Acute stress-induced (takotsubo) cardiomyopathy is a heart failure syndrome which has a similar presentation and mortality to acute myocardial infarction (MI). Often triggered by a major stressful event, these patients have unobstructed coronary arteries and characteristic ballooning of the left ventricle, with subsequent prompt restoration of normal or near normal ejection fraction. However, have recently shown that despite previous preconceptions, takotsubo cardiomyopathy results in a long-term heart failure phenotype with persistent symptoms and subclinical cardiac dysfunction4. We and others have also shown global severe edema of both the left and right ventricular myocardium that does not completely resolve by 4 months after the acute event despite spontaneous normalization of the ejection fraction.
This was a multi-centre, prospective, case-control, mechanistic investigation. Fifty-five patients with acute takotsubo cardiomyopathy were recruited from five Scottish cardiac centres. All patients had invasive coronary angiography and left ventriculography at the time of the diagnosis, specifically they had typical left ventricular ballooning, normal or near normal coronary arteries without any evidence of obstructive or culprit coronary plaque, developed QTc prolongation 24-48 hours after presentation and had modest cardiac biomarker release.
The study was approved by the Institutional Review Board and Research Ethics Committee, and all subjects gave written informed consent. Patients underwent prompt assessment (within 14 days) after the onset of takotsubo cardiomyopathy which was repeated 5 months after the index event. Study assessments included blood sampling, two-dimensional and Doppler echocardiography, and multiparametric cardiac magnetic resonance. The main study outcome was myocardial inflammation assessed by the change in T2 from native to post-USPIO images and the secondary outcome was the presence of systemic inflammation assessed from changes in monocyte sub-populations and serum cytokine concentrations. Data were analysed by a mixed model with random effects for patient and fixed effects for subject group, with age and gender as covariates, followed by post-hoc comparisons of subject groups or time-intervals; p-values for comparisons were calculated using t-tests with degrees of freedom estimated by the Satterthwaite method.
Fifty-five patients presenting with acute takotsubo cardiomyopathy were recruited and assessed at baseline, and 48 were re-studied at a mean of 148±7 days following their index event. They were predominantly middle aged or elderly women. There was a higher change in T2 values in both the ballooning and the non-ballooning segments of patients with acute takotsubo cardiomyopathy compared to control subjects. Indicating an increase in myocardial macrophages. Results were similar when analysed by left ventricular region, with the apex and mid-cavity demonstrating changes compared to control subjects.
At 5-month interview, 42% of patients reported ongoing symptoms. Of these, the majority (70%) of patients were NYHA Class I, 23% were NYHA Class II and 7% were NYHA Class III. Quality of life assessed with MLWHFQ showed a median score of 5 (range of 0-60 out of a maximum of 105) with a median physical domain score of 5 (range 0-30 out of a maximum of 40) and a median emotional domain score of 0 (range 0-17 out of a maximum of 25). The high sensitivity troponin at follow-up was 6.47±0.6 ng/L.
This is the first prospective evaluation of myocardial and systemic inflammation in acute and 5-month convalescent takotsubo cardiomyopathy. Using USPIO-enhanced magnetic resonance imaging, demonstrated a macrophage-mediated cellular inflammatory response in the myocardium, superimposed on myocardial edema. Furthermore, shown systemic peripheral inflammatory responses, some of which appear to persist for at least 5 months. Taken together, data demonstrated both localized and systemic inflammatory responses and uncover a previously unknown mechanistic pathway of takotsubo pathophysiology. These findings provide a potential explanation for the development of the long-term heart failure phenotype and poorer long-term prognosis, as well as suggesting that the acute inflammatory response could be a promising therapeutic target in this condition for which no effective treatment currently exists.
Article demonstrated for the first time that takotsubo cardiomyopathy is accompanied by myocardial and systemic inflammatory activation, with myocardial macrophage infiltration, and acute pro-inflammatory monocyte and cytokine activation. These changes evolve into a low-grade, chronic inflammatory state that remains detectable at least 5 months after acute presentation.