Cardiogenic Shock and Respiratory Failure Complicating Takotsubo Syndrome

Abstract

Objectives. This study’s purpose is to evaluate the incidence, predictors, and outcomes of patients presenting to the cardiac catheterization laboratory with takotsubo syndrome complicated by respiratory failure or shock. Background. The presentation of takotsubo syndrome mimics acute myocardial infarction. It is often diagnosed in the cardiac catheterization laboratory when no coronary obstruction is found. A subset of these patients develops shock or respiratory failure. Methods. This is a retrospective study of patients who underwent cardiac catheterization at the Kaiser Permanente Southern California health system with takotsubo syndrome between 2006 to 2016. Medical records were manually reviewed to identify patient characteristics, treatment, and clinical outcomes. Results. Among 530 patients with takotsubo syndrome, 56 (10.6%) developed shock or respiratory failure and required mechanical or inotropic support. A higher proportion of these patients were men (14.3% vs 5.7%) and Black (10.7% vs 7.0%). In multivariate logistic regression analyses, factors associated with respiratory failure or shock were age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P=.02), chronic obstructive pulmonary disease (OR, 1.9; 95% CI, 1.1-3.5; P=.02), chronic kidney disease (OR, 2.6; 95% CI, 1.3-5.3; P=.01), physical trigger (OR, 5.7; 95% CI, 3.0-10.8; P<.01), and ST elevation on the presenting electrocardiogram (OR, 2.5; 95% CI, 1.4-4.8; P=.04). Patients who required mechanical ventilation or inotropic support had significantly higher mortality (hazard ratio, 3.9; 95% CI, 2.1-7.1; P<.001). Conclusion. Shock or respiratory failure occur in 10.6% of patients presenting with takotsubo syndrome. Men and patients with baseline respiratory or renal disease were disproportionally affected. These patients have significantly worse clinical outcomes.

J INVASIVE CARDIOL 2022;34(4):E274-E280. Epub 2022 March 10.

Key words: mortality, respiratory failure, shock, takotsubo syndrome

Takotsubo syndrome has become an increasingly recognized phenomenon since it was first described in Japan in the 1990s. The syndrome is characterized by transient left ventricular (LV) systolic and diastolic dysfunction and a number of potential wall-motion abnormalities.^1,2 On presentation, takotsubo syndrome often mimics acute coronary syndrome; however, coronary angiography shows no evidence of acute obstruction. The classical pattern of LV wall-motion abnormality is apical ballooning with basal hyperkinesis, and the affected region often extends beyond the distribution of a single coronary artery. In many cases, a significant emotional or physical stressor precipitates an episode of takotsubo syndrome. Current estimates suggest that disease incidence is 15 to 30 cases per 100,000 per year, but many believe that the condition is still underdiagnosed.^1,2

Although takotsubo syndrome is now better understood, a number of questions regarding this condition remain unanswered. The pathophysiology of disease, for example, is incompletely understood and thought to be due to myocardial stunning from a surge of catecholamine release.² Moreover, whereas takotsubo syndrome was initially thought to be a relatively innocuous and self-limiting condition, it is now clear that the condition can be associated with a number of serious complications, including acute heart failure, mitral regurgitation, ventricular arrhythmias, systemic thromboembolism, left ventricular outflow tract obstruction, and cardiogenic shock.^2-4

Recent studies have estimated that cardiogenic shock, in particular, occurs in 6%-20% of takotsubo patients;^1,4 furthermore, it is associated with significant morbidity and mortality in this patient population, with some studies reporting 1-year mortality as high as 61%.⁵ Other studies have more modest 1-year mortality data, suggesting significant variability in disease progression and severity. Much of the research on complications of takotsubo syndrome has been conducted in registry studies from tertiary referral centers;^1,5,6 however, there are limited data on short- and long-term complications of takotsubo syndrome in the community. This study aimed to evaluate factors associated with respiratory failure or shock in a community-based, ethnically diverse cohort of patients presenting with takotsubo syndrome and to describe clinical outcomes.

Methods

Study population. This is a retrospective, population-based study using data from the Kaiser Permanente Southern California (KPSC) Health System, a regional nonprofit health care system with over 4 million members from diverse ethnic and socioeconomic backgrounds. KPSC uses an integrated electronic medical record system that provides information on patient demographics, medications, laboratory results, and documentation from both inpatient and outpatient settings. The study was approved by the KPSC institutional review board. Due to the observational nature of the study, a waiver of informed consent was granted prior to starting the study.

All patients included in the study were ≥18 years old and were admitted with a principal diagnosis of takotsubo syndrome between January 1, 2006 and December 31, 2016. Patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10), codes 429.83 and I51.81. Only patients who underwent coronary angiography were included in the study. Each patient was only included in the study once. The date of first diagnosis of takotsubo syndrome during the study period was used as the index date. The 1-year period prior to the index date was defined as the baseline window. Detailed chart review and data abstraction were performed by 2 physicians (SC and RN) to confirm the diagnosis of takotsubo syndrome, identify the treatment provided, and adjudicate outcomes. Patients younger than 18 years old, those who were non-KP members, and those who had been members for <1 year were excluded from the study cohort. Baseline comorbid conditions were also identified with ICD-9 and ICD-10 codes. Outpatient medications were extracted from pharmacy dispensing records. The possible triggers in each patient were adjudicated and grouped into emotional, physical, both, or no obvious trigger. Need for intensive care unit admission for inotropic support or mechanical ventilation was identified by reviewing medical records.

Outcomes. The primary outcome was all-cause mortality. Mortality data were extracted from a mortality data file maintained at KPSC, with integrated death information derived from multiple sources, including insurance enrollment records, hospital death records, California state death master files, and Social Security Administration death master files.

Statistical analysis. Continuous variables were expressed as mean ± standard deviation; categorical variables were expressed as counts and percentages. Continuous data were analyzed with Student’s t test or the Wilcoxon rank-sum test. Differences in categorical data were analyzed with Fisher’s exact test or chi-square test. Short-term mortality rates (ie, at day of presentation, 30 days, 90 days, and 1 year) were reported. Kaplan-Meier estimates were used to compare the long-term survival of patients with takotsubo syndrome. A multivariate logistic-regression model was used to assess the statistical significance of association between candidate prognostic variables and need for intensive care unit admission for respiratory failure or shock. After each factor was tested independently in a univariate logistic regression model, those that achieved a significance level of P<.10 were selected for testing in a multivariate stepwise (backward elimination) logistic-regression model. Variables associated with P<.05 were retained in the final model. The goodness of fit of the model was evaluated by calculating the Hosmer-Lemeshow statistic.⁷

Cox proportional hazards regression models were used to estimate the association between intensive care unit admission and long-term survival. Hazard ratio (HR) and 95% confidence intervals (CIs) were estimated. The proportional hazards assumption was evaluated and not rejected using the methods developed by Grambsch and Therneau.⁸ A 2-sided P-value of <.05 was considered statistically significant for all analyses. All statistical analyses were completed using STATA 14 (Stata Corp).

Results

Patient characteristics. From January 2006 to December 2016, a total of 26,545 patients underwent cardiac catheterization at a KPSC hospital for a principal diagnosis of acute coronary syndrome. Of this group, 530 patients (2.0%) were diagnosed with takotsubo syndrome after coronary angiography. Among patients diagnosed with takotsubo syndrome, 474 patients were hemodynamically stable and 56 patients (10.6%) had shock or respiratory failure and required intensive care unit admission for inotropic support and/or mechanical ventilation.

A higher proportion of patients requiring inotropic or mechanical ventilatory support were male (14.3% vs 5.7%) or Black (10.7% vs 7.0%) (Table 1, Part 1 and Table 1, Part 2). Patients who developed shock or respiratory failure were more likely to have a physical trigger for takotsubo syndrome (62.5% vs 24.5%).

In multivariate logistic regression analyses, factors associated with respiratory failure or shock included age (OR, 0.97; 95% CI, 0.94-0.99; P=.02), chronic obstructive pulmonary disease (OR, 1.9; 95% CI, 1.1-3.5; P=.02), chronic kidney disease (OR, 2.6; 95% CI, 1.3-5.3; P=.01), a physical trigger (OR, 5.7; 95% CI, 3.0-10.8; P<.01), and ST-segment elevation on the presenting electrocardiogram (OR, 2.5; 95% CI, 1.4-4.8; P=.04) (Table 2). Notably, cardiovascular comorbidities including pre-existing atrial fibrillation, valvular heart disease, and stroke were not associated with intensive care unit admission.

Short- and long-term outcomes. The follow-up period was 1965 ± 1208 days. During the follow-up, 82 deaths (15.5%) occurred. There were significant differences in short- and long-term mortality between groups (Table 3). At 30 days, there were 4 deaths (0.84%) among the hemodynamically stable patients and 3 deaths (5.4%) among those who progressed to shock or respiratory failure (P=.03); at 90 days, there were 5 deaths (1.1%) among the hemodynamically stable patients and 5 deaths (8.9%) in the shock or respiratory failure group (P<.01). Finally, at 1 year, there were 12 deaths (2.5%) among hemodynamically stable patients and 9 deaths (16.1%) among the shock or respiratory failure cohort (P<.001). Figure 1 shows the Kaplan-Meier survival estimates for the 2 cohorts. Associations between intensive care unit admission and mortality are shown in Table 4. After adjusting for age, sex, race/ethnicity, income level, and baseline medical comorbidities (model 3), we found that need for inotropic or mechanical ventilatory support was associated with a 3.9-fold increased risk of all-cause mortality (HR, 3.9; 95% CI, 2.1-7.1; P<.001).

Causes of death. In the subset of takotsubo syndrome patients with shock, eventual causes of death included sepsis (n = 3), cardiovascular failure (n = 1), respiratory failure (n = 1), renal failure (n = 1), and central nervous system failure (n = 1); cause of death was unclear in 1 patient and another was transitioned to comfort measures only. In patients who were hemodynamically stable, causes of death included sepsis (n = 1), respiratory failure (n = 2), and renal failure (n = 1); 2 patients were transitioned to hospice and cause of death was unclear in the remaining patients (n = 6).

Discussion

This study provides data on characteristics and outcomes of patients with takotsubo syndrome complicated by shock or respiratory failure. The main findings of the study are: (1) shock or respiratory failure occurred in 10.6% of patients presenting with takotsubo syndrome; (2) a disproportionate number of patients with shock or respiratory failure were male or Black; (3) factors associated with need for mechanical or inotropic support are chronic obstructive pulmonary disease, chronic kidney disease, and ST-segment elevation on presenting electrocardiogram; and (4) patients who required inotropic or mechanical ventilatory support had significantly higher mortality.

Although previously thought to have a benign clinical course, recent studies suggest that takotsubo syndrome can lead to significant complications with substantial morbidity and mortality.^4-6,9-12 In this community-based cohort, 10.6% of patients who presented with takotsubo syndrome developed shock or respiratory failure and required inotropic support or mechanical ventilation. The incidence of shock and respiratory failure in our cohort is higher than in earlier studies on complications of takotsubo syndrome,^1,4,11 but similar to reports from recent series.⁶

Much of the recent literature on takotsubo syndrome has come from European registries with largely homogenous cohorts.^1,5,6 The patient population in this study differs from previous cohorts in its ethnic and racial diversity. Findings from this cohort advance our understanding of the presentation and outcomes of takotsubo syndrome in racial and ethnic minority groups. This cohort is also unique in that it drew patients from a group of community-based hospitals, in contrast to previous studies, which were based at tertiary referral centers. As such, patients from this study represent a comprehensive range of disease severity.

In this study, a significantly greater proportion of patients who progressed to shock or respiratory failure were male. Although takotsubo syndrome is much more common in women,¹³ male patients appear to have worse outcomes.^6,14,15 These observations suggest a hormonal influence on the clinical course of takotsubo syndrome. There is evidence that estrogen attenuates vasoconstriction induced by norepinephrine.¹⁶ Estrogen may be cardioprotective by modulating the activity of the sympathetic nervous system.¹⁷

We observed that a higher proportion of patients who developed shock or respiratory failure were Black, although this association did not reach statistical significance. A study that evaluated 206 takotsubo patients from a hospital in Philadelphia also reported that Black patients suffered more complications, including higher rates of mechanical ventilation, cardiac arrest, and acute kidney injury.¹⁸ Whether the differences observed represent biological and epigenetic factors that vary across racial ethnic groups, or disparities related to differences in socioeconomic factors and inequalities, are important issues to evaluate.

More patients who progressed to cardiogenic shock or respiratory failure in this study had a physical trigger (rather than emotional or no triggers), suggesting that secondary takotsubo syndrome is often associated with a more severe disease phenotype. Similar observations were also made in other studies.^4,5,19 Factors associated with cardiogenic shock or respiratory failure were chronic obstructive pulmonary disease, chronic kidney disease, and ST-segment elevation on presenting electrocardiogram. Although the exact underlying mechanism of takotsubo syndrome remains unknown, some have theorized that the disease may be a form of microvascular acute coronary syndrome.²⁰ Chronic kidney disease has previously been implicated as a contributor to coronary vascular dysfunction and decreased coronary flow reserve,²¹ suggesting a mechanism by which it may portend a more severe disease course in takotsubo syndrome. Ischemic changes on electrocardiogram in this setting may arise from dysfunction at the microvascular level rather than in epicardial coronary arteries as seen in acute coronary syndrome.

Patients with shock or respiratory failure had significantly worse clinical outcomes, as measured by 30-day, 90-day, and 1-year mortality, when compared with patients who were hemodynamically stable. The mortality in our cohort was lower when compared with one of the early studies describing cardiogenic shock in takotsubo syndrome,⁹ but was in accordance with a large recent European registry study.⁶ Non-cardiovascular mortality accounted for the majority of deaths in both hemodynamically stable patients and those who required mechanical or inotropic support. Aside from the previously described risk factors for severe disease, it is unclear why some patients develop hemodynamic compromise. Some have speculated about a relatively greater sympathetic surge or an increased susceptibility to catecholamine-mediated myocardial stunning as the underlying etiology.^1,4 Others have suggested that susceptible individuals may have multifactorial injury from both of these mechanisms, leading to a severe disease phenotype.¹⁰ Ultimately, this study and others like it can help stratify takotsubo syndrome patients who are at risk for hemodynamic compromise, and allow for timely admission to intensive care units.

Study limitations. Our study had a few notable limitations. It was observational in nature and may not account for unmeasured confounding variables. In addition, underestimation of takotsubo syndrome is possible, as we only included patients who underwent coronary angiography and did not include patients diagnosed based on clinical suspicion and echocardiography. On the other hand, all cases were reviewed and only cases independently confirmed by physician adjudication were included in the study. Patients in this cohort all had access to health insurance, so findings may not be generalizable to others with limited access to care.

Conclusion

Intensive care unit admission due to shock or respiratory failure occurs in 10.6% of patients presenting with takotsubo syndrome. Male patients and those with baseline respiratory or renal disease are disproportionally affected. These patients have significantly worse clinical outcomes.

Affiliations and Disclosures

From the ¹Department of Internal Medicine, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California; and ²Department of Cardiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript accepted March 24, 2021.

Address for correspondence: Ming-Sum Lee, MD, PhD, Department of Cardiology, Kaiser Permanente Los Angeles Medical Center, 1526 North Edgemont St, Floor 2, Los Angeles, CA 90027. Email: mingsum.lee@kp.org

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