Identification of two preclinical canine models of atrial fibrillation to facilitate drug discovery.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia occurring in humans, and new treatment strategies are critically needed. The lack of reliable preclinical animal models of AF is a major limitation to drug development of novel antiarrhythmic compounds. OBJECTIVE: The purpose of this study was to provide a comprehensive head-to-head assessment of 5 canine AF models. METHODS: Five canine models were evaluated for the efficacy of AF induction and AF duration. We tested 2 acute models: short-term atrial tachypacing (AT) for 6 hours with analysis of AF at hourly increments, and carbachol injection into a cardiac fat pad followed by short-term AT. We also tested 3 chronic models: pacemaker implantation followed by either 4 weeks of AT and subsequent atrial burst pacing or intermittent long-term AT for up to 4-5 months to generate AF ≥4.5 hours, and finally ventricular tachypacing to induce heart failure followed by atrial burst pacing to induce AF. RESULTS: Careful evaluation showed that acute AT, AT for 4 weeks, and the heart failure model all were unsuccessful in generating reproducible AF episodes of sufficient duration to study antiarrhythmic drugs. In contrast, intermittent long-term AT generated AF lasting ≥4.5 hours in ∼30% of animals. The acute model using carbachol and short-term AT resulted in AF induction of ≥15 minutes in ≥75% of animals, thus enabling testing of antiarrhythmic drugs. CONCLUSION: Intermittent long-term AT and the combination of local carbachol injection with successive short-term AT may contribute to future drug development efforts for AF treatment.

A Novel Model of Chronic Kidney Disease in Rats: Dietary Adenine in Combination with Unilateral Nephrectomy.

BACKGROUND: Adenine at 0.75% in the diet (AD) triggers renal impairment in rats. This model of kidney disease is largely reversible when AD feeding is stopped. Testing of novel drugs parallel to AD administration may result in unwanted interference. OBJECTIVES: We hypothesized that combining AD with unilateral nephrectomy (UNx) would result in progressive chronic kidney disease (CKD) even after cessation of AD. METHODS: In an explorative study, 16 rats with UNx (AD-1K rats) and 10 sham-operated rats (AD-2K rats) received AD-supplemented feed for 3 weeks, followed by 4 weeks of standard chow. Ten sham-operated rats receiving only standard chow served as controls. Laboratory parameters in blood and urine were frequently assessed during and after cessation of AD feeding. Comprehensive pathological examinations were performed in all rats at the end of the experiment. RESULTS: Rats with UNx were more affected by impaired glomerular filtration rate, anemia, hyperphosphatemia, and hypocalcemia. After cessation of AD feeding, recovery was poorest in AD-1K rats, paralleled by increased proteinuria indicative of progressive CKD. Scores in histopathological damage of the kidneys indicative of CKD were seen in both AD-fed groups, with key parameters being more affected in AD-1K rats. Histopathological changes in the heart were most prominent in AD-1K rats. CONCLUSIONS: Combining AD feeding with UNx provides a time window after cessation of AD feeding for the testing of drugs without interference. Our findings in rats may have implications for research in other target animal species as well.