Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Plasma osteopontin levels, but not its myocardial expression, reflect heart failure severity in recently diagnosed dilated cardiomyopathy.

BACKGROUND: Elevated levels of the extracellular matrix glycoprotein osteopontin (OPN) may be detected in both myocardium and plasma under various pathological conditions affecting the heart. Several studies demonstrated increased plasma OPN levels in patients with heart failure due to dilated cardiomyopathy (DCM), while other studies showed high OPN expression levels in the myocardium of such patients. However, very little is known about OPN levels in both plasma and myocardium of the same individual with DCM. Therefore, we aimed to compare plasma OPN levels and levels of myocardial OPN expression in patients with recent-onset DCM (Ro-DCM). METHODS: We examined plasma OPN as well as creatinine, C­reactive protein (CRP), brain natriuretic peptide (BNP), and troponin I levels in 25 patients with Ro-DCM. Furthermore, all subjects underwent transthoracic echocardiography, selective coronary angiography, and endomyocardial biopsy (EMB) for the assessment of myocardial OPN expression. RESULTS: No significant correlation between myocardial OPN expression and clinical, biochemical, or echocardiographic parameters was found. In log transformation analysis, plasma OPN levels correlated significantly with BNP levels (r = 0.46, p = 0.031), with CRP levels (r = 0.52, p = 0.015), and with early diastolic mitral annular velocity (r = -0.57, p = 0.009). There was a borderline association between the plasma OPN log value and New York Heart Association class (p = 0.053). CONCLUSION: Plasma OPN levels reflect heart failure severity in patients with Ro-DCM. Myocardial OPN expression is not associated with either plasma OPN levels or markers of heart failure in these individuals.

Long-term experience with implantable treprostinil pumps in pulmonary arterial hypertension.

OBJECTIVES: To compare clinical parameters and quality of life in patients with pulmonary arterial hypertension (PAH) at the time of diagnosis, at the time of LenusPro pump implantation and during intravenous treptostinil treatment. METHODS: Seven patients with severe PAH treated with intravenous treptostinil via implantable LenusPro pumps were evaluated, including NYHA classification, six­minute walking test, BNP and quality of life assessment using the EQ-5D-5L questionnaire before and after pump implantation. RESULTS: No significant changes were observed in NYHA class and six­minute walking distance test. There was however a significant improvement in the quality of life and a decrease in BNP levels. The mean EQ-5D-5L index assessed during subcutaneous treptostinil treatment was significantly worse when compared to that assessed during its intravenous application (0.39 ± 0.24 vs 0.78 ± 0.28, p ˂ 0.05); the same is true about the pain/discomfort dimension. Complications occurred, namely one nonfatal pneumothorax, one nonfatal hemothorax, and one event of nonfatal treptostinil intoxication after refilling. CONCLUSIONS: In patients who do not tolerate subcutaneous treptostinil treatment, the use of the LenusPro implantable pump results in a significant improvement in quality of life with an acceptable safety profile (Tab. 2, Fig. 2, Ref. 19).

Predictors of survival in patients with pulmonary hypertension and acute right heart failure.

OBJECTIVES: The aim of this study was to analyse survival of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) hospitalized due to an acute right heart failure (ARHF) with emphasis on risk factors and effectiveness of treatment following current guidelines. METHODS: We retrospectively analysed 117 hospitalizations of 70 patients (59 PAH patients; 11 CTEPH patients, mean age 53.1 ± 16.77 years, 54 % females) between 2004 and 2013. RESULTS: 96 cases were hospitalized at cardiology wards (CW) while 21 at intensive care unit (ICU). The overall hospital mortality was 12.8 %, CW mortality was 4 %, and ICU mortality was 52.4 %. Higher risk of in-hospital mortality was associated with younger age, lower sodium levels, severe forms of PAH (heritable PAH, CTD-PAH) and need of PAH combination treatment. The one-year survival from the first ARHF hospitalization was 67.6 % (95 % CI 57.1-80 %), the two-year survival was 41.9 % (95 % CI 30.8-56.9 %). The presence of ascites was a predictor of long-term mortality. CONCLUSIONS: Mortality in patients with PH and ARHF remains very high. Identification of its risk factors could be used as basis of risk-adapted therapy (Tab. 5, Fig. 2, Ref. 14).

Plasma osteopontin levels in patients with dilated and hypertrophic cardiomyopathy.

BACKGROUND: Osteopontin (OPN) is an extracellular matrix glycoprotein that plays a role in a variety of cellular activities associated with inflammatory and fibrotic responses. Increased OPN levels in myocardium and plasma have been demonstrated in patients with dilated cardiomyopathy (DCM). However, nothing is known about OPN levels in patients with hypertrophic cardiomyopathy (HCM). Therefore, the aim of our study was to compare plasma OPN levels in patients with these two most common cardiomyopathies. PATIENTS AND METHODS: We examined plasma OPN as well as creatinine, C­reactive protein (CRP), brain-type natriuretic peptide (BNP), and troponin I levels in 64 patients with DCM, 43 patients with HCM, and 75 control subjects. Transthoracic echocardiography was also performed on all cardiomyopathy patients. RESULTS: Plasma OPN levels were significantly elevated in patients with DCM compared with HCM patients (95 ± 43 vs. 57 ± 21 ng/ml; p < 0.001) and control subjects (54 ± 19 ng/ml; p < 0.001); however, there was no difference between HCM patients and control subjects. New York Heart Association (NYHA) class III or IV disease was more frequently present in DCM patients than in HCM subjects (44 % vs. 2 %, p < 0.0001). In multivariate analysis, BNP and CRP levels together with NYHA class were found to be significant predictors of plasma OPN levels in DCM patients (p = 0.002, p = 0.029, and p < 0.001 for BNP, CRP, and NYHA, respectively). CONCLUSION: Plasma OPN levels were associated with overall heart failure severity rather than with specific cardiomyopathy subtype in patients suffering from DCM or HCM, respectively.

Utility of cardiac CT for evaluating delayed contrast enhancement in dilated cardiomyopathy.

BACKGROUND: The presence of myocardial fibrosis is associated with adverse outcome in dilated cardiomyopathy (DCM). Delayed contrast-enhanced cardiac magnetic resonance (DE-CMR) currently represents the gold standard in noninvasive evaluation of myocardial scarring. However, a significant number of patients are unable to undergo DE-CMR study for various reasons. We sought to determine the diagnostic accuracy of cardiac CT (CCT) compared with CMR in the investigation of the presence of delayed contrast enhancement (DCE) in subjects with DCM. METHODS: We prospectively enrolled 17 consecutive patients with DCM, who were initially referred to our institution because of recently manifested heart failure due to unexplained left ventricular systolic dysfunction. In all subjects, CCT and DE-CMR were performed within 1 week. RESULTS: CCT and DE-CMR showed satisfactory agreement in detecting DCE (agreement in 82% cases, κ = 0.56) with 50% sensitivity, 100% specificity, and a positive predictive value of 100%. CONCLUSION: CCT may be a valuable method for detecting DCE in patients with DCM. CCT thus might be considered as an alternative method to DE-CMR in the assessment of the presence and extent of myocardial fibrosis in subjects who are not suitable for DE-CMR examination.

Cystatin C Is Associated with the Extent and Characteristics of Coronary Atherosclerosis in Patients with Preserved Renal Function.

Cystatin C (CysC), an endogenous inhibitor of cysteine proteases and a sensitive and accurate marker of renal function, is associated with the severity of coronary atherosclerosis assessed by angiography and future cardiovascular events according to previous studies. We aimed to evaluate the association between CysC levels and coronary plaque volume, composition and phenotype assessed by intravascular ultrasound and intravascular ultrasound-derived virtual histology in patients with preserved renal function. Forty-four patients with angiographically documented coronary artery disease and complete intravascular imaging were included in the study. Patients were categorized into tertiles by CysC levels. Subjects in the high CysC tertile had significantly higher mean plaque burden (48.0 % ± 6.9 vs. 42.8 % ± 7.4, P = 0.029), lower mean lumen area (8.1 mm2 ± 1.7 vs. 9.9 mm2 ± 3.1, P = 0.044) and a higher number of 5-mm vessel segments with minimum lumen area < 4 mm2 (17.9 ± 18.9 vs. 6.8 ± 11.7, P = 0.021) compared to patients in the lower tertiles. In addition, CysC levels demonstrated significant positive correlation with the mean plaque burden (r = 0.35, P = 0.021). Neither relative, nor absolute plaque components differed significantly according to CysC tertiles. The Liverpool Active Plaque Score was significantly higher in the high CysC tertile patients (0.91 ± 1.0 vs. 0.18 ± 0.92, P = 0.02). In conclusion, our study demonstrated a significant association of increased CysC levels with more advanced coronary artery disease and higher risk plaque phenotype in patients with preserved renal function.

Feasibility of cerebral blood flow and oxygenation monitoring by continuous transcranial Doppler combined with cerebral oximetry in a patient with refractory cardiac arrest treated by extracorporeal life support.

The adequacy of cerebral blood flow and the level of regional oxygen saturation during CPR and early post-resuscitation phases assuring favorable neurological outcome are not known. We demonstrate the feasibility of cerebral blood flow and oxygenation monitoring by a continuous transcranial Doppler combined with cerebral oximetry in a patient with refractory cardiac arrest treated by extracorporeal life support.

Prediction of coronary vessel involvement on the basis of atherosclerosis risk factor analysis.

The prediction of coronary vessel involvement by means of noninvasive tests is one of the fundamental objectives of preventive cardiology. This review describes the current possibilities of coronary vessel involvement prediction by means of ultrasonographic examination of carotid arteries, analysis of polymorphisms in the genes encoding enzymes responsible for production of nitric oxide and carbon monoxide and assessment of levels of certain proinflammatory cytokines. In the presented work these noninvasive markers are correlated with the extent of coronary vessel involvement as assessed by coronary angiography, intravascular ultrasound and virtual histology (Fig. 5, Ref. 40).

Ischemic peripheral arterial disease and recurrent iliofemoral venous thrombosis in a 24-year-old man with antiphospholipid syndrome.

The following is a case report of a young man with antiphospholipid syndrome, present with a recurrent iliofemoral venous thrombosis and premature peripheral arterial disease. This case report highlights the high risk of recurrent thrombosis upon discontinuation of anticoagulation therapy, particularly in the presence of persistent spontaneously increased aPTT and a high antiphospholipid antibody titer. The case report also reviews the potential of endovascular treatment of iliac vein thrombosis and points out the good 24-month patency rates of stents implanted into the pelvic vein region.Key words: antiphospholipid syndrome - iliofemoral deep vein thrombosis - recurrent thrombosis - accelerated atherosclerosis - peripheral arterial disease.

Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction and left ventricular dysfunction: a 24- month follow up study.

OBJECTIVE AND BACKGROUND: Despite the use of reperfusion therapies, outcomes in patients with large myocardial infarction (MI), late reperfusion and left ventricular (LV) dysfunction are poor. We investigated long-term safety and efficacy of intracoronary injections of autologous bone marrow-derived mononuclear cells (BMNCs). METHODS: 27 patients with anterior MI (age 59±12 years, mean baseline LV ejection fraction (LVEF) 39±5 %), who underwent percutaneous coronary intervention 4-24 hours after the onset of symptoms, were randomly assigned either to intracoronary BMNCs injection (n=17, BMNCs group, out of which 14 underwent long-term follow-up), or to standard therapy (n=10, Control group). The LVEF, the LV end-diastolic and end-systolic volumes (LVEDV, LVESV) were assessed by echocardiography at discharge, Month 4 and 24. Myocardial perfusion was assessed using SPECT at baseline and Month 4. RESULTS: At 24-month, there was no difference in rates of serious clinical events (36 % vs 50 %, p=0.54). At Month 4 LVEF improved to similar extent in both groups (absolute change +5.8 % vs +7.6 %, p=0.75), with similar infarct size reductions (-10.9 % vs -12.2 %, p=0.47). However, at Month 24, LVEF further improved in BMNCs patients (+12 % vs +8.5 %, p=0.03). This effect resulted from a more pronounced reduction in LVESV (-2.6 ml vs -1.8 ml, p=0.26) and a smaller increase in LVEDV (+16.7 ml vs +17.9 ml, p=0.27) suggesting beneficial long-term effects on LV remodeling. CONCLUSIONS: BMNCs injections in patients with MI and LV dysfunction were associated with a significant improvement of global LVEF during long term follow-up compared to standard therapy (Tab. 3, Fig. 1, Ref. 50). Full Text in PDF www.elis.sk.

[Acute myocardial infarction in young patients--severe failures in the system of acute and secondary care]. / Akutní infarkt myokardu u mladých nemocných - závazné nedostatky v systému akutní a následné péce.

INTRODUCTION: The incidence of cardiovascular (CV) diseases and acute myocardial infarction (AMI) in Czech Republic is de-clining. In spite of this in a proportion of patients AMI occurs in young age. The aim of our project was to assess the character of risk factors, precipitating diseases and the quality of care in young AMI survivors. METHODS: We included 132 patients (97 men and 35 women) in whom AIM with ST elevations occurred before age of 45 years in men and age of 50 years in women. Several results were compared to a control group composed of 84 healthy volunteers of comparable age. We assessed the course of the disease, extent of coronary involvement, subsequent therapy and control of risk factors after 3 years from the index event. RESULTS: Smoking represented the main risk factor - 85% patents were active smokers at the time of AMI and 9% were former smokers, 64% patients had a positive family history of CV disease. We found a higher prevalence of dyslipidemia history in men. In spite of high rate of statin use, laboratory examination during follow-up revealed higher triglyceride values and low levels of HDL-cholesterol in both genders. All together 23% of patients had a history of provoking underlying disease or precipitating factors (inflammatory diseases, malignancies, combined thrombophilias, drug abuse). In total 95% of patients underwent coronary angiography during the acute phase of AMI, the median time from pain onset to intervention was 9 hours. Most patients had single vessel disease, 14% had even coronary angiogram without clinically significant stenosis. The subsequent care was satisfactory concerning the rate of drug prescriptions. However, target lipid values were not reached in 78% patients and blood pressure targets in 37%. CONCLUSIONS: In patients who suffered AMI in young age, risk factors are dominated by smoking and positive family history of CV diseases. One fifth of patients suffer from other underlying disease (inflammatory disease, malignancies, combined thrombophilia) or have another precipitating factor (febrile disease, drug abuse). The acute care seems unsatisfactory due to late arrival of most patients to catheterization laboratories (underestimation of the disease, incorrect initial diagnosis). Subsequent therapy is well composed but lacks in intensity.

Reduced thrombin generation and soluble P-selectin after intravenous enoxaparin during PCI.

PURPOSE: The objective of our study was to identify changes in the coagulation and serum concentration of soluble P-selectin (sP-sel) after i.v. bolus of 0.75 mg/kg enoxaparin in a group of 33 patients during PCI. METHODS AND RESULTS: As compared to baseline, i.v. enoxaparin increased anti -Xa activity and FIIa inhibition together with APTT and thrombin time tests within 20 min, that persisted for 60 min. At 6 h, the results of all tests had returned to baseline. In contrast, the level of prothrombin fragments (F1 + 2) decreased persistingly for a period of 6 h (baseline 1.19 ± 0.42 nmol/l, after 20 min 1.03 ± 0.46 nmol/l, after 60 min 1.06 ± 0.43 nmol/l, after 6 h 0.95 ± 0.40 nmol/l, p < 0.001 vs. baseline for all values). In addition, i.v. enoxaparin decreased serum sP-sel level (baseline 111.80 ± 37.05 ng/ml, after 20 min 87.80 ± 33.17 ng/ml, after 60 min 86.45 ± 29.15 ng/ml, after 6 h 92.24 ± 31.34 ng/ml, p < 0.001 vs. baseline value for all). sP-sel level mildly correlated with both F Xa inhibition (r = -0.275, p < 0.05) and F1 + 2 level (r = 0.274, p < 0.05). CONCLUSION: Intravenous enoxaparin induced target F Xa inhibition (>0.6 IU/ml) for 60 min in 82% of study patients. During the 6 h of monitoring, a decrease of thrombin generation (F1 + 2) and sP-selectin levels were observed.

A review of a newly established ECMO program in a university affiliated cardiac center.

Extracorporeal membrane oxygenation (ECMO) is an established rescue treatment option for severe respiratory and cardiac failure in infants and neonates and has recently become widely utilised in adults. ECMO support can be initiated rapidly in an emergency setting both by percutanous implantation and surgically; it allows transportation of patients in cardio-pulmonary collapse and bridging of critically ill patients to be recovered, other support measures or transplantation. The aim of this study was to report authors' initial experience after starting an ECMO program in a university-based cardiac center. The institutionally approved ECMO team bears responsibility for adjudication regarding indication and implementation of ECMO in all patients. Since the establishment of the ECMO team in October 2007, one elective and nine urgent patients in deep cardiogenic and/or ventilatory collapse were treated by ECMO support up to December 2008. Three patients suffered severe acute right heart dysfunction, two patients suffered postcardiotomy refractory cardiogenic shock, two patients had a cardiogenic shock due to postinfarction interventricular septal rupture, two patients experienced severe respiratory failure and one had elective ECMO implantation as a back-up support during high-risk percutaneous coronary intervention. Veno-arterial ECMO was used in eight cases and veno-venous in two cases of isolated respiratory failure. In nine patients, ECMO circuit was instituted by peripheral cannulation, in eight out of nine cases by percutaneous puncture. On one occasion central surgical cannulation was used. In urgent patients, immediate hemodynamic and oxygenation improvement was observed. Average support duration was 6.8 days (range 1-16 days). Five (50 %) patients were successfully weaned from ECMO and survived to hospital discharge. The illness severity in urgent patients defined by SOFA score ranged from 10 to 17, patients dying while on ECMO had higher SOFA scores (14.8±1.6 vs. 10.8±1.5; P=0.0065). Complications included mainly bleeding. ECMO support allows treatment of severely ill patients in imminent cardiovascular and/or ventilatory collapse. Therefore, establishment of an ECMO program in university affiliated cardiac center is fully justified. A multidisciplinary approach is essential. Despite adequate training and education of ECMO team members, this highly invasive therapeutic modality bears an inherent risk of complications.

Genetic variants in haem oxygenase-1 and endothelial nitric oxide synthase influence the extent and evolution of coronary artery atherosclerosis.

The genetic basis for atherosclerosis development and progression is poorly characterized. We aimed to assess the relationship between endothelial nitric oxide synthase (ENOS) 894 G/T, haem oxygenase-1 (HO1) dinucleotide-length promoter polymorphisms and coronary artery atherosclerotic invol vement and its changes during statin therapy. Coronary angiography, intravascular ultrasound (IVUS), IVUS-derived virtual histology (VH) and genetic polymorphism analysis were performed at study entry. Patients were randomized 1:1 to standard or aggressive hypolipidaemic treatment, and a follow-up evaluation was performed after twelve months. Plaque magnitude was significantly higher in carriers of HO1 risk variants when compared with carriers of the protective variants (< 25 GT repeats). Similarly, the total coronary atherosclerotic burden was significantly greater in HO1 risk variant carriers than in HO1 protective variant carriers. Both parameters did not differ with respect to the ENOS genotype. A higher prevalence of thin-cap fibroatheroma (TCFA) in HO1 risk variant carriers was observed, compared with the HO1 protective variant carriers. The prevalence of TCFA was not influenced by the ENOS genotype. Baseline plaque composition did not differ significantly with respect to both polymorphisms. Significant interactions between plaque composition changes and ENOS and HO1 genotypes were observed during statin treatment. In conclusion, the protective HO1 promoter polymorphism correlates with a lower coronary artery plaque burden, whereas the protective ENOS 894 G/T polymorphism seems to favourably influence changes of coronary artery plaque composition during statin therapy, but has no significant correlation to the magnitude of coronary atherosclerosis.

[Cardiotoxicity of cancer therapy]. / Kardiotoxicita onkologické lécby.

Due to advances in oncological care, the number of patients exposed to and surviving after anticancer chemotherapy is steadily increasing. Anticancer agents, however, are often associated with side-effects including cardiotoxicity which has been identified as one of the most serious and potentially life threatening complications. Cardiotoxicity manifestations range from asymptomatic alterations of heart and vasculature function to arterial hypertension, myocardial ischemia, arrhythmias (including QT-prolongation) and overt heart failure. Post-chemotherapy cardiovascular impairment has been associated with increased morbidity and may also contribute to increased mortality in these patients, both early and late after chemotherapy. This review article describes pathophysiology, clinical manifestation, diagnostic algorithms, monitoring and therapy of cardiotoxicity caused by anticancer agents. We also outline and discuss a variety of problems associated with patient management from the viewpoint of clinical cardiology according to latest published findings.

The Role of Pulmonary Artery Wedge Pressure on the Incidence of Atrial Fibrillation and Atrial Tachycardias in Patients With Isolated Pre-capillary Pulmonary Hypertension.

Atrial fibrillation and atrial tachycardias (AF/AT) have been reported as a common condition in patients with pulmonary hypertension (PH). As yet, limited data exists about the significance of the borderline post-capillary pressure component on the occurrence of AF / AT in patients with isolated pre-capillary PH. We retrospectively studied the prevalence of AF / AT in 333 patients (mean age 61 ± 15 years, 44% males) with pre-capillary idiopathic / familiar pulmonary arterial hypertension, and inoperable chronic thromboembolic pulmonary hypertension. The prevalence of AF / AT was analyzed in different categories of pulmonary artery wedge pressure (PAWP). In the study population overall, the mean PAWP was 10.5 ± 3 mmHg, median of 11 mmHg, range 2-15 mmHg. AF / AT was diagnosed in 79 patients (24%). The proportion of AF / AT among patients with PAWP below the median (?11 mmHg) was lower than in subjects with PAWP between 12 and 15 mmHg, 30 (16%) vs. 46 (35%), p = 0.0001. Compared to the patients with PAWP?11 mmHg, subjects with PAWP between 12 and 15 mmHg were older (65 ± 13 years vs. 58 ± 16), with more prevalent arterial hyperte\nsion [100 (70%) vs. 106 (55%)] and diabetes mellitus [50 (35%) vs. 48 (25%)], showed larger size of the left atrium (42 ± 7 vs. 40 ± 6 mm), and higher values of right atrium pressure (12 ± 5 vs. 8 ± 5 mm Hg), p < 0.05 in all comparisons. The prevalence of AF / AT in the group studied increased with the growing post-capillary component.

Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data.

BACKGROUND: We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). METHODS: Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). FINDINGS: In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4 [SD 22.5] g/m(2.7) to 64.1 [18.7] g/m(2.7), p=0.0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% (2.3) to 16.0% (3.8) after 3 years (p=0.02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73 m(2) for men and -0.89 mL/min per 1.73 m(2) for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 (2.3) at baseline to 2.5 (2.4) after 5 years (p=0.0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0.24 (0.3) at baseline to -0.17 (0.3) after 5 years (p=0.0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. INTERPRETATION: By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. FUNDING: Shire Human Genetic Therapies AB.

Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey.

BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. DESIGN: Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. RESULTS: The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. CONCLUSION: These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

Levels of circulating biomarkers at rest and after exercise in coronary artery disease patients.

As traditional risk factors are unable to fully explain the pathogenesis of coronary artery disease (CAD), novel mechanisms became a target of many investigations. Our aim was to study the response of selected markers to physical exercise. High-sensitive C-reactive protein (hs-CRP), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), advanced oxidation protein products (AOPP), soluble receptor for advanced glycation end-products (sRAGE), pregnancy-associated plasma protein A (PAPP-A), E-selectin, vascular endothelial growth factor (VEGF) and B-type natriuretic peptide (BNP) levels were measured in serum of 21 CAD patients and in 22 healthy controls at rest and after exercise bicycle stress test performed up to the maximal tolerated effort. At rest, hs-CRP, AOPP, MMP-9 and BNP were significantly elevated in the CAD patients as compared with controls. In contrast, P-selectin was significantly lower in CAD patients and a tendency to lower levels of sRAGE was noted. After exercise MMP-9 and BNP, increased significantly in both groups. In conclusions, CAD patients have elevated hs-CRP, AOPP, MMP-9 and BNP--novel markers related to cardiovascular risk or left ventricular overload. MMP-9 and BNP increase significantly with exercise in both healthy individuals and CAD patients.