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The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg*[kg.sup.-l]*[day.sup.-1] ramipril (n = 10) or vehicle (n = 11) treatment for 4 wk. Sham animals (n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 [+ or -] 0.7 vs. 3.2 [+ or -] 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 [+ or -] 0.7, P < 0.01 and 2.9 [+ or -] 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH. Rho kinase; hypertrophy; fibrosis; pressure overload; hypertension; diastolic function; myocardium

Titin, a giant protein spanning half the sarcomere, is responsible for passive and restoring forces in cardiac myofilaments during sarcomere elongation and compression, respectively. In addition, titin has been implicated in the length-dependent activation that occurs in the stretched sarcomere, during the transition from diastole to systole. The purpose of this study was to investigate the role of titin in the length-dependent deactivation that occurs during early diastole, when the myocyte is shortened below slack length. We developed a novel in vitro assay to assess myocyte restoring force (RF) by measuring the velocity of recoil in Triton-permeabilized, unloaded rat cardiomyocytes after rigor-induced sarcomere length (SL) contractions. We compared rigor-induced SL shortening to that following calcium-induced (pCa) contractions. The RF-SL relationship was linearly correlated, and the SL-pCa curve displayed a characteristic sigmoidal curve. The role of titin was defined by treating myocytes with a low concentration of trypsin, which we show selectively degrades titin using mass spectroscopic analysis. Trypsin treatment reduced myocyte RF as shown by a decrease in the slope of the RF-SL relationship, and this was accompanied by a downward and leftward shift of the SL-pCa curve, indicative of sensitization of the myofilaments to calcium. In addition, trypsin digestion did not alter the relationship between SL and interfilament spacing (assessed by cell width) after calcium activation. These data suggest that as the sarcomere shortens below slack length, titin-based restoring forces act to desensitize the myofilaments. Furthermore, in contrast to length-dependent activation at long SLs, length-dependent deactivation does not depend on interfilament spacing. This study demonstrates for the first time the importance of titin-based restoring force in length-dependent deactivation during the early phase of diastole. KEY WORDS: connectin * restoring force * skinned myocyte * length-dependent deactivation * titin

Mechanisms of make and break excitation revisited: paradoxical break excitation during diastolic stimulation. Am J Physiol Heart Circ Physiol 282: H565-H575, 2002; 10.1152/ajpheart.00544.2001. Onset and termination of electric stimulation may result in 'make' and 'break' excitation of the heart tissue. Wikswo et al. (30) explained both types of stimulations by virtual electrode polarization. Make excitation propagates from depolarized regions (virtual cathodes). Break excitation propagates from hyperpolarized regions (virtual anodes). However, these studies were limited to strong stimulus intensities. We examined excitation during weak near-threshold diastolic stimulation. We optically mapped electrical activity from a 4 x 4-mm area of epicardium of Langendorff-perfused rabbit hearts (n = 12) around the pacing electrode in the presence (n = 12) and absence (n = 2) of 15 mM 2,3-butanedione monoxime. Anodal and cathodal 2-ms stimuli of various intensities were applied. We imaged an excitation wavefront with 528-[micro]s resolution. We found that strong stimuli (x5 threshold) result in make excitation, starting from the virtual cathodes. In contrast, near-threshold stimulation resulted in break excitation, originating from the virtual anodes. Characteristic biphasic up-strokes in the virtual cathode area were observed. Break and make excitation represent two extreme cases of near-threshold and far-above-threshold stimulations, respectively. Both mechanisms are likely to contribute during intermediate clinically relevant strengths. optical mapping; virtual electrode; pacing

Myofilament properties comprise the rate-limiting step for cardiac relaxation at body temperature in the rat. Am J Physiol Heart Circ Physiol 282: H499-H507, 2002; 10.1152/ajpheart.00595.2001.--The majority of studies aimed at characterizing basic contractile mechanisms have been conducted at room temperature. To elucidate the mechanism of cardiac relaxation under more physiological conditions, we investigated contractile function and calcium handling in ultrathin rat cardiac trabeculae. Active developed tension was unaltered between 22.5 and 30.0 [degrees] C (from 89 [+ or -] 10 to 86 [+ or -] 11 mN/[mm.sup.2], P = not significant) but steeply declined at 37.5 [degrees] C (30 [+ or -] 5 mN/[mm.sup.2]). Meanwhile, the speed of relaxation (time from peak force to 50% relaxation) declined from 22.5 to 30.0 [degrees] C (from 360 [+ or -] 40 to 157 [+ or -] 17 ms) and further declined at 37.5 [degrees] C to 76 [+ or -] 13 ms. Phase-plane analysis of calcium versus force revealed that, with increasing temperature, the relaxation phase is shifted rightward, indicating that the rate-limiting step of relaxation tends to depend more on calcium kinetics as temperature rises. The force-frequency relationship, which was slightly negative at 22.5 [degrees] C (0.1 vs. 1 Hz: 77 [+ or -] 12 vs. 66 [+ or -] 7 mN/[mm.sup.2]), became clearly positive at 37.5 [degrees] C (1 vs. 10 Hz: 30 [+ or -] 5 vs. 69 [+ or -] 9 mN/[mm.sup.2]). Phase-plane analyses indicated that, with increasing frequency, the relaxation phase is shifted leftward. We conclude that temperature independently affects contraction and relaxation, and cross-bridge cycling kinetics become rate limiting for cardiac relaxation under experimental conditions closest to those in vivo. calcium; iontophoresis; fura 2; contraction; force-frequency

Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol 282: H138-H148, 2002.--To gain insight into the pathogenesis of diabetic cardiomyopathy, we investigated cardiac function in terms of the coupling of left ventricular mechanical work and the energetics in Otsuka Long-Evans Tokushima Fatty rats, which are well known as a model of type 2 diabetes mellitus (DM). Neither left ventricular systolic function and mean coronary flow nor coronary flow reserve differed even in late DM rats. The amount of oxygen required for mechanical work and contraction was unaltered, although myosin isozyme was finally transformed from [V.sub.1] to [V.sub.3]. The maximum pacing rate was decreased from 300 to 240 beats/min, and the left ventricular relaxation rate was significantly (P < 0.05) slower only in late DM rats, resulting in decreased oxygen consumption per minute for total [Ca.sup.2+] handling in excitation-contraction coupling mainly consumed by sarco(endo)plasmic reticulum [Ca.sup.2+]-ATPase (SERCA2) without significant changes in basal metabolism or in mitochondrial oxidative phosphorylation. The protein level of SERCA2 in membranes was significantly (P < 0.001) lower in severe DM rats. We conclude that the only lusitropic dysfunction due to the depressed expression of SERCA2 is related to generating diabetic cardiomyopathy even in the present type 2 diabetic rats. oxygen consumption; sarcoplasmic reticulum [Ca.sup.2+]-ATPase

Byline: J. Meliones (1), K. Kocis (2), A. R. Bengur (3), A. R. Snider (3) Keywords: Key words Cardiopulmonary interactions; Congenital heart disease; D-transposition of the great arteries; Diastolic function; Doppler ultrasonography; Inspiratory time Abstract: Author Affiliation: (1) Department of Anesthesia, Duke Children's Hospital, P. O. Box 3046, Duke University Medical Center, Durham, NC 27710--0001, USA e-mail: melio001@mc.duke.edu Tel.: + 1-9 19-6 81 64 03 Fax: + 1-9 19-6 18 83 57, US (2) Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Mich., USA, US (3) Department of Pediatrics, Duke Children's Hospital, Duke University Medical Center, Durham, NC 27710--0001, USA, US Article note: Received: 27 July 1999/Final revision received: 21 January 2000/Accepted: 26 January 2000

The role of angiotensin II in the pathogenesis of diastolic dysfunction in pressure overloaded left ventricular (LV) hypertrophy is investigated by evaluating the effects of angiotensin converting enzyme (ACE) inhibition and angiotensin receptor blockade on diastolic relaxation in dogs. Results show that LV unloading prolonged the diastolic relaxation in hypertrophied hearts. This prolongation is inhibited by both ACE inhibition and receptor blockade.

Research suggests that left ventricular isovolumic relaxation is influenced by ejection in different ways. Positive and negative inotropic effects are observed. Experiments using isolated adult male rabbit hearts are described. Left ventricular pressure and volume measurements are reported in relation to active stress and isovolumic relaxation time.

A study was conducted to determine the early and late effects of myocardial infarction on left ventricular (LV) diastolic function in the rabbit postinfarction model. Random ligation of the circumflex artery or sham operation were performed. The findings indicate that coronary artery ligation in the rabbit provides a reproducible echocardiographic and Doppler model of LV diastolic function consistent with abnormalities seen in humans who suffered from previous myocardial infarction, symptoms of heart failure and preserved LV systolic function.

The relationship between ventricular pacing and postpacing changes in diastolic function during repolarization was analyzed in elderly humans. Analysis of cardiac memory in elderly humans indicated the occurrence of postventricular pacing-related changes in cardiac diastolic function. Mechanical cardiac memory was also mediated by diastolic electromechanical coupling during alterations in diastolic function due to prolonged periods of ventricular pacing.

Restoring forces generated in the left ventricle (LV) of the heart during contraction were quantified by measuring left ventricular pressure (LVP) during diastoles produced by a servomotor system. Left atrial pressure clamping increased the rate of LVP reduction as compared to the normal decline of LVP. It was concluded that restoring forces produced when the LV contracts below its equilibrium volume are present during low end-diastolic pressure.

Examination of the influence of preload reduction on the peak length-tension relation and on physiologically sequenced isometric force decline in isolated mammalian cardiac muscles reveals that preload affects both resting and peak length-tension relation, along with the timing and rate of force decline. Acute preload reduction stimulates an earlier initiation and faster rate of force decline, while prolonged force reduction exerts no influence on force decline. Modulation in isometric force decline due to preload is smaller than due to systolic load.

Examination of the influence of isoproterenol on peak rate of force decline in rat left ventricular papillary muscle as a function of two sequences of relaxation, isotonic-isometric sequence and isometric-isotonic sequence, reveals that loading patterns exhibit a significant influence on the relaxation effects of isoproterenol. The modulation of myocardial relaxation rate induced by isoproterenol depends on the muscle length, both before the contraction phase and at the initiation of isometric relaxation.

Greater differentiation in diagnosis and treatment of congestive heart failure needs to be made between patients with left ventricular (LV) systolic dysfunction and those with LV diastolic dysfunction. The heart has two ventricles. Systolic dysfunction is the inability of the ventricle to properly pump blood into the arteries. Diastolic dysfunction describes an impairment in filling of the ventricle with blood between heart contractions. Treatment for systolic dysfunction focuses on increasing the ventricle's contractibility to increase ejection pressure. Treatment for diastolic dysfunction focuses on slowing the heart rate to allow for proper filling at lower pressures. Patients with significant LV systolic dysfunction benefit from treatment whether or not they have symptoms of congestive heart failure. Mortality is lower among patients with diastolic dysfunction than among those with systolic dysfunction., Data from large and small clinical trials reflect major differences in the pathophysiology, treatment, and prognosis of left ventricular (LV) systolic and diastolic dysfunction. These studies also indicate that medical therapy can benefit patients with LV dysfunction regardless of whether or not they are symptomatic. Because the descriptive term congestive heart failure does not provide for these important distinctions, a new classification of LV dysfunction has been developed in which patients with LV dysfunction are categorized on the basis of normal or abnormal systolic function. This classification is based on a simple assessment of LV function, it is applicable to patients without symptoms, and it reflects differences in treatment and prognosis. Those with clinically significant LV systolic dysfunction (ie, an LV ejection fraction

Recovery of myocardial functions after repetitive, reversible myocardial ischemia and a single episode ischemia were compared in dogs. The specimens were subjected to a single 15 min left occlusion of the left anterior descending coronary artery and two 15 min occlusions with a one hour period of perfusion in between. Postischemic myocardial creep resolved within four hours after the single episode ischemia. Double occlusion prevented recovery during reperfusion suggesting that myocardial creep and stunning contributes to the delay in recovery.

Heart failure is the inability of the heart to meet the demands placed upon it. Congestive heart failure is such an important type of heart failure that the two terms are sometimes used interchangeably. The primary defect in congestive heart failure may lie either in the systole, the contraction of the ventricles, or in the diastole, the ventricular relaxation. In primary systolic failure, the contraction of the ventricles may fail to expel a sufficient quantity of blood into the arterial system, resulting in backing up of blood in the lungs and the venous system. In primary diastolic failure, the filling of the ventricles by blood in preparation for the next systole may be inadequate. Although most cases of congestive heart failure involve some degree of abnormal diastolic function, in as many as 40 percent of cases the systole is normal and the defect lies in the in the diastole. The author provides a detailed review of the underlying physiological mechanisms of diastolic heart failure as well as some insights into pathological mechanisms occurring at the molecular level. Diastolic failure may result from structure damage such as constrictive pericarditis, which impedes the flow of blood into the ventricles during their relaxation. The abnormalities may also be physiological. For example, the ability of the heart muscle to relax may be impaired. Ventricular hypertrophy is common among patients with heart failure. Damaged heart muscle often responds to the workload by increasing in size; this hypertrophy can result in both structural alterations that impede blood flow and also to impaired relaxation. Some of the pathological effects observed in congestive heart failure may be the result of altered expression of ion pumps in the membranes of individual heart muscle cells themselves. (Consumer Summary produced by Reliance Medical Information, Inc.)