Phenotype and prognostic factors in geriatric and non-geriatric patients with transthyretin cardiomyopathy.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile. METHODS AND RESULTS: This retrospective, observational, cohort study characterizes cardiac and extracardiac disorders at diagnosis and assesses prognosis among ATTR-CM patients based on age (geriatric vs. non-geriatric) and amyloidosis subtype (wild type, ATTRwt and hereditary, ATTRv). In total, 943 patients with ATTR-CM were included, of which 306 had ATTRv and 637 had ATTRwt. Among these, 331 (35.1%) were non-geriatric (<75 years), and 612 (64.9%) were geriatric (≥75 years). The population exhibited conduction abnormalities, atrial fibrillation and ischaemic heart disease that progressively deteriorated with age. Among ATTRwt patients, peripheral neuropathy, neurovegetative symptoms, and hearing loss were present across all age groups, but reports of carpal tunnel symptoms or surgery decreased with age. Conversely, among ATTRv patients, reports of extracardiac symptoms increased with age and Val122ILe mutation was highly prevalent among geriatric patients. The 3-year survival was higher among non-geriatric ATTR-CM patients (76%) than geriatric patients (55%) and predictors of 3-year mortality differed. Notably, predictors identified among geriatric patients were alkaline phosphatase (ALP) (HR = 1.004, 95% CI: [0.001-1.100)], troponin T hs (HR = 1.005, 95% CI: [1.001-1.120)] and tricuspid insufficiency (HR = 1.194, 95% CI: [1.02-1.230)]. Whereas, among non-geriatric patients, NT-proBNP (HR = 1.002, 95% CI: [1.02-1.04], global longitudinal strain (HR = 0.95, 95% CI: [0.922-0.989], and glomerular filtration rate (HR = 0.984, 95% CI: [0.968-1.00) were identified. We propose a 3-stage prognostic staging system combining troponin T hs (≥44 ng/L) and ALP levels (≥119 UI/L). In the geriatric population, this model discriminated survival more precisely than the National Amyloidosis Centre staging, particularly for classifying between stage 1 (82%), stage 2 (50%) and stage 3 (32%) for ATTRv and ATTRwt. CONCLUSIONS: These diagnostic and prognostic indicators, along with ATTR subtype, highlight the distinct characteristics of this important, geriatric ATTR-CM patient group. Recognizing these mortality markers can be valuable for geriatricians to improve the prognostic quality management of geriatric patients with ATTR-CM.

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.

Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us?

BACKGROUND: Cardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors. OBJECTIVE: Understanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies. METHODS: We immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction. RESULTS: We show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake. CONCLUSIONS: Internalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

Long-term tafamidis efficacy in patients with transthyretin amyloid cardiomyopathy by baseline left ventricular ejection fraction.

AIMS: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) present with diverse left ventricular ejection fraction (LVEF). This study assessed tafamidis efficacy by baseline LVEF in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study. METHODS AND RESULTS: Patients were randomized to 30 months of tafamidis or placebo treatment in ATTR-ACT. On completion, patients could join an LTE study to receive tafamidis. All-cause mortality (death, heart transplant, or cardiac mechanical assist device implantation) from baseline to the end of follow-up was assessed in patients continuously treated with tafamidis (80 mg meglumine or 61 mg free acid) or delayed tafamidis treatment (placebo in ATTR-ACT; tafamidis in the LTE study) according to baseline LVEF (<50% or ≥50%). Supportive outcomes were evaluated over a shorter follow-up. Patients with baseline LVEF <50% (n = 177: 88 tafamidis- and 89 placebo-treated) had signs of more severe heart failure, a higher proportion were Black, and had variant ATTR-CM than those with LVEF ≥50% (n = 171: 85 tafamidis- and 86 placebo-treated). At the end of follow-up (median 60-64 months), all-cause mortality was numerically higher in patients with baseline LVEF <50%; however, consistent with supportive findings, continuous tafamidis treatment was associated with a 47% reduction in mortality risk compared with delayed tafamidis treatment in patients with LVEF <50% and ≥50% (hazard ratio 0.53 [95% confidence interval 0.367-0.758]; p < 0.001, and 0.53 [0.344-0.818]; p < 0.01, respectively). CONCLUSIONS: Early initiation of tafamidis is associated with reduced mortality in patients with ATTR-CM, irrespective of initial LVEF value. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01994889, NCT02791230.

Prevalence, Characteristics, and Impact on Prognosis of Aortic Stenosis in Patients With Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. METHODS AND RESULTS: We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light-chain (AL) CA. CA patients' echocardiograms were re-analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population-based controls, all types of CA had higher age- and sex-standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09-3.64]; ATTRv: SRR, 3.41; 95%CI [1.64-4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25-14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56-1.14]; ATTRv: SRR, 1.27; 95%CI [0.85-1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71-4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all-cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42-1.19]; P=0.19). CONCLUSIONS: Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Salt substitute recommendations for heart failure patients may influence guideline-directed medical therapies titration.

AIMS: Reducing sodium intake is necessary for patients with chronic heart failure (CHF). Salt substitutes (saltSubs) have become increasingly popular as recommendations by healthcare professionals (HCPs) as well as options for patients and their caregivers. However, their consumption is generally potassium based and remains poorly evaluated in CHF management. Their impact on guideline-directed medical therapies (GDMTs) also remains unknown. The primary objective of this study was to provide a description and estimate of HCP recommendations and reported use of saltSubs in France. Secondary objectives were to identify if there was an association between these recommendations by HCPs and the use of GDMTs. METHODS AND RESULTS: A nationwide, questionnaire-based, cross-sectional, epidemiological study was conducted from September 2020 to July 2021. Data collection included baseline characteristics, the use and recommendations of saltSubs, and the use of GDMTs, which included (i) angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNis), (ii) mineralocorticoid receptor antagonists (MRAs), and/or (iii) beta-blockers (BBs). In total, 13% of HCPs advised saltSubs and 17% of patients and 22% of caregivers reported their consumption. CHF patients advised to take saltSubs did not differ in terms of left ventricular ejection fraction (EF) <40%, ischaemic origin, and New York Heart Association III-IV class, but were more recently hospitalized for acute HF (P = 0.004). HCPs who recommended saltSubs to patients were more likely to advise an anti-diabetic diet (P < 0.001), cholesterol-lowering diet (P < 0.001), and exercise (P = 0.018). In the overall population, ACEi/ARB/ARNi use was less frequent in case of saltSub recommendations (74% vs. 82%, P = 0.012). The concomitant prescription of none, one, two, or three GDMTs was less favourable in case of saltSub recommendations (P = 0.046). There was no significant difference for the presence of MRA (56% vs. 58%) and/or BB (78% vs. 82%). The under-prescription of ACEi/ARB/ARNi was found when patients had EF < 40% (P = 0.029) and/or EF ≥ 40% (P = 0.043). In the subgroup with left ventricular EF ≥ 40%, we found a higher thiazide use (P = 0.014) and a less frequent use of low EF GDMTs (P = 0.044) in case of being recommended saltSubs. CONCLUSIONS: Beyond the well-established risk for hyperkalaemia, our preliminary results suggest a potentially negative impact of saltSubs on GDMT use, especially for ACEis/ARBs/ARNis in CHF management. saltSub recommendations and their availability from open sale outlets should be considered to avoid possible misuse or deference from GDMTs in the future. Informed advice to consumers should also be considered from HCPs or pharmacists.

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.

Catheter ablation of atrial arrhythmias in cardiac amyloidosis: Impact on heart failure and mortality.

BACKGROUND: Atrial arrhythmias (AA) commonly affect patients with cardiac amyloidosis (CA) and are a contributing risk factor for the development of heart failure (HF). This study sought to investigate the long-term efficacy and impact of catheter ablation on HF progression in patients with CA and AA. METHODS: Thirty-one patients with CA and AA undergoing catheter ablation were retrospectively included (transthyretin-ATTR CA 61% and light chain-AL CA 39%). AA subtypes included atrial fibrillation (AFib) in 22 (paroxysmal in 10 and persistent in 12), atrial flutter (AFl) in 17 and atrial tachycardia (AT) in 11 patients. Long-term AA recurrence rates were evaluated along with the impact of sinus rhythm (SR) maintenance on HF and mortality. RESULTS: AA recurrence was observed in 14 patients (45%) at a median of 3.5 months (AFib n = 8, AT n = 6, AFl = 0). Post-cardioversion, medical therapy or catheter ablation, 10 patients (32%) remained in permanent AA. Over a median follow-up of 19 months, all-cause mortality was 39% (n = 12): 3 with end-stage HF, 5 due to late complications of CA, 1 sudden cardiac death, 1 stroke, 1 COVID 19 (and one unknown). With maintenance of SR following catheter ablation, significant reductions in serum creatinine and natriuretic peptide levels were observed with improvements in NYHA class. Two patients required hospitalization for HF in the SR maintenance cohort compared to 5 patients in the AA recurrence cohort (p = 0.1). All 3 patients with deaths secondary to HF had AA recurrence compared to 11 out of the 28 patients whom were long-term survivors or deaths not related to HF (p = 0.04). All-cause mortality was not associated with AA recurrence. CONCLUSION: This study demonstrates moderate long-term efficacy of SR maintenance with catheter ablation for AA in patients with CA. Improvements in clinical and biological status with positive trends in HF mortality are observed if SR can be maintained.

Cardiovascular disease healthcare trajectories: descriptions, similarities, mortality rates of heart failure in France.

AIMS: The primary objectives of this study were to analyse the nationwide healthcare trajectories of heart failure (HF) patients in France, 2 years after their first hospitalization, and to measure sequence similarities. Secondary objectives were to identify the association between trajectories and the risk of mortality. METHODS AND RESULTS: A retrospective, observational study was conducted using data extracted from the Echantillon Généraliste des Bénéficiaires database, covering the period from 1 January 2008 to 31 December 2018. Follow-up concluded upon death or at the end of the study. We developed a methodology specific to healthcare data by extracting frequent healthcare trajectories and measuring their similarity for use in a survival machine learning analysis. In total, 11 488 HF patients were included and followed up for an average of 2.9 ± 1.3 years. The mean age of the patients was 78.0 ± 13.2 years. The first-year mortality rate was 31.7% and increased to 78.8% at 5 years. Fifty per cent of patients experienced re-hospitalization for reasons related to cardiovascular diseases. We identified 1707 hospitalization sequences, and 21 sequences were associated with survival, while 15 sequences were linked to mortality. In all our models, age and gender emerged as the most significant predictors of mortality (permutation feature importance: 0.099 ± 0.00078 and 0.0087 ± 0.00018, respectively; weights could be interpreted in relative terms). Specifically, the age at initial hospitalization for HF was positively associated with mortality. Gender (male: 49.5%) was associated with poorer prognoses. Healthcare trajectories, including non-surgical device treatments, valve replacements, and atrial fibrillation ablation, were associated with a better prognosis (permutation feature importance: 0.0047 ± 0.00011, 0.0014 ± 0.000073, and 0.00095 ± 0.000097, respectively), except in cases where these invasive treatments preceded or followed hospitalization for cardiac decompensation. The predominant negative prognosis sequences were mostly those that included HF-related hospitalizations before or after other-related hospitalizations (permutation feature importance: 0.0007 ± 0.000091 and 0.00011 ± 0.000045, respectively). CONCLUSIONS: We highlight the value of healthcare trajectories on frequent hospitalization sequences, mortality, and prognosis and indicate the necessary prognostic value of HF re-hospitalization. Our work may be an essential tool for better identification of at-risk patients in order to increase and improve personalized care in the future.

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.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

AIMS: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. METHODS AND RESULTS: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 µmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 µmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. CONCLUSIONS: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

[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.

FACE study: 2-year follow-up of adaptive servo-ventilation for sleep-disordered breathing in a chronic heart failure cohort.

BACKGROUND: Sleep-disordered breathing (SDB) is a common comorbidity in patients with heart failure (HF) and is associated with worse prognosis. OBJECTIVES: This study evaluated the effects of adaptive servo-ventilation (ASV) on morbidity and mortality in a large heterogeneous population of HF patients with different etiologies/phenotypes. METHODS: Consecutive HF patients with predominant central sleep apnea (± obstructive sleep apnea) indicated for ASV were included; the control group included patients who refused or stopped ASV before three months follow-up. Six homogenous clusters were determined using the latent class analysis (LCA) method. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of chronic HF). RESULTS: Of 503 patients at baseline, 324 underwent 2-year follow-up. Compared to control group, 2-year primary endpoint event-free survival was significantly greater in patients in ASV group only in univariable analysis (1.67, 95% [1.12-2.49]; p = 0.01). Secondary endpoints, event-free of cardiovascular death or heart failure-related hospitalization and all-cause death or all-cause hospitalization were positively impacted by ASV (univariate and multivariable analysis). LCA identified two groups, with preserved and mid-range left ventricular ejection fraction (LVEF) and severe hypoxia, in whom ASV increase prognosis benefit. CONCLUSIONS: Patients with HF and SDB are a highly heterogeneous group identified using LCA. Systematic deep phenotyping is essential to ensure that ASV is prescribed to those benefit from therapy, as ASV use in patients with severe hypoxic burden and those with HFpEF was associated with a significant reduction in cardiovascular events and mortality. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01831128.

Incidence and survival of transthyretin amyloid cardiomyopathy from a French nationwide study of in- and out-patient databases.

BACKGROUND: Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin amyloid cardiomyopathy (ATTR-CM) in France between 2011 and 2019 using real world data. We used the French nationwide exhaustive data (SNDS database) gathering in- and out-patient claims. As there is no specific ICD-10 marker code for ATTR-CM, diagnosis required both amyloidosis (identified by E85. ICD-10 code or a tafamidis meglumine delivery) and a cardiovascular condition (identified by ICD-10 or medical procedure codes related to either heart failure, arrhythmias, conduction disorders or cardiomyopathies), not necessarily reported at the same visit. Patients with probable AL-form of amyloidosis or probable AA-form of amyloidosis were excluded. RESULTS: Between 2011 and 2019, 8,950 patients with incident ATTR-CM were identified. Incidence rates increased from 0.6 / 100,000 person-years in 2011 to 3.6 / 100,000 person-years in 2019 (p < 0.001), reaching 2377 new cases in 2019. Sex ratios (M/F) increased from 1.52 in 2011 to 2.23 in 2019. In 2019, median age at diagnosis was 84.0 years (85.5 for women and 83.5 for men). Median survival after diagnosis was 41.9 months (95% CI [39.6, 44.1]). CONCLUSIONS: This is the first estimate of nationwide ATTR-CM incidence in France using comprehensive real-world databases. We observed an increased incidence over the study period, consistent with an improvement in ATTR-CM diagnosis in recent years.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM).

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.

Burden of untreated transthyretin amyloid cardiomyopathy on patients and their caregivers by disease severity: results from a multicenter, non-interventional, real-world study.

Background: The humanistic burden of transthyretin amyloid cardiomyopathy (ATTR-CM) is poorly defined. Methods: An international study to comprehensively characterize the burden of ATTR-CM on patients naïve to disease-modifying therapy and their unpaid primary caregivers using study-specific and established surveys (patients: Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS], 12-Item Short Form Health Survey [SF-12], Hospital Anxiety and Depression Scale [HADS], Patient-Reported Outcomes Measurement Information System [PROMIS] Fatigue and Dyspnea; caregivers: SF-12, HADS, PROMIS Fatigue, Zarit Burden Interview [ZBI]). All data were summarized descriptively. Results: 208 patient and caregiver pairs were included. 86% of patients were male, median age was 81 years, and 91% (141/155 with genetic testing) had wild-type ATTR-CM. Patient responses characterized the mental and physical burden of ATTR-CM, which was numerically higher among those who were New York Heart Association (NYHA) class III (n = 43) vs. class I/II (n = 156). NYHA class III patients had particularly low KCCQ-OS (36) and SF-12 physical component (27) scores, and 67% had a HADS depression score ≥8. Caregivers (median age 68 years; 85% female; 59% spouse of the patient; median duration of caregiving 1.5 years) reported that NYHA III patients more frequently required help with a range of physical activities than NYHA class I/II patients. 51% of caregivers to NYHA class III patients reported at least a mild-to-moderate burden in the ZBI. A plain language summary of this paper can be found as a supplemental material. Conclusions: Untreated ATTR-CM is a burden to both patients and their caregivers.