26 research outputs found
Neprilysin as a Biomarker: Challenges and Opportunities
Neprilysin (NEP) inhibition is a successful novel therapeutic approach in heart failure with reduced ejection fraction. Assessing individual NEP status might be important for gathering insights into mechanisms of disease and optimising individualised patient care. NEP is a zinc-dependent multisubstrate-metabolising oligoendopeptidase localised in the plasma membrane with the catalytic site facing the extracellular space. Although NEP activity in vivo is predominantly tissue-based, NEP can be released into the circulation via ectodomain shedding and exosomes. Attempts to determine circulating NEP concentrations and activity have not yet resulted in convincingly coherent results relating NEP biomarkers to heart failure disease severity or outcomes. NEP is naturally expressed on neutrophils, opening up the possibility of measuring a membrane-associated form with integrity. Small studies have linked NEP expression on neutrophils with inflammatory state and initial data might indicate its role in heart failure with reduced ejection fraction. Future studies need to assess the regulation of systemic NEP activity, which is assumed to be tissue-based, and the relationship of NEP activation with disease state. The relationship between tissue NEP activity and easily accessible circulating NEP biomarkers and the impact of the latter remains to be established
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Impact of Right Ventricular Performance in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiac Surgery
Background: Extracorporeal membrane oxygenation following cardiac surgery safeguards endâorgan oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (RV) dysfunction. We sought to determine the prognostic impact of RV function and to improve established riskâprediction models in this vulnerable patient cohort. Methods and Results: Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60â74), and 74 patients were male. During a median followâup of 27 months (interquartile range 16â63), 75 patients died. Fiftyâone patients died within 30 days, 75 during longâterm followâup (median followâup 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function (P<0.001 for receiver operating characteristics comparisons). Specifically, RV freeâwall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Scoreâ3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%CI 0.24â0.68; P=0.001) for 30âday mortality and 0.48 (95%CI 0.33â0.71; P<0.001) for longâterm mortality for a 1âSD (SD=â6%) change in RV freeâwall strain. Combined assessment of the additive EuroSCORE and RV freeâwall strain improved risk classification by a net reclassification improvement of 57% for 30âday mortality (P=0.01) and 56% for longâterm mortality (P=0.02) compared with the additive EuroSCORE alone. Conclusions: RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for shortâ and longâterm mortality
The inflammationâbased modified Glasgow prognostic score is associated with survival in stable heart failure patients
Abstract Aims The progression of heart failure is presumably dependent on the individual inflammatory host response. The combination of the inflammatory markers, albumin, and Câreactive protein, termed modified Glasgow prognostic score (mGPS), has been derived from cancer patients and validated in multiple cohorts. This study aimed to investigate the impact of the easily available mGPS on survival of stable patients with heart failure with reduced ejection fraction (HFrEF). Methods and results Patients with stable HFrEF undergoing routine ambulatory care between January 2011 and November 2017 have been identified from a prospective registry at the Medical University of Vienna. Comorbidities, laboratory data as well as the nutritional risk index at baseline were assessed. Allâcause mortality was defined as the primary study end point. The mGPS was calculated, and its association with heart failure severity and impact on overall survival were determined. Data were analysed for a total of 443 patients. The mGPS was 0 for 352 (80%), 1 for 76 (17%), and 2 for 14 (3%) patients, respectively. Elevation of mGPS was associated with worsening of routine laboratory parameters linked to prognosis, especially NTâproBNP [median 1830Â pg/mL (IQR 764â3455) vs. 4484Â pg/mL (IQR 1565â8003) vs. 6343Â pg/mL (IQR 3750â15401) for mGPS 0, 1, and 2, respectively; PÂ <Â 0.001] and nutritional risk index. In the Cox regression analysis, the increase of mGPS was associated with adverse outcome in the univariate analysis [crude hazard ratio 3.00 (95% CI 2.14â4.21), PÂ <Â 0.001] and after adjustment for multiple covariates as age, gender, body mass index, and glomerular filtration rate as well as heart failure severity reflected by NTâproBNP and New York Heart Association class [adj. hazard ratio 1.87 (95% CI 1.19â2.93), PÂ =Â 0.006]. Conclusions Enhanced inflammation and nutritional depletion are more common in advanced heart failure. The inflammationâbased score mGPS predicts survival in HFrEF patients independently of NTâproBNP emphasizing the significance of the individual proâinflammatory response on prognosis
Tricuspid regurgitation: recent advances in understanding pathophysiology, severity grading and outcome
International audienceHeightened interest in tricuspid regurgitation (TR) stems from the consistent association of mortality with greater severity of TR, and a low use of surgical solutions in the setting of high in-hospital mortality attributed to the late presentation of the disease. The delay in intervention is likely related to a limited understanding of the valvular/ventricular anatomy and disease pathophysiology, along with an underestimation of TR severity by standard imaging modalities. With the rapid development of transcatheter solutions which have shown early safety and efficacy, there is a growing need to understand and accurately diagnose the valvular disease process in order to determine appropriate management solutions. The current review will describe both normal and pathologic tricuspid valvular anatomy, the classification of these anatomic substrates of TR, the strengths and limitations of the current guidelines-recommended multi-parametric echocardiographic approach and the role of multi-modality imaging, as well as the role of transcatheter device therapy in the management of the disease
Neprilysin inhibition does not alter dynamic of proenkephalinâA 119â159 and proâsubstance P in heart failure
Abstract Aims As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEPâthe tachykinin and enkephalin systemsâto the initiation of ARNi therapy in HFrEF. Methods and results Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalinâA 119â159 (PENK) and proâsubstance P (proâSP) were serially determined. ProenkephalinâA 119â159 and proâSP correlated strongly with each other (rs = 0.67, P  0.05 between groups). Conclusions Although enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and proâSP in HFrEF
An Integrated Imaging and Circulating Biomarker Approach for Secondary Tricuspid Regurgitation
Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate the expression of complementary biomarkers in sTR and to evaluate the effectiveness of integrating their assessment into the diagnostic process. We enrolled 576 HFrEF patients recording echocardiographic and biochemical measurements, i.e., N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin, C-terminal pro-endothelin-1 (CT-pro-ET1), and copeptin. Plasma levels of the aforementioned neurohormones were significantly elevated with increasing sTR severity (p < 0.001 for all). CT-pro-ET1 and MR-proANP were the closest related to severe sTR (adj. OR 1.46; 95%CI 1.11–1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13–1.87, p = 0.004, respectively). In patients with moderate-to-severe sTR, adding selected biomarkers (i.e., CT-pro-ET1 and MR-proANP) resulted in a substantial improvement in the discriminatory power regarding long-term mortality (C-statistic: 0.54 vs. 0.65, p < 0.001; continuous NRI 57%, p < 0.001). Circulating biomarkers closely relate to sTR severity and correlate with hemodynamic and morphologic mechanisms of sTR. Specifically, MR-proANP and CT-pro-ET1 are closely linked to the presence of severe sTR, and a combined assessment with the guideline recommended echocardiographic grading significantly improves individual risk stratification