Feline hypertrophic cardiomyopathy: reduced microvascular density and involvement of CD34+ interstitial cells

Abstract

The sequence of pathological events in feline hypertrophic cardiomyopathy (fHCM) is still largely unknown, although we know that fHCM is characterized by interstitial remodeling in a macrophage-driven pro-inflammatory environment and that myocardial ischemia might contribute to its progression. This study aimed to gain further insights into the structural changes associated with interstitial remodeling in fHCM with special focus on the myocardial microvasculature and the phenotype of the interstitial cells. Twenty-eight hearts (16 hearts with fHCM and 12 without cardiac disease) were evaluated in the current study, with immunohistochemistry, RNA-in situ hybridization, and transmission electron microscopy. Morphometrical evaluations revealed a statistically significant lower microvascular density in fHCM. This was associated with structural alterations in capillaries that go along with a widening of the interstitium due to the accumulation of edema fluid, collagen fibers, and mononuclear cells that also proliferated locally. The interstitial cells were mainly of fibroblastic or vascular phenotype, with a substantial contribution of predominantly resident macrophages. A large proportion expressed CD34 mRNA, which suggests a progenitor cell potential. Our results indicate that microvascular alterations are key events in the pathogenesis of fHCM and that myocardial interstitial cell populations with CD34+ phenotype play a role in the pathogenesis of the disease.

Feline myocardial transcriptome in health and in hypertrophic cardiomyopathy—A translational animal model for human disease

“…Additional pathways that are involved in cellular proliferation, cardiac hypertrophy, microtubule and cytoskeletal organization, angiogenesis and endothelial function were found to be activated in the HCM samples; their activation is consistent with the histopathology changes in HCM [5,[9][10][11][12][13][14]. These included the cell surface receptor integrin and ILK signaling [59,60], reelin signaling mediated by PI3K/Akt, Rho or STAT3 [61,62], the stathmin 1 pathway (which results in microtubulus stabilization when phosphorylated by PI3K, PKA or MAPK), and the CREB response (which is mediated by RhoGTPases and MAPK) [60].…”

“…To ensure that these inclusion criteria were met, gross and histopathology examinations were conducted and supervised by a board-certified specialist in veterinary pathology as the gold standard in all cats to confirm HCM in the cats clinically diagnosed with the disease, the absence of cardiac diseases in the healthy cats and the absence of systemic diseases in all cats. As previously published, HCM criteria comprised of increased left ventricular wall thickness, cardiomyocyte degeneration, cardiomyocyte disarray, interstitial fibrosis, accumulation of inflammatory cells, and microvascular changes [10][11][12][13][14]. Only hearts from male cats were included to limit the potential influence of sex on the results, since sex differences in myocardial gene expression have been reported for non-failing human hearts, healthy cats, and cats with HCM [34,36,38].…”

“…Histopathological and immunohistological investigations reported an increase in interstitial macrophages in the HCM LV [10,11]. A proliferation of resident macrophages (Iba-1/MHC II positive/calprotectin-negative) was suspected but the type of these macrophages (M1 or M2) was not determined [10,11]. Only scattered T-cells (CD3-positive) were found.…”

“…The disease is characterized by primary left ventricular hypertrophy and diastolic dysfunction [4,5] and is typically associated with variable clinical presentation and disease progression; many patients remain asymptomatic for years while others develop end-stage cardiomyopathy and severe outcomes such as congestive heart failure and sudden death [7][8][9]. Histopathological changes include cardiomyocyte degeneration, cardiomyocyte disarray, interstitial fibrosis, accumulation of inflammatory cells, and microvascular changes [5,[9][10][11][12][13][14]. This overall similarity of feline and human HCM suggests a comparable pathogenesis [4][5][6]15].…”

“…These studies used either left ventricular samples only or provided no regional information ('myocardial samples', 'myocardial/heart tissue), patient sex was not considered in the analysis [28][29][30][31]. While a few studies have investigated gene expression in cats with HCM using reverse transcription quantitative polymerase chain reaction (RT-qPCR) or microarrays [10,11,22,[32][33][34][35], high-throughput RNA sequencing (RNA-seq) has so far not been used, hence knowledge on all DEG and pathways involved in feline HCM is still lacking.…”