Fine tuning contractility: atrial sarcomere function in health and disease

Abstract

The molecular mechanisms of sarcomere proteins underlie the contractile function of the heart. Although our understanding of the sarcomere has grown tremendously, the focus has been on ventricular sarcomere isoforms due to the critical role of the ventricle in health and disease. However, atrial-specific or -enriched myofilament protein isoforms, as well as isoforms that become expressed in disease, provide insight into ways this complex molecular machine is fine-tuned. Here, we explore how atrial-enriched sarcomere protein composition modulates contractile function to fulfill the physiological requirements of atrial function. We review how atrial dysfunction negatively affects the ventricle and the many cardiovascular diseases that have atrial dysfunction as a comorbidity. We also cover the pathophysiology of mutations in atrial-enriched contractile proteins and how they can cause primary atrial myopathies. Finally, we explore what is known about contractile function in various forms of atrial fibrillation. The differences in atrial function in health and disease underscore the importance of better studying atrial contractility, especially as therapeutics currently in development to modulate cardiac contractility may have different effects on atrial sarcomere function.

Keywords: atria; cardiomyopathy; contractility; myofilament; sarcomere.

Figure 1.

Contractile protein contributions to atrial and ventricular function. A: left ventricular pressure-volume loop schematic. Sarcomere contributions to the various phases are marked with arrows. Atrial pressure volume loop shown at scale to the bottom left of the left ventricular loop. AC, active contraction; AoV, aortic valve; IVC, isovolumic contraction; IVR, isovolumic relaxation; MV, mitral valve; PF, passive filling; XB, cross-bridge. B: left atrial pressure-volume loop schematic. The pump, reservoir, and conduit function are marked with different color lines. Sarcomere contributions to the various stages are marked with arrows.

Figure 2.

Sarcomere components with differential chamber expression. A: schematic of a half-sarcomere running from Z-disk to M-line. Thick and thin filaments are illustrated with proteins labeled in B and C. The two primary titin isoforms, N2B and N2BA are shown. Both isoforms are expressed in atria and ventricle, with atria containing a larger percentage of N2BA. B: thin filament proteins have cardiac-specific isoforms, but do not have significant differences in isoform expression between the chambers of the healthy heart. C: thick filament schematic showing primarily ventricular isoforms (top half) and primarily atrial isoforms (bottom half). α-TM, α-tropomyosin; cTnT, cardiac troponin-T; cTnC, cardiac troponin-C; cTnI, cardiac troponin-I; β-MHC, β-myosin heavy chain; ELC-V, ventricular myosin essential light chain; RLC-V, ventricular myosin regulatory light chain; cMyBP-C, cardiac myosin binding protein-C; titin sort N2B and long N2BA isoforms; myosin binding protein H-like; RLC-A, atrial myosin essential light chain; ELC-A, atrial myosin essential light chain; α-MHC, α-myosin heavy chain.

Figure 3.

Interplay between electrical, fibrotic, mechanical, and electrical remodeling and their contributions to atrial fibrillation. Schematic showing the mechanisms and interdependence of excitation/contraction coupling (blue), fibrotic (yellow), hemodynamic (green), and contractile (orange) changes that occur in atrial fibrillation. Primary mechanisms including ischemia, hypertension, and genetics, are integrated into the pathways with red arrows. APD, action potential duration; ERP, effective refractory period; AF, atrial fibrillation; PKA, protein kinase-A; CaMKII, calmodulin-dependent protein kinase II; AV, atrioventricular node; EC, excitation-contraction coupling.