Fabry disease: recent advances in pathology, diagnosis, treatment and monitoring

<p>Abstract</p> <p>Background</p> <p>In Fabry disease (α-galactosidase A deficiency) accumulation of Globotriaosylceramide (Gb3) leads to progressive organ failure and premature death. The introduction of enzyme replacement therapy (ERT) was the beginning of a new era in this disorder, and has prompted a broad range of research activities. This review aims to summarize recent developments and progress with high impact for Fabry disease.</p> <p>Methods</p> <p>A Pubmed analysis was performed using the search terms "Fabry disease", "Anderson-Fabry disease", "alpha-galactosidase A" and "Gb3". Of the given publications by 31st January 2009 only original articles recently published in peer reviewed journals were included for this review. Case reports were included only when they comprised a new aspect. In addition we included relevant conference abstracts when the results had not already been published as original articles.</p> <p>Results</p> <p>Apart from Gb3-accumulation cellular and organ specific damages may be related also to inflammatory and immunological consequences. It will be interesting whether this may lead to new therapeutic strategies in the treatment of Fabry disease. Since newborn screening is still difficult in Fabry disease, detection of patients in populations at risk is of great importance. Undiagnosed patients with Fabry disease may still be found in cohorts of subjects with renal diseases, cardiomyopathy and TIA or stroke. Efforts should be undertaken to identify these individuals and initialise ERT in order to hault disease progression. It has also been demonstrated that Gb3-accumulation leads to pre-clinical damages and it is believed that early treatment may be the only possibility so far to prevent irreversible organ damage.</p

Influence of socioeconomic factors on pregnancy outcome in women with structural heart disease

OBJECTIVE: Cardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease.  METHODS: The Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled ≥10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient-centre-country).  RESULTS: A total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the individual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate.  CONCLUSION: While there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by individual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome

Heart rate reserve during dipyridamole stress test applied to potential heart donors in brain death

BACKGROUND: A blunted heart rate reserve (HRR) during dipyridamole stress echocardiography (DSE) is a prognostically unfavorable sign of cardiac autonomic dysfunction. Short-term adjustments of heart rate (HR) are thought to rise from changes in neural input to the heart. DSE is applied in potential heart donors to rule out underlying coronary artery disease and left ventricular dysfunction. The aim of this study is to assess HRR during DSE in brain death. METHODS: We enrolled two groups: group 1 (N.=49, 22 men, 54.6\ub18.8 years) with patients in brain death enrolled in the nationwide marginal donor heart recruiting program; group 2 (N.=49, 18 men, 66.4\ub112.0 years) referred to DSE for suspected or known coronary artery disease. All underwent DSE (0.84 mg/kg in 6 ) by quality-controlled readers certified via web-based training (1487/CE Lazio-1). We assessed left ventricular contractile reserve (LVCR) as stress/rest ratio of force (systolic blood pressure/end-systolic volume). HRR was calculated as the peak/rest HR ratio from 12-lead EKG. RESULTS: The two study groups were similar for prevalence of inducible ischemia (4/49 vs. 9/49, P=NS). Group 1 showed higher resting HR (group 1: 88.1\ub115.5 bpm vs. group 2: 66.5\ub111.5 bpm, P&lt;0.01) and similar peak HR (group 1: 94.7\ub115.3 bpm vs. group 2: 89.5\ub119.3 bpm, P=0.144), with blunted HRR (group 1: 1.08\ub10.10 bpm vs. group 2: 1.36\ub10.31 bpm, P&lt;0.01). HRR was unrelated to LVCR. CONCLUSIONS: HRR is almost abolished and unrelated to LVCR in brain-dead patients during DSE. The modulation of neural input to the heart is essential to determine HRR, and plays no significant role in determining the inotropic response during DSE

Electrophysiological findings in patients with isolated left ventricular non-compaction

AIMS: Patients with isolated left ventricular non-compaction (IVNC) are at high risk for developing ventricular tachyarrhythmias. However, no analysis of invasive electrophysiological (EP) findings in these patients has yet been performed. METHODS AND RESULTS: We performed a retrospective analysis of EP findings in 24 patients with IVNC. Ventricular tachyarrhythmias were inducible in nine patients; of these, two patients had sustained monomorphic ventricular tachycardia (VT) and two patients had ventricular fibrillation. No specific electrocardiographic or echocardiographic finding was predictive of VT inducibility. Three of the 9 patients with inducible VT experienced ventricular tachyarrhythmias during the follow-up of 61.4+/-50 months, whereas no tachyarrhythmias or sudden deaths were noted in 12 patients without inducible VT during the follow-up of 30+/-19 months (3 patients in the latter group were lost to follow-up). Supraventricular tachyarrhythmias were inducible in seven patients. CONCLUSION: Our present study provides the first comprehensive analysis of EP findings in patients with IVNC. Ventricular and supraventricular arrhythmias can readily be induced in these patients, whereas the inducibility of a sustained monomorphic VT is relatively low. Further studies including long-term follow-up are required to investigate the role of EP testing for arrhythmic risk stratification in these patients

Isolated left ventricular noncompaction as a cause for heart failure and heart transplantation: a single center experience

Objectives: To determine the prevalence of isolated left ventricular noncompaction (IVNC) as a cause of heart failure and heart transplantation. Methods: There were 960 patients seen in the heart failure clinic from 1987 to 2005, with a complete evaluation including echocardiography at our center (study population, 82% men, mean age 52 years). The following data were collected: type of heart disease, age at echocardiography and at heart transplantation, and frequency of heart transplantation. Echocardiographic diagnosis of IVNC was based on our published criteria. Results: The etiologies of heart failure were coronary artery disease (CAD; 37%), idiopathic dilated cardiomyopathy (33%), valvular heart disease (11%), congenital heart disease (5%), IVNC (3%), hypertensive heart disease (3%), hypertrophic cardiomyopathy (2%), myocarditis (1%), and <1% other diagnoses. Heart transplantation was performed in 253 patients (26%) due to idiopathic dilated cardiomyopathy (42%), CAD (39%), valvular heart disease (5%), congenital heart disease (5%), IVNC (2%), or other etiologies (</=1% each). Conclusions: The most common causes for heart failure remain idiopathic dilated cardiomyopathy, CAD and valvular heart disease. Strictly using the criteria for the definition of IVNC, IVNC is a rare underlying cardiomyopathy for both, heart failure (2.7%) and heart transplantation (2%) in our center

Anderson-Fabry disease: long-term echocardiographic follow-up under enzyme replacement therapy

AIMS: Anderson-Fabry disease affects various organ systems due to glycosphingolipid accumulation. Enzyme replacement therapy (ERT) has been reported to decrease left ventricular wall thickening (LVWT) and to improve diastolic dysfunction. METHODS AND RESULTS: This prospective study included 29 patients (patients; mean age 37 +/- 13 years) with genetically, enzymatically and/or biopsy-proven Anderson-Fabry disease and long-time ERT. Data on symptoms, cardiac medications and history of hypertension were collected and all patients had comprehensive echocardiographic examination prior to ERT and at follow-up. Disease was at an early stage with a total mean Mainz severity score index of only 18.6 +/- 13.0. Prior to ERT, 79% of patients reported acroparesthesia. The median creatinine level was 121 +/- 108 mcmol/L and LVWT was present in nine patients (31%). Binary appearance of the interventricular septum was found in 20% and posterobasal fibrosis in 83%. At median follow-up of 37 months, acroparesthesia decreased to 55% (P = 0.016). There was no change in creatinine levels. The incidence of LVWT was unchanged, only an increase in interventricular septal wall thickness from 11.7 +/- 0.4 to 12.5 +/- 0.5 was observed (P = 0.009). Left atrial size and the percentage of patients with binary appearance and posterobasal fibrosis were unchanged. There was a small improvement in diastolic function (29% decrease of E/Ea; P > 0.002). CONCLUSION: Our Anderson-Fabry cohort had successful long-time ERT with impressive amelioration of subjective symptoms. Although there was not much improvement in cardiac changes apart from a slight improvement of diastolic function, at least, there was no progression of cardiac disease. For complete reversibility of cardiac changes in Anderson-Fabry disease, ERT might have to be started earlier in life and/or prescribed for a longer time

Position Paper on the Management of Pregnancy-Associated Superficial Venous Thrombosis. Balkan Working Group for Prevention and Treatment of Venous Thromboembolism

Venous thromboembolism (VTE) is a multifactorial disease that can possibly affect any part of venous circulation. The risk of VTE increases by about 2 fold in pregnant women and VTE is one of the major causes of maternal morbidity and mortality. For decades superficial vein thrombosis (SVT) has been considered as benign, self-limiting condition, primarily local event consequently being out of scope of well conducted epidemiological and clinical studies. Recently, the approach on SVT has significantly changed considering that prevalence of lower limb SVT is twice higher than both deep vein thrombosis (DVT) and pulmonary embolism (PE). The clinical severity of SVT largely depends on the localization of thrombosis, when it concerns the major superficial vein vessels of the lower limb and particularly the great saphenous vein. If untreated or inadequately treated, SVT can potentially cause DVT or PE. The purpose of this review is to discuss the complex interconnection between SVT and risk factors in pregnancy and to provide evidence-based considerations, suggestions, and recommendations for the diagnosis and treatment of this precarious and delicate clinical entity

Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy

OBJECTIVE: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation