Pharmacologically-induced Takotsubo syndrome: A lesser recognized entity of clinical significance

“It’s not stress that kills us; it is our reaction to it.” –Hans Selye Our physical form copes with stress through hypothalamus–pituitary–adrenal axis. The acute release of neurotransmitters from the sympathetic and central nervous systems, as well as hormones from the adrenal cortex and medulla, pituitary, and other endocrine glands, mediates the response to acute stress.[1] Response to this type of stress is generally adaptive with an increase in heart rate, blood pressure, myocardial contractility, thermogenesis, and metabolic rate. Occasionally, there can be an alarm reaction or exhaustion with stress of a unique type which can temporarily paralyze a part or whole of the myocardium and masquerade as an acute coronary syndrome or heart failure. Adrenergic vasoconstrictors, hyperadrenergic state due to alcohol or opioid withdrawal, inhibitors of catecholamine reuptake, anaphylactic reaction that is accompanied by catecholamine release, and psychological or somatic stress all can mimic unusual stress responses to some extent.[2] We can partly simulate it by infusing pharmacological agents such as catecholamines including dobutamine. Dobutamine stress echocardiography is a choreographed state of events to increase inotropy and chronotropy. Dobutamine-induced stress cardiomyopathy or Takotsubo syndrome (TTS) has been well described in several case reports.[3-15] TTS is defined as transient regional systolic dysfunction in the absence of obstructive coronary artery disease, typically accompanied by ST-segment changes/T-wave inversions with mildly raised troponin levels. Currently, the known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, genetic predisposition, and thyroidal dysfunction.[3] Dobutamine is one of the more than 15 dozen drugs capable of inducing TTS secondary to sympathetic overactivation. However, drugs not associated with sympathetic activation have also been reported to trigger TTS.[16-18] A systematic review has shown that over two-thirds of drug-induced Takotsubo cardiomyopathy cases are due to direct or indirect catecholamine stimulation.[17,18] Iatrogenic impact of certain drugs, namely antidepressants, chemotherapy, and antiarrhythmics accounts for the rest of the drug-triggered TTS [Figures 1 and 2]. Chemotherapy-triggered TTS is a noteworthy phenotype which has been explained largely because of increased oxidative stress.[18] It has been suggested that catecholamines, cytokines, free radicals, growth factors, allergens, and prostaglandins increase adrenoceptor sensitivity in susceptible individuals, leading to microvascular dysfunction and/or direct cardiotoxicity.Figure 1: Therapeutic agents implicated in the pathogenesis of Takotsubo syndrome. TTS: Takotsubo syndromeFigure 2: List of drug withdrawal associated with catecholamine surge. TTS: Takotsubo syndromeTTS is being increasingly recognized both due to heightened awareness and the wide-spread use of coronary angiography. From being considered a benign entity, it’s not-to-good prognosis on follow-up is being reported more and more.[19] In this issue of the Journal, Mastebhakti et al. have reported a middle-aged female patient being investigated for possible liver transplantation.[20] During dobutamine stress echocardiography, this patient developed an acute myocardial infarction-like situation with evolutionary changes in troponin levels and electrocardiography but with near-normal coronary angiogram. Echocardiography showed apical ballooning variety of TTS which resolved over 1 week. Dobutamine is a racemic synthetic catecholamine with partial alpha-1 agonism, strong ß1 agonism, and weak ß-2 receptor agonism. It is used essentially as an inotrope. Dobutamine stimulates adenylyl cyclase, leading to increased cyclic adenosine monophosphate which activates cytoplasmic phosphokinase that phosphorylates many intracellular molecules resulting in greater cytosolic calcium and hence enhanced contractility of myofilaments. Dobutamine produces a marked calorigenic effect, which is the consequence of complex α and β adrenergic metabolic effects. Dobutamine-induced TTS has been described either during the infusion in 85% or after the infusion has been terminated in 15%.[3] Dobutamine-triggered TTS supports the calcium overload-energy failure hypothesis. However, the drug is probably only a trigger and not the cause of TTS which lies in variable B-receptor density distribution and responsiveness. Apicobasal adrenoceptor gradient has been proposed for the typical imaging pattern of TTS.[3] Dobutamine can also cause mitochondrial uncoupling and increased oxidative stress through accelerated glycolytic pathway. Nearly 90% of these cases have typical apical ballooning. Major adverse cardiac events occur in 35% of dobutamine-induced TTS;[14] however, inverted TTS has also been described in a few cases.[3] Inhaled B2-adrenergic receptor agonists have also been implicated in the pathogenesis of TTS.[21] Even epinephrine and methamphetamine use has been associated with TTS.[22] Synthetic Catecholamines and Pathogenesis of Takotsubo Syndrome A popular hypothesis for the pathogenesis of TTS is the overactivation of sympathetic nervous system either endogenously or exogenously. It is supported by the occurrence of TTS in some patients of catecholamine-secreting tumors.[3] There is the suggestion that paradoxically, there can be negative inotropy with ß2-receptors while maintaining positive inotropy with ß1 agonism. One of the earliest series of nine cases[23] reported three different phenotypes of TTS following epinephrine (six cases) or dobutamine infusion [three cases, Figure 3].Figure 3: Dotted lines define the left ventricular cavity in end-systole. The left panel shows apical ballooning (Type 1) and mid-ventricular (Type 3) variety. The right panel shows inverted Takotsubo syndrome (Type 2). TTS: Takotsubo syndrome, LV: Left ventricularAnother group reported a single case of TTS during dobutamine stress echocardiography along with a review of literature involving 21 patients.[3] In this series, only three patients had nonapical TTS. Another review of literature collected data on 33 epinephrine-induced TTS and showed that nearly half of the patients had nonapical TTS [Figure 4].[24] There is a recent report of two such cases[25] with midventricular variety.[25] Many cases of TTS have been reported after topical application of epinephrine.[26] Catecholamine-induced TTS is a specific and most common secondary form characterized by rapid onset of symptoms, high rate of complications during the acute phase, good short-term prognosis, and frequent apical sparing on echocardiogram.[24] Other catecholamines and indirect catecholamine-like compounds such as isoproterenol, albuterol, phenylephrine, midodrine, ergonovine, and pseudoephedrine have been shown to induce TTS.[16] There are several cases of TTS reported with abuse of cocaine.[16]Figure 4: Eighty-one-year-old patient on noradrenaline infusion. (a) End-systolic parasternal long axis view after definity injection. Apical segments are hyperkinetic with adequate perfusion while the midventricular and basal segments are akinetic with normal perfusion. (b) (apical 4-chamber view) shows practically zero longitudinal strain in basal segments on acoustic speckle trackingAnti-depressive Agents and Takotsubo Syndrome Despite the high prevalence of depression among patients with TTS, certain antidepressants may trigger TTS. According to a data review, the TTS risk is highest in serotonin-norepinephrine reuptake inhibitors use, i.e., lithium, duloxetine, milnacipran, venlafaxine, and phentermine.[16] In addition, the use of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine or selective norepinephrine reuptake inhibitors (SNRIs) as atomoxetine and cocaine, or tetracyclic antidepressants such as nortriptyline and maprotiline, may induce TTS.[17] SNRIs block the reuptake of neurotransmitters in the presynaptic membrane, which increases the level of circulating noradrenaline. This process leads to the activation of the sympathoadrenal system. The mechanism of action of SSRIs on the development of TTS is not fully understood and catecholamine surge is one of the hypotheses. Chemotherapy TTS has been associated with a broad spectrum of anticancer drugs treatment with 5-fluorouracil, capecitabine, trastuzumab, and immune checkpoint inhibitors was found in 36.5%, 9.7%, 9.7%, and 9.7% of chemotherapy-related TTS cases.[18] The exact mechanism of chemotherapy-induced cardiotoxicity of 5-fluorouracil and capecitabine is not fully known. However, coronary spasm, thromboxane A2 activation, oxidative stress, direct toxic effect of metabolites, increased capillary permeability, and electrolyte imbalances are the most likely effects.[15-18] Malignancy is a stressful condition and TTS after chemotherapy may be coincidental rather than causative. Antiarrhythmic Drugs Based on several case reports, antiarrhythmic drugs have been identified as risk factors for TTS development, especially drugs such as flecainide, sotalol, amiodarone, lidocaine, and xylocaine[15-18] prolonged QT interval has been frequently observed in all varieties of primary TTS and may play a role in pathogenesis or may be an accompaniment. Flecainide leads to marked inhibition of the upstroke of the cardiac action potential, delayed inactivation of the slow sodium channel, and blocks the delayed rectifier potassium channels, resulting in a prolonged QT interval, potentially preceding a TTS. Amiodarone by blocking potassium rectifier currents leads to an increase in the action potential duration and prolongation of the effective refractory period in cardiomyocytes and therefore can prolong QTc interval. The exact mechanism of the genesis of TTS with antiarrhythmic drugs is unsettled. In summary, nearly in two-third of cases of therapy-triggered TTS, catecholamine surge is the plausible explanation. This also includes TTS following acute withdrawal of opioids, alcohol, beta-adrenergic receptor blockers, anticonvulsants, etc. In other cases, oxidative stress, reversible direct toxic effects, allergy or anaphylaxis, etc., play a role.[27,28] There is no need to raise unnecessary alarm with regard to the use of these agents mentioned above; however, the physician should be aware of such freak epiphenomena.