Mental stress, atheroma, myocardial ischaemia and injury: the link is inflammation

Introduction

A large amount of data from both observational and experimental studies has shown that mental stress can increase the risk of clinical cardiovascular events by precipitating myocardial infarction (MI) or causing myocardial injury and damage.1 To understand how mental stress can cause MI and myocardial injury, it is essential to recall the latest Fourth Universal Definition of MI that was published in 2018 by a joint task force of the European Society of Cardiology, American College of Cardiology, American Health Association and World Heart Federation.2 The document classified MI into five types. The most common form of MI, due to acute plaque rupture and consequent coronary thrombosis, is labelled as type 1 MI. Type 2 MI occurs when the MI is secondary to an ongoing systemic disease such as severe hypertension, tachycardia, sepsis or shock. Type 2 MI must be distinguished from direct myocardial damage, where the insult is caused by a non-ischaemic condition, now labelled as myocardial injury (figure 1). Mental stress can lead to direct myocardial injury, as in Takotsubo cardiomyopathy, also known as broken heart syndrome, because it often occurs after a stressful or emotional event. Mental stress can also accelerate plaque progression, instability and thrombosis (type 1 MI). Furthermore, mental stress can precipitate systemic disease conditions, which then cause type 2 MI. Thus, mental stress can result in adverse clinical cardiovascular events by precipitating either type 1 or type 2 MI, as well as producing direct myocardial injury.

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This article reviews the observational studies and experimental trials linking mental stress with myocardial ischaemia and adverse cardiovascular events. It then looks at the relationship between cardiovascular disease and systemic inflammation. Inflammation has been found to be fundamental to rapid plaque progression, which invariably precedes plaque rupture and coronary thrombosis. There is also increasing evidence indicating that inflammation is the underlying pathophysiology in mental stress-induced direct myocardial injury. Furthermore, in many mental diseases, systemic inflammation has also been found to be present, supporting that inflammation could be the common pathophysiology linking mental stress with cardiovascular events. By recognising the link between mental stress, inflammation and cardiovascular events, clinicians could better manage cardiovascular and mental diseases by offering behavioural or anti-inflammatory treatment in addition to the usual cardiovascular and psychiatric drugs or other interventional treatment strategies.

Mental stress and cardiovascular events

Experimental studies

Although observational studies can show the association between stress and adverse clinical cardiovascular outcomes, they cannot prove causation. However, we now have increasing experimental studies to establish the link between mental stress, myocardial ischaemia and subsequent cardiovascular events. There have been few reports of trials of mental stress-induced myocardial ischaemia (MSIMI) due to technical challenges, as the methods for inducing mental stress and the manner of diagnosing objective myocardial ischaemia are yet to be standardised.

A meta-analysis of MSIMI in patients with coronary artery disease (CAD) in 2014 found only five trials, including a total of 555 patients, with follow-ups ranging from 35 days to 8.8 years.18 The presence of MSIMI increased the subsequent development of cardiac events or total mortality (RR: 2.2, 95% CI: 1.59 to 3.15). Another meta-analysis in 2020 analysed 20 studies of MSIMI in patients with CAD.19 This paper studied the prevalence of MSIMI, the factors associated with it and the methods used in diagnosing the disease. Out of 3164 studied patients with CAD, 902 had MSIMI, giving an overall prevalence of 32% (95% CI: 26% to 38%). Patients with a previous MI or coronary artery bypass graft were more likely to have MSIMI. Mental stress was induced by 5 minutes of one or more activities such as mental arithmetic, public speaking or anger recall. Using more than one method to produce mental stress resulted in a higher prevalence of MSIMI.

Diagnostic techniques for detecting myocardial ischaemia include electrocardiography, echocardiography, single-photon emission computed tomography (CT) or radionuclide ventriculography. Ischaemia has been diagnosed by a decrease in left ventricular function, wall motion abnormalities (WMAs), ST depression or myocardial perfusion defects. Using different diagnostic techniques and measurements has produced different prevalence rates for MSIMI. The highest rate for MSIMI was found with WMA (51%) and echocardiography (41%). The researchers found that using two diagnostic techniques and measurements detected significantly more cases of MSIMI than using only one. The authors concluded that MSIMI is widespread, but standardisation of the diagnostic methodology is needed to study the topic properly.

A more recent report in 2021 pooled two prospective cohort studies enrolling 918 patients with CAD; it focused on subsequent cardiovascular outcomes in patients with MSIMI compared with those exhibiting conventional stress-induced ischaemia.20 In their sample, 16% had MSIMI, 31% had conventional stress-induced myocardial ischaemia and 10% had both. Median follow-up was 5 years, and the primary endpoint was a composite of cardiovascular death or non-fatal MI, with a secondary endpoint of heart failure hospitalisation. The primary endpoint was 6.9 per 100 patient-years in those with MSIMI and 2.6 per 100 patient-years for those without MSIMI (HR: 2.5, 95% CI: 1.8 to 3.5). The secondary event rate was 12.6 per 100 patient-years for those with MSIMI and 5.6 per 100 patient-years for those without MSIMI (HR: 2.0, 95% CI: 1.5 to 2.5). In comparison, the primary endpoint event rate was 4.8 per 100 patient-years in those with conventional stress-induced ischaemia and 2.5 per 100 patient-years for those without it (HR: 2.0, 95% CI: 1.5 to 2.8). For the secondary endpoints, event rates in those with and without conventional stress-induced ischaemia were 8.4 and 5.6, respectively (HR: 1.6, 95% CI: 1.3 to 2.0). It appears that MSIMI is worse than conventional stress-induced ischaemia when predicting future adverse cardiovascular events in patients with CAD.

In the above study, the risks posed by the presence of MSIMI were even more clearly shown if patients with no ischaemia were taken as the control group. While the primary event rate was 2.3 per 100 patient-years in the no-ischaemia control group, the conventional stress-induced ischaemia group had an event rate of 3.1 (HR: 1.4, 95% CI: 0.9 to 2.1), the MSIMI group had an event rate of 4.8 (HR: 2.0, 95 % CI: 1.1 to 3.7), and the group with both conventional stress and MSIMI had a primary event rate of 8.1 (HR: 3.8, 95% CI: 2.6 to 5.6). Patients with MSIMI are thus at higher risk of adverse events than those with conventional stress-induced ischaemia, and the prognosis is the worst for patients with both conventional and mental stress ischaemia. The relatively low incidence of adverse cardiovascular events in patients with conventional stress-induced ischaemia, although surprising to some, has also been shown in a prospective randomised, single-centre trial of 535 patients with CAD followed up for a mean of 10 years.21 Among the patients with chronic CAD with multivessel disease, those with and without a baseline positive conventional stress test ischaemia had similar survival-free cardiovascular event rates (HR 1.0, 95% CI: 0.80 to 1.27). Thus, by using only the standard conventional stress test techniques, many patients at high risk of CAD adverse events can be missed. Even if patients cannot be formally tested for MSIMI, alert clinicians should look for its presence during history intake to identify this vulnerable group and then arrange for more intensive therapy.

Cardiovascular disease and inflammation

When thrombosis occurs at the site of an unstable atheromatous plaque in a coronary artery, total occlusion can develop, leading to severe ischaemia with myocardial cell death and resulting MI—now classified in the Fourth Universal Definition as type 1 MI.2 A debate has erupted about whether more severe stenosis causes more frequent MIs since some studies suggest that the mildly stenotic lipid-rich plaque with thin caps is more likely to rupture, leading to thrombosis and MI.22 23 This matter is now resolved by recalling the seminal work on plaque progression from Japan (figure 2).24 25 Patients with plaque progression of over 15% on four serial angiograms performed in a year were selected from a database of about 15 000 patients. This study showed that some plaques do not progress (control group), while some do not progress for a period and then suddenly and rapidly progress in size (type 1 progression). Others grow and progress gradually (type 2 progression). It is the type 1 progression that accounts for most of the adverse cardiovascular events. In the type 1 plaque progression group, 71% of patients developed unstable angina or MI; in contrast, the type 2 plaque progression group had no MIs and only 14% experienced angina.24 Meanwhile, in the control group with no plaque progression, only 2% developed angina.25 As shown in figure 2, at the time of the fourth angiogram, patients with type 1 plaque progression had a mean stenosis of 88%, and those with type 2 had a mean stenosis of 67%. However, at the time of the third angiogram, patients with type 1 plaque progression had a mean stenosis of only 47%, while patients with type 2 plaque progression had more severe stenosis with a mean of 59%. It is not the degree of stenosis of the plaque at any one time that is important, but its rate of progression that correlates with adverse clinical events.

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It is now increasingly clear that inflammation plays a major role in coronary atheroma progression. In patients with unstable angina, inflammation-induced neutrophil activation was found in the blood of the aorta as well as the coronary vascular bed far from the site of the culprit plaque.26 This shows that vulnerable plaque rupture is not a local event but the result of generalised inflammation in the body. The relationship between inflammation and plaque progression was elegantly demonstrated in a prospective study of patients with angina waiting for coronary angioplasty over a mean period of 4.8 months.27 Of all 124 patients, 35 (28%) experienced atheroma plaque progression during that period. Inflammatory markers such as neopterin, high-sensitivity C reactive protein (CRP), matrix metalloproteinase-9 and soluble intercellular adhesion molecule 1 were significantly elevated in the patients with stenosis progression compared with those with no progression. The study suggests that the presence of inflammatory molecules and cells determines whether a plaque will progress and become unstable to cause adverse clinical cardiovascular events. Therefore, it is the plaque inflammatory mechanism involving endothelial and macrophage activation, not the degree of stenosis, that predicts plaque progression and myocardial vulnerability.

Today, the relationship between stenosis, plaque vulnerability and clinical events has been established. It is not the degree of stenosis that is important, but the amount of inflammation in the plaque.28 29 The more inflammation associated with the atheromatous plaque, the more it is likely to progress and rupture, resulting in thrombosis and unstable clinical coronary events. During the acute event, the culprit plaque is expected to be severely stenosed, but prior to the event, an angiographic coronary study cannot predict whether any plaque will subsequently progress and rupture. Mental stress is increasingly reported to be involved in the pathogenesis of atherosclerosis by causing increased vascular inflammation that leads to more rapid plaque progression, ending in thrombosis, MI and adverse clinical cardiovascular events.30 31

In addition to plaque thrombosis, mental stress can cause direct myocardial injury. As shown in figure 1, it is essential to distinguish type 2 MI from acute myocardial injury. In type 2 MI, a systemic condition results in reduced coronary blood flow, causing ischaemia and damage to the myocardium.32 In contrast, in myocardial injury from myocarditis, troponin elevation is not due to ischaemia but results directly from muscle damage brought on by toxins, infection, vaccination or other inflammatory stimuli.33–36 Takotsubo cardiomyopathy is the classic situation of mental stress-induced myocardial injury and damage.37 Initially thought to be due to an excessive sympathetic drive related to mental stress, it is increasingly being acknowledged that the pathogenesis of Takotsubo cardiomyopathy is an inflammatory process.38 Compared with matched controls, a study of 55 patients with Takotsubo cardiomyopathy showed elevated serum monocyte and inflammatory marker levels. With multiparametric cardiac resonance imaging, these patients were found to have myocardial macrophage inflammatory infiltrate, confirming that Takotsubo cardiomyopathy is indeed a disease of myocardial inflammation.39 Inflammation plays a primary pathophysiological role in Takotsubo cardiomyopathy and other types of myocarditis and is likely to be of primary importance in all types of mental stress-induced myocardial injury.40

Mental stress and inflammation

With the above strong medical evidence linking mental stress to cardiac disease and cardiac disease to inflammation, the final piece of the jigsaw is to look for trial evidence linking mental stress to systemic inflammation. Its discovery would assist in establishing the link between systemic inflammation, mental stress and cardiovascular events. Evidence linking mental stress to inflammation was found in a study of 293 healthy people, selected from a pool of 6088, who had baseline health screening for cancer with a positron emission tomography (PET)/CT scan of the brain.41 The amygdala is the region of the brain involved in emotional stress. Over a follow-up of 3.7 years, baseline amygdala activity was associated with increased bone marrow activity (r=0.47; p<0.001), arterial inflammation (r=0.49; p<0.001) and cardiovascular events (HR: 1.59, 95% CI: 1.27 to 1.98; p<0.001). This interesting report points to a strong linkage between mental stress, inflammation and increased cardiovascular events.

Using data from over 140 000 participants in the UK Biobank, the association between circulating CRP with anxiety and depression was tested.42 There was a clear association between higher CRP levels and both higher depression and anxiety scores, with the association being stronger with depression and among women than men. Genetic analysis of the biodata showed that people with genetically predicted higher interleukin (IL)-6 activity were at increased risk of depressive symptoms, again suggesting that inflammation was involved in mental disorders. A meta-analysis of 41 studies on anxiety, post-traumatic stress and obsessive-compulsive disorders looked at the relationship of prolonged mental stress with chronic inflammation as measured by cytokines and CRP.43 Proinflammatory cytokines, especially IL-1β and IL-6, are significantly higher in patients who are anxious compared with healthy controls, again pointing to an essential role of inflammation in these disease conditions.

Neuroimaging using PET, magnetic resonance imaging and magnetic resonance spectroscopy has shown that brain regions such as the basal ganglia, cortical reward, amygdala, insula and anterior cingulate cortex are affected by the introduction of peripheral inflammatory stimuli.44 These studies confirm that inflammation is an intrinsic part of neuropsychiatric disease conditions. Mental diseases are thus more than conditions where the patient’s thinking faculties are impaired. The absence of structural anatomical abnormalities obscures the fact that there is actually inflammation throughout the body of patients with mental disease. The systemic inflammation present with mental stress and disease, therefore, can lead to myocardial ischaemia and injury with resulting adverse clinical events.

Anti-inflammatory drugs in cardiovascular and mental diseases

If inflammation is intrinsically involved in the pathogenesis of atheromatous plaque progression and plaque instability leading to MI, anti-inflammatory drugs should have a role to play in cardiovascular therapeutics. A study of canakinumab, a monoclonal antibody targeting IL-1β, was carried out on 10 061 patients with a prior MI and a CRP above 2 mg/L.45 Canakinumab at 50 mg, 150 mg or 300 mg was given subcutaneously every 3 months. The primary endpoint was non-fatal MI, non-fatal stroke or cardiovascular death. After a median follow-up of 3.7 years, the primary endpoint event rate per 100 patient-years was 4.5 in the placebo group, 4.11 in the 50 mg canakinumab group (HR: 0.93, 95% CI: 0.80 to 1.07; p=0.300), 3.86 in the 150 mg canakinumab group (HR: 0.85, 95% CI: 0.74 to 0.98; p=0.021) and 3.90 in the 300 mg canakinumab group (HR: 0.86, 95% CI: 0.75 to 0.99; p=0.031). Therefore, while canakinumab did reduce cardiovascular events, the results were not particularly promising.

After an unsuccessful trial with methotrexate, cardiologists may have finally found the right anti-inflammatory therapy for IHD in colchicine. Among 4745 patients enrolled in a study within 30 days after an MI, the composite primary endpoint was significantly reduced by 0.5 mg colchicine once daily (HR: 0.77, 95% CI: 0.61 to 0.96; p=0.02), after a median of 22.6 months.46 Moreover, in a study of stable chronic coronary disease, a small trial of 532 patients with a median follow-up of 3 years found that 0.5 mg daily colchicine significantly reduced the primary endpoint composite of acute coronary syndrome, cardiac arrest or stroke (HR: 0.33, 95% CI: 0.18 to 0.59; p<0.001, number needed to treat (NNT) 11).47 The value of colchicine in chronic coronary disease was further confirmed in a larger trial of 5522 patients followed up for 28.6 months.48 The composite primary endpoint was again very significantly reduced by a low dose of 0.5 mg daily colchicine (HR: 0.69, 95% CI: 0.57 to 0.83; p<0.001). Composites of the primary endpoint, including MI and revascularisation, were also significantly reduced. These findings strongly suggest that a low dose of colchicine (0.5 mg daily) is helpful in reducing adverse cardiovascular events for patients with recent MI and for those with stable coronary disease.

For mental diseases such as depression, anxiety, bipolar disorder, autism, schizophrenia, post-traumatic stress, addiction and obsessive-compulsive disorder, major inflammatory markers, including tumour necrosis factor-α (TNF-α) and IL-6, have been found to be elevated.49 50 Patients in remission from atypical depressive symptoms had lower levels of TNF-α and IL-6 compared with those with no remission.51 However, well-conducted, large-scale trials with long follow-up on anti-inflammatory drugs are still unavailable, although numerous small studies have tested anti-inflammatory drugs in addition to conventional therapy for anxiety, depression and a variety of other conditions. Nevertheless, meta-analyses have suggested benefits for mental disorders with anti-inflammatory drugs. A Danish meta-analysis of anti-inflammatory medications in depression looked at 36 trials including about 10 000 patients.52 Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, glucocorticoids, statins and minocycline are useful in treating depression and improving depression scores and depressive symptoms. Another Chinese meta-analysis of 26 trials showed that anti-inflammatory agents, whether as monotherapy or add-ons to antidepressants, reduce depressive symptoms and produce higher response and remission rates.53 In particular, NSAIDs, omega-3, statins and minocycline were all found to be effective.

Inflammatory markers link cardiovascular and mental diseases

Although Takotsubo, or stress-induced cardiomyopathy, was first reported in Japan in the 1990s, a clear link between mental stress, atheroma, myocardial ischaemia and injury has eluded the medical fraternity for a long time.54 55 Two major deficiencies exist in our previous understanding of cardiac diseases that have slowed our ability to see the link between mental stress and the heart. The first deficiency is that the distinction between myocardial ischaemia and injury was not clear, and the definition was not standardised until the important Fourth Universal Definition of MI in 2018.2 We now know that there are two different ways the heart muscle can be damaged: by ischaemia, when the problem usually is due to atheromatous plaques or by direct heart muscle injury or myocarditis, a condition increasingly recognised during the coronavirus disease 2019 (COVID-19) pandemic.36 56 The second deficiency lies in our inadequate understanding of atheroma progression and subsequent myocardial ischaemia. It is only recently that instead of plaque size or content, inflammation and plaque progression have been identified as the pivotal pathologies leading to MI and adverse clinical cardiac events.25 28

Studies experimentally inducing myocardial ischaemia or injury can result in morbidity and mortality, so these are faced with ethical and methodological obstacles in humans. Large animal models for studying coronary atheroma have limitations because animal models of mental stress—although a hot topic of research—may not accurately represent human stress since animals are highly adaptable to their environment.57–59

Although there have recently been several review articles on mental stress and cardiovascular disease, no new large prospective clinical studies of MSIMI have been reported.60–62 The methodology for inducing mental stress and the method of diagnosing myocardial ischaemia have not been standardised. Reported trials included only between 35 and 660 patients, and the largest series reporting over 900 patients was only possible because of pooling together two different studies.19 20

Nevertheless, once sufficient evidence shows that inflammatory markers are elevated not only in cardiac conditions but also in mental disorders, the link between them will become clear.44 63–65 As shown in tables 1 and 2, a large number of studies have shown that serum inflammatory markers are elevated in both mental and cardiac conditions.

A hypothesis of how clinical cardiovascular events from type 1 MI, type 2 MI or myocardial injury are precipitated by inflammation is shown in figure 3. Systemic inflammation can be induced by various conditions, including infections, vaccination, systemic toxins and excessive mental or physical stress. Inflammation produces a widespread severe systemic oxidative state, which overwhelms the body’s anti-oxidant defences, resulting in systemic organ damage, including cardiovascular and mental diseases. Inflammation and oxidation can cause rapid plaque progression and thrombosis, with the resulting MI manifesting adverse clinical cardiovascular events.66 The oxidative stress from inflammation can also cause direct myocardial injury, with myocarditis producing adverse clinical cardiovascular events.67 Patients with psychiatric diseases such as depression, anxiety, bipolar disorder, post-traumatic stress disorders, addiction and schizophrenia can exhibit inflammatory cytokine signalling alterations and increased oxidative stress.68 The close connection between mental stress and cardiovascular diseases through the common pathology of inflammation and oxidation is thus becoming more apparent.

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Conclusion

The human body functions as a whole system, and disease in one organ system can affect another. Mental stress causes inflammation, which can then lead to cardiovascular events. Similarly, when MI occurs, anxiety and depression are often accompanying conditions, and patients suffering from these mental complications have a worse subsequent prognosis.69–71 Even risk factors for cardiovascular events, such as hypertension and sleep quality, are affected by mental stress.72 73 When systemic inflammation is precipitated, for example, by infection or autoimmune conditions, mental disease, cardiac disease or both can result. In summary, the focus of a good clinician should never be confined to one particular organ system but rather encompass the patient holistically, constantly aware of the possibility of interconnected disorders. This holistic approach is particularly important for patients with cardiovascular, neuropsychiatric and inflammatory diseases.