RESUMEN

AIM: Increased diagnostic awareness and specific disease treatments have changed the landscape of transthyretin cardiac amyloidosis (ATTR). Patients with wild-type ATTR (ATTRwt) are increasingly being diagnosed, potentially changing the clinical profile and prognosis compared with existing retrospective data. We aimed to study the clinical characteristics, distribution of red flags and prognosis of contemporary ATTRwt patients. METHODS: From January 1st 2017, to December 31st 2022, 213 consecutive patients were diagnosed with ATTRwt and prospectively followed up. Data on clinical characteristics, biomarkers, echocardiography findings, hospitalization due to worsening heart failure (WHF) and all-cause mortality were collected. RESULTS: A 37% increase in newly diagnosed patients from 2017-2019 (n = 90) vs. 2020-2022 (n = 123) was observed. The majority of patients presented with NAC disease stage I in the latter period (49% in 2017-2019 vs. 58% in 2020-2022, p = .16). Red flags were primarily cardiac-related, including elevated NT-proBNP, impaired left ventricular longitudinal systolic strain with an apical sparing pattern, heart failure with increased left ventricular wall thickness and elevated troponins. NAC disease stage I as well as low NT-proBNP levels (<1000 ng/L) were significantly associated with better survival (both p < .001). When compared with NAC disease stage II + III combined, patients with NAC disease stage I had a significantly lower risk of WHF hospitalization or death (log rank test: p = .0001). Independent predictors of the combined endpoint WHF hospitalization or death were NT-proBNP (HR 1.03 [95% CI 1.00-1.07], p < .049) and prior implantation of permanent pacemaker (HR 2.01 [1.30-3.11], p = .002). CONCLUSION: Increased diagnostic awareness resulted in a 37% increase in newly diagnosed patients in 2020-2022 vs. 2017-2019. As expected all-cause mortality but also the morbidity in terms of risk of hospitalization with WHF were significantly lower in patients with NAC disease stage I, as well as in those with low NT-proBNP levels <1000 ng/L. These findings underline the importance of continuous attention to diagnostic awareness, as early diagnosis is critical for initiating both general and specific ATTR treatment, thus improving prognosis.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Ecocardiografía , Insuficiencia Cardíaca , Péptido Natriurético Encefálico , Humanos , Masculino , Femenino , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/mortalidad , Anciano , Pronóstico , Cardiomiopatías/diagnóstico , Cardiomiopatías/sangre , Cardiomiopatías/mortalidad , Péptido Natriurético Encefálico/sangre , Persona de Mediana Edad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/sangre , Fragmentos de Péptidos/sangre , Anciano de 80 o más Años , Estudios Prospectivos , Hospitalización/estadística & datos numéricos , Biomarcadores/sangre , Estudios Retrospectivos

Asunto(s)

Neuropatías Amiloides Familiares , Neuropatías Diabéticas , Radiculopatía , Humanos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Diabéticas/diagnóstico , Radiculopatía/diagnóstico , Radiculopatía/etiología , Diagnóstico Diferencial , Masculino , Persona de Mediana Edad , Femenino

RESUMEN

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. OBJECTIVE: To evaluate the prevalence of RTA in individuals with ATTRv. METHODS: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 + ) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. RESULTS: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. CONCLUSION: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.

Asunto(s)

Acidosis Tubular Renal , Neuropatías Amiloides Familiares , Humanos , Femenino , Masculino , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Persona de Mediana Edad , Adulto , Acidosis Tubular Renal/genética , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/epidemiología , Acidosis Tubular Renal/complicaciones , Prevalencia , Estudios Transversales , Mutación

RESUMEN

Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.

Asunto(s)

Neuropatías Amiloides Familiares , Biomarcadores , Factor 15 de Diferenciación de Crecimiento , Humanos , Masculino , Femenino , Biomarcadores/sangre , Persona de Mediana Edad , Factor 15 de Diferenciación de Crecimiento/sangre , Proyectos Piloto , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/genética , Anciano , Uromodulina/sangre , Uromodulina/genética , Prealbúmina/genética , Prealbúmina/metabolismo , Adulto , Tasa de Filtración Glomerular , Estudios de Casos y Controles , Cistatina C/sangre

RESUMEN

Despite the presence of various signs of cardiac amyloidosis ("red flags"), the introduction into routine practice of new non-invasive diagnostic methods (Speckle Tracking technology using echocardiography, myocardial scintigraphy with technetium pyrophosphate, genetic testing, screening for free light chains of immunoglobulins to exclude AL-amyloidosis), which have high specificity and sensitivity, transthyretinic (ATTR) cardiomyopathy is still a difficult to diagnose disease, especially in the early stages when treatment is most effective. The article presents a clinical case of ATTR-amyloidosis with predominant heart damage, manifested by severe diastolic heart failure resistant to treatment. The timing, from the moment of the first episode of decompensation of heart failure to death, is 4 months, which confirms the rapid progression of severe biventricular dysfunction of the heart. Despite the presence of cardiac and extracardial "red flags" of ATTR-amyloidosis in the patient, the diagnosis was established at autopsy. The paper analyzes possible errors of early diagnosis at the outpatient and inpatient stages of patient management.

Asunto(s)

Progresión de la Enfermedad , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/diagnóstico , Masculino , Resultado Fatal , Ecocardiografía/métodos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/fisiopatología , Persona de Mediana Edad , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología

RESUMEN

Background - Laboratory liver anomalies are common in cardiac amyloidosis; however, their significance regarding liver stiffness is unknown. The aim of this study was to investigate the prevalence, clinical significance, and prognostic value of liver stiffness measurement (LSM) anomalies in transthyretin cardiac amyloidosis (ATTR-CA). Methods - Consecutive patients diagnosed with ATTR-CA who underwent liver stiffness assessment were included in the study. Demographic, clinical, laboratory, transthoracic echocardiography and liver stiffness data were retrospectively collected. LSM was obtained through either transient elastography or supersonic shear imaging. Patient cohort was divided in two groups according to a 10 kPa threshold. Follow up data were collected for the occurrence of hospitalization for heart failure and all-cause death. Results - Two hundred and eighty-four patients with ATTR-CA - 26 (9 %) hereditary variant ATTR, 258 (91 %) wild-type ATTR - were included. A LSM over 10 kPa was found in 4 (15 %) and 98 (38 %) patients with ATTRv and ATTRwt respectively (p = 0.02). Among patients with ATTRwt, high LSM was more frequent in advanced stages of ATTR-CA and was associated with increased risk of hospitalization for heart failure after multivariate analysis with a hazard ratio of 2.41 [1.05-5.55] (p = 0.04). Among patients with NYHA stage 1, 28 % presented high LSM associated with high NT-proBNP levels. Integration of high LSM with NT-proBNP and estimated glomerular filtration rate provided a better estimate of patient survival. Conclusion - LSM over 10 kPa is found in up to 36 % of patients with ATTR-CA and is associated with advanced stages of cardiomyopathy and increased risk of hospitalization for heart failure in ATTRwt patients.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Diagnóstico por Imagen de Elasticidad , Humanos , Masculino , Femenino , Pronóstico , Anciano , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/fisiopatología , Estudios Retrospectivos , Prevalencia , Persona de Mediana Edad , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Cardiomiopatías/epidemiología , Cardiomiopatías/diagnóstico , Diagnóstico por Imagen de Elasticidad/métodos , Hígado/diagnóstico por imagen , Estudios de Seguimiento , Anciano de 80 o más Años , Relevancia Clínica

RESUMEN

BACKGROUND: Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored. METHODS: We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls. RESULTS: The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation. CONCLUSIONS: Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.

Asunto(s)

Neuropatías Amiloides Familiares , Biomarcadores , Prealbúmina , Humanos , Prealbúmina/genética , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Biomarcadores/sangre , Masculino , Femenino , Amiloide/sangre , Amiloide/metabolismo , Amiloide/genética , Mutación

RESUMEN

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and progressive cardiomyopathy caused by amyloid fibril deposition in myocardial tissue. Diagnostic challenges have historically hampered timely detection. Recent advances in noninvasive diagnostic techniques have facilitated ATTR-CA diagnosis. We aimed to examine the development of a regional network for the diagnosis and management of ATTR-CA and describe a cohort of patients with ATTR-CA, investigate diagnostic pathways and assess clinical outcomes according to diagnosis periods. METHODS: We performed a survey study analyzing answers from 11 cardiology centers and we conducted a retrospective study including patients with ATTR-CA attending a referral center between 1 January 2012 and 31 December 2022, and categorized by the period of diagnosis (2012-2016 and 2017-2022). RESULTS: Over the years, a growing number of patients reached a diagnosis and were treated in the surveyed nonreferral centers of the region. The retrospective study showed a more significant diagnostic delay in the earlier period rather than the later one [13.4 (5-30.2) vs. 10.6 (5.0-17.9) months, P = 0.04]. Patients diagnosed after 2017 showed a greater survival rate than those diagnosed earlier ( P = 0.02). In the multivariate analysis, the year of diagnosis from 2017 remained independently associated with mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.28-0.79; P = 0.005]. CONCLUSION: This study emphasized the shift toward noninvasive diagnostic criteria. It revealed a positive impact on patient survival and disease management with the use of disease-modifying therapies and diagnostic developments in more recent years. The findings underscore the importance of disease awareness and networking to reduce diagnostic delays and enhance patient journeys for ATTR-CA.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Diagnóstico Tardío , Derivación y Consulta , Humanos , Estudios Retrospectivos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/terapia , Neuropatías Amiloides Familiares/mortalidad , Masculino , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Femenino , Anciano , Derivación y Consulta/estadística & datos numéricos , Factores de Tiempo , Italia , Persona de Mediana Edad , Anciano de 80 o más Años , Encuestas de Atención de la Salud , Tiempo de Tratamiento , Valor Predictivo de las Pruebas , Vías Clínicas

RESUMEN

AIMS: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience reduced functional capacity. We evaluated changes in functional capacity over extensive follow-up using cardiopulmonary exercise testing (CPX). METHODS: ATTR-CM patients underwent CPX and blood testing at baseline, first [V1, 8 (6-10) months] and second follow-up (V2) at 35 (26-41) months after start of disease-specific therapy. RESULTS: We included 34 ATTR-CM patients, aged 77 (±6) years (88.2% men). CPX showed two patterns with functional capacity improvement at V1 and deterioration at V2. Peak work capacity ( P = 0.005) and peak oxygen consumption (VO 2 , P = 0.012) increased at V1 compared with baseline and decreased at V2. The ventilation to carbon dioxide relationship slope (VE/VCO 2 ) increased at V2 compared with baseline and V1 ( P = 0.044). A cut-off for peak VO 2 at 14 ml/kg·min showed more events (composite of death and heart failure hospitalization): less than 14 vs. greater than 14 ml/kg·min ( P  = 0.013). Cut-offs for VE/VCO 2 slope at 40 showed more events greater than 40 vs. less than 40 ( P  = 0.009). CONCLUSION: ATTR-CM patients showed an improvement and deterioration in the short-term and long-term follow-up, respectively, with a better prognosis for those with peak VO 2 above 14 ml/kg·min and for a VE/VCO 2 slope below 40.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Prueba de Esfuerzo , Tolerancia al Ejercicio , Consumo de Oxígeno , Humanos , Masculino , Femenino , Anciano , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/fisiopatología , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/terapia , Prueba de Esfuerzo/métodos , Cardiomiopatías/fisiopatología , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/sangre , Estudios de Seguimiento , Anciano de 80 o más Años , Factores de Tiempo , Valor Predictivo de las Pruebas

RESUMEN

OBJECTIVE: Cardiac amyloidosis (CA) is a cardiomyopathy characterized by amyloid infiltration in the myocardium. Transthyretin cardiac amyloidosis (TTR-CA), commonly presenting as heart failure with preserved ejection fraction (HFpEF), was the focus of our study, which aimed to identify red flags that heighten suspicion of CA in HFpEF patients. METHODS: We prospectively included patients diagnosed with HFpEF. All patients were assessed for TTR-CA red flag features, cardiac and extra-cardiac, as outlined in the 'Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the European Society of Cardiology.' Technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy was performed in 167 HFpEF patients suspected of having TTR-CA. Patients testing positive and negative for TTR-CA were compared based on these red flag features. RESULTS: Out of 167 HFpEF patients, 19 (11.3%) were diagnosed with TTR-CA. In the TTR-CA group, 17 (89.5%) patients were 65 years or older. The presence of three or more red flags differentiated the TTR-CA positive and negative groups (P = 0.040). Features such as low voltage and pseudo infarct patterns were more prevalent in the TTR-CA group (P < 0.001 and P < 0.048, respectively). Left ventricular global longitudinal strain (LV-GLS) was lower in the TTR-CA positive group (P < 0.001). Multivariate analysis identified four variables-older age, pseudo infarct pattern, low/decreased QRS voltage, and LV-GLS-as strong, independent predictors of TTR-CA, with significant odds ratios (ORs) of 7.8, 6.8, 16.9, and 1.2, respectively. CONCLUSION: In this study, TTR-CA etiology occurs in approximately one in every ten HFpEF patients. The presence of three or more red flags increases the likelihood of TTR-CA. Older age, pseudo infarct pattern, low/decreased QRS voltage, and reduced LV-GLS are the most significant red flags indicating TTR-CA in HFpEF patients.

Asunto(s)

Cardiomiopatías , Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Masculino , Anciano , Volumen Sistólico/fisiología , Estudios Prospectivos , Persona de Mediana Edad , Cardiomiopatías/fisiopatología , Cardiomiopatías/diagnóstico , Cardiomiopatías/diagnóstico por imagen , Amiloidosis/fisiopatología , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Amiloidosis/diagnóstico por imagen , Neuropatías Amiloides Familiares/fisiopatología , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/diagnóstico por imagen

RESUMEN

BACKGROUND: In patients with transthyretin cardiac amyloidosis (ATTR-CA), renal dysfunction is a poor prognostic indicator. Limited data are available on variables that portend worsening renal function (wRF) among ATTR-CA patients. OBJECTIVES: This study assesses which characteristics place patients at higher risk for the development of wRF (defined as a drop of ≥10% in glomerular filtration rate [GFR]) within the first year following diagnosis of ATTR-CA. METHODS: We included patients with ATTR-CA (n = 134) evaluated between 2/2016 and 12/2022 and followed for up to 1 year at our amyloid clinic. Patients were stratified into two groups: a group with maintained renal function (mRF) and a group with wRF and compared using appropriate testing. Significant variables in the univariate analysis were included in the multivariable logistic regression model to determine characteristics associated with wRF. RESULTS: Within a follow-up period of 326 ± 118 days, the median GFR% change measured -6% [-18%, +8]. About 41.8% (n = 56) had wRF, while the remainder had mRF. In addition, in patients with no prior history of chronic kidney disease (CKD), 25.5% developed de novo CKD. On multivariable logistic regression, only New York Heart Association (NYHA) class ≥III (odds ratio [OR]: 3.9, 95% confidence interval [CI]: [1.6-9.3]), history of ischemic heart disease (IHD) (OR: 0.3, 95% CI: [0.1-0.7]), and not receiving SGLT-2i (OR: 0.1, 95% CI: [0.02-0.5]) were significant predictors of wRF. CONCLUSION: Our study demonstrated that the development of de novo renal dysfunction or wRF is common following the diagnosis of ATTR-CA. Additionally, we identified worse NYHA class and no prior history of IHD as significant predictors associated with developing wRF, while receiving SGLT-2i therapy appeared to be protective in this population.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Tasa de Filtración Glomerular , Humanos , Masculino , Femenino , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/fisiopatología , Anciano , Cardiomiopatías/diagnóstico , Cardiomiopatías/fisiopatología , Cardiomiopatías/etiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Persona de Mediana Edad , Estudios de Seguimiento , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Progresión de la Enfermedad , Riñón/fisiopatología , Factores de Tiempo , Incidencia , Medición de Riesgo/métodos

RESUMEN

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.

Asunto(s)

Estenosis de la Válvula Aórtica , Cardiomiopatías , Sistema de Registros , Humanos , Masculino , Femenino , Prevalencia , Anciano , Estudios Retrospectivos , Estenosis de la Válvula Aórtica/epidemiología , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Pronóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/mortalidad , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/mortalidad , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Factores de Riesgo , Ecocardiografía , Persona de Mediana Edad , Amiloidosis/epidemiología , Amiloidosis/mortalidad , Amiloidosis/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/epidemiología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/complicaciones , Prealbúmina/genética , Válvula Aórtica/diagnóstico por imagen

RESUMEN

Aim: The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.

Asunto(s)

Cardiomiopatías , Prueba de Paso , Humanos , Prueba de Paso/métodos , Cardiomiopatías/fisiopatología , Cardiomiopatías/diagnóstico , Hospitalización/estadística & datos numéricos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/fisiopatología , Ensayos Clínicos como Asunto/métodos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico

RESUMEN

BACKGROUND: Current echocardiographic risk factors for prognosis in cardiac amyloidosis (CA) do not distinguish between the two main subtypes: transthyretin cardiomyopathy (TTR) and immunoglobulin light chain cardiomyopathy (AL), each of which require distinct diagnostic and therapeutic approaches. Additionally, only traditional parameters have been studied with little data on advanced techniques. Accordingly, we sought to determine whether differences exist in 2D transthoracic echocardiography (2DE) predictors of survival between the CA subtypes using a comprehensive approach. METHODS: 220 patients (72±12 years) with confirmed CA (AL=89, TTR=131) who underwent 2DE at the time of CA diagnosis were enrolled. Left ventricular (LV) dimensions, indexed mass (LVMi), global longitudinal strain (LVGLS), apical-sparing ratio (LVASR), diastology, right ventricular (RV) size and function indices including tricuspid annular systolic excursion (TAPSE), RV free-wall (RVFWS) and global (RVGLS) strain, indexed left (LA) and right atrial volumes (LAVi and RAVi), LA strain (reservoir and booster) and RV systolic pressure (RVSP) were measured. A propensity-score weighted stepwise variable selection Cox proportional hazards model derived from NYHA class and renal impairment status at diagnosis was used to determine the associations between 2DE parameters and mortality specific to CA subtype over a median follow-up of 36-months. RESULTS: After adjusting for age, atrial fibrillation and treatment, parameters associated with survival were RVFWS (p=0.003, HR 1.15, 95% CI[1.053,1.245]) and RVSP (p=0.03, HR 1.03, 95% CI[1.004,1.063]) in AL and LVASR (p=0.007, HR 6.68, 95% CI[1.75,25.492]) and RAVi (p=0.049, HR 1.03, 95% CI[1.000,1.052]) in TTR. CONCLUSIONS: Echocardiographic prognosticators for survival are specific to cardiac amyloid subtype. These results potentially provide information critical for clinical decision-making and follow-up in these patients.

Asunto(s)

Cardiomiopatías , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Masculino , Femenino , Anciano , Cardiomiopatías/fisiopatología , Cardiomiopatías/diagnóstico , Cardiomiopatías/diagnóstico por imagen , Pronóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/fisiopatología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico por imagen , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Ecocardiografía/métodos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/fisiopatología , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/mortalidad , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Factores de Riesgo , Valor Predictivo de las Pruebas , Función Ventricular Izquierda/fisiología , Amiloidosis/diagnóstico , Amiloidosis/fisiopatología , Amiloidosis/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Tasa de Supervivencia/tendencias

RESUMEN

Aortic valve stenosis and cardiac amyloidosis, particularly transthyretin-related, often coexist and share a common clinical and demographic profile. Several pathophysiological hypotheses have been proposed regarding the causes of this association, neither of which fully substantiated in practice. The key to detect the coexistence of cardiac amyloidosis and aortic valve stenosis lies in clinical suspicion. It is possible to hypothesize concurrent cardiac amyloidosis in patients with aortic valve stenosis with the aid of clinical, electrocardiographic, echocardiographic, and extracardiac "red flags". Subsequent non-invasive diagnostic steps are often sufficient to establish a definitive diagnosis. The early diagnosis of this condition is pivotal since the presence of dual pathology worsens patient's prognosis, especially without intervention. Available data on treatment show a better outcome in terms of survival and cardiovascular events in patients undergoing percutaneous correction of valvular heart disease rather than medical therapy alone, regardless of the presence of cardiac amyloidosis. Furthermore, it seems that cardiac amyloidosis does not impact survival after transcatheter aortic valve replacement, even if higher rates of rehospitalizations have been described. Indeed, percutaneous treatment of valvular heart disease is currently considered the primary therapeutic option. Subsequently a disease-modifying treatment for transthyretin amyloidosis may be considered in order to delay disease progression and improve outcomes, even if specific data are still lacking.

Asunto(s)

Estenosis de la Válvula Aórtica , Humanos , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Pronóstico , Amiloidosis/diagnóstico , Amiloidosis/terapia , Amiloidosis/complicaciones , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Cardiomiopatías/diagnóstico , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/terapia , Ecocardiografía

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Humanos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/terapia , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Cardiomiopatías/etiología , Guías de Práctica Clínica como Asunto , Prealbúmina/genética , Prealbúmina/metabolismo

RESUMEN

Awareness of transthyretin amyloid cardiomyopathy (ATTR-CM) has increased over the years due to diagnostic and therapeutic developments. Timely initiation of novel disease-modifying treatments improves both morbidity and mortality, which underlines the necessity for a prompt diagnosis. Nevertheless, early diagnosis of ATTR-CM remains challenging. This is a retrospective observational cohort study of patients diagnosed with ATTR-CM. Between 2016 and 2023, 87 patients were diagnosed with cardiac amyloidosis of which 65 (75%) patients with ATTR-CM and 22 (25%) patients with light chain amyloidosis. This study included 65 ATTR-CM patients (mean age 77 ± 7 years; 86% male) of whom 59 (91%) with wild-type ATTR-CM (ATTRwt) and six (9%) with variant ATTR-CM. We observed a surge in ATTR-CM diagnoses from 3 patients/year (2016-2020) to 16 patients/year (2021-2023), driven by ATTRwt. Nevertheless, the interval between the onset of heart failure symptoms and ATTR-CM diagnosis has not changed significantly (2016-2020 27.3 months [18.6-62.4]; 2021-2023 30.0 months [8.6-57.2]; p = 0.546), driven by time to referral. Red flags for ATTR-CM preceded diagnosis by several years: left ventricular hypertrophy (79%, 5.8 years [3.3-7.0]) and carpal tunnel syndrome (49%, 6.8 years [2.3-12.1]). Despite the presence of typical red flags, symptom-to-diagnosis duration has remained similar driven by time to referral. Improved recognition of red flags for ATTR-CM could reduce the time to diagnosis and improve overall recognition.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Neuropatías Amiloides Familiares/diagnóstico , Cardiomiopatías/diagnóstico , Factores de Tiempo , Diagnóstico Precoz , Anciano de 80 o más Años , Ecocardiografía , Prealbúmina/genética

RESUMEN

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia. METHODS: Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%). RESULTS: Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation. CONCLUSION: A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.

Asunto(s)

Neuropatías Amiloides Familiares , Cardiomiopatías , Ecocardiografía , Prealbúmina , Humanos , Masculino , Femenino , Anciano , República de Corea , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/patología , Cardiomiopatías/genética , Cardiomiopatías/diagnóstico , Prealbúmina/genética , Persona de Mediana Edad , Estudios de Cohortes , Pueblo Asiatico/genética , Genotipo , Mutación , Insuficiencia Cardíaca/diagnóstico , Anciano de 80 o más Años

RESUMEN

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Asunto(s)

Neuropatías Amiloides Familiares , Proteínas de Neurofilamentos , Calidad de Vida , Humanos , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Masculino , Proteínas de Neurofilamentos/sangre , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Enfermedades del Sistema Nervioso Periférico/sangre , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Anciano de 80 o más Años , Estudios Prospectivos , Adulto

RESUMEN

BACKGROUND: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes. METHODS AND RESULTS: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P=0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P<0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes. CONCLUSIONS: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Asunto(s)

Neuropatías Amiloides Familiares , Benzoxazoles , Biomarcadores , Cardiomiopatías , Péptido Natriurético Encefálico , Troponina T , Humanos , Masculino , Femenino , Biomarcadores/sangre , Péptido Natriurético Encefálico/sangre , Anciano , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/mortalidad , Neuropatías Amiloides Familiares/diagnóstico , Benzoxazoles/uso terapéutico , Troponina T/sangre , Cardiomiopatías/sangre , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/mortalidad , Cardiomiopatías/diagnóstico , Resultado del Tratamiento , Factores de Tiempo , Persona de Mediana Edad , Anciano de 80 o más Años , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Estudios Retrospectivos , Prealbúmina/metabolismo