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MENTAL STRESS IS A CAUSE OF HEART DISEASE
From scepticism to certainty
Professor Murray Esler *
There has been a recent resurgence of support for the idea, often in the past banished
to the realm of medical folklore, that mental stress and psychological illness is a cause
of cardiovascular disease. This support, however, has been in the face of a high level of
scepticism, very explicitly illustrated in the deliberations of a panel charged with
reviewing the topic for an Australian national health body on which one of us served.
The opening address of the chairman included the opinion, “there is no evidence that
stress causes heart disease, nor will there ever be”. In this manuscript I aim to correct
the chairman’s error.
(a) Acute mental stress: “Triggering” of heart attacks
It has always seemed plausible that short-term mental stress can act as a trigger for the
development of abnormal heart rhythm and sudden death in patients with existing heart
disease. For many years this claimed relation of acute mental stress to heart attacks
was largely based on individual anecdotes, such as the celebrated case of the famous
18th century English surgeon, John Hunter, who wrote that he was at the mercy of any
scoundrel who aggravated him, then proved the point by dying suddenly in the middle of
a stormy meeting of the board of his hospital.
Some people are predisposed through genetic flaws to heart risk at times of mental
stress, such as those with inherited variants of the long QT interval syndrome, in whom
abnormal ion transport in cardiac myocytes causes electrical instability of the heart
muscle (Zipes, 1991). In recent years systematic evidence has been gathered at times
of disasters, including war, missile attacks on civilians and earthquakes, which also
strongly supports the proposition of a mental stress-heart attack link. Research linking
mental stress to sudden death is often disputed because of disagreement over what
constitutes a stress, and whether stress can be accurately measured.
Evidence that rates of sudden, non-traumatic death is markedly increased during
earthquakes, the 1994 Los Angeles earthquake providing a very telling example (Leor,
Poole & Kloner, 1996), is free of this criticism, as here no finessing is needed in the
psychological measurement of stress. During an earthquake, no doubt everyone is
terrified. Are heart attacks during community disasters a special case only, or of more
general relevance? In individual personal life, “emotional earthquakes” do occur. In my
practice of cardiology I have seen heart attacks triggered by armed robbery, assaults,
and even a racehorse winning by a “nose”.
The biological mechanisms by which acute mental stress triggers heart attacks are clear
(Rozanski, Blumenthal & Kaplan, 1999). First, this occurs almost exclusively in those
with existing atherosclerotic coronary artery narrowing, although this may have been
clinically silent and unrecognised. In the presence of coronary artery stenosis and
myocardial ischaemia, the preferential activation of the sympathetic nervous outflow to
the heart with acute mental stress (Esler, Jennings & Lambert, 1989) can cause
ventricular arrhythmias. Increased adrenaline secretion by the adrenal medulla activates
platelets, predisposing to thrombosis.
The accompanying blood pressure surge can fissure coronary artery plaques, providing
a focus for this thrombosis, leading to myocardial infarction. Delineating these biological
mediators of heart risk in acute mental stress (Rozanski, Blumenthal & Kaplan, 1999)
provides a potential target for pharmaceutical prevention, to inhibit platelet activation
and block adrenergic cardiovascular stimulation.
Panic disorder and heart risk
Panic disorder sufferers often fear that they have heart disease, because of the nature of
their symptoms, but in the past have been reassured that this is not the case.
Epidemiological studies, however, indicate that there is an increased risk of myocardial
infarction and sudden death in patients with panic disorder (Kawachi, Colditz, Ascherio,
Rimm, Giovannucci, Stampfer & Willett, 1994; Kawachi, Sparrow, Vokanas & Weiss,
1994; Albert, Chae, Rexrode, Manson & Kawachi, 2005). This increased cardiac risk
applies not only to men who are of such an age that unrecognized underlying coronary
artery disease may be present, but also exists in pre-menopausal women who in general
have low coronary risk.
Mechanisms of Cardiac Risk in Panic Disorder
The epidemiological studies cited indicate that there is an increased risk of sudden death
and myocardial infarction in patients with panic disorder. In my own extensive clinical
experience with the cardiological management of panic disorder sufferers, I have
encountered case material which indicates the range of cardiac complications which can
occur during panic attacks, variously; triggered cardiac arrhythmias, recurrent
emergency room attendances with angina and ECG changes of ischaemia, coronary
artery spasm in attacks occurring during coronary angiography (Figure 1) and
myocardial infarction associated with coronary spasm and thrombosis (Mansour,
Wilkinson, Jennings, Schwarz, Thompson & Esler, 1998).
 Figure 1:
Left Panel: Coronary artery spasm in
the left anterior descending coronary
artery during a panic attack,
documented at coronary angiography.
Patient was a 51 year old woman with
unmedicated panic disorder and
anginal pain during panic attacks
Right Panel: Reversal of the spasm
with glyceryl trinitrate (GTN)
Sympathetic Nervous System Activation During Panic Attacks
The recent research studies of my group suggests that activation of the sympathetic
nervous system during panic attacks may be a mediating mechanism (Wilkinson,
Thompson J, Lambert, Jennings, Schwarz, Jeffrys, Turner & Esler, 1998; Alvarenga,
Richards, Lambert & Esler, 2006).
Using subcutaneous multifibre sympathetic nerve recording my group has documented
stimulation of the sympathetic nervous system during panic attacks (Figure 2),
accompanied by a surge of secretion of adrenaline from the adrenal medulla.
Sympathetic nervous tone at rest is normal, but our results indicate that the sympathetic
nerves of panic disorder sufferers release adrenaline as a cotransmitter.
This adrenaline in sympathetic nerves of panic disorder sufferers is presumab
ly taken up
from plasma during panic attacks, or synthesised in situ by the adrenaline synthesising
enzyme, phenylethanolamine methytransferase, which has been shown in experimental
animals to be induced by chronic mental stress (Micutkova, Krepsova, Sabban,
Krizanova & Kvetnansky, 2004) and is present in sympathetic nerves in panic disorder
(Esler, Eikelis, Schlaich, Lambert G, Alvarenga, Dawood, Kaye, Barton, Pier, Brenchley,
Jennings & Lambert E, 2008).
This sympathetic neural adrenaline cotransmission is potentially a cause of cardiac
arrhythmias.
 REST
 PANIC ATTACK
Figure 2: Multiunit sympathetic nerve recording of postganglionic sympathetic fibres
innervating the skeletal muscle vasculature, from the peroneal nerve at the head of the
fibula. The size of multiunit sympathetic bursts increased remarkably during a panic attack,
by recruitment of individual firing fibres.
Chronic mental stress
Many, not the least some medical expert witnesses in workplace litigation cases before
the courts, remain unconvinced that chronic mental stress can cause cardiovascular
disease.
Evidence of recent years, however, does provide a strong case for a causal relationship,
with both essential hypertension and coronary heart disease.
Hypertension
The general public hav
e needed little persuasion that chronic mental stress can cause
hypertension, sometimes even using the word “hypertensive” as a psychological
descriptor, for describing excitable or agitated behaviour. Many personally relate to the
“tense” in hypertension, and perhaps may be too ready to attribute their elevated blood
pressure to stress in their job, or in their domestic life.
Epidemiological research provides strong support for the notion that behavioural and
psychological factors may be important in the pathogenesis of essential hypertension. Of
particular importance in this regard are long-term follow-up studies of human
populations, such as the celebrated study of cloistered nuns in Umbria (Timio,
Verdechioa, Rononi, Gentili, Francucci, & Bichisao, 1988) who lived in a secluded and
unchanging environment, and in whom blood pressure did not show the expected rise
with age.
Also important are studies linking hypertension development to chronic mental stress in
the workplace (Steptoe & Willemsen, 2004; Rosengren, Hawken, Ounpuu, Sliwa,
Zubaid, Almahmeed, Blackett. Sitthi-amorn, Sato & Yusuf, 2004; Chandola, Brunner &
Marmot, 2006). Additional pertinent observations have been made on human
populations who demonstrate blood pressure elevation soon after migration (Poulter,
Khaw, Hopwood, Mugambi, Peart, Rose & Sever, 1990), this rise in pressure being
attributed primarily to mental stress, although changes in physical activity and diet are
also operative.
The recent research of the Baker Heart Research Institute group identifies the presence
of stress biomarkers in patients with essential hypertension (Esler, Eikelis, Schlaich,
Lambert G, Alvarenga, Dawood, Kaye, Barton, Pier, Brenchley, Jennings & Lambert E,
2008).
This research approach, which breaks radically with the epidemiological methodology of
the past, has established that the stress hormone, adrenaline, is released as a
neurotransmitter from autonomic (sympathetic) nerves in essential hypertensive
patients, but not in health (Figure 3)(Rumantir, Jennings, Eisenhofer, Lambert, Kaye,
Seals & Esler, 2000).
This provides strong evidence that patients with high blood pressure have been exposed
to recurrent stress in that, as discussed above, the same finding is found in patients with
panic disorder, who exhibit repeated stressor responses in panic attacks. Additionally,
an internal jugular vein sampling technique disclosed brain neurotransmitter changes in
essential hypertension patients analogous to those seen in experimental models of
mental stress in animals (Esler, Eikelis, Schlaich, Lambert G, Alvarenga, Dawood, Kaye,
Barton, Pier, Brenchley, Jennings & Lambert E; Ferrier, Jennings, Eisenhofer, Lambert,
Cox, Kalff, Kelly & Esler, 1993).
These research findings provided the lynchpin for the judgement that mental stress is a
proven cause of high blood pressure, published in the 27 March 2002 Government of
Australia Gazette (Members of Specialist Medical Review Council, 2002) following a
request for adjudication on this matter by the Minister.
Arterial and coronary sinus venous plasma adrenaline specific radioactivity in patients with
essential hypertension, representing the ratio of tritiated to unlabelled adrenaline during a
peripheral venous infusion of tritiated adrenaline, at a rate of 0.35 Curies/m2 body surface area.
Adrenaline isotope dilution in transit through the heart is indicative of cardiac release of
adrenaline.
Stress is a now-proven cause of coronary heart disease
Numerous epidemiological studies, many of which are recent, indicate that mental
stress, including that in the workplace, can cause coronary heart disease. One
mechanism of the stress-heart disease link involves stress causing adverse changes in
coronary heart disease risk factors (Rosengren, Hawken, Ounpuu, Sliwa, Zubaid,
Almahmeed, Blackett. Sitthi-amorn, Sato & Yusuf, 2004; Chandola, Brunner & Marmot,
2006). Coronary artery disease and heart attacks commonly have roots in the metabolic
syndrome, a condition in which overweight, high blood pressure, insulin resistance and
hypercholesterolaemia cluster together.
Recent very persuasive evidence from the Whitehall II study in London public servants
(Chandola, Brunner & Marmot, 2006) demonstrates in a prospective study that chronic
stress at work is an important risk factor for the subsequent development of the
metabolic syndrome.
Two well-documented patterns of adverse work environment have been demonstrated to
contribute to the development of coronary heart disease. The first is the “High Job
Strain” workplace (Karasek, Baker, Marxer, Ahlbom & Theorell, 1981; Karasek, Theorell,
Schwartz, Schnall, Pieper & Michela, 1988; Pieper, LaCroix & Karasek, 1989),
characterised by a lack of control over the pace of work and its targets and deadlines.
The second is the “Effort-Reward Imbalanced” workplace (Siegrist, 1996), typified by
demanding work which causes little personal gratification.
Perhaps the most compelling evidence for the stress/heart link is recent, that from the
celebrated INTERHEART study, published as two consecutive papers in the Lancet in
2004 (Rosengren, Hawken, Ounpuu, Sliwa, Zubaid, Almahmeed, Blackett. Sitthi-amorn,
Sato & Yusuf, 2004; Yusuf, Hawken, Ounpuu, Dans, Avezum, Lanas, McQueen, Budaj,
Pais, Varigos & Lisheng, 2004). This study, headed by Professor Salim Yusuf, was
performed in more than 24,000 participants, in 52 countries.
Chronic mental stress was strongly linked to the development of coronary heart disease.
The stress scale was a composite documenting summed stress in the workplace and in
the home. The strength of the causal link was as strong as that for high blood pressure,
cigarette smoking and hypercholesterolaemia.
Low “Locus of Control” in life (work and home), corresponding to the “High Job Strain”
workplace described above in the INTERHEART study was strongly linked to the
development of coronary heart disease.
Many would regard the INTERHEART study as definitive, the final step in proving a
causal link of mental stress to heart disease, although the prior evidence, summarized in
earlier reviews in Circulation (Rozanski, Blumenthal & Kaplan, 1999) and the Journal of
the American College of Cardiology (Rozanski, Blumenthal, Davidson, Saab &
Kubzansky, 2005), was actually very persuasive.
As detailed in these reviews, many rigorous studies of prospective design have
documented the existence of a strong and presumably causal stress/heart disease
linkage (Karasek, Baker, Marxer, Ahlbom & Theorell, 1981; Karasek, Theorell, Schwartz,
Schnall, Pieper & Michela, 1988; Pieper, LaCroix & Karasek, 1989; Siegrist, 1996;
Marmot, Bosma, Hemingway, Brunner & Stansfeld, 1997; Matthews & Gump, 2002;
Johnson, Stewart, Hall, Fredlund & Theorell, 1996; Johnson, Hall & Theorell, 1989;
Rosengren, Tibblin & Wilhelmsen, 1991; Peter, Siegrist, Hahlqvist, Reuterwall, Theorell
& Group, 2002; Kivimaki, Leino-Arjas, Luukkonen, Riihimaki, Vahtera & Kirjonen, 2002).
Depressive illness and heart disease
There is strong evidence that patients with major depressive disorder are at increased
risk of developing coronary heart disease (Frasure-Smith, Lesperance & Talajiic, 1993;
Anda, Williamson, Jones, Macera C, Eaker E, Glassman A & Marks, 1993; Musselman,
Evans & Nemeroff, 1998). Indeed, an Expert Working Group of the National Heart
Foundation of Australia concluded: “there was strong and consistent evidence across all
reviews that depression is an independent risk factor for clinical coronary heart disease
and its prognosis” (Bunker, Colquhoun, Esler, Hickie, Hunt, Jelinek, Oldenburg, Peach,
Ruth, Tennant & Tonkin, 2003).
This elevated risk is independent of classical risk factors such as smoking, obesity,
hypercholesterolemia, diabetes and hypertension. The association is present in males
and females, across different age groups and in subjects living in different countries. The
risk of coronary heart disease is increased 1��-2 fold in those with minor/subsyndromic
depression and 3-4�� fold in subjects with major depression. Put simply, the relative risk
of developing CHD is proportional to the severity of the depression.
While the mechanism of increased cardiac risk attributable to depressive illness at this
stage is uncertain, the research of several groups indicates the probable importance of
the existing high level of chronic sympathetic nervous system activation in the
generation of cardiac risk (Esler, Turbott, Schwarz, Leonard, Bobik, Skews & Jackman,
1982; Gold P, Wong, Goldstein, Gold H, Ronsaville, Esler, Alesci, Masood, Licinio,
Geracioti, Perini, DeBellis, Holmes, Vgontzas, Charney, Chrousos, McCann & Kling,
2005; Barton, Dawood, Lambert E, Esler, Haikerwal, Hotchkin, Brenchley, Socratous,
Kaye, Hickie & Lambert G, 2007).
In a range of other clinical contexts ongoing stimulation of the cardiac sympathetic
outflow has been demonstrated to contribute to myocardial infarction, ventricular
arrhythmias and sudden death. Activation of the sympathetic outflow to the heart is
common in patients unexpectedly developing ventricular tachycardia and ventricular
fibrillation outside hospital (Meredith, Broughton, Jennings & Esler, 1991).
In heart failure there is similarly a high level of stimulation of the cardiac sympathetic
nerves to that seen in depressive ilness, where it has been directly linked to the
development of ventricular arrhythmias and sudden death (Esler M, Kaye, Lambert,
Esler D & Jennings, 1997).
Should this chronic sympathetic activation be targeted pharmacologically in patients with
drug-resistant depressive illness, perhaps with beta-adrenergic blocking drugs, which
prolong life in patients with cardiac failure (Packer, Bristow, Cohn, Cloucci, Fowler &
Gilbert, 1995)? This remains a hypothetical question.
Integration of the new concepts into clinical cardiovascular medicine
It has not been easy to integrate this evidence linking psychiatric illness and mental
stress with the development of cardiovascular disease into the clinical practice of
medicine. This is partly because the evidence for such a link was slow in materializing
and, in some areas still remains incomplete.
Perhaps, more importantly, the spectre of workplace litigation hangs over the field,
clouding the arguments and polarizing medical opinion. Now that a consensus seems to
have been reached that mental stress, including in the workplace, is an important cause
of coronary heart disease and hypertension, it is hoped that the primary outcome will be
the implementation of measures to reduce stress in the workplace, such as worker
empowerment to end the low job control scenario, rather than a rash of lawsuits.
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