POWER Myocardial Fatigue Study: a Biomechanical Assessment of Contractility of Human Myocardium

Study Overview
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Brief Summary
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To gain a comprehensive understanding of the biomechanical behaviour of human heart to explore the concept of myocardial fatigue in response to a temporal range of preload, afterload and drug-induced inotropy using in-vitro contractile assays.

Detailed Description
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A continuum of pathological states from fatigue, injury to damage of the myocardium has been proposed which complements the continuous spectrum of HF and reconciles the seemingly disparate plethora of mechanisms behind the pathophysiology of HF. Unlike skeletal muscle where mechanical stress can be readily removed upon fatigue, an impaired left ventricle continues to receive preload from the right ventricle and cannot rest, maintaining cardiac output only at the expense of increasing filling pressures (as in HF with preserved ejection fraction). If concurrently faced with high afterload from vascular stiffness, ventricular-arterial decoupling occurs, driving mechanical inefficiency and diminishing cardiac output (as in HF with reduced ejection fraction). Chances of recovery is linked to the degree of fatigue, cardiomyocyte loss and replacement with non-contractile fibrosis. Assuming that the myocardium is in a state of chronic fatigue before reaching advanced stages of fibrosis, cases such as aortic stenosis or hypertensive heart disease may potentially be reversible if the pathological load is promptly removed. This study will be re-synthesizing existing knowledge of the biomechanical behaviour of healthy and diseased cardiac myocytes and muscle in a new light of the theoretical constructs of myocardial fatigue, aligned with the existing energy-starvation theory. It will be a proof-of-concept study. Just as Frank-Starling's relationship between preload and cardiac output emerged from pre-clinical studies on muscle behaviour with subsequently major clinical implications, this study represents a necessary stepping stone to adding a new layer of insight into the pathophysiology of heart failure (HF).

Official Title
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Profiling Biomechanical Responses and Workload of the Human Myocardium to Explore the Concept of Myocardial Fatigue and Reversibility

Conditions
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Heart Failure, Fatigue; Muscle, Heart, Myocardial Dysfunction, Exhaustion; Heart

Intervention / Treatment
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* Other: In-vitro contractile fatigue protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All adult patients between 18 to 85-years old undergoing open-heart surgery who can undergo the consent process for the study Healthy donor hearts that are deemed non-transplantable and consent received from a legal representative Exclusion Criteria: This criterion is kept to a minimum since the availability of human myocardial samples is finite and dependent on the limited number of patients undergoing cardiac surgery annually within the local hospital. Patients who do not have the mental capacity to undergo the consent process For the safety of researchers, patients with evidence of ongoing blood-borne infections such as HIV, or a recent positive test for COVID-19 (within 10 days of last PCR test).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Diseased cardiac tissue<br>Heart muscle or cells (cardiomyocytes) will be obtained from patients undergoing cardiac surgery, namely coronary artery bypass grafting or for severe valvular heart disease. | Other: In-vitro contractile fatigue protocol<br>* Using contractility assays for muscle slices or the work-loop assay for isolated heart cells, the tissue preparation will undergo a series of contraction and relaxation under varying levels of preload, afterload, stimulation frequency and under other experimental conditions such as drug-induced inotropism.<br>|
| Healthy cardiac tissue<br>Healthy donor hearts from deceased individuals that are not transplantable due to technical reasons | Other: In-vitro contractile fatigue protocol<br>* Using contractility assays for muscle slices or the work-loop assay for isolated heart cells, the tissue preparation will undergo a series of contraction and relaxation under varying levels of preload, afterload, stimulation frequency and under other experimental conditions such as drug-induced inotropism.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the force generated by the muscle cell and/or muscle slice | This will be based on the effects of changing load and/or exposure to drug-induced inotropic effects | Within a day for each experiment | 
| Changes in the velocity of shortening by the muscle cell and/or muscle slice | This will be based on the effects of changing load and/or exposure to drug-induced inotropic effects | Within a day for each experiment | 
| Changes in the end-systolic force-length relationship of the muscle cell and/or muscle slice | This will be based on the effects of changing load and/or exposure to drug-induced inotropic effects, and calculated by integrating the above force and length changes. | Within a day for each experiment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the phosphorylation potential | This will be calculated by determining the above concentration of adenosine triphosphate and its metabolic by-product including inorganic phosphate, at different times of the contraction fatigue protocol (e.g. before, during, and after). | Within a day for each experiment | 
| Changes in the phosphocreatine/ATP ratio | This will be calculated by determining the above concentration of phosphocreatine and ATP at different times of the contraction fatigue protocol (e.g. before, during and after). | Within a day for each experiment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial Fatigue, Preload, Afterload, Cardiac Work-loop, Cardiomyocytes, Biomechanical model