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BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
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Neuropatías Amiloides Familiares , Anticuerpos , Cardiomiopatías , Insuficiencia Cardíaca , Proteínas Recombinantes , Humanos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/complicaciones , Anticuerpos/administración & dosificación , Anticuerpos/efectos adversos , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Imagen por Resonancia Magnética , Prealbúmina , Método Doble Ciego , Enfermedad Crónica , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Infusiones IntravenosasRESUMEN
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.).
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Amiloidosis , Cardiomiopatías , Prealbúmina , ARN Interferente Pequeño , Humanos , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Prealbúmina/genética , Prealbúmina/metabolismo , ARN Interferente Pequeño/uso terapéutico , Amiloidosis Familiar/complicaciones , Amiloidosis Familiar/tratamiento farmacológico , Amiloidosis Familiar/genética , Hígado/metabolismo , Método Doble Ciego , Amiloidosis/complicaciones , Amiloidosis/tratamiento farmacológico , Amiloidosis/genéticaRESUMEN
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.
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BACKGROUND: Cardiac and neurological involvements are the main clinical features of hereditary transthyretin (ATTRv) amyloidosis. Few data are available about ATTRv amyloid nephropathy (ATTRvN). METHODS: We retrospectively included 30 patients with biopsy-proven ATTRvN [V30M (26/30) including two domino liver recipients, S77Y (2/30), V122I (1/30) and S50R (1/30) variants] from two French reference centers. We described the pathological features by comparing amyloid deposits distribution to patients with AL or AA amyloidosis, and sought to determine clinicopathological correlation with known disease-modifying factors such as TTR variant, gender and age at diagnosis. RESULTS: In comparison with AL and AA amyloidosis, ATTRv patients had similar glomerular, arteriolar and arterial amyloid deposits, but more cortical and medullary tubulointerstitial (33%, 44%, 77%, P = .03) involvement. While the presence of glomerular deposits is associated with the range of proteinuria, some patients with abundant glomerular ATTRv amyloidosis had no significant proteinuria. V30M patients had more glomerular (100% and 25%, odds ratio = 114, 95% confidence interval 3.85-3395.00, P = .001) deposits, and higher estimated glomerular filtration rate [50 (interquartile range 44-82) and 27 (interquartile range 6-31) mL/min/1.73 m², P = .004] than non-V30M patients. We did not find difference in amyloid deposition according to gender or age at diagnosis. CONCLUSION: ATTRvN affects all kidney compartments, but compared with AL/AA amyloidosis, ATTRvN seems to involve more frequently tubulointerstitial areas. V30M patients represents the dominant face of the disease with a higher risk of glomerular/arteriolar involvement. ATTRvN should thus be considered in patients, and potential relatives, with ATTRv amyloidosis and kidney dysfunction, regardless of proteinuria level.
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Neuropatías Amiloides Familiares , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Enfermedades Renales , Humanos , Estudios Retrospectivos , Prealbúmina/genética , Placa Amiloide/patología , Neuropatías Amiloides Familiares/patología , Riñón , Enfermedades Renales/patología , Proteinuria/patologíaRESUMEN
AIMS: Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS). METHODS AND RESULTS: THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n'= 210), compared with a mixed (n = 298), phenotype: higher median (Q1-Q3) interventricular septal thickness [18 (16-21) vs. 16 (13-20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both). CONCLUSION: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745.
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AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. METHODS AND RESULTS: A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75â mg/kg and an NT-proBNP ≤500â ng/L or ≤1000â ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). CONCLUSION: Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Enfermedades Cardiovasculares , Neuropatías Amiloides Familiares/diagnóstico , Cardiomiopatías/diagnóstico , Progresión de la Enfermedad , Diuréticos , Humanos , Prealbúmina/genéticaRESUMEN
RATIONALE: Adaptive servo ventilation (ASV) is contraindicated in patients with systolic heart failure (HF) who have a left ventricular ejection fraction (LVEF) below 45% and predominant central sleep apnoea (CSA). However, the effects of ASV in other HF subgroups have not been clearly defined. OBJECTIVE: The European, multicentre, prospective, observational cohort trial, FACE, evaluated the effects of ASV therapy on morbidity and mortality in patients with HF with sleep-disordered breathing (SDB); 3-month outcomes in patient subgroups defined using latent class analysis (LCA) are presented. METHODS: Consecutive patients with HF with predominant CSA (±obstructive sleep apnoea) indicated for ASV were included from 2009 to 2018; the non-ASV group included patients who refused/were noncompliant with ASV. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention or unplanned hospitalisation for worsening of chronic HF). MEASUREMENTS AND MAIN RESULTS: Baseline assessments were performed in 503 patients, and 482 underwent 3-month follow-up. LCA identified six discrete patient clusters characterised by variations in LVEF, SDB type, age, comorbidities and ASV acceptance. The 3- month rate of primary outcome events was significantly higher in cluster 1 patients (predominantly men, low LVEF, severe HF, CSA; 13.9% vs 1.5%-5% in other clusters, p<0.01). CONCLUSION: For the first time, our data identified homogeneous patient clusters representing clinically relevant subgroups relating to SDB management in patients with HF with different ASV usage, each with a different prognosis. This may improve patient phenotyping in clinical practice and allow individualisation of therapy.
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Insuficiencia Cardíaca , Síndromes de la Apnea del Sueño , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Estudios Prospectivos , Síndromes de la Apnea del Sueño/terapia , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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Amiloidosis , Cardiomiopatías , Cardiopatías , Amiloidosis/diagnóstico , Amiloidosis/terapia , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Corazón , Cardiopatías/diagnóstico , Cardiopatías/terapia , Humanos , MiocardioRESUMEN
BACKGROUND: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. METHODS: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. RESULTS: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).
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Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Prealbúmina/antagonistas & inhibidores , Administración Oral , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/complicaciones , Benzoxazoles/efectos adversos , Cardiomiopatías/complicaciones , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Análisis de Supervivencia , Prueba de PasoRESUMEN
Background CT can provide information regarding myocardial perfusion and expansion of the extracellular space, which is relevant to patients with cardiac amyloidosis (CA). Purpose To evaluate the role of CT in the diagnosis and prognosis of CA. Materials and Methods In this prospective study (Commission National de l'Informatique et des Libertés registration no. 1431858), participants with CA, participants with nonamyloid cardiac hypertrophy (NACH), and participants without hypertrophy were included between April 2017 and December 2018. The confirmed diagnosis of CA was determined according to established criteria (ie, proven with positive bone scintigraphy or endomyocardial biopsy). All participants were imaged with dynamic CT perfusion imaging at whole-heart cardiac CT. Extracellular volume measured at CT and myocardial perfusion parameters calculated on CT perfusion maps were compared among different participant groups. Differences between continuous data were tested using the unpaired t test, Mann-Whitney rank-sum test, or the Kruskal-Wallis test. Results A total of 84 participants with CA, 43 participants with NACH, and 33 participants without hypertrophy were included. Participants with CA exhibited a higher value of extracellular volume measured at CT (mean, 54.7% ± 9.7 [standard deviation]) than participants with NACH (mean, 34.6% ± 9.1; P < .001) and participants without hypertrophy (mean, 35.9% ± 9.9; P = .001). Mean myocardial blood volume and mean myocardial blood flow were lower in participants with CA (mean myocardial blood volume: 4.05 mL/100 g of myocardium ± 0.80; mean myocardial blood flow: 73.2 mL/100 g of myocardium per minute ± 25.7) compared to participants with NACH (mean myocardial blood volume: 5.38 mL/100 g of myocardium ± 1.20, P < .001; mean myocardial blood flow: 89.6 mL/100 g of myocardium per minute ± 31.3, P = .007) and participants without hypertrophy (mean myocardial blood volume: 5.68 mL/100 g of myocardium ± 1.05; mean myocardial blood flow: 106.3 mL/100 g of myocardium per minute ± 29.8; P < .001 for both). Extracellular volume measured at CT (hazard ratio >0.56 vs ≤0.56 = 4.2 [95% CI: 1.4, 11.8]), mean slope (hazard ratio ≤3.0 sec-1 vs >3.0 sec-1 = 0.2 [95% CI: 0.1, 0.8]), and time to peak (hazard ratio >20 seconds vs ≤20 seconds = 11.6 [95% CI: 1.3, 101.6]) were predictive of mortality in participants with CA. Conclusion Participants with cardiac amyloidosis exhibited an increase in extracellular volume at CT and abnormal CT perfusion parameters. Extracellular volume and several perfusion parameters were predictive of mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Zimmerman in this issue.
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Amiloidosis/diagnóstico por imagen , Cardiomiopatías/diagnóstico por imagen , Imagen de Perfusión Miocárdica , Tomografía Computarizada por Rayos X , Anciano , Biomarcadores/sangre , Ecocardiografía , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.
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Anemia de Células Falciformes/fisiopatología , Corazón/fisiopatología , Adulto , Anemia de Células Falciformes/diagnóstico , Gasto Cardíaco , Análisis por Conglomerados , Ecocardiografía , Femenino , Humanos , Masculino , Pronóstico , Insuficiencia de la Válvula Tricúspide/diagnóstico , Insuficiencia de la Válvula Tricúspide/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: We evaluated the diagnostic performance of 18F-NaF PET/MRI in patients with suspected cardiac amyloidosis (CA). METHODS: Twenty-seven consecutive patients underwent myocardial PET 1 hour after injection of 4 MBq/kg 18F-NaF with simultaneous MRI including cine-MRI, T1 and T2 mapping, first-pass and late gadolinium enhancement (LGE). 18F-NaF uptake was measured visually and semi-quantitatively by calculating myocardium-to-blood pool (M/B) ratios. CA was confirmed histologically. RESULTS: Transthyretin (TTR)-CA was diagnosed in 16 patients, light-chain (AL)-CA in 7, and no-CA in 4. Visual interpretation of 18F-NaF images revealed a relative increase in myocardial uptake in only 3 patients, all with TTR CA, and a relative decrease in 13, including 7 AL CA, 3 no-CA, and 3 TTR CA. M/B ratios were significantly higher in TTR CA (1.00 ± 0.12) than in AL CA (0.81 ± 0.06, P = 0.001) or in no-CA (0.73 ± 0.16, P = 0.006). The optimal M/B cut-off to distinguish TTR CA from AL CA was ≥ 0.90 (Fischer, P = 0.0005). By comparison, classification of patients using 99mTc-HMDP heart-to-mediastinum ratios with the previously published cut-off ≥ 1.21 reached higher significance (P < 0.0001). Among MRI parameters, myocardial T1, LGE score, and extracellular volume were higher in CA than in no-CA patients, 1409 ± 76 vs 1278 ± 35 ms (P = 0.004), 10.35 ± 5.30 vs 3.50 ± 3.42 (P = 0.03), and 46 ± 10 vs 33 ± 8 % (P = 0.01), respectively. CONCLUSION: 18F-NaF PET/MRI shows good diagnostic performance when semi-quantification is used. However, contrast is low and visual interpretation may be challenging in routine. PET/MRI could constitute a one-stop-shop evaluation of amyloid load and cardiac function in patients needing rapid work-up.
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Amiloidosis/diagnóstico por imagen , Cardiomiopatías/diagnóstico por imagen , Imagen por Resonancia Magnética , Imagen de Perfusión Miocárdica , Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Fluoruro de SodioRESUMEN
CONTEXT: A growing number of elderly patients hospitalized for Acute Heart Failure (AHF) are being managed in cardiogeriatrics departments, but their characteristics and prognosis are poorly known. This study aimed to investigate the profile and outcome (rehospitalization at 90 days) of patients hospitalized for AHF in cardiogeriatrics departments in the Val-de-Marne area in the suburbs of Paris, and to compare them to AHF patients hospitalized in cardiology departments in the same area. METHODS: Observational study, ICREX-94, conducted in seven cardiology departments in France and three specific cardiogeriatrics departments in Val-de-Marne. RESULTS: A total of 308 patients were hospitalized for AHF between October 2017 and January 2019. During the 90 days following discharge, 29.6% patients were readmitted to the hospital. Compared with patients hospitalized in cardiology departments, patients in cardiogeriatrics departments were older (p < 0.001), less independent (living more often alone or in an institution) (p < 0.001), more often depressed (p < 0.001), had more often major neurocognitive disorder (p < 0.001), had a higher Human Development Index (HDI, p < 0.001), and were less often diagnosed with amyloidosis (p < 0.001). There was no difference in outcome whether patients were discharged from cardiology or cardiogeriatrics departments. The most frequent precipitating factors underlying AHF decompensation between the first and second hospitalization were arrhythmia and infection. CONCLUSION: AHF patients discharged from cardiogeriatrics departments, compared to cardiology departments, showed clinical differences but had the same prognosis regarding AHF rehospitalization at 90 days.
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Insuficiencia Cardíaca , Enfermedad Aguda , Anciano , Francia/epidemiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Hospitalización , Humanos , Alta del Paciente , PronósticoRESUMEN
Different types of amyloid deposits involve the heart. Transthyretin and light chain amyloidosis are the most frequent. Diagnostic performance, typing and treatments have improved in the last decade, and prognosis of cardiac amyloidosis is now significantly better thanks to targeted therapies. In this article, we will describe the clinical manifestations of cardiac amyloidosis, the diagnostic approach and detail the characteristics and specific treatments of the most frequent types of cardiac amyloidosis. We will focus on the histopathological aspects, especially on the importance of amyloid typing.
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Amiloidosis , Amiloide , Amiloidosis/diagnóstico , Humanos , PronósticoRESUMEN
BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.
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Neuropatías Amiloides Familiares/terapia , Cardiomiopatías/terapia , Prealbúmina/genética , ARN Interferente Pequeño/genética , Tratamiento con ARN de Interferencia/métodos , Función Ventricular Izquierda , Remodelación Ventricular , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/mortalidad , Neuropatías Amiloides Familiares/fisiopatología , Biomarcadores/sangre , Cardiomiopatías/genética , Cardiomiopatías/mortalidad , Cardiomiopatías/fisiopatología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Admisión del Paciente , Fragmentos de Péptidos/sangre , Prealbúmina/metabolismo , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/metabolismo , Tratamiento con ARN de Interferencia/efectos adversos , Tratamiento con ARN de Interferencia/mortalidad , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
CONTEXT: The left ventricular filling pressure (LVFP) is correlated to right atrial pressure (RAP) in heart failure. We compared diagnostic value of the inferior vena cava (IVC) measurements to the one of the 2016 echocardiographic recommendations to estimate LVFP in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS: Invasive hemodynamics and echocardiography were obtained within 48 hours in 132 consecutive patients with left ventricular ejection fraction ≥50%, and suspected pulmonary hypertension. Increased LVFP was defined by a pulmonary artery wedge pressure (PAWP) >15 mmHg. RESULTS: Of 83 patients in sinus rhythm, a score of the 2016 recommendations ≥ 2 (E/e' ratio >14 and/or tricuspid regurgitation velocity >2.8 m/s and/or indexed left atrial volume>34 mL /m²) had a positive predictive value (PPV) of 63% for PAWP>15 mmHg, whereas a dilated IVC (>2.1 cm) and/or non-collapsible (≤50%) had a PPV of 82%. The net reclassification improvement was 0.39 (P < .05). In atrial fibrillation (AF), a dilated and/or non-collapsible IVC had an 86% PPV for PAWP>15 mmHg. The correlation between RAP and PAWP was 0.60, with 75.7% concordance (100/132) between dichotomized pressures (both RAP>8 mmHg and PAWP>15 mmHg and vice versa). CONCLUSION: The IVC size and collapsibility is valuable to identify patients with HFpEF with high LVFP in both sinus rhythm and AF.
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Insuficiencia Cardíaca , Cateterismo Cardíaco , Ecocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Humanos , Volumen Sistólico , Vena Cava Inferior/diagnóstico por imagen , Función Ventricular Izquierda , Presión VentricularRESUMEN
PURPOSE: Increased cardiac uptake (CU) on early-phase 99mTc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on 99mTc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI). METHODS: We reviewed all patients referred for suspicion of CA, who underwent 99mTc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU. RESULTS: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively). CONCLUSIONS: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.
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Amiloidosis , Cardiopatías , Amiloidosis/diagnóstico por imagen , Cardiopatías/diagnóstico por imagen , Humanos , Pronóstico , Cintigrafía , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. METHODS: These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. RESULTS: The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. CONCLUSIONS: A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.
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Neuropatías Amiloides Familiares , Médicos Generales , Neuropatías Amiloides Familiares/diagnóstico , Consenso , Humanos , PrealbúminaRESUMEN
Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.
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Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Estudios de Asociación Genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Alelos , Biomarcadores , Biología Computacional/métodos , Ecocardiografía , Femenino , Estudios de Asociación Genética/métodos , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/genéticaRESUMEN
Aims: Cardiac transthyretin (ATTR) amyloidosis is an increasingly recognized, progressive, and fatal cardiomyopathy, the natural history of which remains unclear. We sought to establish and validate a new prognostic staging system applicable to patients with both wild-type ATTR (ATTRwt) and hereditary variant ATTR (ATTRv) amyloid cardiomyopathy. Methods and results: Eight hundred and sixty-nine patients with cardiac ATTR amyloidosis (553 with ATTRwt and 316 with ATTRv) attending the UK National Amyloidosis Centre were stratified into three disease stages at baseline on the basis of cut points in two universally measured biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). Stage I was defined as NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min, Stage III was defined as NT-proBNP >3000 ng/L and eGFR <45 ml/min, and the remainder were Stage II. The staging system was validated in a cohort of 318 patients with cardiac ATTR amyloidosis from France. Median survival among 393 (45%) Stage I patients was 69.2 months, 334 (38%) Stage II patients was 46.7 months, and 142 (16%) Stage III patients was 24.1 months (P < 0.0001). After adjusting for age, compared with Stage I, the hazard ratio (HR) for death for Stage II was 2.05 [confidence interval (CI) 1.54-2.72, P < 0.001] and for Stage III was 3.80 (CI 2.73-5.28, P < 0.001). HRs and statistical significance were little altered by transthyretin genotype and were maintained in the validation cohort. Conclusion: This simple, universally applicable staging system stratifies patients with both ATTRwt and ATTRv amyloid cardiomyopathy into prognostic categories. It will be of value in the design of forthcoming clinical trials of novel amyloid-specific therapies.