A Comparative Investigation of the Pulmonary Vasodilating Effects of Inhaled NO Gas Therapy and Inhalation of a New Drug Formulation Containing a NO Donor Metabolite (SIN-1A).

Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.

Sex similarities and differences in the reverse and anti-remodeling effect of pressure unloading therapy in a rat model of aortic banding and debanding.

Investigating the effect of sex on pressure unloading therapy in a clinical scenario is limited by several nonstandardized factors. Hence, we sought to study sex-related similarities and differences under laboratory conditions. Pressure overload was induced in male and female rats by aortic banding (AB) for 6 and 12 wk. Age-matched sham-operated animals served as controls. Pressure unloading was performed by aortic debanding at week 6. Different aspects of myocardial remodeling were characterized by echocardiography, pressure-volume analysis, histology, qRT-PCR, and explorative proteomics. Hypertrophy, increased fetal gene expression, interstitial fibrosis, and prolonged active relaxation were noted in the AB groups at week 6 in both sexes. However, decompensation of systolic function and further deterioration of diastolic function only occurred in male AB rats at week 12. AB induced similar proteomic alterations in both sexes at week 6, whereas characteristic differences were found at week 12. After debanding, regression of hypertrophy and recovery of diastolic function took place to a similar extent in both sexes. Nevertheless, fibrosis, transcription of ß-myosin-to-α-myosin heavy chain ratio, and myocardial proteomic alterations were reduced to a greater degree in females than in males. Debanding exposed anti-remodeling properties in both sexes and prevented the functional decline in males. Female sex is associated with greater reversibility of fibrosis, fetal gene expression, and proteomic alterations. Nevertheless, pressure unloading exposes a more pronounced anti-remodeling effect on the functional level in males, which is attributed to the more progressive functional deterioration in AB animals.NEW & NOTEWORTHY The present study is the first to assess the role of sex on pressure unloading-induced reverse and anti-remodeling in a rat model of aortic banding and debanding. Our data indicate that female sex is associated with a greater reversibility of fibrosis, fetal gene expression, and proteomic alterations compared with males. Nevertheless, pressure unloading exposes more anti-remodeling effect on the functional level in males, which is attributed to the more rapid functional deterioration in aortic-banded animals.

Non-invasive myocardial work as an independent predictor of postprocedural NT-proBNP in elderly patients undergoing transcatheter aortic valve replacement.

Aortic stenosis has become the most prevalent valvular disease with increasing life expectancy and the ageing of the population, representing a significant clinical burden for health care providers. Its treatment has been revolutionized by transcatheter aortic valve replacement (TAVR) as a safe and minimally invasive option for elderly patients. Left ventricular (LV) functional measurement is of particular importance before TAVR, however, increased afterload significantly influences the conventional echocardiographic parameters. Non-invasive myocardial work examines myocardial deformation in the context of instantaneous LV pressure, thus, it might be a more reliable measure of LV function. Accordingly, we aimed to study non-invasive myocardial work and its relationship with functional outcome following TAVR.We enrolled 90 TAVR candidates (80 [75-84] years; 44% female). Using echocardiography, we quantified ejection fraction (EF), global longitudinal strain (GLS), global myocardial work index (GWI) and global constructive work (GCW) before and 12 months after the procedure. Serum NT-proBNP levels were also measured. EF did not change (52.6 ± 13.1 vs. 54.2 ± 10.5%; p = 0.199), while GLS increased (-13.5 ± 4.6 vs. -15.2 ± 3.8%; p < 0.001). GWI decreased (1913 ± 799 vs. 1654 ± 613 mmHg%; p < 0.001) and so did GCW (2365 ± 851 vs. 2177 ± 652 mmHg%; p = 0.018). History of atrial fibrillation (AF) (ß = 0.349) and preprocedural GCW (ß = -0.238) were independent predictors of postprocedural NT-proBNP (p < 0.001).GLS, GWI and GCW changed after TAVR while there was no alteration in EF. The preprocedural GCW and history of AF were independent predictors of postprocedural NT-proBNP. Accordingly, myocardial work indices may help patient selection and the prediction of the functional outcome in this population.

Pressure overload-induced systolic heart failure is associated with characteristic myocardial microRNA expression signature and post-transcriptional gene regulation in male rats.

Although systolic function characteristically shows gradual impairment in pressure overload (PO)-evoked left ventricular (LV) hypertrophy (LVH), rapid progression to congestive heart failure (HF) occurs in distinct cases. The molecular mechanisms for the differences in maladaptation are unknown. Here, we examined microRNA (miRNA) expression and miRNA-driven posttranscriptional gene regulation in the two forms of PO-induced LVH (with/without systolic HF). PO was induced by aortic banding (AB) in male Sprague-Dawley rats. Sham-operated animals were controls. The majority of AB animals demonstrated concentric LVH and slightly decreased systolic function (termed as ABLVH). In contrast, in some AB rats severely reduced ejection fraction, LV dilatation and increased lung weight-to-tibial length ratio was noted (referred to as ABHF). Global LV miRNA sequencing revealed fifty differentially regulated miRNAs in ABHF compared to ABLVH. Network theoretical miRNA-target analysis predicted more than three thousand genes with miRNA-driven dysregulation between the two groups. Seventeen genes with high node strength value were selected for target validation, of which five (Fmr1, Zfpm2, Wasl, Ets1, Atg16l1) showed decreased mRNA expression in ABHF by PCR. PO-evoked systolic HF is associated with unique miRNA alterations, which negatively regulate the mRNA expression of Fmr1, Zfmp2, Wasl, Ets1 and Atg16l1.