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: 2.06). 06/2011; 11(2):91-112. DOI: 10.1007/s12012-011-9103-5
Source: PubMed

ABSTRACT 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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Available from: Alex P Carll, Aug 09, 2015
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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.
    Toxicological Sciences 10/2012; DOI:10.1093/toxsci/kfs295 · 4.48 Impact Factor
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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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    ABSTRACT: Epidemiological studies strongly link short-term exposures to vehicular traffic and particulate matter (PM) air pollution with adverse cardiovascular (CV) events, especially in those with preexisting CV disease. Diesel engine exhaust is a key contributor to urban ambient PM and gaseous pollutants. To determine the role of gaseous and particulate components in diesel exhaust (DE) cardiotoxicity, we examined the effects of a 4-h inhalation of whole DE (wDE) (target PM concentration: 500 µg/m(3)) or particle-free filtered DE (fDE) on CV physiology and a range of markers of cardiopulmonary injury in hypertensive heart failure-prone rats. Arterial blood pressure (BP), electrocardiography, and heart rate variability (HRV), an index of autonomic balance, were monitored. Both fDE and wDE decreased BP and prolonged PR interval during exposure, with more effects from fDE, which additionally increased HRV triangular index and decreased T-wave amplitude. fDE increased QTc interval immediately after exposure, increased atrioventricular (AV) block Mobitz II arrhythmias shortly thereafter, and increased serum high-density lipoprotein 1 day later. wDE increased BP and decreased HRV root mean square of successive differences immediately postexposure. fDE and wDE decreased heart rate during the 4th hour of postexposure. Thus, DE gases slowed AV conduction and ventricular repolarization, decreased BP, increased HRV, and subsequently provoked arrhythmias, collectively suggesting parasympathetic activation; conversely, brief BP and HRV changes after exposure to particle-containing DE indicated a transient sympathetic excitation. Our findings suggest that whole- and particle-free DE differentially alter CV and autonomic physiology and may potentially increase risk through divergent pathways.
    Toxicological Sciences 04/2012; 128(2):490-9. DOI:10.1093/toxsci/kfs162 · 4.48 Impact Factor
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    • "In that study, ISO was administered in a dose of 20 mg/kg once a week for 5 weeks, and the protective effects were noted. However, it should be emphasized that such experimental design corresponds rather with a model of chronic heart failure (Carll et al. 2011). On the contrary, this study aims at the analysis of acute effect of DEX in the ISO-model of AMI. "
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    ABSTRACT: Positive effects of dexrazoxane (DEX) in anthracycline cardiotoxicity have been mostly assumed to be associated with its iron-chelating properties. However, this explanation has been recently questioned. Iron plays also an important role in the catecholamine cardiotoxicity. Hence in this study, the influence of DEX on a catecholamine model of acute myocardial infarction (100 mg/kg of isoprenaline by subcutaneous injection) was assessed: (i) the effects of an intravenous dose of 20.4 mg/kg were analyzed after 24 h, (ii) the effects were monitored continuously during the first two hours after drug(s) administration to examine the mechanism(s) of cardioprotection. Additional in vitro experiments on iron chelation/reduction and influence on the Fenton chemistry were performed both with isoprenaline/DEX separately and in their combination. DEX partly decreased the mortality, reduced myocardial calcium overload, histological impairment, and peripheral haemodynamic disturbances 24 h after isoprenaline administration. Continuous 2 h experiments showed that DEX did not influence isoprenaline induced atrioventricular blocks and had little effect on the measured haemodynamic parameters. Its protective effects are probably mediated by inhibition of late myocardial impairment and ventricular fibrillation likely due to inhibition of myocardial calcium overload. Complementary in vitro experiments suggested that iron chelation properties of DEX apparently did not play the major role.
    Canadian Journal of Physiology and Pharmacology 03/2012; 90(4):473-84. DOI:10.1139/y2012-009 · 1.55 Impact Factor
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