New hemodynamic insights into takotsubo syndrome (TTS) reveal a potential therapeutic target, as researchers suggest the use of medications that lengthen the heart’s systolic period, improving contractility in the process. The findings, which also characterize the changes such as reduced cardiac contractility and inefficient myocardial energetics caused by TTS, come from a team from the University Heart Center Lübeck in Germany. The researchers translated these findings into pathophysiological considerations by suggesting a decreased phosphorylation of myofilament proteins, which could be addressed by drug treatment. “TTS may be treated with medications that lengthen the systole and improve contractility, such as levosimendan and/or omecamtiv mecarbil, possibly in combination with beta-blockers to protect against the intense adrenergic activation,” the team said. “Several studies have reported the use of levosimendan in TTS and suggest positive effects by accelerating recovery of ventricular function.” Catecholamine surge as a TTS stress trigger The study, which was published Monday online and in the May 23 issue of the Journal of the American College of Cardiology, points to TTS mainly affecting postmenopausal women and accounting for ~3% of all patients and ~6% of female subjects presenting with acute coronary syndrome. Associated with substantial short- and long-term morbidity and mortality, TTS stress triggers may include the role of catecholamine surges, although in a sizeable number of patients, the trigger cannot be identified. Led by Thomas Stiermaier, MD, from the German Center for Cardiovascular Research (DZHK) in Lübeck, the Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops (OCTOPUS) study included 24 TTS patients (95.8% female) with a median age of 72.1±9.5 years. The study also included a control population of 20 participants without cardiovascular diseases. Median age here was 57.2±6.8 years with a 50% female population. Left ventricular (LV) pressure–volume (PV) loops were prospectively recorded in the 24 TTS patients and results compared with the control subjects. This was carried out by performing a standard coronary angiography and left ventriculography achieved via right radial or femoral artery access, where LV volume, LV pressure, and the electrocardiogram were simultaneously recorded. Results Results revealed that TTS was associated with impaired LV contractility (end-systolic elastance 1.74 mm Hg/mL vs 2.35 mm Hg/mL [P=0.024]). The association was extended to maximal rate of change in systolic pressure over time (1,533 mm Hg/s vs 1,763 mm Hg/s [P=0.031]), end systolic volume at a pressure of 150 mm Hg, (77.3 mL vs 46.4 mL [P=0.002]), and a shortened systolic period (286 ms vs 343 ms [P<0.001]). The research team also discovered that in response, the PV diagram was shifted rightward with significantly increased LV end-diastolic (P=0.031) and end-systolic (P<0.001) volumes, which preserved LV stroke volume (P=0.370) despite a lower LV ejection fraction (P<0.001). Further findings also revealed that diastolic function was characterized by prolonged active relaxation (relaxation constant 69.5 ms vs 45.9 ms [P<0.001]); minimal rate of change in diastolic pressure (-1,457 mm Hg/s vs –2,192 mm Hg/s [P<0.001]), Meanwhile, diastolic stiffness (1/compliance) was found to be unaffected during TTS (end-diastolic volume at a pressure of 15 mm Hg (96.7 mL vs 109.0 mL [P=0.942]). Mechanical efficiency was significantly reduced in TTS (P<0.001) considering reduced stroke work (P=0.001), increased potential energy (P=0.036), and a similar total PV area compared with that of control subjects (P=0.357). Cardiomyocyte failure, arrhythmias and Ca2+ overload “In view of a similar total mechanical energy in both groups, the utilization of myocardial work is inefficient in TTS, with a lot of wasted energy during ventricular contraction and relaxation,” the study says. “Furthermore, there is a mismatch between ventricular and vascular properties, again mainly related to reduced ventricular contractility.” The study goes on to discuss the changes TTS integrates in the central nervous system, of which the catecholamine surge is one and a sympathetic overdrive is the other. Suggesting a potential therapeutic approach in patients with TTS, the researchers point to cardiomyocyte failure, arrhythmias, and Ca2+ overload as the hallmarks of TTS. “The toxic effects of catecholamines on the myocardium are characterized by a loss of their inotropic effects through beta-receptor downregulation and activation of inhibitory G proteins,” the researchers said. “Accordingly, myocardial biopsy specimens exhibited sarcoplasmic reticulum Ca2+ ATPase (SERCA) hypoactivity and dephosphorylated phospholamban as potential causes for contractile dysfunction and prolonged relaxation, which were particularly shown in our study.” Study limitations These observations are further discussed in an editorial comment by Jorge Salamanca, MD, and Fernando Alfonso, MD, PhD, who recognized the lack of evidence-based recommendations for the management of this disease. “This is difficult to justify because TTS is now routinely diagnosed in patients who present with electrocardiographic changes, troponin elevation, unobstructed coronary arteries, and a typical transient pattern of LV wall motion abnormalities that usually involve the apical and mid-ventricular myocardium. Therefore, a comprehensive understanding of TTS pathophysiology and specific evidence-based treatments is urgently required,” say the experts, both based at the Hospital de La Princesa, Universidad Autónoma de Madrid (Autonomous University of Madrid). Of the study, the commenters hailed the research as “providing a careful, systematic, and comprehensive set of sophisticated invasive hemodynamic data, particularly the behavior of the left ventricle in TTS patients that “clearly advance the field.” The editorialists also highlighted the study’s limitations, namely the relatively small sample size and the decision to compare results to a control group of subjects free of cardiovascular disease. Other limitations include the decision not to carry out a serial analysis of the hemodynamic changes produced over time, which the co-authors said would provide complementary information on the patients’ evolution. Sources: Stiermaier T, Reil J-C, Sequeira V, et al. Hemodynamic Assessment in Takotsubo Syndrome. J Am Coll Cardiol. 2023;81:1979-1991. Salamanca J, Alfonso F. Novel Hemodynamic Insights in Takotsubo Syndrome. J Am Coll Cardiol. 2023;81:1992-1995. Image Credit: freshidea – stock.adobe.com