Exercise training affects hemodynamics and exercise capacity in cases of heart failure with preserved ejection fraction: a non-randomized controlled trial in individuals aged 65-80 years.

Introduction: Exercise training is an established intervention method for improving exercise capacity and survival rates in patients with heart failure with preserved ejection fraction (HFpEF). However, most reports have focused on European and American patients, with limited data regarding the effects of exercise training on cardiac function, hemodynamics, and exercise capacity in East Asian patients. This study investigated the effects of exercise training on cardiac function, hemodynamics, and exercise capacity in Japanese patients aged 65-80 years with HFpEF. Methods: This single-center, open-label, non-randomized, controlled trial prospectively enrolled 99 outpatients. Eligibility criteria for HFpEF patients were an HFA score ≥5 in addition to clinical symptoms of heart failure and left ventricular diastolic dysfunction. Exercise training in the intervention group consisted of aerobic exercise and strength training thrice weekly for 5 months. Patients in the control group continued the usual treatment for 5 months. Resting cardiac function was evaluated using echocardiography. Peak oxygen uptake (peakVO2), ventilatory equivalent (VE) vs. carbon dioxide output (VCO2) slope, peak cardiac output index, and arteriovenous oxygen difference were calculated using cardiopulmonary exercise testing combined with impedance cardiography. Results: After 5 months of exercise training, remarkable interactions were observed, with peakVO2 as the primary outcome. Additionally, significant interactions were observed between hemodynamic indices and some echocardiographic parameters. The mean percentage change in peakVO2 from baseline was 8.3% in the intervention group. Fifteen study participants (30.1%) in the intervention group achieved a clinically meaningful change of 3.0 ml/min/kg (10% improvement) in peakVO2 from baseline. The group with 3.0 ml/min/kg or 10% improvement in peakVO2 from baseline had a considerably lower prevalence of diabetes mellitus and VE vs. VCO2 slope and considerably higher left atrial-global longitudinal strain values than the group without any notable improvements. Conclusions: Although exercise training can help improve exercise intolerance in Japanese patients aged 65-80 years with HFpEF, its benefits are limited. Our results suggest that HFpEF, complicated by diabetes mellitus and decreased ventilatory efficiency during exercise, may require reconsideration of intervention strategies. This trial was registered with the University Hospital Medical Information Network, a trial registry in Japan (registration number: UMIN000045474).

Negative Influence of Aging on Differentiation and Proliferation of CD8+ T-Cells in Dogs.

Immunosenescence is an age-related change in the immune system characterized by a reduction in naïve T-cells and an impaired proliferative capacity of CD8+ T-cells in older individuals. Recent research revealed the crucial impact of immunosenescence on the development and control of cancer, and aging is one of the causes that diminish the therapeutic efficacy of cancer immunotherapies targeting CD8+ T-cell activation. Despite dog cancer being defined as an age-related disease, there are few fundamental understandings regarding the relationship between aging and the canine immune system. Therefore, we aimed to elucidate the characteristics of immunosenescence in dogs and analyzed the effects of aging on the differentiation status and proliferation of canine CD8+ T cells using T-cell specific stimulation with anti-canine CD3/CD28 antibody-coated beads and interleukin-2. As a result, we found that older dogs have a lower proliferative capacity of CD8+ T-cells and a reduction in the naïve subset in their peripheral blood. Further analysis showed that older dogs had attenuated proliferation of the effector and central memory subsets. These results indicate the importance of maintaining less differentiated subsets to expand CD8+ T-cells in dogs and provide helpful insight into the development of dog immune therapies that require T-cell expansion ex vivo.

Evaluation of the influence of the C-X-C motif chemokine ligand 12 / C-X-C chemokine receptor 4 axis on canine mammary gland tumor cell migration.

C-X-C motif chemokine ligand 12 (CXCL12) is one of the chemokines that binds to C-X-C chemokine receptor 4 (CXCR4) on tumor cell membranes and induces chemotaxis and/or migration. Mammary gland tumors (MGT) are the most common neoplasms in intact female dogs, with local invasion and distant metastasis regarded as problems. However, the influence of the CXCL12/CXCR4 axis on canine MGT cell migration has not been elucidated. This study aimed to evaluate the expression of CXCL12 and CXCR4 in canine MGT cells and tissues and investigate the influence of CXCL12 protein on the migratory ability of MGT cells. CXCL12 expression was evaluated in 10 canine malignant MGT tissues. CXCL12 expression in tumor cells was identified in all examined tissues; however, the staining pattern and intensity differed between the tumors. Immunocytochemistry revealed three canine MGT cell lines as CXCR4-positive. Migratory ability was evaluated using a wound healing assay, and the migration of CXCR4-positive MGT cells was significantly activated by the addition of CXCL12 protein. This influence was canceled by pre-treatment with a CXCR4 antagonist. The results of our study suggest that the CXCL12/CXCR4 axis may be associated with the migration of canine MGT.

Biological features of canine cancer-associated fibroblasts and their influence on cancer cell invasion.

Cancer-associated fibroblasts (CAFs) play an essential role in tumor invasion and metastasis. In dogs, the biological features of CAFs have not been well characterized. The purpose of this study was to investigate differences in the biological activities of canine CAFs and normal fibroblasts (NFs), and their influence on the migration and invasion of cancer cells. Canine CAFs and NFs were harvested from surgically-resected malignant epithelial tumor tissues and skin tissues of dogs. A wound-healing assay was conducted to compare the migratory and invasive abilities of canine CAFs and NFs. The results of this study showed that canine CAFs have a greater migratory and invasive ability than NFs. To observe the indirect and direct interactions between fibroblasts and cancer cells, Boyden chamber assay and 3D co-culture with collagen gel were conducted. The number of migrated and infiltrated cancer cells co-cultured with canine CAFs was greater than that with NFs. In the 3D co-culture, cancer cells showed noteworthy proliferation on the surface of gels containing canine CAFs and invasion into the gel. On the other hand, no infiltration of cancer cells into the gel containing NFs was observed. It was suggested that canine CAFs activate migration and invasion of cancer cells and promote the infiltration of cancer cells into collagen gels.

Thoracic Wall Reconstruction with Dorsal Diaphragmatic Traction and Preservation of Diaphragmatic Attachments in a Dog with Resection of the 11-13th Ribs.

A 9-year-old, 4.7 kg, spayed female Chihuahua presented with a 3.5 cm soft tissue sarcoma on the dorsal right thoracic wall. The tumor was resected, including the 11−13th ribs, resulting in a caudal dorsal thoracic wall defect. The defect was reconstructed with direct traction of part of the diaphragm dorsally, preserving the diaphragmatic attachments to the body wall, and the diaphragm was sutured to the surrounding ribs and muscles. Possible respiratory complications, including paradoxical respiration and exercise intolerance, were not observed during the perioperative or postoperative observation periods. This novel procedure is expected to be an option for caudal thoracic wall reconstruction when the diaphragmatic attachments remain intact even after the resection of the last rib. In addition, this procedure can be performed in dogs weighing <5 kg, with small pleural cavities and without respiratory disorders.

Adhesion and Disintegration Phenomena on Fractal Agar Gel Surfaces.

In the present study, mechanical phenomena on fractal agar gel were analyzed to understand the interfacial properties of hydrophilic biosurfaces. The evaluation of adhesion strength between the fractal agar gel surfaces showed that the fractal structure inhibits the adhesion between the agar gel surfaces. In addition, when the disintegration behavior of an agar gel block was observed between fractal agar gel substrates, the rough structure prevented the sliding of an agar gel block. These findings are useful for understanding the biological significance of rough structure on the biological surfaces.