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.
The pathophysiology is not well understood, but a sudden massive surge of catecholamines such as adrenaline and noradrenaline 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 edema, 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, 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 chronic obstructive pulmonary disease (COPD).
It occurs more commonly in postmenopausal women.
Signs and symptoms The typical presentation of takotsubo cardiomyopathy is chest pain with or without shortness of breath and associated electrocardiogram (ECG) changes mimicking an anterior wall myocardial infarction. 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 the 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. Acute asthma, surgery, subarachnoid hemorrhage, chemotherapy, and stroke are examples of physical stressors. In a few cases, the stress may be a happy event.
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.
Gender 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 being investigated whether 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 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. This observation was confirmed by results of the international GEIST registry, which demonstrated that thyrotoxicosis is associated with significantly increased fatality, whereas hypothyroidism indicates a better survival.
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. Specifically, adrenal stimulation by the sympathetic nervous system has been seen 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 theory 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 earlier thought.Kawai et al. JPJ 2000. It has been observed that vasospasms, even in multiple arteries, do not correlate with the areas of myocardium that are not contracting. However, coronary artery vasospasm is still believed to contribute to the TTS disease process. The theory of vasospasm is not easily distinguished from microvascular dysfunction, and microvascular dysfunction could explain vasospasticity. Impaired microvascular function is seen in a vast majority, if not all, of patients with TTS and is one of the most widely held theories. Most of the dysfunction occurs from 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 vasoconstriction from catecholamines occurs, 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.