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

Heart Failure Clinical Trial

— POWER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04899635
• Other study ID #: PB528721
• Status: Recruiting
• Start date: August 3, 2021
• Est. completion date: April 30, 2025

Study information

• Verified date: June 2024
• Source: University Hospitals Coventry and Warwickshire NHS Trust
• Contact: Patrick Tran
• Phone: 02476964000
• Email: patricktranphd[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2025
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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).

Related Conditions & MeSH terms

• Fatigue
• Fatigue; Muscle, Heart
• Heart Failure
• Myocardial Dysfunction

Intervention

Other:
• In-vitro contractile fatigue protocol
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.

Locations

Country	Name	City	State
United Kingdom	University Hospitals Coventry and Warwickshire	Coventry

Sponsors (2)

Lead Sponsor	Collaborator
University Hospitals Coventry and Warwickshire NHS Trust	Coventry University

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

Banerjee P. Heart failure: a story of damage, fatigue and injury? Open Heart. 2017 Oct 15;4(2):e000684. doi: 10.1136/openhrt-2017-000684. eCollection 2017. — View Citation

Tran P, Joshi M, Banerjee P. Concept of myocardial fatigue in reversible severe left ventricular systolic dysfunction from afterload mismatch: a case series. Eur Heart J Case Rep. 2021 Mar 7;5(3):ytab089. doi: 10.1093/ehjcr/ytab089. eCollection 2021 Mar. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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