Figure 1: Schematic Illustrations of Selected Inotropic Agents and Gene Therapies for Treatment of HF

Schematic illustrations depicting targets and mechanisms of action of selected inotropic agents and gene therapies for treatment of heart failure (HF) highlighting cardiac myosin activators BB-R12 and omecamtiv. (A) 2-deoxy-ATP (dATP) and omecamtiv are cardiac myosin activators that act directly on the contractile apparatus. Gene therapies that act on calcium cycling and regulation work “upstream” of myosin. Drugs and gene therapies that act on the β-adrenergic system or inhibit phosphodiesterase and cyclic AMP work further upstream of the contractile apparatus and calcium regulation. (B) Myosin heads form transient cross-bridges with actin. ATP fuels a conformational change (“power stroke”) causing actin to slide past myosin, shortening sarcomere length and causing contraction. Cardiac myosin activators enable more myosin heads (independent force generators) to interact with actin per cardiac cycle (i.e., more active cross-bridges). This has been characterized as “more hands pulling on the rope” and increases the maximum force of contraction. (C) Molecular modeling indicates dATP detaches from myosin more rapidly than ATP, enabling faster cross-bridge cycling and more rapid force generation (i.e., increase in maximum rate of pressure rise [+dP/dt]). Replicating cells normally have a small supply of dATP for DNA synthesis and repair. Ribonucleotide reductase (R1R2) converts ATP to dATP under tight allosteric regulation but is down-regulated in nonreplicating cardiomyocytes. BB-R12 provides the gene for R1R2 under control of a cardiac troponin promoter, restricting synthesis to cardiomyocytes. dATP increases the maximum force of contraction, increases +dP/dt and −dP/dt, and does not prolong systole. Omecamtiv activates myosin by increasing the transition rate from weak to strong binding states between myosin and actin, increases the maximum force of contraction without a change in +dP/dt or −dP/dt, and prolongs systole. Omecamtiv figure adapted with permission from Malik et al. (12). AC6 = adenylyl-cyclase type 6; β-AR = beta-adrenergic receptor; BB-R12 = AAV6-cTnT-R1R2; cAMP = cyclic AMP; CK = creatine kinase; GRK2 = G-protein-coupled receptor kinase-2; PDE = phosphodiesterase; PLN = phospholamban; R1R2 = ribonucleotide reductase; SERCA2a = sarcoplasmic/endoplasmic reticulum calcium ATPase; SUMO1 = small ubiquitin-related modifier 1.