Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure : a pilot study

Altres ajuts: This work was supported in part by Fundació La Marató de TV3 (201516-10, 201502-30), Societat Catalana de Cardiologia, "la Caixa" Banking Foundation.Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart failure with reduced ejection fraction. Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients' physical functioning after initiation of sacubitril/valsartan treatment. A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker was replaced by sacubitril/valsartan because of clinical indication by the responsible physician. By protocol, patients were reevaluated at 30 days after the start of sacubitril/valsartan. Serum levels of α- (α-EP), γ-Endorphin (γ-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient's functional status. Baseline median levels of circulating α-EP, γ-EP, and sNEP were 582 (160-772), 101 (37-287), and 222 pg/mL (124-820), respectively. There was not a significant increase in α-EP nor γ-EP serum values after sacubitril/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ-EP, and ΔsNEP between 30 days and baseline were 9.3 (−34 − 44), −3.0 (−46.0 − 18.9), and 0 units (−16.4 − 157.0), respectively. In a pre-post sacubitril/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Δα-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients' symptoms improvement

Importance of rigorous evaluation in comparative biomarker studies

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Predicting new-onset HF in patients undergoing coronary or peripheral angiography: results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study

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Blood kidney injury molecule-1 predicts short and longer term kidney outcomes in patients undergoing diagnostic coronary and/or peripheral angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study

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Single-Molecule Counting of High-Sensitivity Troponin I in Patients Referred for Diagnostic Angiography: Results From the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) Study

Contains fulltext : 190538.pdf (publisher's version ) (Open Access)BACKGROUND: The meaning of high-sensitivity troponin I (hsTnI) concentrations in patients without acute myocardial infarction (MI) requires clarity. We hypothesized that among patients referred for diagnostic coronary angiography without acute MI, hsTnI concentrations would correlate with prevalent coronary artery disease (CAD) and predict incident cardiovascular events and mortality. METHODS AND RESULTS: We measured hsTnI using a single-molecule counting assay (99th percentile, 6 ng/L) in samples from 991 patients obtained at the time of angiography. Concentrations of hsTnI were assessed relative to the severity of CAD and prognosis during mean follow-up of 3.7 years. Median hsTnI concentration was 4.19 ng/L; 38% of patients had hsTnI concentrations >/=99th percentile. Across increasing hsTnI quartiles, patients had higher prevalence of angiographic CAD; in multivariate models, hsTnI >/=99th percentile independently predicted obstructive CAD (odds ratio: 2.57; P70% coronary stenosis, hsTnI >/=99th percentile independently predicted incident MI (HR: 1.87; P=0.01), cardiovascular mortality (HR: 2.74; P=0.001), and the composite end point of MI and all-cause death (HR: 2.06; P/=99th percentile even more strongly predicted incident MI (HR: 8.41; P<0.001), cardiovascular mortality (HR: 3.60; P=0.03), and the composite end point of MI and all-cause death (HR: 3.62; P<0.001). CONCLUSIONS: In a large prospective cohort of patients who were free of prevalent MI and undergoing diagnostic coronary angiography, hsTnI concentrations were associated with higher prevalence of CAD and predicted incident MI, cardiovascular death, and all-cause death. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868

Endothelin-1 Measurement in Patients Undergoing Diagnostic Coronary Angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) Study

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Multiple biomarker panel to screen for severe aortic stenosis: results from the CASABLANCA study

Contains fulltext : 200261.pdf (publisher's version ) (Open Access)Objective: Severe aortic valve stenosis (AS) develops via insidious processes and can be challenging to correctly diagnose. We sought to develop a circulating biomarker panel to identify patients with severe AS. Methods: We enrolled study participants undergoing coronary or peripheral angiography for a variety of cardiovascular diseases at a single academic medical centre. A panel of 109 proteins were measured in blood obtained at the time of the procedure. Statistical learning methods were used to identify biomarkers and clinical parameters that associate with severe AS. A diagnostic model incorporating clinical and biomarker results was developed and evaluated using Monte Carlo cross-validation. Results: Of 1244 subjects (age 66.4+/-11.5 years, 28.7% female), 80 (6.4%) had severe AS (defined as aortic valve area (AVA) <1.0 cm(2)). A final model included age, N-terminal pro-B-type natriuretic peptide, von Willebrand factor and fetuin-A. The model had good discrimination for severe AS (OR=5.9, 95% CI 3.5 to 10.1, p<0.001) with an area under the curve of 0.76 insample and 0.74 with cross-validation. A diagnostic score was generated. Higher prevalence of severe AS was noted in those with higher scores, such that 1.6% of those with a score of 1 had severe AS compared with 15.3% with a score of 5 (p<0.001), and score values were inversely correlated with AVA (r=-0.35; p<0.001). At optimal model cut-off, we found 76% sensitivity, 65% specificity, 13% positive predictive value and 98% negative predictive value. Conclusions: We describe a novel, multiple biomarker approach for diagnostic evaluation of severe AS. Trial registration number: NCT00842868

ACCIRT/WRC Newsletter [26 September, 2012]

Marathon running commonly causes a transient elevation of creatine kinase and cardiac troponin I (cTnI). The use of statins before marathon running exacerbates the release of creatine kinase from skeletal muscle, but the effect of statin use on exercise-induced cTnI release is unknown. We therefore measured cTnI concentrations in statin-using (n = 30) and nonstatin-using (n = 41) runners who participated in the 2011 Boston Marathon. All runners provided venous blood samples the day before, within an hour of finishing, and 24 hours after the marathon. cTnI was assessed at each time point via both a contemporary cTnI and high-sensitivity cTnI (hsTnI) assay. Before the marathon, cTnI was detectable in 99% of runners with the use of the hsTnI assay. All participants completed the marathon (finish time: 4:04:09 +/- 0:41:10), and none had symptoms of an acute coronary syndrome. cTnI increased in all runners (p <0.001) immediately after the marathon, and half (hsTnI = 54% vs contemporary cTnI = 47%) exceeded the diagnostic cut-point for an acute myocardial infarction. Statin use did not affect the magnitude of cTnI release (group*time p = 0.47) or the incidence of runners with cTnI elevation greater than the diagnostic cut-point for myocardial infarction (57% vs 51%, p = 0.65). In addition, there was no significant association between statin potency and cTnI release (r = 0.09, p = 0.65). In conclusion, marathon-induced cTnI increases are not altered by statin use

Copeptin does not add diagnostic information to high-sensitivity troponin T in low- to intermediate-risk patients with acute chest pain: Results from the Rule Out Myocardial Infarction by Computed Tomography (ROMICAT) study.

PURPOSE: Copeptin, a stable peptide derived from the AVP precursor, has been linked to presence and severity of myocardial ischemia. We sought to evaluate the predictive value of copeptin and its incremental value beyond that of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute chest pain and low to intermediate risk for acute coronary syndrome (ACS). METHODS: We recruited patients who presented with acute chest pain to the emergency department and had a negative initial conventional troponin T test (&lt;0.03 &mu;g/L). In all patients, hs-cTnT and copeptin measurements were taken. Each patient also underwent cardiac computed tomography (CT) and coronary angiography.RESULTS:Baseline copeptin concentrations, in contrast to hs-cTnT, were not significantly higher in patients with ACS than in those without (P = 0.24). hs-cTnT showed an earlier rise in patients with ACS than copeptin, when analyses were stratified by time. A copeptin concentration &ge;7.38 pmol/L had a negative predictive value (NPV) of 94% and a sensitivity of 51%, whereas hs-cTnT (&ge;13.0 pg/mL) had a NPV of 96% and a sensitivity of 63%. The combination of copeptin and hs-cTnT resulted in a lower diagnostic accuracy than hs-cTnT alone. Finally, on cardiac CT, copeptin concentrations were not associated with coronary artery morphology, although they were related to the presence of left ventricular dysfunction (P = 0.02). CONCLUSIONS: Among patients with acute chest pain and low to intermediate risk for ACS, copeptin concentrations are not independently predictive of ACS and do not add diagnostic value beyond that of hs-cTnT measurements