Placebo and Nocebo Effects in Patients With Takotsubo Cardiomyopathy and Heart-Healthy Controls.

Elisabeth Olliges,Georg Schmidt,Alexander Müller,Stefan Holdenrieder,Simon Schneider,Hansjörg Ebell,Karin Meissner,Christof Burgdorf,Siegmund Braun,Karl-Heinz Ladwig,Daniel Sinnecker,Joram Ronel

doi:10.3389/fpsyt.2019.00549

Abstract

The etiology of takotsubo cardiomyopathy (TTC)—a rare, reversible, and acquired form of cardiac diseases—is not yet fully explained. An exaggerated activation of the sympathetic-nervous-system (SNS) following stressful psychosocial life events is discussed to be of key importance. In this experimental study, we tested whether TTC patients, compared to heart-healthy controls, respond more strongly to supporting placebo interventions and stressful nocebo interventions targeting cardiac function. In a single experimental session, 20 female TTC patients and 20 age matched (mean age 61.5 years, ± 12.89) catheter-confirmed heart-healthy women were examined. Saline solution was administered three times i.v. to all participants, with the verbal suggestion they receive an inert substance with no effects on the heart (neutral condition), a drug that would support cardiac functions (positive condition), and a drug that would burden the heart (negative condition). Systolic and diastolic blood pressure (DBP/SBP), heart rate (HR), endocrine markers cortisol (µg/dl), copeptin (pmol/l), and subjective stress ratings (SUD) were assessed to examine alterations of the SNS and the hypothalamic–pituitary–adrenal axis (HPA). Before and after each intervention SUD was rated. One pre and three post serum cortisol and copeptin samples were assessed, and a long-term electrocardiogram as well as non-invasive, continuous blood pressure was recorded. The study design elucidated a significant increase of SUD levels as a response to the nocebo intervention, while perceived stress remained unaffected during the preceding neutral and positive interventions. Increasing SUD levels were accompanied by higher SBP and an anticipatory increase of HR shortly prior to the nocebo intervention. SBP increased also as a response to positive verbal suggestions (Bonferroni-corrected p-values > .05). Alterations of cortisol and copeptin due to the interventions and significant placebo effects failed to appear. Interestingly no differences between TCC patients and controls could be found.These findings do not support the assumption of an exaggerated activation of the SNS as a discriminatory factor for TTC. Since especially the nocebo intervention revealed negative subjective and objective effects, our results underscore the urgent need to consider carefully the impact of verbal suggestions in the interaction with cardiac patients in daily clinical routine. This study is registered at the Deutsches Register Klinischer Studien (DRKS00009296).

Highlights

Placebo effects are conceptualized as neurobiological phenomena, resulting from the positive psychosocial context, a treatment is embedded in
In a case–control study, we examined the cardiovascular response to placebo and nocebo interventions targeting the cardiac functions in 20 TTC patients on average two years after disease onset and 20 matched heart-healthy individuals
We investigated cardiac, psychological, and endocrine stress responses to placebo and nocebo interventions targeting the heart in patients with a history of TTC and matched heart-healthy controls

Summary

Introduction

Placebo effects are conceptualized as neurobiological phenomena, resulting from the positive psychosocial context, a treatment is embedded in. The current state of research suggests that placebo and nocebo effects are mediated by explicit expectations and shaped by different means; social observational learning [1], classical conditioning [2], and verbal suggestions [3]. The doctor’s verbal suggestions inducing positive or negative outcome expectations are an important feature for placebo and nocebo effects [4,5,6,7]. Placebo analgesia is often associated with the release of endogenous opioids, whereas placebo-induced motor improvement in patients with Parkinson’s disease could be connected to the release of dopamine in the dorsal striatum [8, 9]. The verbal suggestion led to coronary vasoconstriction accompanied by chest pain reduction. Authors concluded that the coronary vasoconstriction was not caused by increased stress levels but by a reduction of sympathetic outflow and/or increase of parasympathetic outflow to the cardiac vessels [12]

Methods

Results

Conclusion