Insights into metabolic remodeling of the hypertrophic and failing myocardium.
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ABSTRACT:
SUBMITTER: Hill BG
PROVIDER: S-EPMC4279713 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
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Insights into metabolic remodeling of the hypertrophic and failing myocardium.
Hill Bradford G BG Schulze P Christian PC
Circulation. Heart failure 20141101 6
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Project description:The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structure-function relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α- to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart.
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Project description:Background Single ventricle (SV) congenital heart disease is fatal without intervention, and eventual heart failure is a major cause of morbidity and mortality. Although there are no proven medical therapies for the treatment or prevention of heart failure in the SV heart disease population, phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are increasingly used. Although the pulmonary vasculature is the primary target of PDE5i therapy in patients with SV heart disease, the effects of PDE5i on the SV heart disease myocardium remain largely unknown. We sought to determine PDE5 expression and activity in the single right ventricle of SV heart disease patients relative to nonfailing controls and to determine whether PDE5 impacts cardiomyocyte remodeling using a novel serum-based in vitro model. Methods and Results PDE5 expression (n=9 nonfailing; n=7 SV heart disease), activity (n=8 nonfailing; n=9 SV heart disease), and localization (n=3 SV heart disease) were determined in explanted human right ventricle myocardium. PDE5 is expressed in SV heart disease cardiomyocytes, and PDE5 protein expression and activity are increased in SV heart disease right ventricle compared with nonfailing right ventricle. Isolated neonatal rat ventricular myocytes were treated for 72 hours with nonfailing or SV heart disease patient serum±sildenafil. Reverse transcription quantitative polymerase chain reaction (n=5 nonfailing; n=12 SV heart disease) and RNA sequencing (n=3 nonfailing; n=3 SV heart disease) were performed on serum-treated neonatal rat ventricular myocytes and demonstrated that treatment with SV heart disease sera results in pathological gene expression changes that are attenuated with PDE5i. Conclusions PDE5 is increased in failing SV heart disease myocardium, and pathological gene expression changes in SV heart disease serum-treated neonatal rat ventricular myocytes are abrogated by PDE5i. These results suggest that PDE5 represents an intriguing myocardial therapeutic target in this population.
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Project description:The heart is a dynamic pump whose function is influenced by its mechanical properties. The viscoelastic properties of the heart, i.e., its ability to exhibit both elastic and viscous characteristics upon deformation, influence cardiac function. Viscoelastic properties change during heart failure (HF), but direct measurements of failing and non-failing myocardial tissue stress relaxation under constant displacement are lacking. Further, how consequences of tissue remodeling, such as fibrosis and fat accumulation, alter the stress relaxation remains unknown. To address this gap, we conducted stress relaxation tests on porcine myocardial tissue to establish baseline properties of cardiac tissue. We found porcine myocardial tissue to be fast relaxing, characterized by stress relaxation tests on both a rheometer and microindenter. We then measured human left ventricle (LV) epicardium and endocardium tissue from non-failing, ischemic HF and non-ischemic HF patients by microindentation. Analyzing by patient groups, we found that ischemic HF samples had slower stress relaxation than non-failing endocardium. Categorizing the data by stress relaxation times, we found that slower stress relaxing tissues were correlated with increased collagen deposition and increased α-smooth muscle actin (α-SMA) stress fibers, a marker of fibrosis and cardiac fibroblast activation, respectively. In the epicardium, analyzing by patient groups, we found that ischemic HF had faster stress relaxation than non-ischemic HF and non-failing. When categorizing by stress relaxation times, we found that faster stress relaxation correlated with Oil Red O staining, a marker for adipose tissue. These data show that changes in stress relaxation vary across the different layers of the heart during ischemic versus non-ischemic HF. These findings reveal how the viscoelasticity of the heart changes, which will lead to better modeling of cardiac mechanics for in vitro and in silico HF models.
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Project description:AimsSR33805, a potent Ca(2+) channel blocker, increases cardiac myofilament Ca(2+) sensitivity in healthy rat cardiomyocytes. Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level.Methods and resultsThe effect of SR33805 (10 µM) was tested on the excitation-contraction coupling of cardiomyocytes isolated from rat with end-stage heart failure. Cell shortening and Ca(2+) transients were measured in intact cardiomyocytes, while contractile properties were determined in Triton X-100 permeabilized myocytes. Acute treatment with SR33805 restored the MI-altered cell shortening without affecting the Ca(2+) transient amplitude, suggesting an increase of myofilament Ca(2+) sensitivity in MI myocytes. Indeed, a SR33805-induced sensitization of myofilament activation was found to be associated with a slight increase in myosin light chain-2 phosphorylation and a more significant decrease on troponin I (TnI) phosphorylation. Decreased TnI phosphorylation was related to inhibition of protein kinase A activity by SR33805. Finally, administration of a single intra-peritoneal bolus of SR33805 (20 mg/kg) improved end-systolic strain and fractional shortening of MI hearts.ConclusionThe present study indicates that treatment with SR33805 improved contractility of ischaemic failing hearts after MI in the rat by selectively modulating the phosphorylation status of sarcomeric regulatory proteins, which then sensitized the myofilaments to Ca(2+). Our results gave a proof of concept that manipulation of the Ca(2+) sensitivity of sarcomeric regulatory proteins can be used to improve contractility of a failing heart.
| S-EPMC3139448 | biostudies-literature
Project description:The normally positive cardiac force-frequency relationship (FFR) becomes flat or negative in chronic heart failure (HF). Here we explored if remodeling of the cardiomyocyte transverse tubular system (t-system) is associated with alterations in FFR and contractile kinetics in failing human myocardium. Left-ventricular myocardial slices from 13 failing human hearts were mounted into a biomimetic culture setup. Maximum twitch force (F), 90% contraction duration (CD90), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2-2 Hz pacing frequency. F1 Hz/F0.5 Hz and F2 Hz/F0.5 Hz served as measures of FFR, intracellular cardiomyocyte t-tubule distance (ΔTT) as measure of t-system remodeling. Protein levels of SERCA2, NCX1, and PLB were quantified by immunoblotting. F1 Hz/F0.5 Hz (R 2 = 0.82) and F2 Hz/F0.5 Hz (R 2 = 0.5) correlated negatively with ΔTT, i.e., samples with severe t-system loss exhibited a negative FFR and reduced myocardial wall tension at high pacing rates. PLB levels also predicted F1 Hz/F0.5 Hz, but to a lesser degree (R 2 = 0.49), whereas NCX1 was not correlated (R 2 = 0.02). CD90 correlated positively with ΔTT (R 2 = 0.39) and negatively with SERCA2/PLB (R 2 = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (R 2 = 0) but rather with TTR (R 2 = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (R 2 = 0.79), suggesting that t-system loss impairs myocardial relaxation especially when NCX1 expression is low. The degree of t-system remodeling predicts FFR inversion and contraction slowing in failing human myocardium. Moreover, together with NCX, the t-system may be important for myocardial relaxation.
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Project description:Gene expression in right atrial myocardium was compared between non-failing control and tachypaced dogs (heart failure was induced by tachycardic pacing for 6 weeks).
2010-05-01 | GSE20665 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)-which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. We evaluated 211 patients with HCM (mean age 47.8 ± 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8, p < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% ± 6.0% vs. 26.6% ± 6.4%, p = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.
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Project description:The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway is a potential pathophysiological mediator of cardiac fibrosis. Soluble ST2 (sST2) is one of the main isoforms of ST2 with strong prognostic value in cardiac disease. The exact role of sST2 in cardiac fibrosis is unknown. The aim of this study was (1) to investigate myocardial expression of the IL-33/ST2 pathway in relation to myocardial fibrosis in end-stage heart failure patients and (2) to study whether plasma sST2 is associated with histologically determined cardiac fibrosis. In 38 patients undergoing left ventricular assist device implantation, mRNA expression of sST2, total ST2, and IL-33 was measured in cardiac tissue obtained during the implantation. In the same tissue, histological fibrosis was digitally quantified and mRNA expression of pro-fibrotic signaling molecules, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGFβ1), was measured. In addition, plasma levels of sST2 were determined. Expression levels of IL-33/ST2 pathway factors in myocardial tissue were significantly associated with cardiac fibrosis and the expression levels of CTGF and TGFβ1. Plasma levels of sST2 did not correlate with tissue expression of ST2, the amount of fibrosis or myocardial expression of pro-fibrotic signaling proteins. The interleukin-33/ST2 pathway is expressed in the failing human heart and its expression is associated with cardiac fibrosis and pro-fibrotic signaling proteins, suggesting a role in pro-fibrotic myocardial remodeling. Soluble ST2 levels in the circulation did not correlate with the amount of cardiac fibrosis or myocardial ST2 expression, however. Therefore, other pathophysiological processes such as inflammation might also substantially affect sST2 plasma levels.
| S-EPMC5846972 | biostudies-literature
Project description:BackgroundDiastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified posttranslationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium.MethodsExperiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from nonfailing and HF hearts and viscoelasticity was characterized after interventions targeting microtubules. Next, intact left ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and posttreatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains.ResultsViscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared with nonfailing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a 2-fold reduction in energy dissipation upon microtubule depolymerization. Post hoc subgroup analysis revealed that myocardium from patients with HF with reduced ejection fraction were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction, which were relatively more viscous. Colchicine reduced viscoelasticity in both HF with preserved ejection fraction and HF with reduced ejection fraction myocardium.ConclusionsFailing cardiomyocytes exhibit elevated viscosity and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.
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Project description:Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.
| S-EPMC5414571 | biostudies-literature