Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare condition that is characterised by a progressive increase of pulmonary vascular resistances that leads to right ventricular failure and death, if untreated. The underlying narrowing of the pulmonary vasculature relies on several independent and interdependent biological pathways, such as genetic predisposition and epigenetic changes, imbalance of vasodilating and vasoconstrictive mediators, as well as dysimmunity and inflammation that will trigger endothelial dysfunction, smooth muscle cell proliferation, fibroblast activation and collagen deposition. Progressive constriction of the pulmonary vasculature, in turn, initiates and sustains hypertrophic and maladaptive myocardial remodelling of the right ventricle. In this review, we focus on the role of inflammation and dysimmunity in PAH which is generally accepted today, although existing PAH-specific medical therapies still lack targeted immune-modulating approaches.

ANMCO POSITION PAPER: Use of sacubitril/valsartan in hospitalized patients with acute heart failure

Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared with enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicentre studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared with enalapril, and good tolerability, safety, and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favourable effects of S/V in attenuating adverse myocardial remodelling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remain suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroad in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome.

Serum Liberation of Fetal Fibronectin Variants in Patients with Pulmonary Hypertension: ED-A+ Fn as Promising Novel Biomarker of Pulmonary Vascular and Right Ventricular Myocardial Remodeling

Background and Aims: Pulmonary Hypertension (PH) represents an aetiologically and clinically heterogeneous disorder accompanied by a severely impaired prognosis. Key steps of PH pathogenesis are vascular and right ventricular myocardial remodelling entailing the re-occurrence of fetal variants of the cell adhesion modulating protein fibronectin (Fn) being virtually absent in healthy adult tissues. These variants are liberated into circulation and are therefore qualified as excellent novel serum biomarkers. Moreover, these molecules might serve as promising therapeutic targets. The current study was aimed at quantifying the serum levels of two functionally important fetal Fn variants (ED-A+ and ED-B+ Fn) in patients suffering from PH due to different aetiologies compared to healthy controls. Methods: Serum levels of ED-A+ and ED-B+ Fn were quantified using novel ELISA protocols established and validated in our group in 80 PH patients and 40 controls. Results were analysed with respect to clinical, laboratory, echocardiographic and functional parameters. Results: Serum levels of ED-A+ Fn (p = 0.001) but not ED-B+ Fn (p = 0.722) were significantly increased in PH patients compared to healthy controls. Thus, the following analyses were performed only for ED-A+ Fn. When dividing PH patients into different aetiological groups according to current ESC guidelines, the increase in ED-A+ Fn in PH patients compared to controls remained significant for group 1 (p = 0.032), 2 (p = 0.007) and 3 (p = 0.001) but not for group 4 (p = 0.156). Correlation analysis revealed a significant relation between ED-A+ Fn and brain natriuretic peptide (BNP) (r = 0.310; p = 0.002), six minutes’ walk test (r = −0.275; p = 0.02) and systolic pulmonary artery pressure (PAPsys) (r = 0.364; p < 0.001). By logistic regression analysis (backward elimination WALD) including a variety of potentially relevant patients’ characteristics, only chronic kidney disease (CKD) (OR: 8.866; CI: 1.779–44.187; p = 0.008), C reactive protein (CRP) (OR: 1.194; CI: 1.011–1.410; p = 0.037) and ED-A+ Fn (OR: 1.045; CI: 1.011–1.080; p = 0.009) could be identified as independent predictors of the presence of PH. Conclusions: Against the background of our results, ED-A+ Fn could serve as a promising novel biomarker of PH with potential value for initial diagnosis and aetiological differentiation. Moreover, it might contribute to more precise risk stratification of PH patients. Beyond that, the future role of ED-A+ Fn as a therapeutic target has to be evaluated in further studies.

Pygo1 regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism

Wnt/β-catenin signalling plays a key role in pathological cardiac remodelling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may realise a tissue-specific clinical targeting strategy. Drosophila Pygo codes for the core interaction factor of Wnt/β-catenin. Two Pygo homologs, Pygo1 and Pygo2, have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease remains unelucidated. Here, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios and increased cell size. The canonical β-catenin/T-cell transcription factor 4 complex was abundant in Pygo1-overexpressingtransgenic(Pygo1-TG) cardiac tissue,and the downstream genes of Wnt signaling, i.e., Axin2, Ephb3, and C-myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodelling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.

Interaction of stroke volume and myocardial phenotype in patients with severe aortic stenosis referred for intervention: outcome data from the BSCMR AS700 study

Funding Acknowledgements Type of funding sources: None. onbehalf The BSCMR Valve Consortium Background Patients with low-flow aortic stenosis (LF-AS) have higher mortality than those with high-flow severe AS. The conventional echocardiographic definition of LF-AS is an indexed stroke volume (SVi) &lt;35ml/m2. Whether this cut-off translates to cardiac magnetic resonance (CMR), and how CMR SVi associates with myocardial remodelling (volume/function/scar) and survival is unclear. Purpose To determine the association between CMR SVi, myocardial remodelling and survival in severe symptomatic AS. Methods In a multi-centre longitudinal outcome study of patients with severe AS listed for either surgical (SAVR) or transcatheter aortic valve intervention (TAVI) at six cardiothoracic centres, survival was assessed and stratified by SVi. Patients underwent preprocedural echocardiography and CMR between January 2003 and May 2015. Standardised core-lab analyses on pre-procedural CMR for biventricular volumes, function and scar quantification were performed. All-cause and cardiovascular mortality were tracked for a minimum of two years after AVR. Results A total of 674 patients with severe AS (age 75 ± 14years; 63% male, aortic valve area 0.4 ± 0.1 cm2/m2) were included. Patients with low SVi by CMR &lt;35ml/m2 were older and had a greater burden of comorbidities (atrial fibrillation [AF], diabetes, high BMI). Independent predictors of SVi were age, AF, increased left atrial volume, aortic valve regurgitant fraction and left ventricular mass (LV) mass index (by CMR). There was no difference in SVi with choice of intervention (TAVI vs SAVR) or presence of late gadolinium enhancement. In multivariate analysis (Table 1), SVi was associated with cardiovascular mortality in the whole cohort (HR 0.97, 95%CI 0.95-0.99, p = 0.02), and all-cause mortality after TAVI (HR 0.97, 95%CI 0.95-0.99, p = 0.006) but not SAVR (p = 0.6). Adjusted mortality hazard increases below 50ml/m2 and plateaus between 35-40ml/m2 (Figure 1A), adjusted for LGE, STS score (Society of Thoracic Surgery score) and wall thickness. Conclusion SVi by CMR is an independent predictor of cardiovascular mortality. Mortality hazard increases progressively below a SVi of 50mL/m2. Abstract Figure 1