October 4, 2026Open Access
Mental Stress-Induced Myocardial Ischemia and Cardiovascular Events in Women after a Premature Myocardial Infarction: A Prospective Cohort Study
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Key result
Mental stress-induced ischemia linked to ~3.2-fold higher CV death or MI in post-MI women.
- HR 3.2
- 95% CI 1.3-7.6
- n=602
Why the study?
Women with premature myocardial infarction have worse outcomes than similarly aged men despite less severe disease, and stress-related factors have been implicated.
Does mental stress-induced myocardial ischemia (MSIMI) increase the risk of cardiovascular death or nonfatal MI in women and men following a premature myocardial infarction?
Key Points
- To examine sex differences in the association of mental stress-induced myocardial ischemia with cardiovascular outcomes following premature myocardial infarction and explore underlying inflammatory and vascular mechanisms.
- Prospective cohort study of 602 participants (mean age 51 years; 46% women; 59% Black) evaluated within 8 months of myocardial infarction across two study waves.
- Participants underwent 99mTc-sestamibi myocardial perfusion imaging at rest and after mental stress (ischemia defined as summed difference score ≥3), alongside measurements of reactive hyperemia index and interleukin-6.
- Primary endpoint was cardiovascular death or nonfatal myocardial infarction over a median follow-up of 34.2 months (IQR, 24.9-37.6 months).
- Mental stress-induced myocardial ischemia occurred in 19.2% of women compared to 13.2% of men (p=0.04).
- The hazard ratio for the primary endpoint was 3.2 (95% CI, 1.3, 7.6) in women versus 1.9 (95% CI, 0.8, 4.5) in men (p for interaction=0.41), with an adjusted population attributable fraction of 27.6% (99% CI, 3.9%, 36.9%) in women and 11.1% (95% CI, -5.8%, 18.4%) in men.
- All primary endpoint events related to mental stress-induced ischemia among women occurred in Black women (HR, 4.3; 95% CI, 1.7-11.1), and adjustments for interleukin-6 or reactive hyperemia index did not attenuate associations.
Study Design
Type
Cohort (n=602)
Blinding
Outcome adjudicators and image readers blinded
Multicenter
Yes
Structured PICO
Does mental stress-induced myocardial ischemia (MSIMI) increase the risk of cardiovascular death or nonfatal MI in women and men following a premature myocardial infarction?
P
Population
602 adults aged 18 to 60 years who recently survived a premature myocardial infarction, followed for a median of 34.2 months.
E
Exposure
Mental stress-induced myocardial ischemia (MSIMI) elicited via a standardized 3-minute public-speaking challenge, defined as a summed difference score ≥3 on 99mTc-sestamibi single-photon emission computed tomography (SPECT) myocardial perfusion imaging.
C
Comparator
Absence of MSIMI (summed difference score <3). The study also compares outcomes between women and men.
O
Outcome
Composite of cardiovascular death or nonfatal MI at a median 34.2 months follow-up, adjudicated by blinded study cardiologists.composite
Main Result
Hazard Ratio: 3.2 (95% CI 1.3–7.6)
Mental stress-induced myocardial ischemia strongly predicts recurrent cardiovascular events and mortality in women with premature MI, accounting for over a quarter of these adverse outcomes.
Limitations
- The interaction between mental stress-induced myocardial ischemia and sex was not statistically significant, meaning the apparent sex difference should be interpreted with caution.
- Small number of events in subgroups (e.g., non-Black women) made race-stratified analyses purely exploratory.
- Data on interleukin-6 and reactive hyperemia index were missing in approximately 20% of participants due to technical issues.
- Exploratory subgroup analyses by sex and race limited by small number of events, especially in non-Black women
- Missing IL-6 and RHI data in approximately 20% of participants due to technical issues
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Our findings suggest that women with heart disease in their 30s, 40s and early 50s are more vulnerable to the damaging effects of psychological stress on their heart.”
“The fact that mental stress was an independent predictor of events, and actually even stronger in terms of effect than conventional stress-induced ischemia, adds to our understanding of ischemia in general.”
“These findings support the importance of psychological stress as a risk factor for women with coronary heart disease and suggest that a microvascular phenomenon may underlie this effect.”
Implication
Mental stress-induced ischemia may flag higher-risk women after premature MI; hypothesis-generating and requires prospective validation before clinical adoption.
Abstract
Background: Women with premature myocardial infarction (MI) have worse outcomes than similarly aged men despite less severe disease, and stress-related factors have been implicated. We examined sex differences in the association of mental stress-induced myocardial ischemia (MSIMI) with cardiovascular outcomes after premature MI and explored vascular and inflammatory mechanisms. Methods: We studied 602 individuals (mean age 51 years; 46% women) within 8 months of MI who underwent 99mTc-sestamibi myocardial perfusion imaging at rest and after mental stress. MSIMI was defined as a summed difference score ≥3. We measured reactive hyperemia index (RHI) as peripheral microvascular reactivity to stress and interleukin-6 (IL-6) as inflammatory response to stress. The primary endpoint was cardiovascular death or nonfatal MI; the secondary endpoint added heart failure hospitalization. Cox proportional hazards models adjusted for sociodemographic factors, clinical, and psychiatric history. Results: MSIMI was more common in women than men (19.2% vs. 13.2%, p=0.04). Over a median follow-up of 34.2 months, 51 primary and 91 secondary endpoint events occurred. The hazard ratio (HR) of MSIMI for the primary endpoint was 3.2 (95% CI, 1.3, 7.6) in women and 1.9 (95% CI, 0.8, 4.5) in men (p for interaction=0.41), which remained similar after multivariable adjustment. The adjusted population attributable fraction was 27.6% (99% CI, 3.9%, 36.9%) in women and 11.1% (95% CI, -5.8%, 18.4%) in men. In exploratory analyses, all MSIMI-related primary endpoint events among women occurred in Black women (HR, 4.3; 95% CI, 1.7-11.1). Associations with the secondary endpoint were weaker and attenuated after adjustment. IL-6 and RHI responses did not attenuate associations. Conclusions: Among women, MSIMI was associated with about threefold increased risk and over one quarter attributable fraction for cardiovascular death or nonfatal MI. Black women were at especially high risk. While larger studies are warranted to confirm sex differences and explore mechanisms, these data underscore the impact of emotional factors on morbidity and mortality in post-MI women.
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Cite This Study
Vaccarino et al. (2026) conducted a cohort in Premature myocardial infarction (n=602). Mental stress-induced myocardial ischemia (MSIMI) vs. No mental stress-induced myocardial ischemia was evaluated on Composite of cardiovascular death or nonfatal MI (HR 3.2, 95% CI 1.3-7.6). Mental stress-induced myocardial ischemia was associated with a threefold increased risk of cardiovascular death or nonfatal MI (HR 3.2) among women following a premature myocardial infarction.
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