What Stress Does to Your Heart – Plus Some COVID-19 Catch-Up

by Michael Jorrin, "Doc Gumshoe" | February 9, 2022 1:01 am

What put me on to this scary topic was an excellent piece by Jane Brody in Science Times on January 4^th. Jane Brody’s weekly column “Personal Health” appears on the inside back page of Science Times every week. (For the non-NYTimes subscribers, Science Times is a section of the Times published every Tuesday.) Jane writes about scientific findings and how they affect people. Her perspective is that of a person who definitely understands the science and wants to express what that might mean to the rest of us. Doc Gumshoe has much the same motivation.

That mental stress[1] has physical consequences is not news. It has been generally assumed that stress is not good for us. However, most of us have been quite vague about the particular ways that stress is harmful, and the specifics of the harm. Jane Brody in her column says that she regrets not telling her father to avoid stress after his near-fatal heart attack. He had been warned to avoid lifting heavy weights. But Jane wishes he had been cautioned about emotional stress, such as over-reacting to frustration when the driver ahead of him was going too slowly in a no-passing zone.

Which reminds me of my own experience many years ago. I was driving up a very long steep hill on Route 22 in New York, and I noticed that the driver behind me was hot on my tail, dodging left and right, hoping to find a quick opportunity to zip by me. Naturally, I stayed in the middle of my lane and kept on at the same pace. At the top of the hill I pulled in to a gas station. The other car pulled in right behind me, and as I was getting out of my ancient VW, the driver stormed up to me and yelled at me about sightseeing while other people had places to get to in a hurry.

I turned to him and said, leisurely, “Calm down, buddy. You’ll have a stroke.” The guy looked stunned. He nodded his head and went back to his own car without another word.

What I thought then was that it was entirely possible that he had already experienced some kind of adverse event as a consequence of an uncontrolled emotional outburst. Actually, it would take a good deal more than an outburst of temper to trigger a stroke. Strokes are caused by interruptions of blood flow to the brain, usually because a blood clot has lodged in an artery in the brain. However, mental stress does have immediate physiological consequences. It’s immediately obvious that the heart beats faster, and it’s easily observed that blood pressure[2] increases. Many more subtle effects have been detected, including constriction and inflammation[3] of the arteries, which can cause blood clotting, insulin resistance, and also an increase in body fat.

Studying stress as a risk factor

The kind of stress resulting from uncontrolled anger was identified as a risk factor for cardiovascular disease[4] in the INTERHEART Study, which took place from 1999 to 2003. The study identified nine cardiac risk factors which they had determined were “modifiable”, meaning that it was possible to avoid or lessen the effect of each of these risk factors. These nine risk factors were smoking, lipids, hypertension[5], diabetes[6], obesity[7], diet[8], physical activity, alcohol[9] consumption, and what they termed “psychosocial stress.” The study was very wide-ranging and comprehensive, taking place in 262 sites in 52 countries and involving 29,972 participants.

Calling these risk factors “modifiable” has a range of implications. At one end, a person can quit smoking and stay off the hooch. But hypertension and diabetes cannot be avoided by a simple exercise of will. These risk factors have to be treated in order to be modified, and many, many people have hypertension and diabetes for years before being diagnosed. “Modifiable” means that the risk factors are not the result of anatomy or genetics.

Even though the INTERHEART study was initiated more than 20 years ago, it was not until August of 2020 that a detailed examination of the association between psychosocial stress and cardiovascular disease was published. (Osborne MT. “Disentangling the Links Between Psychosocial Stress and Cardiovascular Disease,” Circulation: Cardiovascular Imaging,” 2020;13:e010931).

That study leads off by citing instances where acute stress led to markedly increased short-term CVD risk. One example was the Northridge earthquake, in the San Fernando Valley near Los Angeles. That event was linked with a near quadrupling of sudden cardiac death on the day it occurred. And then, in the week following the earthquake, the incidence of cardiac death was unusually low. The implication is that the stress of the earthquake triggered those deaths in individuals with pre-existing cardiac risks.

Another example was the pattern of cardiac deaths that occurred in Germany during the 2006 Football World Cup. On days that the German team played, local cases of acute coronary syndrome increased 2.7 times, and on days when Germany was playing in close games or elimination contests, that rate increased by a factor of 6. In contrast, there was no increase in the rate of acute coronary syndrome on days when the German team did not play.

And a recent Scandinavian study reported that in the week after the death of a child, the parent’s risk of a heart attack tripled.

Those are examples of acute stress and probably outside the territory of usual psychosocial stress. It’s beyond me why having the home team involved in “crucial” soccer matches should constitute significant stress. I guess the take-away is that our bodies don’t question what kind of stress it is – if we experience something as stress, our physiology doesn’t question whether or not we should perceive that something as stress. What these examples do is confirm the relationship between stress and CVD.

Other types of stress


It should be no surprise that a great many people are under nearly constant stress because of how and where they live. In New York City, many people live in apartments that directly face onto the elevated tracks where the subway rushes by every few minutes, emitting huge noises that walls and windows do not keep out. Chronic environmental noise exposure is strongly linked with heightened systemic inflammation, oxidative stress, and risk for CVD and metabolic disease. People living in neighborhoods with lower socioeconomic status – higher crime rate and/or lower income – tend to have higher rates of CVD and other chronic diseases such as type 2 diabetes. But some individuals living under conditions of chronic environmental stress do not experience higher rates of CVD events. These could be said to be neurobiologically resilient. Of particular interest, when some of these resilient individuals are examined, they reveal lower levels of activity in the amygdala, which is the brain center that processes any signs of stress. Some knowledgeable people call the amygdala the brain’s “fear center.” Perceptions that threaten us in any way are identified by the amygdala, which alerts us to the threat.

Stress and our brain

The amygdala responds by sending messages to other parts of the body to prepare us for the possible necessity of either engaging in combat with whatever it is that is causing the stress, or escaping from the potential aggressor – the so-called “fight or flight” response.

Some of the immediate physiologic effects of that response are increases in heart rate and blood pressure, and constriction of the arteries. All of these could be said to prepare us for combat. But also, the fight or flight response sends signals that lead to the accumulation of body fat, perhaps in anticipation of future need for stored sources of energy.

One of the main effects of stress is that the amygdala directs a switch from the parasympathetic nervous system to the sympathetic nervous system. These parallel nervous systems alternate their control over many of our physiologic functions. The parasympathetic nervous system is in control mostly when we are sleeping or at rest. Heart and breathing rates slow, muscles are relaxed, the digestive system is active; we are primed neither for fight nor for flight. The parasympathetic nervous system operates through a set of nerves distinct from those that the sympathetic nervous system employs.

The sympathetic nervous system (SNS) is the one that controls what we do consciously. When your doctor tells you to take a deep breath and hold it, it’s the SNS that sends the signals to your lungs and muscles. Then, when the doctor says to breathe normally, it usually takes a few moments for the SNS to let go and let the parasympathetic nervous system take over.

At the same time that the amygdala, in response to stress, tells the SNS to take command, it also triggers the activity of several glands including the pituitary and adrenal glands. One of the many effects is the release of glucocorticoids, which lead to increased fatty tissue, insulin resistance, and hypertension.

Another effect of SNS stimulation is the release of epinephrine and norepinephrine, which add to the general effects of the SNS in increasing arterial constriction and peripheral vascular resistance.

Stress also has effects on the immune system, causing the release of inflammatory cells and macrophages, which are white blood cells that attack and consume bacteria. However, this stress-induced immune reaction and cytokine production also potentiates atherosclerosis. The glucocorticoids, whose release is triggered by stress, tend to suppress antiviral[10] gene programs such as interferon factors. Thus, stress increases the risk of becoming infected with viruses.

The effects of stress on hormonal activity and inflammation also increases blood coagulation, which, together with the other avenues through which stress produces atherosclerosis, further raises the odds of an acute coronary event.

Measuring stress

There are basically two general approaches to measuring stress. One way is essentially to ask the subject whether he/she is experiencing stress, to what degree, and in what form. This is mostly done by using tools called “psychometric questionnaires,” such as the Perceived Stress Scale-10 and the Perceived Stress Questionnaire. The utility of these is limited, since they only measure a person’s perceived emotional response to stress, which may diverge from the neurologic and physical manifestations of stress.

There are several methods of capturing the physiological impacts of stress. Measuring heart rate variability and skin conductance response can reveal the variability of sympathetic and parasympathetic nervous system activity. Blood, urine, hormone, hair, or saliva can yield measures of sympathetic nervous system activity affecting the pituitary and adrenal glands.

Advanced neuroimaging techniques, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can instantaneously measure the neural response to rapidly-changing stimuli. PET-computed tomography can measure metabolic activity in various body tissues including the brain. Uptake of one particular molecule, F-fluorodeoxyglucose, is associated with anxious temperament in adults and predicts future anxiety in juveniles. Activity in the amygdala, which we identified as the brain center that processes stress signals, predicts subsequent cardiac diseases and events.

These neuroimaging studies have demonstrated strong associations between stress, as measured by those studies, and cardiovascular disease. In an fMRI study in 36 individuals, heightened activation in the amygdala and connectivity with the anterior cingulate cortex was shown to be strongly linked with atherosclerosis. The anterior cingulate cortex is a part of the brain where several cognitive functions take place, such as empathy, impulse control, emotion, and decision-making. In another study in 293 individuals with no prior CVD, activity in the amygdala was robustly linked with subsequent CVD events.

A clinical trial that induced stress in patients with coronary heart disease

This was an analysis of two prospective cohort studies in patients with existing stable coronary heart disease, recently published in JAMA (Vaccarino V, “Association of Mental Stress-Induced Myocardial Ischemia with Cardiovascular Events in Patients with Coronary Heart Disease.” JAMA 2021;326(18):1818-1828). One group, consisting of 618 subjects, participated in the Mental Stress Ischemia Prognosis Study (MIPS), which provoked a degree of stress and also myocardial ischemia by having participants engage in a public speaking task. (Myocardial ischemia occurs when blood flow to the heart is blocked or reduced, depriving the heart of the oxygen it needs to keep pumping.) A second group, 300 subjects, was enrolled in the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Stress levels in all study subjects were assessed using neuroimaging techniques. Participants in the two studies were enrolled between June 2011 and March 2016, and the last follow-up was in February 2020.

The primary end-point of the trial was a composite of cardiovascular death or first or recurrent nonfatal myocardial infarction. A secondary end-point included hospitalizations for heart failure. Of the 918 subjects, 147 (16%) experienced mental stress-induced ischemia and 281 (31%) experienced conventional (i.e., due to an external cause) stress ischemia. Among subjects with mental stress, the pooled event rate – i.e., a composite of both end-points – was 6.9 per 100 patient-years, while in subjects without mental stress, that event rate was 2.6 per 100 patient-years. Subjects who experienced both mental stress-induced ischemia and conventional stress-induced ischemia had a significantly elevated risk of experiencing any one of the studies end-points, 8.1 per 100 patient-years, while the event rate in subjects who did not experience stress-related ischemia was 2.3 per 100 patient-years. Subjects who experienced only conventional stress ischemia did not have a significantly increased event rate, 3.1 per 100 patient-years.

It should be pointed out that the degree of stress in this trial was quite mild, compared with the death of a child or being in the midst of an earthquake – or, for that matter, financial or physical insecurity. It is also a near-certainty that in the several years that the subjects were involved in the study they experienced other forms of stress. However, the differences in the cardiac outcomes between the cohorts grouped as to the type and level of stress they experienced in the study confirm the conclusion that stress contributes to cardiovascular disease.

So, if stress does cause cardiovascular ills, what can be done about it?

Next steps

Dr Michael Osborne, one of the authors of the Circulation study cited above, is involved in a stress-reducing program called SMART-3RP (Stress Reduction and Resiliency Training – Relaxation Response Resiliency Program). The program will use techniques such as mindfulness-based stress reduction, yoga, and transcendental meditation, as well as stress-reducing practices such as physical exercise and good sleep habits.

The stress researchers have thus far abstained from recommending any pharmaceuticals as a means of reducing stress, although antidepressants have been mentioned by some. Speaking for myself, I would be highly surprised if, now that the relationship between stress and heart disease has been brought before the public eye, pharmaceutical companies did not put forward some of their own products as a means to minimize stress and thereby reduce the odds of experiencing a serious cardiac event. It may take a few years, but it’s coming.

I haven’t mentioned it up to this point, but we can be fairly certain that a major cause of stress at this time is the continuing COVID-19 pandemic. Some people definitely experience stress when, in a public place, an unmasked person gets too close. And the daily barrage of news about the pandemic is not exactly relaxing, even if some of the news is relatively positive.

Doc Gumshoe has stayed away from the COVID story for the last while, but a bit of catch-up is probably needed.

Covid-19 Catch-Up

Here’s the overall picture as of Monday, February 7th. The unofficial US COVID toll is 76,513,221 cases and 902,650 deaths. The current 14-day average for new cases is 431,000, and for deaths it is 2,415. It’s generally admitted that those numbers are undercounts – with regard to cases, probably a huge undercount. As regards deaths, another unofficial figure is that, in the past couple of years, there have been upward of one million so-called “excess deaths,” meaning deaths in excess of the annual averages. So, in all probability, the number of COVID-19 deaths in the US is higher than the 902,650 recorded at this date. Some experts have put the likely number of fatalities to be well over one million.

Looking at the case numbers, the pandemic appears to have peaked in mid-January, at least in parts of the US. The daily death counts have stayed relatively level; they do not seem to be on a downward trajectory at this time. But, at least for those of us who are vaccinated and boosted, a closer look at the death counts provides encouraging news.

Weekly average deaths per 100,000 population

Unvaccinated: 7.8 deaths per 100,000 – 78 deaths per million
Vaccinated: 0.6 deaths per 100,000 – 6 deaths per million
Vaccinated & boosted: 0.1 deaths per 100,000 – 1 death per million

These are CDC figures from November 2021, but I see no indication that they have changed much in the past month or so.

Globally, the picture is not that encouraging. According to the John Hopkins dashboard, as of February 1, there have been 5,680,118 deaths. However, this is certainly a major undercount. Over 100 nations on our planet do not record any reliable statistics on the number of deaths that have taken place in their countries, or on how many deaths normally occur in a year, so there is no accurate basis for comparing actual annual deaths with expected deaths. The Economist, a publication in the UK, did a careful estimate of the COVID-19 toll, based on the best data available from a huge range of sources, and came up with a range of the total death toll at this time – between 12 and 22 million deaths.

Sondre Ulvund Solstad, a data scientist who leads The Economist’s modeling work, said “The only fair thing to present at this point is a very wide range. But as more data comes in, we are able to narrow it.”

Here’s what the COVID-19 death toll looks like (per The Economist’s estimate) compared with the previous flu epidemics:

[11]

The assumption that excess mortality is entirely due to COVID-19 is questionable. Or perhaps we should say that some deaths from other causes or diseases might ultimately be due to COVID – for example, deaths in persons who could not get treatment for an emergency because hospitals were swamped with COVID patients, or deaths in persons who did not keep doctor’s appointments because they did not want to risk visiting the doctor’s office. It is also the case that the crime rate, including the murder rate, has gone up since the pandemic started. And traffic deaths are the highest in the past 15 years. So perhaps in a broad sense, we can attribute overall excess mortality to the worst pandemic in a century.

The Omicron variant

By now, everyone knows that Omicron is more transmissible than the SARS-CoV-2 strains that caused all those COVID-19 cases prior to November of 2021. And we know that the experts believe, or at least optimistically speculate, that Omicron causes significantly less severe disease in most people. We know this, because while currently Omicron is the cause of about 95% of tested cases in the US, neither hospitalization nor death rates have increased nearly at the same rate as new cases. Is this merely because hospitalization and death rates lag behind initial infection rates? That might be so if the steep rise in new case rates had begun a couple of weeks ago – we might not yet be seeing the resulting steep increase in hospitalizations, intubations, and death. But the steep rise started about six weeks ago, so if Omicron was as deadly as Delta, we’d be seeing signs of that.

A principal reason that Omicron may cause much less severe disease than previous coronavirus[12] variants is that the virus seems mostly to infect the throat and the nasal passages, and does not travel to the lungs, which is where the most severe COVID pathology takes place. This is especially the case among the vaccinated.

Omicron, as some of us may have heard, is not a single variant. There are at least two sub-variants, thus far. The one that was spotted first has been labeled BA.1. A sibling virus, named BA.2, had been detected, but at first it wasn’t causing much trouble.

However, at this time there is evidence that BA.2 is even more transmissible than BA.1. It has now become the dominant variant in India[13] and Denmark, and it’s picking up momentum in several countries, from South Africa[14] to the Philippines to Sweden[15]. The UK has predicted that BA.2 would become the dominant strain there this early 
Spring. US prevalence is very small, but it seems to be on the rise.

So far, nobody has any notion of whether the people who have recovered from BA.1 will have immunity from BA.2. The general expectation is that after vaccination[16] plus exposure to the coronavirus, subsequent infections (if and when they occur) are increasingly likely to be mild. There is always the possibility of the virus evolving to become more virulent (meaning likely to cause more severe disease), but as I have tried to explain in these pages, a more virulent virus is much less likely to spread, because once symptoms emerge, substantial precautions are quickly adopted. Transmissibility goes hand in hand with asymptomatic infection.

A few brief bulletins

Pfizer and BioNTech are about to launch a clinical trial to evaluate a specific vaccine for the Omicron variant. However, a recent study found that antibodies that can prevent infection from Omicron persist for about four months after the booster shot of the original Pfizer/BioNTech vaccine.

The central importance of cellular immunity, carried out by T-cells, was emphasized by Professor Galit Alter, who heads the Massachusetts Consortium on Pathogen Readiness. She stressed that once they identify cells as being infected, they eliminate them in a targeted way to curb disease. She said, “These mechanisms are shown to be critically important against many, many different viruses, including influenza[17], respiratory syncytial virus, as well as many bacterial infections, and they are critical for eliminating tumors. The T-cell response has not gotten quite as much attention as antibodies, but it is clearly induced by many of these vaccines, and likely to be a key mechanism by which we still continue to respond to the virus.” Even when the vaccines fail to prevent infection, the T-cell responses help clear the infection before it can cause disease.

Finally, the January 29th issue of Lancet published an article entitled “COVID Will Continue but the End of the Pandemic Is Near.” (Lancet 2022 01/29/22 399;10323;417-419). The gist of the article is that the Omicron wave will reach every corner of planet earth, with the estimated global rate of infection at about 125 million cases per day. The unprecedented level of infection suggests that more than 50% of the world will have been infected with Omicron by the end of March, 2022. The article describes the spreading infection and, at the same time, decreasing severity of illness, pointing to examples such as Greece[18], Canada[19], and South Africa, where only a very small percentage of infected persons require hospitalization.

The Lancet paper concludes with this:

“COVID-19 will become another recurrent disease that health systems and societies will have to manage. For example, the death toll from omicron seems to be similar in most countries to the level of a bad influenza season in northern hemisphere countries.

The era of extraordinary measures by government and societies to control SARS-CoV-2 transmission will be over. After the omicron wave, COVID-19 will return but the pandemic will not.”

I think they know what they’re talking about.

*****

The COVID pandemic has focused a lot of attention on vaccines, pro and con. And vaccine controversies have been around for quite a while. The rapid development and production of the highly effective COVID vaccines has been saluted as a major step in disease control, and not just the control of the coronavirus. The science has evolved to the point where effective vaccines against many other diseases are distinctly possible. Doc Gumshoe is going to take a look at the history of vaccines and speculation about their future. Meantime, comments and questions of every flavor are welcome. Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers a couple times a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.[20]]

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