stress-induced cardiovascular disease

 Mental stress is associated with major adverse cardiovascular events. This study found endothelial dysfunction associated with mental stress, noting that a marker for endothelial dysfunction was not only associated with increased cardiovascular outcomes, but also contributed highly to our standard cardiac risk prediction model (see stress endothel dysfunction and MACE jamacardiol2019 in dropbox, or doi:10.1001/jamacardio.2019.3252). thanks to Holly Gooding for referring me to the researcher Viola Vaccarino, who has been involved in many studies on stress and who kindly sent me this and others of her studies 

  

Details:  

-- 569 patients with baseline CAD had flow-mediated vasodilatation of the brachial artery (an assessment of endothelial function) before and after mental stress, from the Mental Stress Ischemia Prognosis Study at Emory University 

    -- baseline CAD was defined as abnormal coronary angiography, documented previous PCI or surgical coronary vascularization, or positive nuclear stress test 

    -- flow-mediated vasodilation (FMD) was assessed noninvasively, documenting endothelium-dependent brachial artery response by ultrasound, measured before and 30 minutes after a mental stress test 

        -- mental stressor: after a 12-hour fast, patients were put in a quiet, dimly lit, temperature-controlled room for a 30-minute rest, and vital signs were measured. The patients were asked to imagine a stressful encounter with a close relative being mistreated, prepare a 2-minute statement, and present it for 3 minutes in front of a video camera and an audience wearing white coats. These patients were told that they would be evaluated by the content and duration of their speech. 

-- mean age 63, 74% men, mean of 15 years of school 

-- current smoking 13%, diabetes 33%, hypertension 77%, dyslipidemia 82%, BMI 29.8, lifetime history of major depression 27%, prior MI 39%, heart failure 24%, prior revascularization 55%, CAD severity by measured Gensini score median 24 (Gensini score quantifies CAD severity, with up to 32 points for a single totally occluded coronary) , ejection fraction 52%, high sensitivity CRP 3.9 

-- meds: aspirin 87%, beta blockers 74%, calcium blockers 22%, ACE 46%, antidepressants 23%, statins 86% 

 

-- main outcomes: 

    -- flow-mediated vasodilation measured pre- and post-stress, as well as the delta (post-stress minus pre-stress levels) 

    -- an adjudicated composite endpoint of major adverse cardiac events (MACE): cardiovascular death, myocardial infarction, unstable angina leading to revascularization, and heart failure hospitalization, after a median follow-up period of 3.0 years 

        -- outcome data was collected at clinic visits at years 1 and 2 and by telephone calls at year 3 

  

Results:  

-- 360 participants (63%) developed transient endothelial dysfunction 

-- 74 patients experienced MACE: 13 cardiovascular deaths, 15 MIs, 34 unstable angina events followed by revascularization, 12 hospitalizations for heart failure 

  

-- difference between the groups with vs without transient endothelial dysfunction: 

    -- beta blocker use: 79% without vs 70% with endothelial dysfunction, p=0.03 

    -- history of depression or heart failure: strong trend to more transient endothelial dysfunction  

    -- pre-stress FMD levels were not associated with the composite or any of the individual MACE endpoints 

  

-- before mental stress: brachial artery diameter 3.7 mm (standard deviation, SD 0.9 mm) and FMD 4.8% (SD 3.7%) 

-- after mental stress: brachial artery diameter decreased by 0.2 mm (SD 0.1), and FMD decreased by 0.9% (SD 0.3%) to 3.9% (SD 3.6%), a 23% decline, p<0.001.

  

-- During mental stress testing:  

    -- systolic BP increased from 128 mmHg to 169 mmHg, p<0.001 

    -- heart rate increased from 61 to 78 bpm, p<0.001 

    -- circulating epinephrine levels increased from 18.9 pg/ml to 32.2 pg/ml, p<0.001 

  

-- Transient endothelial dysfunction associated with the mental stress: 78% MACE increase, HR 1.78 (1.15-2.76) after full adjustment 

    -- post-stress flow mediated vasodilation: 14% increase in MACE after full adjustment for each 1% decline, HR 0.14 (1.04-1.24) 

    -- the delta flow mediated vasodilation: 15% increase after full adjustment for each 1% decline, HR 1.15 (1.03-1.27) 

        -- full adjustment included sex, African-American race, age, hypertension, diabetes, dyslipidemia, prior MI, heart failure, BMI, current smoking, high-sensitivity CRP, medication use, baseline brachial artery diameter and shear rate, coronary artery disease Gensini severity score, prior revascularization, and ejection fraction 

    -- BUT, unlike post-stress endothelial dysfunction, pre-stress FMD levels were not associated with the composite MACE endpoints or any of the individual MACE components 

    -- though there was an additive effect of transient endothelial dysfunction with a low pre-stress FMD level; this group had the highest risk of MACE 

  

-- Controlling for the array of accepted cardiovascular risk factors (sex, age, race, hypertension, dyslipidemia, prior MI, heart failure, BMI, diabetes, smoking history, and high-sensitivity CRP), adding their delta FMD to the standard cardiac risk prediction model led to: 

    -- patients experiencing MACE (n=74): for those with low anticipated cardiovascular risk (<13%) by the standard risk model, 49 were correctly reclassified as low risk by adding in their delta FMD and 17 were classified as high risk (i.e. 20% were reclassified correctly as a result of including FMD) 

        -- high cardiovascular risk (at least 13%): 2 were reclassified as low risk and 6 as high risk 

    -- for those not experiencing a MACE (n=465): 

        -- low anticipated risk(<13%): 434 remained at low risk and 19 were reclassified as high risk as a result of adding in the delta FMD 

        -- high anticipated risk (at least 13%): 6 were reclassified as low risk, and 6 remained at high risk 

    -- overall, a highly statistically significant effect on getting the correct risk reclassification, p=0.008 

--here is a table exemplifying this (may be easier to read)

  

Commentary:  

-- psychological stress is associated with increased cardiovascular morbidity and mortality: a meta-analysis of 41 articles found that both greater reaction to stress and poor recovery from stress were associated with poor cardiovascular status; also, these stress parameters were associated with higher future systolic and diastolic blood pressures (see Greater Cardiovascular Responses to Laboratory Mental Stress Are Associated With Poor Subsequent Cardiovascular Risk Status | Hypertension (ahajournals.org), which provides more info suggesting that chronic acute stressors is associated with chronic hypertension)

-- prior studies had shown that increased stress was associated with decreases in brachial artery FMD, lasting up to four hours after the end of the stressful task 

-- and, lower FMD has itself been associated with adverse cardiovascular outcomes 

  

-- This current study prospectively evaluated the prognostic value of transient endothelial dysfunction measurement after mental stress in patients with CAD, finding that those with a greater decrease in FMD had a higher rate of incident cardiovascular death and major cardiovascular disease outcomes, independent of other patient characteristics and pre-stress FMD levels: ie, there seemed to be the chain of mental stress leading some people to increased  endothelial dysfunction soon after the mental stress, and in that group to longer term severe adverse cardiovascular events 

    -- a significant change in FMD after mental stress was found to be a useful biomarker for subsequent CAD, adding important value to the usual cardiovascular risk factors as a predictor of subsequent MACE

-- suggested potential mechanisms: 

    -- likely that the transient impairment of brachial artery FMD was from sympathetic stimulation: 

        -- stress does induce epinephrine release, as found in this study 

        -- the blood pressure and pulse elevations with mental stress were likely related to the catecholamines 

        -- fewer people had FMD changes when they were on baseline beta blockers, which can blunt the sympathetic response 

    -- there may be other reasons, such as immune responses, oxidative stress, endothelin release 

    -- there does seem to be a strong relationship between brachial artery endothelial dysfunction and coronary artery endothelial dysfunction measured during cardiac catheterization  (see Close relation of endothelial function in the human coronary and peripheral circulations - ScienceDirect ) 

  

-- this study therefore raises the question of how to incorporate an assessment of mental stress responses into overall cardiovascular risk assessment.

    -- older studies have found that analyzing just the stressor, whether physical (eg explosion) or mental (eg stressful speaking as in the above study), is insufficient. Some people have a more intense sympathetic response than others. And those living in emotionally supportive environments tend to have less significant stress responses 

    -- it is likely that some stressors will elicit different responses than others in the same individuals, perhaps related to past experiences (my guess is that someone coming from a war-torn country might have a more profound response to fireworks than other stressors….) 

    -- we need an easy, simple stressor and means to evaluate the individual’s stress response, since I suspect many of us in primary care are unable to replicate the high-pressure speaking stress of this study.... Some thoughts: 

        -- a virtual reality stressor that we can use in the office?? 

        -- older studies have had patients do mental arithmetic under time pressure (where, I suppose, the level of the mathematical challenge would need to be geared to the individual??), or sorting ball-bearings of similar size under time pressure.  

        -- and, perhaps using vital signs as a marker of the stress response, either in the office or outside:

           -- blood pressure variability might be a marker of real-life stress. It is clear from several studies that blood pressure variability is associated with increased cardiovascular disease (eg see http://gmodestmedblogs.blogspot.com/2016/09/blood-pressure-variability-increases.html  or http://gmodestmedblogs.blogspot.com/2015/07/blood-pressure-variability-and-heart.html ).  And, given the clear relationship between mental stress and blood pressure, would blood pressure variability be an accurate surrogate marker of mental stress?? Blood pressure variability is altered by blood pressure medications, and some produce much less variability (eg amlodipine) vs others with much larger swings (hydrochlorothiazide), and there are arguments in the medical literature that this difference should influence our choice of hypertension meds (see http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html ).  But it might be worth seeing if measuring this BP variability were useful. Or perhaps pulse variability (which also may track with catecholamines, and much easier to access), though some meds (b-blockers, non-dihydropyridine calcium channel blockers) clearly affect pulse response. As noted in this article, b-blockers seemed to decrease the endothelial dysfunction (per measured FMD). Maybe we should use them more often in those with significant pulse variation during the day??? An issue to explore, since b-blockers have been relegated to a second tier for blood pressure control (though first-tier for post-MI control)

    --But, in sum, we do need a mental challenge which can elicit stress response pretty reliably, and verified through robust studies. Since measured FMD in this study post-stress was so reliable, we could just do some smaller studies to find a suitable surrogate for changes in FMD, and then test that in a larger study with clinical cardiovascular outcomes?? 

  

-- another issue: are there modifiable stress-reducers that would actually change the cardiovascular outcomes? One would think so, if sympathetic stimulation were the mechanism. But that is just an hypothesis. We need to have trials of non-medical relaxers (meditation, tai chi, yoga, mindfulness, self-performed cognitive behavioral therapy,…) as well as medical ones (beta-blockers, etc) to see if those with higher response to stress have better cardiovascular outcomes

  

Limitations: 

-- this study involved patients with pre-existing coronary artery disease, so might not be applicable to the general population 

-- there are many unanswered questions that would need answers for the results of this study to be clinically useful, as suggested above: a reliable easy stress test, a reliable easy measure of the individual’s response to that stressor, and reliable interventions that would decrease that response when abnormal and also decrease clinical cardiovascular events 

-- this study looked only at cardiovascular events. Are there other benefits (all-cause mortality, cancer, …) or risks from mental stress that should be measured and incorporated into the model? 

-- we do know that individuals react to different potential stressors differently. How does the speak-under-stress model above reflect a more global response to stress? Is there a better stressor that is more globally predictive of the physiological effects of mental stress?  we cannot assume that the most standardized stressor used (the speaking one) sufficiently reflects the response to life’s stressors in the real world.  Would need studies looking at this. As above, perhaps some studies on blood pressure variability in different circumstances? Perhaps using 24-hour ambulatory monitoring? Or other quantitative assessments (?hormones, cortisol, multiple catecholamine assessments??) 

  

So, a pretty powerful study, reinforcing many stress studies dating back decades, finding that mental stress is a very large and important part of cardiovascular risk. One major task at hand is to provide easy-to-use tools to assess the individual response to stress. And, this seems to be really important since our lives are so fundamentally stressful, and at least the speaking stressor in this study seems mathematically to be really important in terms of predicting future clinically important cardiovascular outcomes, as well as improving our current cardiovascular risk predictor assessed by the standard cardiac risk factor model. 

geoff

 

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