Prognostic value of CMR-derived extracellular volume in AL amyloidosis: a multicenter study.

BACKGROUND: This study aimed to assess the prognostic value of cardiac magnetic resonance (CMR) variables and compare them with biological and echocardiographic markers in patients with AL cardiac amyloidosis (CA). METHODS: We conducted a prospective study across three tertiary centres, where patients underwent clinical examination, blood tests, echocardiography, and CMR. The primary endpoint was all-cause mortality. RESULTS: A total of 176 patients with AL CA were included, with a median age of 68 years (IQR 58-75). According to the 2004 Mayo Clinic staging, 121 patients (69%) were in stage 3. During a median follow-up of 22 months (IQR 8-48), 45 patients died, and 55 were hospitalized for heart failure. Patients who died had higher NT-proBNP and troponin levels, and lower LVEF, cardiac output, and longitudinal strain. Among CMR variables, extracellular volume (ECV) was most strongly associated with all-cause mortality. In multivariate Cox models, including Mayo Clinic staging, ECV ≥ 0.45 was independently associated with mortality (HR 2.36, CI 95% 1.47-5.60) and also with heart failure hospitalizations (HR 4.10, 95%CI 2.15-8.8). CONCLUSION: ECV is a powerful predictor of outcomes in AL CA, providing additional prognostic value on top of Mayo Clinic staging.

Rationale and design of the French Observatory of Acute Heart Failure (OFICA2).

BACKGROUND: Acute heart failure (AHF) is a leading cause of hospitalization and mortality - especially in patients aged≥65 years in high-income countries - and represents a high healthcare burden. In the past decade, the epidemiology and management of heart failure (HF) has changed, with the emergence of new medical and interventional therapeutics, but up-to-date real-life data are scarce. AIMS: The main objectives are to describe baseline characteristics (with an emphasis on lifestyle, cognitive status, HF knowledge and treatment adherence), management, and in-hospital and mid-term outcomes of AHF patients in France. Secondary objectives are to investigate determinants of prognosis, modalities of treatment and follow-up, and identify gaps between guidelines and real-life management. METHODS: OFICA2 is a prospective multicentre observational survey that enrolled 1513 patients hospitalized for AHF in 80 participating centres in France during March and April 2021. The diagnosis of AHF was made according to the European Society of Cardiology guidelines definition. Inclusion criteria were age≥18years, health coverage and consent to participate. Detailed information was collected prospectively starting at admission. Thanks to direct linking with the French National Health Database, the anteriority up to 2years before inclusion, as well as a 3-year follow-up is specified for each patient and includes individual information on death, hospital admissions, major clinical events, drug delivery and use of reimbursed health resources. CONCLUSION: This cohort provides a representative snapshot on contemporary AHF, with a particular focus on self-care determinants, and will improve knowledge about AHF presentation, management and outcomes.

Post-capillary pulmonary hypertension in heart failure: impact of current definition in the PH-HF multicentre study.

BACKGROUND AND AIMS: Based on retrospective studies, the 2022 European guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). However, the impact of this definition and its prognostic value has never been evaluated prospectively. METHODS: Stable left HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed up in this multicentre study. The impact of the successive pcPH definitions on pcPH prevalence and subgroup [i.e. isolated (IpcPH) vs. combined pcPH (CpcPH)] was evaluated. Multivariable Cox regression analysis was used to assess the prognostic value of mPAP and PVR on all-cause death or hospitalization for HF (primary outcome). RESULTS: Included were 662 HF patients were (median age 63 years, 60% male). Lowering mPAP from 25 to 20 mmHg resulted in +10% increase in pcPH prevalence, whereas lowering PVR from 3 to 2 resulted in +60% increase in CpcPH prevalence (with significant net reclassification improvement for the primary outcome). In multivariable analysis, both mPAP and PVR remained associated with the primary outcome [hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = .01; HR 1.07, 95% CI 1.00-1.14, P = .03]. The best PVR threshold associated with the primary outcome was around 2.2 WU. Using the 2022 definition, pcPH patients had worse survival compared with HF patients without pcPH (log-rank, P = .02) as well as CpcPH compared with IpcPH (log-rank, P = .003). CONCLUSIONS: This study is the first emphasizing the impact of the new pcPH definition on CpcPH prevalence and validating the prognostic value of mPAP > 20 mmHg and PVR > 2 WU among HF patients.

Rationale and design of the PACIFIC-PRESERVED (PhenomApping, ClassIFication and Innovation for Cardiac dysfunction in patients with heart failure and PRESERVED left ventricular ejection fraction) study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is poorly defined, reflecting an incomplete understanding of its pathophysiology. AIM: To redefine the phenotypic spectrum of HFpEF. METHODS: The PACIFIC-PRESERVED study is a prospective multicentre cohort study designed to perform multidimensional deep phenotyping of patients diagnosed with HFpEF (left ventricular ejection fraction≥50%), patients with heart failure with reduced ejection fraction (left ventricular ejection fraction≤40%) and subjects without overt heart failure (3:2:1 ratio). The study proposes prospective investigations in patients during a 1-day hospital stay: physical examination; electrocardiogram; performance-based tests; blood samples; cardiac magnetic resonance imaging; transthoracic echocardiography (rest and low-level exercise); myocardial shear wave elastography; chest computed tomography; and non-invasive measurement of arterial stiffness. Dyspnoea, depression, general health and quality of life will be assessed by dedicated questionnaires. A biobank will be established. After the hospital stay, patients are asked to wear a connected garment (with digital sensors) to collect electrocardiography, pulmonary and activity variables in real-life conditions (for up to 14 days). Data will be centralized for machine-learning-based analyses, with the aim of reclassifying HFpEF into more distinct subgroups, improving understanding of the disease mechanisms and identifying new biological pathways and molecular targets. The study will also serve as a platform to enable the development of innovative technologies and strategies for the diagnosis and stratification of patients with HFpEF. CONCLUSIONS: PACIFIC-PRESERVED is a prospective multicentre phenomapping study, using novel analytical techniques, which will provide a unique data resource to better define HFpEF and identify new clinically meaningful subgroups of patients.

Development and validation of algorithms to predict left ventricular ejection fraction class from healthcare claims data.

AIMS: The use of large medical or healthcare claims databases is very useful for population-based studies on the burden of heart failure (HF). Clinical characteristics and management of HF patients differ according to categories of left ventricular ejection fraction (LVEF), but this information is often missing in such databases. We aimed to develop and validate algorithms to identify LVEF in healthcare databases where the information is lacking. METHODS AND RESULTS: Algorithms were built by machine learning with a random forest approach. Algorithms were trained and reinforced using the French national claims database [Système National des Données de Santé (SNDS)] and a French HF registry. Variables were age, gender, and comorbidities, which could be identified by medico-administrative code-based proxies, Anatomical Therapeutic Chemical codes for drug delivery, International Classification of Diseases (Tenth Revision) coding for hospitalizations, and administrative codes for any other type of reimbursed care. The algorithms were validated by cross-validation and against a subset of the SNDS that includes LVEF information. The areas under the receiver operating characteristic curve were 0.84 for the algorithm identifying LVEF ≤ 40% and 0.79 for the algorithms identifying LVEF < 50% and ≥50%. For LVEF ≤ 40%, the reinforced algorithm identified 50% of patients in the validation dataset with a positive predictive value of 0.88 and a specificity of 0.96. The most important predictive variables were delivery of HF medication, sex, age, hospitalization, and testing for natriuretic peptides with different orders of positive or negative importance according to the LVEF category. CONCLUSIONS: The algorithms identify reduced or preserved LVEF in HF patients within a nationwide healthcare claims database with high positive predictive value and low rates of false positives.

In-hospital prognostic value of TAPSE/sPAP in patients hospitalized for acute heart failure.

AIMS: Tricuspid annular plane systolic excursion over systolic pulmonary artery pressure (TAPSE/sPAP) assessed by echocardiography appears to be a good non-invasive approach for right ventricular to pulmonary artery coupling assessment. We aimed to assess the in-hospital prognostic value of TAPSE/sPAP among patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS: In total, 333 consecutive patients (mean age 68 ± 14 years, 70% of male, mean left ventricular ejection fraction 44 ± 16%) were hospitalized for AHF across 39 French cardiology departments, with TAPSE/sPAP measured by echocardiography within the first 24 h of hospitalization were included in this prospective study. The primary outcome was in-hospital major adverse cardiovascular events (MACEs) defined as all-cause death, resuscitated cardiac arrest or cardiogenic shock and occurred in 50 (15%) patients. Using receiver operating characteristic curve analysis, the best TAPSE/sPAP threshold for in-hospital MACEs was 0.40 mm/mmHg. TAPSE/sPAP < 0.40 mm/mmHg was independently associated with in-hospital MACEs, even after adjustment with comorbidities [odds ratio (OR): 3.75, 95% CI (1.87-7.93), P < 0.001], clinical severity [OR: 2.80, 95% CI (1.36-5.95), P = 0.006]. Using a 1:1 propensity-matched population, TAPSE/sPAP ratio < 0.40 was associated with a higher rate of in-hospital MACEs [OR: 2.98, 95% CI (1.53-6.12), P = 0.002]. After adjustment, TAPSE/sPAP < 0.40 showed the best improvement in model discrimination and reclassification above traditional prognostic factors (C-statistic improvement: 0.05; χ2 improvement: 14.4; likelihood-ratio test P < 0.001). These results were consistent in an external validation cohort of 133 patients. CONCLUSION: TAPSE/sPAP < 0.40 mm/mmHg assessed by an early echocardiography during an AHF episode is independently associated with in-hospital MACEs suggesting enhanced close monitoring and strengthened heart failure-specific care in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063097.

[Natriuretic peptides in the diagnosis and monitoring of heart failure]. / Peptides natriurétiques dans le diagnostic et le suivi de l'insuffisance cardiaque.

NATRIURETIC PEPTIDES IN THE DIAGNOSIS AND MONITORING OF CARDIAC FAILURE. Heart failure (HF) is a serious and common disease requiring a prompt diagnosis for appropriate management. Natriuretic peptides, such as BNP and NT-proBNP, play a crucial role in diagnosing HF due to their s pecificity and reproducibility. It is important to measuring natriuretic peptides, especially in cases of acute dyspnea, to differentiate cardiac causes from others. Specific thresholds are recommended, with high values strongly suggest HF, while normal levels rule out the diagnosis. Clinical characteristics, such as age, renal function, atrial fibrillation, obesity, and gender, influence natriuretic peptides levels and should be considered in interpretation. For diabetic, hypertensive, and obese patients, early screening for HF through natriuretic peptides measurement is crucial. Furthermore, these natriuretic peptides are useful for monitoring chronic heart failure patients. They assist in confirming decompensation, titrating treatment, evaluating treatment response, and establishing prognosis. However, it's essential to choose a single biomarker (BNP or NT-proBNP) to avoid confusion.

DANS LE DIAGNOSTIC ET LE SUIVI DE L'INSUFFISANCE CARDIAQUE. L'insuffisance cardiaque (IC) est une maladie grave et fréquente nécessitant un diagnostic rapide pour une prise en charge adéquate. Les peptides natriurétiques, tels que le BNP et le NT-proBNP, jouent un rôle essentiel dans le diagnostic de l'IC en raison de leur spécificité et de leur reproductibilité. Il est important de doser les peptides natriurétiques, en particulier lors d'une dyspnée aiguë, pour différencier les causes cardiaques des autres. Des seuils spécifiques sont recommandés, et des valeurs élevées évoquent fortement une IC, tandis que des taux normaux écartent le diagnostic. Les caractéristiques cliniques ­ telles que l'âge, la fonction rénale, la fibrillation atriale, l'obésité et le sexe ­ modifient les taux de peptides natriurétiques et doivent être prises en compte dans l'interprétation. Chez les patients diabétiques, hypertendus et obèses, le dépistage précoce de l'IC par le dosage des peptides natriurétiques est crucial. De plus, ces peptides natriurétiques sont utiles pour le suivi des patients insuffisants cardiaques chroniques. Ils aident à confirmer une décompensation, à titrer le traitement, à en évaluer la réponse et à établir un pronostic. Cependant, il est essentiel de choisir un seul biomarqueur (BNP ou NT-proBNP) pour éviter toute confusion.

Patterns of left ventricular remodeling post-myocardial infarction, determinants, and outcome.

AIM: Left ventricular remodeling (LVR) after myocardial infarction (MI) can lead to heart failure, arrhythmia, and death. We aim to describe adverse LVR patterns at 6 months post-MI and their relationships with subsequent outcomes and to determine baseline. METHODS AND RESULTS: A multicenter cohort of 410 patients (median age 57 years, 87% male) with reperfused MI and at least 3 akinetic LV segments on admission was analyzed. All patients had transthoracic echocardiography performed 4 days and 6 months post-MI, and 214 also had cardiac magnetic resonance imaging performed on day 4. To predict LVR, machine learning methods were employed in order to handle many variables, some of which may have complex interactions. Six months post-MI, echocardiographic increases in LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were 14.1% [interquartile range 0.0, 32.0], 5.0% [- 14.0, 25.8], and 8.7% [0.0, 19.4], respectively. At 6 months, ≥ 15% or 20% increases in LVEDV were observed in 49% and 42% of patients, respectively, and 37% had an LVEF < 50%. The rate of death or new-onset HF at the end of 5-year follow-up was 8.8%. Baseline variables associated with adverse LVR were determined best by random forest analysis and included stroke volume, stroke work, necrosis size, LVEDV, LVEF, and LV afterload, the latter assessed by Ea or Ea/Ees. In contrast, baseline clinical and biological characteristics were poorly predictive of LVR. After adjustment for predictive baseline variables, LV dilation > 20% and 6-month LVEF < 50% were significantly associated with the risk of death and/or heart failure: hazard ratio (HR) 2.12 (95% confidence interval (CI) 1.05-4.43; p = 0.04) and HR 2.68 (95% CI 1.20-6.00; p = 0.016) respectively. CONCLUSION: Despite early reperfusion and cardioprotective therapy, adverse LVR remains frequent after acute MI and is associated with a risk of death and HF. A machine learning approach identified and prioritized early variables that are associated with adverse LVR and which were mainly hemodynamic, combining LV volumes, estimates of systolic function, and afterload.

Impact of sacubitril/valsartan on cardiac and systemic hypoxia in chronic heart failure.

In heart failure patients with reduced ejection fraction, Sacubitril/valsartan (S/V) increased proBNP T71 glycosylation, which is regulated negatively by hypoxia via miR-30a in vitro. Using a cohort of 73 HFrEF patients who were transitioned from standard HF medication to S/V, we found that the increase in proBNP T71 glycosylation after S/V was associated with a decrease in cardiac hypoxia. We further found that plasma levels of K709-acteylated HIF1α, HIF-regulated and HIF-independent biomarkers also evolved consistently with a decrease in hypoxia. We further confirmed that biomarker changes were related to hypoxia, in a rat model subjected to isobaric hypoxia. We measured them in rats subjected to isobaric hypoxia. Overall, these data strongly suggest that optimally treated HFrEF patients exhibited subclinical hypoxia that is improved by S/V. The data also posit proBNP T71 glycosylation as a biomarker of cardiac hypoxia.

Heart failure with preserved ejection fraction: New challenges and new hopes.

Heart failure (HF) is a major public health problem affecting millions of adults worldwide. HF with preserved ejection fraction, i.e. > 50 %, (HFpEF) accounts for more than half of all HF cases, and its incidence and prevalence are increasing with the aging of the population and the growing prevalence of metabolic disorders such as obesity, diabetes and hypertension. Diagnosis of HFpEF requires a combination of numerous echocardiographic parameters and also results of natriuretic peptide assays, to which may be added the need for a stress test. HFpEF is characterized by complex, interrelated pathophysiological mechanisms, which must be understood. This complexity probably accounts for the lack of evidence-based medicine compared with HF with reduced EF. Nevertheless, significant progress has been made recently, with a high level of evidence obtained for the SGLT2 inhibitor class on the one hand, and promising data with new drugs targeting more specifically certain mechanisms such as obesity and inflammation on the other.

Multicentre medicoeconomic evaluation of cardiac magnetic resonance imaging for predicting coronary artery disease in left ventricular dysfunction: The CAMAREC study design.

BACKGROUND: Cardiac magnetic resonance imaging may provide a non-invasive alternative to coronary angiography for differentiating between ischaemic and non-ischaemic cardiomyopathy in cases of unexplained reduced left ventricular ejection fraction. AIM: The CAMAREC study aims to evaluate the diagnostic accuracy of cardiac magnetic resonance imaging in predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction, using coronary angiography as the gold standard for comparison. METHODS: CAMAREC is a prospective cohort study of 406 patients in 10 centres with newly diagnosed, unexplained left ventricular ejection fraction ≤ 45%. Cardiac magnetic resonance imaging and coronary angiography will be conducted within a 2-week interval, starting with cardiac magnetic resonance imaging; independent committees will review the results blindly. Primary outcome is sensitivity of detecting ischaemic scar on cardiac magnetic resonance imaging for predicting significant coronary artery disease on coronary angiography according to Felker's criteria. Secondary outcomes include specificity and positive and negative predictive values (with 95% confidence intervals) of cardiac magnetic resonance imaging for predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction, kappa concordance coefficient between cardiac magnetic resonance imaging and coronary angiography for diagnosing the affected myocardial territory, and the impact of cardiac magnetic resonance imaging on revascularization decisions. Two ancillary studies will evaluate the incremental cost-effectiveness of using cardiac magnetic resonance imaging first versus coronary angiography first, and the sensitivity of pre- and postcontrast T1-mapping for predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction. CONCLUSION: Our study protocol is designed to rigorously evaluate cardiac magnetic resonance imaging as a non-invasive alternative to coronary angiography in patients with unexplained reduced left ventricular ejection fraction. The results will have significant implications for patient management, and may support growing evidence for the clinical utility of cardiac magnetic resonance imaging.

Prognostic value of soluble ST2 in AL and TTR cardiac amyloidosis: a multicenter study.

Background: Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan therapeutic strategies and follow-ups. Cardiac biomarkers, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (Hs-cTnT), remain the cornerstone of the prognostic assessment. An increased level of soluble suppression of tumorigenesis-2 (sST2) is predictive of adverse events [all-cause death and heart failure (HF) hospitalizations] in patients with HF. This study aimed to evaluate the prognostic value of circulating sST2 levels in AL-CA and ATTR-CA. Methods: We carried out a multicenter study including 133 patients with AL-CA and 152 patients with ATTR-CA. During an elective outpatient visit for the diagnosis of CA, Mayo Clinic staging [NT-proBNP, Hs-cTnT, differential of free light chains (DFLCs)] and sST2 were assessed for all AL patients. Gillmore staging [including estimated glomerular filtration rate (eGFR), NT-proBNP] and Grogan staging (including NT-proBNP and Hs-cTnT) were assessed for TTR-CA patients. Results: The median age was 73 years [interquartile range (IQR) 61-81], and 53% were men. The endpoint was the composite of all-cause death or first HF-related hospitalization. The median follow-up was 20 months (IQR 3-34) in AL amyloidosis and 33 months (6-45) in TTR amyloidosis. The primary outcome occurred in 70 (53%) and 99 (65%) of AL and TTR patients, respectively. sST2 levels were higher in patients with AL-CA than in patients with ATTR-CA: 39 ng/L (26-80) vs. 32 ng/L (21-46), p < 0.001. In AL-CA, sST2 levels predicted the outcome regardless of the Mayo Clinic score (HR: 2.16, 95% CI: 1.17-3.99, p < 0.001). In TTR-CA, sST2 was not predictive of the outcome in multivariate models, including Gillmore staging and Grogan staging (HR: 1.17, CI: 95% 0.77-1.89, p = 0.55). Conclusion: sST2 level is a relevant predictor of death and HF hospitalization in AL cardiac amyloidosis and adds prognostic stratification on top of NT-proBNP, Hs cTnT, and DFLC.

Left atrioventricular coupling index assessed using cardiac CT as a prognostic marker of cardiovascular death.

PURPOSE: The purpose of this study was to investigate the prognostic value of left atrioventricular coupling index (LACI) assessed by cardiac computed tomography (CT), to predict cardiovascular death in consecutive patients referred for cardiac CT with coronary analysis. MATERIALS AND METHODS: Between 2010 and 2020, we conducted a single-centre study with all consecutive patients without known cardiovascular disease referred for cardiac CT. LACI was defined as the ratio of left atrial to left ventricle end-diastolic volumes. The primary outcome was cardiovascular death. Cox regressions were used to evaluate the association between LACI and primary outcome after adjustment for traditional risk factors and cardiac CT angiography findings. RESULTS: In 1,444 patients (mean age, 70 ± 12 [standard deviation] years; 43% men), 67 (4.3%) patients experienced cardiovascular death after a median follow-up of 6.8 (Q1, Q3: 5.9, 9.1) years. After adjustment, LACI was positively associated with the occurrence of cardiovascular death (adjusted hazard ratio [HR], 1.07 [95% CI: 1.05-1.09] per 1% increment; P < 0.001), and all-cause death (adjusted HR, 1.05 [95% CI: 1.03-1.07] per 1% increment; P <0.001). After adjustment, a LACI ≥ 25% showed the best improvement in model discrimination and reclassification for predicting cardiovascular death above traditional risk factors and cardiac CT findings (C-statistic improvement: 0.27; Nnet reclassification improvement = 0.826; Integrative discrimination index =0.209, all P < 0.001; likelihood-ratio-test, P < 0.001). CONCLUSION: LACI measured by cardiac CT is independently associated with cardiovascular death and all-cause death in patients without known cardiovascular disease referred for cardiac CT, with an incremental prognostic value over traditional risk factors and cardiac CT findings.

Deconvolution of BNP and NT-proBNP Immunoreactivities by Mass Spectrometry in Heart Failure and Sacubitril/Valsartan Treatment.

BACKGROUND: Elevated BNP and the N-terminal fragment of the proBNP (NT-proBNP) are hallmarks of heart failure (HF). Generally, both biomarkers parallel each other. In patients receiving sacubitril/valsartan, BNP remained stable while NT-proBNP decreased. As BNP and NT-proBNP assays have limited specificity due to cross-reactivity, we quantified by mass spectrometry (MS) the contributing molecular species. METHODS: We included 356 healthy volunteers, 100 patients with acute dyspnoea (49 acute decompensated HF; 51 dyspnoea of non-cardiac origin), and 73 patients with chronic HF and reduced ejection fraction treated with sacubitril/valsartan. BNP and NT-proBNP immunoreactivities (BNPir and NT-proBNPir) were measured by immunoassays (Abbott ARCHITECT and Roche Diagnostics proBNPII) and proBNP-derived peptides and glycosylation at serine 44 by MS on plasma samples. RESULTS: BNPir corresponded to the sum of proBNP1-108, BNP1-32, BNP3-32, and BNP5-32 (R2 = 0.9995), while NT-proBNPir corresponded to proBNP1-108 and NT-proBNP1-76 not glycosylated at serine 44 (R2 = 0.992). NT-proBNPir was better correlated (R2 = 0.9597) than BNPir (R2 = 0.7643) with proBNP signal peptide (a surrogate of proBNP production). In patients receiving sacubitril/valsartan, non-glycosylated NT-proBNP1-76 remained constant (P = 0.84) despite an increase in NT-proBNP1-76 and its glycosylation (P < 0.0001). ProBNP1-108 remained constant (P = 0.12) while its glycosylation increased (P < 0.0001), resulting in a decrease in non-glycosylated proBNP1-108 (P < 0.0001), and in NT-proBNPir. CONCLUSIONS: Glycosylation interfered with NT-proBNPir measurement, explaining the discrepant evolution of these 2 biomarkers in patients receiving sacubitril/valsartan. Both BNPir and NT-proBNPir are surrogates of proBNP1-108 production, NT-proBNPir being more robust in the clinical contexts studied.

N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T hold diagnostic value in cardiac amyloidosis.

AIMS: Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. This study aimed to evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT). METHODS AND RESULTS: Patients with suspected CA (n = 1149) underwent a diagnostic work-up in three centres in Italy, France (n = 343, derivation cohort), and United Kingdom (n = 806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP <180 ng/L or hs-TnT <14 ng/L were found in 7% of patients, and ruled out CA without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT-proBNP <180 ng/L or hs-TnT <14 ng/L, and 10% showed both biomarkers below cut-offs (0.5% false negatives). These cut-offs refined CA prediction when added to echocardiographic scores in patients with a haematologic disease or an increased wall thickness. In the validation cohort, the 86 ng/L hs-TnT cut-off ruled in 20% of patients (2% false positives). NT-proBNP and hs-TnT cut-offs retained their rule-out and rule-in performance also in cohorts with CA prevalence of 20%, 10%, 5% and 1% derived from the original cohort through bootstrap analysis. CONCLUSIONS: Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP <180 ng/L and hs-TnT <14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL-CA or cardiac (pseudo)hypertrophy.

Feasibility and accuracy of linking a heart failure registry to the national claims database using indirect identifiers.

BACKGROUND: Heart failure (HF) registries include rich data on patient inclusion characteristics, but follow-up information is often incomplete. Medicoadministrative databases may provide less clinical information than registries, e.g. on left ventricular ejection fraction (LVEF), but long-term data are exhaustive and reliable. The combination of the two types of database is therefore appealing, but the feasibility and accuracy of such linking are largely unexplored. AIMS: To assess the feasibility and accuracy of linking an HF registry (FRESH; FREnch Survey on Heart Failure) with the French National Healthcare System database (SNDS). METHODS: A probabilistic algorithm was developed to link and match patient data included in the FRESH HF registry with anonymized records from the SNDS, which include: hospitalizations and diagnostic codes; all care-related reimbursements by national health system; and deaths. Consistency was assessed between deaths recorded in the registry and in the SNDS. A comparison between the two databases was carried out on several identifiable clinical characteristics (history of HF hospitalization, diabetes, atrial fibrillation, chronic bronchopneumopathy, severe renal failure and stroke) and on events during 1-year follow-up after inclusion. RESULTS: Of 2719 patients included in the FRESH registry (1049 during decompensation; 1670 during outpatient follow-up), 1885 could be matched with a high accuracy of 94.3% for deaths. Mortality curves were superimposable, including curves according to type of HF and LVEF. The rates of missing data in the FRESH registry were 2.3-8.4% for clinical characteristics and 17.5% for hospitalizations during follow-up. The discrepancy rate for clinical characteristics was 3-13%. Hospitalization rates were significantly higher in the SNDS than in the registry cohort. CONCLUSIONS: The anonymous matching of an HF research cohort with a national health database is feasible, with a significant proportion of patients being accurately matched, and facilitates combination of clinical data and a reduced rate of losses to follow-up.

Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. METHODS: We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. RESULTS: Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-ß (transforming growth factor-ß) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. CONCLUSIONS: Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01113268.

Determinants of left atrioventricular coupling index: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Recent studies have described a novel left atrioventricular coupling index (LACI), which had a better prognostic value in predicting cardiovascular events than individual left atrial (LA) or left ventricular (LV) variables. AIMS: To identify determinants of LACI and its 10-year annual change (ΔLACI), measured by cardiac magnetic resonance (CMR), and to better understand the variables governing this left atrioventricular coupling. METHODS: In the Multi-Ethnic Study of Atherosclerosis, 2112 study participants, free from cardiovascular disease at baseline, had LACI assessed by CMR imaging at baseline (LACIBaseline; 2000-2002) and 10 years later (2010-2012). The LACI was defined as the ratio of LA to LV end-diastolic volumes. Linear regression analyses were performed to identify independent determinants of LACIBaseline and ΔLACI. RESULTS: In the 2112 participants (mean age 58.8±9.1 years; 46.6% male), after adjustment for all covariates, age was independently associated with LACIBaseline (R2=0.10, slope=0.16) and ΔLACI (R2=0.15, slope=0.008; both P<0.001). African Americans had the highest LACIBaseline value (18.0±7.7%). Although there was no difference in LACIBaseline between women and men (P=0.19), ΔLACI was higher in women (1.0±1.1 vs 0.8±1.1%/year; P<0.001). Diabetes and higher body mass index (BMI) were independently associated with LACIBaseline (both P<0.001). LACIBaseline was independently associated with LV myocardial fibrosis markers (native T1: R2=0.11, slope=0.09 [P=0.038]; extracellular volume: R2=0.08, slope=0.28 [P=0.035]) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) concentration (R2=0.10, slope=-1.11; P<0.001), but was not associated with interleukin 6 or high-sensitivity C-reactive protein. CONCLUSIONS: Age, sex, ethnicity, diabetes and BMI were independent determinants of LACI. LACI was independently associated with myocardial fibrosis markers and NT-proBNP concentration.

Coronary Computed Tomography Angiography Analysis of Calcium Content to Identify Non-culprit Vulnerable Plaques in Patients With Acute Coronary Syndrome.

Background: Aside from the culprit plaque, the presence of vulnerable plaques in patients with acute coronary syndrome (ACS) may be associated with future cardiac events. A link between calcification and plaque rupture has been previously described. Aim: To assess whether analysis of the calcium component of coronary plaques using CT angiography, coronary computed tomographic angiography (CCTA) can help to detect additional vulnerable plaques in patients with non-ST elevation myocardial infarction (NSTEMI). Materials And Methods: Cross sectional study of consecutive patients referred for NSTEMI from 30 July to 30 August 2018 with CCTA performed before coronary angiography with systematic optical coherence tomography (OCT) analysis of all coronary arteries within 24 h of clinical onset of NSTEMI. Three types of plaques were defined: culprit plaques defined by angiography (vulnerable culprit plaques-VCP) - plaques with a fibrous cap thickness < 65 microns or thrombus in OCT (vulnerable non-culprit plaque-VNCP) - plaques with a fibrous cap thickness ≥ 65 microns in OCT (stable plaque-SP). Results: A total of 134 calcified plaques were identified in 29 patients (73% male, 59 ± 14 years) with 29(22%) VCP, 28(21%) VNCP and 77(57%) SP. Using CCTA analysis of the calcium component, factors associated with vulnerable plaques were longer calcification length, larger calcification volume, lower calcium mass, higher Agatston score plaque-specific (ASp), presence of spotty calcifications and an intimal position in the wall. In multivariate analysis, ASp, calcification length and spotty calcifications were independently associated to vulnerable plaques. There was no difference between VCP and VNCP. Conclusions: CCTA analysis of calcium component of the plaque could help to identify additional vulnerable plaques in NSTEMI patients.