Cardiac gene activation varies between young and adult cats and in the presence of hypertrophic cardiomyopathy.

Little is known about the difference of myocardial gene transcription in young and adult cats and how transcription is further modified in cats with hypertrophic cardiomyopathy (HCM) and with left atrial (LA) thrombus formation. We hypothesized that selected factors for coagulation, endothelial activation, inflammation, and remodelling are modified with age and are activated in the hearts of cats with HCM. Left atrial and ventricular (LV) samples from 12 cats with HCM (seven without (HCMwoAT] and five with LA thrombi [HCMwAT]), and six young (YC) and six adult (AC) control cats without cardiac disease were investigated for relative expression of the following genes using quantitative polymerase chain reaction: von Willebrand factor, a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13, platelet activating factor, E- and P-selectin, intercellular and vascular adhesion molecules-1, ß2-integrin, vascular endothelial growth factor, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), heat shock protein-70, and myocyte-specific enhancer factor 2C. Significant differences in gene activation were found between YC and AC, and YC and cats with HCM. Compared to AC, MCP-1 and IL-6 were significantly higher in cats with HCM. The presence of an LA thrombus was associated with higher IL-6 expression. These results illustrate the relevance of age and/or lifestyle on gene expression in the feline heart. The gene transcription pattern found in AC hearts might predispose cats to their characteristic cardiac remodelling processes and thrombus formation if disease occurs. It further supports the involvement of inflammation, but not coagulation and endothelial activation, in HCM.

Myocardial transcription of inflammatory and remodeling markers in cats with hypertrophic cardiomyopathy and systemic diseases associated with an inflammatory phenotype.

Feline hypertrophic cardiomyopathy (HCM) is characterized by macrophage-driven myocardial remodeling processes in a pro-inflammatory environment. To further investigate the mechanisms behind these processes, the myocardial transcription of cytokines and remodeling enzymes was comparatively assessed in cats with HCM and cats without cardiac diseases. Sixty-seven cats were included, 17 cats with HCM (including 5 with atrial thrombus; AT), and 50 cats without cardiac diseases. The latter comprised 10 control cats (no cardiac or relevant systemic disease), 34 cats with diseases suspected to be associated with a systemic inflammatory state of which 18 suffered from feline infectious peritonitis (FIP), and 6 cats with multicentric lymphoma. Samples from atria, ventricular free walls and interventricular septum were examined using quantitative reverse transcriptase PCR. The overall highest myocardial marker transcriptions were observed in cats with multicentric lymphoma, FIP and HCM, followed by diseases likely associated with a systemic inflammatory state, and control cats. Inflammatory marker transcription predominated in the myocardium of cats with systemic inflammatory diseases, whereas in HCM the transcription of remodeling enzymes prevailed. Sex significantly influenced the myocardial transcription of several remodeling enzymes. These results suggest a versatile myocardial response depending on the disease and illustrates the relevance of sex for the cardiac response to cardiac and systemic disease in cats. A systemic inflammatory state appears to elicit an inflammatory phenotype in the myocardium, whereas in HCM, the myocardium mediates its own remodeling. In HCM, the identified markers might be involved in the ongoing remodeling processes causing structural and functional changes.

Canine Dilated Cardiomyopathy: Diffuse Remodeling, Focal Lesions, and the Involvement of Macrophages and New Vessel Formation.

Dilated cardiomyopathy (DCM) is among the most common cardiac diseases in dogs. Its pathogenesis is not fully understood, but myocardial remodeling and inflammation are suspected to be involved. The present study aimed to characterize the pathological processes in canine DCM, investigating morphological changes in association with the expression of relevant cytokines and remodeling markers. The myocardium of 17 dogs with DCM and 6 dogs without cardiac diseases was histologically evaluated, and selected cases were further examined by immunohistochemistry, morphometry, and reverse transcription quantitative PCR. In DCM, the myocardium exhibited subtle but statistically significant diffuse quantitative changes. These comprised increased interstitial collagen deposition and macrophage numbers, as well as an overall reduced proportion of contractile tissue. This was accompanied by a significant increase in myocardial transcription of intracellular adhesion molecule (ICAM) 1, inflammatory cytokines, and remodeling enzymes. Laser microdissection showed that cardiomyocytes transcribed most relevant markers including ICAM-1, tumor necrosis factor α, transforming growth factor ß (TGF-ß), matrix metalloproteinase 2 (MMP-2), tissue inhibitor of MMP (TIMP) 1 and TIMP-2. In addition, there were multifocal cell-rich lesions characterized by fibrosis, neovascularization, macrophage infiltration, and cardiomyocyte degeneration. In these, macrophages were often found to express ICAM-1, TGF-ß, and vascular endothelial growth factor; the former two were also expressed by cardiomyocytes. These results characterize the diffuse myocardial remodeling processes that occur in DCM. The observed multifocal cell-rich lesions might result from reduced tissue perfusion. Macrophages and cardiomyocytes seem to actively contribute to the remodeling processes, which ultimately lead to cardiac dilation and dysfunction. The precise role of the involved cells and the factors initiating the remodeling process still needs to be identified.

Feline Hypertrophic Cardiomyopathy: The Consequence of Cardiomyocyte-Initiated and Macrophage-Driven Remodeling Processes?

vHypertrophic cardiomyopathy (HCM) is the most commonly diagnosed cardiac disease in cats. The complex pathophysiology of HCM is still far from clear, but myocardial remodeling is a key process, and cardiomyocyte disarray, interstitial fibrosis, leukocyte infiltration, and vascular dysplasia are described histopathologic features. The present study systematically investigated the pathological processes in HCM, with the aim to shed more light on its pathogenesis. Hearts from 18 HCM cases and 18 cats without cardiac disease (controls) were examined, using light and transmission electron microscopy, immunohistochemistry, and morphometric approaches to identify and quantify the morphological changes. Reverse transcription-quantitative polymerase chain reaction was applied to provide additional mechanistic data on remodeling processes. In HCM, the left and right ventricular free wall and septal myocardium exhibited a significantly reduced overall cellularity, accompanied by a significant increase in interstitial Iba1-positive cells with macrophage morphology. In addition, the myocardium of almost half of the diseased hearts exhibited areas where cardiomyocytes were replaced by cell-rich fibrous tissue with abundant small and medium-sized vessels. HCM hearts also showed significantly higher transcription levels for several inflammatory and profibrotic mediators. Our findings suggest that HCM is the consequence of cardiac remodeling processes that are the result of cardiomyocyte damage and to which macrophages contribute by maintaining an inflammatory and profibrotic environment.

Clinicopathological features and comorbidities of cats with mild, moderate or severe hyperthyroidism: a radioiodine referral population.

OBJECTIVES: This study sought to explore the clinicopathological features and comorbidities of cats with mild, moderate and severe hyperthyroidism in a radioiodine referral population. METHODS: Medical records were reviewed, along with results of serum biochemistry, urinalysis, systolic blood pressure and diagnostic imaging performed at the time of radioiodine referral. Cats were grouped by total thyroxine (TT4) levels as mildly (TT4 60.1-124.9 nmol/l), moderately (TT4 125-250 nmol/l) or severely (TT4 >250 nmol/l) hyperthyroid at the time of diagnosis and referral. RESULTS: Thirty percent (42/140) of the cats were <10 years old at diagnosis. In 24.3% (34/140), hyperthyroidism was diagnosed incidentally. The time between diagnosis and referral for radioiodine was significantly longer in cats with severe hyperthyroidism at the time of referral ( P = 0.004). An increase in severity group between the time of diagnosis and referral occurred in 38.6% (54/140) of cats. At referral, 54.3% (25/46) of cats with mild, 66.7% (42/63) with moderate and 80.6% (25/31) with severe hyperthyroidism were unstable despite ongoing medical or dietary management. The prevalence of cardiac abnormalities was significantly increased in cats with severe hyperthyroidism ( P = 0.014) compared with those with mild or moderate hyperthyroidism. There was no significant difference in the likelihood of renal disease ( P = 0.708) or hypertension ( P = 0.328) between the groups. CONCLUSIONS AND RELEVANCE: Incidental diagnosis of hyperthyroidism occurs commonly, potentially owing to increased disease screening. Cats with severe hyperthyroidism at referral were more likely to be chronically hyperthyroid with a history of poor stabilisation. This subset of patients was significantly more likely to have cardiac abnormalities. Thyrotoxic cardiomyopathy may ultimately affect patient suitability for curative treatments (radioiodine or thyroidectomy) owing to higher anaesthetic risks and potential for decompensation into congestive heart failure with the stress of travel and hospitalisation. Curative therapy should be considered before the development of severe hyperthyroidism.

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases.

BACKGROUND: Age, gender and systemic diseases all influence cardiac function and remodelling. In cats, age and gender associated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whether relevant cytokines and extracellular matrix (ECM) remodelling enzymes are expressed in the myocardium of cats with non-cardiac diseases and whether transcription levels are influenced by age and gender. METHODS: The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire) and nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects. All hearts were assessed for any pathological changes, and the myocardium was analysed for interleukin (IL)-1, -2, -4, -6, -18, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß, matrix metalloproteinase (MMP)-2, -3, -13, tissue inhibitor of MMP (TIMP)-1, -2 and -3 transcriptions using quantitative RT-PCR assays. RESULTS: Despite the absence of any histological evidence of myocardial damage, inflammation and fibrosis, the myocardium of all the cats was found to constitutively transcribe cytokines and ECM remodelling enzymes, with generally higher mRNA concentrations in the atria than in the ventricles. The young and male cats exhibited higher transcription levels throughout the myocardium in comparison to the older and female cats. Furthermore, age-associated transcription pattern differed between male and female cats. CONCLUSION: The constitutive transcription of ECM remodelling enzymes suggests continuous myocardial remodelling throughout the entire life of a cat. The myocardium of young and male cats appears to be in a pro-inflammatory state, whereas in older and female cats the myocardium exhibits a reduced inflammatory reaction to systemic disease. Age-associated cardiac remodelling seems to be influenced by non-hormonal factors in male and female cats.

Myocardial cytokine expression in dogs with systemic and naturally occurring cardiac diseases.

OBJECTIVE: To compare myocardial cytokine expression in dogs with naturally occurring cardiac or systemic diseases and dogs without cardiac or systemic diseases (control dogs) SAMPLE: Myocardial tissue samples from 7 systemic disease-affected dogs (SDDs), 7 cardiac disease-affected dogs (CDDs), and 8 control dogs. PROCEDURES: mRNA expression of interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß1, TGF-ß2, TGF-ß3, and growth differentiation factor-15 in myocardial tissue samples obtained from CDDs, SDDs, and control dogs were analyzed via quantitative PCR assays. RESULTS: In control dogs, only mRNA for TNF-α, TGF-ß1, and TGF-ß3 was detected; concentrations were significantly higher in male than in female dogs. In SDDs and CDDs, all cytokines, growth factors, and growth differentiation factor-15 were expressed. Compared with findings in SDDs, IL-1, IL-6, IL-8, IL-10, TNF-α, and IFN-γ expression was significantly increased in CDDs; specifically, IL-1, IL-8, TNF-α, TGF-ß1, and TGF-ß3 expression was increased in the atria and IL-8, IL-10, TNF-α, and IFN-γ expression was increased in the ventricles of CDDs. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggested that the alterations in cytokine expression in SDDs and CDDs, compared with control dog findings, were a result of inflammatory system activation. The differences in cytokine expression in atria and ventricles between SDDs and CDDs were suggestive of different remodeling processes. A better knowledge of myocardial involvement in SDDs and of immune regulation in CDDs might beneficially affect morbidity and mortality rates and provide new treatment approaches.

Are metal-induced hypersensitivities in harbor seals associated with liver function?

Environmental exposure to metals is believed to affect marine mammal health adversely including immunosuppression or acute as well as chronic inflammatory processes leading to hypersensitivities or autoimmune diseases. Metal-specific hypersensitivities were found in several pinnipeds of the North Sea. However, hypersensitivity is a complex phenomenon whose characteristics are still not completely understood; in particular, effects on health are not well established. In the present study, we compared basic hematological and biochemical parameters of seals with and without metal-specific hypersensitivities. We found altered hematological parameters and liver enzyme patterns in seals with a metal-induced hypersensitivity, including a reduction in macrophages, an increase in lymphocytes, and elevated levels of lactate dehydrogenase. These findings support the suggestion of a chronic influence of metal pollutants on the health of marine mammals of the North Sea.