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Abstract
A woman with a history of chronic idiopathic constipation and remote eating disorders presented to our hospital with generalised weakness and confusion due to severe hypokalaemic rhabdomyolysis. Her initial ECG showed down-sloping ST segment elevations consistent with the ‘shark fin’ sign, and initial echocardiography was consistent with Takotsubo cardiomyopathy (TCM). She later developed hypotension, hypoxaemia and low central venous oxygen saturation consistent with cardiogenic shock. A repeat ECG demonstrated the ‘spiked helmet’ sign, and repeat echocardiography showed new global hypokinesis. She was successfully supported with dobutamine on recognition of her worsening cardiomyopathy. This case highlights how the combination of recognised triggers of TCM such as hypokalaemia and rhabdomyolysis may predispose patients to a more morbid cardiac course and how the severity of such triggers may also influence cardiac morbidity. We additionally highlight the prognostic significance of two ECG patterns associated with TCM.
- Heart failure
- Adult intensive care
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Background
Severe electrolyte derangements including hypokalaemia, hypophosphataemia and sodium derangements are known triggers of rhabdomyolysis with the proposed mechanism being cell membrane disruption leading to poor sodium-potassium-ATPase pump function and resultant myocyte degeneration.1 Takotsubo cardiomyopathy (TCM), a condition characterised by acute transient left ventricular (LV) systolic dysfunction, is theorised to be due to acute catecholamine surge, but studies have described significant alterations in cardiac myocyte energetics as well.2 In fact, several case reports have described TCM due to hypokalaemia, hypocalcaemia, and hyponatraemia, suggesting that electrolyte derangements can pathologically influence cardiac myocytes’ energetics and their response to adrenergic states.3–5 TCM has an increasing incidence, accounting for approximately 2–3% of all patients presenting with acute coronary syndrome (ACS), with an overall rate of in-hospital complications comparable to that of ACS.2 Understanding how multiple versus isolated TCM triggers may impact cardiac prognosis is important, as such complications include heart failure, arrhythmia, LV thromboembolism and cardiogenic shock.2
Case presentation
A woman in her 50s with depression, anxiety, chronic idiopathic constipation and a remote history of eating disorders presented to the emergency department after her mother found her confused on the floor of their home. The patient stated that she had fallen due to generalised weakness and was on the ground for less than 10 min. She described 3 days of mild, progressive, bilateral arm weakness leading up to this event. Her mother had last seen her the day prior when the patient appeared well. The patient’s home medications included prucalopride, linaclotide and no diuretics. She reported taking these daily. She had been hospitalised several years prior for severe electrolyte derangements due to poor oral intake, which had prompted psychiatric hospitalisation for recurrent disordered eating. In the months prior to the current presentation, she reported no issues with body image but also reported persistent poor oral intake due to chronic idiopathic constipation.
On arrival to the hospital, she had a rectal temperature of 33.7°C, blood pressure of 112/82 mm Hg, heart rate of 86 beats per minute, respiratory rate of 17 breaths per minute and an arterial oxygen saturation of 99% in room air. Her body mass index was 20.39 kg/m2. On physical examination, she was unable to answer questions and had no more than 3 out of 5 strength in all extremities and on neck flexion. There was no muscle oedema or tenderness. Her cardiopulmonary and abdominal examinations were unremarkable.
6 hours into admission, the patient developed hypoxaemia, requiring 40 L/min, 70% high-flow nasal cannula to saturate 95%. The hypoxaemia resolved over 24 hours following treatment with intravenous diuretics. However, approximately 72 hours into admission, the patient developed progressive hypotension to 77/58 mm Hg. 12 hours later, she developed progressive dyspnoea at rest, and examination revealed bilateral basilar crackles without an elevated jugular venous pressure. She then required 6 L/min nasal cannula to saturate 97%.
Investigations
Laboratory testing at the time of admission (table 1) revealed several electrolyte derangements, including profound hypokalaemia with a potassium below the detectable limit of 1.5 mEq/L (reference range 3.3–5.5 mEq/L). An elevated beta-hydroxybutyrate to 2.19 mmol/L (reference range <0.27 mmol/L) suggested poor oral intake. The serum thiamine level was >1200 nmol/L (reference range 78–185 nmol/L). The patient also had acute kidney injury with a creatinine of 1.37 mg/dL (baseline 0.7 mg/dL) in the setting of an aspartate aminotransferase level of 2728 U/L (reference range 10–35 U/L), alanine aminotransferase of 483 U/L (reference range 9–59 U/L) and extremely elevated creatine kinase (CK) level of >200 000 U/L (reference range 11–204 U/L). Approximately 36 hours into admission, the patient developed bilateral carpal spasm and paresthesia concerning for tetany due to worsening hyperphosphataemia-mediated hypocalcaemia of rhabdomyolysis. At this time, the serum ionised calcium was 3.94 mg/dL (reference range 4.60–5.08 mg/dL) and phosphate 6.8 mg/dL, and she had a preceding calcium nadir of 6.5 mg/dL (figure 1).
Evolution of hypocalcaemia symptoms (bilateral hand paresthesia, carpal spasm) related to worsening hyperphosphataemia of rhabdomyolysis. The calcium nadir was 6.5 mg/dL, and the phosphate peak was 6.8 mg/dL.
‘Blood tests’
The high-sensitivity troponin level was 279 ng/L (reference range <12 ng/L), and the patient’s initial ECG showed tall R waves, down-sloping ST segment elevations and loss of the ST segments in leads V2 to V5 consistent with the ‘shark fin’, ‘triangle’ and ‘lambda’ sign (figure 2).6 Given her initial oxygen requirement and ECG findings, a transthoracic echocardiogram (TTE) was acquired, which showed apical akinesis consistent with TCM.
ECG showing tall R waves, down-sloping ST segment elevations and loss of the ST segments in leads V2 to V5 consistent with the ‘shark fin’, ‘triangle’ and ‘lambda’ sign. Given the patient’s high probability of Takotsubo cardiomyopathy after acquisition of initial transthoracic echocardiogram, left heart catheterisation was deferred. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.
At the time of the patient’s recurrent hypoxaemia with concurrent hypotension, a chest X-ray showed bilateral perihilar alveolar opacities and a right-sided pleural effusion, and the N-terminal pro b-type natriuretic peptide level was >70 000 pg/mL (normal <125.0 pg/mL, figure 3). Additionally, simultaneous central venous and arterial oxygen saturation measurements on 6 L/min nasal cannula were 41% and 97%, respectively. A repeat TTE showed a new severely hypokinetic right ventricle and worsening LV systolic function from 30–35% to 25–30%. A repeat ECG showed evolving ST segments in V2 to V5, with lead V4 now demonstrating the ‘spiked helmet’ sign (figure 4).7
Chest X-ray taken at the time of patient’s recurrent hypoxaemia with concurrent hypotension. Bilateral perihilar alveolar opacities and right-sided pleural effusion suggested worsening left-sided congestive heart failure.
Repeat ECG showing evolving ST segments in V2 to V5, with lead V4 demonstrating the ‘spiked helmet’ sign. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.
Due to concern for a potential LV thrombus on echocardiography, cardiac MRI was performed, which showed diffuse T2 high signal intensity of the LV suggesting the presence of myocardial oedema, worse on apical segments and consistent with a diagnosis of TCM.
Outcome and follow-up
The patient’s hypokalaemia was corrected to normal within 24 hours with resultant improvement in creatine kinase to 380 U/L over 10 days. Serum calcium repletion to 8 mg/dL led to rapid improvement in carpal spasms, and her renal function improved to her baseline function after 16 days of hospitalisation (figure 1).
Regarding her cardiac course, the high-sensitivity troponin peaked at 1645 ng/L by 11 hours of admission. After norepinephrine therapy was transitioned to dobutamine, the central venous oxygen saturation increased from 41% to 67% (figure 5). Dobutamine infusion at 2.5 µg/kg/min was continued for 36 hours of total therapy. Repeat lactate measurements taken before and during vasopressor administration never exceeded 1.6 mmol/L (reference range 0.5–2.2 mmol/L). Repeat ECG on day 6 of admission showed resolving ST-segment elevation in the anterolateral leads and no reperfusing T-waves. The ECG changes normalised by day 9 of admission. 2 weeks after discharge, she was seen in the outpatient clinic and was doing well on carvedilol 6.25 mg two times per day, losartan 12.5 mg daily and dapagliflozin 10 mg daily. Her LV ejection fraction improved to 57% with no regional wall abnormalities 4 months after discharge.
Progressive hypotension due to worsening Takotsubo cardiomyopathy. After norepinephrine therapy was transitioned to dobutamine, the central venous oxygen saturation increased from 41% to 67%. Dobutamine was successfully stopped after 36 hours. Hr., hour.
Discussion
This patient with a history of eating disorders presented with critical hypokalaemia in the setting of poor oral intake and use of prucalopride and linaclotide, two medications approved by the US Food and Drug Administration for chronic idiopathic constipation. Prucalopride is a high-affinity, highly selective agonist of 5-hydroxytryptamine receptor 4 (5-HT4) that promotes gastrointestinal (GI) motility.8 While previous drugs designed for the same purpose had significant adverse cardiovascular effects due to interactions with other 5-HT receptors, trial data for prucalopride have demonstrated a consistent cardiovascular safety profile.8 Linaclotide is a high-affinity guanylate cyclase C agonist that promotes colonic epithelial cell secretion of chloride and bicarbonate, which facilitates flow of water into the intestine and acceleration of GI transit.9 While diarrhoea is a known side effect of both medications, the only apparent report of critical hypokalaemia related to either medication was an abstract describing linaclotide-induced secretory diarrhoea leading to hypokalaemic rhabdomyolysis.10 As our patient did not report severe diarrhoea, her medications were unlikely the primary drivers of her hypokalaemia, which was instead likely due to occult food restriction.
While prior reports have demonstrated that isolated hypokalaemia and rhabdomyolysis can precipitate TCM, this case is only the second report linking hypokalaemic rhabdomyolysis to TCM.11 12 Unlike the prior report, however, this patient developed acute decompensated heart failure and required inotropic support for cardiogenic shock.11 Interestingly, the severity of our patient’s potassium (<1.5 mEq/L) and CK (>200 000 U/L) derangements is much greater than in the prior report, with the prior report noting a potassium of 1.6 mEq/L and CK of 1391 U/L.
While the pathophysiology of TCM is incompletely understood, an endogenous catecholamine surge and increased myocardial β-adrenergic sensitivity—particularly in the apex—appear to lead to the characteristic LV apical ballooning in preclinical models.2 However, this hypothesis is challenged in human studies that demonstrate dobutamine stress testing only rarely causes TCM and the mean presenting heart rate and blood pressure of TCM patients are lower than expected for a true catecholamine surge.13 Other mechanisms potentially involved in the development of TCM include coronary vasospasm and microvascular reactivity, neurocardiogenic myocardial stunning, alterations to myocardial metabolism and myocardial inflammation. Hypokalaemia affects both coronary vessels and myocardial cells, leading to increased coronary vascular resistance and increased ventricular contractile force.14 Whether these effects explain the relationship between TCM and hypokalaemia via the vasopasm theory remains to be explored. How rhabdomyolysis contributes to the development of TCM is also unknown, but prior reports have associated rhabdomyolysis with TCM.12 15 Regardless of how hypokalaemia and rhabdomyolysis cause TCM, our patient’s progression to cardiogenic shock suggests the presence of multiple TCM triggers, and more severe metabolic abnormalities may lead to increased TCM morbidity.
Next, the ECGs of this case highlight how particular ECG patterns in TCM patients may serve as red flags signalling a more morbid cardiac course. Our patient’s first ECG showed a pattern known as the ‘shark fin’, ‘triangle’ or ‘lambda’ sign, marked by steep, prominent R waves with down-sloping ST segment elevation and loss of the ST segments (figure 2).6 This pattern is typically seen within the first 24 hours of a TCM patient’s admission, and it is associated with the development of cardiogenic shock and increased mortality.16 This electrocardiographic morphology may be due to epicardial or microvascular ischaemia, LV cavity expansion or the increased metabolic demand of catecholamine surge, as the pattern has been described in ST-elevation myocardial infarction, stress cardiomyopathy and myocarditis.6 Of note, the presence of diffuse T2 high signal intensity of the LV in our patient supports how the myocardial oedema of TCM and myocarditis may facilitate this pattern.6 Our patient’s second ECG demonstrated the ‘spiked helmet’ sign, marked by an upward slope preceding the QRS complex, a sharp R wave and a convex ST segment elevation that is thought to result from prolonged repolarisation or extremely prolonged QT segment intervals.7 Similar to the ‘shark fin’, ‘triangle’ or ‘lambda’ sign, this pattern is associated with critical illness and death.17
The recommended management of cardiogenic shock in patients with TCM is based on limited evidence. Because a catecholamine surge is felt to be integral to the pathophysiology of TCM, expert consensus currently recommends avoiding inotropes due to a theoretical worsening of cardiomyopathy related to the administration of excess catecholamines.18 19 Some guidelines recommend levosimendan, a non-catecholamine inotrope, if mechanical support is not available, and a recent case report described the successful use of another non-catecholamine inotrope, milrinone, to manage a hemodynamically unstable patient with TCM.2 18–20 Of note, there are no robust data suggesting inotropes are contraindicated in TCM patients who require haemodynamic support.21 However, in the selection of vasopressors for TCM patients requiring haemodynamic support, the identification of LV outflow tract (LVOT) obstruction (seen in approximately 20% of TCM patients) is important, as inotropes can cause haemodynamic harm through increased heart rate and subsequent decreased diastolic filling that worsens LVOT obstruction. Conversely, the selection of phenylephrine in such patients would provide the benefits of decreased heart rate and increased diastolic filling, thus augmenting cardiac output in patients with LVOT obstruction.18 Although our patient appeared to tolerate and benefit from the inotropic support of low-dose dobutamine, further research is required to determine if dobutamine and other catecholaminergic agents can be used safely and effectively in lieu of mechanical support in selecting TCM patients who do not have LVOT obstruction.
Learning points
Increased cardiac morbidity may be seen in Takotsubo cardiomyopathy (TCM) patients with multiple TCM triggers, and the severity of metabolic triggers may influence the severity of TCM.
The ‘shark fin’ and ‘spiked helmet’ signs both portend increased TCM morbidity.
Further research is required to determine if dobutamine and other catecholaminergic agents can be used safely and effectively in haemodynamically unstable TCM patients who do not have left ventricular outflow tract obstruction.
Ethics statements
Patient consent for publication
Footnotes
X @ASanchez_PS
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: EH and SN. AS composed the initial draft of this report. MS provided critical revisions to the entire manuscript with subsequent approval of revisions by all authors. AS created all figures and served as the guarantor of this report. The following authors gave final approval of the manuscript: AS, EH, SN and MS.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.