Time-Related Microcirculatory Dysfunction in Patients With Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TCM) has been described as an acute reversible heart failure syndrome resulting from a transient contractile dysfunction of a large region of the left ventricular myocardium in the absence of epicardial coronary obstruction or plaque rupture.¹ In these patients, acute microvascular impairment has been previously demonstrated at the time of clinical presentation by measuring the index of microvascular resistance (IMR).² In the present study, we sought to prospectively assess the presence of microcirculatory dysfunction by invasively measuring the IMR in patients presenting with TCM. Specifically, we sought to elucidate whether a time-dependent trend in microvascular damage resolution exists.

During a 6-month period, 15 consecutive patients with high diagnostic suspicion of TCM were prospectively included in our study. Initial inclusion criteria were defined as the presence of symptoms and regional wall motion abnormality and/or ballooning compatible with TCM and the absence of significant coronary stenosis. Diagnoses relied on the Mayo Clinic diagnostic criteria, including clinical presentation, electrocardiogram and troponin level changes, a characteristic morphology at the left ventricular angiogram, and absence of significant lesions on coronary angiography.³ Eventually, 1 patient was excluded because of the presence of myocarditis criteria on magnetic resonance imaging. The Hospital de la Princesa Ethics Committee approved the protocol, and each patient provided written informed consent.

After angiography, invasive physiological assessment of the microcirculation was systematically obtained in every patient. A pressure wire (Certus; St Jude Medical) was advanced until the wire sensor was located in the left anterior descending artery, with the transducer distance at 7 to 10 cm from the guide tip. Intravenous adenosine (140 μg/kg/min) was administered to induce steady-state maximal hyperemia. When a hyperemic state was reached, three 1-mL injections of room-temperature saline were given. The IMR was calculated as the ratio between distal coronary pressure at maximal hyperemia and the inverse of hyperemic mean transit time. According to previous studies, the upper normal limit of the IMR was set at 22.⁴ The IMR temporal correlation was analyzed using the Spearman test.

All 14 patients were women with a mean (SD) age of 74 (13) years. The most common trigger of TCM was emotional stress (6 [42.9%]). A typical apical TCM ventricular morphology was identified in 11 patients (78.6%). The most frequent electrocardiographic change was T-wave inversion in precordial leads, which was present in 11 patients (78.6%). Most patients (9 [64.3%]) presented with a Killip class I, and 1 patient was in cardiogenic shock. Angiographic mean (SD) left ventricular ejection fraction was 41% (9%). Coronary angiography revealed no significant epicardial coronary lesions in any patient. The median (interquartile range) time from symptom onset to the IMR measurement was 25 (7-60) hours. The median (interquartile range) left ventricular end-diastolic pressure was 16 (8-24) mm Hg, and the median (interquartile range) coronary flow reserve was 1.4 (1.0-2.7). All patients had microvascular dysfunction (ie, an IMR greater than 22) with a mean (SD) IMR of 53 (22). Importantly, a significant negative linear correlation was observed between the extent of microvascular dysfunction and the time from symptom onset to the IMR measurement (R, −0.72; P = .03) (Figure).

The mechanism of reversible microvascular dysfunction still remains unknown but appears to differ from that seen in ischemic heart disease. As cardiac microcirculation is directly innervated by the brain stem that induces vasoconstriction, it is tempting to speculate that microvascular injury might have a direct neurogenic etiology in this entity.⁵ However, our findings suggesting a time-related recovery of microvascular dysfunction cannot establish causality. Further research should provide novel insights on the role of microvascular dysfunction of patients with TCM.

Our study confirms the presence of microvascular dysfunction in a prospective cohort of consecutive patients with TCM. Moreover, our findings suggest that microvascular injury plays a role in the pathophysiology of TCM. Indeed, microvascular damage with temporal evolution toward resolution might closely correlate with myocardial stunning recovery.

Corresponding Author: Fernando Alfonso, MD, PhD, Cardiology Department, Hospital Universitario de la Princesa, IIS-IP, Universidad Autónoma de Madrid, Calle de Diego de León, 62, Madrid 28006, Spain (falf@hotmail.com).

Published Online: March 8, 2017. doi:10.1001/jamacardio.2016.5993

Author Contributions: Drs Rivero and Alfonso had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rivero, Cuesta, Garcia-Guimaraes, Antuna, Alfonso.

Acquisition, analysis, or interpretation of data: Rivero, Cuesta, Bastante, Alvarado, Antuna, Alfonso.

Drafting of the manuscript: Rivero, Alvarado, Antuna, Alfonso.

Critical revision of the manuscript for important intellectual content: Cuesta, Garcia-Guimaraes, Bastante, Antuna, Alfonso.

Administrative, technical, or material support: Bastante.

Supervision: Rivero, Cuesta, Garcia-Guimaraes, Alfonso.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.