Cardiac Muscle Membrane Stabilization in Myocardial Reperfusion Injury

Abstract

The phospholipid bilayer membrane that surrounds each cell in the body represents the first and last line of defense for preserving overall cell viability. In several forms of cardiac and skeletal muscle disease, deficits in the integrity of the muscle membrane play a central role in disease pathogenesis. In Duchenne muscular dystrophy, an inherited and uniformly fatal disease of progressive muscle deterioration, muscle membrane instability is the primary cause of disease, including significant heart disease, for which there is no cure or highly effective treatment. Further, in multiple clinical forms of myocardial ischemia-reperfusion injury, the cardiac sarcolemma is damaged and this plays a key role in disease etiology. In this review, cardiac muscle membrane stability is addressed, with a focus on synthetic block copolymers as a unique chemical-based approach to stabilize damaged muscle membranes. Recent advances using clinically relevant small and large animal models of heart disease are discussed. In addition, mechanistic insights into the copolymer-muscle membrane interface, featuring atomistic, molecular, and physiological structure-function approaches are highlighted. Collectively, muscle membrane instability contributes significantly to morbidity and mortality in prominent acquired and inherited heart diseases. In this context, chemical-based muscle membrane stabilizers provide a novel therapeutic approach for a myriad of heart diseases wherein the integrity of the cardiac muscle membrane is at risk.

Keywords: copolymer; heart; ischemia; reperfusion.

Graphical abstract

Figure 1

Health Relevance Clinically relevant pathways to cardiac reperfusion injury with focus on cardiac membrane instability and the novel use of synthetic membrane stabilizers. CPR = cardiopulmonary resuscitation; MI = myocardial infarction.

Central Illustration

Chemical-Based Membrane Stabilizer Discovery Platform Integrating Insights From Vesicles to In Vivo Overarching goal: stabilizing the cardiac muscle membrane in disease using synthetic chemistry.

Figure 2

Schematic Representation of Block Copolymer P188 Interaction With the Cardiac Sarcolemma Blue spheres = polyethylene oxide block; red spheres = polypropylene oxide block.

Figure 3

Timing and Location of Membrane Stabilizer Delivery are Essential Elements to Clinical Efficacy in STEMI/Percutaneous Coronary Intervention

Figure 4

Copolymer-Muscle Membrane Interface (A) Diblock copolymer structures with unique single chemical end groups where blue represents polyethylene oxide units and red represents polypropylene oxide units. (B) Conceptualization of anchor and chain working model, wherein the relatively more hydrophobic tert-butyl end group anchors the polypropylene oxide block more deeply in the phospholipid bilayer (right).