The pig as a model of tachycardia and dilated cardiomyopathy

Chronic Supraventricular Tachycardia (SVT) can produce a dilated cardiomyopathy which has a poorly understood association with ventricular dysfunction in humans and animals. The purpose of this study was to produce a model of chronic SVT and dilated cardiomyopathy using swine, which have a cardiac anatomy similar to man. Eight pigs were implanted with chronic atrial catheters and a pacemaker, with four additional sham-operated pigs serving as controls. We examined ventricular function and morphology at baseline (120 +/- 3 bpm), pacing baseline (240 bpm), and at 1, 2 and 3 weeks of rapid atrial pacing (240 bpm). Ventricular ejection fractions fell significantly from baseline following 1 week (left: 38 +/- 3% vs baseline 61 +/- 1%; right: 31 +/- 5% vs baseline 56 +/- 1%; p less than 0.05) and deteriorated further by 3 weeks of SVT (left: 26 +/- 4%, right: 19 +/- 3%; p less than 0.05). Significant biventricular chamber dilation developed by 2 weeks of SVT (left: 50 +/- 5 cc vs paced baseline 27 +/- 2 cc; right: 67 +/- 6 cc vs paced baseline 28 +/- 3 cc; p less than 0.05) and continued to increase by week 3 of SVT (left: 66 +/- 11 cc; right: 78 +/- 8 cc; p less than 0.05). Five additional paced pigs, without chronic atrial catheters, were followed using echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of Ketoconazole on experimental paracoccidioidomycosis in the Syrian hamster: immunological and histopathological study

Summary The effect of Ketoconazole (KTZ) on the hamster experimental intratesticular paracoccidioidomycosis was studied employing different treatment schedules. KTZ long course treatment beginning at an early stage of the infection was effective in preventing fungal proliferation, dissemination to lymph nodes, spleen and kidneys, and in maintaining low levels of humoral and cellular specific immune responses. KTZ short course treatment starting at an advanced stage of disease resulted in a more severe histopathological picture without significant changes in the immunological profile. The drug prolonged the life span of hamsters infected with Paracoccidioides brasiliensis, but did not prevent mortality. Toxic necrosis of the bone marrow occurred in normal animals receiving 120 mg/kg/day of KTZ but with lower doses no morphologic alterations were observed in heart, lungs, kidneys, adrenals, spleen, liver, intestine or bone marrow.     

The Syrian golden hamster strain LPN: a useful animal model for human cholelithiasis

The purpose of this study was to specify the main mechanisms at the origin of gallstone formation in very young (5-week old) or young adult (9-week old) LPN hamsters fed a sucrose-rich (normal lipid) lithogenic diet for one and four weeks, respectively. It was also to compare these mechanisms in the two strains of hamsters (LPN and Janvier) or when an anti-lithiasic diet was given by substituting 10% of the sucrose by beta cyclodextrin. The LPN strain of hamsters showed a very high incidence of cholesterol gallstones (73%) after receiving the lithogenic diet. The gallstone formation is very rapid and occurs in less than one week in very young hamsters which show a high cholesterol synthesis rate in the liver. The cholesterol and phospholipid concentrations in the bile, cholesterol saturation index (CSI) and hydrophobic index (HI) increased significantly, concomitantly with a higher liver cholesterol synthesis in very young hamsters and with a lower bile acid synthesis (neutral pathway: cholesterol 7alpha-hydroxylase, CYP7A1 and acidic pathway: sterol 27 hydroxylase, CYP27A1) in young adult hamsters. No significant changes in the lipoprotein receptor expression (LDLr, SR-BI) were observed after feeding the lithogenic diet. Adding ten per cent beta-cyclodextrin, a cyclic oligosaccharide that binds cholesterol and bile acids to the lithogenic diet at the expense of sucrose, induced a decrease in cholesterol bile secretion and in the CSI and HI and prevented cholesterol gallstone formation. Similarly, another strain of Syrian Golden hamsters (" Janvier ") which originally exhibited a smaller bile cholesterol concentration, lower liver cholesterol synthesis and higher CYP7A1/CYP27A1 activity ratio did not carry cholesterol gallstones when fed the lithogenic diet. The main parameters always found at the origin of cholelithiasis in the Hamster are discussed: a higher hepatic cholesterogenesis (HMGCoAR), a higher HMGCoAR/CYP7A1 activity ratio, a lower cholesterol ester storage capacity, a higher CYP27A1/CYP7A1 activity ratio correlated to a higher cholesterol secretion in the bile and higher CSI and HI. In LPN hamsters, the incidence of cholesterol gallstones is nil when CSI + HI < 0.8 and positive for CSI + HI > 0.9. An overall comparison of the data obtained in LPN Hamsters and in Man suggests that this hamster strain appears to be an interesting model for human cholelithiasis.     

Ameliorating effects of amlodipine on plasma and myocardial catecholamines in BIO 53.58 Syrian hamsters, a model of dilated cardiomyopathy

Our previous study has shown that the concentrations of norepinephrine, epinephrine and dopamine in the plasma of BIO 53.58 hamsters (a model of dilated cardiomyopathy: DCM) at 18 weeks of age (severe cardiomyopathic stage) were twice those of age-matched F1B control and conversely the myocardial norepinephrine level was decreased. The present study was undertaken to examine the effect of amlodipine on catecholamine concentration, myocardial receptors and histopathological changes in BIO 53.58 hamsters. Oral administration of amlodipine (10 mg/kg/day) for 7 weeks in 11 week-old-BIO 53.58 hamsters brought about marked decreases in the concentrations of norepinephrine, epinephrine and dopamine in the plasma, compared with those in vehicle-treated BIO 53.58 hamsters. This was accompanied by a concomitant increase in the concentration of myocardial catecholamine concentration. In other words, the concentrations of catecholamines in plasma and myocardium of amlodipine administered BIO 53.58 hamsters approximated to the control level in age-matched F1B. In addition, amlodipine administration caused a significant reduction of calcium deposition with a tendency toward a decrease in the myocardial necrosis, and it had little effect on the affinity and number of specific binding for (+)-[3H]PN 200-110, (-)-[125I]iodocyanopindolol (CYP) and [3H]prazosin in the myocardium. In conclusion, the present study shows that administration of amlodipine in BIO 53.58 hamsters may exhibit ameliorating effect on plasma and myocardial catecholamines with a significant reduction of calcium deposition. These data may offer further support for the use of amlodipine in patients with DCM.     

Evaluation of the rabbit as a model for Chagas' disease. I. Parasitological studies

In order to investigate the value of the rabbit as an experimental model for Chagas' disease, 72 animals have been inoculated by intraperitoneal and conjunctival route with bloodstream forms, vector-derived metacyclic trypomastigotes and tissue culture trypomastigotes of Trypanosoma cruzi strains Y, CL and Ernane. In 95.6% of the animals trypomastigotes had been detected at the early stages of infection by fresh blood examination. The course of parasitemia at the acute phase was strongly influenced by the parasite strain and route of inoculation. At the chronic phase parasites had been recovered by xenodiagnosis and/or hemoculture in 40% of the examined animals. The xenodiagnosis studies have shown selective interactions between the T. cruzi strains and the four species of vectors used, inducing significant variability in the results. The data herein present are consistent with the parasitological requirements established for a suitable model for chronic Chagas' disease.     

Inactivated rabies virus vectored SARS-CoV-2 vaccine prevents disease in a Syrian hamster model

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials.     

Titin mutations as the molecular basis for dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a heterogeneous cardiac disease characterized by ventricular dilatation and systolic dysfunction. Recent genetic studies have revealed that mutations in genes for cardiac sarcomere components lead to DCM. The cardiac sarcomere consists of thick and thin filaments and a giant protein, titin. Because one of the loci of familial DCM was mapped to the region of the titin gene, we searched for titin mutations in the patients and identified four possible disease-associated mutations. Two mutations, Val54Met and Ala743Val, were found in the Z-line region of titin and decreased binding affinities of titin to Z-line proteins T-cap/telethonin and alpha-actinin, respectively, in yeast two-hybrid assays. The other two mutations were found in the cardiac-specific N2-B region of titin and one of them was a nonsense mutation, Glu4053ter, presumably encoding for a truncated nonfunctional molecule. These observations suggest that titin mutations may cause DCM in a subset of the patients.     

Pathological and biochemical analysis of dilated cardiomyopathy of broiler chickens--an animal model

Forty-seven birds (M/F = 33/14) with natural outbreak dilated cardiomyopathy (DCM) of right ventricle (RV) and 33 birds with artificially cool-induced DCM hearts were studied. Clinically, 20 severe and 13 mild DCM cases were induced during five weeks and the peak morbidity was in the 2nd week. The progressive dilatation of RV and hypokinesis of septum was shown by echocardiography. At autopsy, the ratio of heart weights to the body weights was increased, the ratio of RV weight to the total ventricle significantly increased, especially in the severe DCM cases (P < 0.05). The RV was dilated and the wall thickness was increased and finally both RV and left ventricle (LV) were markedly dilated and the septum became thinner. The struts, weave and coil demonstrated by silver impregnation stain were fragmented, dissociated and overstretched. The promatrix metalloproteinases (MMP)-2, -9 and active MMP-2 were markedly increased in natural outbreak DCM cases, especially in the RV (P < 0.05). The proMMP-2 and active MMP-2 was increased in the cool induced DCM cases, especially in the RV of severe DCM (P < 0.05). These indicated that both the natural outbreak and the artificially induced DCM of broiler chickens are ideal DCM animal models.     

An epidemiological model for the dynamics of Chagas' disease.

A model for the transmission dynamics of Chagas' disease is presented. The structure of the model is similar to that of the Ross-Macdonald model for malaria but includes an extra infectious compartment (chronically ill individuals) which is characteristic of Chagas' disease. In Chagas' disease there are two-main forms of transmission, by blood transfusion and by vector biting. The former is more common in urban environments and the latter is characteristic of rural settings. The characteristic long chronic (frequently asymptomatic) stage of Chagas' disease is potentially a risk factor that could enhance disease transmission by blood transfusion. The model evaluates the relative importance of both transmission modes in populations of constant size. The main results indicate that there is a strong tendency of the disease to reach an asymptotically stable endemic equilibrium point. Also, the magnitude of the basic reproductive number is very sensitive to the length of the chronic stage of the disease and hence it follows that early detection of cases (reducing the length of this stage) is important for the eventual eradication of the disease.     

Argininosuccinate synthetase as a marker of transformed Syrian hamster epidermal cells

Thirteen continuous lines of Syrian hamster epidermal cells were isolated following direct treatment of epidermal cells with N-methyl-N′-nitro-N-nitrosoguanidine, or from epidermal cells cultured from animals treated transplacentally with 7,12-dimethylbenz(a)anthracene or dimethylnitrosamine. The epidermal origin of the lines was evidenced by the presence of desmosomes with radiating tonofilaments, keratin fibers, and the ability of the cells to use citrulline in place of arginine corresponding with their high argininosuccinate synthetase activity.     

The hamster as a model for embryo implantation: insights into a multifaceted process

Defects in preimplantation embryonic development, uterine receptivity, and implantation are the leading cause of infertility, pregnancy problems and birth defects. Significant progress has been made in our basic understanding of these processes using the mouse model, where implantation is ovarian estrogen-dependent in the presence of progesterone. However, an animal model where implantation is progesterone-dependent must also be studied to gain a full understanding of the embryo and uterine events that are required for implantation. In this regard, the hamster is a useful model and this review summarizes the information currently available regarding mechanisms involved in synchronous preimplantation embryo and uterine development for implantation in this species.     

Hemodynamic and histomorphometric characteristics of dilated cardiomyopathy of Syrian hamsters (Bio TO-2 strain)

The natural history of the disease of the dilated strain Bio TO-2 of cardiomyopathic hamsters (CMH) is not totally characterized. We investigated its hemodynamic and histomorphometric characteristics at 140, 180, 220, 260, and 300 days of age. Forty CMH and 40 controls were investigated (8 at each stage). Mean arterial pressure (MAP, carotid artery catheter) and cardiac output and femoral blood flow (CO, FBF, transit time method) were measured in anesthetized animals. Systemic (SVR) and femoral (FVR) vascular resistances were calculated. Atria, left and right ventricles (LV, RV), lungs, and liver were weighed. LV cavity area, LV and RV wall thicknesses and collagen densities were determined (computer-assisted image analyzer). Pulmonary and hepatic congestion were assessed (arbitrary scales). Compared with controls, MAP, CO and FBF were significantly lower in CMH throughout the study (on average: -22%, -34%, -33%, respectively), FVR was significantly increased (+15%), but SVR was not significantly modified. Concerning histomorphometric characteristics, differences between groups significantly increased with age for most variables: at 300 days, atria (+292%), RV (+13%), lungs (+44%), and liver (+23%) weights, LV cavity area (+130%), LV (+364%) and RV (+181%) collagen densities were significantly increased in CMH vs controls, whereas LV (-40%) and RV (-23%) wall thicknesses were significantly decreased. At 260 and 300 days, CMH showed significant pulmonary congestion without hepatic alteration. Bio TO-2 CMH progressively develop an alteration of cardiac function leading to decreased MAP and musculo-cutaneous blood flow associated with cardiac remodeling including atria hypertrophy and LV dilation, wall thinning and a rise in collagen density.