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Sphericalization of the left ventricular (LV) chamber shape in patients with mitral regurgitation (MR) contributes to increased LV wall stress and energy consumption. On the basis of previous observations, we hypothesized the existence of regional differences in the force-frequency relation (FFR) within the LV that may contribute to its shape. Accordingly, in the present study, we assessed regional variation in the FFR in patients undergoing surgery for chronic, nonischemic MR with class II-III heart failure symptoms and related our findings to the in vivo LV shape. FFRs (steady-state isometric twitches, 0.2-3.4 Hz, 37[degrees]C) were evaluated in MR myocardium from the LV subepicardial free wall (MR-FW) and papillary muscle (MR-PM) and from the subepicardial free wall in coronary artery bypass graft patients with normal LV contraction patterns [nonfailing (NF)]. Ascending slope, optimal stimulation frequency, and maximal twitch tension of the FFR were depressed in MR-FW and MR-PM compared with NF (P < 0.05). FFR depression was greater in MR-PM than in MR-FW. Between 107 and 134 beats/min, twitch tension became weaker in MR-PM, whereas it increased in MR-FW. Elevation of intracellular cAMP with forskolin eliminated FFR depression in MR-FW but not in MR-PM. MR-PM also had a 35% lower myosin heavy chain content and slowed twitch kinetics. In MR patients, the echocardiographic end-diastolic LV shape (end-diastolic eccentricity index = long axis/short axis) correlated with the ratio of ascending FFR slopes such that the end-diastolic eccentricity index increased 10% per 15% increase in slope ratio (r = 0.88, P = 0.01). These regional differences in the frequency dependence of contractility between the free wall and papillary myocardium may contribute to changes in LV shape in MR as well as during exercise. human myocardium; ventricular function; regional contractility

The kinetic effects of the cardiac myosin point mutations R403Q and R453C, which underlie lethal forms of familial hypertrophic cardiomyopathy (FHC), were assessed using isolated myosin and skinned strips taken from beterozygous (R403Q/+ and R453C/+) male mouse hearts. Compared with wild-type (WT) mice, actin-activated ATPase was increased by 38% in R403Q/+ and reduced by 45% in R453C/+, maximal velocity of regulated thin filament ([V.sub.RTF]) in the in vitro motility assay was increased by 8% in R403Q/+ and was not different in R453C/+, myosin concentration at half-maximal [V.sub.RTF] was reduced by 30% in R403Q/+ and not different in R453C/+, and the characteristic frequency for oscillatory work production (b frequency), determined by sinusoidal analysis in the skinned strip at maximal calcium activation, was 27% lower in R403Q/+ and 18% higher in R453C/+. The calcium sensitivity for isometric tension in the skinned strip was not different in R403Q/+ (p[Ca.sub.50] 5.64 [+ or -] 0.02) and significantly enhanced in R453C/+ (5.82 [+ or -] 0.03) compared with WT (5.58 [+ or -] 0.02). We conclude that isolated myosin and skinned strips of R403Q/+ and R453C/+ myocardium show marked differences in cross-bridge kinetic parameters and in calcium sensitivity of force production that indicate different functional roles associated with the location of each point mutation at the molecular level. myosin heavy chain; ATPase; myosin motility; isometric tension; sinusoidal analysis

Two myosin isoforms are expressed in myocardium, [alpha][alpha]-homodimers ([V.sub.1]) and [beta][beta]-homodimers ([V.sub.3]). [V.sub.1] exhibits higher velocities and myofibrillar ATPase activities compared with [V.sub.3]. We also observed this for cardiac myosin from normal ([V.sub.1]) and propylthiouracil-treated ([V.sub.3]) mice. Actin velocity in a motility assay ([V.sub.actin]) over [V.sub.1] myosin was twice that of [V.sub.3] as was the myofibrillar ATPase. Myosin's average force ([F.sub.avg]) was similar for [V.sub.1] and [V.sub.3]. Comparing [V.sub.actin] and [F.sub.avg] across species for both [V.sub.1] and [V.sub.3], our laboratory showed previously (VanBuren P, Harris DE, Alpert NR, and Warshaw DM. Circ Res 77: 439-444, 1995) that mouse [V.sub.1] has greater [V.sub.actin] and [F.sub.avg] compared with rabbit [V.sub.1]. Mouse [V.sub.3] [V.sub.actin] was twice that of rabbit [V.sub.actin]. To understand myosin's molecular structure and function, we compared [alpha]- and [beta]-cardiac myosin sequences from rodents and rabbits. The rabbit [alpha]- and [beta]-cardiac myosin differed by eight and four amino acids, respectively, compared with rodents. These residues are localized to both the motor domain and the rod. These differences in sequence and mechanical performance may be an evolutionary attempt to match a myosin's mechanical behavior to the heart's power requirements. contractile proteins; heart; motility assay; molecular motor

Alteration of troponin T (TnT) isoform expression has been reported in human and animal models of myocardial failure. The two adult beef cardiac TnT isoforms (Tn[T.sub.3] and Tn[T.sub.4]) were isolated for comparative functional analysis. Thin filaments were reconstituted containing pure populations of the isoforms. The in vitro motility assay was used to directly compare the effect of the two TnT isoforms on force and unloaded shortening as a function of free calcium. We found no significant differences between the two isoforms in terms of calcium sensitivity, cooperativity, or maximal activation (velocity and force) as assessed in a fully calcium-regulated system. Activation by myosin strong binding was similar for thin filaments containing either of the two TnT isoforms. Whereas maximally activated velocity and cooperativity was depressed at pH 6.5, no difference between thin filaments containing the two isoforms was detected. From the small magnitude of the TnT isoform shifts detected in myocardial failure and the lack of significant mechanical effect detected in the motility assay, variable TnT isoform expression is unlikely to be any functional significance in heart failure. thin filament; myocardial failure; in vitro motility

Analysis of the expression of Ca2+-release channel, phospholamban, calsequestrin and cardiac slow-twitch muscle Ca2+-ATPase (SERCA2a) protein in pressure overload (PO) rabbit hearts reveals a decrease in the mRNA levels that encode SERCA2a, phospholamban and cardiac ryanodine receptor after 2 days of PO. Ca2+-ATPase protein, ATPase phosphoenyzme and ATP-dependent Ca2+ uptake also reduce due to PO. Thus, PO hypertrophy modulates the release of SRCa2+ and uptake of Ca2+ in the rabbit hearts.