Abstract 33: Contractile Dysfunction In The Mouse Heart Caused By Phospholipase C beta1b Mediated Activation Of Protein Kinase Calpha

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
David R Grubb ◽  
Yi Ma ◽  
Jieting Luo ◽  
Bryony Crook ◽  
Nicola Cooley ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Contractile Dysfunction ◽  
Functional Responses ◽  
Rat Cardiomyocytes

The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is elevated in diseased myocardium and activity increases with disease progression. PLCβ1b and the alternative splice variant, PLCβ1a, were expressed in mouse hearts using adeno-associated viral constructs (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG- PLCβ1a) delivered intravenously. Functional responses were assessed in vivo and confirmatory mechanistic studies were conducted in neonatal rat ventricular myocytes (NRVM). FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart, but was highest in left ventricle, where expression was observed in >90% of the cells and was localized to the sarcolemma and T-tubules. Heightened PLCβ1b expression caused a rapid loss of contractility and down-regulation of Phospholamban expression. The loss of contractility induced by PLCβ1b was reversed by inhibition of protein kinase Cα (PKCα). PLCβ1a did not affect contractile function or phospholamban expression. Mechanistic analysis performed in neonatal rat cardiomyocytes confirmed PLCβ1b increased the membrane association of PKCα as well as downstream dephosphorylation of phospholamban and depletion of the Ca2+ stores of the sarcoplasmic reticulum, both of which were mediated by PKCα. Trans-aortic constriction (TAC) resulted in progressive hypertrophy together with reduced contractility in PLCβ1a expressing mice. In PLCβ1b-expressing mice, TAC induced a similar hypertrophic response, but did not cause further contractile depression above that due to PLCβ1b expression alone, suggesting that PLCβ1b is responsible for lowering contractility in response to pressure overload. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b is a cardiac-specific signaling system, and thus provides an ideal therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium.

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

scholarly journals Loss of Protein Kinase Novel 1 (PKN1) is associated with mild systolic and diastolic contractile dysfunction, increased phospholamban Thr17 phosphorylation, and exacerbated ischaemia-reperfusion injury

2017 ◽  
Vol 114 (1) ◽  
pp. 138-157 ◽  
Author(s):  
Asvi A Francois ◽  
Kofo Obasanjo-Blackshire ◽  
James E Clark ◽  
Andrii Boguslavskyi ◽  
Mark R Holt ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Cell Injury ◽  
Contractile Function ◽  
Myocardial Infarct ◽  
Neonatal Rat ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion ◽  
Sirna Knockdown

Abstract Aims PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection. Methods and results Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischaemia and reperfusion (I/R). Myocardial infarct size was doubled in PKN1 KO hearts compared to WT hearts. PKN1 was basally phosphorylated on the activation loop Thr778 PDK1 target site which was unchanged during I/R. However, phosphorylation of p42/p44-MAPK was decreased in KO hearts at baseline and during I/R. In cultured neonatal rat ventricular cardiomyocytes (NRVM) and NRVM transduced with kinase dead (KD) PKN1 K644R mutant subjected to simulated ischaemia/reperfusion (sI/R), PhosTag® gel analysis showed net dephosphorylation of PKN1 during sI and early R despite Thr778 phosphorylation. siRNA knockdown of PKN1 in NRVM significantly decreased cell survival and increased cell injury by sI/R which was reversed by WT- or KD-PKN1 expression. Confocal immunofluorescence analysis of PKN1 in NRVM showed increased localization to the sarcoplasmic reticulum (SR) during sI. GC-MS/MS and immunoblot analysis of PKN1 immunoprecipitates following sI/R confirmed interaction with CamKIIδ. Co-translocation of PKN1 and CamKIIδ to the SR/membrane fraction during sI correlated with phospholamban (PLB) Thr17 phosphorylation. siRNA knockdown of PKN1 in NRVM resulted in increased basal CamKIIδ activation and increased PLB Thr17 phosphorylation only during sI. In vivo PLB Thr17 phosphorylation, Sarco-Endoplasmic Reticulum Ca2+ ATPase (SERCA2) expression and Junctophilin-2 (Jph2) expression were also basally increased in PKN1 KO hearts. Furthermore, in vivo P-V loop analysis of the beat-to-beat relationship between rate of LV pressure development or relaxation and end diastolic P (EDP) showed mild but significant systolic and diastolic dysfunction with preserved ejection fraction in PKN1 KO hearts. Conclusion Loss of PKN1 in vivo significantly reduces endogenous cardioprotection and increases myocardial infarct size following I/R injury. Cardioprotection by PKN1 is associated with reduced CamKIIδ-dependent PLB Thr17 phosphorylation at the SR and therefore may stabilize the coupling of SR Ca2+ handling and contractile function, independent of its kinase activity.

Abstract 16870: Dissociation of Mitochondrial HK-II Triggers Mitochondria Specific Autophagy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shigeki Miyamoto ◽  
David J Roberts ◽  
Valerie P Tan-Sah
Keyword(s):  
Energy Production ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Hexokinase Ii ◽  
Survival Pathway ◽  
Mitochondrial Membrane Depolarization ◽  
Neonatal Rat Ventricular Myocytes

Introduction: There is emerging evidence that the metabolic pathway interplays with the survival pathway to preserve cellular homeostasis. Hexokinases (HKs) catalyze the first step of glucose metabolism and hexokinase-II (HK-II) is the predominant isoform in the heart. Our recent study revealed that HK-II positively regulates general autophagy in the absence of glucose. Mitochondrial HK-II (mitoHK-II) is regulated by Akt and provides cardioprotection while it is decreased in the ischemic heart. Hypothesis: We tested the hypothesis that mitoHK-II dissociation triggers mitochondria specific autophagy (mitophagy). Results: As previously reported, mitoHK-II levels were decreased by ~40% in the perfused mouse heart subjected to global ischemia and in neonatal rat ventricular myocytes (NRVMs) subjected to simulated ischemia. To assess the role of mitoHK-II dissociation, mitoHK-II dissociating peptide (15NG) was expressed in NRVMs. MitoHK-II was decreased by 40% in NRVMs expressing 15NG which was accompanied with Parkin translocation to mitochondria and ubiquitination of mitochondrial proteins. This response was attenuated by Parkin knockdown and reversed by the recovery of mitoHK-II by co-expression of HK-II but not by that of mitochondria binding deficient mutant. 15NG expression did not induce mitochondrial membrane depolarization nor PINK1 stabilization at mitochondria, suggesting that the effects of mitoHK-II dissociation is not dependent on the previously established mitochondria depolarization/PINK1 pathway. This was confirmed by the experiments using PINK1 siRNA. Modest dissociation of mitoHK-II (by 20%) did not induce mitophagic responses but remarkably enhanced FCCP induced mitophagy, indicating that these two pathways are synergetic. We will be analyzing 15NG transgenic mice generated in our lab to determine the mitophagic role of mitoHK-II dissociation in vivo. Conclusions: These results suggest that mitoHK-II dissociation can regulate Parkin dependent mitophagy, in conjunction with depolarization dependent mechanisms and that HK-II could confer cardioprotection by switching the cell from an energy production to an energy conservation mode under ischemia.

A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart

2008 ◽  
Vol 294 (5) ◽  
pp. H2231-H2241 ◽  
Author(s):  
Guangmao Cheng ◽  
Michael R. Zile ◽  
Masaru Takahashi ◽  
Catalin F. Baicu ◽  
D. Dirk Bonnema ◽  
...  
Keyword(s):  
Contractile Function ◽  
Pressure Overload ◽  
Network Density ◽  
Contractile Dysfunction ◽  
Microtubule Network ◽  
Microtubule Stability ◽  
Hypertrophied Myocardium ◽  
Direct Support

Contractile dysfunction in pressure overload-hypertrophied myocardium has been attributed in part to the increased density of a stabilized cardiocyte microtubule network. The present study, the first to employ wild-type and mutant tubulin transgenes in a living animal, directly addresses this microtubule hypothesis by defining the contractile mechanics of the normal and hypertrophied left ventricle (LV) and its constituent cardiocytes from transgenic mice having cardiac-restricted replacement of native β4-tubulin with β1-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac β4-tubulin with mutant hemagglutinin-tagged β1-tubulin was well tolerated in vivo. When LVs in intact mice and cardiocytes from these same LVs were examined in terms of contractile mechanics, baseline function was reduced in mice with genetically hyperstabilized microtubules, and hypertrophy-related contractile dysfunction was exacerbated. However, in mice with genetically hypostabilized cardiac microtubules, hypertrophy-related contractile dysfunction was ameliorated. Thus, in direct support of the microtubule hypothesis, we show here that cardiocyte microtubule network density, as an isolated variable, is inversely related to contractile function in vivo and in vitro, and microtubule instability rescues most of the contractile dysfunction seen in pressure overload-hypertrophied myocardium.

scholarly journals Osteocrin, a novel myokine, prevents diabetic cardiomyopathy via restoring proteasomal activity

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xin Zhang ◽  
Can Hu ◽  
Xiao-Pin Yuan ◽  
Yu-Pei Yuan ◽  
Peng Song ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Injury ◽  
Neonatal Rat ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Proteasomal Activity ◽  
Virus Serotype

AbstractProteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.

scholarly journals Cardiomyocyte-Specific RIP2 Overexpression Exacerbated Pathologic Remodeling and Contributed to Spontaneous Cardiac Hypertrophy

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing-jing Yang ◽  
Nan Zhang ◽  
Zi-ying Zhou ◽  
Jian Ni ◽  
Hong Feng ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cardiac Remodeling ◽  
Specific Inhibitor ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Hek293 Cells ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo. Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro. The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling.

Abstract 419: Stim1 is Associated With Calcium Microdomains That are Required for Myofilament Remodeling and Signaling During Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Cory Parks ◽  
Ryan D Sullivan ◽  
Salvatore Mancarella
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Excitable Cells ◽  
Rat Cardiomyocytes ◽  
Cell Contractility

Stromal Interaction Protein 1 (STIM1) is the intracellular component of the store operated calcium channels. It is a ubiquitous Ca2+ sensor, prevalently located in the sarcoplasmic reticulum. In non-excitable cells, STIM1 is a key element in the generation of Ca2+signals that lead to gene expression and cell proliferation. A growing body of literature now suggests that STIM1 is important for normal heart function and plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM1 and the Ca2+ signaling in excitable cells are not clearly established. We show that in neonatal rat cardiomyocytes, the spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilaments remodeling and spatially segregated activation of pro-hypertrophic factors. Indeed, in vivo data obtained from an inducible cardiac restricted STIM1 knockout mouse, exhibited left ventricular dilatation associated with reduced cardiac contractility, which was corroborated by impaired single cell contractility. Furthermore, mice lacking STIM1 showed less adverse structural remodeling in response to pathological pressure overload-induced cardiac hypertrophy (transverse aortic constriction, TAC). We further show that the Ca2+ pool associated with STIM1 is the ON switch for extracellular signal-regulated kinase (ERK1/2)-mediated cytoplasm to nucleus signaling. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling, signaling and cardiac function, even when excitation-contraction coupling is present.

scholarly journals The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Qing-Qing Wu ◽  
Wei Deng ◽  
Yang Xiao ◽  
Jiao-Jiao Chen ◽  
Chen Liu ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Protective Effects ◽  
Lipoxygenase Inhibitor ◽  
Rat Cardiomyocytes ◽  
Nrf2 Activation

Zileuton has been demonstrated to be an anti-inflammatory agent due to its well-known ability to inhibit 5-lipoxygenase (5-LOX). However, the effects of zileuton on cardiac remodeling are unclear. In this study, the effects of zileuton on pressure overload-induced cardiac remodeling were investigated and the possible mechanisms were examined. Aortic banding was performed on mice to induce a cardiac remodeling model, and the mice were then treated with zileuton 1 week after surgery. We also stimulated neonatal rat cardiomyocytes with phenylephrine (PE) and then treated them with zileuton. Our data indicated that zileuton protected mice from pressure overload-induced cardiac hypertrophy, fibrosis, and oxidative stress. Zileuton also attenuated PE-induced cardiomyocyte hypertrophy in a time- and dose-dependent manner. Mechanistically, we found that zileuton activated PPARα, but not PPARγ or PPARθ, thus inducing Keap and NRF2 activation. This was confirmed with the PPARα inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPARα knockdown abolished the anticardiac remodeling effects of zileuton in vivo. Taken together, our data indicate that zileuton protects against pressure overload-induced cardiac remodeling by activating PPARα/NRF2 signaling.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

Structural analysis of pressure versus volume overload hypertrophy of cat right ventricle

1985 ◽  
Vol 249 (2) ◽  
pp. H371-H379 ◽  
Author(s):  
T. A. Marino ◽  
R. L. Kent ◽  
C. E. Uboh ◽  
E. Fernandez ◽  
E. W. Thompson ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Contractile Function ◽  
Operative Procedure ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Volume Overload ◽  
Structural Basis ◽  
Contractile Dysfunction

Pressure overload of cat right ventricle causes progressive abnormalities of in vitro contractile function at a time when in vivo contractile function is normal. In marked contrast, the same degree and duration of volume overload of cat right ventricle results in neither in vitro nor in vivo contractile dysfunction. The purpose of the present quantitative structural study was to determine whether there were any histological alterations in pressure-overloaded myocardium that might be causally related to the contractile dysfunction found only in this model. Four experimental groups of eight cats each were studied: a group with pulmonary arterial banding to create a pressure overload, sham-operated controls for this group, a group with atrial septal defects to create a volume overload, and sham-operated controls for this group. Seven to ten weeks after each operative procedure, right ventricular pressure was elevated only in the pressure-overloaded group, pulmonary-to-systemic blood flow ratio was increased only in the volume-overloaded group, and right ventricle-to-body weight ratio was significantly and comparably increased in both the pressure- and the volume-overloaded groups. There was a single striking histological distinction between myocardium hypertrophying in response to pressure as opposed to volume overload: the volume density of cardiocytes in papillary muscles from pressure-overloaded right ventricles was decreased significantly with a proportional increase in connective tissue. Given the critical importance of these two myocardial components to both systolic and diastolic cardiac function, these data provide a potential structural basis for at least some of the functional abnormalities observed in pressure but not in volume overload hypertrophy of the cat right ventricle.

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