mental stress and heart disease

 A study of mental stress-induced myocardial ischemia in patients with coronary heart disease (CHD) found it to be associated with increased cardiovascular events (see cad mental stress jama2021 in dropbox, or doi:10.1001/jama.2021.17649)

 

Details: 

-- 2 prospective cohort studies in patients with stable coronary heart disease from Emory University in Georgia, between June 2011 and March 2016, with follow-up until February 2020

    -- Mental Stress Ischemia Prognosis Study (MIPS), 618 participants who were 30-79 years of age and had documented CHD

    -- Myocardial Infarction and Mental Stress Study 2 (MIMS2), 300 participants who were hospitalized for a verified MI in the past eight months and were 18-60 years old at the time of the MI;  50% were women by study design

-- 918 total patients in the total sample

-- mean age 60, 34% women in combined study, 40% Black/55% white

-- hyperlipidemia in 80%, hypertension 80%, diabetes 35%, current smoker 20%/ever-smoker 60%, MI in 33% of MIPS and 100% of MIMS2 studies, heart failure 20%

-- meds: statins 85%, aspirin 85%, b-blockers 80%, ACE 50%, antidepressants 20%

-- patients were given a standardized mental stress test: in the morning after a 12-hour fast, they then had a public speaking task where they are given two minutes to prepare a speech and three minutes to deliver it in front of an evaluative audience of at least four people. At that time, there was also a conventional (exercise or pharmacological) stress test, using a single-photon emission computed tomography

-- during mental stress testing: BP increased 29/14 mmHg, heart rate by 14 bpm

-- psych: Beck Depression Inventory 11 (score of >13 = mild depression), Cohen Perceived Stress Scale-10 15 (scale 0-40, higher is worse)

-- primary outcome: composite of cardiovascular death, or first or recurrent nonfatal myocardial infarction

-- secondary outcome: primary outcome plus hospitalizations for heart failure

 

Results: (the article separates the 2 cohorts, but I will summarize just the combined totals):

-- mental stress-induced ischemia alone: 147 of 918 patients, 16%

-- conventional stress ischemia alone: 281 of 918 patients, 31%

-- ischemia from both stresses: 96 patients, 10%

 

-- Composite of cardiovascular death, or first or recurrent nonfatal MI (primary outcome) after five-year median follow-up:

    -- primary outcome in 156 participants

        -- patients with mental stress-induced ischemia:  pooled event rate 6.9 per 100 patient years versus 2.6 per 100 patient years among patients without mental stress-induced ischemia

            -- adjusted hazard ratio for patients with versus without mental stress-induced ischemia: 2.5 (1.8-3.5)

                -- adjusted for:  age, sex, race, ever smoking, BMI, history of hypertension, diabetes, heart failure, left ventricular ejection fraction, previous MI, current medications, and instruments above assessing depressive symptoms and perceived stress

        -- compared to patients with no ischemia, event rate 2.3 per 100 patient years:

            -- patients with mental stress-induced ischemia alone: increased risk of 4.8 per 100 patient years, HR 2.0 (1.1-3.7)

            -- patients with both mental stress ischemia and conventional stress ischemia, event rate 8.1 per 100 patient years, HR 3.8 (2.6-5.6)

            -- patients with conventional stress ischemia alone: event rate 3.1 per 100 patient-years, HR 1.4 (0.9-2.1). [Not a statistically significant increase]

 

-- Secondary endpoint (including hospitalization for heart failure): in 319 participants, event rate 12.6 per 100 patient-years with and 5.6 per 100 patient-years without mental stress-induced ischemia, adjusted HR 2.0 (1.5-2.5)

 

-- analysis broken down by age, sex, race, MI history, diabetes, heart failure, conventional stress ischemia: all were worse when mental stress-ischemia present, though more in men than women and those with vs without prior MI

-- analysis controlling for psychological factors did not change the association with mental stress-induced ischemia and either the primary or secondary endpoints

-- adjustment for duration of exercise in those with conventional stress test did not diminish the association between mental stress-induced ischemia and outcome, HR 3.0 (1.8-5.1)

 

Commentary: 

-- in patients with stable coronary heart disease in this study, mental stress-induced ischemia was significantly associated with increased cardiovascular death or nonfatal MI.

    -- notably, those with only conventional stress ischemia (in the absence of mental stress-induced ischemia) did not have a statistically significant increased primary endpoint after five years

    -- there was a statistically significant role of mental stress-induced ischemia even controlling for conventional stress ischemia.

    -- also, there was an additive effect: having both ischemias was much worse than each individually, when compared to those with no ischemia

-- so, interesting that the relationship between conventional stress ischemia alone and cardiac events did not reach statistical significance (though it was very close to the mathematical cutpoint). But, does that suggest that at least part of the relationship in other studies between ischemia and bad cardiac outcomes may be from the unmeasured effects of mental stress-induced ischemia in some patients???? And that we should develop a stream-lined test to assess this and not have to arrange a stressful public speaking scenario?? Older studies have used simpler methods: eg, having the person sort similar size ball bearings under time pressure. That might work and be feasible, but would need to be validated.

    -- and, by the way, is this whole picture confounded by the fact that those with conventional stress-induced ischemia are often put on b-blockers, which are likely an effective strategy in those with mental stress-induced ischemia, where the b-blockers block the sympathetic catecholamine response to mental stress??

    -- also, mechanistically, mental stress-induced ischemia likely involves catecholamines that might increase endothelial dysfunction and induce coronary artery contraction/spasm, whereas exercise leads to decreases in systemic resistance/vasodilation. And, mental stress is associated with increased systemic inflammatory response. So, mental stress-induced ischemia may pick up coronary artery disease at a lower burden of atherosclerosis. Is that an issue? Maybe: older studies have shown that 78-97% of lesions in patients with acute coronary syndromes were less than 75% stenotic, and half less than 50% (the issue is that smaller plaques may be newer, have larger lipid cores taking up >40% of their volume, have more inflammation and thinner/weaker fibrous caps (in part related to the inflammation and metaloproteinases), and are the most vulnerable to sheer stress and rupture (and the resulting acute coronary syndromes). So, is mental stress-induced ischemia more sensitive and therefore more predictive of future cardiac events? Is it the canary in the coal mine???

-- there were many studies on stress and coronary artery disease decades ago, finding that stress-induced myocardial ischemia was really common (some studies finding it more common than exercise-induced), though this was done by regular old exercise stress tests. Also, typically the ischemic changes found on EKG were asymptomatic (??asymptomatic because mental stress testing is more sensitive in picking up much earlier lesions, and there is some discordance between symptoms and stress-test findings related to these smaller lesions identified??)

-- the effects of stress on the body have been studied extensively over the past many decades; a PubMed search today found 1,110,459 results in a search for “stress”. Many studies were done in the 1970s to 1990s, leading to the development of the field of psychoneuroimmunology, and the initiation of a journal with that name. These studies have found many important interactions between stress and human disease (the list is really large, so will limit a lot), including:

    -- the elaboration of stress hormones (catecholamines and cortisol)

    -- the effect of cortisol on pretty much all other hormones in the body (i.e. collateral effects from cortisol on most hormonal systems), with profound whole-body effects

    -- many potential effects on the heart: increased platelet activation, increased fibrinogen levels, stress cardiomyopathy (“acute myofibrillar degeneration”), increased myocardial sensitivity to catecholamines by higher cortisol levels, increased ventricular ectopy (presumably from sympathetic stimulation), coronary artery vasoconstriction, more endothelial dysfunction, more inflammation, increased ventricular mass: for example a study in workers put in stressful jobs showed increased left ventricular mass (presumably related to sympathetic stimulation): see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633295/ for a review of stress and cardiovascular disease

    -- effects on the immune system: changes in cytokine production, decreased antibody production in response to vaccines, decreased cellular responses, decreased natural killer (NK) cell activity (important for surveillance/prevention of cancer and infections): see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361287/ or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019042/ )

        -- stress can be associated with inflammation, both peripherally and in the brain (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476783/ ), including depletion of neurons in the hypothalamus, which can lead to decreased memory formation.

        -- A review article found that hypnosis and relaxation improve immune responses (see hypnosis relaxation and improved immune function stress2002 in dropbox, or Gruzelier JH. Stress (2002) vol 5 (2): 147-163) [there are many articles finding that strong support systems decrease the physiological effects of stress; this article reinforces that relaxation and hypnosis help]

        -- an impressive old study found that intradermal injection of a sensitizing agent (which typically led to a type 4, cell-mediated response, as is found with a positive PPD) in one arm vs saline in another led to the expected reaction with the sensitizing agent in the control group. But, in those hypnotized to believe that the placebo saline injection was the actual sensitizer, there was a typical appearing positive PPD-like response on the saline arm (though biopsy of the other side with the true sensitizer did show appropriate cellular infiltration but without the apparent PPD-like bump/erythema). Pretty interesting…..  (I believe the study was in the 1960s, though cannot find the actual reference in this well-before-internet article)

 

Limitations:

-- there were no granular, individual-level data on the mental stress of public speaking in terms of measurable markers of stress (catecholamine levels..). Did people with larger changes in serum markers (who likely internalized the stress more), have more cardiac events? If so, that would further support their conclusion that mental stress itself led to cardiac events, with perhaps a dose-response related to the level of catecholamines

    -- specifically, what is the role of stress-relievers (social support systems, relaxation, hypnosis, mindfulness, yoga, meditation)?? Some of the older studies actually measured the hormonal responses (cortisol, catecholamines) as a marker of the response to stress, and found that higher levels were more predictive of some outcomes (eg, stress-induced increases in blood pressure). Should we be assessing these patient-level responses to stress (it being omnipresent in current society) and using that to stratify those at higher risk of adverse outcomes?

-- this study only assessed the effect of an acute mental stress on cardiac events in people with underlying cardiac disease, which brings up several issues:

    -- acute stressors are omnipresent in our society.  Does the physiologic effects of public speaking mirror the effects of other stressors?

    -- is the effect of acute stressors in the predictive value of finding ischemic changes on cardiac testing the same for people without baseline heart disease? Does an accumulation of acute stressors over time lead to more heart disease and adverse outcomes? How does this tie in with the known cardiac risk factors? would this apply to people without baseline CHD? Would need a longer study to assess this, especially since those without baseline heart disease take longer to manifest that clinically

    -- there are physiological differences in the human response to acute vs chronic stressors (eg see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633295/ ). What is the relationship between repetitive acute stressors and chronic stress, with its physiologic effects? Hard to do a human study on this (submit a large number of people to acute stressors for a long time and compare outcomes to another group without acute stressors….???seems unlikely). Animal studies in the past have found that repetitive acute stressors do lead to chronic changes (eg, acute stress leading to transient increases in blood pressure ) in fact does lead to chronic changes (chronic hypertension).  Observational human studies assessing workers assigned to more stressful jobs have found increased left ventricular mass and cardiac symptoms vs those assigned to less stressful jobs. But not clear about long-term outcomes, and hard to assess without a truly randomized study with long-term follow-up (which, as noted above, will never happen….)

 

So, why is this study important? It reinforces the role of stress in terms of cardiac outcomes, something many of us knew (and for many decades, since so many studies were done in the 1970's to 1990’s). But it also raises the real issues:

-- are we clinicians consistently asking about stressors in people’s lives?

-- when we find important stressors (as we will probably quite often), do we consistently address them? Much of this is not something we can fix with a med (though some will have depression/anxiety, and meds might relieve some of these symptoms), much needs the help of other team members (counseling, etc, though we all do some of that), some need priority interventions (domestic violence), some need non-medical interventions (eg yoga, mindfulness, meditation, ?moving to Hawaii, or Bali before the adverse effects of climate change ruins everything), some requires larger social interventions (livable housing, access to food)......

    -- And, dealing with stress-related disease does require a pretty integrated approach to care, one that involves an array of providers (clinicians, social workers, counselors, etc) working together; this type of collaboration may not be available in many health care sites (but really should be….)

geoff

 

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