Takotsubo syndrome and dialysis: an uncommon association?

Introduction

Takotsubo syndrome (TS), also termed stress-induced cardiomyopathy, broken heart syndrome, and transient left apical ballooning syndrome, presents as transient left ventricular dysfunction, electrocardiographic changes that can mimic acute myocardial infarction, and minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. ¹ The name of this syndrome was derived in reference to the pot with a round bottom and narrow neck used for trapping octopuses in Japan. ²

The precise pathophysiologic mechanisms of TS are incompletely understood, but considerable evidence indicates that sympathetic stimulation is central to its pathogenesis. Enhanced sympathetic stimulation is central to TS; however, the mechanism by which catecholamine excess precipitates myocardial stunning in the variety of regional ballooning patterns that characterize this syndrome is unknown. Several hypotheses have been proposed to identify mechanisms by which catecholamine excess precipitates myocardial stunning: plaque rupture, multi-vessel epicardial spasm, microcirculatory dysfunction, catecholamine toxicity in cardiomyocytes, and activation of myocardial survival pathways. ³ Additionally, the most common temporal patterns of onset are characterized by peak occurrence during the morning hours, during summer months, and on Mondays.^4–6 These aspects are similar to those of myocardial infarction (MI) but different from those of other cardiac conditions. ⁷

Many medical diseases have been associated with TS, such as infectious diseases, ⁸ respiratory diseases, ⁹ endocrine disorders, ¹⁰ allergic diseases, ¹¹ sepsis, ¹² and even suicidal behavior. ¹³ We previously investigated the association between chronic kidney disease and cardiovascular diseases including MI, ¹⁴ pulmonary embolism, ¹⁵ and stroke. ¹⁶ In the present study, we evaluated the association between treatment with dialysis and TS in patients with end-stage renal disease.

Methods and Results

Search method

Research of TS has dramatically increased in recent years. In the PubMed database alone, we identified 3630 documents containing the term “Takotsubo”, with our search including all articles published from the inception of the database to 31 December 2017. We systematically explored the PubMed database using the search terms “Takotsubo cardiomyopathy” and/or “stress-induced cardiomyopathy” and/or “Takotsubo syndrome” in combination with “dialysis” and “uremia.” A further search of Google Scholar was performed. For each case, we collected data regarding sex, age, renal diagnosis, type and duration of dialysis, possible triggers, outcome, author, journal, and year of publication. The end date of the electronic search was 31 December 2017. Of 3630 articles found, we selected 8 articles reporting 10 cases. The search strategy is illustrated in Figure 1.

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Figure 1.

Search strategy.

Findings

The details of the 10 patients are shown in Table 1. Most patients were women (80%), and their age ranged from 51 to 84 years. Diabetes mellitus and hypertension were diagnosed in four patients each, and glomerular disease was diagnosed in three patients. Only one patient was treated with peritoneal dialysis; all others were treated with hemodialysis. An infectious trigger was recognized in five patients, while a psychological trigger was reported in only one. The outcome was unfavorable in only one patient (meningitis).

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Table 1.

Systematic review of case reports of patients treated with dialysis complicated by onset of Takotsubo syndrome.

Sex/age(years)	Underlying causes	Dialysis:type and duration	Trigger	Outcome	Authors/year
M/65	Diabetic nephropathy	Hemodialysis, 9 years	Meningitis	Tetraplegia, respiratory suppression	Kusaba et al., 2004 33
F/55	Unknown	Hemodialysis, unknown	Epilepsy	Favorable	Garea Garcia-Malvar et al., 2014 34
F/84	Nephritic syndrome	Hemodialysis, 2 years	Sustained chest discomfort	Favorable	Fukui et al., 2006 35
F/51	Membranous nephropathy	Hemodialysis, 1979–81Renal transplant, 1981–2Hemodialysis, 1982–95Renal transplant, 1995–2009Peritoneal dialysis, 2009–present	Stressful life event	Favorable	Musone et al., 2012 36
F/69	Hypertension	Hemodialysis, unknown	Unknown	Favorable	Mutler et al., 2013 37
F/61	Glomerulonephritis	Hemodialysis, 20 years	Chest pain and dyspnea during dialysis	Favorable	Takemoto et al., 2009 38
F/57	Unknown	Peritoneal dialysis, 3 years	Abdominal pain due to peritonitis	Favorable	Hassan et al., 2011 39
F/*	Diabetes mellitus, hypertension	Hemodialysis, unknown	Pneumonia	Favorable	Shin et al., 2013 40
F/*	Diabetes mellitus, hypertension	Hemodialysis, unknown	Infectious colitis	Favorable	Shin et al., 201340
M/*	Diabetes mellitus, hypertension	Hemodialysis, unknown	Pneumonia	Favorable	Shin et al., 2013 40

M, male; F, female.

*Shin et al. ⁴⁰ indicated only the age range for the three cases reported (54–68 years).

Discussion

Development of TS is commonly triggered by emotional or physical stress. The latter favors catecholamine excess, which is potentially harmful to the heart, ¹ and catecholamine hypersecretion and actions on β-adrenoceptors could be the cause of cardiac damage in patients with TS. ¹⁷ Catecholamine hyperactivity is also the cause of the typical regional negative inotropism of different segments of the heart, characterized by different densities of β₁ and β₂ adrenoceptors. ¹⁷ Myocardial contraction is stimulated by activation of the sympathetic nervous system during stressful conditions, and the effect of catecholamines on the myocardium depends upon the distribution of sympathetic nerves in this tissue. The local concentration of catecholamines reportedly varies in different myocardial regions due to heterogeneities in sympathetic nerve innervation and local intramyocardial stores. ¹⁸ However, Vink and Blankestijn ¹⁹ reported that sympathetic activation is most likely to represent an early event in the pathophysiology of chronic kidney failure. Masue et al. ²⁰ compared the hormonal mechanisms of blood pressure (BP) reduction during hemodialysis between patients with normotension and hypertensive uremia and found that hemodialytic BP reduction may be associated with abnormal sympathetic nerve responsiveness. BP may be highly variable during hemodialysis, whereas it appears to remain stable during peritoneal dialysis procedures, suggesting more variable catecholamine plasma levels during hemodialysis than during peritoneal dialysis. These concepts could explain, at least in part, the higher prevalence of TS in patients undergoing hemodialysis than peritoneal dialysis. However, we must take into consideration that the prevalence of patients undergoing hemodialysis treatment is much higher than the prevalence of uremic patients undergoing peritoneal dialysis treatment, and these data could bias our hypothesis.

The age and sex distribution of TS is not different between the general population and patients undergoing dialysis, and TS affects women after their fifth decade of life. ²¹ In one study, 826 patients with TS in the GEIST Registry were evaluated, and all-cause mortality was compared between patients with and without diabetes mellitus. ²² The authors found that the prevalence of diabetes was higher than 20%, and diabetic patients with TS were more likely to be older and male and have a higher prevalence of hypertension and physical triggers. Moreover, the multivariate regression analysis identified diabetes as an independent predictor of adverse outcomes. ²² In another study, patients with TS showed a prevalence of dyslipidemia comparable with that of patients with MI, indicating that dyslipidemia in these patients may represent unrelated issues. ²³

Our data suggest that in patients undergoing dialysis, physical triggers could be more important than psychological triggers, and diabetes mellitus is not an uncommon finding in uremic patients with TS. However, such a comorbidity does not appear to be related to increased short-term negative outcomes. In fact, diabetes-induced endothelial dysfunction in various vascular beds contributes to a wide range of complications and plays a negative role in microcirculatory regulation. ²⁴

Infection was also found to be associated with TS in patents undergoing dialysis. This finding is not surprising because patients with diabetes and chronic kidney disease are more prone to complications, including acute cardiovascular disease and infections. ²⁵ The reported risk factors for sepsis-induced myocardial dysfunction are a younger age, history of diabetes mellitus, history of heart failure, elevated brain natriuretic peptide level, and positive blood culture result. ²⁶ In a recent analysis of the limited available evidence on this topic (13 cases), women were more prevalent than men, the mean age was 57 years, and bacterial infections were more frequent. The clinical outcome is favorable in most cases of TS and was likewise favorable in the cases of the present review. ¹² However, two case series of in-hospital mortality of patients with TS showed that men with sepsis exhibited significantly higher in-hospital mortality.^27,28 Infection results in sympathetic nervous system overstimulation and increases catecholamine plasma levels, which exert direct toxic effects on the heart that are dependent upon inflammation, oxidative stress, and abnormal calcium handling. These changes result in myocardial stunning, apoptosis, and necrosis. ²⁹

In general, however, clinical outcomes have been shown to be sex-related. A systematic review showed that the in-hospital mortality rate was 4.5%, with even higher rates among male patients (odds ratio, 2.6). ³⁰ A Japanese series showed a significant difference between in-hospital and out-hospital patients with TS. The former group, characterized by a higher proportion of male patients, showed a higher incidence of chronic comorbidities and acute medical illnesses and a higher mortality rate (17.9% vs. 5.4%). ²⁸

Conclusion

TS does not appear to be a frequent finding in patients undergoing dialysis, or it does not appear to be frequently reported. We suspect that there are more confounding factors associated with TC in patients undergoing dialysis. In any case, uncommon does not mean negligible, and the association between TS and dialysis requires investigation of further comorbidities. Based on this very limited evidence, it seems that although patients undergoing dialysis represent patients with highly complicated conditions, TS does not seem to negatively influence their clinical outcomes, at least in the short term. However, its management requires appropriate clinical skills because the prognosis could also depend on comorbidities. In contrast to previously common opinions, the mortality rates among patients with TS are not significantly different from those among patients with MI, ³¹ and TS should no longer be simply considered a benign disease. In fact, although the prognosis of TS is generally thought to be favorable with complete recovery of left ventricular function, the prognosis depends on many factors, including comorbidities, clinical presentation, sex, and in-hospital or out-hospital setting. ³² A high level of caution and correct management of all aspects of TS, especially in patients with complicated conditions, is necessary to obtain a favorable outcome.