Diabetes Mellitus and Recurrent Tako-Tsubo Syndrome

Tako-tsubo syndrome or cardiomyopathy also referred to as transient apical ballooning syndrome, stress cardiomyopathy or broken heart syndrome is a well-recognized syndrome typically characterized by transient and reversible left ventricular dysfunction that develops in the setting of acute severe emotional or physical stress. Increased catecholamine levels have been proposed to play a central role in the pathogenesis of the disease, although the specific pathophysiology of this condition remains to be fully determined. At present, there have been few reports of Takotsubo cardiomyopathy associated with diabetes mellitus. In this report, we present a 3-years follow-up in a patient with previous multiple recurrences of Takotsubo triggered by diabetic ketoacidosis with resolution and full recovery after strict diabetic control.


Introduction
Tako-tsubo syndrome (TTS) or Cardiomyopathy (TC) is an increasingly recognized entity characterized by transient (reversible) apical and mid left ventricular (LV) dysfunction in the absence of significant coronary artery disease that is potentially triggered by severe emotional, physical stress, medical illness (acute exacerbations of multiple medical conditions such as asthma, sepsis, gastrointestinal bleeding or 3 hypoglycemia) procedures or surgeries [1][2][3][4][5]. Increased catecholamine levels have been proposed to play a central role in the pathogenesis of this condition [6].
The Takotsubo phenomenon was first described in 1991 by Dote et al. [1], who named the syndrome "Takotsubo like cardiomyopathy" because the appearance resembles a pot historically used in Japan to catch octopi. Other names of this syndrome are Stress-induced Cardiomyopathy, apical ballooning syndrome, broken heart syndrome, ampulla cardiomyopathy [1][2][3][4][5].
Typically, it recovers to normal LV function in 1-4 weeks. It may account for up to 2% of suspected acute coronary syndrome (ACS), TTS or TC is much more common in women than men, particularly post-menopausal women [1][2][3]7]. In a review of six prospective and four retrospective studies women accounted for 80 to 100 percent of cases, with a mean age of 61 to 76 years [7].
Tako-tsubo cardiomyopathy is a diagnosis of exclusion [8]. Researchers at the Mayo Clinic proposed diagnostic criteria in 2004, which include; • Transient hypokinesis, akinesis, or dyskinesis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond a single epicardial vascular distribution and frequently, but not always, a stressful trigger; • The absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; • New ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and • The absence of pheochromocytoma and myocarditis [2]. Numerous etiologies have been described, including catecholamine release during stress [2][3][4][5]9,10], and microvascular spasm or ischemia [11,12].
Recurrent TC disease is rare and only few cases have been previously reported [4,5,16,17]. Diabetes has been reported to be protective against TC and a few reported TC in diabetic patient indicating low prevalence (10-20%) [19][20][21], in contrast to the high prevalence of diabetes in ACS (52%) in our previous study [22].
We present in this report a 3-year follow-up of a rare case of recurrent apical ballooning syndrome in a woman with several hospitalizations for chest pain, dyspnea, and electrocardiographic (ECG) changes triggered by diabetic ketoacidosis (DKA) and remarkable resolution and full recovery after strict glycemic control.

The Case
A 56-year-old female with poorly controlled type 2 diabetes due to medication noncompliance who had 4 hospital admissions over 3 years (2013-2016) for chest pain, dyspnea, acute ST-T elevation, cardiac biomarkers elevation, left ventricular apical severe hypokinesis and ballooning diagnosed by echocardiography. She always received acute coronary syndrome (ACS) management at presentation and had urgent coronary angiogram during the initial three presentations and all revealed normal coronary arteries. The common associated factor in all admissions was the presence of DKA at all presentations. After DKA treatment, she was kept on anti-failure medications in the form of angiotensin converting enzyme inhibitor (ACEI), beta blocker (β-blocker), diuretic and aspirin. She recovered fully in few weeks' time after last event (1/2016) with normalization of LV function and wall motion in follow up echocardiography (6 months the yearly) and she stopped her cardiac medications except ACEI and beta blocker. Currently, she is stable with much better compliance with diabetic treatment, glycemic control, HbA1c with no further DKA presentation and last echocardiography 36 months after the last TC event showed completely normal LV systolic function.
Emotional and physical stresses often precipitate the clinical presentation. This suggests a relationship between cortical brain activity (a central catecholamine surge) and myocardial stunning [1,2,24,25].
Studies have found that patients with TC have statistically significant higher levels of serum catecholamines (norepinephrine, epinephrine, and dopamine) than patients with myocardial infarctions [25][26][27]. Increase beta-2-adrenoceptor activity in the setting of a high catecholaminergic state has been proposed as possible reproducible model for this entity, inducing cardiac dysfunction and myocyte injury though calcium leakage due to hyperphosphorylation of the ryanodine receptor 2 [28]. The apical portions of the left ventricle have the highest concentration of sympathetic innervations found in the heart and increased beta-2 concentration gradient from apex to base could play an important role in the apical myocardial dysfunction and ballooning commonly found in TC cases [21][22][23][24][25]. Combining the results from multiple studies plasma norepinephrine levels were elevated in 74% of cases [14].
Catecholamine excess has reversible toxic effects on myocardium that have been documented in cases of pheochromocytoma [27][28][29][30][31][32]. Histological examination of biopsy samples from the affected left ventricle of patients with TC has shown intracellular accumulation of glycogen, many vacuoles, disorganized cytoskeleton and contractile structure, contraction band necrosis and increased extracellular matrix proteins, which is associated with clinical states of catecholamine excess [33][34][35]. These alterations resolved nearly completely after functional recovery.
Takotsubo cardiomyopathy is associated with minor release of cardiac enzymes so suggests some microscopic damage to the myocytes. The absence of causative coronary artery disease on angiography and the wall motion abnormalities point to an insult that is microscopic in nature.
Recurrent TC disease is rare and only few cases have been previously reported [4,5,16,17]. Data on diabetes as a trigger for TC is scarce and previous reports suggest even a protective role of diabetes against TC [19,20,21,36] as compared to the higher prevalence of diabetes in ACS as shown in our previous study [22]. This the only one documentation regarding recurrent TC triggered by DKA [4]. We strongly believe that the abovementioned catecholamine and neuro-hormonal axis is probably the underlying mechanism that is stressed and over stimulated during DKA as in our patient, overwhelming and counteracting the baseline autonomic neuropathy known in diabetic patient.

Current Research in Diabetes & Obesity Journal
There is no controlled data to define the optimal medical regimen to treat TC during DKA, but it has been postulated that it is reasonable to treat the underlying cause, strict glycemic control and with the standard medications for LV systolic dysfunction. These include ACE I, β-blocker (or combined α-and β-blocker), and diuretics, which may be necessary for volume overload states [2]. Aspirin and statin are also reasonable treatment [8,37,38].
It was reported that thrombosis occurs in takotsubo cardiomyopathy cases, which might reflect vasoconstriction, platelet activation, or prothrombotic effects of extremely high epinephrine levels that of course will be more exaggerated in diabetic patients [39][40][41][42][43]. In one study, 5% of patients with TC developed LV thrombus, and all patients with LV thrombus, were started on anticoagulation and one patient developed stroke [43]. It is reasonable to continue anti-coagulation until the thrombus resolve and left ventricular function improves [5,44].
In our case, after compliance with treatment and strict glycemic control, she recovered well her TC and regular followup echocardiography every 6-12 months remained with normal LV systolic function with no wall motion abnormalities. She was maintained only on ACEI, beta blocker and stopped other cardiac medications. She continues to be asymptomatic lead an active life 3 years after the last TC event.

Conclusion
To the best of our knowledge, we report a unique first case of multiple recurrences of TC triggered by diabetic ketoacidosis. Our patient was diagnosed 4 times with TC based on the widely accepted Mayo guidelines for TC Prevention with good glycemic control, medications compliance, and avoidance of other triggers have been the key to prevent further cardiac events.
Chronic management of TC is primarily empirical, but there is emerging data supporting the role for alpha and beta blockade. In diabetic patients who are stable, it appears advantageous to prevent excessive sympathetic activation by combining alpha and beta blockade during episodes of ketoacidosis, we also advice ACEI long term if tolerated.
We hope our case contribute to the understanding of this interesting rare condition and will further help in the management of patients with similar conditions. Lastly, a more complete understanding of the pathophysiology of this syndrome in diabetics awaits further research.