Spontaneous Cardiomyopathy Research Articles

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit.

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice. Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.

Abstract 13202: Cellular Iron Regulates Mitochondrial Dynamics Through the RNA-Binding Protein Tristetraprolin (TTP)

Background: Iron is a critical molecule for normal cellular and physiologic processes including mitochondrial energy production. Previous work in our lab has established the RNA-binding protein TTP as a protein whose expression is induced by iron deprivation. TTP functions by binding to AU-rich elements in the 3’UTR of mRNAs and promotes their degradation. Many of the targets of TTP encode metabolically active proteins that function in pathways requiring iron. Recently, we have identified Mitofusin 1 (MFN1), a critical component of the mitochondrial fusion machinery, as a novel target of TTP. Published reports have shown MFN1/2 double knockout mice develop spontaneous cardiomyopathy. Conversely, under conditions of ROS induced cellular stress, MFN1 knockout in cardiomyocytes has been associated with protection from cell death. We hypothesize that the level of MFN1 closely matches the metabolic demands of the cell and, therefore, induction of TTP by low iron reduces the level of MFN1 to fragment the mitochondria and limit the cell’s ability to proliferate during conditions of iron insufficiency. Results: Twenty-four hours of iron chelation using either desferoxamine (DFO) or 2-2, bipyridyl (BPD) induced TTP expression at both the mRNA and protein levels in a dose-dependent manner. In silico analysis of the MFN1 3’UTR revealed four conserved AU-rich elements. Basal levels of MFN1 were increased in TTP KO cells indicating TTP actively targets MFN1 mRNA. Additionally, iron chelation decreased MFN1 mRNA expression in WT but not TTP KO cells. Confocal imaging of mitochondria showed profound fragmentation in WT cells exposed DFO that was abrogated in TTP KO cells. Functionally, iron chelation induced complete growth arrest in WT cells that was partially escaped by TTP KO cells. The increase in proliferation was accompanied by higher rates of cell death in TTP KO cells. Conclusions: Our studies show that TTP expression is upregulated under conditions of iron deficiency and in turn represses the expression of the mitochondrial fusion protein MFN1 to alter mitochondrial dynamics. By remodeling the mitochondria under conditions of iron deprivation we propose a critical role for TTP in coordinating growth arrest to protect metabolically active cells from cell death.

Abstract 12522: Downregulation of Aryl-hydrocarbon Receptor Nuclear Translocator (ARNT) Exacerbates Cardiac Insulin Resistance After High Fat Diet

Introduction: Altered cardiac insulin sensitivity, substrate utilization, and energetics have been reported in diabetic cardiomyopathy. However, the mechanism behind insulin resistance in the heart in diabetes remain poorly understood. Hypoxia inducible factors (HIFs) have been linked to cellular metabolism, and their deletion in the heart resulted in metabolic changes. We have previously demonstrated that cardiac-specific knockout of ARNT, the obligatory binding partner of HIFs, causes spontaneous cardiomyopathy bearing similarity to diabetic cardiomyopathy, and its levels are reduced in genetic- and diet-induced obesity models. Here, we hypothesize that downregulation of ARNT in vivo exacerbates cardiac insulin resistance after high fat diet (HFD). Results: Mice with cardiac-specific heterozygous deletion of ARNT (cs-ARNT +/- ) had normal cardiac function at baseline, and had comparable food intake and weight gain during HFD treatment. We then evaluated cardiac substrate utilization using an ex vivo heart perfusion system. When perfused with a buffer without insulin, hearts from wild type (WT) and cs-ARNT +/- mice displayed comparable substrate utilization both after normal chow and after HFD. Addition of insulin to the perfusion system led to comparable increase in glucose utilization in hearts from normal chow-fed WT and ARNT +/- mice. However, the increased glucose utilization in response to insulin was attenuated in hearts from WT mice after HFD, while hearts from cs-ARNT +/- after HFD demonstrated virtually no increase in glucose utilization in response to insulin. This difference was not due to cardiac function as the cardiac work (assessed by heart rate and developing pressure) is comparable among all groups. Using neonatal rat cardiomyocytes, we also demonstrated that ARNT knockdown decreased glucose uptake and AKT phosphorylation in response to insulin, consistent with a blunted insulin-signaling pathway. Conclusion: Cardiac-specific ARNT heterozygote deletion exacerbates insulin resistance in a diet-induced obesity model, and the reduction of ARNT levels in various mouse models of diabetes is likely be a maladaptive response. Therefore, increasing ARNT signaling can be a potential therapy for diabetic cardiomyopathy.

English

Methods and results: A retrospective study was conducted over a 5 year period from 2010 to 2015. One hundred and twenty nine consecutive patients <40 years of age were admitted for evaluation and were reviewed. The mean age was 37.7 years (range 28-40), 76.7% (99) were males and 23.3% (30) were females. This was similar to the figures for more than 40 years cohort, 74.1% males and 25.9% females. Sixty two percent were urban and 13.2% were non-Kashmiri security forces. Predominant presentation was acute myocardial infarction (47.3%) followed by angina on effort (44.2%), atypical chest pain (7%), and unstable angina (1.6%). Among males 59.5% had angiographically documented coronary artery disease while only 23% of females had coronary artery disease documented. Three females presented with anterior wall myocardial infarction secondary to infective endocarditis, spontaneous left main coronary dissection and takotsubo cardiomyopathy respectively.

Pathology and cardiovascular safety pharmacology data from a cynomolgus monkey with spontaneous hypertrophic cardiomyopathy

Pathology and cardiovascular safety pharmacology data from a cynomolgus monkey with spontaneous hypertrophic cardiomyopathy

VIP Gene Deletion in Mice Causes Cardiomyopathy Associated with Upregulation of Heart Failure Genes

RationaleVasoactive Intestinal Peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, is absent in pulmonary arteries of patients with idiopathic pulmonary arterial hypertension (PAH). We previously determined that targeted deletion of the VIP gene in mice leads to PAH with pulmonary vascular remodeling and right ventricular (RV) dilatation. Whether the left ventricle is also affected by VIP gene deletion is unknown. In the current study, we examined if VIP knockout mice (VIP−/−) develop both right (RV) and left ventricular (LV) cardiomyopathy, manifested by LV dilatation and systolic dysfunction, as well as overexpression of genes conducive to heart failure.MethodsWe examined VIP−/−and wild type (WT) mice using Magnetic Resonance Imaging (MRI) for evidence of cardiomyopathy associated with biventricular dilation and wall thickness changes. Lung tissue from VIP−/− and WT mice was subjected to whole-genome gene microarray analysis.ResultsLungs from VIP−/− mice showed overexpression of cardiomyopathy genes: Myh1 was upregulated 224 times over WT, and Mylpf was increased 72 fold. Tnnt3 was increased 105 times and tnnc2 181 fold. Hearts were dilated in VIP−/− mice, with thinning of LV wall and increase in RV and LV chamber size, though RV enlargement varied. Weights of VIP−/− mice were consistently lower.ConclusionsCritically-important heart failure-related genes are upregulated in VIP−/− mice associated with the spontaneous cardiomyopathy phenotype, involving both left and right ventricles, suggesting that loss of the VIP gene orchestrates a panoply of pathogenic genes which are detrimental to both left and right cardiac homeostasis.

Spontaneous Cardiomyopathy in Young Sprague-Dawley Rats

Cardiovascular safety signals in nonclinical studies remain among the main reasons for drug attrition during pharmaceutical research and development. Drug-induced changes can be functional and/or associated with morphological alterations in the normal heart histology. It is therefore crucial to understand the normal variations in histology to discriminate test article-related changes from background lesions. Rodent progressive cardiomyopathy is probably the most commonly encountered change in control animals of nonclinical toxicity studies. A multisite study mimicking standard short-term toxicity studies using young male Sprague-Dawley rats was performed to better characterize this finding. Using an enhanced sectioning method for this research study, it was observed that the incidence of background cardiomyopathy was 100%. The vast majority of the microscopic findings were inflammatory in nature, with associated necrotic changes (defined as necrosis/inflammatory cell infiltrate) and these changes were mainly located in the myocardium of the mid region of the ventricles (the left side being predominantly affected). The monitored environmental factors in this study (multiple facilities, study duration, handling) did not have an effect on the incidence or severity of the spontaneous cardiomyopathy. In addition, cardiac-specific serum troponin levels were measured and were within the published control range.

Cloning of Prepro-Adrenomedullin and mRNA Expression in Cats

The objective of this paper was to evaluate the sequence of feline prepro-adrenomedullin (AM) and its tissue distribution and to investigate whether expression of feline AM mRNA increases in association with spontaneous cardiomyopathy. The feline prepro-AM cDNA sequence and deduced amino acids were 564 base pairs and 188 residues, respectively. The cDNA sequences of feline prepro-AM including AM and proadrenomedullin N-terminal 20 peptide showed high homology with those of other mammalian species. The mRNA expression of AM was detectable in various normal tissues. The mRNA levels of AM were elevated in hearts with cardiomyopathy compared with normal hearts. This study suggests that AM has an important role as a neurohumoral factor in cats with spontaneous heart diseases.

Spontaneous Cardiomyopathy in Cynomolgus Monkeys (Macaca Fascicularis)

A previously undescribed spontaneous cardiomyopathy was identified by routine light microscopic examination of the heart from four clinically healthy purpose-bred cynomolgus monkeys that ranged from four to nine years of age and included 2 males and 2 females. Special stains of Sirius red, Masson's trichrome, and Mallory's phosphotungstic acid hematoxylin (PTAH); and immunohistochemistry using anti-CD68, troponin-I, and desmin antibodies were used to facilitate lesion characterization and assess cardiomyocyte viability. Microscopically, the apical to mid-ventricular myocardium to subendocardium had foci of cardiomyocyte disarray with cytoplasmic pallor to stippling and karyomegaly, vacuolization of the perimyseal connective tissue, a meshwork of fibrous tissue that concentrated around medium-sized blood vessels and dissected between or less often replaced affected cardiomyocytes; and a minimal, predominantly macrophage infiltrate. The disrupted cardiomyocytes were immunoreactive to desmin and troponin-I antibodies and had a normal cross-striation pattern by PTAH, indicating the chronic cardiomyopathy was not associated with active cardiomyocyte damage. The consistent distribution and morphology of the cardiomyopathy suggested a common etiology and pathogenesis. The features were reminiscent of chronic catecholamine-induced experimental cardiomyopathy and stress cardiomyopathy in monkeys and humans, respectively. This report documents another spontaneous heart lesion in clinically healthy monkeys for consideration during interpretation of toxicology studies.

Genomic analysis of genetic markers associated with inherited cardiomyopathy (round heart disease) in the turkey (Meleagris gallopavo)

In turkeys, spontaneous cardiomyopathy or round heart (RH) disease is characterised by dilated ventricles and cardiac muscle hypertrophy. Although the aetiology of RH is still unknown, the disease can have a significant economic impact on turkey producers. In an initial attempt to identify genomic regions associated with RH, we utilised the chicken genome sequence to target short DNA sequences (sequence-characterised amplified regions, SCARs) identified in previous studies that had significant differences in frequency distribution between RH+ and RH- turkeys. SCARs were comparatively aligned with the chicken whole-genome sequence to identify flanking regions for primer design. Primers from 32 alignments were tested and target sequences were successfully amplified for 30 loci (94%). Comparative re-sequencing identified putative SNPs in 20 of the 30 loci (67%). Genetically informative SNPs at 16 loci were genotyped in the UMN/NTBF turkey mapping population. As a result of this study, 34 markers were placed on the turkey/chicken comparative map and 15 markers were added to the turkey genetic linkage map. The position of these markers relative to cardiac-related genes is presented. In addition, analysis of genotypes at 109 microsatellite loci presumed to flank the SCAR sequences in the turkey genome identified four significant associations with RH.

Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure

A requirement for integrin-mediated adhesion in cardiac physiology is revealed through targeted deletion of integrin-associated genes in the murine heart. Here we show that targeted ablation of the integrin-linked kinase (ILK) expression results in spontaneous cardiomyopathy and heart failure by 6 wk of age. Deletion of ILK results in disaggregation of cardiomyocytes, associated with disruption of adhesion signaling through the beta1-integrin/FAK (focal adhesion kinase) complex. Importantly, the loss of ILK is accompanied by a reduction in cardiac Akt phosphorylation, which normally provides a protective response against stress. Together, these results suggest that ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure.

Interactive Effects of Dietary Sodium and Chloride on the Incidence of Spontaneous Cardiomyopathy (Round Heart) in Turkeys

Two pen trials were conducted in Utah, altitude 1,630 m, with Large White female turkey poults to evaluate effects of dietary Na and chloride (Cl) concentrations on live performance and deaths caused by spontaneous cardiomyopathy (STC, “round heart”) from 0 to 35 d of age. A randomized block 2 × 2 factorial arrangement with four replicate pens per treatment was used. Pen size was 3.8 × 5.6 m. In each trial, four starter diets were formulated from a common basal diet (corn-soy-meat) to obtain the following sodium and chloride concentrations: High Na (0.24%):High Cl (0.40%); High Na (0.24%):Low Cl (0.16%); Low Na (0.14%):High Cl (0.40%); and Low Na (0.14%):Low Cl (0.16%). Supplements were NaCl, NaHCO3, NH4Cl, or combinations. After laboratory analysis, true values of Na were slightly lower than expected, Cl was near expected values to slightly low, and K was 1.145%.Body weight and feed conversion ratio at 35 d of age were unaffected in both trials. In both experiments, STC mortality was significantly reduced by the Low Na:High Cl treatment compared to the other treatments. In conclusion, a diet containing 0.10 to 0.12% Na and 0.38 to 0.40% Cl, significantly improved poult livability by reducing STC mortality without adverse effects on poult weight or feed conversion ratio.

心房性ナトリウム利尿ペプチド分解酵素選択的阻害剤の心筋症自然発症ハムスターにおける心肥大および心筋組織線維化抑制作用

心房性ナトリウム利尿ペプチド分解酵素選択的阻害剤の心筋症自然発症ハムスターにおける心肥大および心筋組織線維化抑制作用

Effect of graded levels of dietary nitrite on pulmonary hypertension in broiler chickens and dilatory cardiomyopathy in turkey poults

In two separate trials, day-old broiler chicks and turkey poults were fed graded levels of dietary sodium nitrite in order to investigate the possible role of nitrite-induced methaemoglobinaemia on the incidence of chicken pulmonary hypertension and spontaneous turkey cardiomyopathy (STC). A transient low level of methaemoglobinaemia was observed after 7 days of exposure to dietary nitrite, but the levels returned to normal afterwards in spite of the presence of nitrite in the diet throughout the experiment. No effect on pulmonary hypertension, as measured by the right ventricle weight to total ventricle weight ratio, was observed in chickens exposed to dietary nitrite. The group of turkey poults receiving 1200 mg/kg nitrite in the diet had a higher incidence of STC than controls (20 v. 5%), although the difference was not statistically significant. The levels of nitrite-induced methaemoglobinaemia were probably too low to be considered as the aetiology of increased STC incidence.

Effect of lighting treatment on the productivity, health, behaviour and sexual maturity of heavy male Turkeys

1. Turkey poults (1620) were used to compare the effects of three lighting programmes on heavy strain males reared to 188 d: constant light (24L:0D, CON); increasing light (6L:18D at 7 d gradually increasing to 20L:4D by 63 d, INC); a pattern identical to INC followed by a decrease in daylength from 84 d to 10L:14D at 112 d (DID). 2. Lighting affected growth pattern but had no effect on body weight at 118 d or overall food to gain ratio. 3. Both INC and DID lighting reduced overall mortality in comparison to CON light primarily because of a reduction in the incidence of skeletal disease and spontaneous cardiomyopathy. INC and DID lighting increased the incidence of cannibalism. 4. Turkeys given INC or DID lighting had a superior ability to walk in comparison to those birds given CON light. 5. INC and DID males stood, ate and drank more frequently, and sat less often than CON turkeys during behavioural observation. 6. There were no lighting effects on carcase composition except that INC and DID birds had heavier keel bones. The ultimate force per cm2 (stress) required to break femora was greater for turkeys given INC and DID lighting (P = 0.065). 7. Plasma testosterone concentrations at 117 d were 272.5, 115.2 and 29.5 pg/ml for turkeys given CON, INC and DID lighting, respectively (P = 0.072). Testosterone concentration was not related to growth rate.

Effect of Protein Restriction during Brooding on Spontaneous Turkey Cardiomyopathy

The effect of early protein restriction on poult performance and mortality due to spontaneous turkey cardiomyopathy were examined in a facility that historically had a high incidence of the condition. Two thousand male turkey poults were divided into two equal subgroups for the first 4 weeks of life: one received standard commercial rations for the first 4 weeks (high-protein subgroup), and the other received rations with a protein content approximately 70% of the first subgroup (low-protein subgroup). Rations were the same after 4 weeks of age (standard commercial rations). At 16 weeks of age, turkeys in the low-protein subgroup weighed an average of 12.32 kilograms (27.1 pounds), whereas turkeys in the high-protein subgroup weighed an average of 12.73 kilograms (28.0 pounds). Total mortality for the low-protein subgroup was 10.1%, whereas total mortality for the high-protein subgroup was 15.7%. Total mortality due to spontaneous turkey cardiomyopathy in the high-protein subgroup was greater than twice that in the low-protein subgroup (10.4% versus 4.6%). These results show that lowering the protein content of the feed in the first 4 weeks significantly reduces mortality due to spontaneous turkey cardiomyopathy, but body weight gain is also reduced.

The Relation of Egg Specific Gravity to the Incidence of Spontaneous Cardiomyopathy in Tom Turkeys

The specific gravity and weight of eggs were determined for two groups of 600 eggs each, originating from Nicholas and British United Turkey of America (BUTA) turkey breeder flocks. A total of 137 Nicholas and 190 BUTA toms hatched from these eggs were used for the experiment. At days 21, 33, 40, 47, 56, and 61, toms that showed retarded growth were euthanatized, along with a corresponding number of normal birds. Both groups were measured for body weight, heart weight, separate weights of left and right ventricles, and combined atrial weight. At market age, the remaining toms were weighed, and the hearts were checked at processing for lesions characteristic of spontaneous turkey cardiomyopathy (STC). STC was found in 10.2% of Nicholas and 8.4% of BUTA toms. No correlation could be found between specific gravity of eggs and incidence of STC. Body weights of affected toms were reduced during the growing period. At processing, 2.8% of toms had lesions of STC, and mean body weight was 1298 g lower than average. The ratios of combined atrial weight:body weight, right ventricular weight:body weight, left ventricular weight:body weight, and total heart:body weight were significantly higher at all times in affected toms than in controls, and the differences were the greatest at 3 weeks of age.

Calcium-activated force in a turkey model of spontaneous dilated cardiomyopathy: Adaptive changes in thin myofilament Ca 2+ regulation with resultant implications on contractile performance

Using saponin skinned fibers, we investigated whether decreased myofilament calcium responsiveness and contractile activation may in part contribute to heart failure in an animal model of idiopathic spontaneous cardiomyopathy (SCM). We addressed the question as to whether there are adaptive changes at the level of the thin myofilaments in turkey poults with SCM. The calcium concentration ([Ca 2+]) required for 50% activation ([Ca 2+] 50%) was 0.80±0.12 μ m ( n=12) vs. 0.76±0.08 μ m ( n=12) and the Hill coefficient was 1.98±0.20 ( n=12) vs. 2.14±0.38 ( n=12) for control and SCM muscles respectively. Maximal Ca 2+-activated force was not different between control fibers and fibers from failing hearts (3.83±0.88 g/mm 2 vs. 3.65±0.39 g/mm 2). These data indicate there are no differences in calcium-activation between fibers from control and failing myocardium. The effects of caffeine, an agent that increases myofilament Ca 2+ sensitivity, were also studied. Addition of 10 m m caffeine resulted in a 0.06 pCa unit leftward shift of the force-pCa relationship in control hearts and 0.14 pCa units in SCM hearts. Caffeine (30 m m) increased force by 26±2.1% ( n=7) in control fibers and 44.5±8.7% ( n=8) in myopathic fibers at a pCa of 6.0. The increased responsiveness of muscles from failing hearts to caffeine indicates adaptive changes at the level of the thin myofilaments. Addition of dibutyryl-3′,5′-cyclic-Adenosine Monophosphate (D-cAMP) resulted in a 0.21 pCa rightward shift on the calcium axis to higher intracelluar calcium concentrations in control myocardium and 0.38 pCa units in SCM failing myocardium. The muscles were also sinusoidally oscillated at frequencies ranging between 0.01 and 100 Hz. In this analysis the frequency at which dynamic stiffness is minimum is taken as a measure of cross-bridge cycling rate. In control muscles, the frequency of minimum stiffness (f min) was 1.20±0.11 ( n=4) whereas it was 0.71±0.08 Hz ( n=4) in myopathic muscles. The addition of 10 μ m D-cAMP shifted f min from 1.20±0.11 Hz to 1.68±0.09 Hz (Δ= 0.48±0.06) in control fibers whereas in SCM fibers it caused greater shift of f min from 0.71±0.08 Hz to 1.73±0.08 Hz (Δ= 1.02±0.07). This differential effect of D-cAMP indicates adaptive changes at the level of the myofilaments. Our studies indicate that adaptive changes at the level of the thin myofilaments can potentially alter the “apparent” calcium-force relationship in failing myocardium and contractile performance, and that failing myocardium has the potential to generate similar levels of force as normal non-failing myocardium.

Spontaneous cardiomyopathy and nephropathy in the owl monkey (Aotus sp.) in captivity

Clinical and pathologic data were reviewed for 72 owl monkeys that died between January 1987 and May 1990 at the Center for Reproduction and Conservation of Nonhuman Primates in Iquitos, Peru. Tissue samples from 39 animals were examined. Hypertrophic cardiac disease (51% of animals examined), dilative cardiomyopathy (26%), and nephropathy (87%) were the most common diagnoses. The incidence of all three diseases appeared to increase with time in captivity. Nephropathy was less severe in colony-born animals.

Cardiac ultrastructural abnormalities in Syrian hamsters with spontaneous cardiomyopathy or subjected to cardiac overloads.

Ultrastructural and morphometric abnormalities of Syrian hamster cardiomyopathy were compared to those observed in two different models of cardiac hypertrophy produced by mechanical overload (abdominal aortic stenosis, 60-day duration) or by isoproterenol injection during 15 days in normal Syrian hamsters of the same strain. Aspects of increased protein synthesis were observed in all three groups of animals. This was the only abnormality observed in the aortic stenosis group. Cardiomyopathy was different from the two other types of overload by the existence of large calcium deposits inside of the myocytes, by the presence of thin filaments and amorphous material accumulation suggesting abnormal synthesis and by a significant reduction of myofibrils at the heart-failure phase. Nuclear abnormalities with nuclear constrictions suggesting a division process and an increased number of myocytes with two nuclei were present in both spontaneous cardiomyopathy and isoproterenol-induced cardiopathy. Therefore, Syrian hamster cardiomyopathy appears to be different from cardiopathy induced by hemodynamic overload but, in spite of specific aspects, resembles that induced by isoproterenol injections, strengthening the hypothesis of a pathogenic role of catecholamines in the Syrian hamster cardiomyopathy.