Merits of Non-Invasive Rat Models of Left Ventricular Heart Failure

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, 27599 USA.
Cardiovascular toxicology (Impact Factor: 1.72). 06/2011; 11(2):91-112. DOI: 10.1007/s12012-011-9103-5
Source: PubMed


Heart failure (HF) is characterized as a limitation to cardiac output that prevents the heart from supplying tissues with adequate oxygen and predisposes individuals to pulmonary edema. Impaired cardiac function is secondary to either decreased contractility reducing ejection (systolic failure), diminished ventricular compliance preventing filling (diastolic failure), or both. To study HF etiology, many different techniques have been developed to elicit this condition in experimental animals, with varying degrees of success. Among rats, surgically induced HF models are the most prevalent, but they bear several shortcomings, including high mortality rates and limited recapitulation of the pathophysiology, etiology, and progression of human HF. Alternatively, a number of non-invasive HF induction methods avoid many of these pitfalls, and their merits in technical simplicity, reliability, survivability, and comparability to the pathophysiologic and pathogenic characteristics of HF are reviewed herein. In particular, this review focuses on the primary pathogenic mechanisms common to genetic strains (spontaneously hypertensive and spontaneously hypertensive heart failure), pharmacological models of toxic cardiomyopathy (doxorubicin and isoproterenol), and dietary salt models, all of which have been shown to induce left ventricular HF in the rat. Additional non-invasive techniques that may potentially enable the development of new HF models are also discussed.

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    • "The signaling mechanisms associated with β-AR overactivation have been studied in using isoproterenol (ISO)-treated animals [3]. It was demonstrated that ISO treatment induces myocardial oxidative stress [4] and synthesis of proinflammatory cytokines [5], [6]; these mechanisms were also involved in long-term β-AR stimulation-induced cardiac damage, such as cardiac hypertrophy, necrosis and fibrosis. "
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    ABSTRACT: Sustained β-adrenergic stimulation is a hallmark of sympathetic hyperactivity in cardiovascular diseases. It is associated with oxidative stress and altered vasoconstrictor tone. This study investigated the β-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of β-adrenoceptor overactivation. Mice lacking the β1- or β2-adrenoceptor subtype (β1KO, β2KO) and wild-type (WT) were treated with isoproterenol (ISO, 15 μ, 7 days). ISO significantly enhanced the maximal vasoconstrictor response (Emax) of the aorta to phenylephrine in WT (+34%) and β1KO mice (+35%) but not in β2KO mice. The nitric oxide synthase (NOS) inhibitor L-NAME abolished the differences in phenylephrine response between the groups, suggesting that ISO impaired basal NO availability in the aorta of WT and β1KO mice. Superoxide dismutase (SOD), pertussis toxin (PTx) or PD 98,059 (p-ERK 1/2 inhibitor) incubation reversed the hypercontractility of aortic rings from ISO-treated WT mice; aortic contraction of ISO-treated β2KO mice was not altered. Immunoblotting revealed increased aortic expression of Giα-3 protein (+50%) and phosphorylated ERK1/2 (+90%) and decreased eNOS dimer/monomer ratio in ISO-treated WT mice. ISO enhanced the fluorescence response to dihydroethidium (+100%) in aortas from WT mice, indicating oxidative stress that was normalized by SOD, PTx and L-NAME. The ISO effects were abolished in β2KO mice. The β2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term β2-AR activation might results in endothelial dysfunction.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "At 15 months of age, 16 rats were implanted with radiotelemeters (model TA11CTA-F40; Data Sciences International, St Paul, MN) for the purpose of recording ECG, heart rate (HR), core body temperature, and activity wirelessly as previously described (Lamb et al., 2012). Lean male SHHF rats acquire cardiac hypertrophy by 3 months of age and transition into dilated cardiomyopathy and heart failure at 18 months of age (Carll et al., 2011b). All studies conformed to the guidelines of the U.S. EPA Institutional Animal Care and Use Committee. "
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    ABSTRACT: Acute air pollutant inhalation is linked to adverse cardiac events and death, and hospitalizations for heart failure. Diesel exhaust (DE) is a major air pollutant suspected to exacerbate preexisting cardiac conditions, in part, through autonomic and electrophysiologic disturbance of normal cardiac function. To explore this putative mechanism, we examined cardiophysiologic responses to DE inhalation in a model of aged heart failure-prone rats without signs or symptoms of overt heart failure. We hypothesized that acute DE exposure would alter heart rhythm, cardiac electrophysiology, and ventricular performance and dimensions consistent with autonomic imbalance, while increasing biochemical markers of toxicity. Spontaneously Hypertensive Heart Failure rats (SHHF, 16 months) were exposed once to whole DE (4 h, target PM(2.5) concentration: 500 µg/m(3)) or filtered air. DE increased multiple heart rate variability (HRV) parameters during exposure. In the 4 h after exposure, DE increased cardiac output, left ventricular volume (end diastolic and systolic), stroke volume, HRV, and atrioventricular (AV) block arrhythmias while increasing electrocardiographic measures of ventricular repolarization (i.e., ST- and T-amplitudes, ST area, Tpeak-Tend duration). DE did not affect heart rate relative to Air. Changes in HRV positively correlated with post-exposure changes in bradyarrhythmia frequency, repolarization, and echocardiographic parameters. At 24 hours post-exposure, DE-exposed rats had increased serum C-reactive protein and pulmonary eosinophils. This study demonstrates that cardiac effects of DE inhalation are likely to occur through changes in autonomic balance associated with modulation of cardiac electrophysiology and mechanical function, and may offer insights into the adverse health effects of traffic related air pollutants.
    Full-text · Article · Oct 2012 · Toxicological Sciences
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    • "Telemeter implantation was performed by surgeons at Charles River Laboratory in adherence with preoperative, anesthetic, and surgical procedures described previously (Carll et al., 2010). Lean male SHHFs acquire cardiac hypertrophy by 3 months of age and transition into dilated cardiomyopathy and heart failure (HF) at 18 months of age as a consequence of hypertension and hyperleptinemia (Carll et al., 2011b). Rats were shipped after a 10-day recovery period to our Association for Assessment and Accreditation of Laboratory Animal Care International-approved animal facility, housed individually in 42-× 21-× 20-cm Plexiglas cages with pine-shave bedding in a room (22°C ± 1°C, 50% ± 5% relative humidity, 12-h light:dark cycle 0600:1800 h), and provided standard Purina rat chow (5001; Brentwood, MO) and water ad libitum. "
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    Full-text · Article · Apr 2012 · Toxicological Sciences
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