Myofilament Calcium Regulation in Human Myocardium

Abstract

Background-We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure. Methods and Results-Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F max ) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01Ϯ0.22 versus 0.86Ϯ0.13 mol/L, respectively (PϽ0.05). Addition of cAMP resulted in a 0.56 mol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 mol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts. Conclusions-We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.

Effects of Cariporide and Losartan on Hypertrophy, Calcium Transients, Contractility, and Gene Expression in Congestive Heart Failure

“…Recent studies indicate that systolic function is reduced by impaired calcium sensitivity in heart failure. [21][22][23] The present study suggests that losartan and, to a lesser degree, cariporide improve cardiomyocyte systolic function by increasing calcium sensitivity.…”

Functional consequences of caspase activation in cardiac myocytes

“…Structurally, cardiac troponin T connects tropomyosin to the TnC-TnI complex and confers calcium sensitivity and cooperativity to the activity of the TnC-TnI complex on actomyosin ATPase (6,(15)(16)(17)(18). The C terminus of TnT is necessary for submaximal activation whereas the N terminus is essential for maximal activation.…”

“…Changes in myofilament calcium responsiveness and calcium-cycling proteins have been hallmarks of experimental and human heart failure (6-10). Reduced calcium sensitivity or decreased cooperation between the thick and thin myofilaments results in reduced contractile activation and force development (6). In human and experimental heart failure, several changes in the myofibrillar proteins have been reported to occur (7)(8)(9)(10).…”

Alterations in Thin Filament Regulation Induced by a Human Cardiac Troponin T Mutant That Causes Dilated Cardiomyopathy Are Distinct from Those Induced by Troponin T Mutants That Cause Hypertrophic Cardiomyopathy

“…Investigations using tissue from hearts affected by a number of aetiologies (including non-familial DCM) have shown a consistent pattern of reduced unloaded shortening speed and reduced myofibrillar ATPase activity (38 -40). Reports are less clear over possible changes in Ca 2ϩ sensitivity that has been suggested to be increased or unaltered; however, recent work suggests that additional factors such as sarcomere length and phosphate concentration are involved in determining which way the Ca 2ϩ sensitivity will change (41)(42)(43). The reduced unloaded shortening speed correlates with the reduced ATPase and sliding speed caused by the ⌬Lys-210 mutation in troponin T. The effects of the ⌬Lys-210 mutation also correlate with the altered properties of troponin extracted from failing hearts.…”