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The amount of work the heart can perform during ejection is governed by the inherent contractile properties of individual myocytes. One way to alter contractile properties is to alter contractile proteins such as myosin heavy chain (MyHC), which is known to demonstrate isoform plasticity in response to disease states. The purpose of this study was to examine myocyte functionality over the complete range of MyHC expression in heart, from 100% [alpha]-MyHC to 100% [beta]-MyHC, using euthyroid and hypothyroid rats. Peak power output in skinned cardiac myocytes decreased as a nearly linear function of [beta]-MyHC expression during maximal ([r.sup.2] = 0.85, n = 44 myocyte preparations) and submaximal ([r.sup.2] = 0.82, n = 31 myocyte preparations) [Ca.sup.2+] activation. To determine whether single myocyte function translated to the level of the whole heart, power output was measured in working heart preparations expressing varied ratios of MyHC. Left ventricular power output of isolated working heart preparations also decreased as a linear function of increasing [beta]-MyHC expression ([r.sup.2] = 0.82, n = 34 myocyte preparations). These results demonstrate that power output is highly dependent on MyHC expression in single myocytes, and this translates to the performance of working left ventricles. myosin heavy chain; myocardium; myocardial contractility; cardiac muscle

The purpose of this study was to examine the role of myosin heavy chain (MHC) in determining loaded shortening velocities and power output in cardiac myocytes. Cardiac myocytes were obtained from euthyroid rats that expressed [Alpha]-MHC or from thyroidectomized rats that expressed [Beta]-MHC. Skinned myocytes were attached to a force transducer and a position motor, and isotonic shortening velocities were measured at several loads during steady-state maximal [Ca.sup.2+] activation ([P.sub.pCa4.5]). MHC expression was determined after mechanical measurements using SDS-PAGE. Both [Alpha]-MHC and [Beta]-MHC myocytes generated similar maximal [Ca.sup.2+]-activated force, but [Alpha]-MHC myocytes shortened faster at all loads and generated ~170% greater peak normalized power output. Additionally, the curvature of force-velocity relationships was less, and therefore the relative load optimal for power output ([F.sub.opt]) was greater in [Alpha]-MHC myocytes. [F.sub.opt] was 0.31 [+ or -] 0.03 [P.sub.pCa4.5] and 0.20 [+ or -] 0.06 [P.sub.pCa4.5] for [Alpha]-MHC and [Beta]-MHC myocytes, respectively. These results indicate that MHC expression is a primary determinant of the shape of force-velocity relationships, velocity of loaded shortening, and overall power output-generating capacity of individual cardiac myocytes. cardiac muscle contraction; sarcomere proteins

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 ( DLG1 ) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current ( I to ) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease. NEW & NOTEWORTHY The gene encoding SAP97 ( DLG1 ) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1- encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.