Pathogenesis of Acute Stress Induced (Tako-tsubo) Cardiomyopathy: Energy Shut-Down or Intense Inflammation?

Study Overview
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Brief Summary
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Tako Tsubo Cardiomyopathy (TTC), also known as Broken Heart Syndrome, is a disorder of the heart that occurs most commonly in women (although it occasionally occurs in men) and is usually related to a stressful event. Symptoms are often similar to a heart attack, and include chest pain and shortness of breath. Although Tako Tsubo Cardiomyopathy is not a new medical condition, it has not been widely recognised until the last decade. Currently the investigators don't have an exact understanding of how or why the heart is affected in this way, and so the investigators are conducting a study to help understand what causes Tako Tsubo Cardiomyopathy.

Detailed Description
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The investigators aim to study the reciprocal modulation of fatty acids and glucose metabolism in the Tako Tsubo Cardiomyopathy physiology, in both humans and an animal model, and to investigate which metabolic pathway is preferentially adopted by acute Tako Tsubo Cardiomyopathy myocytes during this severe functional shut down with largely preserved variability. The human model will be used to determine the preferential stimulated uptake of glucose/fatty acids under optimal metabolic conditions for each (hyperinsulineamic euglycemic clamp for 18F-Fludeoxyglucose (18F-FDG) and fasting for 14Fluorine-18Fluoro-6-Thia-Heptadecanoic Acid (18F-FTHA cardiac Positron Emission Tomography)). In the rat model the investigators will examine both the metabolic tracer uptake (using micro Positron Emission Tomography-Computed Tomography) as well as the downstream modulation of the two metabolic pathways (transcriptional regulators, mitochondrial respiration, expression of the uncoupling proteins, levels of Adenosine Triphosphate generation and reactive oxygen species production). The investigators aim to test the hypothesis that inflammation plays a pivotal role in the pathophysiology of this condition by further exploring: 1) In the rat model define time course, extent and subtypes of cellular infiltrate, 2) In the rat model of Tako Tsubo Cardiomyopathy, demonstrate the presence of inflammatory macrophages using in-vivo Ultrasmall Superparamagnetic Iron Oxide-cardiac magnetic resonance imaging and whether this relates to numbers and types of macrophages present as determined by immunohistochemical analysis, 3) In clinical patients, define the time course of specific peripheral blood monocyte subsets and the serum levels of inflammatory cytokines versus matched controls and 4) In clinical patients, establish the compartmentalisation of tissue macrophages in the left ventricle its time course resolution using Ultrasmall Superparamagnetic Iron Oxide-enhanced cardiac magnetic resonance. The investigators will assess the psycho-emotional factors involved in Tako Tsubo Cardiomyopathy given that in the majority of cases intense emotional trauma is immediately preceding onset.

Official Title
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Pathogenesis of Acute Stress Induced (Tako-tsubo) Cardiomyopathy: Energy Shut-Down or Intense Inflammation? The TERRIFIC Study

Conditions
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Tako-tsubo Cardiomyopathy

Intervention / Treatment
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* Procedure: Magnetic resonance imaging
* Biological: Acute Inflammatory Activation study
* Radiation: PET CT
* Behavioral: Psychological assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients diagnosed with TTC in the past 12 days, able to give consent and who have not lost capacity of consent between the time of diagnosis (usually made at coronary catheterisation, for which they are consented clinically) and time of being approached for inclusion in the study. Age and gender matched healthy controls willing to participate and able to give consent. Exclusion Criteria: Unwillingness to participate Patients with contraindications to MR scanning Pregnant or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| TTC Patients<br>Patients diagnosed with Tako-tsubo cardiomyopathy. | Procedure: Magnetic resonance imaging<br>* Cardiac MRI and short MRI following USPIO infusion<br>Biological: Acute Inflammatory Activation study<br>* Blood sampling for exploration of type and level of inflammatory response<br>Radiation: PET CT<br>* PET study for metabolic pathway study<br>Behavioral: Psychological assessment<br>* Assessment by a psychologist<br>|
| Health Volunteers<br>Participants who have normal hearts. | Procedure: Magnetic resonance imaging<br>* Cardiac MRI and short MRI following USPIO infusion<br>Biological: Acute Inflammatory Activation study<br>* Blood sampling for exploration of type and level of inflammatory response<br>Radiation: PET CT<br>* PET study for metabolic pathway study<br>Behavioral: Psychological assessment<br>* Assessment by a psychologist<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Inflammation as measured by Cardiac Magnetic Resonance Imaging | As measured by cardiac MRI | Three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evidence of psycho-emotional factors following intense physical or emotional stress as measured by Hospital Anxiety and Depression Scale | As measured by psychiatric interview | Three years | 
| Evidence of alterations of the metabolism of myocardium by Cardiac Positron Emission Tomography | As measured by PET CT | Three years | 
| Systemic Inflammation as measured by inflammatory markers | As measured by inflammatory markers | Three years |