Study suggests mental stress-induced ischemia increases risk of death, non-fatal MI

Is testing for mental stress-induced myocardial ischemia needed for individuals with stable coronary heart disease (CHD)?

According to a pooled analysis of two prospective cohort studies, mental stress-induced myocardial ischemia—compared with no mental stress-induced ischemia—is associated with an increased risk of death or non-fatal myocardial infarction (MI). However, in the absence of further evidence, it is still unknown if testing for mental stress-induced myocardial ischemia has clinical value as a prognostic tool, Viola Vaccarino, MD, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, and fellow researchers reported in JAMA.

Vaccarino and colleagues looked at patients with stable CHD enrolled in two prospective studies in the Emory University Health system from June 2011 to March 2016—the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). The last follow-up analysis was February 2020.

“Pooling the 2 study populations with meta-analysis yielded a total sample of 918 participants with a mean age of 60 years (SD, 10 years), 40% Black, 55% White, and 34% women,” Vaccarino and colleagues wrote. “Of the total sample, 147 (16%) had mental stress–induced ischemia, 281 (31%) had conventional stress ischemia, and 96 (10%) had both.”

For the primary endpoint of cardiovascular death or first or recurrent nonfatal MI, the pooled event rate was 6.9 per 100 patient years for those patients diagnosed with mental stress-induced ischemia and 2.6 per 100 patient years for those not diagnosed with mental stress-induce ischemia—pooled multivariable adjusted HR 2.5 (95% CI, 1.8-3.5).

The researchers found that for the secondary endpoint (a composite of MI and heart failure hospitalizations), “the event rate was 12.6 per 100 patient-years for patients with mental stress–induced ischemia and 5.6 per 100 patient-years for those without mental stress–induced ischemia (adjusted HR, 2.0 [95% CI, 1.5-2.5]). The corresponding absolute rate difference was 4.3 (95% CI, 2.4-6.2) per 100 patient-years for the primary end point and 7.0 (95% CI, 4.4-9.6) per 100-patient years for the secondary end point,” the study authors noted and added that results were similar in the reduced model—HR 2.4 (95% CI, 1.7-3.4) for the primary end point and 2.0 (95% CI, 1.5-2.5) for the secondary end point.

Among other findings were the following, according to study authors:

  • “Compared with patients with no ischemia (event rate, 2.3 per 100 patient-years), patients with mental stress–induced ischemia alone had a significantly increased risk (event rate, 4.8 per 100 patient-years; HR, 2.0; 95%CI, 1.1-3.7) as did patients with both mental stress ischemia and conventional stress ischemia (event rate, 8.1 per 100 patient-years; HR, 3.8; 95% CI, 2.6-5.6).
  • “Patients with conventional stress ischemia alone did not have a significantly increased risk (event rate, 3.1 per 100 patient-years; HR, 1.4; 95% CI, 0.9-2.1).
  • “Patients with both mental stress ischemia and conventional stress ischemia had an elevated risk compared with patients with conventional stress ischemia alone (HR, 2.7; 95% CI, 1.7-4.3). The secondary end point occurred in 319 participants.”

In an editorial accompanying the study, Paco E. Bravo, MD and Thomas P. Cappola, MD, ScM, both from the Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, wrote: “The results of the study by Vaccarino et al largely confirm prior observations from smaller studies and extend the generalizability of the findings to women, Black individuals, and younger individuals with stable CHD, populations that are often underrepresented in biomedical research. In addition, this study reports for the first time the complex interplay that seems to exist between inducible ischemia by mental stress and conventional stress testing, which can result in distinct ischemia phenotypes that may have different risk profiles. In particular, it is remarkable that mental stress ischemia (without conventional stress ischemia) appears to be a stronger risk factor than conventional stress ischemia (without concomitant mental stress ischemia) for cardiovascular death, nonfatal myocardial infarction, or heart failure hospital admission.”

Inclusion criteria for both protocols were patients with stable CHD recruited from hospitals and clinics affiliated with the Emory University system that shared protocols, staff, facilities and equipment. In the MIPs study, eligibility requirements were being 30-79 years old with a documented history of CHD. The MIMS2 study included patients who had been “hospitalized for a verified myocardial infarction (MI) within the past 8 months and were 18 to 60 years of age at the time of the MI. MIMS2 also included 50% women by design.” Exclusion criteria were pregnancy or medical comorbidities that shortened life expectancy.

To determine mental stress, patients were tested after a 12-hour fast with a standardized public speaking task as the stress inducer.

“Patients were given 2 minutes to prepare a speech and 3 minutes to deliver it in front of an evaluative audience of at least 4 people,” the study authors wrote. “Blood pressure and heart rate were recorded throughout the test, and the rate-pressure product was calculated. Subjective ratings of distress were obtained with the Subjective Units of Distress Scale.”

In order to determine ischemia, the study authors “performed 3 technetium Tc 99m (99mTC) sestamibi SPECT scans at rest, during mental stress, and during conventional stress, following standard protocols. Testing was performed on two separate days up to 1 week apart on a dedicated SPECT camera (Philips Cardio MD).

“Antianginal medications were withheld for 24 hours prior to stress testing. On the mental stress day, 99mTC sestamibi was injected 1 minute into the speech task. On the conventional stress day, participants underwent a standard Bruce protocol, or, if unable to exercise, a pharmacological stress test with regadenoson (Astellas),” wrote Vaccarino and colleagues.

Bravo and Cappola noted that the study “…provides compelling evidence demonstrating the strong association between mental stress ischemia and the risk of future cardiac events and mortality among individuals with stable CHD.”

Still, they noted that questions remain for future studies:

“To what extent is mental stress ischemia therapeutically modifiable? Can screening for and treatment of mental stress ischemia lead to improved outcomes? Is mental stress testing reproducible and feasible in clinical practice? Are there additional at-risk populations in whom mental stress ischemia testing should be considered?,” they wrote. “Answers to these important questions will help determine whether mental stress should become an actionable clinical item in the management of individuals with known or suspected CHD.”

Limitations of the study from Vaccarino and colleagues include assessing mental stress in the laboratory, not everyday life; using only a single mental stressor; and conducting the study at a single center. Researchers also noted that “the study does not establish the clinical value or feasibility of mental stress-induced ischemia testing in patient care.”

  1. A pooled analysis of two prospective cohort studies, mental stress-induced myocardial ischemia, when compared with no mental stress-induced ischemia, is associated with an increased risk of death or non-fatal myocardial infarction.

  2. In the absence of further evidence, it is still unknown if testing for mental stress-induced myocardial ischemia has clinical value as a prognostic tool.

Candace Hoffmann, Managing Editor, BreakingMED™

This work was supported by grants from the National Heart, Lung, and Blood Institute, the National Institute of Mental Health, the National Center for Advancing Translational Sciences, and the National Institute of Child Health and Human Development.

Vaccarino disclosed no relevant relationships.

Neither Bravo or Cappola disclosed any relevant relationships.

Cat ID: 358

Topic ID: 74,358,730,358,192,146,52,925