Takotsubo Cardiomyopathy Complicating Diabetic Ketoacidosis, Hypothermia and Hypernatremia in a Comatose Patient

Takotsubo cardiomyopathy (TCM) is a transient wall motion abnormality of the left ventricular apex associated with emotional or physical stress. In the setting of diabetic ketoacidosis (DKA), it is thought to be caused by the compound effect of a catecholamine surge and the noxious effect of acidosis and ketones leading to myocardial stunning. In this report, the first of its kind in the Middle East, we describe the case of a 71-year-old comatose patient, who was being treated for DKA and hypernatremia and was incidentally diagnosed with TCM. We also review 15 case reports of DKA-induced TCM published to date in the literature, many of which had an atypical presentation and good outcomes. Furthermore, we discuss possible risk factors for TCM in our case and supporting literature. It is recommended to maintain increased vigilance and attempt early identification of such conditions in acutely ill patients to prevent life-threatening complications.


Introduction
Takotsubo cardiomyopathy (TCM) is a transient wall motion abnormality of the left ventricle typically associated with emotional or physical stress [1].While the pathophysiology of TCM remains unknown, various hypotheses have been discussed including myocardial ischemia, left ventricular outlet tract obstruction, autonomic nervous system dysfunction and microvascular dysfunction [1], with the most postulated pathology being neurohormonal release of catecholamines [2].In addition, another mechanism suggested is the intricate relationship and interplay between the catecholamines and steroids and the effect of this interplay on myocytes.Numerous case reports showcased the role of steroid administration or excess in precipitating TCM, which is likely explained by the well-studied role of steroid hormones in stimulating the synthesis and potentiating the actions of catecholamines on the myocytes [3].On the other hand, multiple reports have also demonstrated the triggering of TCM in steroid-insufficient patients.Possible processes explaining this association could be found in adrenalectomized animal models, where the toxicity of catecholamines on the steroid-starved cardiac tissue was demonstrated [4].Other theories include uncoupling of excitation-contraction and aberrant calcium transport in the steroid-starved myocardial cells [5].
The presenting symptoms range from common ones like chest pain and dyspnea to rare reports of vomiting, palpitations, nausea, syncope, or cardiogenic shock.The most common ECG finding is ST elevation (in 44% of patients) followed by T-wave inversion (in 41%) [6].Other findings include ST depression (in 8%) and left bundle branch block (LBBB; in 5%) [6].In addition, patients with TCM characteristically show apical akinesia or hypokinesia and an apical balloon-like dilation pattern associated with preservation of contractility of the heart base [1,2].
The treatment of TCM remains individualized, based on the hemodynamic stability, with the mainstay of treatment being addressing the underlying etiology and the prevention of sympathetic activity by betaadrenergic blockade [7].
Although there are several studies reporting diabetic ketoacidosis (DKA)-associated TCM, there is a scarcity of literature on the symptomatology of this presentation, especially in comatose patients.As the Middle East has the highest prevalence of diabetes worldwide [8], it is vital to examine the pathophysiology and symptomatology of TCM as it represents a rare but potentially fatal complication of DKA [9].
In this report, we present the case of a 73-year-old comatose woman who presented with DKA, was incidentally found to have ST elevation on cardiac telemetry in the ICU with elevated troponin-I but nonobstructed coronary arteries and was eventually diagnosed with TCM.Our patient is the first case in the Middle East to have DKA-associated TCM and the first reported DKA-associated TCM case to have associated hypernatremia.

Case Presentation
A 71-year-old bedridden, cachectic Middle Eastern female was brought by her relatives to the emergency department (ED) with a three-day history of progressive fatigue, poor appetite, loss of sensorium, nausea and vomiting.Her relatives denied any fever or shortness of breath, but reported a one-day history of a mild non-productive cough along with abdominal pain for which she was given pain medications and discharged at another emergency department.Patient mobilizes with assistance to the bathroom and eats well orally.Her past medical history is notable for hypertension (on 5mg lisinopril once daily [OD]), hypercholesterolemia (on atorvastatin 20 mg OD) and poorly controlled type 2 diabetes mellitus (home glucose monitoring ~ 200mg/dl) on oral medications (on empagliflozin 10mg OD, sitagliptin/metformin 50/1g OD, gliclazide modified release 60mg OD).Patient is also on daily calcium supplements (on calcium carbonate 600 mg OD).Surgical history is significant for abdominal surgery three years ago.
On initial evaluation, she was lethargic and severely drowsy with no response to verbal commands, with a Glasgow Coma Scale (GCS) of 6/15 (E4V1M1), pupils equal and reactive to light, and signs of severe dehydration.The patient was hypothermic (34.7•C) with blood pressure of 156/59 mmHg, heart rate of 114/min, respiratory rate of 36/min, and 96% O2 saturation on room air.Peripheries were cold and clammy.Abdomen was soft and nontender and chest was clear to auscultation bilaterally.The remainder of the examination was unremarkable.
Laboratory investigations identified severe DKA (random glucose level of 450mg/dl, serum bicarbonate level of 2 mmol/l and pH of 6) as well as severe hypernatremia of 170 mmol/l which were treated in ED with 2 L of sodium chloride 0.9% followed by 150ml/hr infusion and free water nasogastric flushes, 100ml of bicarbonate, 20mg enoxaparin SQ, 10U of insulin glargine followed by 5U/hr insulin infusion, pantoprazole and 2g of ceftriaxone intravenously.Labs also showed mild acute kidney injury (AKI), neutrophilic leukocytosis, potassium of 2.4 mmol/l and ketonuria.Chest X-ray (CXR) was unremarkable.Patient was then shifted to the High Dependency Unit for further treatment where her leukocytosis, creatinine, acidosis and electrolytes responded to treatment and were all corrected.
Incidentally, the patient was found to have ST elevations of the inferolateral leads consistent with an inferolateral ST-elevation myocardial infarction (STEMI).The patient was therefore taken to the Cath Lab for coronary angiography, which revealed right coronary artery (RCA)-dominant circulation and no significant obstructive coronary artery disease (Figure 1).Subsequently, troponin studies and an echocardiogram were ordered, which revealed a troponin-I of 10.61 ng/mL and echocardiographic features suggestive of TCM with ejection fraction (EF) of 35-40% (Figure 2).Patient was then started on aspirin, betablocker and high-dose statin.Her troponin then started to trend downward.The hospital course was complicated by a persistently low GCS despite correction of acidosis and electrolytes, which was concerning for cerebral edema or cerebral venous thrombosis.Magnetic Resonance Venography (MRV) was negative for venous thrombosis, however brain Magnetic Resonance Imaging (MRI) identified subcortical white and gray matter infarcts with pan-ventriculomegaly, postulated to be from normal pressure hydrocephalus or possible leukomalacia and subcortical infarcts.Electroencephalography (EEG) also demonstrated diffuse slowing of brain activity in theta>delta range suggesting encephalopathy.Lumbar puncture excluded meningitis.Nerve conduction study was also significant for a moderately severe length-dependent sensorimotor axonal neuropathy consistent with diabetic polyneuropathy or critical illness polyneuropathy.Patient was thus started on thiamine replacement and a percutaneous endoscopic gastrostomy (PEG) tube was inserted due to low caloric intake as well as swallowing dysfunction.Ultrasound Kidney-Ureter-Bladder showed irregular echogenicities consistent with blood clots.Computed Tomography Abdomen showed fatty liver with old granuloma, dorsolumbar spine degeneration and bilateral pleural effusion with atelectasis.
Following her prolonged hospital stay due to nosocomial infections (e.g.aspiration pneumonia, wound infection, and PEG site abscess), the patient was eventually discharged on Day 37 with instructions for home nursing care and physiotherapy with special attention to the nutritional requirements and PEG tube maintenance.Medications on discharge included a five-day course of ceftriaxone 1gm twice daily (BID), pantoprazole 40 mg OD via PEG tube, two tablets of calcium carbonate BID via PEG tube, insulin glargine subcutaneously (SQ) 26 Units (U) OD, insulin NovoRapid SQ 14U pre-feed and 10U during feeds BID and Glucerna 80ml/hr for 20hrs.Since discharge, the patient has had recurrent admissions (UTI, PEG leak, pneumonia) with the last admission being due to seizures.There was no follow-up echocardiogram or workup related to her TCM diagnosis.

Discussion
In this paper, we describe the case of TCM in a comatose patient, with underlying DKA, hypothermia and hypernatremia.TCM, also known as stress-induced cardiomyopathy, apical ballooning syndrome or "broken heart" syndrome, is a reversible cardiomyopathy characterized by left ventricular dysfunction typically with apical hypokinesia and ballooning with a clinical presentation mimicking acute coronary syndrome (ACS; ST elevation, T wave inversion, Q wave abnormalities on ECG as well as raised cardiac enzymes) in the absence of angiographic evidence of coronary occlusion [2,10].Four classifications based on pattern of wall motion abnormalities have been reported: Takotsubo type (most common), reverse Takotsubo type, mid-ventricular type, and localized type [11].Another classification divided TCM into apical (most common), midventricular, basal, or focal subtypes [6].
Patients often present in the context of emotional and physical stress [2].Patients with hyperlipidemia, pulmonary hypertension, subarachnoid hemorrhage, migraines, hyperthyroidism, collagen vascular diseases, anxiety states, and stress have higher odds of developing TCM [8].Mayo Clinic's modified criteria of TCM comprise transient left ventricular systolic dysfunction, regional wall motion abnormalities beyond a single coronary artery, non-obstructive coronary angiography, new ECG changes or elevated cardiac enzymes, and ruling out pheochromocytoma or myocarditis [12].Furthermore, TCM typically resolves within two months [13].
Our patient is the first case of DKA-associated TCM in the Middle East.The literature examining this association has been reviewed (Table 1) [9,[14][15][16][17][18][19][20][21][22][23][24][25][26][27] and showed a total of 15 cases.Most cases have been reported in the USA, with the first case being reported by a Taiwanese hospital in 2007 [14].The ages of reported cases ranged between 18 and 81 years with an average of 53.5 years and median of 57 years.Our case serves as the second oldest case.Male cases percentage was 18.75% in our literature review, which conforms to the previously reported male cases percentage of 9.4-22.8%[28].There is scarcity of literature on the symptomatology of DKA-associated TCM, especially in comatose patients where typical symptoms of TCM that tend to mimic ACS cannot be expressed.Our patient, due to her persistently low GCS, was unable to express the classical ACS-like symptoms of TCM (e.g.sudden chest pain, shortness of breath, syncope, etc.) and presented instead with traditional DKA symptoms (fatigue, poor appetite, loss of sensorium, nausea, vomiting, abdominal pain) with TCM incidentally discovered on ECG without hemodynamic instability.Meanwhile, our literature review revealed that the symptomatology was divided almost equally into DKA-symptoms [15,23,24,26], TCM-symptoms [14,[18][19][20]22,27] and mixedsymptoms groups (Table 1) [15][16][17]21,25].It should be noted that DKA-specific symptoms and classic cardiac TCM symptoms can overlap, necessitating a high index of suspicion in patients with risk factors for TCM.
Our case was treated for TCM with aspirin, beta-blocker, and high-dose statin, with no long-term TCMspecific treatment.Our literature review revealed that treatment approaches to DKA-associated TCM included: supportive treatment, antiplatelets, anticoagulants, diuretic, nitrates, beta-blockers, inotropes, mechanical support and extracorporeal membrane oxygenation system (ECMO) (Table 1).It should be noted that despite inotropes, specifically beta agonists, being relatively contraindicated in TCM [29], four studies have included inotropes as part of DKA-associated TCM management [16,17,22,25].However, further studies are needed to elucidate the indications, benefits, and risks of inotropes in DKA-associated TCM cases complicated by cardiogenic shock.
While our case developed significant morbidity shown by the long hospital stay with complicating infections and persistent encephalopathy with recurrent seizures, almost all the review cases had good outcomes, except for one reported case by Wu et al. [9] who passed away due to adult respiratory distress syndrome (ARDS) progression after resolution of TCM.
As can be seen by our literature review, the association between TCM and DKA has rarely been reported.Theories included those posited by Nanda et al. [15], who explained that severe acidosis's effect on myocardial calcium channels and myocardial apoptosis along with ketonemia's effect on glucose utilization; Mhanna et al. [22] who suggested that catecholamine excess was the culprit in the mechanism of TCM in the setting of DKA; and Gordon et al. [18] who postulated that catecholamine surge compounded with ketoacidosis contributes to dysfunction myocardial calcium channels, leading to myocardial stunning and resultant TCM.Of note, our literature review showed that some cases of DKA presented with TCM despite exhibiting mild [14] or moderate [19,25] acidosis.
On the other hand, it has been argued that due to autonomic neuropathy, diabetes decreases both direct and indirect adrenergic stimulation of the myocardium, with an expected decrease in the occurrence of TCM, and would thus exert a "cardioprotective effect".Madias et al. [30] demonstrated that in patients with TCM, the prevalence of diabetes mellitus is lower than the general population, possibly due to the cardioprotective effect of autonomic neuropathy.This prompts further investigations to consolidate the understanding of the underlying pathophysiology of TCM in diabetic patients.
Multiple cases reported hypothermia in cases of DKA-associated TCM [16,17,19,22], with most of the cases having concomitant shock [16,19,22].Hypothermia can also be caused by hypothyroidism, adrenal insufficiency, neurological pathologies, certain substances/medications [31] as well as DKA due to unavailability of glucose as a substrate for heat generation [32].Hypothermia has also been described to contribute to catecholamine release when coupled with acidosis [18].
While multiple cases described the association between hyponatremia and TCM, our case is only the third to report hypernatremia in TCM [33,34].We hypothesize that hypernatremia could serve as an additional stressor by increasing catecholamine release and decreasing left ventricular inotropy [35].Hypokalemia has also been reported to be associated with TCM [36][37].In addition, encephalopathy is a well-reported cause of TCM [38].This patient's major risk factors, namely hypertension and type 2 diabetes, are known to predispose to cardiac remodeling, which in the setting of acute illness such as DKA and hypernatremia, may precipitate sudden cardiac decompensation.We can postulate that cachexia, severe electrolyte derangements, and DKA can impact the sympathetic nervous system, and this could lead to TCM or predispose patients to develop TCM in the presence of a catecholamine surge.
This study highlights the importance of considering the diagnosis of TCM in patients presenting with acute illness even if they have no comorbidities that would provide a causal link, and also emphasizes the relevance of continuous telemetry and a low threshold for ordering targeted cardiac investigations in patients undergoing physical and psychological stress such as DKA.
Our study has certain limitations.Firstly, our literature review was derived from case reports rather than cohort studies or experimental studies, limiting the conclusions derived from our review.Secondly, despite careful searches, we have probably not included all reported cases of DKA-associated TCM.However, our review is the most complete review of all published DKA-associated TCM cases to date.

Conclusions
This case study describes a rare instance of TCM in a comatose patient with DKA, hypothermia, and hypernatremia.Despite the patient's low GCS preventing the expression of typical TCM symptoms, incidental ECG findings led to the diagnosis, underscoring the importance of proactive cardiac monitoring in similar scenarios.Our literature review revealed only 15 reported cases of DKA-associated TCM, with this case being the second oldest and one of the few involving hypernatremia.Several pathophysiological mechanisms explaining the cause of TCM have been postulated, including a catecholamine surge.However, this effect is compounded by the deleterious effects of ketoacidosis on the myocardium in the setting of DKA, leading to myocardial stunning.This case study and literature review emphasise the need for further research to understand the pathophysiology and optimize management strategies for TCM in the context of severe metabolic stressors like DKA.
areas of drafting, revising and critically assessing the literature review.All authors reviewed the article and agreed to be accountable for all aspects of the work.

FIGURE 1 :FIGURE 2 :
FIGURE 1: Coronary angiography showing no significant coronary artery disease in RCA (a) (White arrow) and LCA (b) (Black arrow)

EF
Abbas, et al.[25] 25-year-old woman with acute encephalopathy.Labs showed Glu = 614 mg/dl, HCO3 = 2 mmol/l Troponin = 1.68 ng/ml.Echo showed left ventricular systolic dysfunction with EF of 25% and wall motion abnormalities of the basal and mid-anterior wall and septum.Endomyocardial biopsy was negative for healthy 25-year-old woman presented with loss of consciousness, weakness and lethargy.HR = Troponin = 0.27 ng/ml, peaking at 4.68 ng/ml.BNP = 329.Initial ECG demonstrated sinus tachycardia with borderline prolonged QT.Echo showed EF of 20-25% with basal and mid anterior wall motion abnormalities and BP =113/68.Initial Glu was incalculably high, pH as well as basal and mid-septal abnormalities.On day 6, coronary angiography revealed normal coronaries.Viral and autoimmune work-up was negative for cardiomyopathy.Right ventricular biopsy was negative.