.31 (1.15-1.49) unpartnered vs partnered for 1-year readmission; unpartnered women: 37.6% readmission vs unpartnered men: 26.8%	No significant sex-marital status interaction (P = 0.69); effect attenuated after psychosocial adjustment
3	Sex, marital status	HR = 1.28 (1.15-1.42) unpartnered vs partnered for 1-year readmission; unpartnered women had highest readmission	Significant sex-marital status interaction; psychosocial factors partially mediate risk
4	Age group (18-30 vs 31-45), sex	Telomere length shorter in MI patients aged 31-45 vs controls (P < 0.05); females with MI had shorter telomeres than female controls (P < 0.01)	No longitudinal MI risk data; small sample; case-control design
5	SES and depression combined	HR = 1.47 (1.36-1.60) for low SES + depression vs high SES, no depression (AMI risk)	Large population; no stratification < 40; depression by ICD codes; median 11.6 years follow-up
6	Time (≤ 1 year vs > 1 year), OSA status	HR for MACCE after 1 year in OSA: 3.87 (1.20-12.46); overall HR = 1.55 (0.94-2.57) for OSA vs non-OSA	Mean age 575; not exclusive to young adults; median 1-year follow-up
7	Sex (women vs men)	Adjusted OR for depressive symptoms at AMI: 1.64 (1.36-1.98) women vs men	Data collected at AMI admission only; no MI risk prediction; age up to 55; no follow-up
8	BMI (< 25 vs ≥ 25), hypertension status	Stronger inverse association of mediterranean diet with AMI in BMI < 25 and normotensive individuals	Case-control; median age 61; not restricted to young adults; no follow-up
9	Education level, sex	Men with high education had higher type A and work strain; women with low education had more type A behavior	Small sample; only men in main analysis; older data; case-control; no follow-up
10	Sleep duration categories (≤ 6 hours, 7 hours, 8 hours, ≥ 9 hours)	OR = 1.38 (1.15-1.67) for short sleep (≤ 6 hours) and non-ideal CVH	Cross-sectional; broad age range; outcome is CV health, not MI; no follow-up
11	Age (per year increase), high-risk subgroup vs low-risk	OR = 1.125 (1.063-1.190) per year age for high-growth atherosclerosis group	Cross-sectional autopsy study; subclinical outcome; no direct MI data; no follow-up
12	Sex, AMI subtype (type 1 vs others)	Women: Depression OR = 3.09 (2.37-4.04), men OR = 1.77 (1.15-2.73); family history stronger in men	Case-control; age 18-55; no exclusive < 40 data; robust adjustment; no follow-up
13	Sex	Non-traditional RFs rare (e.g., hypothyroidism, CTD, SCAD); no significant sex differences	Retrospective; in-hospital outcomes only; no effect estimates for non-traditional RFs; no follow-up

OR: Odds ratio; HR: Hazard ratio; HIV: Human immunodeficiency virus; RR: Relative risk; SLE: Systemic lupus erythematosus; OSA: Obstructive sleep apnea; MI: Myocardial infarction; AMI: Acute myocardial infarction; ICD: Implantable cardioverter-defibrillator; MACCE: Major adverse cardiac and cerebrovascular events; BMI: Body mass index; CV: Cardiovascular; RFs: Risk factors; CTD: Connective tissue disease; SCAD: Spontaneous coronary artery dissection.

Table 5 Risk of bias assessment

Study ID	Study design	Quality tool	Score	Quality classification	Key limitations
1	Cohort	NOS	7	High	Administrative data, coding errors
2	Cohort	NOS	7	High	Residual confounding, observational design
3	Cohort	NOS	6	Moderate	Retrospective data, potential selection bias
4	Case-control	NOS	5	Moderate	Small sample size, cross-sectional design
5	Cohort	NOS	8	High	Limited exposure detail
6	Cohort	NOS	7	High	Short follow-up, single center
7	Cohort	NOS	7	High	Potential residual confounding
8	Case-control	NOS	6	Moderate	Recall bias, dietary assessment
9	Case-control	NOS	5	Moderate	Small sample, self-reported exposures
10	Cross-sectional	AHRQ	7	Moderate	Self-report, cross-sectional design
11	Cross-sectional	AHRQ	6	Moderate	Surrogate outcome, autopsy data
12	Case-control	NOS	7	High	Potential selection bias
13	Cohort	NOS	5	Moderate	Retrospective design, limited non-traditional risk data

NOS: Not otherwise specified; AHRQ: Agency for healthcare research and quality.