Recurrent multiform Takotsubo cardiomyopathy in a patient with epilepsy: Broken heart or brain?

Takotsubo cardiomyopathy (TC) is known as a reversible left ventricular dysfunction resembling an acute myocardial infarction, without significant coronary obstructions or acute plaque rupture at angiographic investigation. On admission apical and midventricular hypo-/a-/dys-kinesia and compensatory basal hyperkinesia are usually observed; however, the pattern of wall motion abnormalities is very heterogeneous and a considerable proportion of all cases (around 23% according to the literature) is made up of basal and midventricular hypo-/a-/dys-kinesia with normal kinesia of the apex (“reverse Takotsubo”) [1]. Epileptic crises are the second most frequent disorder of the central nervous system that trigger TC [2]. We report a “classical” TC associated with a tonico-clonic generalized seizure, followed by two episodes of “reverse” TC, after seven months and five years respectively. In October 2009, a 64 year old woman was admitted to the Emergency Department for typical chest pain after an intense fright, followed by a tonico-clonic generalized seizure. Her medical history included a general convulsive crisis in 2000 and anti-epileptic medications (stopped in 2006). Physical examination revealed blood pressure of 131/70, a heart rate of 104 beats/min with extrasystolia, oxygen saturation of 97%, no heart murmurs and no pulmonary edema. An electrocardiogram An electrocardiogram showed sinus tachycardia with ectopic premature ventricular beats and QS complex in leads V1 and V2 [Fig. 1 A]. A transthoracic echocardiogram showed an extensive area of apical akinesia of the left ventricle and a severely reduced systolic function. The CK-MB and TnT peaks were 16.2μg/L and 0.54ng/mL respectively. A coronary angiography and a ventriculography revealed coronary arteries free from injury and a left ventricular ejection fraction of 42%. The ninth-day echocardiogram showed a septum-limited hypokinesia and a LVEF of 57%, confirming the diagnosis of TC. In May 2010 the patient came back to our Department due to a further episode of chest oppression which had started at rest the day before. Her vital parameters were stable and the ECG did not show any important signs except for the presence of septal Q waves [Fig. 1 B]. CK-MB and TnT peaks were 6.5μg/L and 0.18ng/mL respectively. A trans-thoracic echocardiogram showed a mildly dilated left ventricle with a large area of hypokinesia in the medium-basal segments and severe mitral functional regurgitation, with central jet [Fig. 2 A–B]; the LVEF was significantly reduced (35%). Owing to the recent report of healthy coronary arteries, a cardio-CT was performed on the seventh day; it confirmed the patency of the coronary tree (Agatston score: 0) and showed a decrease in the medium-basal hypokinesia with recovery of the ejection fraction. An eleventh-day echocardiogram showed recovery of LVEF (52%) and a mild mitral regurgitation, consistent with a diagnosis of “reverse Takotsubo”. In July 2014 the patient was evaluated for a short-term memory disturbance and the concomitant onset of mild oppressive precordial pain. At the Emergency Department an echocardiogram showed akinesia of the interventricular septum and hypokinesia of medium and basal portions of the anterior and inferior wall of the left ventricle, with an ejection fraction of 44% and a medium grade mitral regurgitation (no significant alterations at ECG [Fig. 1 C]; TnT peak: 175ng/L). The neurological presentation was interpreted as a post-critical amnesia following a partial epileptic seizure. Six days after the onset, the LVEF recovered and the mitral regurgitation became mild, confirming the diagnosis of a further “reverse TC”. According to a recent review [3], our patient belongs to that 5% of the population presenting TC relapse within six years; a previous study [4] reported a higher rate (11.4%) over the first 4years. This case shows that Takotsubo cardiomyopathy is a multiform, dynamic clinical entity that may occur with but also without an evident trigger and with different myocardial involvement even in the same individual. The triple recurrence not only suggests a predisposition but also leads to some pathogenetic considerations. Several studies have shown that the sympathetic innervation becomes progressively more sparse from base to apex of the heart, while an opposite beta-receptor concentration gradient exists, so that the apical myocardium seems to be more responsive than the basal to adrenergic stimuli [5]. The resulting cardiotoxic effect may explain the classical apical ballooning [6]; it has been proposed that the “reverse TC” pattern may result from differences between individuals in beta-receptor density gradient as well as in regional adrenergic sensitivity [7]. What we suggest is that the pathophysiology of TC cannot be based on mere anatomic and subcellular pre-existing conditions: the type and the intensity of stimuli could play a substantial and possibly crucial role in the way the myocardium is damaged. Furthermore, the first TC was associated with a generalized seizure, in line with the majority of cases reporting a relation between TC and epilepsy [2] while the second crisis was partial and seizures less frequently trigger a reverse type of TC, thus increasing the complexity of the case. To explain the heterogeneous echocardiographic pattern in consecutive relapses, the hypothesis that previously affected myocardium is protected via a phenomenon analogous to regional ischemic preconditioning has been proposed [8]; however, this is not applicable to our patient, since the first TC was “classical” and the following two were both “reverse”. This case also highlights the role of catecholamines in the genesis of both TC and epileptic seizure: since in the first episode the patient reported that the chest pain arose before the convulsive crisis, the same intense emotional stress may have triggered each of them simultaneously, suggesting the importance of adrenergic sprouting in the pathogenesis of both conditions. It is also possible that the catecholamines released during the seizure led to the worsening of LVEF. To the best of our knowledge, this is the third case reported in the literature of a relapsing association between TC and epileptic crises in the same patient [9,10]; however, there are more than sixty cases of a single presentation of this relationship [2], suggesting that these patients need close cardiologic follow-up.