Clinical characteristics and risk factors for death in patients with stress cardiomyopathy in the ICU

Introduction

Stress cardiomyopathy (SC), also referred to as ‘takotsubo syndrome’ or ‘apical ballooning syndrome’, was first described in 1990. As reflected in its Japanese name ‘takotsubo’, the left ventricle (LV) has an octopus trap-like appearance at end systole in acute attacks (1). This condition is characterized by transient diastolic and systolic LV dysfunction, with various wall-motion abnormalities. SC usually occurs after physical or psychological stress and predominantly affects postmenopausal women, although in several registries and case series, up to 10% of SC patients are male (2,3).

The pathophysiology of SC is complex and not fully understood. Through enhanced adrenergic stimulation and excess catecholamine concentration, inflammatory, genetic, neuroendocrine, and metabolic factors may participate in the pathogenesis of the reversible myocardial stunning related to SC (3-5). Patients in the intensive care unit (ICU) have multiple critical illnesses causing severe stress, including respiratory hypoxia, hypercapnic respiratory failure, sepsis, coma, and shock, and thus they have a high risk of SC. Several mechanisms or aetiologies may explain the occurrence of SC in ICU and are may be combined: catecholamine toxicity, psychological stress, neurological impairment, ischemia and left ventricular outflow track obstruction (6). Previous studies have reported that SC incidence in the ICU ranged from 1.5% to 5.6% (6-8). One study showed that >20% of patients admitted to the ICU displayed SC-like LV apical ballooning (9). The initial diagnosis of SC is challenging, especially for ICU patients as they are given sedation or intubation and thus are unable to complain of their symptoms. Identifying specific clinical features might contribute to the screening of SC in the ICU. Hence, we conducted a retrospective investigation of the clinical features and outcomes of SC patients in need of intensive care therapy at a university-affiliated hospital in China. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/apm-21-3223).

Methods

Ethical approval and consent

All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The Fourth Hospital of Hebei Medical University (No. 2021KS045). Individual consent for this retrospective analysis was waived.

Design and setting

This retrospective observational study involved 55 patients with SC in a general ICU at The Fourth Hospital of Hebei Medical University from April 2015 to March 2021. We defined SC in accordance with the International Takotsubo (InterTAK) Diagnostic Criteria (10) (Table 1). The criteria for exclusion were: (I) age <18 years, (II) previous medical history of atrial fibrillation (AF), and (III) lack of fulfilment of the InterTAK Diagnostic Criteria. After excluding 2 patients on the basis of the above criteria, 53 patients were included in the study (Figure 1). The patients were divided into 2 groups: the survival group and nonsurvival group. Clinical characteristics of the patients were collected. A comparison of the clinical features, electrocardiogram (ECG), transthoracic echocardiography (TTE), and laboratory data in the survival group (n=19) and nonsurvival group (n=34) was carried out. The research was conducted in accordance with the principles outlined in the Declaration of Helsinki.

Figure 1 Study flow chart. SC, stress cardiomyopathy.

Data collection

We collected demographic parameters such as age, sex, body mass index, stress triggers, medical history, symptoms, and drugs on admission. The Acute Physiology and Chronic Health Evaluation (APACHE) II score at admission to the ICU and Sequential Organ Failure Assessment (SOFA) score at diagnosis of SC were documented. Diastolic blood pressure (DBP), heart rate (HR), systolic blood pressure (SBP), ECG, TTE, hemoglobin, lactic acid, and serum creatinine were detected and documented at diagnosis of SC. In addition, the estimated glomerular filtration rate (eGFR) was determined using the isotope dilution mass spectrometry (IDMS)-traceable Modification of Diet in Renal Disease equation (IDMS-MDRD) (11). Peak creatine kinase-MB, peak troponin-I, peak brain natriuretic peptide, acute heart failure complications, ICU interventions, and clinical outcomes were also collected. The TTEs and ECGs were independently reviewed by an experienced intensivist and an experienced cardiologist to reaffirm the diagnosis of SC.

Statistical analyses

SPSS version 23 (IBM Corp., Armonk, NY, USA) was used for statistical analyses. Data are expressed as average value ± standard deviation or median (interquartile range) for continuous data with normal distribution or non-normal distribution, respectively. Frequency (%) was used for categorical data. The Kolmogorov-Smirnov test was applied to evaluate the normality of the distribution. The Mann-Whitney U-test and Student’s t-test were utilized to compare continuous data with non-normal and normal distributions, respectively. The χ² or Fisher exact test was applied to compare categorical data between different groups. Mean imputation was performed for mean values of missing variables. Logistic regression models were used to identify multivariate and univariate risk factors for 28-day mortality in SC patients. The variables with significant difference in univariate analysis were included in the multivariate model. All statistical tests were 2-sided. P<0.05 was regarded as statistically significant.

Results

Fifty-five patients with SC participated in this retrospective observational study. Two patients were excluded due to a history of AF, and the remaining 53 patients were included in the study (Figure 1). The mean age of the participants was 70.70±12.13 years (range, 33–89 years). Almost half (47.17%) of the participants were male, and the mean body mass index (BMI) was 23.01±3.43 (kg/m²). The majority of patients had clear stress triggers, including physical (88.68%) and emotional (7.55%) triggers. The most common physical stress trigger was sepsis (37.74%), followed by operative procedure (28.30%), comatose state (11.32%), and cancer pain (3.77%). The other physical triggers (7.55%) included ventricular tachycardia, cardiac arrest, hemoptysis, and hematemesis. The patients’ previous medical histories included malignancy (69.81%), hypertension (41.50%), diabetes (26.42%), coronary heart disease (16.98%), prior stroke (15.09%), chronic obstructive pulmonary disease (3.77%), hyperlipidemia (1.89%), and epilepsy (1.89%). Due to sedation and tracheal intubation, 49.06% of SC patients in the ICU were unable to express their symptoms, 33.96% of patients had dyspnea, and only 3.77% of patients presented with chest pain. The most common acute heart failure complication was acute respiratory failure (79.25%), followed by systolic heart failure (77.36%), and cardiogenic shock (39.62%). Eighteen (33.96%) patients had new-onset AF. During intensive care treatment, 86.79% of patients used norepinephrine, 77.36% brain natriuretic peptide, and 50.94% levosimendan. In some cases, support techniques were also used: 79.25% of patients required mechanical ventilation, 33.96% were on continuous renal replacement therapy (CRRT), and 3.77% were implanted with an intra-aortic balloon pump (IABP). The mean APACHE II score upon admission to the ICU was 21.17±8.41, and the mean SOFA score at diagnosis of SC was 9.30±4.56. The 28-day mortality rate in SC patients in the ICU was 64.15% (Table 2).

SC patients in the ICU were assigned to 2 groups: the survival group and nonsurvival group. A comparison of the clinical features, ECG, TTE, and laboratory data of the survival (n=19) and nonsurvival groups (n=34) is shown in Tables 3,4. No significant difference was observed between the groups in sex ratio, age, medical history, symptoms, or drugs on admission. Participants in the nonsurvival group showed a higher prevalence of systolic heart failure (88.24% vs. 57.89%, P=0.029) than those in the survival group. The maximum norepinephrine dose [0.8 (0.43, 2.00) vs. 0.35 (0.13, 0.64), P=0.008] and the SOFA score (10.76±4.40 vs. 6.68±3.64, P=0.001) at diagnosis of SC were higher in the nonsurvival group. Although there was no significant difference in APACHE II score between the groups [23.00 (15.00, 29.25) vs. 16.00 (13.00, 24.00), P=0.058], the nonsurvival group had an increasing trend (Table 3). No significant difference was observed between the groups in SBP, DBP, or HR at diagnosis of SC. New-onset AF (47.06% vs. 10.53%, P=0.007) was more frequent in the patients who died, but there was no significant difference between the 2 groups in other ECG changes, such as ST elevation, ST depression, inverted T-waves, and left bundle branch block (P>0.05). As shown by the TTE results, compensatory hyperkinesia in the basal segments and a typical pattern of apical ballooning with akinesia in the apical LV segments were observed in most patients (n=50). The results also revealed obviously reduced LV ejection fraction in the survival and nonsurvival groups (37.7%±10.97% and 33.68%±7.24%, respectively), and the nonsurvival group had a decreasing trend. Although there was no significant difference between the groups in peak values of troponin-I, creatine kinase-MB, and brain natriuretic peptide (P=0.111), the nonsurvival group showed an increasing trend. Patients in the nonsurvival group showed a higher prevalence of eGFR <60 mL/min (70.56% vs. 36.84%, P=0.017) than those in the survival group.

Univariate analysis found that 5 variables (SOFA score at diagnosis of SC, eGFR <60 mL/min at diagnosis of SC, maximum norepinephrine dose, new-onset AF, and systolic heart failure) were correlated with 28-day mortality in SC patients in the ICU. Multivariate analysis showed that the risk factors for 28-day mortality in SC patients in the ICU were SOFA score at diagnosis of SC [odds ratio (OR), 1.262; 95% confidence interval (CI): 1.008–1.580; P=0.042], eGFR <60 mL/min at diagnosis of SC (OR, 6.049; 95% CI: 1.224–29.897; P=0.027), and new-onset AF (OR, 7.789; 95% CI: 1.063–57.088, P=0.043) (Table 5).

Discussion

In this retrospective study, the clinical manifestations of patients with SC in the ICU were investigated, and the risk factors that influenced 28-day mortality were evaluated. In our study, nearly half of the participants were men. At 88.68%, patients with physical triggers were far more common than those with emotional triggers. Only 3.77% of patients presented with chest pain. The proportion of patients in our study with complications of systolic heart failure and cardiogenic shock, was 77.36% and 39.62%, respectively. A total of 86.79% of patients were given norepinephrine, and 79.25% of patients needed invasive mechanical ventilation. The 28-day mortality rate of patients with SC in the ICU was 64.15%. The independent risk factors of 28-day mortality in patients who had SC in the ICU were SOFA score at SC diagnosis, eGFR <60 mL/min at diagnosis of SC, and new-onset AF.

In 2005, Park et al. (9) reported a SC incidence of 28% in a medical ICU, although this report comes from a study without coronarography. More recently, Rowell et al. and Oras et al. reported SC incidences of 3.5% and 5.6% respectively (7,8). The APACHE II score has been validated as an accurate predictor of clinical outcomes and mortality in critically ill patients (12). Jo et al. (13) identified APACHE II score as significant predictors for in-hospital mortality in critically ill patients with SC, which developed in the medical or surgical ICU. In our study, although there was no significant difference in APACHE II score between the groups, the nonsurvival group had an increasing trend. Previous studies have reported that SC patients were predominantly women, especially postmenopausal women, and an associated stressor was identified in most patients. Emotional triggers were more common than physical triggers (4,14-18). However, the InterTAK Registry has reported that physical stimuli (including fracture, infection, disorders in central nervous system, acute respiratory failure, and stress after operation) were more commonly seen compared to emotional stimuli (including interpersonal conflict, anger anxiety, panic, fear, and grief), at 36.0% vs. 27.7%, respectively. Our study showed that nearly half of the patients were men and that at 88.67%, physical triggers were far more common. Indeed, SC related to physical stress has been found to occur more frequently in male patients than female (4), which provides an explanation for the higher number of male patients in our study. Physical stress-triggered SC was accompanied by more complications, which might be the reason for its higher rate (19). Patients with multiple organ failure were admitted into the ICU. Therefore, compared with emotional factor-triggered SC, patients with physical stress-triggered SC were more likely to be admitted into the ICU. Belcour et al. (20) reported that the prevalence of SC in patients admitted to the ICU for convulsive status epilepticus ranged from 34% to 62%, age and Simplified Acute Physiology Score II were the risk factors. Sepsis is a frequent cause of admission to ICUs and one of the leading causes of death among hospitalized patients. The most common ICU acquired infections were catheter-related bloodstream infections, pneumonia and abdominal infections. The presence of organ dysfunction and shock, severity of underlying diseases, comorbidities, and a few characteristics of infection were the related risk factors for death in ICU patients with sepsis (21). Doyen et al. (22) reported that sepsis and pulmonary diseases were the most common reasons (38.50% and 46.20%, respectively) for SC in the ICU. In our study, sepsis was the most frequent trigger (37.74%), which was similar to the findings of Doyen’s study. We found that respiratory and hemodynamic instability in SC patients in the ICU was increased in comparison with SC patients in a cardiology setting. Based on InterTAK Registry data, Templin et al. (19) demonstrated that the usage of ventilation (17.3%) and catecholamines (12.2%) was lower and the occurrence of cardiogenic shock (9.9%) was decreased among patients with SC admitted to cardiology units. Brinjikji et al. (23) found that 31% of SC cases were complicated with heart failure. According to their results, respiratory status was affected by the complication of heart failure in only 6.7% of SC patients. Muratsu et al. (24) reported that 26% of patients in their study had the complication of heart failure. In our study, 77.36% and 39.62% of patients had complications of systolic heart failure and cardiogenic shock, respectively. Norepinephrine was given to 86.79% of patients, and 79.25% of patients needed invasive mechanical ventilation. These differences might have resulted from the different target patient groups; the patients transferred to the ICU had relatively severe illnesses.

We explored the 28-day mortality rate of SC patients in the ICU. Our results showed a 28-day mortality rate of 67.50% in these patients. The mortality rate of SC patients in our study was much higher compared with those in the cardiology unit (67.50% in our study vs. 4.1%, respectively) (19). The status of the patients in the ICU was more unstable and patients more frequently presented with multiple organ failure in comparison with SC patients in a cardiology unit, who generally only had heart failure with a much lower mortality rate. There have been no large randomized controlled trials investigating the mortality rate of SC patients in ICUs. One prospective single-center study reported that 30.8% of SC patients in the ICU died within 30 days (22). Oras et al. (7) reported that the 30-day mortality rate of hemodynamically unstable patients with SC in the ICU was 42%. There are 2 reasons for the higher mortality rate in our ICU than in the literature. First, the tertiary nature of our hospital, with severely ill patients and those directly transferred from other hospitals admitted first, might have contributed to the high mortality rate. Another reason may be that the proportion of patients with malignancies in our study was 69.80%, indicating that the basic condition of SC patients in our study was poor. The reason for the high proportion of malignant patients in our study was that our hospital also includes Hebei Cancer Hospital, which is a large comprehensive grade A tertiary hospital focusing on the diagnosis and treatment of cancer. Desai et al. (25) noted that patients suffering from malignancy had an increased risk of developing SC. Additionally, Joy et al. (26) reported that outcomes are significantly worse in patients with SC and malignancy. In this study, further analysis showed that the SOFA score, eGFR <60 mL/min at diagnosis of SC, maximum norepinephrine dose, new-onset AF, and systolic heart failure may have been risk factors of 28-day mortality in SC patients in the ICU. Subsequent analyses found that new-onset AF was an independent risk factor for mortality. As a major cardiac disorder affecting adults, AF is related to significant morbidity and mortality (27). Indeed, previous investigations have demonstrated that patients in critical condition with new-onset AF are at elevated risk of in-hospital death (28). AF may result in adverse events in SC patients via adverse hemodynamic effects, including atrial contraction loss, rapid ventricular rate, and atrioventricular synchronicity loss, contributing to a decline in cardiac output when the ejection fraction is depressed. Stiermaier et al. (29) showed that left atrium dysfunction was an additional characteristic of acute SC. Disturbances in the left atrium were potentially caused by systolic and diastolic dysfunction in LV, which resulted in overloaded pressure and volume in the left atrium and thus contributed to AF onset during SC. Additionally, SC exerted a direct effect on the left atrium. The autonomic nervous system might have also played an important role. Both parasympathetic and sympathetic tone have been found to participate in AF pathogenesis (30). Additionally, excess secretion of catecholamine and enhanced activity in sympathetic nerves are widely accepted mechanisms in SC (31). Sympathetically driven episodes of AF were also deemed conceivable in view of the presumed pathophysiologic connection with catecholamine excess and sympathetic overdrive. Another potential factor was inflammation. In this study, the most common frequent trigger was sepsis. Increased levels of circulating interleukin-6 and -10 have been reported in SC, and systemic inflammation is thought to result in initiating and perpetuating AF (32-35).

The SOFA score at diagnosis of SC was the next independent risk factor for 28-day mortality in this study, and is considered an excellent assessment for predicting short-term mortality in sepsis and other life-threatening conditions (36). In our study, SOFA score was considered an independent risk factor for 28-day mortality, and eGFR <60 mL/min at diagnosis of SC was another independent risk factor for 28-day mortality. After analysis of the results, we proposed the following reason: SC is an increasingly recognized form of acute heart failure. Notably, decreased cardiac output due to worsening LV function could result in injured renal function via underperfusion, the sympathetic nervous system, and the activated renin-angiotensin-aldosterone axis (37). One systematic review involving observational studies reported that decreased eGFR was related to an elevated risk of coronary heart disease (38). A meta-analysis found that low eGFR was related to cardiovascular and all-cause mortality in the general population (39). El-Battrawy et al. (40) reported eGFR <60 mL/min as an independent predictor of adverse outcomes in SC.

Limitations

Our study had some limitations. First, our work was a retrospective, single-center, observational study. The number of patients included was relatively low. Second, there were problems in acquiring certain data, including C-reactive protein, the duration time of AF, and the dynamic changes in cardiac function parameters. Thus, further prospective multicenter research is required on this topic.

Conclusions

Male SC patients with physical stress were relatively more common in the ICU than in the cardiology unit. The 28-day mortality rate was 67.50%. New-onset AF was common in SC patients in the ICU. New-onset AF, SOFA score at diagnosis of SC, and eGFR <60 mL/min at diagnosis of SC may have influenced patients’ short-term prognosis. Positively addressing new-onset AF in SC patients in the ICU may contribute to the improvement of patient outcomes.

Acknowledgments

We thank the patients for their cooperation during the treatment process.

Funding: This study was supported by the Public Health Foundation of Hebei Province of China (20160156) and the Department of Science and Technology of Hebei Province of China (20277707D).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-3223

Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-3223

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-3223). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The Fourth Hospital of Hebei Medical University (No. 2021KS045). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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