No abstract

Our previous studies have revealed the abundant expression of T-cadherin--a glycosylphosphatidylinositol (GPI)-anchored member of cadherin superfamily--in endothelial and mural cells in the heart and vasculature. The upregulation of T-cadherin in vascular proliferative disorders such as atherosclerosis and restenosis suggests the involvement of T-cadherin in vascular growth and remodeling. However, the functional significance of this molecule in the vasculature remains unknown. The effect of T-cadherin on angiogenesis in vivo was evaluated using Matrigel implant model. We demonstrate that T-cadherin overexpression in L929 cells injected in Matrigel inhibits neovascularization of the plug. In vitro T-cadherin inhibits the directional migration of endothelial cells, capillary growth, and tube formation but has no effect on endothelial cell proliferation, adhesion, or apoptosis in vitro. These data suggest that T-cadherin expressed in the stroma could act as a negative guidance cue for the ingrowing blood vessels and thus could have an important potential therapeutic application.

Background Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH). Methods We enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg. Results The patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, − 3.3 to − 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group. Conclusions In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH. Trial registration Russian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849. Registered 20 April 2012. This manuscript adheres to the CONSORT guidelines.

Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4+ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.

Heart failure withpreserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used toimprove the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms ofdevelopment of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory statecauses a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with someevidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

The slightly elevated Lp(a) concentration along with changes in the level of T lymphocyte subpopulations was first shown to significantly potentiate the risk of progressive and multiple CA lesion in the examinees. The correlation of IgM anti-Lp(a) autoAb with the lymphocyte activation marker sCD25 and that of IgG anti-Lp(a) autoAb with Th1 have demonstrated that Lp(a) is involved in the autoimmune inflammatory processes in atherosclerosis.

Left atrial (LA) dysfunction seems to play a central role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), is associated with disease severity and poor outcomes and potentially impacts management. Identifying LA myopathy can help guide tailored therapy for HFpEF. Echocardiography allows the accurate measurement of atrial size and function, where LA strain appears to be a sensitive measure of intrinsic LA myopathy. Several therapies and devices that decompress of left atrium are being tested for HFpEF. Further investigation is required to understand the specific atrial effects of statins, mineralocorticoid receptor antagonists, and other therapies.

Background Diagnosis of early heart failure with preserved ejection fraction (HFpEF) may be challenging because exertional dyspnea is not specific for heart failure, and biomarkers and indicators of volume overload may be absent at rest. We aimed to characterize the contribution of abnormal left atrial (LA) mechanical properties to exercise intolerance in early HFpEF (normal left ventricular filling pressures at rest but elevated during exercise). Methods Diastolic stress testing (DST) was performed in 104 patients with left ventricular ejection fraction ≥50%, in sinus rhythm, and no more than LV diastolic dysfunction grade I, referred for assessment of exertional dyspnoea. Patients exercised supine cycle ergometry at 60 rpm starting with a 3-min period of low-level 25-W workload followed by 25-W increments in 3-minute stages to maximum tolerated levels. According to DST, 43 patients were diagnosed with HFpEF (average mitral E-to-annular e′ ratio [E/e′] &gt; 14, and peak TR velocity &gt;2.8 m/sec at maximal exertion) and 61 as non-cardiac dyspnea (NCD). During the test, two-dimensional images, mitral E/e′, peak tricuspid regurgitation (TR) velociry, and two-dimensional LA mechanical parameters (longitudinal LA strain [LASR] and strain rate [LASRR] during reservoir phase and LA stiffness assessed as a ratio of mitral E/e′ ratio to LASR) were analysed at baseline, and at peak. Results HFpEF and NCD patients were similar in regard to the LA volume index (34.4 [30.2;39.4] vs. 33.6 [28.4;37.1] ml/m2), and NT-proBNP level (132 [80;238] vs. 129 [80;197] pg/ml). As compared with NCD patients, HFpEF patients displayed reduced LA reservoir function assessed by LASR (22.3 [18.9;25.6] vs. 24.2 [21.2;29.8] % at rest, and 25.3 [21.4;30.2] vs. 29.0 [24.2;33.3] % with exercise) and LASRR (0.78 [0.58;0.96] vs. 0.90 [0.68;1.12] /s at rest, and 1.10 [0.79;1.31] vs. 1.24 [1.03;1.56] s–1 with exercise) with increased LA stiffness (0.57 [0.44;0.70] vs. 0.42 [0.30;0.49] mmHg/% at rest, and 0.61 [0.46;0.74] vs. 0.40 [0.32;0.51] mmHg/% with exercise, all P &lt; 0.05). Additionally, HFpEF patients showed smaller exercise elevation in LASRR (+31 [-5;77] vs. +47 [12;85] % as compared with resting values, P &lt; 0.05). Exercised LA stiffness and reservoir strain correlated with exercise LV filling pressures estimated by mitral E/e′ ratio (r = 0.72 and r =–0.35, P &lt; 0.001). LA stiffness showed a good diagnostic accuracy (area under the curve 0.75), and LA stiffness &gt; 0.46 mmHg/% demonstrated reasonable sensitivity (79%) and specificity (71%) to diagnose HFpEF. Neither LV global longitudinal strain and ejection fraction at rest nor their exercise-induced elevation differed between HFpEF and NCD. Conclusion Impaired LA reservoir function and increased stiffness are associated with exercise intolerance in patients with early HFpEF, while LV systolic function seems preserved in this stage of the disease. LA stiffness provides HFpEF diagnostic potential in ambulatory patients with dyspnea