RESUMEN
BACKGROUND: Variant transthyretin amyloidosis (ATTRv) is a rare multisystemic disorder caused by mutations in the transthyretin (TTR) gene. The aim of the present work was to describe the clinical profile of asymptomatic carriers (AC) and Coutinho stage 1 ATTRv patients in Spain. METHODS: National, multicentre, cross-sectional study that included 86 AC and 19 patients diagnosed in the previous 12 months to enrolment. Clinical and demographical data, TTR gene mutations, red flags anamnesis, neurological and cardiological assessments were collected. RESULTS: The mean age of patients was 56.8 years at onset and 58.6 years at diagnosis; 53% of patients and 51% of AC were from non-endemic areas. Val50Met was the most frequent mutation in both groups. Neuropathy impairment score data (mean 17.7 ± 20.5) and small-fibre function in lower limbs assessed with SUDOSCAN revealed that patients were diagnosed at early stages of neurological impairment. Peripheral polyneuropathy (84.2%), autonomic neuropathy (73.7%), cardiac (63.2%) and gastrointestinal (47.4%) alterations were the most common symptoms in patients. Autonomic neuropathy, gastrointestinal impairment, carpal tunnel syndrome, cardiac and ocular alterations were potentially related to ATTRv in the AC group. CONCLUSIONS: The EMPATIa study provides a detailed description of AC and Coutinho stage 1 ATTRv patients across Spain, confirming the multisystemic clinical profile of the disease. This study reveals a diagnosis delay around 1.8 years, highlighting the importance of a profound disease awareness to reach a diagnose in earlier stages of neurological impairment.
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Neuropatías Amiloides Familiares , Prealbúmina , Humanos , Neuropatías Amiloides Familiares/genética , Persona de Mediana Edad , Masculino , Femenino , España , Estudios Transversales , Prealbúmina/genética , Anciano , Mutación/genética , AdultoRESUMEN
The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Prealbúmina , Humanos , Prealbúmina/genética , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estabilidad Proteica , Mutación , CinéticaRESUMEN
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.
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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 RetrospectivosAsunto(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 , FemeninoRESUMEN
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.
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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 , MutaciónRESUMEN
Left-to-right differences in the histopathologic patterns of transthyretin-derived amyloid (ATTR) deposition in the atria of older adults have not yet been investigated. Hence, this study evaluated heart specimens from 325 serial autopsy subjects. The amount of ATTR deposits in the seven cardiac regions, including both sides of atria and atrial appendages, was evaluated semiquantitatively. Using digital pathology, we quantitatively evaluated the immunohistochemical deposition burden of ATTR in the myocardium. We identified 20 sporadic ATTR cardiac amyloidosis cases (nine males). All patients had ATTR deposition in the left atrial regions of the myocardium. In the semiquantitative analysis, 14 of the 20 cases showed more severe ATTR deposition on the left atrial regions than on the right side, with statistically significant differences in the pathology grading (p < 0.01 for both the atrium and atrial appendage). Quantitative analysis further supported the difference. Moreover, six had ATTR deposition in the epineurium and/or neural fibers of the atria. Cluster analysis revealed that ATTR deposition in the myocardium was significantly more severe in males than in females. The heterogeneous distribution of amyloid deposits between atria revealed in this study may impair the orderly transmission of the cardiac conduction system and induce arrhythmias, which may be further aggravated by additional neuropathy in the advanced phase. This impairment could be more severe among males. These findings emphasize that atrial evaluation is important for individuals with sporadic ATTR cardiac amyloidosis, particularly for early detection.
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Autopsia , Atrios Cardíacos , Prealbúmina , Humanos , Masculino , Femenino , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Anciano , Anciano de 80 o más Años , Prealbúmina/metabolismo , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , Neuropatías Amiloides Familiares/metabolismo , Neuropatías Amiloides Familiares/patología , Amiloide/metabolismo , Amiloidosis/metabolismo , Amiloidosis/patologíaRESUMEN
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/sangreRESUMEN
Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.
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Neuropatías Amiloides Familiares , Antioxidantes , Suplementos Dietéticos , Estrés Oxidativo , Prealbúmina , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo , Prealbúmina/metabolismo , AnimalesRESUMEN
Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The x-ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation-prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless, 19F-NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4% and 7% (ΔG ~ 1.5-1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (ΔG ~ 1.6 kcal/mol). Our data provide a molecular-level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.
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Prealbúmina , Prealbúmina/química , Prealbúmina/genética , Prealbúmina/metabolismo , Humanos , Modelos Moleculares , Cristalografía por Rayos X , Conformación Proteica , Multimerización de Proteína , Agregado de Proteínas , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/metabolismo , Sitios de Unión , Sustitución de AminoácidosRESUMEN
ABSTRACT: Amyloidosis is a protein misfolding disorder characterized by the extracellular deposition of insoluble amyloid fibrils, derived from abnormally folded proteins. These fibrils disrupt tissue structure and function, leading to organ dysfunction. The condition encompasses various subtypes, each associated with distinct precursor proteins and clinical manifestations. 99mTc-PYP scintigraphy is used widely and holds significant importance for diagnosis. 68Ga-FAPI is also a promising radiotracer for various diseases. To our knowledge, this is the first case of a patient with hereditary transthyretin amyloidosis with cardiac involvement, which FAPI PET showed diffuse increased myocardial uptake.
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Neuropatías Amiloides Familiares , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/complicaciones , Radioisótopos de Galio , Masculino , Persona de Mediana EdadRESUMEN
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.
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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/fisiopatologíaRESUMEN
BACKGROUND: The usefulness of monitoring treatment effect of tafamidis using magnetic resonance imaging (MRI) extracellular volume fraction (ECV) has been reported. OBJECTIVE: we conducted a meta-analysis to evaluate the usefulness of this method. METHODS: Data from 246 ATTR-CMs from six studies were extracted and included in the analysis. An inverse variance meta-analysis using a random effects model was performed to evaluate the change in MRI-ECV before and after tafamidis treatment. The analysis was also performed by classifying the patients into ATTR-CM types (wild-type or hereditary). RESULTS: ECV change before and after tafamidis treatment was 0.33% (95% CI: -1.83-2.49, I2 = 0%, p = 0.76 for heterogeneity) in the treatment group and 4.23% (95% CI: 0.44-8.02, I2 = 0%, p = 0.18 for heterogeneity) in the non-treatment group. The change in ECV before and after treatment was not significant in the treated group (p = 0.76), but there was a significant increase in the non-treated group (p = 0.03). There was no difference in the change in ECV between wild-type (95% CI: -2.65-3.40) and hereditary-type (95% CI: -9.28-4.28) (p = 0.45). CONCLUSIONS: The results of this meta-analysis suggest that MRI-ECV measurement is a useful imaging method for noninvasively evaluating the efficacy of tafamidis treatment for ATTR-CM.
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Neuropatías Amiloides Familiares , Benzoxazoles , Cardiomiopatías , Imagen por Resonancia Magnética , Humanos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/patología , Benzoxazoles/uso terapéutico , Benzoxazoles/farmacología , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/patología , Imagen por Resonancia Magnética/métodos , Resultado del TratamientoAsunto(s)
Neuropatías Amiloides Familiares , Anemia Ferropénica , Cardiomiopatías , Humanos , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/epidemiología , Cardiomiopatías/epidemiología , Cardiomiopatías/complicaciones , Anemia Ferropénica/epidemiología , ComorbilidadRESUMEN
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.
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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 ClínicaRESUMEN
INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.
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Neuropatías Amiloides Familiares , Benzoxazoles , Cardiomiopatías , Células Endoteliales , Factor de Transcripción STAT3 , Tromboplastina , Factor de Necrosis Tumoral alfa , Humanos , Cardiomiopatías/metabolismo , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/prevención & control , Cardiomiopatías/patología , Cardiomiopatías/genética , Benzoxazoles/farmacología , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Células Cultivadas , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/patología , Tromboplastina/metabolismo , Tromboplastina/genética , Factor de Transcripción STAT3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Fibrinolíticos/farmacología , Fosforilación , Relación Dosis-Respuesta a Droga , Prealbúmina/metabolismo , Prealbúmina/genética , Masculino , Transducción de Señal/efectos de los fármacos , Femenino , Aorta/metabolismo , Aorta/efectos de los fármacos , Aorta/patología , Anciano , Persona de Mediana EdadRESUMEN
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.
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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 , MutaciónRESUMEN
BACKGROUND: Aortic stenosis (AS) and transthyretin (ATTR) cardiac amyloidosis (CA) share the same clinical profiles and cardiac phenotype. Amyloid deposits have been frequently reported in aortic valves of patients with severe AS referred for surgical aortic valve replacement (SAVR). The aim of this study was to determine the clinical and myocardial status of patients with aortic valve amyloidosis after aortic valve surgery. METHODS AND RESULTS: We performed a retrospective descriptive study of 46 patients who underwent SAVR for severe AS with amyloid deposits upon histological analysis. All patients were screened for cardiac involvement. Amyloid deposits typing was successful in 35 (76%) patients and 28 (80%) were ATTR. Two (4%) had positive bone scintigraphy and among the 5 myocardial biopsies performed during surgery, 80% were positive for ATTR deposits. CONCLUSION: ATTR is the predominant type in the presence of amyloid deposits on the aortic valve after surgery for severe AS but is only rarely accompanied by cardiac uptake on bone scintigraphy. Early stages of myocardial involvement are frequent and myocardial biopsy is more sensitive for detection of mild amyloid deposits than bone scintigraphy.
Asunto(s)
Neuropatías Amiloides Familiares , Estenosis de la Válvula Aórtica , Válvula Aórtica , Humanos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Persona de Mediana Edad , Neuropatías Amiloides Familiares/patología , Neuropatías Amiloides Familiares/cirugía , Neuropatías Amiloides Familiares/diagnóstico por imagen , Anciano de 80 o más Años , Miocardio/patología , Biopsia , Implantación de Prótesis de Válvulas Cardíacas , Cardiomiopatías/patología , Índice de Severidad de la EnfermedadRESUMEN
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 ClínicasRESUMEN
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 14âml/kg·min showed more events (composite of death and heart failure hospitalization): less than 14 vs. greater than 14âml/kg·min ( P â=â0.013). Cut-offs for VE/VCO 2 slope at 40 showed more events greater than 40 vs. less than 40 ( P â=â0.009). 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 14âml/kg·min and for a VE/VCO 2 slope below 40.