In previous studies we have shown that oral Ang-(1–7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1–7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1–7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1–7) included into hydroxypropyl- β -cyclodextrin (HP β CD) or empty HP β CD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric, and biochemical parameters, redox process, and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased body mass gain, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR. Furthermore, the MetS rats presented increased in liver angiotensinogen , AT1R , ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both Ang-(1–7) and A-1317 oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating β cell capacity by increasing HOMA- β and QUICKI, whereas Ang-(1–7) reduced HOMA- β and QUICKI. In addition, Ang-(1–7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1–7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggested that this effect was mainly via MRGD via activation of AMPK and increasing β cell function.

No abstract

Background Myocardial fibrosis (MF) is a common finding and a potential adverse prognostic marker in several cardiac diseases, including in severe aortic stenosis (AS). While histological analysis obtained through endomyocardial biopsy remains the gold-standard for MF assessment, non-invasive cardiac imaging may offer surrogate biomarkers for fibrosis. We tried to assess the correlation between MF quantification at histopathology and cardiac magnetic resonance (CMR)-derived tissue characterization data in patients with severe AS. Methodology Single-center prospective cohort enrolling 71 patients with severe symptomatic high-gradient AS undergoing surgical aortic valve replacement (SAVR) (mean age 71±9 years; 49% male, mean valvular transaortic gradient 60±20 mmHg; mean left ventricle [LV] ejection fraction 58±9%). Those with past history of myocardial infarction or cardiomyopathy were excluded. All patients underwent pre-operative CMR study with LV tissue characterization and quantification. Normal T1 mapping value was defined as >1021ms as per center protocol. Myocardial tissue was obtained during SAVR either through myocardial biopsy at basal LV septum or harvested from surgical myectomy specimens. Masson's trichrome stain was used for collagen/fibrosis assessment. Automatic quantification was obtained at QuPathTM digital pathology software after applying a dedicated artificial intelligence algorithm on ultra-high-resolution digital slide scanning images. Results Histology-confirmed MF was observed in all patients (median percentage of fibrotic myocardial tissue 15% [IQR 9–22%]). Median global T1 mapping and extracellular volume (ECV) percentage was 1048ms (IQR 1027–1078) and 24% (IQR 20–30%), respectively. Late gadolinium enhancement (LGE) with a non-ischemic pattern was present in 42 patients (59%) with a median LGE mass of 5.8g [IQR 1.0–10.2]; median percentage of 3.7% [IQR 0.6–10.4]. While neither T1 mapping (global or basal LV septum), ECV nor LGE had any significant correlation with histology-confirmed MF (Figure 1) the vast majority had significantly elevated global and basal LV septum T1 mapping – 81% and 92%, respectively. Conclusion In this single-center prospective study, microscopic MF was present in all patients with severe symptomatic high-gradient AS, was accompanied by elevated T1 mapping values but no correlation was found between myocardial fibrosis at histopathology analysis and CMR-derived LV tissue characterization parameters. This may not only stem from sampling (single point biopsy vs. whole myocardial tissue assessment) but also from distinct evaluation of different types of fibrosis by different methods. Funding Acknowledgement Type of funding sources: None.

Background Left ventricular (LV) remodeling in patients with severe aortic valve stenosis (AS) is a complex process that goes beyond hypertrophic response and may involve reparative/replacement fibrosis. Currently, cardiac magnetic resonance (CMR) is the gold-standard imaging technique for detecting focal myocardial fibrosis through late gadolinium enhancement (LGE). However, myocardial fibrosis prevalence and distribution is quite variable among series. Our goal was to assess LGE prevalence and distribution pattern in severe symptomatic high-gradient AS. Methodology Single-center prospective cohort of 132 patients with severe symptomatic high-gradient AS (mean age 73±11 years; 48% male, mean valvular transaortic gradient 60±20 mmHg; mean aortic valve area 0.7±0.2 cm2/m2; mean LV ejection fraction by 2D echocardiogram 58±9%), all with normal flow (except one) undergoing surgical aortic valve replacement. Those with previous history of acute myocardial infarction, ischemic cardiomyopathy or other cardiomyopathy were excluded. All patients performed 1.5T CMR assessment with LV myocardium tissue characterization prior to surgery. Segmental LGE presence was assessed by two independent operators and classified according to the AHA 16 segment model, using 5-standard deviations from remote myocardium as the signal intensity cut-off for LGE identification and quantification. Results Overall, 96 patients (74%) had non-ischemic LGE (median LGE mass 3.2 g [IQR 0.2–8.3] g; median percentage of LGE myocardial mass 2.5% [IQR 0.1–6.1]%); 22 patients [17%] with exclusively junctional LGE); in one patient an incidental ischemic scar (subendocardial distribution) was identified. No cases of subepicardial distribution were found. Intramyocardial LGE was most frequently observed in basal and mid-anterior and inferior interventricular septum – see Figure 1. In these segments, LGE was most often junctional at right-ventricular insertion points (54%), followed by mid-wall LGE (32%) or both sites involvement (14%). Conclusion LGE is frequent in symptomatic high-gradient AS patients with preserved left ventricular ejection fraction, most often presenting as junctional enhancement in basal/mid-anterior and inferior interventricular septum. Future studies may address whether distinct LGE patterns may impact patient prognosis. Funding Acknowledgement Type of funding sources: None.

No abstract