Animal Models of Heart Failure

Houser, Steven R.; Margulies, Kenneth B.; Murphy, Anne M.; Spinale, Francis G.; Francis, Gary S.; Prabhu, Sumanth D.; Rockman, Howard A.; Kass, David A.; Molkentin, Jeffery D.; Sussman, Mark A.; Koch, Walter J.

doi:10.1161/res.0b013e3182582523

Cited by 385 publications

(239 citation statements)

References 250 publications

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“…Before performing reverse‐phase protein microarray, therefore, we used the rat brain as a Ca v 2.2‐α–positive sample and the gastrocnemius muscle as a Ca v 2.2‐α–negative sample to evaluate target specificity of Ca v 2.2‐α antibody (Figure 2). Additionally, we do realize a possible limitation of small animals for extrapolating the findings obtained in this study to humans, although the rat has contributed markedly to assessment of the pathophysiology and treatment of CHF and to the advancement of clinical care 53, 54, 55. Large animals could be an appropriate alternative for translational experiments.…”

Section: Discussionmentioning

confidence: 94%

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Zhang

Cao

et al. 2018

JAHA

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BackgroundAttenuated cardiac vagal activity is associated with ventricular arrhythmogenesis and related mortality in patients with chronic heart failure. Our recent study has shown that expression of N‐type Ca2+ channel α‐subunits (Cav2.2‐α) and N‐type Ca2+ currents are reduced in intracardiac ganglion neurons from rats with chronic heart failure. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Ventricular myocardium receives projection of neuronal terminals only from the AVG. In this study we tested whether a decrease in N‐type Ca2+ channels in AVG neurons contributes to ventricular arrhythmogenesis.Methods and ResultsLentiviral Cav2.2‐α shRNA (2 μL, 2×107 pfu/mL) or scrambled shRNA was in vivo transfected into rat AVG neurons. Nontransfected sham rats served as controls. Using real‐time single‐cell polymerase chain reaction and reverse‐phase protein array, we found that in vivo transfection of Cav2.2‐α shRNA decreased expression of Cav2.2‐α mRNA and protein in rat AVG neurons. Whole‐cell patch‐clamp data showed that Cav2.2‐α shRNA reduced N‐type Ca2+ currents and cell excitability in AVG neurons. The data from telemetry electrocardiographic recording demonstrated that 83% (5 out of 6) of conscious rats with Cav2.2‐α shRNA transfection had premature ventricular contractions (P<0.05 versus 0% of nontransfected sham rats or scrambled shRNA‐transfected rats). Additionally, an index of susceptibility to ventricular arrhythmias, inducibility of ventricular arrhythmias evoked by programmed electrical stimulation, was higher in rats with Cav2.2‐α shRNA transfection compared with nontransfected sham rats and scrambled shRNA‐transfected rats.ConclusionsA decrease in N‐type Ca2+ channels in AVG neurons attenuates vagal control of ventricular myocardium, thereby initiating ventricular arrhythmias.

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Section: Discussionmentioning

confidence: 94%

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Zhang

Cao

et al. 2018

JAHA

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“…2005; Monnet and Chachques 2005; Canty and Suzuki 2012; Houser et al. 2012; Isorni et al. 2015; Mohammed et al.…”

Section: Introductionmentioning

confidence: 99%

The Structure-function remodeling in rabbit hearts of myocardial infarction

Niu

et al. 2017

Physiol Rep

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Animal models are of importance to investigate basic mechanisms for ischemic heart failure (HF). The objective of the study was to create a rabbit model through multiple coronary artery ligations to investigate the postoperative structure‐function remodeling of the left ventricle (LV) and coronary arterial trees. Here, we hypothesize that the interplay of the degenerated coronary vasculature and increased ventricle wall stress relevant to cardiac fibrosis in vicinity of myocardial infarction (MI) precipitates the incidence and progression of ischemic HF. Echocardiographic measurements showed an approximately monotonic drop of fractional shortening and ejection fraction from 40% and 73% down to 28% and 58% as well as persistent enlargement of LV cavity and slight mitral regurgitation at postoperative 12 weeks. Micro‐CT and histological measurements showed that coronary vascular rarefaction and cardiac fibrosis relevant to inflammation occurred concurrently in vicinity of MI at postoperative 12 weeks albeit there was compensatory vascular growth at postoperative 6 weeks. These findings validate the proposed rabbit model and prove the hypothesis. The post‐MI rabbit model can serve as a reference to test various drugs for treatment of ischemic HF.

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“…Initially, cardiac remodeling is a beneficial compensatory process, which reduces cardiac wall stress and increases cardiac output, but remodeling ultimately results in the inability of the heart to meet hemodynamic demands. Despite a number of important therapeutic advances in the treatment of symptomatic HF, the prevalence, mortality and cost associated with HF continue to increase (4). Therefore, the development of novel therapeutic strategies to attenuate cardiac remodeling and prevent heart failure is an urgent goal for the biomedical community.…”

Section: Introductionmentioning

confidence: 99%

Sanguinarine protects against pressure overload-induced cardiac remodeling via inhibition of nuclear factor-κB activation

Deng

Fang

Liu

et al. 2014

Molecular Medicine Reports

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Abstract. Cardiac remodeling is a major determinant of heart failure characterized by cardiac hypertrophy and fibrosis. Sanguinarine exerts widespread pharmacological effects, including antitumor and anti-inflammatory responses. In the present study, the effect of sanguinarine on cardiac hypertrophy, fibrosis and heart function was determined using the model induced by aortic banding (AB) in mice. AB surgery and sham surgery were performed on male wild-type C57 mice, aged 8-10 weeks, with or without administration of sanguinarine from one week after surgery for an additional seven weeks. Sanguinarine protected against the cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by the heart weight/body weight, lung weight/body weight and heart weight/tibia length ratios, echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The inhibitory effect of sanguinarine on cardiac remodeling was mediated by inhibiting nuclear factor (NF)-κB signaling pathway activation. The findings indicated that sanguinarine protected against cardiac hypertrophy and fibrosis via inhibiting NF-κB activation. These findings may be used to develop a potential therapeutic drug for treating cardiac remodeling and heart failure. IntroductionHeart failure (HF) is a major health and economic burden worldwide, and its prevalence is continuously increasing (1). The key pathophysiological process that ultimately results in heart failure is cardiac remodeling in response to chronic pathological stresses, such as hypertension and myocardial ischemia (2). Cardiac remodeling, which involves myocyte hypertrophy along with interstitial cell proliferation and extracellular matrix remodeling, induces structural and functional changes, mainly in the left ventricle (3). Initially, cardiac remodeling is a beneficial compensatory process, which reduces cardiac wall stress and increases cardiac output, but remodeling ultimately results in the inability of the heart to meet hemodynamic demands. Despite a number of important therapeutic advances in the treatment of symptomatic HF, the prevalence, mortality and cost associated with HF continue to increase (4). Therefore, the development of novel therapeutic strategies to attenuate cardiac remodeling and prevent heart failure is an urgent goal for the biomedical community.Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy fumaria species, has been demonstrated to exert widespread pharmacological actions, including antimicrobial, antitumor and anti-inflammatory responses (5-8). In particular, sanguinarine was reported to possess cardioprotective outcomes, such as antihypertension, antiplatelet and positive inotropic effects (9). However, the influence of sanguinarine on cardiac remodeling was unknown.The aim of the present study was to investigate whether sanguinarine improved cardiac hypertrophy and fibrosis in mice. Materials and methodsMaterials and animal models. Sanguinarine (>98%) wa...

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Animal Models of Heart Failure

Cited by 385 publications

References 250 publications

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

The Structure-function remodeling in rabbit hearts of myocardial infarction

Sanguinarine protects against pressure overload-induced cardiac remodeling via inhibition of nuclear factor-κB activation

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Animal Models of Heart Failure

Cited by 385 publications

References 250 publications

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca 2+ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

The Structure-function remodeling in rabbit hearts of myocardial infarction

Sanguinarine protects against pressure overload-induced cardiac remodeling via inhibition of nuclear factor-κB activation

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Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis

Reduced N‐Type Ca ²⁺ Channels in Atrioventricular Ganglion Neurons Are Involved in Ventricular Arrhythmogenesis