Stress-Induced Cardiomyopathy

Abstract

The irreversible termination of individual life activities and metabolism means all fatal problems ultimately terminate the heart function. It’s very important to protect the patient’s life if we have treatment to maintain heart function and care about patients’ heart response. It is known that many diseases induced heart dysfunction including Chagas disease, burn injury, smoking and other bad stresses. Chronic stress causes these physical symptoms and emotional symptoms. Due to the awareness created by the media and internet, patients are generally aware that they should seek help immediately for chest pain. Therefore, attention and studies on stress-induced heart dysfunction would help uncover the pathophysiological mechanisms of cardiac response to non-heart diseases and provide an insight of heart-protection drugs. At the same time, physicians should be aware of this new condition and how to diagnose and treat it, even though the causal mechanisms are not yet fully understood. This special chapter will discuss on the cardiac response to the stresses especially on our associated research in recent decades such as Trypanosoma cruzi (T. cruzi)-induced cardiomyopathy and burn injury–induced cardiomyopathy, and on some very popular stresses such as behavior, motion, mental, and smoking.

1. Introduction

Stress-induced cardiomyopathy is caused by intense emotional or physical stress leading to rapid and severe reversible cardiac dysfunction. This condition can occur following a variety of emotional stressors such as grief, fear, extreme anger, and surprise. On the other hand, many physical stressors (i.e., stroke, seizure or acute asthma) can also trigger the condition. Suspicion of stress cardiomyopathy is based on clinical symptoms, abnormal electrocardiogram (ECG), mildly elevated serum cardiac troponin, significantly elevated serum natriuretic peptide levels (BNP or NT-proBNP), and noninvasive cardiovascular imaging. Stress-induced cardiomyopathy symptoms following severe stress are often indistinguishable from a heart attack and may include: (1) chest pain, dyspnea, or both during stress period (often sudden and intense) [1]; (2) shortness of breath, (3) rapid or irregular heartbeat, (4) sweating and (5) dizziness [2]. The exact pathophysiology of stress-induced cardiomyopathy remains elusive, and several mechanisms may be involved (Figure 1).

Figure 1.

Schematic diagram of the pathological mechanism of stresses-induced cardiac dysfunction. β-AR, estrogen receptor beta; ROS/RNS, reactive oxygen/nitrogen species; MAPK, mitogen-activated protein kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; SERCA2, sarcoplasmic reticulum calcium ATPase 2; RyR, ryanodine receptor; Nrf2, nuclear factor erythroid-derived 2-like 2; ATP, adenosine triphosphate; PDE5A, phosphodiesterase 5A; SIRT1, Sirtuin 1; PGC1-alpha, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; OKG, cGMP-dependent protein kinase or protein kinase G.

Considering the causes of stress-induced cardiomyopathy, the exact cause of stress-induced cardiomyopathy is unclear. In patients without coronary heart disease, emotional stress can lead to severe, reversible left ventricular dysfunction. Although the mechanism of stress-induced cardiomyopathy is unclear, excessive sympathetic stimulation may be central to its etiology, perhaps involving excess catecholamines (Figure 1), but the link between the two is unclear. One possibility is ischemia due to epicardial coronary spasm; additionally increased sympathetic tone can lead to vasoconstriction in patients without coronary artery disease [3]. Other studies have demonstrated that these patients have reduced coronary flow reserve and regional deficits in cardiac imaging [4]. Another possible mechanism for catecholamine-mediated myocardial stunning is direct muscle cell damage, as the density of adrenergic receptors in the apex is higher than in other areas of the myocardium [1]. Elevated levels of catecholamines lead to a concentration-dependent decrease in muscle cell viability, which can be explained by the marked release of creatine kinase in cells and the decreased viability due to calcium overload mediated by circulating AMPs [5]. Animal models suggest that catecholamines are a potential source of free radicals, which in turn may contribute to cardiomyopathy by promoting lipid peroxidation, increasing membrane permeability and muscle cell damage (Figure 1) [6]. Myocyte dysfunction may be caused by increased trans-sarcolemmal calcium influx and cellular calcium overload as free radicals interfere with the transport capacity of sodium and calcium transporters (Figure 1) [7]. Abnormal coronary blood flow has recently been reported in patients with stress-related myocardial dysfunction in the absence of obstructive disease [8]. Evidence that stress cardiomyopathy may be caused by neurogenic myocardial stunning also revealed a unique pattern of ventricular synergy with meta-iodobenzyl guanidine myocardial scintigraphy, suggesting the presence of cardiac sympathetic hyperactivity and maintaining coronary blood flow [9]. The distribution of primary cardiac injury did not correspond to the perfusion area of a single coronary artery. Plasma levels of catecholamines and stress-related neuropeptides are usually higher than the patient’s physiological levels. Unlike polymorphonuclear inflammation in stress cardiomyopathy infarcts, contractile band necrosis is a distinct form of stress-induced cardiomyocyte injury characterized by hypercontraction of sarcomeres, eosinophilic transverse bands, and interstitial mononucleitis, and endomyocardial biopsy shows contractile band necrosis in patients with this syndrome [1]. Research shows that contractile band necrosis is a type of cell death detected as early as 2 min after cell injury, resulting in the release of cardiac enzymes [10]. Excessive circulating catecholamines and focal myocarditis contractile bands were found in the circulatory system of pheochromocytoma, suggesting a circulating catecholamine dependence of focal myocarditis [11], subarachnoid hemorrhage [12, 13], eclampsia [13], and in persons who died from fatal asthma necrosis [14]. All together, these suggest that catecholamines may be the link between emotional stress and heart damage (Figure 1).

A surge of stress hormones may temporarily damage the heart, many studies have found. Triggers of stress cardiomyopathy due to stress hormones include: (1) financial stress; (2) surgical stress; (3) bereavement stress; (4) asthma attack stress; (5) chronic disease or diagnostic stress; (6) other. Risk factors for stress cardiomyopathy are also quite different from any physical discomfort, mainly including: (1) age: most cases occur in people over 50; (2) intense physical or emotional events: such as a loved one accidental death, medical diagnosis, sudden economic decline or unemployment, divorce, physical abuse, car accident, major surgery, natural disaster, or intense fear; (3) side effects of certain medications: some are used to treat severe allergic reactions, diabetic neurological problems, depression symptoms or hypothyroidism drugs, etc. may cause a surge in stress hormones, leading to stress cardiomyopathy; (4) gender: this condition affects women much more than men; (5) neurological disorders; (6) previous or current mental illness.

Stress-induced cardiomyopathy is diagnosed by looking for certain markers to distinguish it from other heart conditions. Possible tests should include: (1) blood tests: to check the levels of certain fats, cholesterol, sugars, and proteins in the blood; (2) chest X-ray: common imaging tests of the lungs, heart, and aorta; (3) coronary angiography: this the procedure is usually done in conjunction with cardiac catheterization; (4) echocardiography: this test uses sound waves to take dynamic pictures of the heart’s chambers and valves; (5) electrocardiogram (ECG): this test measures the electrical activity of the heart and can help determine whether a part of the heart is enlarged, overworked, or damaged; (6) Magnetic Resonance Imaging (MRI): uses large magnets, radio waves, and a computer to produce images of the heart and blood vessels.

2. Behavior-induced cardiomyopathy

Over the past decade, research on psychosocial risk factors for heart disease has made great strides [15]. According to epidemiological studies [16], behavioral risk factors for heart disease can be divided into five categories [17]: (1) physical health behaviors; (2) negative emotional and mental states; (3) chronic stress; (4) social isolation and lack of social support; and (5) lack of a sense of purpose.

2.1 Physical health behaviors

New research suggests that poor sleep quality and inappropriate rest and relaxation are also behavior-related risk factors for heart disease [18]. As far as sleep is concerned, recent meta-analyses have shown that both insomnia and long or short sleep duration are risk factors for heart disease [19]. Excessive sleep duration can be a potential marker of depression or medical comorbidities, while too short sleep duration can be caused by multiple factors, including sleep deprivation or sleep deprivation due to worrying and other causes of insomnia. As the workload becomes heavier and the pace of life becomes faster, the boundaries between work and leisure are disappearing, and the value of relaxation has become more important. Theoretically, relaxation may benefit physiological and cognitive functions, but so far, epidemiological studies in this area are relatively lacking.

2.2 Affective disorders and negative emotional states

2.2.1 Depression

Studies have consistently shown that depression is an important risk factor for heart disease [20], and a series of meta-analyses have demonstrated a significant effect of depression on prognosis, including a meta-analysis of 54 studies showing that depression nearly doubled the risk of heart disease in a community cohort population [21].

2.2.2 Anxiety symptoms and syndromes

In recent years, studies have identified anxiety as one of the risk factors for heart disease [22]. Many meta-analyses of community cohorts and patient cohorts have shown that anxiety symptoms increase the risk of heart disease [23]. Other studies have shown that patients with generalized anxiety disorder, panic attacks, and post-traumatic stress syndrome have an increased risk of heart disease events [24].

2.2.3 Pessimism

Mental outlook is also one of the determinants of health, with optimists being more positive, having enhanced social functioning and better recovery from myocardial infarction or heart surgery [25]. Recent epidemiological data suggest that pessimism increases the risk of cardiac events, stroke, and/or all-cause mortality [26].

2.2.4 Anger and hostility

Anger and hostility have been extensively studied [27]. However, a meta-analysis of healthy people and patients with heart disease found that anger and/or hostility only increased the rate of cardiac events [28].

2.3 Chronic stress

So far, most studies on chronic stress have focused on situational stress [29], and work stress [30] is the most widely studied one. A recent meta-analysis showed that occupational stress was associated with increase in heart disease events [31]. Separation and divorce are two other common stressors that increase the risk of death [32], and independent epidemiological studies have also shown an association between marital stress and cardiovascular events [33].

It is worth mentioning that personal stress perception may also be one of the important factors affecting health [34]. A study that assessed levels of stress perception and perceptions of whether stress was harmful to health in 28,753 participants showed that stress increased mortality only in those who self-assessed risk harmful to health [35]. A complementary study showed that guiding individuals to understand stress as a positive effect improved cognitive and cardiovascular responses to stress. Combining the above two studies, we should further study the individual’s perception of stress and the impact of its regulation on health.

2.4 Social isolation and lack of social support

Epidemiological studies consistently show that small social networks, lack of social support, loneliness, and/or feelings of lack of emotional support increase the risk of cardiac events [36]. Like other psychosocial risk factors, the likelihood of adverse cardiac events increases with the degree of lack of social support, and a positive social overall can nearly triple survival [37].

2.5 Lack of sense of purpose

Observational studies have shown that a strong sense of purpose in life is central to leading an active life, and that a lack of purpose in life can lead to boredom, increase risk of depression, and diminish resilience. Although only a few studies have assessed the pathophysiological outcomes of lack of purpose, a large number of recent studies have shown that lack of purpose increases the risk of death [38].

2.6 Psychosocial functioning

Negative psychosocial factors contribute to the development of disease by forming negative behaviors and direct pathophysiological effects. These effects vary by type of psychosocial stress, but as a whole include autonomic dysfunction, cardiovascular hyperresponsiveness, insulin resistance, central obesity, increased risk of hypertension, endothelial and platelet dysfunction, and brain adverse changes in adaptive and cognitive function, etc. [39].

Conversely, positive psychosocial factors favor healthy behaviors and promote beneficial physiological effects, including enhanced immune and endothelial and autonomic function. In addition, positive psychosocial functioning contributes to increased vitality, which in turn increases presence, purpose, and resistance [40].

3. Bad emotion-induced cardiovascular disease (CVD)

With the transition from the biomedical model to the biopsychosocial medical model, the psychosomatic relationship of cardiovascular disease has attracted more attention. Most cardiovascular diseases have both biomedical and psychosocial factors in the pathogenesis; in terms of clinical symptoms, there are both somatic and psychological symptoms. Growing research is finding a strong link between mood and morbidity and mortality of CVD, as one of the common public health problems worldwide [41], arousing social concern [42]. With the transition from the traditional biomedical model to the modern biopsychosocial medical model, the psychosomatic relationship of CVD has attracted more attention. The effect of emotion on cardiovascular health can be explained by certain association mechanisms, but the specific and clear association mechanism has not yet formed a consensus.

Emotion is a short-lived, strong attitude and experience that an individual is stimulated by the living environment, accompanied by obvious physiological changes and external manifestations of a psychological state [43]. Psychologists divide emotions into two dimensions: negative emotions and positive emotions. Negative emotion is a negative emotion triggered by anticipation of future events and memory of past time, which can manifest in different forms (such as panic, anxiety, depression, hostility, etc.) [44].

3.1 Emotion and cardiomyopathy research

Previous studies have found that patients with acute myocardial infarction are often in varying degrees of negative emotional states after experiencing a sense of near-death [44, 45]. Some studies have also shown that patients with heart failure have poor quality of life, and the incidence of anxiety and depression are 62% and 65%, respectively [46]. On the one hand, negative emotions are one of the independent predictors of poor prognosis in hospitalized patients with CVD [47]. Conversely, positive emotions are associated with a reduced risk of CVD [45, 47]. However, the internal mechanism of the two is still unclear.

3.2 Biological mechanisms of emotional effects on cardiomyopathy

The study found that the biological mechanism of the influence of emotion on cardiomyopathy is mainly reflected in the two aspects of vascular endothelial injury and inflammatory response, as well as the activity of the autonomic nervous system (Figure 1) [48].

3.2.1 Emotional changes cause endothelial damage and inflammation

The early manifestation of cardiomyopathy is the damage of the vascular endothelium [49]. Studies have found that there is a correlation between emotional state and the state of the cardiovascular endothelium [50]. Massachusetts area in the United States found that positive mood (joy) was inversely correlated with inducible nitric oxide synthase promoter methylation [51], which play an important role in maintaining the homeostasis of vascular function.

3.2.2 The autonomic nervous system as a mechanism for the link between mood and cardiomyopathy

The autonomic nervous system has an important regulatory mechanism for the cardiovascular system, including the sympathetic nervous system and the parasympathetic nervous system (Figure 1) [52]. Heart rate variability (HRV) is a commonly used index for evaluating autonomic nerve function and the risk of sudden cardiac death. HRV analysis can effectively evaluate the state of cardiac autonomic nerve function. It is a relatively independent index for predicting the short- and long-term prognosis of various CVDs and sudden cardiac death [53]. Liu [54] found that when healthy individuals were exposed to negative emotional stress, the production of cardiac autonomic nerve function was significantly different. Similar changes in the pathological state of coronary heart disease suggest that long-term negative emotions may be one of the reasons for individual parasympathetic nerve damage.

4. Mental stress-induced cardiomyopathy

There is increasing evidence that, in addition to traditional factors, mental stress plays an important role in the occurrence and development of cardiovascular disease [55]. The psychological stress generated in daily life and work can lead to the occurrence of myocardial ischemia, which is clinically referred to as mental stress-induced cardiomyopathy (MSIC) [56]. In addition to affecting the quality of life of patients, mental stress-induced myocardial ischemia (MSIMI) can also lead to a worsening clinical prognosis and an increased risk of death. Its pathogenesis and pathogenesis are different from those of exercise stress or drug-related myocardial ischemia. The incidence of MSIMI is 20–70%, and it will double the adverse cardiac events [57]. Therefore, in-depth understanding of the pathogenesis of MSIMI and timely diagnosis and treatment, is of great clinical significance.

4.1 Features of MSIC

Understanding the clinical features of MSIC will help clinicians identify MSIC patients early and treat them in a timely manner.

4.1.1 Depression or anxiety

Depression and anxiety are risk factors for cardiomyopathy, aggravate the process of heart disease, and affect the prognosis of heart disease. Patients with heart disease complicated by depression or anxiety have a higher incidence of MSIC after mental stress [58].

4.1.2 Brain function

During mental stress, changes in brain function are related to the occurrence of MSIC. Studies have shown that compared with patients with heart disease without depression, patients with heart disease and severe depression have increased activity in the parietal cortex after mental stress stimulation [59]. Another study showed that mental stress-induced vasoconstriction is associated with modulation of brain function, with stress increasing activation in the insula and parietal cortex but decreasing activation in the medial prefrontal cortex [60].

4.1.3 Cardiac markers

Changes in cardiac markers may be associated with MSIC. Highly sensitivity cardiac troponin I (hs-cTnI) is an indicator of myocardial infarction or myocardial injury and is associated with myocardial ischemia caused by mental stress. Studies have shown that compared with heart disease patients without MSIC, patients with heart disease combined with MSIMI have higher serum hs-cTnI levels, and increased N-terminal pro-B-type natriuretic peptide and mean systolic blood pressure after mental stress [55]. Numerous studies have shown that myocardial hypoxia can lead to the elevation of B-type natriuretic peptide (BNP). Elevated BNP levels may be a marker of myocardial ischemia in a meta-analysis of 2784 patients eligible for standard noninvasive stress testing [61].

4.1.4 Other factors

After psychological stress, coronary heart disease patients with severe left ventricular dysfunction have a higher risk of MSIC than patients with normal left ventricular function [62]. The product of heart rate and systolic blood pressure and peripheral arterial tension were measured in resting state and 30 min after mental stress, respectively. It was found that higher hemodynamics and vasoconstriction response were high risk factors for MSIC [63].

4.2 Pathogenesis of MSIC

4.2.1 Hypothalamic-pituitary-adrenal (HPA) axis

When people cope with mental stress, the paraventricular nucleus of the hypothalamus will secrete corticotropin-releasing hormone, which will cause the anterior pituitary to secrete corticotropin, which will stimulate the adrenal cortex to produce cortisol. Decreased baroreceptor reflex sensitivity can lead to myocardial ischemia and even severe arrhythmia and sudden death. Broadley et al. [64] found that the application of metyrapone, a drug that blocks cortisol release, prevented mental stress-related endothelial dysfunction and reduced baroreflex sensitivity. In addition, Seldenrijk et al. [65] showed that, in healthy elderly populations, an enhanced cortisol response to stressful stress was associated with an increased risk of coronary artery calcification.

4.2.2 Sympathetic nervous system

During mental stress, the excitability of the cardiac sympathetic nervous system increases, and the activated sympathetic nervous system promotes the release of catecholamines (including epinephrine, norepinephrine, and dopamine), resulting in increased blood pressure, increased heart rate, increased myocardial contractility, and cardiac output (Figure 1) [63]. The study of Wittstein et al. [1] showed that under strong mental stress in patients with stress cardiomyopathy, the level of catecholamines increased rapidly, and the excitability of the sympathetic nervous system was significantly enhanced, which led to the disturbance of neurohumoral regulation, resulting in increased myocardial vitality, myocardial damage, myocardial reversibility and left ventricular dysfunction (Figure 1).

4.2.3 Inflammatory factors

Inflammation is closely related to mental stress and cardiovascular disease. When the body responds to mental stress, blood vessels constrict and blood flow increases, prompting white blood cells and platelets to release inflammatory mediators [56]. When the stress is weak, the body can play a defensive role through the inflammatory response. When the stress is strong, excessive inflammatory mediators lead to vascular endothelial damage, which further promotes inflammatory response and inflammatory mediators, as well as promotes inflammatory cells to infiltrate myocardial tissue, leading to myocardial ischemia necrosis and cardiovascular disease [56]. Hammadah et al. [56] showed that the levels of inflammatory factors such as interleukin-6, monocyte chemoattractant protein-1, and matrix metalloproteinase-9, increased in patients with heart disease after mental stress. The level of matrix metalloproteinase-9 was negatively correlated with cortisol after stress. In conclusion, the relationship between inflammation-related factors and MSIC remains to be further explored (Figure 1).

4.2.4 Gene polymorphisms

Genetic factors are one of the important reasons for the onset of cardiovascular diseases. Mental and psychological diseases are also closely related to an individual’s response to stressful stimuli. For example, the serotonin transporter gene (SLC6A4) polymorphism is associated with emotion regulation in humans, and S allele carriers cause more severe fear and anxiety under mental stress [50]. Studies on the Val66Met single nucleotide polymorphism of brain-derived neurotrophic factor (BDNF) have shown that BDNFMet/Val carriers have a higher incidence of cognitive and mental disorders and coronary heart disease [51, 66].

5. Trypanosoma cruzi infection-induced cardiomyopathy

Chagas disease is named after Carlos Ribeiro Justiniano Chagas, a Brazilian doctor and researcher who discovered the disease in 1909. In May 2019, according to the decision of the Seventy-second World Health Assembly, World Day against Chagas Disease was set on April 14 (the day in 1909, when Carlos Chagas diagnosed the first human case of the disease in a two-year-old girl named Berenice). Chagas disease, also known as American trypanosomiasis, is a life-threatening disease caused by the protozoan parasite Trypanosoma cruzi. (T. cruzi) [67]. An estimated 6–7 million people worldwide are infected with T. cruzi, mostly in Latin America, the parasite that causes Chagas disease [68]. Chagas disease is primarily found in endemic areas of 21 countries in the Latin American continent and is mostly transmitted to humans through contact with the feces or urine of triatomine bugs (vector-borne) [69]. Although the majority of these infected individuals reside in Mexico, Central America, and South America, migration patterns have resulted in large numbers of infected individuals in formerly nonaffected areas, including Europe, Japan, Australia, Canada, and the United States [70], with an estimated 300,000 individuals in the United States alone [71]. These bed bugs are also known as “kissing bugs” and have many other names depending on the geographic area.

5.1 Global distribution

Chagas disease was once completely confined to rural areas of the American continent—mostly Latin America (excluding the Caribbean islands). Most of the infected people live in urban environments (urbanization), mainly due to increased population mobility over the past few decades, with an increasing number of infections found in the United States, Canada, many European countries, and some African, Eastern Mediterranean, and Western Pacific countries [72].

5.2 Transmission

In Latin America, Trigonoscuta cruzi is mainly transmitted by contact with the feces/urine of infected blood-sucking Triton bugs. These parasite-carrying insects typically live in cracks in the walls or roofs of rural or suburban houses and surrounding structures such as chicken coops, pens and warehouses [71]. Normally, they hide during the day and become active at night, feeding on blood from animals, including humans. They usually bite on exposed areas of the skin, such as the face (hence it is often referred to as a “kissing bug”) and defecate/urine close to the bite. Parasites enter the body when a person involuntarily applies their feces or urine to the bite, eyes, mouth, or any skin breakage. T. cruzi can also be spread by: (1) ingestion of food or drink contaminated with T. cruzi, such as through contact with the feces or urine of infected Trypanosoma bugs or marsupials (this transmission often results in outbreaks of simultaneous infection of several populations, severe cases or morbidity more frequently and with a higher number of deaths or fatalities); (2) passed from an infected mother to a newborn during pregnancy or childbirth; (3) transfusion of blood or blood products from infected donors; (4) organ transplantation using infected donor organs; and (5) laboratory accident.

5.3 Symptoms and signs

Chagas disease is divided into four phases: incubation phase, acute phase, interminate phase and chronic phase.

5.3.1 Incubation phage

The incubation period for T. cruzi ranges from 1 to 2 weeks after vector-borne transmission [69] and up to 3–4 months after transfusion or transplant transmission [73]. The disease in incubation phase is unknown and may be more than a week.

5.3.2 Acute phase

The initial acute phase lasts about 2 months after infection. During the acute phase, a large number of parasites circulate in the blood. However, most cases are asymptomatic or mild and nonspecific. In less than 50% of people bitten by triatomine bugs, the typical first sign seen can be a skin lesion or bruising and swelling on one eyelid. In addition, fever, headache, swollen lymph nodes, pallor, muscle pain, difficulty breathing, swelling, and abdominal or chest pain may also present. In the acute phase, fever (missing or intermittent), rash, hepatosplenomegaly, lymphadenopathy, and non-inflammatory edema may be present and may be limited to the face or systemic. Trypanosoma’s enter tissues during or after parasemia, causing myocarditis and endocarditis, sinus tachycardia, mitral systolic murmur, cardiac hypertrophy, and meningoencephalitis. Symptoms disappear after more than 4 to 12 weeks. Severe cases are more common in neonates, young children, the elderly and immunosuppressed. Heart failure or ventricular fibrillation and meningoencephalitis caused by early myocarditis during this period can often lead to death. When more advanced electrocardiographic findings are present, including right bundle-branch block (RBBB), atrial fibrillation, or ventricular arrhythmias, they signal a worse prognosis [74].

5.3.3 Interminate phase

The interminate phase is almost asymptomatic, but progresses to a chronic, symptomatic phase, including the gradual development of irreversible life-threatening and disabling comorbidities, especially to those who are immunosuppressed. Physical examination is normal, and resting electrocardiogram is normal. Only special inspection method can find abnormalities. This is the beginning of the chronic phase. This type can persist for 20 to 30 years, or even life.

5.3.4 Chronic stage

During the chronic phase, the parasite hides mainly in the muscles of the heart and digestive tract. Ten to thirty years later, up to 30% of patients develop cardiac disorders and up to 10% develop gastrointestinal (typically enlarged esophagus or colon), neurological, or mixed lesions. In later years, infections in these patients can lead to myocardial and neurological damage, followed by arrhythmias or progressive heart failure and sudden death. The disease usually begins years or decades after the onset of parasitemia. (1) Cardiomyopathy in endemic areas: trypanosomiasis cardiomyopathy is the main cause of heart disease and sudden death. Patients often develop congestive heart failure with an enlarged heart. Two-thirds of patients have cardiac conduction disorders, often right bundle branch block, polygenic premature contractions, and myocardial necrosis. The disease course can be short and sudden death, or death from long-term heart failure. In addition, emboli from the apex or atrium can cause sudden death due to cerebral or pulmonary embolism. (2) Dilation of multiple organs: in Brazil, Chile, and some parts of Argentina, there are multiple organ expansions, mainly the esophagus and colon. Difficulty swallowing is often caused by esophageal expansion, constipation caused by colon expansion, and volvulus may also occur, such as acute abdomen. As for the giant stomach, giant duodenum, giant bronchus, giant ureter, etc. have been reported but rare.

5.4 Pathogenesis and pathological changes

5.4.1 Research achievements from relevant research institutions

T. cruzi can colonize any nucleated cell. Most of the symptoms in the acute phase of the disease are thought to be caused by damage to host cells by T. cruzi. For the chronic phase-related pathogenesis, there are currently two theories. One theory is that T. cruzi persists, leading to chronic inflammation [75], and the other theory is that it is caused by autoimmune damage [76]. Possible mechanisms include antigen cross-reactivity [77], direct cell-mediated cytotoxicity [78], antigenic Submitting changes [79], and cardiac mitochondrial dysfunction [80] etc.

Pathological changes in the acute phase showed mononuclear cell infiltration [81], interstitial edema [82], accumulation of amastigotes in muscle cells of subcutaneous tissue [83], and formation of pseudocysts at the invasion site of Trypanosoma [83]. Myocarditis with cardiac enlargement is usually seen in acute-phase deaths. In patients with sudden death in the chronic phase (mostly due to ventricular arrhythmia or conduction block), the heart size is usually normal or only slightly enlarged. In other patients with chronic Chagas heart disease, cardiac hypertrophy, dilation, and thickening can be seen, especially in the apex of the heart, resulting in apical aneurysm. Mural thrombosis and lung and peripheral organ embolism may be seen in some patients. Microscopic examination showed mononuclear cell infiltration, myocardial fiber hypertrophy, degeneration, necrosis and edema. Microscopic changes in megaesophagus or megacolon are similar to those of the heart.

5.4.2 Research achievements from our institution

We firstly have shown that cardiac mitochondria-response plays a very important roles in T. cruzi–induced cardiomyopathy [80, 84, 85, 86, 87, 88, 89, 90, 91, 92], and established the third theory that oxidative stress was involved in cardiac mitochondrial dysfunction [84, 86, 88] and heart dysfunction [80, 93, 94, 95, 96, 97]. In detail, we have contributed to the understanding of the mechanism behind the decline of MnSOD and enhancement of SIRT1/PGC1/PARP-1 in correlation with T. cruzi–induced consistently oxidative heart damage [90, 91, 92, 97]. From this research, we have observed that (1) MnSODtg mice/MnSOD overexpression in cell lines are beneficial in preserving T. cruzi–induced mitochondrial/heart dysfunction [90]; (2) MnSOD^−/+ mice were worse of T. cruzi infection–induced heart dysfunction [91]; and (3) inhibition of PARP-1 would prevent T. cruzi–induced heart function [92]. We also have observed T. cruzi–induced oxidative stress occurred in adipose tissues by utilizing oxidative markers, which is a novel finding [96, 98]. We have contributed to an understanding of T. cruzi–induced oxidative etiopathogenesis [85, 86, 88, 89]. Additionally, we have isolated high quality heart mitochondria to (1) recognize T. cruzi–induced oxidative mitochondrial proteins by using combination of BN-PAGE [84] and TOP MALDI MS/MS [88, 95]; (2) ascertain that mitochondrial complex III Qo site was prime source of T. cruzi–induced ROS generation [86]; and (3) find that administration of antioxidants improved T. cruzi–induced oxidative damage in heart mitochondria and heart tissues [85, 89]. We have conducted a thorough analysis of mitochondrial bioenergetic function as well as the biochemical and molecular factors that are deregulated and contribute to compromised adenosine triphosphate (ATP) production in the myocardium during T. cruzi infection. Our team is focused on the discovery and development of novel therapeutics against T. cruzi. We found that combination treatment (antioxidants and anti-parasites) is beneficial in arresting the T. cruzi–induced inflammatory and oxidative pathology and chronic heart failure in Chagasic rats. We have proven that the T. cruzi–induced oxidative alterations in circulation are correlated with heart tissue, suggesting that Chagasic human patients’ circulation can replace heart tissue, as issue we are planning to investigate. We also confirmed that this was the case in human patients with Chagasic cardiomyopathy development and assessed different ways to oxidatively modify mitochondrial respiratory complexes (Figure 1) [80, 94].

6. Tobacco- and e-cigarettes-induced cardiomyopathy

6.1 Tobacco-induced cardiomyopathy

The tobacco-induced cardiomyopathy accounts for 9.4 million, or 16.6%, of the 56 million deaths worldwide each year [99]. Smoking causes 1.62 million (18%) deaths from heart disease worldwide [100], and cause severe ill health, with an estimated 40.6 million daily lost to heart disease [100].

Tobacco use (smoked and smokeless) and exposure to secondhand tobacco causes heart disease through a variety of mechanisms, including inflammation, blood vessels shrinkage, clot formation, and reduced oxygen supply (Figure 1) [101, 102, 103]. Smoking-mediated thrombosis appears to be a major factor in the pathogenesis of acute cardiovascular disease [101]. Nicotine stimulates the heart, which increases the demand for oxygen to the heart muscle, triggering angina. Smokers are more likely to develop acute cardiovascular disease at a young age and early in their illness [101]. The associated effects of exposure to secondhand smoke on the heart are almost as severe as the effects of smoking itself, and likely through the same biological mechanisms [104]. Exposure to secondhand smoke in as little as 1 h can increase the risk of heart attack [105].

Risk of damage to the cardiovascular system increases with duration of smoking and the amount and type of smoking tobacco products consumed. However, the close relationship between dose and response is not linear [101]. Even with low exposure levels, the risk increases substantially—people who smoke only one cigarette a day have half the risk of coronary heart disease as those who smoke at least 20 cigarettes a day [106]. In addition to being a major independent risk factor for coronary heart disease, smoking may act synergistically with other major risk factors for coronary heart disease, such as high cholesterol, untreated hypertension, and diabetes [107, 108]. In 2017, an estimated 382 000 deaths from coronary heart disease were attributable to exposure to secondhand smoke [106], accounting for 4.3% of total deaths from coronary heart disease and 31% of total deaths from exposure to secondhand smoke [106]. In the same year, exposure to secondhand smoke was also estimated to be responsible for an estimated 8.8 million disability-adjusted life-years (DALYs) lost to coronary heart disease [106]. Various systematic reviews and meta-analyses have shown that adults exposed to secondhand smoke have a 23–30% increased risk of coronary heart disease in countries with high to low-income levels [101, 109, 110, 111, 112]. Cohort studies conducted in multiple countries in the 1970s and 1980s showed that children’s exposure to secondhand smoke has adverse effects on cardiovascular disease, including premature atherosclerosis [113, 114]. A major challenge in these studies is accurately assessing lifetime exposure to secondhand smoke. The cumulative total lifetime exposure to secondhand smoke may be much higher than reflected during the study period [104], which may lead to an underestimation of the true risk of exposure to secondhand smoke and the impact on heart disease [104]. A recent study led by the tobacco industry claims that electronic nicotine delivery systems (ENDS) are less harmful than cigarettes [115, 116]. However, ENDS may be more toxic than inhaled ones at low in conventional cigarettes and tobacco products, but they are not harmless, and there are risks associated with use and secondhand exposure [41, 117]. ENDS linked to increased risk of cardiovascular disease Association [118, 119]. The toxic substances contained in these products can lead to causes impaired endothelial function, arterial stenosis, increased heart rate and increased blood pressure [120, 121, 122]. Concomitant use with smoking (this is most ENDS common practice of users), effects of a combination of two or more products [123]. Tobacco control measures have been shown to benefit heart health place. For example, raising tobacco taxes is directly related to reducing tobacco consumption. Associated with improved heart health [124].

6.2 E-cigarettes-induced cardiomyopathy

Due to the many pathogenic and negative effects on the heart from smoking on the heart, the market for smoking and nicotine replacement has grown rapidly in recent years. Since 2006, e-cigarettes have become more popular due to their perceived safety profile compared to traditional cigarette smoking. An electronic cigarette (or e-cigarette) is a battery-operated device for heating solutions (or e-liquids) containing nicotine, propanediol alcohol and vegetable glycerin [120, 125, 126]. E-cigarettes not only attract smokers who are trying to quit smoking, but are also becoming more popular among non-smokers, who have even become the main force in the e-cigarette market. Since the advent of electronic cigarettes, its design has constantly changed, but there has been little regulatory control. Common forms of e-cigarettes are the first generation of disposable “Cigalikes”, the second generation of rechargeable devices, and the third generation of water tanks, pens and personalized large cigarettes, boxes, and pod-based devices.

The team of Nicholas D Buchanan of The Ohio State University School of Medicine published a paper in the journal Cardiovascular Research, reviewing clinical studies related to the cardiovascular risk of e-cigarettes. This review discusses recent relevant studies from the existing literature, focusing on components and potential cardiovascular risks associated with e-cigarette vapor exposure and on evaluating and broadly discussing data from preclinical and epidemiological studies on the cardiovascular effects of acute (short-term) and chronic (long-term) exposure to e-cigarettes [127]. e-cigarettes increased hyperlipidemia [128], sympathetic dominance [129], endothelial dysfunction [130], DNA damage [131], macrophage activation [132, 133]. Multiple studies suggest e-cigarettes may increase CVD risk.

7. Burn-induced cardiomyopathy

7.1 Research achievements from relevant research institutions

Severe burns can lead to severe hemodynamic and cardiodynamic disturbances, which can lead to sepsis, multiple organ failure, and death. Cardiac stress is a hallmark of acute-phase response to burns, and poorer burn recovery outcomes are associated with severe cardiac insufficiency [134, 135, 136]. Severe burn injury has a profound and widespread effect on an individual’s cardiovascular system. Early features include myocardial contractile dysfunction and increased vascular permeability.

Plasma levels of catecholamines, vasopressin, angiotensin-II [137] and neuropeptide-Y [138] are significantly elevated after severe burns, which may be responsible for the deleterious effects on cardiovascular function. Nearly 7% of children with 70% burn area develop dilated cardiomyopathy (DCM) [139, 140]. Burn-induced cardiomyopathy usually develops several weeks to several months after injury [139, 141]. The initial cardiac response to severe burns is characterized by reduced cardiac output and metabolic rate (Figure 1). Other hemodynamic features of burn shock include stroke volume, venous return, coronary blood flow, peak systolic blood pressure, mean arterial pressure, estimated myocardial work, stroke work, myocardial oxygen consumption, myocardial oxygenation, myocardial contractility, decreased force and myocardial compliance [142]. This initial response will result in left-right heart failure and decreased cardiac contractility and is thought to be mediated by circulating vasoconstrictors (Figure 1).

Physiologically, burn-induced myocardial dysfunction is characterized by decreased isovolumic relaxation, impaired contractility, and decreased left ventricular diastolic compliance [143, 144] resulting in decreased cardiac output and metabolic rate [138, 145], leading to myocardial oxygen demand, leading ultimately to right and left heart deficits (Figure 1) [143, 146]. Following burn injury, the volume of circulating plasma is markedly reduced due to increased capillary permeability [147] and a concomitant decrease in cardiac output. Depending on the extent of the burn injury, this defect may directly lead to a severe hypermetabolic response [148] and is positively correlated with the size of the original injury [148]. Poor functional recovery from severe burns is associated with high mortality, high infection rates, and cardiac insufficiency [136, 149, 150].

Cardiac stress-induced increases in plasma catecholamines mediate postburn hypermetabolic responses [136, 151, 152]. Upregulation of catecholamines and other catabolic agents such as glucagon and cortisol may induce hyperdynamic cardiovascular responses [134]. Elevated catecholamines and other catabolic agents are further exacerbated by the substantial loss of plasma volume following burns. Hypovolemic shock, typified by severe burns and major tissue trauma, results in marked tachycardia, increased myocardial oxygen demand, and decreased contractility (Figure 1) [134]. This eventually leads to increased mortality during acute hospitalization [153]. Severe burns suffer from a profound hypermetabolic response mediated by a surge in plasma catecholamines. Sustained release of large circulating catecholamines may be detrimental to the myocardium, increasing myocardial oxygen delivery and leading to focal degeneration and hypertrophy of the myocardium [134]. Elevated plasma catecholamine levels persist for months to years resulting in cardiac stress and cardiac physiologic disturbance for at least 2 years [154]. This in turn leads to cardiac insufficiency, regional myocardial hypoxia, and cardiac death [155]. Therefore, clinical concern about catecholamine levels is related to burn-induced cardiomyopathy, myocarditis, pathological myocardial injury and necrosis [156, 157].

7.2 Research achievements from our laboratory

We applied mature animal burn models including rat and mouse, established by UTMB Health’s Blocker Burn Center, to identify the heart tissue-specific up−/down-regulated genes/proteins/metabolisms via transcriptomics/proteomics/metabolomics, and have many hypothesizes based on the differences. Briefly, the SIRT1-PGC1α-NFE2L2-ARE pathway [158], and PDE5A-cGMP-PKG pathway [159] were involved in the burn-induced cardiomyopathy. To confirm our above observations, we treated burn injury animals with PDE5A inhibitor [159, 160] (Sildenafil), and APMK inhibitor (Domorsorphin)/APMK activator (A769662)/PGC1α activator (ZLN005) [158] to partially/completely recoveries of burn-induced cardiomyopathy. Another important contribution for burn-induced cardiomyopathy was that burn injury disrupts the heart mitochondria (mt) with evidence of cardiomyocyte mtDNA damage [159, 161], mt electron transport chain (ETC) dysfunction, mt membrane potential damage, disrupted mt integrity and significant increase of mt ROS production [159, 161]. Treatment with mitochondrial-target drug (Mito-TEMPO) can be beneficial for burn injury–induced cardiomyopathy (Figure 1) [161].

Acknowledgments

We would like to acknowledge David J. Chavarria, who assisted in the correction of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

BNP

B-type natriuretic peptide

CVD

cardiovascular disease

BDNF

brain-derived neurotrophic factor

ECG

electrocardiogram

ENDS

electronic nicotine delivery systems

HRV

heart rate variability

HDL

high-density lipoprotein

hs-cTnI

highly sensitive cardiac troponin I

LDL

low-density lipoprotein

MSIC

mental stress-induced cardiomyopathy

MSIMI

mental stress-induced myocardial ischemia

mt

mitochondria

T. cruzi

Trypanosoma cruzi