Synthesis and Biological Activity of the Pyridine-Hexacyclic-Steroid Derivative on a Heart Failure Model

Background: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. Objective: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. Methods: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. Results: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. Conclusion: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

Prognostic Implications of a Modified Seattle Heart Failure Model Score following Transcatheter Aortic Valve Replacement

Background: The Seattle heart failure model (SHFM) score is a well-known risk predictor of mortality in patients with heart failure. We validated this score in patients receiving transcatheter aortic valve replacement (TAVR) and aimed to generate further risk discrimination by adding invasive hemodynamics parameters. Methods: Patients who underwent TAVR at our institute between 2015 and 2020 were included and followed for 2 years from index discharge. Patients were randomly assigned to the derivation cohort or the validation cohort. In the derivation cohort, the original SHFM score was modified by adding baseline hemodynamics parameters to evaluate the primary outcomes: 2-year incidence of mortality or readmission from heart failure. The model performance of the modified SHFM score was evaluated in the validation cohort. Results: A total of 217 patients (median age: 86 (83, 88) years old, 64 (29%) men) were included. From the derivation cohort (N = 108), a novel modified SHFM score was constructed: 6 × (original SHFM score <88.1%) + 5 × (pulmonary capillary wedge pressure > 14 mmHg) + 4 × (cardiac index < 2.26 L/min/m2), which had an improved discrimination compared with the original model (area under the curve: 0.887 versus 0.679, p = 0.014). In the validation cohort (N = 109), the modified SHFM score showed accurate predictive discrimination of the 2-year cumulative incidence of the primary endpoint into three groups (a low score group with 0–5 points, 3%; an intermediate score group with 6–10 points, 12%; and a high score group with 11–15 points, 43%, p < 0.001). Conclusion: A modified SHFM score consisting of the original SHFM score and invasive hemodynamics parameters predicted mortality and morbidity following TAVR. Evaluation of the external validity of this score in other cohorts needs further investigation.

Effect of sacubitril/valsartan on inflammation and oxidative stress in doxorubicin-induced heart failure model in rabbits

Our study evaluates the effects of sacubitril/valsartan (SAC/VAL) in the rabbit model of doxorubicin-induced heart failure. Twenty rabbits (5 per group) were administered with doxorubicin (DOX, 1.5 mg kg−1, i.v.) to induce heart failure. Specific biomarkers such as BNP, CnT, CRP and ROMs were determined. The cardiac enzymatic anti-oxidant systems were recorded with their electrographic profiles. HR, SBP, DBP and MAP were restored at 5 or 10 mg kg−1 (p.o.) of SAC/VAL compared to DOX, followed by reduced levels of creatinine and BNP (p < 0.001). Significant improvements (p < 0.05) compared to DOX were also noticed in CAT, SOD and LPO with the same doses of SAC/VAL. Specific biomarkers such as BNP, CnT, CRP and ROMs descended significantly (p < 0.001) with treatment when compared to their baseline values. Our findings implied that SAC/VAL treatment reduced the inflammation and oxidative stress to improve the cardiac function.

Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.