Abstract for Paper VII

The Frank–Starling Law and Familial Hypertrophic Cardiomyopathy; Some new striking aspects of muscle structures

Similarities between the biochemistries of Familial Hypertrophic Cardiomyopathy (FHCM) and the Frank–Starling Law of the Heart indicate a common factor. Evaluation of varied data from mammalian striated muscle demonstrates the presence of two types of thin-filaments in the sarcomere that are of unequal length and that the shorter one is not anchored to the end of the sarcomere (Z-band). My interpretation of the data is that only in cardiac muscle these non-anchored thin-filaments are of a critical short length and this peculiarity is responsible for major functional differences between cardiac and skeletal muscles. Structural perturbations to the cardiac sarcomere that impinge on this critical length appear as a shift to greater Ca²⁺ sensitivity of contraction with slowed relaxation, as is found in both the Frank–Starling Law and FHCM. It is further proposed that in FHCM the diastolic stress, poor relaxation, resulting from accommodation of a mutant protein responsible for the increase in Ca²⁺ sensitivity also produces chronic strain in titin. This strain, via changes in binding of nuclear-acting factors to titin, will trigger events leading to myofilament disarray. Change induced in a single critical dimension does explain how so many different genetic mutations throughout the sarcomere can give rise to the same pathophysiology. The clinically approved Ca²⁺-sensitizer Levosimendan promotes the Ca²⁺ activation of thick-filaments as a result of its binding to troponin-C. This drug action yields an increase in the Ca²⁺ cooperativity of contraction with a decrease in Ca²⁺ sensitivity resulting in improved diastolic relaxation. The considerations here suggest the use of Levosimendan or similar, for the treatment, or prophylaxis of poor cardiac muscle relaxation that is the root cause of FHCM or other diastolic failures. The co-administration of a calcium channel blocker, e.g. Diltiazem, could moderate any undesirable increased contraction and accompanying energy consumption without loss of the relaxation gains given by Levosimendan.