Assuntos
Modelos Animais de Doenças , Doença de Fabry , Mitocôndrias Cardíacas , Fenótipo , Animais , Doença de Fabry/fisiopatologia , Doença de Fabry/genética , Doença de Fabry/patologia , Doença de Fabry/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/metabolismo , Camundongos , Masculino , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismoRESUMO
While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.
Assuntos
Aprendizado Profundo , Doença de Fabry , Leucoaraiose , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Fabry/diagnóstico por imagem , Estudos Retrospectivos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , BiomarcadoresRESUMO
BACKGROUND: There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD). OBJECTIVES: This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort. METHODS: Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m2); stage 3, ventricular impairment (LV ejection fraction <50% or E/e' ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke. RESULTS: A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy. CONCLUSIONS: In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification.
Assuntos
Doença de Fabry , Humanos , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Prognóstico , Função Ventricular Esquerda , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Volume SistólicoRESUMO
Enzyme replacement therapy (ERT) is a mainstay of treatment for Anderson-Fabry disease (AFD), a pathology with negative effects on the heart and kidneys. However, no reliable biomarkers are available to monitor its efficacy. Therefore, we tested a panel of four microRNAs linked with cardiac and renal damage in order to identify a novel biomarker associated with AFD and modulated by ERT. To this end, 60 patients with a definite diagnosis of AFD and on chronic ERT, and 29 age- and sex-matched healthy individuals, were enrolled by two Italian university hospitals. Only miR-184 met both conditions: its level discriminated untreated AFD patients from healthy individuals (c-statistic = 0.7522), and it was upregulated upon ERT (P < 0.001). On multivariable analysis, miR-184 was independently and inversely associated with a higher risk of cardiac damage (odds ratio = 0.86; 95% confidence interval [CI] = 0.76-0.98; P = 0.026). Adding miR-184 to a comprehensive clinical model improved the prediction of cardiac damage in terms of global model fit, calibration, discrimination, and classification accuracy (continuous net reclassification improvement = 0.917, P < 0.001; integrated discrimination improvement [IDI] = 0.105, P = 0.017; relative IDI = 0.221, 95% CI = 0.002-0.356). Thus, miR-184 is a circulating biomarker of AFD that changes after ERT. Assessment of its level in plasma could be clinically valuable in improving the prediction of cardiac damage in AFD patients.
Assuntos
Doença de Fabry , MicroRNAs , Biomarcadores , MicroRNA Circulante , Terapia de Reposição de Enzimas , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Coração , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêuticoRESUMO
BACKGROUND: Abnormalities of cardiac sympathetic innervation have been demonstrated in Anderson-Fabry disease (AFD). We aimed to investigate the relationship between regional left ventricular (LV) denervation and regional function abnormalities. METHODS: Twenty-four AFD patients (43.7 ± 12.8 years) were studied by 123I-metaiodobenzylguanidine (MIBG) cardiac imaging and speckle-tracking echocardiography. Segmental tracer uptake was estimated according to 0 to 4 score, and total defect score (TDS) was calculated for each patient. RESULTS: Segmental longitudinal strain worsened as MIBG uptake score increased (P < 0.001). By ROC analysis, a segmental longitudinal strain > - 16.2% predicted a segmental MIBG uptake score ≥1, with 79.7% sensitivity and 65.3% specificity. Segmental MIBG uptake defects were found in 13 out 24 AFD patients. LV mass index (60.8 ± 10.1 vs. 41.4 ± 9.8 g/h2.7), relative wall thickness (0.51 ± 0.06 vs. 0.40 ± 0.06), systolic pulmonary artery pressure (35.2 ± 6.7 vs. 27.2 ± 4.2 mmHg), and longitudinal strain (- 14.3 ± 2.7 vs. -19.4 ± 1.8%) were significantly higher in patients with segmental defect (all P < 0.01). At multivariate linear regression analysis, global longitudinal strain was independently associated with TDS (B = 3.007, 95% confidence interval 1.384 to 4.630, P = 0.001). CONCLUSIONS: Reduced cardiac MIBG uptake reflects the severity of cardiac involvement in AFD patients. LV longitudinal function impairment seems to be an earlier disease feature than regional myocardial denervation.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Doença de Fabry/fisiopatologia , Compostos Radiofarmacêuticos/farmacocinética , Sistema Nervoso Simpático/fisiopatologia , Sístole/fisiologia , Disfunção Ventricular Esquerda/etiologia , Adulto , Doença de Fabry/complicações , Feminino , Ventrículos do Coração/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único , Adulto JovemRESUMO
In Anderson-Fabry disease (AFD) the impact of left ventricular (LV) function on cardiac outcome is unknown. Noninvasive LV pressure-strain loop analysis is a new echocardiographic method to estimate myocardial work (MW). We aimed to evaluate whether LV function was associated with outcome and whether MW had a prognostic value in AFD. Ninety-six AFD patients (41.8 ± 14.7 years, 43.7% males) with normal LV ejection fraction were retrospectively evaluated. Inclusion criteria were sinus rhythm and ≥ 2-year follow-up. Standard echocardiography measurements, myocardial mechano-energetic efficiency (MEE) index, global longitudinal strain (GLS) and MW were evaluated. Adverse cardiac events were defined as composite of cardiac death, malignant ventricular tachycardia, atrial fibrillation and severe heart failure development. During a median follow-up of 63 months (interquartile range 37-85), 14 events occurred. Patient age, cardiac biomarkers, LV mass index, left atrium volume, E/Ea ratio, LV ejection fraction, MEE index, GLS and all MW indices were significantly related to adverse outcome at univariate analysis. After adjustment for clinical and echocardiographic parameters, which were significant at univariate analysis, GLS and MW resulted independent predictors of adverse events (p < 0.01). By ROC curve analysis, constructive MW ≤ 1513 mmHg% showed the highest sensitivity and specificity in predicting adverse outcome (92.9% and 86.6%, respectively). MW did not improve the predictive value of a model including clinical data, LV diastolic function and GLS. LV function impairment (both systolic and diastolic) is associated with adverse events in AFD. MW does not provide additive information over clinical features and systolic and diastolic function.
Assuntos
Cardiomiopatias/etiologia , Ecocardiografia Doppler , Doença de Fabry/complicações , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Pressão Ventricular , Adulto , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Doença de Fabry/diagnóstico , Doença de Fabry/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
In Anderson-Fabry disease (AFD), left ventricular (LV) radial function has been scarcely investigated. We hypothesized that LV function may be affected by disease specific mechanisms and sought to comprehensively evaluate LV radial, circumferential and longitudinal function in a large population of AFD patients looking at the influence of LV geometry and fibrosis. We prospectively studied 94 consecutive AFD patients (41.5 ± 14.5 years; 41 men) with preserved LV ejection fraction (EF) utilizing speckle-tracking echocardiography. A subset of patients underwent gadolinium-enhanced cardiac magnetic resonance. Cases were compared to 48 healthy subjects matched for age and sex. LV concentric hypertrophy was found in 33 AFD patients while LV concentric remodeling (relative wall thickness ≥ 0.43) in 16 out 61 patients with normal LV mass. AFD patients had lower radial, longitudinal and circumferential strains than controls, independently by LV geometry pattern. Patients with LV hypertrophy showed reduced global longitudinal strain (p < 0.001) and early diastolic untwisting rate (p = 0.002) as compared to patients with normal geometry. In the whole AFD population, neither radial strain nor circumferential strain correlated with LV mass, while global longitudinal strain and early diastolic untwisting rate did (both p < 0.001). Late gadolinium enhancement was significantly associated with longitudinal strain, twisting rate and early diastolic untwisting rate, with twisting rate being the most powerful independent predictor (ß = - 0.461; p = 0.002). Findings demonstrate impairment of LV radial strain in AFD patients with preserved EF, even in a pre-hypertrophic stage. Development of LV hypertrophy and fibrosis make worse mostly longitudinal dysfunction.
Assuntos
Ecocardiografia Doppler em Cores , Ecocardiografia Doppler de Pulso , Doença de Fabry/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Doença de Fabry/fisiopatologia , Feminino , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Disfunção Ventricular Esquerda/fisiopatologia , Adulto JovemRESUMO
PURPOSE: Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. METHODS: In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. RESULTS: GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. CONCLUSIONS: The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.
Assuntos
Doença de Fabry , Esclerose Múltipla , Estudos Transversais , Humanos , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Mutação , Prevalência , alfa-GalactosidaseRESUMO
AIMS: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder associated with multi-organ dysfunction. While native myocardial T1 mapping by magnetic resonance (MR) allow non-invasive measurement of myocyte sphingolipid accumulation, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and MR are able to identify different pathological patterns of disease progression. We investigated the relationship between T1 mapping and 18F-FDG uptake by hybrid PET-MR cardiac imaging in AFD female patients. METHODS AND RESULTS: Twenty AFD females without cardiac symptoms underwent cardiac PET-MR using 18F-FDG for glucose uptake. In all patients and in seven age- and sex-matched control subjects, T1 mapping was performed using native T1 Modified Look-Locker Inversion-recovery prototype sequences. 18F-FDG myocardial uptake was quantified by measuring the coefficient of variation (COV) of the standardized uptake value using a 17-segment model. T1 values of AFD patients were lower compared with control subjects (1236 ± 49 ms vs. 1334 ± 27 ms, P < 0.0001). Focal 18F-FDG uptake with COV >0.17 was detected in seven patients. COV was 0.32 ± 0.1 in patients with focal 18F-FDG uptake and 0.12 ± 0.04 in those without (P < 0.001). Patients with COV >0.17 had higher T1 values of lateral segments of the mid ventricular wall, compared with those with COV ≤0.17 (1216 ± 22 ms vs. 1160 ± 59 ms, P < 0.05). CONCLUSION: In females with AFD, focal 18F-FDG uptake with a trend towards a pseudo-normalization of abnormal T1 mapping values, may represent an intermediate stage before the development of myocardial fibrosis. These findings suggest a potential relationship between progressive myocyte sphingolipid accumulation and inflammation.
Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Doença de Fabry/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Adulto , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Meios de Contraste , Progressão da Doença , Doença de Fabry/patologia , Feminino , Fluordesoxiglucose F18 , Gadolínio DTPA , Humanos , Estudos Prospectivos , Compostos RadiofarmacêuticosRESUMO
BACKGROUND AND AIM: In autosomal dominant polycystic kidney disease (ADPKD) cardiac abnormalities have been observed before the onset of hypertension or renal dysfunction. We sought to characterize, in ADPKD patients, left ventricular (LV) function and its changes after somatostatin-analogue octreotide-LAR treatment. METHODS: In a 1:1:1 cross-sectional study, we evaluated LV function by speckle-tracking echocardiography in 34 ADPKD patients from one ALADIN-trial center and in 34 age- and gender-matched healthy controls and 34 equally-matched renal controls with non-cystic chronic kidney disease. Changes in LV function were compared in the 16 and 18 ADPKD patients originally randomized to 3â¯year-treatment with octreotide-LAR or placebo, respectively. RESULTS: LV twist and untwisting rates were lower in ADPKD patients that in healthy or renal controls (6.1⯱â¯2.6° vs. 11.1⯱â¯2.1° and 10.2⯱â¯3.7°; -49.5⯱â¯18.1°/s vs. -79.8⯱â¯12.2°/s and -84.3⯱â¯25.9°/s, respectively, all pâ¯<â¯0.001). The correlation between LV mass or diastolic BP and untwisting rate was positive in ADPKD patients (râ¯=â¯0.38, pâ¯=â¯0.025 and râ¯=â¯0.44, pâ¯=â¯0.011, respectively), not significant in healthy controls and negative in renal controls (râ¯=â¯-0.38; pâ¯=â¯0.023 and râ¯=â¯-0.40, pâ¯=â¯0.012, respectively. LV untwisting rate improved from -49.9⯱â¯18.6°/s to -70.3⯱â¯27.5°/s with octreotide-LAR, but did not change with placebo (pâ¯=â¯0.027 for treatment effect). At adjusted linear regression analysis, octreotide-LAR therapy emerged as the only independent predictor of untwisting rate improvement at final visit [beta coefficient -0.504 (95% CI -46.905--6.367), pâ¯=â¯0.014]. CONCLUSIONS: In ADPKD patients LV function is early impaired. Somatostatin-analogue therapy might help in preventing or ameliorating LV dysfunction in this population. Clinical Trial Registration http://www.clinicaltrials.gov, NCT0030928.
Assuntos
Ventrículos do Coração/fisiopatologia , Octreotida/administração & dosagem , Rim Policístico Autossômico Dominante/complicações , Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Administração Oral , Adulto , Antineoplásicos Hormonais/administração & dosagem , Estudos Transversais , Relação Dose-Resposta a Droga , Ecocardiografia Doppler , Feminino , Seguimentos , Taxa de Filtração Glomerular , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/fisiopatologia , Estudos Prospectivos , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND AND OBJECTIVES: Progressive nephropathy is one of the main features of Fabry disease (FD). It has been supposed that an early phase, clinically silent disease occurs in childhood and adolescence and is characterized by glomerular hyperfiltration (HF). Surprisingly, although HF has been reported in several studies, its prevalence is at present unknown. The focus of our study was to determine the prevalence of HF in a cohort of patients with FD and to identify the factors associated with a high risk of HF. METHODS: To address this issue, a retrospective observational study of 87 patients with genetically confirmed FD was performed. HF was defined as an estimated glomerular filtration rate (eGFR) > 130 mL/min/1.73 m2 corrected for age (> 40 years: -1 mL/min/1.73 m2/year). RESULTS: HF occurred in 21 patients (24% of our population), and increased to 50% when only young adults were considered. Hyperfiltrating patients were younger and had lower proteinuria levels than those without HF. The prevalence of cardiovascular and other manifestations of FD was significantly lower in hyperfiltering patients. CONCLUSIONS: Our study showed a negative correlation between eGFR and age, and with proteinuria levels and the presence of cardiovascular and other manifestations of FD. These data favor the view that HF in Fabry patients could be related predominantly to a predisease state. Even in the absence of a "measured" GFR, HF should be regarded as an early marker of Fabry nephropathy, and its recognition and confirmation by true GFR seems a relevant feature to address the issue of the potential benefit of nephroprotective treatments at the early stage of Fabry nephropathy.
Assuntos
Doença de Fabry/complicações , Doença de Fabry/fisiopatologia , Taxa de Filtração Glomerular , Nefropatias/etiologia , Nefropatias/fisiopatologia , Glomérulos Renais/fisiopatologia , Adolescente , Adulto , Idoso , Biomarcadores , Estudos de Coortes , Doença de Fabry/diagnóstico , Feminino , Humanos , Nefropatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
AIMS: Little is known about regional longitudinal strain (LS) distribution in early stages of Anderson-Fabry disease (AFD) cardiomyopathy. We investigated regional left ventricular (LV) patterns of LS strain and base-to-apex behaviour of LS in treatment-naïve AFD patients. METHODS AND RESULTS: Twenty-three consecutive AFD patients at diagnosis and 23 healthy controls without cardiovascular risk factors and matched for age and sex to the patients, underwent a comprehensive evaluation of target organs. An echo-Doppler exam, including determination of regional and global LS strain (GLS) was obtained. The average LS of 6 basal (BLS), 6 middle (MLS), and 5 apical (ALS) segments and relative regional strain ratio [ALS/(BLS + MLS)] were also calculated. Ejection fraction and diastolic indices did not differ between the two groups. LV mass index was greater in AFD (P < 0.01). GLS (P = 0.006), BLS (P < 0.0001), and MLS (P = 0.003), but not ALS, were lower in AFD patients and relative regional strain ratio was higher in AFD (P < 0.01) than in controls. These analyses were confirmed separately in the two genders and even after excluding patients with wall hypertrophy. By subdividing AFD patients according to lysoGB3 levels, 9 patients with lysoGB3 ≥ 1.8 ng/L had lower ALS compared to 11 patients with lysoGB3 < 1.8 ng/L (P < 0.01). CONCLUSION: In naïve AFD patients, we observed an early reduction of LV LS, involving mainly LV basal myocardial segments. Nevertheless, the association found between the higher lysoGB3 levels and the lower apical cap LS demonstrates that apical segments LS, despite still normal, is not spared at diagnosis.
Assuntos
Cardiomiopatias/diagnóstico por imagem , Doença de Fabry/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Adolescente , Adulto , Idoso , Cardiomiopatias/fisiopatologia , Estudos Transversais , Ecocardiografia Doppler , Doença de Fabry/fisiopatologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Hybrid 18F-fluorodeoxyglucose (FDG) positron emission tomography and magnetic resonance imaging may differentiate mature fibrosis or scar from fibrosis associated to active inflammation in patients with Anderson-Fabry disease, even in nonhypertrophic stage. This study was designed to compare the results of positron emission tomography and magnetic resonance cardiac imaging with those of speckle-tracking echocardiography in heterozygous Anderson-Fabry disease females. METHODS AND RESULTS: Twenty-four heterozygous females carrying α-galactosidase A mutation and without left ventricular hypertrophy underwent cardiac positron emission tomography and magnetic resonance using 18F-FDG for glucose uptake and 2-dimensional strain echocardiography. 18F-FDG myocardial uptake was quantified by measuring the coefficient of variation (COV) of the standardized uptake value using a 17-segment model. Focal 18F-FDG uptake with COV >0.17 was detected in 13 patients, including 2 patients with late gadolinium enhancement at magnetic resonance. COV was 0.30±0.14 in patients with focal 18F-FDG uptake and 0.12±0.03 in those without (P<0.001). Strain echocardiography revealed worse global longitudinal systolic strain in patients with COV >0.17 compared with those with COV ≤0.17 (-18.5±2.7% versus -22.2±1.8%; P=0.024). For predicting COV >0.17, a global longitudinal strain >-19.8% had 77% sensitivity and 91% specificity and a value >2 dysfunctional segments 92% sensitivity and 100% specificity. CONCLUSIONS: In females carrying α-galactosidase A mutation, focal 18F-FDG uptake represents an early sign of disease-related myocardial damage and is associated with impaired left ventricular longitudinal function. These findings support the hypothesis that inflammation plays an important role in glycosphingolipids storage disorders.
Assuntos
Ecocardiografia Doppler/métodos , Doença de Fabry/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal , Tomografia por Emissão de Pósitrons/métodos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Idoso , Biomarcadores/sangue , Técnicas de Imagem de Sincronização Cardíaca , Meios de Contraste , Doença de Fabry/genética , Feminino , Fluordesoxiglucose F18 , Gadolínio DTPA , Humanos , Pessoa de Meia-Idade , Mutação/genética , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade , Troponina/sangue , Disfunção Ventricular Esquerda/genética , alfa-Galactosidase/genéticaRESUMO
PURPOSE: Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. METHODS: Cardiac sympathetic innervation was assessed by 123I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. RESULTS: Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r2 = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). CONCLUSION: Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD.
Assuntos
3-Iodobenzilguanidina , Doença de Fabry/patologia , Coração/inervação , Miocárdio/patologia , Neurônios/patologia , Sistema Nervoso Simpático/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Fibrose , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Simpático/diagnóstico por imagemRESUMO
BACKGROUND: In 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing effects of switching on the disease course are limited and inconclusive, we performed a systematic review and meta-analysis of existing data. METHODS: Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015. The following parameters were analyzed: clinical events, changes in organ function or structure, disease-related symptoms, lyso-Gb3 plasma levels, and adverse effects. CONCLUSIONS: The nine studies (217 patients) included in our systematic review showed only marginal differences in most of the evaluated parameters. Seven of these studies were included in the meta-analysis (176 patients). The pooled incidence rate of major adverse events was reported for five studies (150 patients) and was equal to 0.04 events per person-year. No significant change was observed after the shift in glomerular filtration rate, whereas left ventricular mass index, left ventricular posterior wall dimension, and ejection fraction were significantly reduced over time. Our data showed that the switch to agalsidase alfa was well tolerated and associated with stable clinical conditions.Genet Med 19 3, 275-282.
Assuntos
Doença de Fabry/tratamento farmacológico , Isoenzimas/farmacologia , alfa-Galactosidase/farmacologia , Progressão da Doença , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/metabolismo , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glicolipídeos/metabolismo , Glicolipídeos/farmacologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Proteínas Recombinantes , Esfingolipídeos/metabolismo , Esfingolipídeos/farmacologia , Resultado do Tratamento , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismoRESUMO
Polycystic ovarian syndrome (PCOS) affects 4% to 12% of women in reproductive age, representing a clinical condition that could predispose to cardiovascular diseases. We report a case of a 34-year-old woman with PCOS, presenting with chest pain, onset two days before, and ST segment-elevation myocardial infarction. She was not pregnant or in a postpartum state. Subsequent cardiac angiography revealed spontaneous left anterior descending coronary artery dissections, managed by conservative approach. The patient was discharged in medical therapy after 5days. This is the first observation of spontaneous coronary artery dissection occurring in a PCOS patient.
Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Anomalias dos Vasos Coronários/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Síndrome do Ovário Policístico/complicações , Doenças Vasculares/congênito , Síndrome Coronariana Aguda/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/uso terapêutico , Adulto , Aspirina/uso terapêutico , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Angiografia Coronária , Anomalias dos Vasos Coronários/tratamento farmacológico , Eletrocardiografia , Feminino , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/tratamento farmacológicoRESUMO
BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD), is a genetic disorder of the heart, which mainly involves the right ventricle. It is characterized by hypokinetic areas at the free wall of the right ventricle (RV) or both ventricles, where myocardium is replaced by fibrous or fatty tissue. ARVD is an important cause of ventricular arrhythmias in children and young adults. Although the transmission of the disease is based on hereditary, in young adults it may not show any symptoms. The main differential diagnoses with other frequent etiological causes of sudden arrhythmia are: idiopathic outflow tract ventricular tachycardia of the RV, myocarditis, dilated cardiomyopathy and sarcoidosis. CASE PRESENTATION: We describe an unusual case of a 44-year-old woman who was hospitalized for ventricular tachycardia, deep asthenia and dyspnoea with no previous history of cardiac disease. The patient had a ten-year history of palpitations, which started immediately after her last pregnancy. She was diagnosed with both acute/subacute viral myocarditis and arrhythmogenic right ventricular dysplasia, based on established clinical and cardiac MRI criteria. After the diagnosis the patient received an automatic implantable cardioverter defibrillator. Currently, she is on clinical follow-up with no apparent further complications. CONCLUSION: Analyzing this rare case, we have shown the link between myocarditis and arrhythmogenic right ventricular dysplasia, and how important is to perform a cardiac MRI, in the context of acute myocarditis and ventricular arrhythmia.
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Displasia Arritmogênica Ventricular Direita/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Miocardite/diagnóstico , Miocárdio/patologia , Doença Aguda , Adulto , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/terapia , Desfibriladores Implantáveis , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Humanos , Miocardite/complicações , Miocardite/terapiaRESUMO
BACKGROUND & AIMS: Short-term studies have shown that somatostatin analogues are effective in patients with polycystic kidney and liver disease. We evaluated the long-term effects of long-acting release octreotide (octreotide LAR), a somatostatin inhibitor, vs placebo in these patients. METHODS: We performed a controlled study of adults with polycystic kidney and liver disease (estimated glomerular filtration rate, 40 mL/min/1.73m(2) or more) at a single center in Italy. We analyzed data from 27 patients randomly assigned to groups given octreotide LAR (40 mg, n = 14) or placebo (n = 13) each month for 3 years. The primary outcome was absolute and percentage change in total liver volume (TLV), which was measured by magnetic resonance imaging at baseline, after 3 years of treatment, and then 2 years after treatment ended. RESULTS: Baseline characteristics were similar between groups. After 3 years, TLV decreased by 130.2 ± 133.2 mL in patients given octreotide LAR (7.8% ± 7.4%) (P = .003) but increased by 144.3 ± 316.8 mL (6.1% ± 14.1%) in patients given placebo. Change vs baseline differed significantly between groups (P = .004). Two years after treatment ended, TLV had decreased 14.4 ± 138.4 mL (0.8% ± 9.7%) from baseline in patients given octreotide LAR but increased by 224.4 ± 331.7 mL (11.0% ± 14.4%) in patients given placebo. Changes vs baseline still differed significantly between groups (P = .046). Decreases in TLV were similar in each sex; the change in TLV was greatest among subjects with larger baseline TLV. No patient withdrew because of side effects. CONCLUSIONS: In a placebo-controlled study of patients with polycystic kidney and liver disease, 3 years of treatment with octreotide LAR significantly reduced liver volume; reductions were maintained for 2 years after treatment ended. Octreotide LAR was well-tolerated. ClinicalTrials.gov number: NCT02119052.
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Cistos/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Octreotida/uso terapêutico , Rim Policístico Autossômico Dominante/complicações , Adulto , Feminino , Humanos , Itália , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Placebos/administração & dosagem , Estudos Prospectivos , Método Simples-Cego , Tempo , Resultado do TratamentoRESUMO
PURPOSE: Whether cardiac sympathetic nervous function abnormalities may be present in patients with Anderson-Fabry disease (AFD) remains unexplored. We investigated the relationship between left ventricular (LV) function and cardiac sympathetic nervous function in patients with AFD. METHODS: Twenty-five patients (12 men, mean age 43 ± 13 years) with genetically proved AFD and preserved LV ejection fraction and ten age and gender-matched control subjects underwent speckle tracking echocardiography and (123)I-meta-iodobenzylguanidine (MIBG) imaging from which early and late heart to mediastinum (H/M) ratios and myocardial washout rate values were calculated. RESULTS: In AFD patients, a significant correlation between late H/M ratio and LV mass index (r = -61, p = 0.001), left atrial volume (r = -0.72, p < 0.001), systolic pulmonary artery pressure (r = -0.75, p < 0.001), and early diastolic untwisting rate (r = -0.66, p < 0.001) was found. Ten AFD patients exhibited a late H/M ratio below two fold standard deviation of control subjects (≤1.75). Patients showing late H/M ratio ≤ 1.75 had significantly higher LV mass index, relative wall thickness, left atrial volume and systolic pulmonary artery pressure, lower systolic longitudinal strain and an early diastolic untwisting rate compared to patients with late H/M ratio > 1.75. At multivariable linear regression analysis, early diastolic untwisting rate was the only independent predictor of late H/M ratio ≤ 1.75 (odds ratio 1.15, 95 % confidence interval 1.07-1.31, p < 0.05). CONCLUSION: The present findings provide the first demonstration of a cardiac sympathetic derangement in AFD patients with preserved LV ejection fraction, which is mostly related to LV diastolic dysfunction.