Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure.

Takotsubo cardiomyopathy (TTC) is characterized by transient systolic dysfunction of the left ventricle and changes of electrocardiographic or cardiac markers, resembling an acute coronary syndrome. Although the etiology of TTC is still unknown, a wide variability in the psychological and physical triggers for TTC is present. In this article, we describe the case of 69-year-old female with a history of epilepsy and who presented in the emergency room with a new-onset generalized tonic-clonic seizure activity. After finding out that her biochemistry results indicated severe hyponatremia, a diagnosis of TTC was established through echocardiography and angiography. Copyright:

Takotsubo cardiomyopathy (TTC) is characterized by transient systolic dysfunction of the left ventricle and changes of electrocardiographic or cardiac markers, resembling an acute coronary syndrome. Mostly, TTC develops following emotional or physical stress in the absence of obstructive coronary disease or without angiographic evidence of acute plaque rupture [1-4]. The pathophysiology of TTC is unclear. An excessive release of catecholamines following emotional or physical stress seems to have a pivotal role in the development of TTC [5]. On the other hand, TTC can be triggered by some noncardiac clinical conditions such as hyponatremia and seizure [6-10]. In this article, we describe a case of TTC that developed following seizure and severe hyponatremia.

CASE REPORT

A 69-year-old female having a history of epilepsy was presented to the emergency room with a new-onset generalized tonic–clonic seizure activity. Upon admission, there was no chest pain or any cardiac symptom. Her medical history indicates she had hypertension and epilepsy, and these were treated with indapamide, carbamazepine, and levetiracetam. Her physical examination was unremarkable. Moreover, routine laboratory values revealed her serum sodium level was 112 mmol/L, initial troponin was 7.13 ng/mL (normal range 0.0–0.06 ng/mL), and serum carbamazepine concentration was 7.1 ng/mL (therapeutic range 4–12 ng/mL). The first electrocardiogram (ECG) showed sinus rhythm with diffuse upsloping 1 mm ST-segment elevation (Fig. 1). After transthoracic echocardiography (TTE), there was apical hypokinesia with an estimated ejection fraction (EF) of 36% (Fig. 2). Although TTC was suggested after initial clinical findings, the patient underwent coronary angiography to rule out coronary artery disease. After the procedure, it was found that coronary angiography revealed no stenosis in any coronary artery (Fig. 3) and that left ventriculography showed anteroapical, inferoapical, and apical akinesis (Fig. 4).

FIGURE 1

Electrocardiogram showing sinus rhythm with diffuse 1 mm upsloping ST-segment elevation.

FIGURE 2

Transthoracic echocardiography demonstrating apical hypokinesia with an ejection fraction estimated at 36% in apical 4-chamber view. (A) Left ventricle systole. (B) Left ventricle diastole, red arrow; apical hypokinesia. (LA: left atrium; RA: Right atrium; RV: Right ventricle).

FIGURE 3

Coronary angiography showing normal coronary arteries.

FIGURE 4

Left ventriculography demonstrating apical ballooning in the right anterior oblique view. (A) Left ventricle in systole. (B) Left ventricle in diastole.

Hypothyroidism and adrenal insufficiency, both are causes of hyponatremia, were ruled out by determining thyroid-stimulating hormone levels [1.5 µIU/mL (normal range 0.5–6.2 µIU/mL)] and serum cortisol levels [20 µg/dL (normal range 10–20 µg/dL)]. After suffering from withdrawal to both indapamide and carbamazepine, the patient was subsequently treated with an intravenous infusion of 3% saline, and her sodium then increased to 135 mmol/L at the end of the first week. In this context, it was thought that TTC develops by hyponatremia due to indapamide and carbamazepine. There was then a discharge on aspirin (100 mg/d), metoprolol (50 mg twice daily), ramipril (5 mg/d), subcutaneous enoxaparin (0.8 mL twice daily), valproic acid (500 mg twice daily), and levetiracetam (500 mg twice daily) and a discontinuation of carbamazepine and indapamide treatment. Full recovery of EF (60%) was demonstrated through TTE at two weeks of discharge (Fig. 5). After two months, the patient was referred to the hospital after suffering from recurrent hyponatremia with a serum sodium level of 115 mmol/L. However, she presented with no cardiac symptoms and seizure. ECG and TTE also did not show any ST-segment changes or wall motion abnormality. Because of this, treatment with carbamazepine, after being stopped on the first hospital admission, had to be started and continued with a lower limit of therapeutic range [4.55 ng/mL (therapeutic range 4–12 ng/mL)] to prevent epileptic seizures.

FIGURE 5

Control TTE showing full recovery in apical 4-chamber view after two weeks. (A) Left ventricle systole. (B) Left ventricle diastole.

DISCUSSION

Although its pathophysiology is unclear, TTC is defined as a reversible left ventricular hypokinesis. It was proposed that coronary artery vasospasm, transient obstruction of the left ventricular outflow tract, and microcirculatory dysfunction are the possible causes of this disease [11].

Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its severity is determined according to serum sodium levels that are categorized into three: mild (serum sodium, 130–134 mmol/L), significant (125–129 mmol/L), and severe (<125 mmol/L) [12]. While asymptomatic patients do not require immediate correction, symptomatic hyponatremia is a medical emergency that needs prompt and prudent treatment. Moreover, acute severe hyponatremia is associated with neurologic symptoms, such as seizures and coma, and should be treated meticulously to prevent cerebral edema and encephalopathy. In present case, several clinical factors revealed that seizure is not associated with acute severe hyponatremia. First, the patient has been suffering from recurrent seizures due to epilepsy for a long time. Second, hyponatremia in this patient is chronic and recurrent. This patient is suffering from severe hyponatremia due to several contributing factors including drugs such as carbamazepine and indapamide. The association between hyponatremia and carbamazepine has been well described. However, the mechanisms on how carbamazepine causes hyponatremia are not fully understood. Carbamazepine may increase the secretion of antidiuretic hormone (ADH) from the posterior pituitary and sensitize the osmoreceptors to ADH in the distal convoluted tubules [13]. It can be noted that several case reports have established a causal relationship between indapamide and severe hyponatremia [14]. In this case, these two drugs (carbamazepine and indapamide) with different activity are thought to cause hyponatremia.

According to the a few previous case reports, TTC is associated with severe hyponatremia in several cases, even with the absence of adrenal insufficiency and hypothyroidism [6, 9, 10]. In our case, we ruled out hypothyroidism and adrenal insufficiency. On the second admission, the patient had been taking carbamazepine without receiving indapamide for two months, and this eventually decreased serum sodium level similarly.

On the first admission, the serum sodium level was 112 mEq/L when TTC occurred, whereas it did not occur on the second admission when the serum sodium level was 115 mEq/L. In this context, we can assume that the recurrence of hyponatremia may not induce TTC. Singh et al. reported that there was a negative correlation between the use of renin angiotensin aldosterone system blockers and the recurrence of TTC [15]. However, we speculate that if the medication was started after the first TTC, it might have prevented the recurrence of TTC in spite of recurrent hyponatremia.

There is also an association between seizure and Takotsubo cardiomyopathy [16]. The mechanism of seizure-associated TTC can be explained by excessive catecholamine release during epileptic seizures. On the first admission, despite the reason of TTC occurrence was seizure instead of hyponatremia, the patient had a history of seizures. Because of this, we are unable to determine whether TTC occurred together with the previous seizures. In fact, both hyponatremia and seizure might separately cause TTC; however, we conclude that both hyponatremia and seizure were predisposing factors together in the present case.