takotsubo cardiomyopathy takotsubo cardiomyopathy takotsubo cardiomyopathy or takotsubo syndrome (tts), also known as stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the muscular portion of the heart. it usually appears after a significant stressor, either physical or emotional; when caused by the latter, the condition is sometimes called broken heart syndrome. examples of physical stressors that can cause tts are sepsis, shock, subarachnoid hemorrhage, and pheochromocytoma. emotional stressors include bereavement, divorce, or the loss of a job. reviews suggest that of patients diagnosed with the condition, about 70–80% recently experienced a major stressor, including 41–50% with a physical stressor and 26–30% with an emotional stressor. tts can also appear in patients who have not experienced major stressors. takotsubo cardiomyopathyother namestransient apical ballooning syndrome, apical ballooning cardiomyopathy, stress-induced cardiomyopathy, broken-heart syndromeschematic representation of takotsubo cardiomyopathy (a) compared to a normal heart (b)specialtycardiology the pathophysiology is not well understood, but a sudden massive surge of catecholamines such as adrenaline and norepinephrine from extreme stress or a tumor secreting these chemicals is thought to play a central role. excess catecholamines, when released directly by nerves that stimulate cardiac muscle cells, have a toxic effect and can lead to decreased cardiac muscular function or "stunning". further, this adrenaline surge triggers the arteries to tighten, thereby raising blood pressure and placing more stress on the heart, and may lead to spasm of the coronary arteries that supply blood to the heart muscle. this impairs the arteries from delivering adequate blood flow and oxygen to the heart muscle. together, these events can lead to congestive heart failure and decrease the heart's output of blood with each squeeze. takotsubo cardiomyopathy occurs worldwide. the condition is thought to be responsible for 2% of all acute coronary syndrome cases presenting to hospitals. although tts has generally been considered a self-limiting disease, spontaneously resolving over the course of days to weeks, contemporary observations show that "a subset of tts patients may present with symptoms arising from its complications, e.g. heart failure, pulmonary oedema, stroke, cardiogenic shock, or cardiac arrest". this does not imply that rates of shock/death of tts are comparable to those of acute coronary syndrome (acs), but that patients with acute complications may co-occur with tts. these cases of shock and death have been associated with the occurrence of tts secondary to an inciting physical stressor such as hemorrhage, brain injury sepsis, pulmonary embolism or severe copd. it occurs more commonly in postmenopausal women. the name "takotsubo" comes from the japanese word takotsubo "octopus trap", because the left ventricle of the heart takes on a shape resembling an octopus trap when affected by this condition. a study published in the journal of the american heart association in october 2021 found a steady annual increase in takotsubo cardiomyopathy among both women and men from 2006 to 2017, with the sharpest increases among women 50 and older. signs and symptoms the typical presentation of takotsubo cardiomyopathy is chest pain with or without shortness of breath and associated electrocardiogram (ecg) changes mimicking a myocardial infarction of the anterior wall. during the course of evaluation of the patient, a bulging out of the left ventricular apex with a hypercontractile base of the left ventricle is often noted. it is the hallmark bulging-out of the apex of the heart with preserved function of the base that earned the syndrome its name takotsubo "octopus trap", in japan, where it was first described. stress is the main factor in takotsubo cardiomyopathy, with more than 85% of cases set in motion by either a physically or emotionally stressful event that prefaces the start of symptoms. examples of emotional stressors include grief from the death of a loved one, fear of public speaking, arguing with a spouse, relationship disagreements, betrayal, and financial problems. acute asthma, surgery, subarachnoid hemorrhage, chemotherapy, and stroke are examples of physical stressors. in a few cases, the stress may be a happy event, such as a wedding, winning a jackpot, a sporting triumph, or a birthday. risk factors stress trigger although there have been documented cases of tts without a triggering stressor, it is widely recognized that tts is preceded by a stressful or emotional event. case series looking at large groups of patients report that some patients develop takotsubo cardiomyopathy after experiencing emotional stress. some patients have a preceding clinical stressor (such as a brain injury, asthma attack or exacerbation of a chronic illness) and research has indicated that this type of stress may even occur more often than emotionally stressful triggers. roughly one-third of patients have no preceding stressful event. a 2009 large case series from europe found that takotsubo cardiomyopathy was slightly more frequent during the winter season. this may be related to two possible/suspected pathophysiological causes: coronary spasms of microvessels, which are more prevalent in cold weather, and viral infections – such as parvovirus b19 – which occur more frequently during the winter. sex women, specifically postmenopausal women, are at greatest risk of developing tts. this has led some researchers to theorize about the possible protective effects of estrogen in preventing tts. genetic risk factors it is currently being investigated if certain genetic traits associated with catecholamine receptors found on cardiac muscle cells play a role in the development of tts. there is limited evidence tying tts directly to a specific genetic expression or mutation, however there is currently a widely held hypothesis supporting the idea of the interaction between environmental factors and the interplay of genetic predisposition leading to the susceptibility to microvascular alterations that contribute to the tts disease process. hormonal dysregulation certain endocrine diseases including pheochromocytoma and thyrotoxicosis have been identified as potential risk factors for tts. the relationship between thyroid function and stress cardiomyopathy is marked by a dual phenotype, where both impending primary hyperthyroidism and a high set point of thyroid homeostasis (encoding type 2 allostatic load) are common phenomena. a multi-centre observation study found normal thyroid function to be the exception rather than the rule in tts. especially hyperthyroidism is highly prevalent in takotsubo cardiomyopathy, and it seems to predict a poor prognosis in terms of complications and mortality. pathophysiology the cause of takotsubo cardiomyopathy is not fully understood, but several mechanisms have been proposed. it is well documented that elevated catecholamine levels have been implicated in the vast majority of tts cases. theories suggest a link between brain activation of stress-related biochemicals (including neuropeptides) and the effects these chemicals have on areas of the heart, especially neuropeptide y. more specifically, adrenal stimulation by the sympathetic nervous system has been noted in cases ranging from physical events such as ischemic stroke, to emotional events such as depression or loss of a loved-one. how these increased levels of catecholamines act in the body to produce the changes seen with tts is not clearly understood. research supports the widely-held understanding that microvascular dysfunction and coronary vasospasm caused by a rapid influx of catecholamines to cardiac myocytes results in apical stunning and transient cardiomyopathy. microvascular dysfunction/transient vasospasm: some of the original researchers of takotsubo suggested that multiple simultaneous spasms of coronary arteries could cause enough loss of blood flow to cause transient stunning of the myocardium. other researchers have shown that vasospasm is much less common than initially thought. it has been noted that when there are vasospasms, even in multiple arteries, that they do not correlate with the areas of myocardium that are not contracting. however, the idea of coronary artery vasospasm is still believed to contribute to the tts disease process. the theory of vasospasm is not easily separated from that of microvascular dysfunction and in fact, microvascular dysfunction could explain vasospasticity. impaired microvascular function is seen in a vast majority, if not all, of patients with tts and is currently one of the most supported theories. most of the dysfunction occurs as a result of abnormalities within the endothelial linings of blood vessels supplying the heart. in tts, these highly sensitive interior linings of the vessels have reduced functionality which create dysregulation of vascular tone and predispose the individual to vasoconstriction. when the increased vasoconstrictor effects of catecholamines are introduced, the result is acute cardiac ischemia. catecholamine-induced myocyte injury: it has been suggested that the response to catecholamines (such as epinephrine and norepinephrine, released in response to stress) leads to heart muscle dysfunction that contributes to takotsubo cardiomyopathy. the effects of this toxicity can be greater in those with a predisposition to anxiety or panic disorders. delivery of catecholamines (epinephrine, norepinephrine) via circulating blood and through direct delivery from cardiac nerves is increased by the stimulation of stress control centers of the brain. during an emotionally or physically stressful event, brain centers initiate the sympathetic nervous pathways and increase myocardial activity. excessive catecholamine stimulation has a toxic effect on cardiac muscle cells which creates necrosis of the contractile units of cells similarly seen during acute myocardial infarction. the increased workload of cardiac muscle created by the stimulation of catecholamines, increases the need for more blood and oxygen to these muscles to sustain function. when these demands are unable to be met, the heart is starved of blood and oxygen and begins to die. included in the cytotoxic sequela of catecholamine toxicity is the molecular transformation of the cardiac myocyte to produce apical stunning. mid-ventricular obstruction, apical stunning: it has been suggested that a mid-ventricular wall thickening with outflow obstruction is important in the pathophysiology. this stunning is largely seen as a protective effect produced by the flood of excess catecholamines into the cardiac muscle cell. overstimulation of catecholamine receptors create physiological changes in the receptor which has an inverse effect on cardiac cellular function. termed 'cellular-trafficking', this property of the cardiac muscle cell is actually a molecular transformation of the cell to produce a down-regulation of catecolaminergic sensitivity. this means that in the presence of excess epinephrine, a normal cardiac contraction is inhibited in an effort to reduce energy demands, prevent hyperactivity and spare the integrity of the cell. further bolstering this idea is the concentration of these kinds of receptors in the heart. higher concentrations of the receptor effected to produce cardiac stunning are found closer to the apex of the ventricle. this is what creates the classic ballooning effect of the ventricle. it is likely that there are multiple factors at play that could include some amount of vasospasm and failure of the microvasculature. these factors can overlap and create the complex sequela leading to ischemia and left ventricle contraction abnormality. for instance, estrogen, which confers protection to women by improving blood flow to heart muscle, is one biochemical pathway implicated in the tts disease process. once this protective mechanism is reduced through the decreased production of estrogen after menopause, there is thought to be an increase in endothelial dysfunction predisposing an individual to vasoconstriction and cardiac ischemia. an inciting stressful event elicits the release of catecholamines into the blood stream to create increased heart muscle activity and metabolism. this leads to further cardiac microvascular endothelial dysfunction through oxidative stress, alteration of ion-mediated channels, and electrolyte disturbances which ultimately alter myocardial cell membrane permeability and dysfunction. coupled with direct heart muscle toxicity, this crescendo of factors are implicated in the ballooning and heart failure characteristically seen in tts. a 2019 case involved a 60-year-old woman presenting with takotsubo cardiomyopathy due to over-consumption of wasabi, mistaking it for avocado. diagnosis several well regarded institutions of medical research have produced clinical criteria useful in diagnosing tts. one of the first sets of guidelines was initially published in 2004 and again in 2008 by the mayo clinic. other research institutions proposing diagnostic criteria include the japanese takotsubo cardiomyopathy study group, gothenburg university, johns hopkins university, the takotsubo italian network and the heart failure associates tts taskforce of the european society of cardiology. all of the research institutions agree on at least two main criteria needed to accurately diagnose tts: 1) transient left ventricular wall motion abnormality and 2) the absence of a condition obviously explaining this wall motion abnormality (coronary artery lesion, hypoperfusion, myocarditis, toxicity, etc.). other commonly acknowledged criteria necessary for diagnosis include characteristic ekg changes and mild to modest elevation in cardiac troponin. transient apical ballooning syndrome or takotsubo cardiomyopathy is found in 1.7–2.2% of patients presenting with acute coronary syndrome.