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Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease.

ABSTRACT: Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absence of specific biomarkers that can aid in the early diagnosis and management of this challenging syndrome. Currently, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are guideline-recommended biomarkers for the diagnosis and prognosis of heart failure (HF) and PH. Endothelin-1 (ET-1), vascular endothelial growth factor-D (VEGF-D), and microRNA-206 have also been recently identified as new potential circulating biomarkers for patients with PH-LHD. In this review, we aim to present the current state of knowledge of circulating biomarkers that can be used to guide future research toward diagnosis, refine specific patient phenotype, and develop therapeutic approaches for PH-LHD, with a particular focus on PH-HFpEF. Potential circulating biomarkers identified in pre-clinical models of PH-LHD are also summarized here.

SUBMITTER: Todd N

PROVIDER: S-EPMC7575769 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease.

Todd Noah N Lai Yen-Chun YC

Frontiers in medicine 20201007

Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absenc ...[more]

PMID: 33117832

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Project description:BackgroundHeart failure is a severe condition often involving pulmonary hypertension (PH). Soluble low-density lipoprotein receptor with 11 ligand-binding repeats (sLR11) has been associated with pulmonary artery hypertension. We examined whether sLR11 correlates with PH in left heart disease and can be used as a predictive marker.MethodWe retrospectively analyzed patients with severe mitral regurgitation who underwent right heart catheterization before surgery for valve replacement or valvuloplasty from November 2005 to October 2012 at Juntendo University. We measured sLR11 levels before right heart catheterization and analyzed correlations with pulmonary hemodynamics. We compared prognoses between a group with normal sLR11 (≤9.4 ng/ml) and a group with high sLR11 (>9.4 ng/ml). Follow-up was continued for 5 years, with end points of hospitalization due to HF and death due to cardiovascular disease.ResultsAmong 34 patients who met the inclusion criteria, sLR11 correlated with mean pulmonary artery pressure (r = 0.54, p<0.001), transpulmonary pressure gradient (r = 0.42, p = 0.012), pulmonary vascular resistance (r = 0.36, p<0.05), and log brain natriuretic peptide (BNP). However, logBNP did not correlate with pulmonary vascular resistance (p = 0.6). Levels of sLR11 were significantly higher in the 10 patients with PH (14.4±4.3 ng/ml) than in patients without PH (9.9±3.9 ng/ml; p = 0.002). At 5 years, the event rate was higher in the high-sLR11 group than in the normal-sLR11 group. The high-sLR11 group showed 5 hospitalizations due to HF (25.0%) and 2 deaths (10.0%), whereas the normal-sLR11 group showed no hospitalizations or deaths. Analyses using receiver operating characteristic curves showed a higher area under the concentration-time curve (AUC) for sLR11 level (AUC = 0.85; 95% confidence interval (CI) = 0.72-0.98) than for BNP (AUC = 0.80, 95%CI = 0.62-0.99) in the diagnosis of PH in left heart disease.ConclusionsConcentration of sLR11 is associated with severity of PH and offers a strong predictor of severe mitral regurgitation in patients after surgery.

Project description:Left heart disease (LHD) frequently causes lung vascular remodelling and pulmonary hypertension (PH). Yet, pharmacological treatment for PH in LHD is lacking and its pathophysiological basis remains obscure. We aimed to identify candidate mechanisms of PH in LHD and to test their relevance and therapeutic potential. In rats, LHD was induced by supracoronary aortic banding. Whole genome microarray analyses were performed, candidate genes were confirmed by RT-PCR and Western blots and functional relevance was tested in vivo by genetic and pharmacological strategies. In lungs of LHD rats, mast cell activation was the most prominently upregulated gene ontology cluster. Mast cell gene upregulation was confirmed at RNA and protein levels and remodelled vessels showed perivascular mast cell accumulations. In LHD rats treated with the mast cell stabiliser ketotifen, or in mast cell deficient Ws/Ws rats, PH and vascular remodelling were largely attenuated. Both strategies also reduced PH and vascular remodelling in monocrotaline-induced pulmonary arterial hypertension, suggesting that the role of mast cells extends to noncardiogenic PH. In PH of different aetiologies, mast cells accumulate around pulmonary blood vessels and contribute to vascular remodelling and PH. Mast cells and mast cell-derived mediators may present promising targets for the treatment of PH. Whole rat genome microarray analyses were performed in lung homogenates of three rats with established PH following supracoronary aortic banding and in three sham-operated controls. Out of a total of 28,000 analysed genes, differential expression defined as 2-fold change with p<0.05 was evident for 120 genes. Of these, 76 were upregulated and 44 downregulated in aortic banding compared with control lungs gene. Enrichment analysis revealed regulation of mast cell specific genes - 13 out of 20 genes were significantly upregulated in aortic banding compared with control lungs. To test for a putative functional role of mast cells in lung vascular remodelling and PH in LHD, we applied a pharmacological approach by treatment of aortic banding rats with the mast cell stabiliser ketotifen. Microarray analysis then compared rats that were treated with untreated. In brief, congestive heart failure (CHF) was induced in juvenile rats by supracoronary aortic banding and rats were analyzed 9 weeks thereafter when they had established left heart failure with preserved ejection fraction and secondary pulmonary hypertension. Three heart failure rats were untreated, and 3 received the mast cell stabilizer ketotifen (1 mg/kg-1 bodyweight/day-1) with the drinking water. Sham rats underwent the same surgical procedure but without placement of a clip on the supracoronary aorta. Microarray analyses: Lungs from banded and control rats were excised and total RNA was extracted (Stratagene Absolutely RNA Miniprep Kit; Stratagene, La Jolla, USA). Three Âµg total RNA from three control and three banded rats each were processed according to the One-Cycle Target Labeling protocol (GeneChip Expression Analysis, Affymetrix, Santa Clara, USA). Before and after amplifications, the total RNA/complementary RNA concentrations were checked with NanoDrop ND-1000 (Thermo Scientific, Wilmington, USA) and quality was controlled (Experion electrophoresis station, BioRad; Hercules, USA). Samples were hybridized to GeneChipÂ® Rat Genome 230 2.0 arrays (Affymetrix; Santa Clara, USA) containing 31,000 probe sets covering 28,000 rat genes.

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Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease.

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Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease.

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