Decrease In Left Ventricular Fractional Shortening Research Articles

β-blocker improves survival, left ventricular function, and myocardial remodeling in hypertensive rats with diastolic heart failure

Chronic beta-blocker therapy improves survival and left ventricular (LV) systolic function in patients with congestive heart failure. However, its efficacy in diastolic heart failure (DHF) with preserved normal LV systolic function remains uncertain. Dahl salt-sensitive hypertensive rats fed a high-salt diet from 7 weeks of age were randomized to groups that were either not treated (DHF; n = 20) or treated with metoprolol (MP) from 7 weeks of age (DHF+7wkMP; n = 22) or from 17 weeks of age (DHF+17wkMP; n = 8). Both LV function and remodeling were evaluated by serial echocardiography, followed by hemodynamic and pathologic studies. Hypertension and pressure-overload LV hypertrophy were established by 17 weeks of age in DHF rats. At about 20 weeks of age DHF rats experienced overt heart failure, which was accompanied not by a decrease in LV fractional shortening but by diastolic filling abnormalities. The LV concentric hypertrophy was strikingly attenuated in DHF+7wkMP rats but not in DHF+17wkMP rats. However, LV myocardial fibrosis and the further progression of diastolic dysfunction were prevented in both MP-treated groups. Survival at 21 weeks of age was significantly improved in DHF+7wkMP (86%) and DHF+17wkMP (75%) rats compared with DHF rats (25%). In this study, MP prevented not only the development of LV hypertrophy but also the progression of diastolic dysfunction, and improved survival in rats with DHF. The preventive effect of MP on myocardial fibrosis is suggested as one of the mechanisms contributing to halt the progression of diastolic dysfunction, a finding that may lead to clinical benefits in regard to DHF caused by hypertension.

Dobutamine Stress Echocardiography in Hypertrophic Cardiomyopathy

Aims: Myocardial ischemia in the absence of coronary artery disease is common in patients with hypertrophic cardiomyopathy (HCM). Dobutamine stress echocardiography (DSE) induces left ventricular (LV) new wall motion abnormalities (NWMA) in some patients with HCM. We evaluated the effects of dobutamine on LV performance and hemodynamics in HCM. Methods and Results: Eighteen patients with non-obstructive HCM underwent DSE. Dobutamine was administered at dosages of 5, 10, 20, 30 and 40 µg/kg/min with increments at intervals of 3 min. Seven patients developed NWMA, whereas the other 11 did not. During DSE, heart rate increased significantly more in NWMA patients,whereas LV outflow tract gradient (OTG) increased significantly and similarly in both groups. At peak dobutamine dose, NWMA patients had a significant increase in LV end-systolic diameter and volume and a significant decrease in LV fractional shortening and ejection fraction. Posterior wall thickening increased significantly, whereas septal thickening did not increase throughout DSE in both groups. Conclusions: In a subgroup of patients with HCM, DSE induces NWMA, associated with a greater increase in heart rate, irrespective of LVOTG. NWMA induce a depression of global LV systolic performance. The septum shows no contractile reserve, regardless of NWMA. These phenomena may be the result of induction of ischemia and/or impaired LV systolic function due to fast heart rate.

Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant–coronary ligation rat model

ObjectivesThe present study investigated the effects of tumor necrosis factor (TNF)-alpha and angiotensin II (ANG II) on cardiac remodeling and dysfunction at the early stage of acute myocardial infarction (MI) by using a novel heterotopic cardiac transplantation–coronary ligation model. BackgroundA recent clinical study has demonstrated a possible role of monocytosis in the development of left ventricular (LV) remodeling in patients with acute MI reperfusion. MethodsWe performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce MI in the donor heart and to evaluate the hearts of both donors and recipients in Lewis rats. ResultsA significant decrease in LV fractional shortening and positive rate of rise in LV pressure and a significant increase in LV end-diastolic dimension/body weight and LV end-diastolic pressure were observed in the recipient hearts in the ligation group on day 7. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group. In contrast, ANG II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Furthermore, the recipients’ transient LV remodeling and dysfunction were completely abolished by the intravenous administration of a TNF-alpha antagonist. ConclusionsWe developed a novel cardiac transplantation–coronary ligation model capable of inducing MI in the absence of downstream hemodynamic effects and allowing differential quantification of indexes of cardiac remodeling in vivo, including the local and remote effects of ANG II and TNF-alpha on cardiac remodeling.

Apoptosis and oncosis in the early progression of left ventricular dysfunction in the cardiomyopathic hamster.

The genetic defect in the cardiomyopathic (CM) hamster is a mutation in the glycoprotein-sarcoglycan (a component of the dystrophin-glycoprotein complex). Apoptosis has been identified in skeletal muscle of dystrophin-deficient mice, and therefore the role of myocardial apoptosis in relation to oncosis in causing myocardial necrosis was assessed at the onset of left ventricular (LV) dysfunction in CM hamsters. LV size and function were evaluated in normal and CM hamsters (CHF147 line) by echocardiography at 1, 2, 3, and 5 months (mo) of age. The decrease of LV fractional shortening was found to be most marked (45%) between 1 and 2 mo of age. Apop totic nuclei were identified at each time point using in situ end-labeling of DNA strand breaks (TUNEL), together with immunolabeling of myocytes; DNA fragmentation (laddering) and nuclear morphology were also assessed. Myocyte oncotic necrosis was assessed at 2 mo by Evans blue dye (EBD), wheat germ agglutinin, hematoxylin/eosin staining, and electron microscopy. Apoptotic nuclei were not detected in age-matched normal hamsters. In the CM hamsters apoptotic myocyte nuclei comprised an average of 0.041% of myocyte nuclei between 1 and 5 mo, an increase at 2 mo (to 0.076%) was not significant, and DNA laddering was not detected. The number of myocyte nuclei per unit area decreased by 32% between 1 and 2 mo, and in 2 mo old CM hamsters myocardial staining with EBD was positive in 9.82% of the myocardial cross sectional areas examined, most of which was consistent with sarcolemmal rupture and oncosis with inflammatory cell infiltration. It is concluded that myocyte oncosis provides the major mechanism for the decreased number of myocyte nuclei and the early decrease of cardiac function between 1 and 2 mo of age in the CM hamster, with only a small contribution of myocyte apoptosis.

An angiotensin-converting enzyme inhibitor improves left ventricular systolic and diastolic function in transfusion-dependent patients with β-thalassemia major

Background Cardiac complications are the major cause of death in patients with β-thalassemia major. The purpose of this study was to assess the impact of long-term treatment with the angiotensin-converting enzyme inhibitor enalapril on left ventricular (LV) performance, with an emphasis on diastolic LV function because diastolic dysfunction has been found to be an early event in an asymptomatic thalassemic population with only mild impairment of LV systolic function. Methods We used echocardiography to study the impact of treatment with oral enalapril on the evolution of standard M-mode and Doppler indices, along with a recently introduced Doppler index of combined systolic and diastolic LV performance. Results Patients were found to have significantly increased LV end-diastolic dimensions (LVEDD), LV end-systolic dimensions (LVESD), and left atrial dimensions and decreased LV fractional shortening (LVFS) compared with controls. After treatment with enalapril, LVESD decreased from 3.58 ± 0.3 cm to 3.23 ± 0.4 cm (P <.01) and LVFS increased from 32.6% ± 4.0% to 38.0% ± 3.1% (P <.001). Patients at baseline were found to have a significantly higher E-wave velocity, E/A ratio, and Doppler index compared with controls. The E-wave deceleration time was significantly shorter compared with that of controls. After treatment with enalapril, the E/A ratio decreased from 2.10 ± 0.42 to 1.50 ± 0.30 (P <.05), E-wave deceleration time increased from 0.12 ± 0.02 seconds to 0.15 ± 0.03 seconds (P <.01), and the Doppler index decreased from 0.46 ± 0.10 to 0.37 ± 0.14 (P <.05). Conclusions Enalapril was well tolerated in asymptomatic or minimally symptomatic patients with LV dysfunction resulting from β-thalassemia major. Echocardiographically we demonstrated significant improvement in LV systolic and diastolic function. Whether this translates to improved long-term prognosis and survival remains to be further evaluated. (Am Heart J 2001;141:e7.)

Dissociation between regional dysfunction and beta-adrenergic receptor signaling in heart failure.

We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered beta-adrenergic receptor (beta-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 +/- 3 days). Heart failure was documented by decreased LV fractional shortening (P < 0.0001) and increased left atrial pressure (P < 0.0001). In heart failure, despite marked differences in basal regional function (percent wall thickening: IVS, 33 +/- 10% vs. PLW, 13 +/- 7%; P = 0.0003), there were no differences between the two regions in beta-AR responsiveness, measured by regional wall thickening in response to dobutamine infusion and any measurement of adrenergic signaling. Adenylyl cyclase activity, beta-AR number, and beta-AR/Gs coupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 +/- 0.20 vs. 0. 12 +/- 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 +/- 0. 15 vs. 0.13 +/- 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.

Growth hormone preserves cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors) and enhances cardiac function in cardiomyopathic hamsters.

Growth hormone (GH) improves cardiac function in experimental models of heart failure and human dilated cardiomyopathy. However, the mechanism by which GH increases myocardial contractility is not entirely clear. Our aim was to examine the effects of GH on cardiac function and cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors, RyR) in the hearts of UM-X7.1 cardiomyopathic hamsters during the development of heart failure. Experimental and healthy control hamsters were examined at the age of 20 weeks. Recombinant human GH (2 mg/kg/day, s.c.) or vehicle was then administered for 3 weeks. We examined (i) the in vivo left ventricular (LV) size and LV systolic function using transthoracic echocardiography, (ii) the density (Bmax) and affinity (Kd) of high-affinity [3H] ryanodine binding sites in crude homogenates from normal and cardiomyopathic hamster hearts. Vehicle-treated UM-X7.1 hamsters exhibited significant increases in left ventricular end-diastolic diameter and end-systolic diameter (LVESd), and a significant decrease in LV fractional shortening (FS). GH-treatment attenuated the increase in LVESd and reduced the LV chamber size, and also significantly increased LVFS. Vehicle-treated UM-X7.1 hamsters exhibited a significantly lower Bmax than control hamsters (0.34 +/- 0.04 vs 0.44 +/- 0.06 pmol/mg, p < 0.05), and the treatment with GH in UM-X7.1 hamsters significantly attenuated the reduction of Bmax (0.42 +/- 0.03 pmol/mg vs vehicle-treated group (0.34 +/- 0.04 pmol/mg), p < 0.05). Kd did not differ significantly between the experimental groups. In normal control hamsters, GH treatment with this dose did not significantly enhance LV systolic function or the density of RyRs. There was no significant difference in terms of the connective-tissue volume-fraction, myocyte size and capillary density between the GH- and vehicle-treated groups of UM-X7.1 hamsters. GH treatment may improve cardiac function by preserving the density of RyRs and enhancing cellular function in cardiomyopathic hamster hearts.

Effects of ryanodine on cardiac contraction, excitation-contraction coupling and “treppe” in the conscious dog

The effects of ryanodine on left ventricular (LV) function and hemodynamics were studied in 16 conscious dogs, chronically instrumented for measurements of LV pressures and dimensions. Systemic infusion of ryanodine (0.5-4 micrograms/kg i.v.) resulted in a dose-dependent depression of cardiac contraction. For example, ryanodine, 4 micrograms/kg i.v., decreased LV fractional shortening by 30.5 +/- 4.1%, LV dP/dt by 41.5 +/- 4.0% and Vcfc by 37.8 +/- 4.1%, while increasing the isovolumic relaxation time constant, tau, from 23.1 +/- 1.4 to 34.1 +/- 3.6 ms without a major effect on preload or afterload. Ryanodine also depressed (P < 0.05) the plateau phase of the mechanical restitution and post-extrasystolic potentiation responses, indicating a direct effect on excitation-contraction coupling. The heart rate dependent positive staircase ("Treppe") was significantly enhanced (P < 0.05) after ryanodine infusion, i.e. LV dP/dt rose by 43.1 +/- 4.7% with an increase in heart rate from 150 to 240 beats/min in the presence of ryanodine 4 micrograms/kg, but by only 7.5 +/- 2.1% without ryanodine. The more pronounced "Treppe" in the conscious dog under the condition of impaired SR calcium release caused by ryanodine, supports the concept that the classical Bowditch "Treppe" reflects either a state of myocardial depression due to alteration in SR calcium handling, or enhanced availability of trans-sarcolemmal Ca2+ influx. This finding may help to understand the discrepancy in the importance of the "Treppe" between conscious animals and more isolated preparations.