Excitation-contraction coupling in isolated myocardium from dogs with compensated left ventricular hypertrophy

To examine the relationship between left ventricular (LV) function and intracellular calcium modulation in the presence of myocyte hypertrophy, we compared LV muscles from nine dogs with compensated LV hypertrophy (LVH) induced by chronic aortic banding with 11 controls. Mechanical properties were studied in LV muscles (control, n = 25; LVH, n = 23) stretched to the length at which maximal isometric tension developed at 30 degrees C and stimulated at 0.33 Hz; a subset of LVH muscles was loaded with the intracellular calcium indicator aequorin. In LV myocardium from dogs with compensated LVH, both the contraction duration and calcium transients were prolonged at baseline, and the response to phosphodiesterase inhibitors was impaired in keeping with findings in both human and experimental models of pressure-overload hypertrophy and failure. However, in contrast to findings in the failing myocardium, the positive inotropic response to increasing intracellular calcium was preserved in myocardium from dogs with compensated LVH.

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Abstract 16422: Lower Mitochondrial-derived Peptide Humanin in Young Adults Born Preterm vs. Term and Association With Left Ventricular Ejection Fraction

Circulation ◽

10.1161/circ.142.suppl_3.16422 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Daniela Ravizzoni Dartora ◽

Adrien Flahualt ◽

Carolina Nobre Pontes ◽

Gabriel Altit ◽

Alyson Deprez ◽

...

Keyword(s):

Young Adults ◽

Ejection Fraction ◽

Experimental Models ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Lv Function ◽

Ventricular Ejection Fraction ◽

Mitochondrial Alterations ◽

Increased Risk

Introduction: Preterm (PT) birth is associated with increased risk of cardiovascular diseases (CVD) and heart failure. We previously reported left ventricular (LV) mitochondrial dysfunction in a rat model mimicking the deleterious conditions associated with PT birth. Whether mitochondrial function is altered in humans born PT and associated with LV function changes is unknown. We aimed to determine if serum humanin levels, a mitochondrial-derived peptide with cytoprotective effects, are altered in humans born PT and are associated with impaired myocardial function. Methods: Data were obtained from 55 young adults born PT (<30 weeks of gestational age, GA) compared to 54 full-term (T) controls of the same age. Serum humanin levels were determined by ELISA and LV ejection fraction (LVEF) by echocardiography. Results are shown as median (interquartile range) and comparisons between groups were performed using non-parametric tests. Results: Individuals were evaluated at 23.3 (21.4, 25.3) years, and age and sex distribution were similar between groups. Median GA was 27.5 (26.2, 28.4) weeks in the PT group. Humanin levels (pg/ml) were 132.9 (105.1, 189.3) and 161.1 (123.6, 252) in the PT and the T groups, respectively (p=0.0414). LVEF was within the normal range and similar between groups. Lower LVEF was associated with lower humanin levels (p<0.001), and this association was observed both in the term (p=0.002) and the preterm (p=0.047) groups. Conclusions: Serum humanin levels are lower in adult born PT. Since lower humanin levels are also associated with lower LVEF, our results suggest that mitochondrial alterations could play a role in the long-term adverse cardiovascular consequences of PT birth. Humanin analogs improve LV function in experimental models. Our results pave the way for future studies exploring humanin as a therapeutic avenue for the prevention and treatment of CVD in individuals born PT.

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Role of sarcoplasmic reticulum in loss of load-sensitive relaxation in pressure overload cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.1.h68 ◽

1994 ◽

Vol 266 (1) ◽

pp. H68-H78 ◽

Cited By ~ 1

Author(s):

C. R. Cory ◽

R. W. Grange ◽

M. E. Houston

Keyword(s):

Sarcoplasmic Reticulum ◽

Cardiac Hypertrophy ◽

Atpase Activity ◽

Pressure Overload ◽

Fold Increase ◽

Left Ventricular ◽

Isometric Tension ◽

Tension Development ◽

Sequestration Potential

The loss of load-sensitive relaxation observed in the pressure-overloaded heart may reflect a strategy of slowed cytosolic Ca2+ uptake to yield a prolongation of the active state of the muscle and a decrease in cellular energy expenditure. A decrease in the potential of the sarcoplasmic reticulum (SR) to resequester cytosolic Ca2+ during diastole could contribute to this attenuated load sensitivity. To test this hypothesis, both in vitro mechanical function of anterior papillary muscles and the SR Ca2+ sequestration potential of female guinea pig left ventricle were compared in cardiac hypertrophy (Hyp) and sham-operated (Sham) groups. Twenty-one days of pressure overload induced by coarctation of the suprarenal, subdiaphragmatic aorta resulted in a 36% increase in left ventricular mass in the Hyp. Peak isometric tension, the rate of isometric tension development, and the maximal rates of isometric and isotonic relaxation were significantly reduced in Hyp. Load-sensitive relaxation were significantly reduced in Hyp. Load-sensitive relaxation quantified by the ratio of a rapid loading to unloading force step in isotonically contracting papillary muscle was reduced 50% in Hyp muscles. Maximum activity of SR Ca(2+)-adenosinetriphosphatase (ATPase) measured under optimal conditions (37 degrees C; saturating Ca2+) was unaltered, but at low free Ca2+ concentrations (0.65 microM), it was decreased by 43% of the Sham response. Bivariate regression analysis revealed a significant (r = 0.84; P = 0.009) relationship between the decrease in SR Ca(2+)-ATPase activity and the loss of load-sensitive relaxation after aortic coarctation. Stimulation of the SR Ca(2+)-ATPase by the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase resulted in a 2.6-fold increase for Sham but only a 1.6-fold increase for Hyp. Semiquantitative Western blot radioimmunoassays revealed that the changes in SR Ca(2+)-ATPase activity were not due to decreases in the content of the Ca(2+)-ATPase protein or phospholamban. Our data directly implicate a role for decreased SR function in attenuated load sensitivity. A purposeful downregulation of SR Ca2+ uptake likely results from a qualitative rather than a quantitative change in the ATPase and possibly one of its key regulators, phospholamban.

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Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis

Circulation ◽

10.1161/circ.142.suppl_3.14952 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Mihály Ruppert ◽

Christian Karime ◽

Alex A Sayour ◽

Attila Oláh ◽

Dávid Nagy ◽

...

Keyword(s):

Heart Failure ◽

Systolic Function ◽

Pressure Overload ◽

Volume Overload ◽

Detailed Comparison ◽

Left Ventricular ◽

Lv Function ◽

Arterial Elastance ◽

Lv Remodeling ◽

Av Shunt

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.

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Myocardial mechanical alterations during gradual onset long-term hypertension in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1981.241.3.h435 ◽

1981 ◽

Vol 241 (3) ◽

pp. H435-H441 ◽

Cited By ~ 2

Author(s):

J. M. Capasso ◽

J. E. Strobeck ◽

E. H. Sonnenblick

Keyword(s):

Blood Pressure ◽

Pressure Overload ◽

Left Ventricular ◽

Isometric Tension ◽

Left Renal Artery ◽

Ventricular Performance ◽

Time To Peak ◽

Gradual Onset ◽

Significant Depression ◽

Female Wistar Rats

Although a suddenly produced load leads to depressed myocardial contractility, the effects of a slowly induced physiological overload have not been defined. Therefore, a more gradual pressure overload was produced in female Wistar rats by hypertension due to constriction of the left renal artery. Hypertension (systolic blood pressure greater than or equal to 150 mmHg) developed within 3 wk, and blood pressure continued to increase for the next 5 wk. Heart weights in hypertensive animals were elevated by 34% after the onset of hypertension. Isometric and isotonic contractions from left ventricular papillary muscles were recorded at 5, 10, 20, and 30 wk after the onset of hypertension. Total and actively developed isometric tension at all initial muscle lengths were significantly greater in hypertensive animals throughout the 30-wk period. Time to peak tension and time to half relaxation were significantly prolonged. Force-velocity curves demonstrated a significant depression in velocity of shortening at all relative loads in hypertensive muscles that progressed with the duration of hypertension. These studies suggest that myocardial hypertrophy may impart the ability to maintain ventricular performance in terms of force development while speed of shortening decays.

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Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aortic-constricted rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00744.2002 ◽

2003 ◽

Vol 94 (4) ◽

pp. 1627-1633 ◽

Cited By ~ 15

Author(s):

Beatriz S. Scopacasa ◽

Vicente P. A. Teixeira ◽

Kleber G. Franchini

Keyword(s):

Diastolic Pressure ◽

Systolic Pressure ◽

Pressure Overload ◽

Colchicine Treatment ◽

Average Diameter ◽

Left Ventricular ◽

Lv Function ◽

Right Ventricular Mass ◽

Lv Mass ◽

Phenylephrine Infusion

To investigate the effects of colchicine on left ventricular (LV) function and hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC), we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine 0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC, colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between LV mass (LVM) and right ventricular mass, LV wall thickness, and average diameter of cardiac myocytes. Systolic gradient across TAoC (∼45 mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure increase (+dP/d t) were comparable in TAoC-T and TAoC rats. However, the baseline and increases of LV systolic pressure-to-LVM and +dP/d t-to-LVMratios induced by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats. Baseline and increases of +dP/d t-to-LVM ratio were reduced in TAoC compared with SO rats. TAoC rats increased polymerized fraction of tubulin compared with SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced LVH to pressure overload but preserved LV function.

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Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00063.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. H752-H761 ◽

Cited By ~ 7

Author(s):

William M. Yarbrough ◽

Catalin Baicu ◽

Rupak Mukherjee ◽

An Van Laer ◽

William T. Rivers ◽

...

Keyword(s):

Pressure Overload ◽

Left Ventricular ◽

Lv Function ◽

Type I ◽

Matrix Remodeling ◽

Protective Effects ◽

Ecm Remodeling ◽

Hypertrophic Response ◽

Lv Mass ◽

And Function

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

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Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart

Circulation ◽

10.1161/circ.132.suppl_3.17904 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Jaemin Byun ◽

Dominic P Del Re ◽

Peiyong Zhai ◽

Akihiro Shirakabe ◽

Junichi Sadoshima

Keyword(s):

Cardiac Hypertrophy ◽

Mammalian Cells ◽

Diastolic Pressure ◽

Systolic Function ◽

Pressure Overload ◽

Wall Stress ◽

Left Ventricular ◽

Lv Function ◽

Mouse Heart ◽

And Control

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p<0.05) and TAC-control mice (75%, p<0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p<0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p<0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p<0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p<0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.

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Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

Circulation Research ◽

10.1161/res.121.suppl_1.87 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Jenna C Edwards ◽

Madeleine Dionne ◽

T. D Olver ◽

Jan R Ivey ◽

Pamela K Thorne ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Function ◽

Strain Rate ◽

Pressure Overload ◽

Left Ventricular ◽

Volume Index ◽

Lv Function ◽

Swine Model ◽

Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

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Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽

10.1161/circ.132.suppl_3.16434 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Lin Zhao ◽

Guangming Cheng ◽

Yanjuan Yang ◽

Anweshan Samanta ◽

Rizwan R Afzal ◽

...

Keyword(s):

Therapeutic Potential ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Lv Function ◽

Ang Ii ◽

Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

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GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01042.2004 ◽

2005 ◽

Vol 289 (4) ◽

pp. H1643-H1651 ◽

Cited By ~ 53

Author(s):

Xiang-Bin Xu ◽

Jin-Jiang Pang ◽

Ji-Min Cao ◽

Chao Ni ◽

Rong-Kun Xu ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Pressure Overload ◽

Chronic Administration ◽

Posterior Wall ◽

Left Ventricular ◽

Cardiomyocyte Apoptosis ◽

Lv Function ◽

Cardiac Cachexia

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 μg/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.

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