Sacubitril/valsartan has an underestimated impact on the right ventricle in patients with sleep-disordered breathing, especially central sleep apnoea syndrome.

BACKGROUND: Sacubitril/valsartan has been demonstrated to significantly improve left ventricular performance and remodelling in patients with heart failure. However, its effects on the right ventricle in patients with chronic heart failure and sleep-disordered breathing (SDB) have not been studied. AIM: To investigate the impact of sacubitril/valsartan treatment on right ventricular function in patients with SDB. METHODS: This was a subanalysis of an observational prospective multicentre study involving 101 patients. At inclusion, patients were evaluated by echocardiography and nocturnal ventilatory polygraphy, which allowed patients to be divided into three groups: "central-SDB"; "obstructive-SDB"; and "no-SDB". RESULTS: After 3 months of sacubitril/valsartan therapy, a positive impact on right ventricular function was observed. In the general population, tricuspid annular plane systolic excursion increased by +1.32±4.74mm (P=0.024) and systolic pulmonary artery pressure decreased by -3.1±10.91mmHg (P=0.048). The central-SDB group experienced the greatest echocardiographic improvement, with a significant increase in tricuspid annular plane systolic excursion of +2.1±4.9mm (P=0.045) and a significant reduction in systolic pulmonary artery pressure of -8.4±9.7mmHg (P=0.001). CONCLUSIONS: Sacubitril/valsartan improved right ventricular function in patients with heart failure and SDB after only 3 months of treatment. The greatest improvement in right ventricular function was observed in the central-SDB group.

Study and quantification of the enantiodiscrimination power of four polymeric chiral LLCs using NAD 2D-NMR.

Identifying and understanding the role of key molecular factors involved in the orientation/discrimination phenomena of analytes in polymer-based chiral liquid crystals (CLCs) are essential tasks for optimizing computational predictions (molecular dynamics simulation) of the existing orienting systems, as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. From this perspective, we propose to quantify and compare the enantiodiscrimination power of four homochiral polymer-based lyotropic liquid crystals (LLCs) toward a given chiral solute using their 2H residual quadrupolar couplings (2H-RQCs) measured by anisotropic natural abundance deuterium 2D-NMR (ANAD 2D-NMR). Two families of chiral polymers are investigated in this study: (i) poly-peptide polymers (PBLG and PCBLL), and (ii) polyacetylene polymers (PDA and L-MSP, a new system never published so far). As model solute, we investigate the case of camphor, an interesting rigid bicyclic chiral molecule possessing ten 2H-RQCs (10 inequivalent monodeurated isotopomers per enantiomer). In order to analyse the orientational behaviour of each enantiomer in a single oriented sample, while simplifying the identification of the (D/L)-isomer signals on spectra, a D-isomer enriched scalemic mixture (ee(D) = 30%) was used. Orientational data of camphor in each mesophase were calculated for the first time using the computer program ConArch+, modified to accept 2H-RQCs as anisotropic data input. Differences in enantiodiscriminations provided by the four aligning systems are examined and discussed in terms of structural and chemical features between polymers. The new L-MSP mesophase described in this work exhibits very promising enantiodiscrimination capacities.

Exploring the enantiomeric 13C position-specific isotope fractionation: challenges and anisotropic NMR-based analytical strategy.

Trying to answer the intriguing and fundamental question related to chiral induction/amplification at the origin of homochirality in Nature: "Is there a relationship between enantiomeric and isotopic fractionation of carbon 13 in chiral molecules?" is a difficult but stimulating challenge. Although isotropic 13C-PSIA NMR is a promising tool for the determination of (13C/12C) ratios capable of providing key 13C isotopic data for understanding the reaction mechanisms of biological processes or artificial transformations, this method does not provide access to any enantiomeric 13C isotopic data unless mirror-image isomers are first physically separated. Interestingly, 13C spectral enantiodiscriminations can be potentially performed in situ in the presence of enantiopure entities as chiral-europium complexes or chiral liquid crystals (CLCs). In this work, we explored for the first time the capabilities of the anisotropic 13C-{1H} NMR using PBLG-based lyotropic CLCs as enantiodiscriminating media in the context of the enantiomeric position-specific 13C isotope fractionation (EPSIF), within the requested precision of the order of the permil. As enantiomeric NMR signals are discriminated on the basis of a difference of 13C residual chemical shift anisotropy (13C-RCSA) prior to being deconvoluted, analysis of enantiomeric mixtures becomes possible. The analytical potential of this approach when using poly-γ-benzyl-L-glutamate (PBLG) is presented, and the preliminary quantitative results on small model chiral molecules obtained at 17.5 T with a cryogenic NMR probe are reported and discussed. A promising analytical approach based on anisotropic irm-13C-NMR spectrometry to potentially reveal the natural 13C/12C isotopic enantiofractionation effects in organic chiral molecules is proposed and discussed.

Sacubitril-valsartan initiation in chronic heart failure patients impacts sleep apnea: the ENTRESTO-SAS study.

AIMS: Optimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril-valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation. METHODS AND RESULTS: The ENTRESTO-SAS trial is a six-centre, prospective, open-label real-life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ25-75 : 56-73) years, 81.4% male, 36.5% New York Heart Association III-IV, N-terminal pro-B-type natriuretic peptide level of 1564 (701-3376) ng/L, left ventricular ejection fraction of 30 (25-34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta-blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea-hypopnoea indices (AHIs): G1 (n = 49, AHIcentral  ≥ 5/h and AHIobstructive  < 15/h); G2 (n = 27, AHIobstructive  ≥ 15/h); and G3 (n = 42, AHIcentral  < 5/h and AHIobstructive  < 15/h). At 3 months, the AHI (main predefined outcome) decreased significantly by -7.10/h (IQ25-75 : -16.10 to 0.40; P < 0.001) in G1 + G2 without positive airway pressure treatment (45 patients, median initial AHI of 24.20 (IQ25-75 : 16.40-43.50)/h). Of these, 24.4% presented an AHI decrease ≥50% and 37.78% had a final AHI < 15/h (tendency for improvement from an initial value of 20%: P = 0.0574). For G1 patients (n = 37), AHI significantly decreased from a median of 22.90 (16.00-43.50)/h to 19.20 (12.70-31.10)/h (P = 0.002). For G2 patients (n = 8), AHI decreased from a median of 30.10 (26.40-47.60)/h to 22.75 (14.60-36.90)/h (statistically non-significant, P = 0.059). CONCLUSIONS: In this real-life population, SV treatment for 3 months in SA patients is associated with a significant decrease in AHI. These results support the current guidelines that recommend first an optimization of the HFrEF treatment in patients with HFrEF and central SA. A potential positive airway pressure sparing effect merits further investigation.

Deuterium Residual Quadrupolar Couplings: Crossing the Current Frontiers in the Relative Configuration Analysis of Natural Products.

The determination of the 3D structure (configuration and preferred conformation) of complex natural and synthetic organic molecules is a long-standing but still challenging task for chemists, with various implications in pharmaceutical sciences whether or not these substances have specific bioactivities. Nuclear magnetic resonance (NMR) in aligning media, either lyotropic liquid crystals (LLCs) or polymer gels, in combination with molecular modeling is a unique framework for solving complex structural problems whose analytical wealth lies in the establishment of nonlocal structural correlations. As an alternative to the already well-established anisotropic NMR parameters, such as RDCs (residual dipolar couplings) and RCSAs (residual chemical shift anisotropies), it is shown here that deuterium residual quadrupolar couplings (2H-RQCs) can be extracted from 2H 2D-NMR spectra recorded at the natural abundance level in samples oriented in a homopolypeptide LLCs (poly-γ-benzyl-l-glutamate (PBLG)). These 2H-RQCs were successfully used to address nontrivial structural problems in organic molecules. The performance and scope of this new tool is examined for two natural chiral compounds of pharmaceutical interest (strychnine and artemisinin). This is the first report in which the 3D structure/relative configuration of complex bioactive molecules is unambiguously determined using only 2H-RQCs, which, in this case, are at 2H natural abundance.

Telemonitoring versus standard care in heart failure: a randomised multicentre trial.

AIMS: The aim was to assess the effect of a telemonitoring programme vs. standard care (SC) in preventing all-cause deaths or unplanned hospitalisations in heart failure (HF) at 18 months. METHODS AND RESULTS: OSICAT was a randomised, multicentre, open-label French study in 937 patients hospitalised for acute HF ≤12 months before inclusion. Patients were randomised to telemonitoring (daily body weight measurement, daily recording of HF symptoms, and personalised education) (n = 482) or to SC (n = 455). Mean ± standard deviation number of events for the primary outcome was 1.30 ± 1.85 for telemonitoring and 1.46 ± 1.98 for SC [rate ratio 0.97, 95% confidence interval (CI) 0.77-1.23; P = 0.80]. In New York Heart Association (NYHA) class III or IV HF, median time to all-cause death or first unplanned hospitalisation was 82 days in the telemonitoring group and 67 days in the SC group (P = 0.03). After adjustment for known predictive factors, telemonitoring was associated with a 21% relative risk reduction in first unplanned hospitalisation for HF [hazard ratio (HR) 0.79, 95% CI 0.62-0.99; P = 0.044); the relative risk reduction was 29% in patients with NYHA class III or IV HF (HR 0.71, 95% CI 0.53-0.95; P = 0.02), 38% in socially isolated patients (HR 0.62, 95% CI 0.39-0.98; P = 0.043), and 37% in patients who were ≥70% adherent to body weight measurement (HR 0.63, 95% CI 0.45-0.88; P = 0.006). CONCLUSION: Telemonitoring did not result in a significantly lower rate of all-cause deaths or unplanned hospitalisations in HF patients. The pre-specified subgroup results suggest the telemonitoring approach improves clinical outcomes in selected populations but need further confirmation.

Multinuclear NMR in polypeptide liquid crystals: Three fertile decades of methodological developments and analytical challenges.

NMR spectroscopy of oriented samples makes accessible residual anisotropic intramolecular NMR interactions, such as chemical shift anisotropy (RCSA), dipolar coupling (RDC), and quadrupolar coupling (RQC), while preserving high spectral resolution. In addition, in a chiral aligned environment, enantiomers of chiral molecules or enantiopic elements of prochiral compounds adopt different average orientations on the NMR timescale, and hence produce distinct NMR spectra or signals. NMR spectroscopy in chiral aligned media is a powerful analytical tool, and notably provides unique information on (pro)chirality analysis, natural isotopic fractionation, stereochemistry, as well as molecular conformation and configuration. Significant progress has been made in this area over the three last decades, particularly using polypeptide-based chiral liquid crystals (CLCs) made of organic solutions of helically chiral polymers (as PBLG) in organic solvents. This review presents an overview of NMR in polymeric LCs. In particular, we describe the theoretical tools and the major NMR methods that have been developed and applied to study (pro)chiral molecules dissolved in such oriented solvents. We also discuss the representative applications illustrating the analytical potential of this original NMR tool. This overview article is dedicated to thirty years of original contributions to the development of NMR spectroscopy in polypeptide-based chiral liquid crystals.

2 H and 13 C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

In this work, the practical/analytical potential of an L-valine-derived polyacetylene (PLA) lyotropic liquid crystal (LLC) is examined to spectrally discriminate enantiomers (racemic mixture) or enantiotopic directions of a large collection (23) of (pro)chiral model compounds (from rigid to flexible and polar to apolar ones), thus covering various important aspects of enantiomorphism. Experimental 2 H-{1 H} (deuterated analytes and at natural abundance level) and 13 C-{1 H} NMR results are discussed in terms of the difference of 2 H-RQCs or 13 C-RCSAs and compared to those obtained in polypeptide-type LLCs (PBLG). The analysis of the NMR results provides an overview of the enantiodifferentiation capabilities of PLA and gives useful/practical hints for the chemist to select the most appropriate chiral oriented system. Astonishing NAD NMR results were obtained in the case of one of the simplest, chiral alkanes, 3-methylhexane. From a theoretical viewpoint, the data collected highlight the key molecular factors involved in orientation/discrimination processes, as a basis for optimizing computational prediction (molecular dynamics simulation), as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. In addition, a new, robust and efficient protocol to synthesize PLA and its enantiomer (PDA) on a large scale and with small polydispersities is proposed.

2 H and 13 C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

Invited for this month's cover are the collaborating groups of Dr. Philippe Lesot (DR CNRS) at Université Paris-Sud/Université Paris-Saclay, France, and Professor Michael Reggelin at TU Darmstadt, Germany. The cover shows the proton-decoupled natural abundance deuterium (NAD-{1 H}) Q-resolved Fz 2D-NMR spectrum of (±)-3-methylhexane measured in the anisotropic lyotropic chiral liquid-crystalline phase formed by a concentrated solution of a helically chiral polyarylacetylene in chloroform solvent. Seventeen out of the twenty possible deuterium quadrupolar doublets are observed, demonstrating the enormous enantiodifferentiating capability of the system, even for an unfunctionalized chiral alkane. Read the full text of the article at 10.1002/cplu.201800493.

Impact of sacubitril-valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO-SAS study design.

AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. METHODS AND RESULTS: The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. CONCLUSIONS: In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients.

Integrated Computational Protocol for the Analysis of Quadrupolar Splittings from Natural-Abundance Deuterium NMR Spectra in (Chiral) Oriented Media.

Despite its low natural abundance, deuterium NMR spectroscopy in weakly oriented (chiral) solvents gives easy access to deuterium residual quadrupolar couplings (2 H-RQCs). These are formally equivalent to one-bond residual dipolar couplings ((13 C-1 H)-RDCs) for calculation of the Saupe tensor, and provide similar information for the study of molecular structure and orientational behavior. Because the quadrupolar interaction is one order of magnitude larger than the dipolar one, 2 H-RQC analysis is a much more sensitive tool for the detection of subtle structural differences and also tiny differences in molecular alignment, such as those observed for different enantiomers in chirally aligned media. To promote the analytical advantages of anisotropic, natural-abundance deuterium NMR (NAD NMR) spectroscopy in the organic chemistry community, we describe a 2 H-RQC/DFT-based integrated computational protocol for the evaluation of the order parameters of aligned solutes by using singular-value decomposition. Several examples of 2 H-RQC-assisted analysis of chiral and prochiral molecules dissolved in various polypeptide lyotropic chiral liquid crystals are reported. The role of the molecular shape in the ordering mechanism was investigated through the determination of intertensor angles between alignment tensors and inertia tensors by using the proposed protocol.

Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data.

Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 µM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting ≥ 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel.

Detection of quadrupolar nuclei by ultrafast 2D NMR: exploring the case of deuterated analytes aligned in chiral oriented solvents.

Anisotropic (2)H ultrafast (ADUF) 2D NMR spectroscopy for studying analytes dissolved in chiral liquid crystals (CLC) is investigated for the first time and the analytical possibilities of this method are evaluated. We demonstrate that these unconventional sub-second 2D experiments are compatible with the basic gradient units (40-60 G cm(-1)) that are implemented in routine spectrometers and allow the recording of (2)H signals of weakly aligned deuterated solutes in sub-second experimental times.

Correlation 2D-NMR experiments involving both 13C and 2H isotopes in oriented media: methodological developments and analytical applications.

Correlation 2D-NMR experiments for (13)C and (2)H isotopes turn out to be powerful methods for the assignment of the quadrupolar doublets in the (2)H NMR spectra of isotopically modified (polydeuterated or perdeuterated) or unmodified solutes in homogeneously oriented solvents, such as thermotropic systems or lyotropic liquid crystals. We review here the different pulse sequences, which have been employed, their properties, and their most salient applications. These 2D-NMR sequences have been used for (i) (13)C-(2)H correlation with and without (1)H relay and (ii) (2)H-(2)H correlation with (13)C relay. The (13)C-(2) H correlation experiments without (1)H relay have been achieved for specifically deuterated or non-selectively deuterated analytes, but also more recently for isotopically unmodified ones thanks to the high sensitivity of very high-field NMR spectrometers (21.1 T) equipped with cryogenic probes. The (13)C-(2)H correlation 2D-NMR experiments are especially useful for the assignment of overcrowded deuterium spectra because the (2)H signals are correlated to (13)C signals, which benefit from a much larger dispersion of chemical shifts. In this contribution, particular attention will be paid to the use of correlation 2D-NMR experiments for (2)H and (13)C nuclei in weakly aligning, polypeptide oriented chiral solvents, because these methods are useful and original tools for enantiomeric and enantiotopic analyses.

Antiplatelet drug response status does not predict recurrent ischemic events in stable cardiovascular patients: results of the Antiplatelet Drug Resistances and Ischemic Events study.

BACKGROUND: The biological response to antiplatelet drugs has repeatedly been shown to predict the recurrence of major adverse cardiovascular events (MACEs). However, most studies involved coronary artery disease patients with recent vessel injury shortly after the initiation of antiplatelet therapy. Data on stable cardiovascular patients are scarce, and the added predictive value of specific assays (the vasodilator phosphoprotein assay for the clopidogrel response and serum thromboxane B2 for the aspirin response) and aggregation-based assays relative to common predictors has rarely been addressed. METHODS AND RESULTS: Stable cardiovascular outpatients participating in the Antiplatelet Drug Resistances and Ischemic Events (ADRIE) study (n=771) were tested twice, at 2 separate visits, with specific and aggregation-based assays. Follow-up lasted 3 years, and <1% of patients were lost to follow-up. MACEs were adjudicated by an independent committee. Multivariate survival analyses included relevant variables identified in univariate analysis and platelet function test results. The C-index was used to express the prognostic value of various multivariate models. MACEs, the primary end point, occurred in 16% of patients. Hypertension, smoking, older age, and elevated low-density lipoprotein cholesterol were predictive of MACE recurrence, with a C-index of 0.63 (P<0.001). Neither the specific nor the aggregation-based assays added significant predictive value for the primary end point. CONCLUSIONS: Biological antiplatelet drug responsiveness, measured with specific or aggregation-based assays, has no incremental predictive value over common cardiovascular risk factors for MACE recurrence in stable cardiovascular outpatients. These results do not support platelet function testing for MACE risk evaluation in stable cardiovascular patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00501423.

Conformation and dynamics of 18-membered hexathiametacyclophanes: a two step racemization as studied by deuterium NMR in chiral lyotropic liquid crystals.

The conformation and interconversion dynamics of two derivatives of the 18-membered hexathia metacyclophane 1 and 2 were studied by (1)H NMR spectroscopy in isotropic solvents and by (2)H NMR in chiral liquid crystalline (CLC) solutions, as well as by molecular structure computations. For the analysis of the dynamic effects, we made use of the concepts of "average symmetry" and "isodynamic groups", introduced by Altmann (Altmann, Proc. R. Soc.1967, 184, A298). Compound 1, which is unsubstituted in the inner aromatic site, has, according to the NMR and molecular force field calculations, a boat shaped ground conformation with C(2) symmetry. It is highly flexible and in the NMR spectrum exhibits two successive dynamic processes. There is a low temperature (170-210 K, E(a) = 10.5 kcal/mol) alternate "wing flipping", which corresponds to interchange between pairs of enantiomers and results, in the fast exchange limit, in an average prochiral molecule with C(2v) symmetry. This process is followed, at higher temperatures (290-320 K, E(a) = 28.5 kcal/mol), by an umbrella flipping type inversion with an average structure of D(2h) symmetry. This second process involves averaging of effective enantiotopic into homotopic sites and can only be studied in chiral solvents. The origin of the chiral discrimination and of their stepwise averaging is discussed. Compound 2, which is substituted with methoxy groups at the inner sites of the benzene rings, is much less flexible and exhibits dynamic effects in the NMR spectrum only at temperatures above 370 K. We were able to study the kinetic parameters of this process in isotropic solvents (E(a) = 21.4 kcal/mol). As for 1, the detailed mechanism of this process can in principle be established using dynamic NMR in CLC; however, experimental limitation precluded us from doing so. Possible alternatives and their effect on the 1D and 2D exchange spectra in CLC are discussed in a concluding section.

Admission NT-proBNP levels, renal insufficiency and age as predictors of mortality in elderly patients hospitalized for acute dyspnea.

BACKGROUND: Assay of baseline B-type peptide (BNP and NT-proBNP) is useful for heart failure (HF) prognostication. In contrast, the prognostic value of NT-proBNP assay performed on admission of elderly subjects for acute dyspnea is uncertain. The aim of this study was to determine the vital prognostic value of NT-proBNP assay and other relevant variables available on admission in elderly patients hospitalized for acute dyspnea. METHODS: 254 patients over 70 years of age who were initially hospitalized with acute dyspnea were prospectively studied. The log-rank test and Cox proportional-hazards regression models were used to determine the prognostic value of NT-proBNP and creatinine clearance, measured within 24 h of initial admission, as well as age, gender, vascular risk factors and other clinical variables. RESULTS: Mean age was 81+/-7 years, and 52% of the patients were women. During a median follow-up of 34 months, 134 patients (55%) died and 9 patients (4%) were lost to follow-up. The median survival time was 25 months, and almost half the deaths occurred during the first 6 months. In multivariate analysis the following three variables were independently associated with mortality (shown with their accompanying hazard ratios (HR)): NT-proBNP>2856 pg/mL (median), HR=1.6[95%CI:1.3-5.2]; creatinine clearance <30 mL/min, HR=1.7[95%CI:1.2-2.5]; and age>80 years, HR=1.7[95%CI:1.1-2.6]. The median survival time among patients with an admission NT-proBNP level of >2856 pg/mL (median) was 14 months, compared to >36 months in the rest of the population. CONCLUSION: The admission NT-proBNP level, age, and creatinine clearance are predictive of vital outcome in elderly patients hospitalized for acute dyspnea.

Use of N-terminal prohormone brain natriuretic peptide assay for etiologic diagnosis of acute dyspnea in elderly patients.

BACKGROUND: B-type peptide assay (brain natriuretic peptide [BNP] and N-terminal prohormone brain natriuretic peptide [NT-proBNP]) is useful for the diagnosis of heart failure (HF), but few data are available on the use of these markers in elderly subjects. The aim of this study was to evaluate NT-proBNP assay for the diagnosis of acute left HF in patients older than 70 years hospitalized for acute dyspnea. METHODS: We prospectively enrolled 256 elderly patients with acute dyspnea. They were categorized by 2 cardiologists unaware of NT-proBNP values into a cardiac dyspnea subgroup (left HF) and a noncardiac dyspnea subgroup (all other causes). RESULTS: Mean age was 81 +/- 7 years, and 52% of the patients were women. The diagnoses made in the emergency setting were incorrect or uncertain in 45% of cases. The median NT-proBNP value was higher (P < .0001) in patients with cardiac dyspnea (n = 142; 7906 pg/mL) than in patients with noncardiac dyspnea (n = 112; 1066 pg/mL). The area under the receiver operating characteristic curve was 0.86 (95% CI 0.81-0.91). At a cutoff of 2000 pg/mL, NT-proBNP had a sensitivity of 86%, a specificity of 71%, and an overall accuracy of 80% for cardiac dyspnea. The use of 2 cutoffs (< 1200 and > 4500 pg/mL) resulted in an 8% error rate and a gray area englobing 32% of values. CONCLUSION: NT-proBNP appears to be a sensitive and specific means of distinguishing pulmonary from cardiac causes of dyspnea in elderly patients. An optimal diagnostic strategy requires the use of 2 cutoffs and further investigations of patients with values in the gray area.