Clinical trial NCT04899635: POWER Myocardial Fatigue Study: a Biomechanical Assessment of Contractility of Human Myocardium
Official title: Profiling Biomechanical Responses and Workload of the Human Myocardium to Explore the Concept of Myocardial Fatigue and Reversibility
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Heart Failure
Fatigue; Muscle, Heart
Myocardial Dysfunction
Exhaustion; Heart
Keywords: Myocardial Fatigue
Preload
Afterload
Cardiac Work-loop
Cardiomyocytes
Biomechanical model
Lead sponsor: University Hospitals Coventry and Warwickshire NHS Trust
Sponsor class: OTHER
Collaborators: name: Coventry University
First posted: 2021-05-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Human cardiac tissues (atrial appendages and ventricular tissue biopsies) are obtained from patients undergoing elective or inpatient open-heart surgery, namely coronary artery bypass grafting and valvular replacement. If available, explanted failing hearts are also recruited for experimentation. A control population consists of healthy donor hearts that are deemed non-transplantable and collected by the Arden Tissue Bank at UHCW.

Brief 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.

Detailed 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).

Eligibility criteria: 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).

Primary outcomes:
measure: Changes in the force generated by the muscle cell and/or muscle slice
timeFrame: Within a day for each experiment
measure: Changes in the velocity of shortening by the muscle cell and/or muscle slice
timeFrame: Within a day for each experiment
measure: Changes in the end-systolic force-length relationship of the muscle cell and/or muscle slice
timeFrame: Within a day for each experiment
Secondary outcomes:
measure: Changes in the phosphorylation potential
timeFrame: Within a day for each experiment
measure: Changes in the phosphocreatine/ATP ratio
timeFrame: Within a day for each experiment
Other outcomes:
Locations:
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire
Study officials:
References:
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.
citation: 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.