Role of the central autonomic nervous system intrinsic functional organisation and psychosocial factors in primary microvascular angina and Takotsubo syndrome

Magdalena Maria Cattaneo, Emanuele Pravatà, Micol Provenzi, Marco Moccetti, Alain Kaelin, Isabella Sudano, Luigi Biasucci, Camilla Gallino, Costanzo Limoni, Carlo Calanchini, Augusto Gallino, Filippo Crea, Mattia Cattaneo, Magdalena Maria Cattaneo, Emanuele Pravatà, Micol Provenzi, Marco Moccetti, Alain Kaelin, Isabella Sudano, Luigi Biasucci, Camilla Gallino, Costanzo Limoni, Carlo Calanchini, Augusto Gallino, Filippo Crea, Mattia Cattaneo

Abstract

Introduction and objective: Dysfunctional central autonomic nervous system network (CAN) at rest may result in aberrant autonomic responses to psychosocial stressors. We hypothesised that patients with primary microvascular angina (MVA) or Takotsubo syndrome (TTS) would exhibit a peculiar functional organisation of the CAN, potentially associated with psychological patterns.

Methods: Patients underwent a psychosocial evaluation: a clinical diagnostic interview, Millon Clinical Multiaxial Inventory III, State-Trait Anxiety Inventory form Y and Short Form 36 Health Survey (SF-36). The strength of intrinsic functional connectivity (FC) between various nodes of the CAN was investigated using cerebral resting state functional MRI (RS-fMRI).

Results: We evaluated 50 (46 women) stable patients: 16 patients with MVA, 17 patients with TTS and 17 patients with previous acute myocardial infarction (AMI). Compared with AMI, patients with MVA showed a lower (higher impairment) SF-36 Body-Pain score (p 0.046) and a higher SF-36 Mental-Health score (p 0.039). Patients with TTS showed the strongest FC between two nodes of the CAN (sympathetic midcingulate cortex and parasympathetic primary motor area) (F 6.25, p 0.005) using RS-fMRI.

Conclusions: The study implements an innovative collaborative research among cardiologists, neuroscientists and psychiatrists ('Neuro-psycho-heart Team'). MVA showed a discrepancy between the highest level of self-reported body pain and the best mental health score, which might suggest a mechanism of somatisation. TTS exhibited an increased functional integration between two areas of the CAN involved in interoceptive pain awareness and negative emotional status. We implemented an innovative research collaboration among cardiologists, neuroscientists and psychiatrists. These data are hypothesis generating and suggest potential prospective investigations on pathophysiology and implementation of psychotherapy and stress-reducing techniques as therapeutic strategies.

Trial registration number: NCT02759341.

Keywords: autonomic regulation; cardiomyopathy apical; endothelial function; microvascular; syndrome X.

Conflict of interest statement

Competing interests: AG reports grants from the Swiss Heart Foundation and the ABREOC for unrelated work; IS reports grants from Swiss Heart Foundation and Swiss National Foundation for unrelated work.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study schedule and drop-outs. The figure shows the 3-visit study schedule along with the distribution of dropouts. AMI, acute myocardial infarction; fMRI, functional magnetic resonance imaging; MVA, microvascular angina; TTS, Takotsubo syndrome.
Figure 2
Figure 2
Main analysis of resting state functional connectivity (FC) using functional MRI (fMRI). The resting state FC measured by fMRI did not differ among the groups. The box-plots show Pearson’s correlation coefficients as follows: (A) whole central autonomic nervous system network (CAN) mean FC. (B) Sympathetic network (sCAN) mean FC. (C) Parasympathetic network (pCAN) mean FC. (D) sCAN-pCAN between-networks mean FC. AMI, acute myocardial infarction; MVA, microvascular angina; TTS, Takotsubo syndrome.
Figure 3
Figure 3
Exploratory analysis of resting state (RS) functional connectivity (FC) using functional MRI (fMRI). Plots and matrices represent colour-coded region of interest (ROI)-to-ROI pair FC of sympathetic-parasympathetic synchronisation. (A) The colour indicates the z-score between each pair of ROIs. As shown (*), the Takotsubo syndrome (TTS) group showed a stronger connectivity compared with acute myocardial infartion (AMI) group between the sCAN midcingulate cortex (sCAN-MCC) and the pCAN primary motor area (pCAN-PM) (p=0.022) and a borderline stronger connectivity compared with microvascular angina (MVA) group (p=0.050). A full list of the fMRI regions of interest based on Beissner et al is in the online supplementary material. (B) The figure shows the location of the two above-mentioned areas in the central nervous system (sCAN-MCC, pCAN-PM). a-Insula, anterior insula; CAN, central autonomic nervous; FDR, false discovery rate; L, left; MCC, midcingulate cortex; MVA, microvascular angina; MTG, medial temporal gyrus; pCAN, parasympathetic CAN; p-Insula, posterior insula; PM, primary motor area; R, right; sCAN, sympathetic CAN; SMG, supramarginal gyrus; sSSC, secondary somatosensory cortex; VMPFC, ventromedial prefrontal cortex.

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