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.

proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action.

BACKGROUND: Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). METHODS: Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. RESULTS: We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. CONCLUSIONS: These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

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.

Characterization of non-response to cardiac resynchronization therapy by post-procedural computed tomography.

INTRODUCTION: Causes of non-response to cardiac resynchronization therapy (CRT) include mechanical dyssynchrony, myocardial scar, and suboptimal left ventricular (LV) lead location. We aimed to assess the utility of Late Iodine Enhancement Computed Tomography (LIE-CT) with image subtraction in characterizing CRT non-response. METHODS: CRT response was defined as a decrease in LV end-systolic volume > 15% at 6 months. LIE-CT was performed after 6 months, and analyzed global and segmental dyssynchrony, myocardial scar, coronary venous anatomy, and position of LV lead relative to scar and segment of latest mechanical contraction. RESULTS: We evaluated 29 patients (age 71 ± 12 years; 72% men) including 18 (62%) responders. All metrics evaluating residual dyssynchrony such as wall motion index and wall thickness index were worse in non-responders. There was no difference in presence and extent of scar between responders and non-responders. However, in non-responders, the LV lead was more often over an akinetic/dyskinetic area (72% vs. 22%, p = .007), a fibrotic area (64% vs. 8%, p = .0007), an area with myocardial thickness < 6 mm (82% vs. 22%, p = .002), and less often concordant with the region of maximal wall thickness (9% vs. 72%, p = .001). Among the 11 non-responders, eight had at least another coronary venous branch visualized by CT, including three (27%) coursing over a potentially interesting myocardial area (free of scar, with normal wall motion, and with a myocardial thickness ≥6 mm). CONCLUSION: LIE-CT with image subtraction allows a comprehensive characterization of patients after CRT and may provide clues for management of non-responders.

Hepatopulmonary syndrome-attributed extreme hypoxemia and polycythemia revealing liver cirrhosis.

We report an unusual case of severe hepatopulmonary syndrome with previously unrecognized cirrhosis, presenting with acute on chronic dyspnoea, extreme hypoxemia, secondary polycythemia as well as direct identification of arteriovenous communications on computed tomography angiography. Hepatopulmonary syndrome, defined as the combination of hepatopathy, arterial deoxygenation and pulmonary vascular dilatation, is increasingly recognized as a life-threatening complication in advanced liver disease and transplant candidacy. It is usually diagnosed in chronic liver disease patients following pre-transplant evaluation or mild dyspnea investigation. Diagnosis relies on the indirect evidence of pulmonary arteriovenous communications suggested by echocardiography with a bubble study. Clinicians need to be aware of this rare but potential acute presentation at the emergency room.

Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness.

AIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III-IV. Median LVWT was 18 (16-21) mm. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79]. Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P < 0.001). In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. CONCLUSION: Five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR-FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly, those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE.

Comparison between visual grading and planimetric quantification of microvascular obstruction extent assessment in reperfused acute myocardial infarction.

OBJECTIVES: Current methods for infarct size and microvascular obstruction (MVO) quantification by cardiac magnetic resonance (CMR) imaging rely on planimetry. This method is time-consuming. We sought to evaluate a direct assessment of MVO severity based on visual evaluation and to compare it to a reference method. METHODS: CMR was performed in 112 consecutive patients after reperfused myocardial infarction. MVO was estimated by direct visual assessment based on a three-grade severity scale (MVO 1, mild; MVO 2, moderate; MVO 3, severe) on late gadolinium-enhancement (LGE). RESULTS: MVO was present in 69 patients (61.6 %). Quantitative MVO extent significantly increased accordingly to visual MVO grading (p < 0.01). Correlation between visual grading and quantitative assessment was excellent (r = 0.92, IQR 0.88-0.95, p < 0.001). CMR inter- and intraobserver variability for visual MVO evaluation was low (κ = 0.93 and κ = 0.96, respectively), whereas quantitative MVO assessment suffered from moderate agreement (interobserver, bias = -0.81 ± 1.8 g LV; intraobserver, -0.83 ± 2.1 g LV). Visual evaluation was significantly faster than reference method (0.65 ± 0.37 vs. 10.2 ± 2.9 min, p < 0.0001). CONCLUSIONS: MVO severity based on direct visual assessment on LGE images is feasible, rapid, reproducible and agrees very well with quantitative methods, with a very low inter- and intraobserver variability. Our approach could be used for routine evaluation in patients undergoing CMR after acute myocardial infarction. KEY POINTS: • Microvascular obstruction direct visual evaluation is feasible, rapid and highly reproducible. • Microvascular obstruction direct visual evaluation correlates well with quantification by planimetry. • Microvascular obstruction or no-reflow phenomenon is determined on late gadolinium-enhanced images. • Cardiac MRI is useful for myocardial damage assessment after myocardial infarction.

Effects of exercise on postexercise ventricular-arterial coupling and pulsatile efficiency in patients with systolic dysfunction.

BACKGROUND: A suboptimal ventricular-arterial (VA) interaction may have a prolonged depressing effect on the failing heart after functional reserves forced to their limits under stress conditions such as exercise. The continuation of excessive load in the postexercise period may be more important than the load during exercise, because the sum of postexercise periods generally exceeds exercise time itself. We sought that exercise-induced changes in postexercise VA coupling and pulsatile efficiency in patients with heart failure (HF). METHODS: Thirty consecutive HF with reduced ejection fraction (EF) and thirty age-, sex- and peak VO2 -matched subjects with preserved EF were enrolled. Pre- and postexercise echocardiographic and tonometric measurements were taken to calculate left ventricular and arterial elastances, arterial compliance and wave reflections, and steady and pulsatile power. RESULTS: VA coupling significantly deteriorated in HF group (from 1·50 ± 0·47 to 2·00 ± 0·75 mmHg/mL, P < 0·01), but control group maintained basal favourable coupling status after exercise (from 1·04 ± 0·29 to 1·03 ± 0·24 mmHg/mL, P = 0·77). Pulsatile percentage of total power significantly increased with exercise in HF group, whereas it showed a significant decrease in control group. The change in pulsatile power fraction was correlated with the change in augmentation pressure (r = 0·41, ß = 3·00, P < 0·01) and inversely correlated with the change in total arterial compliance (r = -0·29, ß = -8·52, P = 0·02). CONCLUSION: Our data indicate that exercise-induced VA decoupling and pulsatile inefficiency extend into postexercise phase in patients with systolic dysfunction. The exact duration of these derangements requires further studies.

Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure.

BACKGROUND: Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. METHODS AND RESULTS: Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but less so to BNP. In addition, we observed an increase in furin activity that is positively related to the plasma levels of proBNP, NT-proBNP and BNP overproduction (all P < 0.001, all ρ > 0.88), and negatively related to the degree of proBNP glycosylation (ρ = -0.62, P < 0.001). CONCLUSION: These comprehensive results provide a paradigm for the post-translational modification of natriuretic peptides in ADHF: as proBNP glycosylation decreases, furin activity increases. This synergistically amplifies the processing of proBNP into BNP and NT-proBNP. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/. Identifier: NCT01374880.

Changes in ventricular-arterial coupling during decongestive therapy in acute heart failure.

AIMS: Coupled arterial and left ventricular properties are poorly documented in acute heart failure. The aim of this prospective noninvasive study was to document early changes in ventricular-arterial coupling in patients with acutely decompensated HF (ADHF). METHODS AND RESULTS: We studied 19 patients hospitalized for ADHF (age 62 ± 15 years, NYHA class 3 or 4). Patients with shock and sustained arrhythmias were excluded. All the patients received intravenous loop diuretics, and none received intravenous vasodilators or inotropes. Ongoing chronic treatments were maintained. Echocardiography and radial artery tonometry were performed simultaneously on admission and after clinical improvement (day 4 ± 1 after admission). Classical echocardiographic parameters were measured, including stroke volume (SV). End-systolic pressure (Pes) was derived from reconstructed central aortic pressure, and arterial elastance (Ea) was calculated as Ea = Pes/SV. End-systolic LV elastance (Ees) was calculated with the single-beat method. Ventricular-arterial coupling was quantified as the Ea/Ees ratio. Following IV diuretic therapy, mean weight loss was 5 ± 2 kg (P < 0·01) and BNP fell from 1813 (median) (IQR = 1284-2342) to 694 (334-1053) pg/mL (P < 0·01). Ea fell by 29%, from 2·46 (2·05-2·86) to 1·78 (1·55-2·00) mmHg/mL (P < 0·01), while Ees remained unchanged (1·28 (1·05-1·52) to 1·13 (0·92-1·34) mmHg/mL). The Ea/Ees ratio therefore fell, from 2·13 (1·70-2·56) to 1·81 (1·56-2·08) (P < 0·02). CONCLUSION: An early improvement in ventricular-arterial coupling was observed after diuretic-related decongestive therapy in ADHF patients and was related to a decrease in effective arterial elastance rather than to change in LV contractility.

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.

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.

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.

[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.

In-hospital Prognostic Value of TAPSE/sPAP in Patients Hospitalized for Acute Heart Failure.

AIMS: TAPSE/sPAP (tricuspid annular plane systolic excursion over systolic pulmonary artery pressure) assessed by echocardiography appears to be a good noninvasive 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: 333 consecutive patients (mean age 68 ± 14 years, 70% of male, mean LVEF 44 ± 16%) hospitalized for AHF across 39 French cardiology department, with TAPSE/sPAP measured by echocardiography within the 24 first hours 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 characteristics curves 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 (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; Chi-2 improvement: 14.4; LR-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 HF-specific care in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063097.

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.

Monitoring persistent platelet reactivity in patients with unprotected left main stenting.

OBJECTIVE: This study sought to determine the rate and potential clinical impact of persistent platelet reactivity (PPR) in unprotected left main (ULMD) stenting. BACKGROUND: PPR under aspirin or thienopyridines is associated with acute events after angioplasty. METHODS: We prospectively included 125 patients referred for ULMD stenting. For the first 64 patients (ALMA-1), angioplasty was performed under aspirin and clopidogrel without platelet reactivity assessment. For the last 61 patients (ALMA-2), platelet reactivity was assessed before angioplasty: in patients with aspirin-related PPR, aspirin twice daily was given and in those with clopidogrel-related PPR, clopidogrel double dose or prasugrel was used. RESULTS: Overall, patients' mean age was 69 ± 13 years, 37% were diabetic, and 37% had non-ST segment elevation myocardial infarction (NSTEMI). Patients' characteristics were similar in both studies with isolated left main in 14% and associated with 1-, 2-, or 3-vessel disease in 23%, 36%, and 27%, respectively. Mean SYNTAX score was 23 ± 9. Procedural characteristics were similar using provisional T stenting in 69%, T stenting in 27%, and other techniques in 4%. In ALMA-2, 28% patients had PPR for aspirin, 29% for clopidogrel, and 8% for both. Aspirin twice daily was given in 28% of patients, clopidogrel double dose in 26%, and prasugrel in 31%. The rate of 1-year major adverse cardiovascular and cerebrovascular events (MACCE) was lower in ALMA-2 versus ALMA-1 (8.2% vs. 20.8%; P = 0.04) as a composite end-point of cardiovascular death or stent thrombosis (0.0% vs. 8.3%; P = 0.02). CONCLUSION: PPR under aspirin and thienopyridines is frequent in ULMD stenting and could be related to subsequent major events.

Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure.

AIMS: Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). METHODS AND RESULTS: A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. CONCLUSION: The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.

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.