Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE107569 | GEO | 2017/12/14
SECONDARY ACCESSION(S): PRJNA420646
REPOSITORIES: GEO
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Project description:BACKGROUND:To better understand reverse left ventricular (LV) remodeling, we developed a murine model wherein mice develop LV remodeling after transverse aortic constriction (TAC) and a small apical myocardial infarct (MI) and undergo reverse LV remodeling after removal of the aortic band. METHODS AND RESULTS:Mice studied were subjected to sham (n=6) surgery or TAC+MI (n=12). Two weeks post-TAC+MI, 1 group underwent debanding (referred to as heart failure debanding [HF-DB] mice; n=6), whereas the aortic band remained in a second group (heart failure [HF] group; n=6). LV remodeling was evaluated by 2D echocardiography at 1 day, 2 weeks and 6 weeks post-TAC+MI. The hearts were analyzed by transcriptional profiling at 4 and 6 weeks and histologically at 6 weeks. Debanding normalized LV volumes, LV mass, and cardiac myocyte hypertrophy at 6 weeks in HF-DB mice, with no difference in myofibrillar collagen in the HF and HF-DB mice. LV ejection fraction and radial strain improved after debanding; however, both remained decreased in the HF-DB mice relative to sham and were not different from HF mice at 6 weeks. Hemodynamic unloading in the HF-DB mice was accompanied by a 35% normalization of the HF genes at 2 weeks and 80% of the HF genes at 4 weeks. CONCLUSIONS:Hemodynamic unloading of a pathophysiologically relevant mouse model of HF results in normalization of LV structure, incomplete recovery of LV function, and incomplete reversal of the HF transcriptional program. The HF-DB mouse model may provide novel insights into mechanisms of reverse LV remodeling.
| S-EPMC5935139 | biostudies-literature
Project description:Wild type, female, C57BL/6 mice were subjected to sham (n=6) surgery, or TAC + MI to cause progressive LV remodeling (n=12). At 2wks post-TAC, one group of mice underwent de-banding (HF-DB, n=6), whereas in a second group of mice the band remained intact (HF; n = 6). LV remodeling was evaluated by 2D echocardiography at 14 days post-TAC+MI , and 4 wks post-debanding. At 6 wks the hearts were excised and analyzed for changes in gene expression using transcriptional profiling. e-banding in the HF-DB mice resulted in normalization of LV volumes and LV mass, and normalization of cardiac myocyte hypertrophy at 6wks, without significant changes in myofibrillar collagen in the HF and HF-DB mice. Both LV ejection fraction (LVEF) and LV radial strain improved numerically following de-banding; however, both measurements remained significantly depressed in the HF-DB mice compared to sham, and were not significantly different from HF mice at 6wks. Reverse LV remodeling in the HF-DB mouse hearts was accompanied by a partial (80%) normalization of the genes that became dysregulated during LV remodeling, whereas 20% of genes remained persistently dysregulated following reverse LV remodeling.
2017-12-14 | GSE107568 | GEO
Project description:Wild type, female, C57BL/6 mice were subjected to sham (n=6) surgery, or TAC + MI to cause progressive LV remodeling (n=13). At 2wks post-TAC, one group of mice underwent de-banding (HF-DB, n=6), whereas in a second group of mice the band remained intact (HF_shDB; n = 7). LV remodeling was evaluated by 2D echocardiography at 14 days post-TAC+MI , and 2 wks post-debanding. At 4 wks the hearts were excised and analyzed for changes in gene expression using transcriptional profiling.
2017-12-14 | GSE107567 | GEO
Project description:Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure
| PRJNA420646 | ENA
Project description:Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure (2 weeks heart failure, 2 weeks reversal)
| PRJNA420795 | ENA
Project description:Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure (2 weeks heart failure, 4 weeks reversal)
| PRJNA420797 | ENA
Project description:Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg(-1)·d(-1), sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R(2)=0.74, P<0.01) and global LV function (R(2)=0.47, P<0.01).Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.
| S-EPMC4820805 | biostudies-other
Project description:In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequent and have important impact on disease progression, morbidity, and mortality, and therefore warrant clinical attention. Pulmonary hypertension related to left heart disease (LHD) by far represents the most common form of PH, accounting for 65-80% of cases. The proper distinction between pulmonary arterial hypertension and PH-LHD may be challenging, yet it has direct therapeutic consequences. Despite recent advances in the pathophysiological understanding and clinical assessment, and adjustments in the haemodynamic definitions and classification of PH-LHD, the haemodynamic interrelations in combined post- and pre-capillary PH are complex, definitions and prognostic significance of haemodynamic variables characterizing the degree of pre-capillary PH in LHD remain suboptimal, and there are currently no evidence-based recommendations for the management of PH-LHD. Here, we highlight the prevalence and significance of PH and RV dysfunction in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), and provide insights into the complex pathophysiology of cardiopulmonary interaction in LHD, which may lead to the evolution from a 'left ventricular phenotype' to a 'right ventricular phenotype' across the natural history of HF. Furthermore, we propose to better define the individual phenotype of PH by integrating the clinical context, non-invasive assessment, and invasive haemodynamic variables in a structured diagnostic work-up. Finally, we challenge current definitions and diagnostic short falls, and discuss gaps in evidence, therapeutic options and the necessity for future developments in this context.
| S-EPMC4800173 | biostudies-literature
Project description:Autonomic dysfunction is a feature of chronic heart failure (HF). This study tested the hypothesis that chronic open-loop electrical vagus nerve stimulation (VNS) improves LV structure and function in canines with chronic HF.Twenty-six canines with HF (EF ?35%) produced by intracoronary microembolizations were implanted with a bipolar cuff electrode around the right cervical vagus nerve and connected to an implantable pulse generator. The canines were enrolled in Control (n = 7) vs. VNS therapy (n = 7) or a crossover study, with crossovers occurring at 3 months (C × VNS, n = 6; VNS × C, n = 6). After 6 months of VNS, LVEF and LV end-systolic volume (ESV) were significantly improved compared with Control (?EF Control -4.6 ± 0.9% vs. VNS 6.0 ± 1.6%, P < 0.001) and (?ESV Control 8.3 ± 1.8 mL vs. VNS -3.0 ± 2.3 mL, P = 0.002. Plasma and tissue biomarkers were also improved. In the crossover study, VNS also resulted in a significant improvement in EF and ESV compared with Control (?EF Control -2.3 ± 0.65% vs. VNS 6.7 ± 1.1 mL, P < 0.001 and ?ESV Control 3.2 ± 1.2 mL vs. VNS -4.0 ± 0.9 mL, P < 0.001). Initiation of therapy in the Control group at 3 months resulted in a significant improvement in EF (Control -4.7 ± 1.4% vs. VNS 3.7 ± 0.74%, P < 0.001) and ESV (Control 1.5 ± 1.2 mL vs. NS -5.5 ± 1.6 mL, P = 0.003) by 6 months.In canines with HF, long-term, open-looped low levels of VNS therapy improves LV systolic function, prevents progressive LV enlargement, and improves biomarkers of HF when compared with control animals that did not receive therapy.
| S-EPMC3895958 | biostudies-literature
Project description:ABSTRACTAdvanced Heart Failure (AHF) is a complex syndrome that affects the physiology of the heart to maintain efficient blood circulation resulting in multiorgan failure and, eventually, death. Left Ventricular Assist Devices (LVADs) have become the cornerstone therapy for AHF patients, both as a bridge to transplantation and as a decisive therapy. Recently the results of the MOMENTUM 3 Trial were published. The trial compared HeartMate 3 LVAD with HeartMate II LVAD in a randomized trial in The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3). Of 366 patients, 190 were assigned to the centrifugal-flow pump group (HeartMate 3) and 176 to the axial-flow (HeartMate II) pump group. In the intention-to-treat population, the primary end point occurred in 151 patients (79.5%) in the centrifugal-flow pump group, as compared with 106 (60.2%) in the axial-flow pump group (P < 0.001 for noninferiority). Reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (P < 0.001).The results of the MOMENTUM 3 Trial are a big achievement in the cardiovascular world. Any improvement in LVADs that reduces the risk of stroke, perhaps the most feared complication of these devices, would be meaningful. Besides, given the observed lower rate of pump thrombosis and reoperation for pump malfunction, it already seems likely that the HeartMate 3 will supplant the HeartMate II in clinical practice. In addition, the risks that are associated with reoperation undoubtedly counterbalanced any unintentional bias in performing that intervention.
| S-EPMC6292364 | biostudies-other