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Background and Objectives: Previous studies have shown that a multiple blood biomarker strategy prior to aortic valve replacement (AVR) may be useful for risk stratification in patients undergoing surgical AVR (SAVR). The usefulness of this approach in patients with low-flow low-gradient aortic stenosis (LF-LG AS) has not been examined. The objective of this study was to determine the prognostic value of combined measures of multiple blood biomarkers in patients with LF-LG AS treated conservatively or by AVR. Methods: 168 patients were prospectively enrolled in the TOPAS (Truly or Pseudo-severe Aortic Stenosis) study at our institute. Clinical and echocardiographic data were collected for each patient. Eight biomarkers of myocardial stress, inflammation, renal function (brain natriuretic peptide, creatine kinase-mb, interleukin-6, alanine transaminase, lactate dehydrogenase, alkaline phosphatase, procalcitonin, ferritin) were measured from blood samples collected at baseline. The cohort was divided into 3 groups according to the number of elevated biomarkers. Uni- and multivariable survival analyses were performed to evaluate the association between the number of elevated biomarkers and all-cause mortality. Results: Mean age was 73 years (68% male). After a median follow-up of 3.41 years, 69 (35%) patients died. Patients with 0-3, 4-6, and >6 elevated biomarkers had 8 years survival estimates of 75%, 52%, and 19%, respectively (log-rank p<0.0001). Using multivariable Cox analysis adjusted for age, sex, BMI, AVR as a time-dependent variable, renal function and STS score, patients with >6 elevated biomarkers had an increased risk of all-cause mortality as compared to the group of patients with 0-3 elevated biomarkers (referent group), HR=3.82, p<.0001, and as compared to the group of patients with 4-6 elevated biomarkers HR=2.81, p<.0001. There was no significant difference in all-cause mortality between patients with 4-6 elevated biomarkers and the referent group p=0.38. Conclusion: In this series of patients with LF-LG AS, a higher number of elevated biomarkers was associated with an increased rate of mortality. These results suggest that a multiple blood biomarkers approach may be useful to enhance the risk stratification in this cohort.

Background: Pulmonary arterial hypertension (PAH) is a fatal lung disease of multifactorial etiology, with no curative treatment. Several studies have previously suggested that hypermethylation of the BMPR2 promoter may be associated with gene repression and disease progression. However, the underlying mechanisms have yet to be discovered. Sin3A/B (Switch-Independent 3) plays a critical role in the transcriptional regulation of genes through various epigenetic mechanisms. Here, we investigated for the first time the role of SIN3a in the regulation of BMPR2 methylation and expression in PAH. Methods: Expression of SIN3a was analyzed by qRT-PCR and western blot in lung tissues from PAH patients and rodent models of PAH. Using a gain- and loss-of-function approach, we investigated the role of SIN3a on cell proliferation (BrdU assay) and migration (Boyden chamber assay), and BMPR2 levels in primary human pulmonary arterial smooth muscle cells (hPASMC) and endothelial cells (hPAEC). The methylation level was analyzed by MS-PCR. The therapeutic potential of SIN3a was tested in vivo in the Sugen/Hypoxia (SuHx) mouse and monocrotaline (MCT) rat models of PAH using an adeno-associated virus 1 encoding human SIN3a. Results: We found a significant downregulation of SIN3a expression in the lung samples from PAH patients, SuHx mice, and MCT rats. In hPASMC and hPAEC, our results showed that SIN3a inhibits cell proliferation, migration, and upregulates BMPR2 through two distinct pathways. In hPASMC, our data showed that SIN3a upregulates BMPR2 expression by inhibiting the methylation level of the BMPR2 promoter. In hPAEC, SIN3a restored BMPR2 expression independently of the methylation status by upregulating the FOXK2 transcription factor. In vivo , our results showed that restoring SIN3a expression by gene therapy significantly decreased MCT- and SuHx-induced PAH as illustrated by decreased vascular and RV remodeling, hypertrophy, PAP and RVSP. Conclusions: Altogether, our study revealed that SIN3a plays a critical role in the regulation of BMPR2 expression by modulating the lung epigenetic landscape. Additionally, our study identifies lung-targeted SIN3a gene therapy as a new promising therapeutic strategy for treating PAH patients.