Causes of Myocardial Infarction in Younger Patients: Troponin-elevation in Persons ≤65 Years Old in Olmsted County

Abstract

Background

The burden and pathophysiologic mechanisms of myocardial infarction (MI) in younger patients remain understudied. Prior studies have been limited by selected cohorts and lack of awareness of non-atherothrombotic causes.

Objective

We sought to determine the incidence and outcomes of MI according to unique pathophysiologic mechanism in a large community cohort aged ≤65 years, and to evaluate sex-differences in etiology

Methods

We identified all residents of Olmsted County, Minnesota aged ≤65 years who experienced an event associated with a cTnT >99th percentile of upper reference range (≥0.01ng/mL) 1/2003 to 3/2018. Records and imaging were individually scrutinized. Patients classified as MI were assigned to one of six adjudicated pathophysiologic mechanisms: Atherothrombosis, spontaneous coronary artery dissection (SCAD), embolism, vasospasm, MI with non-obstructed coronary arteries not meeting another category (MINOCA-U) and supply/demand mismatch secondary MI (SSDM). We determined incidence and long-term all-cause and cardiovascular mortality for each group.

Results

There were 4116 myocardial injury events in 2780 patients (36% female) over 15-years. Excluding periprocedural MI, 1474 events were classified as index MI, of which 68% were due to atherothrombosis. The population incidence of MI was much lower in women, particularly in MI due to atherothrombosis (48 vs 137 and 23 vs 105/100,000 person-years).

Incidence of SCAD was much higher in women (3.2 vs 0.9/100,000 person-years) with 55% of cases mis-classified as MINOCA or atherothrombosis at index presentation. Women with atherothrombosis were similar in age to men (55±8 vs 54±8 years), with similar disease extent at angiography but greater burden of risk factors. Proportionately, non-atherothrombotic causes comprised the majority of MI in women (atherothrombosis 47% vs 75%, SSDM 34% vs 19%, SCAD 11% vs 0.7%, embolism 2% vs 2%, vasospasm 3% vs 1%, MINOCA-U 3% vs 2%). Five-year all-cause mortality was highest after SSDM (SSDM 33%, atherothrombosis 8%, embolism 8%, SCAD 0%) with low cardiovascular mortality in all groups.

Conclusions

This community-based study demonstrates non-atherothrombotic causes comprise an important burden of acute MI in persons ≤65 years, particularly women. These cause-specific findings have implications for individualized management and risk stratification and provide epidemiologic benchmarking for future studies.

Condensed Abstract

This community-cohort study assessed the incidence of non-atherothrombotic MI. All persons<=65-years with a cTnT>=0.01ng/mL 2003–2018 were classified as MI or myocardial injury. MI was sub-categorized into atherothrombosis, SCAD, embolism, vasospasm, MI with non-obstructed coronary arteries (MINOCA-U) and supply/demand mismatch secondary MI (SDM). There were 4116 myocardial injury events in 2780 patients (36% female) over 15-years. Of 1474 index MIs, 68% were atherothrombotic. Incidence of MI was much lower in women, particularly atherothrombosis (48 vs 137 and 23 vs 105/100,000 person-years). SCAD was much higher in women (3.2 vs 0.9/100,000 person-years) with 55% mis-classified as MINOCA or atherothrombosis.

Introduction

Over the last decade there has been an increase in awareness that acute myocardial infarction (MI) may be caused by non-atherosclerotic etiologies, particularly in younger patients (1, 2). Despite this, causes such as spontaneous coronary artery dissection (SCAD), coronary embolism, and coronary vasospasm remain under-recognized and may be misclassified as MI due to non-obstructive coronary artery disease (MINOCA) of unknown etiology or as atherothrombotic disease. This can result in potential harm, such as from percutaneous intervention being performed in SCAD misdiagnosed as atherothrombosis, conservative therapy in atherothrombosis misdiagnosed as SCAD, or missed evaluation for sources of coronary embolus to prevent recurrent embolism. Diagnostic accuracy of the underlying mechanism of MI requires meticulous scrutiny of the angiogram and is enhanced when undertaken by expert reviewers (3). Longer term detrimental consequences of missed cause-specific diagnosis include provision of ineffective secondary preventative therapies and miscalculation of future risk. A deeper understanding of the population burden of individual pathophysiologic causes of MI is crucial for improved awareness and for assessing the impact of targeted interventions.

The distribution of individual causes of MI is likely different in a younger vs older population, with a greater proportion of MI due to non-atherothrombotic causes such as spasm or SCAD expected in younger cohorts. Large multi-center registry studies such as Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) (4–6) highlighted the greater burden of non-atherothrombotic disease in a ≤55 yr old population and the value of pathophysiologic MI classification in young persons, particularly women, rather than UDMI alone. These studies, however, cannot provide estimates of cause-specific population incidence due to selection biases inherent to registry design and entry criteria that excluded MIs with atypical presentations such as non-qualifying symptoms or ECG. Moreover, registries of SCAD and embolic MI have shown that an important number of cases occur in patients aged 55–65 yrs and thus missed in studies confined to ≤55 yrs (1, 2).

To the best of our knowledge there have been no community-based studies determining incidence, and outcomes of individual causes of MI in a younger population, and to evaluate sex-differences. To address these knowledge gaps, and to ensure maximal capture of events, we adjudicated consecutive cases with a cardiac troponin T (cTnT) increase above the 99^th percentile indicative of myocardial injury in a United States community population aged ≤65 over a 15-year period. We performed cause-specific classification of each event, determined population incidence of MI according to unique pathophysiologic mechanism, and evaluated long-term all-cause and cardiovascular mortality.

Methods

Patient population

The Olmsted Cardiac TrOponin in Persons Under Sixty-six (OCTOPUS) registry included all residents of Olmsted County, MN ≤65 years old who experienced an event associated with a fourth-generation cTnT above the 99^th percentile URL (cTnT ≥ 0.01 ng/mL) between 1/2003 and 3/2018. Olmsted County is situated in Minnesota, United States and has a total population of 162,847 persons (52% male, 78% white) with a median age of 38 years (USA census 2020)(7). The population characteristics are similar to the national demographics for white persons in the USA (7). Medical care is primarily delivered by a small number of providers, chiefly the Mayo Clinic and Olmsted Medical Center. A linked record system, the Rochester Epidemiology project (REP), has been in place since the 1970s, recording all medical care provided in the county (8). The REP enrolls all patients who are resident in Olmsted County, Mn unless they opt-out from participation. In 2023, 98.7% of persons resident in Olmsted County were included in the REP cohort(7). This allows for comprehensive examination of disease incidence in a defined population. A pre-planned subgroup analysis was performed of all persons aged ≤55 years old. The study was approved by an institutional review committee, and all subjects gave informed consent.

Collection of cases

Cases were defined as any clinical episode associated with a cTnT concentration above the 99th percentile upper reference limit (≥0.01ng/mL) in any community, clinic, or hospital location within Olmsted County. To ensure complete case capture, elevated cTnT was the sole inclusion criterion (Figure 1). cTnT was measured using a sandwich electrochemiluminescence immunoassay (Elecsys 2010, Roche Diagnostic Corp, Indianapolis, Ind). Delta cTnT was defined as the difference (rise or fall) in cTnT concentrations between two measurements less than 1 week apart (9). The same assay was used throughout the study period. Registry recruitment was stopped in March 2018 following transition to high-sensitivity cTnT.

Figure 1:

Outline of study design, event adjudication and cause classification

Mechanisms of myocardial infarction and myocardial injury

The mechanism of troponin elevation was retrospectively classified by 2 cardiologists after detailed review of each clinical record and impressions of the responsible cardiologists and internists, 12-lead ECG, and, where applicable, echocardiography, coronary angiography, computerized tomography, and magnetic resonance imaging. Any difference was resolved through consensus review undertaken in-person with all medical records and imaging available. Patients were classified as MI or myocardial injury using the 4^th Universal definition of MI (UDMI) (10). MI was defined as a rise and fall in cTnT with at least one concentration above the 99^th percentile upper reference limit, accompanied by clinical evidence of acute myocardial ischemia: ischemic symptoms, ischemic ECG changes, imaging evidence of loss of viable myocardium/new regional wall motion abnormality or acute thrombus seen at angiography/autopsy (10). Patients not meeting criteria for MI were classified as myocardial injury.

Cases meeting criteria for spontaneous MI were adjudicated into one of six categories based on pathophysiologic mechanism of MI (Figure 1). The 6 pathophysiologic categories were (1) Atherothrombosis (MI due to atherosclerotic disease with or without thrombus), (2) SCAD, (3) coronary embolism, (4) coronary vasospasm, (5) MINOCA-Undefined (MINOCA-U) and (6) supply/demand mismatch secondary MI (SSDM) - MI secondary to hypotension, arrhythmia, anemia etc without an acute intra-coronary event. Classification of each category according to the 4^th UDMI is shown in Figure 1. For purposes of illustrating differences in etiologies by age-range and sex (Figure 4), we grouped the small individual samples of SCAD, embolism, vasospasm and MINOCA-U as non-atherosclerotic coronary disease (NAC). MINOCA-U was defined according to American Heart Association (AHA) guidelines (11) as atherosclerosis ≤ 50% with no alternate diagnosis identified from history (e.g. SSDM), angiography (either index or retrospective review), imaging or other investigation. This group includes a mixture of un-identified type 1 and type 2 MIs. Since intra-coronary imaging/CMR were not performed routinely, MINOCA-U captured suspected rather than confirmed MINOCA cases. Coronary embolism was diagnosed using previously described major and minor criteria combinations (2) that included evidence of systemic embolization and embolic sources in addition to coronary angiogram features.

Figure 4:

Long-term all-cause and cardiovascular mortality in persons ≤65 presenting with MI, divided by etiology. NAC - non-atherosclerotic coronary disease (SCAD, embolism, vasospasm, MINOCA-U). SSDM – secondary MI due to supply/demand mismatch.

We recorded Takotsubo syndrome and myopericarditis as myocardial injury conditions of clinical interest since these often present as possible MI, (Figure 1). Takotsubo syndrome diagnosis was made using the international diagnostic criteria (12). Myopericarditis diagnosis was based on documented clinical features, impressions of the responsible cardiologists during the episode of care, and review of relevant imaging. MI following percutaneous coronary intervention or coronary artery bypass grafting was classified separately and excluded from further analysis. For patients with multiple episodes of myocardial infarction, only the index case was included.

Clinical characteristics, patient demographics and comorbidities were extracted via the REP database using ICD codes from inpatient and outpatient encounters on or prior to the index event using ICD codes as previously described (13). Laboratory values closest to the date index event, and within one year in all cases, were used.

Diagnostic re-classification

For patients who underwent coronary angiography, each angiogram was reviewed by experienced interventional cardiologists (RG, CER) for determination of final diagnosis. Initial reviews were performed independently. Disparity was resolved through formal in-person group review (DRH, RG, CER) and consensus. Adjudicators were not blinded to clinical information. The diagnostic impression of the initial clinical team at the time of event was also recorded. This enabled determination of extent and direction of re-classification. Population incidence and long-term outcomes were determined according to final diagnosis.

Presence and extent of coronary artery disease

The extent of CAD was determined according to number of vessels (1, 2 or 3) with >50% and >70% stenosis and the Gensini score (14). The Gensini score is a previously validated score calculated from the location and extent of CAD, with each lesion scored according to severity of stenosis and location. A more severe stenosis is assigned a higher score: 1 point for <25% stenosis, 2 for 26–50%, 4 for 51–75%, 8 for 76–90%, 16 for 91–99% and 32 points for 100% stenosis. This value is multiplied by a factor based on location (x5 for left main, x1.5 for mid LAD, x0.5 for 2^nd diagonal etc). A score was calculated for each coronary territory (LAD, Cx, RCA) and a total score calculated (14). If the coronary angiogram was not available, any available CT coronary angiograms or stress tests were reviewed for evidence of coronary artery disease. Gensini score and % stenosis were only calculated for patients with invasive angiography.

Adjudication of cause of death

Cause of death is collected prospectively as part of the REP including all death certificates, autopsy reports and electronic death certificate files from the State of Minnesota Department of Vital and Health Statistics. Cause of death was determined after review of full medical records by the coroner and autopsy data, where available. It was divided into cardiovascular and non-cardiovascular causes using the American Heart Association categories for cardiovascular deaths (International Classification of Diseases codes I00 to I99) as previously described (15).

Statistical analysis

Continuous variables were summarized as mean with standard deviation and nominal and ordinal variables were summarized as count with percentage. Patient baseline demographics were compared between MI groups using analysis of variance (ANOVA) test for continuous variables and chi squared goodness of fit test for categorical variables.

The annual incidence rate for each MI subgroup was calculated for each year over the study. The numerator for this calculation was the number of events classified in the data as the MI subgroup of interest. The denominator was taken from the REP database and is the number of people in Olmsted County ≤65 years old in each specific year. The rate was then scaled to 100,000 person-years to standardize and allow for accurate comparisons. A mean value across all years in the study was calculated and the average annual incidence was presented as a summary statistic. The results were also stratified by sex and the rates were compared using the Wilcoxon rank sum test. A survival analysis was conducted to examine all-cause and CV mortality in the study population at 5 years. Given the competing event of non-CV death in the latter outcome, a competing risk framework was used for the analysis to accurately estimate marginal probabilities. For all patients who did not have a death date, the date of last follow up was set as the date of the REP database pull. Time to event was calculated as time from the index event to death or last follow up, censoring all patients still alive after 5 years. For all-cause mortality patient status was denoted as deceased (1) or alive/censored (0) and for CV mortality patient status was denoted as CV death (1), non-CV death (2) or alive/censored (0). The cuminc function in R was used to calculate estimates of the cumulative incidence function separately for each mortality outcome of interest and compare between groups using Gray’s test.

Our study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (16). Missing data was <5% for any individual baseline patient characteristic variable in the overall study cohort, except for smoking status (27% missing). Listwise deletion was used for any comparison of baseline characteristics. This means that participants missing the variable of interest had their entire record removed, however only for that specific calculation where the value was missing. There was no missing data for any MI classification or time-to-event variables. . P-values < 0.05 were considered statistically significant throughout the analysis. All analyses were completed using R version 4.2.2.

Results

Between 1/2003 and 3/2018, there were a total of 4116 cTnT positive events in 2790 persons (64% male, Figure 1). Ten patients withdrew research consent and were excluded. After exclusion of peri-procedural MI (n=12) there were 1474 persons with at least 1 MI. Classification of index MI by etiology showed: 988 (67%) due to atherothrombosis, 346 (23%) SSDM, 53 (4%) SCAD, 29 (2%) embolism, 19(1%) vasospasm and 39 (3%) MINOCA-U. Vasospasm was epicardial in 17 (89%) patients and microvascular in 2 patients (11%). In the myocardial injury group, there were 56 patients with Takotsubo syndrome and 76 with myopericarditis. The remaining 1162 patients had myocardial injury alone and were excluded from further analysis. Baseline characteristics according to individual pathophysiologic cause are detailed in Table 1.

Table 1: Baseline characteristics according to individual cause of MI/myocardial injury event.

COPD -chronic obstructive pulmonary disease, cTnT – cardiac troponin T, Myocardial infarction with non-obstructive coronary artery disease -Unknown (MINOCA-U), NSTEMI – non-ST elevation myocardial infarction Supply Demand Mismatch (SSDM), Spontaneous Coronary Artery Dissection (SCAD), STEMI – ST elevation myocardial infarction

Unique pathophysiologic mechanism		Atherothrombosis	SSDM	SCAD	Embolism	Vasospasm	MINOCA-U	Myocarditis	Takotsubo
UDMI classification		T1MI	T2MI	T2MI	T2MI	T2MI	T1MI and T2MI	Myocardial injury	Myocardial injury
		n=988	n=346	n=53	n=29	n=19	n=39	n=76	n=56
Age (years)		55±8	52±11	51±9	47±10	46±11	51±9	40±14	54±10
Sex (% male)		789 (80%)	200 (58%)	7 (13%)	19 (66%)	7 (37%)	25 (64%)	50 (66%)	11 (20%)
Hypertension		546 (55%)	217 (63%)	23 (43%)	8 (28%)	9 (47%)	20 (51%)	21 (28%)	29 (52%)
Heart failure		51 (5%)	24 (7%)	0 (0%)	1 (3%)	0 (0%)	4 (10%)	2 (3%)	3 (5%)
Diabetes		408 (41%)	142 (41%)	12 (23%)	10 (35%)	2 (11%)	14 (36%)	16 (21%)	11 (20%)
Hypercholesterolemia		947 (96%)	223 (65%)	41 (77%)	27 (93%)	15 (79%)	31 (80%)	33 (43%)	34 (61%)
Prior stroke		20 (2%)	11 (3%)	1 (2%)	1 (3%)	0 (0%)	2 (5%)	0 (0%)	1 (2%)
COPD		41 (4%)	12 (3.5%)	0 (0%)	0 (0%)	0 (0%)	2 (5%)	2 (3%)	3 (5%)
Hemoglobin (g/dl)		13.4±3.8	12.0±3.7	12.6±2.8	14.1±3.4	11.6±4.4	13.4±4.1	12.7±3.2	12.9±3.0
Creatinine (mg/dl)		1.0±0.7	1.7±2.2	0.8±0.1	1.2±0.9	0.9±0.2	0.9±0.3	0.9±0.3	1.0±0.6
Max. cTnT (ng/ml)		2.1±3.8	0.3±0.5	1.1±1.1	4.5±4.9	0.9±2.8	0.7±1.4	0.6±0.7	0.9±2.0
Smoking status	Current	179 (18%)	63 (18%)	3 (6%)	5 (17%)	7 (37%)	12 (31%)	13 (17%)	16 (29%)
	Ex smoker	279 (28%)	90 (26%)	14 (26%)	6 (21%)	2 (11%)	8 (21%)	14 (18%)	13 (23%)
	Never smoker	241 (24%)	110 (32%)	24 (45%)	10 (34%)	3 (16%)	13 (33%)	33 (43%)	11 (20%)
	Unknown	289 (29%)	83 (24%)	12 (23%)	8 (28%)	7 (37%)	6 (15%)	16 (21%)	16 (29%)
Angiogram		929 (94%)	118 (34%)	53 (100%)	27 (93%)	18 (95%)	39 (100%)	49 (64%)	48 (86%)
STEMI		357 (36%)	2 (0.6%)	7 (13%)	16 (55%)	1 (5%)	7 (18%)
NSTEMI		631 (64%)	344 (99.4%)	46 (87%)	13 (45%)	18 (95%)	32 (82%)

Diagnostic re-classification

Diagnostic re-classification of the index event after angiographic scrutiny occurred in 4% of cases (n=61, Figure 2). Most reclassifications were in cases that presented prior to 2012 (n=49, 80%). The most frequent direction of diagnostic changes were from MINOCA-U and atherothrombosis at initial event to SCAD and coronary embolism at final classification. Only 2/39 (5%) of final MINOCA-U classification were in cases presenting after 1/2012.

Figure 2:

Reclassification of cause of myocardial infarction. Diagnostic labeling at index presentation was amended in 4% of cases after detailed retrospective review. Figure illustrates direction of change in cause classification, noting the majority occurred from an initial incorrect diagnosis of atherosclerosis or MINOCA. For the patients with SCAD missed at index presentation, 31 (86%) were SCAD type II, 1 (3%) type 1, 1 (3%) type III, 3 (8%) type 4)

Cause-specific incidence of MI in a community cohort

There were marked sex differences in incidence and cause of MI. The population incidence of MI was much lower in women (48/100,000 vs 137/100,000 person-years), particularly in MI due to atherothrombosis (23/100,000 vs 105/100,000 person-years). Atherothrombosis was the most common cause of MI in women (47% of MIs) but collectively, non-atherothrombotic MI comprised more than half of events (Central illustration), most commonly SSDM (34%), SCAD (11%) and MINOCA-U (3%). In men, 75% of MI was atherothrombotic, 19% SSDM, 2% vasospasm and 2% MINOCA-U. Annual incidence of MI in men and women stratified by the 6 pathophysiologic mechanisms is described in Table 2. Incidence confined to a ≤55 year-old subgroup is shown in Supplemental Table 2. When evaluated by age-range, the most common cause of MI in men was atherothrombosis across all age groups. However, in women 45 and under, SSDM was the most common cause of MI and the acute non-atherothrombotic coronary causes (SCAD, embolism, spasm and MINOCA-U) were collectively as common as atherothrombosis (Figure 4). Use of cardiovascular magnetic resonance (CMR), intra-coronary imaging and invasive provocation testing for coronary spasm and microvascular disease are detailed in the Central illustration. For the 140 patients with non-atherothrombotic cardiac MI (n=140), 47 (34%) underwent CMR, 27 (19%) intra-coronary imaging and 2 (1%) invasive provocation testing (acetylcholine, adenosine).

Central Illustration:

Causes and annual incidence of MI and myocardial injury in Olmsted County, stratified by sex

Table 2: Cause-specific average annual incidence of MI/myocardial injury event.

Annual incidences are presented per 100,000 persons of Olmsted County residents aged 18–65 and represent the mean value (with SD) over the study period. MINOCA-U: myocardial infarction with non obstructive coronary artery disease, SCAD – spontaneous coronary artery dissection, SSDM – supply demand mismatch

	Incidence /100,000 person-years
	All	Men	Women	P -value (M v F)
Atherothrombosis	61 (16)	105 (28)	23 (8)	<0.001
SSDM	20 (6)	24 (8)	16 (6)	0.005
SCAD	3.2 (1.8)	0.9 (1.3)	5.2 (3.2)	<0.001
Embolism	1.7 (1.4)	2.4 (1.9)	1.2 (1.4)	0.013
Vasospasm	1.1 (0.9)	0.9 (1.3)	1.2 (1.6)	0.854
MINOCA-U	2.5 (2.4)	3.4 (2.9)	1.7 (2.4)	0.046
Takotsubo syndrome	3.3 (1.8)	1.3 (1.6)	5.1 (3.2)	0.001
Myopericarditis	3.3 (1.3)	5.3 (1.8	1.6 (1.8)	<0.001

Sex differences in atherothrombotic MI

Sex differences in the clinical characteristics of atherothrombotic MI are shown in Table 3. Women with atherothrombotic MI were more likely to have hypertension and diabetes compared to men but had lower maximum cTnT concentrations. However, there was no difference in number of vessels with >50% stenosis or Gensini score as an angiographic index of coronary disease burden between men and women with atherothrombotic MI.

Table 3: Baseline characteristics in atherothrombotic MI stratified by sex.

COPD – chronic obstructive pulmonary disease, cTnT – cardiac troponin T, Hb – hemoglobin, eGFR – estimated glomerular filtration rate. NB percentage stenoses on angiogram are expressed as a % of persons who underwent angiography.

		Male	Female	p-value
		n= 789	n= 199
Age		54±8	55±8	0.48
Hypertension		420 (53%)	126 (63%)	0.01
Diabetes		299 (38%)	109 (55%)	<0.001
Smoking	Current smoker	135 (17%)	19 (10%)	0.05
	Ex-smoker	223 (28%)	32 (16%)
	Never smoker	193 (24%)	49 (25%)
	Unknown	238 (30%)	38 (19%)
Heart failure		41 (5%)	10 (5%)	0.92
Hypercholesterolemia		759 (96%)	188 (95%)	0.28
Stroke		12 (2%)	8 (4%)	0.03
COPD		34 (4%)	7 (4%)	0.62
Active cancer		34 (4%)	16 (8%)	0.03
Max. cTnT (ng/ml)		2.2±3.8	1.8±4.0	0.13
Hb (g/dl)		13.7±3.7	11.9±3.9	<0.001
eGFR (ml/min)	>60	633 (82%)	131 (68%)	<0.001
	41–60	106 (14%)	39 (20%)
	21–40	18 (2%)	8 (4%)
	<=20	20 (3%)	16 (8%)
	NA	12 (2%)	5 (3 %)
Invasive Angiography performed		749 (95%)	180 (91%)	0.17
Number of patients with at least one stenosis>70%		665 (89%)	148 (82%)
Number of patients with at least one stenosis>50%		706 (94%)	163 (91%)
Number of vessels with >50% stenosis		1.6±0.9	1.6±0.9	0.6
number of vessels with >70% stenosis		1.2±0.8	1.3±0.8	0.2
Total Gensini Score		31.7±33.8	34.5±35.3	0.3

Sex differences in myocarditis and Takotsubo syndrome

Men had a higher incidence of myocarditis compared to women, while women had a higher incidence of Takotsubo syndrome compared to men (Table 2).

Long term mortality

Patients were followed for a median of 5.6 years (inter-quartile range 2.3–10.8 years). Kaplan-Meier estimation of long-term mortality is shown in Figure 4 and cardiovascular mortality in Figure 5. Five-year all-cause mortality and cardiovascular mortality were highest in persons with SSDM Table 4.

Table 4:

5 year all-cause and cardiovascular mortality following MI/myocardial injury event using Kaplan-Meier estimates (95% confidence intervals in brackets)

	All-cause mortality	Cardiovascular mortality
Atherothrombosis	8.29% (6.52%, 10.06%)	4.32% (3.02%, 5.61%)
SSDM	32.81% (27.60%, 38.02%) %	8.00% (5.02%, 10.98%)
SCAD	0%	0%
Embolism	8.39% (0%, 19.95%)	0%
Vasospasm	15.79% (0%, 32.66%)	5.26% (0%, 15.59%)
MINOCA-U	10.54% (0.63%, 20.46%)	2.56% (0%, 7.59%)
Myocarditis	8.72% (1.95%, 15.48%)	1.32% (0%, 3.89%)
Takotsubo syndrome	25.55% (13.82%, 37.28%)	7.41% (0.33%, 14.49%)

Discussion

The major findings of this large community-based study of patients with MI ≤ 65 years-old over a 15-year period include: 1. While atherothrombosis remains the most common cause of younger MI in both sexes, more than half of MI in women were due to non-atherothrombotic causes. 2. Women had a much lower population incidence of MI, particularly of atherothrombosis. 3. One in ten MIs in women were due to SCAD, and this diagnosis was frequently missed on initial presentation.

Several aspects of study design enabled unique insights. Use of uniform cTnT assay during a 15-year period as the only inclusion criterion, and expert scrutiny of all events with cTnT >99^th percentile ensured maximal capture of MI events. Prior studies have often additionally required chest pain and/or ECG changes as MI diagnostic criteria, thereby missing atypical presentations, and lacked the use of a standard cTnT assay and guideline-recommended threshold (6, 17). The current study, with complete capture plus accrual of events over 15 years from a validated community cohort ensured sufficient sample size for a deeper epidemiologic understanding of rarer causes of MI. Community cohort design mitigated the selection bias inherent to registry studies. We found a higher proportion of non-atherothrombotic MIs compared to prior work such as VIRGO, likely due to these differing inclusion criteria. We chose a higher age limit for our study (65 years vs 50 or 55 years) because registries of SCAD and emboli have shown that an important number of non-atherosclerotic MIs occur in patients aged 55–65 and would have been missed had we confined our study to a much younger population (1, 2) but we did do a pre-specified analysis in a subgroup age ≤55. We performed comprehensive case review by multiple subject-matter experts for maximal accuracy in cause classification. This precision enabled use of specific and clinically actionable categories for diagnosis based on underlying pathophysiologic mechanism of MI.

Four percent of cases were found to have been misclassified at the index angiogram, demonstrating the impact of increased awareness over time of nonatherosclerotic causes of MI. We found the true incidence of SCAD to be markedly higher than previous estimates (18), with 60% of SCAD having been mis-labeled at index presentation and incorrectly diagnosed as atherothrombosis or MINOCA. These cases typically had distal or branch vessel SCAD, demonstrating the importance of close attention to the entire coronary vasculature at the time of angiography to evaluate for easily missed diagnoses. During the study period (2003–2018), recognition of non-atherosclerotic MI and particularly SCAD increased and only 20% of the 61 of misclassified cases occurred after 2012.

Truly unclassifiable MINOCA (MINOCA-U) appears to be rare, comprising 2.6% of MIs in the current population study, compared to 5.3% in the VIRGO registry (2008–2012) (5), 9.5% in the CRUSADE registry (2001–2005) (19) and 7.7% in the SWEDEHEART registry (2003–2013) (20). This may reflect an increase in awareness and recognition of non-atherosclerotic conditions over the past decade, noting that 1/3 of MIs in our cohort that had been initially labeled as MINOCA-U were reclassified from this umbrella category to a single diagnosis, most often SCAD (11). It may also reflect an increased use of multimodality imaging (intra-coronary and CMR) leading to reclassification of MINOCA to atherothrombosis with non-obstructive plaque rupture, myocarditis or SCAD (21). In our cohort, use of multimodality imaging increased over the study time period and it is notable that only 2/39 (5%) of final MINOCA-U classification were in cases presenting after 1/2012. While data for use of CMR and intra-coronary imaging are not presented for SWEDEHEART, CRUSADE or VIRGO, the time period of these studies was prior to guidelines recommending multimodality imaging in MINOCA.

An advantage of this study design was the ability to classify events according to single pathophysiologic mechanism. The Fourth UDMI groups non-coronary SSDM mechanisms such as MI due to anemia or hypotension with MI due to acute non-atherosclerotic coronary pathologies such as SCAD or spasm together as type 2 MI (T2MI). In all-comers with MI, where the vast majority of T2MI events are due to non-coronary SSDM, this allows a clear framework for classification of MI, stratified into T1MI (atherothrombosis) and T2MI. In younger persons where SCAD, embolism and vasospasm are more common, the UDMI framework is complemented by pathophysiologic classification of MI as this informs management decisions. Other classification frameworks such as VIRGO h(11)ave been suggested for use in young persons (4), noting that 1 in 8 MIs in women<55 years old did not easily fit into the UDMI classification, however have not been adopted in clinical practice. Thirty percent of patients met the AHA diagnostic criteria for MINOCA (11) (<50% epicardial coronary artery disease), with the majority of these being SSDM and the remainder being SCAD, embolism and vasospasm. Reported prognosis of MINOCA varies widely, with both higher (22), similar (23) and lower (24) mortality reported in prior studies compared to atherothrombotic MI. Our data suggests an explanation for this discrepancy: MI due to SSDM has a high mortality (25, 26), whereas mortality is much lower in SCAD, embolism and vasospasm disorders. As expected, our incidence of MINOCA was higher than in ACTION-GWTG (17) as the ACTION cohort only included patients who underwent angiography and the majority of patients with SSDM do not undergo angiographic work up (36% in our cohort). Similar to VIRGO, we found that MINOCA-U patients were more likely to be female (90% in VIRGO) with lower prevalence of traditional cardiovascular risk factors and lower peak troponin values than patients with atherothrombotic MI (27).

Patients with SSDM had higher rates of all-cause mortality compared to other etiologies of MI, despite a lower maximum cTnT. This is in keeping with prior work in all-comers with MI due to SSDM (25, 26) and likely relates to a sicker population who are more likely to die from their underlying non-cardiac diseases. We previously reported 20% mortality from non-cardiac causes at 1 year in this population(25). Patients with Takotsubo syndrome also had higher rates of all-cause mortality, primarily driven by non-cardiac mortality in ours and prior work (25). Takotsubo syndrome is often a disease of older persons with a mean age at presentation of 67 years-old in large registry studies so incidence in the population as a whole will be higher than our population of age 65 and under (28).

The pathophysiologic classification of MI allowed us to understand more deeply the epidemiology of MI due to atherothrombotic disease). We found atherothrombotic MI to be 4x more common in younger men than younger women, and peak cTnT levels to be higher despite younger men having on average lower burdens of atherosclerotic risk. Whether this indicates sex differences in the effects of risk factor exposure, with men experiencing greater coronary risk, or whether it reflects behavioral biases such as women being less likely present for medical care or to receive diagnostic tests for MI (29) (5) remains uncertain and requires further study. Encouragingly, we saw high rates of angiography in both men and women in our atherothrombosis population (95% vs 91%, p=0.14), suggesting sex-differences in selection for diagnostic testing may have improved with time. The finding of a much higher proportion of nonatherosclerotic causes of MI in women compared with men might in part explain the lower rates of secondary prevention prescriptions in women in studies that did not distinguish between atherothrombotic and non-atherothrombotic causes of MI (6, 30). Further study in a cohort with routine use of intra-coronary imaging and CMR will better inform the etiology of non-atherothrombotic causes of MI.

Study Limitations

The population only included persons in whom a cTnT was drawn and therefore would not have captured pre-hospital mortality. Young patients, particularly women, may not have had a cTnT drawn; however in US practice, cTnT is often measured broadly. Co-morbidities were recorded as dichotomous variables with no adjustment for severity. Olmsted county has a limited racial and ethnic diversity and therefore findings may not be generalizable to other populations, however prior work suggests that cardiovascular trends in the region parallel those seen nationally (31). A minority of patients did not undergo invasive angiography which could have led to misclassification. Misclassification may also have occurred due to missed subtle findings on angiogram review (eg SCAD), absence of routine intracoronary imaging and CMR as adjunctive testing. Incidence of the non-atherosclerotic causes of MI and incidence of myocarditis may be different in a population with higher rates of multimodality imaging,. Angiographic review was performed unblinded from clinical data, with risk of confirmation bias. Provocation testing for microvascular and epicardial spasm was not routine and the true incidence of coronary artery spasm is therefore likely underestimated. 36% of patients with SSDM underwent coronary angiography and it is possible some SSDM MI’s were unrecognized atherothrombosis or T2MI. We used a conventional 4^th generation cTnT assay across the study period. The transition to 5^th generation (high sensitivity) cTnT assay with sex specific thresholds has resulted in greater detection of myocardial infarction and injury events (32, 33). Whether this would have resulted in greater detection of specific causes of MI is not known.

Conclusions

Non-atherosclerotic MI comprise an important burden of acute MI in persons ≤65, particularly in women. We report the cause-specific incidence in a community-based population, providing benchmarking for future studies of individualized management based on underlying cause of MI.

Figure 3:

Sex differences in cause of myocardial infarction according to age at presentation. X-axis represents all patients up to that age. In men, atherothrombosis was the commonest cause of MI at all ages, but SSDM and NAC were as common as atherothrombosis in women<45. NAC - non-atherosclerotic coronary disease (SCAD, embolism, vasospasm, MINOCA-U). SSDM – secondary MI due to supply/demand mismatch.