ARC Journal of Diabetes and Endocrinology

AUTHOR DETAILS

Walid Hassan*, Tarek Abou Ghazala, Sahar Sharaf Eldin, Mohamed Ali Salah, Malik Kamal Malik, Nadir El Akhdar

Department of Cardiovascular Disease, International Medical center, Jeddah, Saudi Arabia
*Professor of Medicine and Senior Consultant, Director of the Cardiac Center of Excellence
International Medical center, Jeddah 21451, Saudi Arabia
[email protected]
³"Ponderas" Hospital, Bucharest, Romania
[email protected],

KEYWORDS

Takotsubo, Recurrence, Diabetes, Ketoacidosis

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 hypoglycemia) procedures or surgeries [1,2,3]. Increased catecholamine levels have been proposed to play a central role in the pathogenesis of this condition [4].
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].
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 [1,2,3,5]. 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 [5].
Tako-tsubo cardiomyopathy is a diagnosis of exclusion [6].Researchers at the Mayo Clinic proposed diagnostic criteria in 2004, which include; (1) 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; (2) the absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) the absence of pheochromocytoma and myocarditis [2].
Numerous etiologies have been described, including catecholamine release during stress [2, 7, 8], and microvascular spasm or ischemia [9, 10].
Acute complications of TC include arrhythmias, pulmonary edema, cardiogenic shock, transient LV outflow tract obstruction, mitral valve dysfunction, acute thrombus formation, stroke and Death [11]. There are no established treatment algorithms for TC at present, but as most patients present with an ACS or heart failure (HF), they are treated according to ACS/HF guidelines. Tako-tsubo cardiomyopathy is generally a benign condition; in-hospital mortality is 0-8% [11-16].
Recurrent TC disease is rare and only few cases have been previously reported [14, 15].
Diabetes has been reported to be protective against TC and a few reported TC in diabetic patient indicating low prevalence (10-20%) [17, 18, 19], in contrast to the high prevalence of diabetes in ACS (52%) in our previous study [20].
We present in this report 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).

THE CASE

A 53 year old female with poorly controlled type 2 diabetes due to medication non compliance who had 4 hospital admissions over the last 3 years 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 always recovered fully in few weeks time with normalization of LV function and wall motion in follow up echocardiography and usually she stopped all her cardiac medications. Currently, she is stable with much better compliance with treatment, glycemic control, HbA1c and last echocardiography 6 months after the last TC event showed completely normal LV systolic function.

DISCUSSION

Tako-tsubo syndrome or cardiomyopathy is a recently recognized entity. Many theories have been presented for the possible pathophysiology of TC. Studies have proposed the mechanism as an association with excessive sympathetic stimulation, microvascular dysfunction, spasm and metabolic abnormalities [1-5, 16, 21].
Emotional and physical stresses often precipitate the clinical presentation. This suggests a relationship between cortical brain activity (a central catecholamine surge) and myocardial stunning [1,2,22,23].
Studies have found that patients with TC have statistically significant higher levels of serum catecholamines (norepinephrine, epinephrine, and dopamine) than patients with myocardial infarctions [23-26]. 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 [27]. 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 [19-23]. Combining the results from multiple studies plasma norepinephrine levels were elevated in 74% of cases [12].
The pathogenesis of TC may be multifactorial, similar to catecholamine induced cardiomyopathy [25], pheochromocytoma [26] and subarachnoid hemorrhage [27]
. Catecholamine excess has reversible toxic effects on myocardium that have been documented in cases of pheochromocytoma [26-30]. 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 [31, 32, 33].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 [14, 15].
Data on diabetes as a trigger for TC is scarce and previous reports suggest even a protective role of diabetes against TC [17, 18, 19, and 34] as compared to the higher prevalence of diabetes in ACS as shown in our previous study [20].
No previous documentation regarding recurrent TC triggered by DKA as in our case. We strongly believe that the above mentioned 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.
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 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 [6, 35, 36].
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 [37-41]. 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 [41]. It is reasonable to continue anti-coagulation until the thrombus resolve and left ventricular function improves [42].

THE MOLECULAR MECHANISMS OF PROGENITOR ENDOTHELIAL CELL DYSFUNCTION IN DIABETES MELLITUS

Alteration of structure and function of the EPCs has identified in type 1 and type 2 DM [20]. The mechanisms underlying EPC reduction in diabetes predominantly include weak bone marrow mobilization, decreased proliferation, and shortened survival [36]. It has suggested that in DM glucose toxicity, lipid toxicity and reactive oxidative species (ROS) via enhancing inflammation may regulate proliferation BM-EPCs [6, 9, 20]. The key mechanism of this response is the activation of matrix metalloproteinase-9 (MMP-9) through intracellular signal systems, i.e. Akt / STAT and nitric oxide dependent signaling [37]. Maturation and mobbing of the BM-EPCs are under control of growth factors, such as chemokine stromal cell-derived factor-1 (SDF-1), VEGF, granulocyte colonystimulating factor (G-CSF), and alpha-chemokine that binds to G-protein-coupled CXCR4 [38, 39]. Lataillade JJ et al (2000) reported that SDF-1 may stimulate the growth of EPCs' colonies, chemotaxis and cell expansion [39]. Nevertheless, SDF-1 is able to improve survival of the EPCs in culture through suppression of their apoptosis [40]. SDF-1 exerts pleiotropic effects regulating chemoattraction and adhesion of EPCs in CXCR4-dependend mechanisms playing an essential role in the trafficking of EPCs in various tissue including heart and vasculature [41]. It is importantly that SDF-1 gene expression in EPCs and endothelial cells is regulated by the transcription factor hypoxiainducible factor-1 (HIF-1), which is under control of reduced oxygen tension in the tissues [42]. VEGF has exhibited autocrine action in EPCs suppressing apoptosis and protect a survival effect [43]. GM-CSF may accelerate re-endotheliazation and reduce microvascular inflammation through mobbing of EPCs [44]. There is evidence that "residence" EPCs originated from myeloid cells could trans-differentiate into endothelial cells in the same manner [34].
DM is characterized reduced expression of angiopoetic factors (SDF-1, VEGF, G-CSF, CXCR4) in heart and vasculature [18]. Moreover, differentiation and mobbing of EPCs after ischemia-reperfusion injury in DM is defective [46]. The initial role in these processes belongs to over-production of ROS, decreased superoxide dismutase activity, and probably SDF-1 genotype polymorphism [18, 42, 47], whereas epigenetic changes in EPCs are considered an important mechanism, which links hyperglycemia, lipid toxicity and metabolic memory [6, 9, 48]. Finally, weak functionality of EPCs in type 1 and type 2 DM is resulting mutual related molecular mechanisms affected cellular signal systems, paracrine regulation and epigenetic modification. Therefore, poor differentiation, mobbing and proliferation of BM-EPCs and PB-EPCs lead to decreased circulating pool of primitive cells and worsening reparative capability [40].

ENDOTHELIAL PROGENITOR CELLS AND CV RISK

Reduced number and weak functionality of circulating EPCs have been demonstrated sufficiently correlation with vascular endothelial dysfunction and independently association with both traditional (aging, hypertension, hypercholesterolaemia, smoking, diabetes, C-reactive protein level) and nontraditional (insulin resistance, adipocyte dysfunction) CV risk factors, Framingham risk factor score [49-51], as well as frequency of major CV events, revascularization, hospitalization rate and death from CV causes [52-54]. Most importantly, EPCs isolated from peripheral blood of the patients with known CAD have exhibited an impaired migratory and weak proliferative response [50], which have confirmed being of "EPC impaired phenotypes" pre-existing in subjects with CV risk factors prior established CV disease [55, 56]. However, the circulating level of EPCs in patients with established higher CV risk is very variable and does not fully correlate with number of CV risk factors [57, 58], although number of BM-EPCs has closely predicted asymptomatic atherosclerosis [59, 60] and CV disease [61]. One found that lowered number of circulating EPCs originated from bone marrow have accompanied with hypercholesterolemia-induced expression of pro-inflammatory molecules by the vessel wall [62]. Additionally, the level of circulating CD34+KDR+ EPCs may help to identify patients at increased CV risk [55].
However, there are controversies regarding number and colony-forming ability of circulating BMEPCs and PB-EPCs in individuals with established CV disease and metabolic disease, i.e. DM, metabolic syndrome, obesity. The first controversial reflects disproportion between circulating level of EPCs depending stage of CV disease. To update our knowledge, at the early stage of CV disease especially in patients with asymptomatic atherosclerosis, moderated increase of the EPCs' count in circulation was found [63]. In contrast, lowered level of EPCs might clarify a severity of atherosclerosis or DM-related vasculopathy [64, 65]. The next controversial relates to the level and functionality of EPCs in subjects with obese, metabolic syndrome and DM. Interestingly, at the early stage of metabolically inactive obesity ("not fully" metabolic syndrome) BM-EPCs number may increase and an ability of primitive cells to mobbing, differentiation and colony forming might be not distinguished healthy individuals [66]. In contrast, development of insulin resistance, metabolic syndrome and type 2 DM has closely associated with weak ability of EPCs to mobbing, and the lowered level of circulating EPCs was determined [67]. In contrast, Asnaghi V et al (2006) [68] have reported that clonogenic potential of circulating EPCs in patients with type 1 DM may increase. Finally, heterogeneity of EPCs and the variable changes in the EPCs' phenotypes at the different stages of CV disease and development of DM are limiting factors to determine the predictive value of count and functionality of EPCs in CV risk calculation.

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 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.