Inflammation and vascular diseases.

Chronic venous disease and cardiovascular atherothrombotic diseases have a high prevalence worldwide. The aetiopathogenesis of both these vascular conditions may share certain aetiopathogenetic moments. Abnormal blood flow, altered intravascular tension, and subsequent endothelial dysfunction may all play an important role. Another plausible alternative is the correlation of some risk factors of both diseases, in particular obesity and metabolic syndrome with all its components and an impact on atherogenesis as well as chronic venous disease. The relationship may even be causal, that is a chronic vessel wall inflammation which is present in advanced venous insufficiency might accelerate atherogenesis. On the other hand, altered haemodynamics in right ventricular dysfunction with a subsequent elevation in venous pressure can worsen or induce venous insufficiency, and/or undoubtedly cause symptoms and signs typical of chronic venous disease. As suggested by the findings published recently in the Gutenberg Health Study, particularly its subanalysis regarding the relationship of venous disease and cardiovascular diseases, the venous and arterial beds can be affected by common aetiopathogenetic factors or both the systems can interfere with each other.

Are proton pump inhibitors an effective and safe drug not only in the prophylaxis of gastrointestinal bleeding in antithrombotic treatment?

Proton pump inhibitors (PPIs) are popular and widely used “gastroprotectives”. More than 10% of our population is treated. In addition to classical indications such as gastroduodenal peptic disease or gastroesophageal reflux disease, they are indicated for the reduction of hemorrhagic complications in the digestive tract during antithrombotic treatment. The effect of PPIs on reducing upper gastrointestinal bleeding in antithrombotic treatment (rivaroxaban, acetylsalicylic acid or a combination) was called into question by a recently published randomised mega-study - COMPASS pantoprazole. Treatment of PPIs is accompanied by a number of significant drug interactions, in particular a severe reduction in  the bioactivation of clopidogrel and a reduction in the absorption of acetylsalicylic acid or dabigatran. As a result, the effect of these antithrombotics is reduced. A number of observational studies - in the indication of PPIs in the treatment of gastroduodenal or gastrooesophageal disease or when used in the treatment of PPIs in antithrombotic treatment - found a greater incidence of major vascular events and an increase in mortality. So are PPIs effective in protecting gastrointestinal bleeding and are they safe?

Diosmin/hesperidin: a cooperating tandem, or is diosmin crucial and hesperidin an inactive ingredient only?

With the advent of novel monocomponent venoactive drugs containing the flavonoid diosmin, the need has arisen to answer the question of therapeutic equivalence of the widely used micronized purified flavonoid fraction (MPFF) contained in Detralex and of the currently introduced monocomponent venoactive drugs. Experimental work provides evidence that each of the two dominant components, i.e. diosmin and hesperidin, has its specific and distinctive pharmacodynamic effect. There is also evidence of a mutual synergistic effect, e.g. in antiexudative action. Clinical studies have been carried out with MPFF for the most part, and effect has clearly been established in this particular form. Conversely, the results of studies documenting the effect of diosmin alone have been conflicting. Mutual comparisons failed to confirm equivalence of MPFF and monocomponent diosmin in any of the studies. This fact is clearly reflected in the relevant guidelines where the use of MPFF in chronic venous disease is recommended unequivocally (level of evidence 1 and strength of evidence B) while, in the case of monocomponent diosmin, it is stated that treatment can be considered (2C). It can be concluded that both experimental and clinical studies document that only a complex of biologically active flavonoids - a micronized purified flavonoid fraction - has evidence of effect and is recommended by relevant guidelines.

Anticoagulant therapy in the elderly.

Elderly and fragile patients have a higher risk of atrial fibrillation, a higher risk of systemic embolism. They are therefore often candidates for long-term anticoagulation medication. At the same time, they have an increased risk of bleeding due to age and co-morbidities, which anticoagulation therapy necessarily potentiates. New Oral Direct Anticoagulants (NOAC) registered in the Czech Republic - dabigatran, rivaroxaban, apixaban or edoxaban - are a good alternative to the currently dominant warfarin in many of these indications. Their great advantage is that they do not need to be regularly monitored on a laboratory basis and are considered to be safer, especially to significant reduction of the risk of intracranial haemorrhage. Each drug in the group of direct oral anticoagulants has some specificity resulting from pharmacological properties or the results of registration studies, so it is possible to individually determine an optimal anticoagulation strategy. Older, respectively fragile patients are characterized by reduced body weight, limited renal function, and multiple comorbidities (associated with many co-medications). For a number of seniors, it is advantageous to use a reduced dose of these drugs. Consideration of benefit and risk is often complicated in elderly patients, but this should be repeatedly done during the therapy. Key words: anticoagulation therapy - apixaban - dabigatran - edoxaban - fragile patient - geriatrics - rivaroxaban.

[Mountain sickness]. / Výsková nemoc.

Mountaineering brings many health risks, one of which is mountain sickness. Its mildest form - acute mountain sickness - is mainly characterized by subjective symptoms (headache, loss of appetite, insomnia, weakness, nausea and rarely also vomiting). Advanced and life-threatening forms are characterized by tissue edema - cerebral or pulmonary high altitude edema. The common denominator of these acute forms is the low oxygen tension leading to hypoxemia and tissue ischemia. Sum of maladaptive or adaptive processes can modify the clinical picture. Underlying mechanisms of the chronic forms of pulmonary disease are the adaptation processes - pulmonary hypertension and polycythemia leading to heart failure.The only causal therapeutic intervention is to restore adequate oxygen tension, descend to lower altitudes or oxygen therapy. Pharmacotherapy has only a supportive effect. The prophylaxis includes stimulation of the respiratory center by carbonic anhydrase inhibitors (acetazolamide) antiedematous treatment with glucocorticoids (dexamethasone), increase lymphatic drainage of the lungs and brain by ß2-agonists (salmeterol) or mitigation of pulmonary hypertension by calcium channel blockers or phosphodiesterase-5 inhibitors (sildenafil or tadalafil).

[Extended options of anticoagulant treatment in thromboembolism]. / Rozsirující se moznosti antikoagulacní lécby tromboembolické nemoci.

Thromboembolic disease (TD) is a relatively common disease with acute risk of death and potential long-term consequences in term of postthrombotic syndrome or chronic pulmonary hypertension. Anticoagulant therapy is the basic therapeutic procedure; thrombolytic therapy and the introduction cava filter are appropriately indicated for individual cases. In past few years, new direct oral anticoagulant drugs (NOAC) have occurred - Xa factor or thrombin inhibitors which have demonstrated the same efficacy and even higher safety in comparison to conventional treatment. In mid 2014, 3 drugs of this group are registered in Czech Republic - rivaroxaban (Xarelto®), dabigatran (Pradaxa®) and apixaban (Eliquis®). These drugs have comparable efficacy and safety but they differ in schedule of dose administration. Rivaroxaban and apixaban can be administered immediately after diagnosis of venous thrombosis or hemodynamically stable pulmonary embolism. LMWH application has to precede few days the administration of dabigatran. Limitation of new drugs is their price. Unavailability of antidotes is temporary because current researches continue to find one for dabigatran and another for both of xabans. Duration of anticoagulant treatment after acute phase depends on the presence of thrombosis risk factors and the individual bleeding risk. Minimal duration of anticoagulant therapy is 3 months, commonly 6-12 months and in high risk patients it is "long term" treatment. Good results of new anticoagulant drugs in trials in term of thromboembolism recurrence prevention may change established habits in TD patients with long term treatment.

[Anticoagulant therapy in secondary prevention of coronary events]. / Antikoagulacní lécba v sekundární prevenci koronárních príhod.

Secondary prevention of atherothrombotic events is the domain of antiplatelet therapy and according to present risk is used one drug strategy or combination of acetylsalicylic acid with ADP receptor blockers. The importance of the combination of dual antiplatelet therapy together with xabans or dabigatran was investigated in 6 clinical trials. Only one of them (ATLAS ACS 2-TIMI 51) indicated that treatment with small dose of rivaroxaban (2 × 2.5 mg) may be added to dual strategy of acetylsalicylic acid and clopidogrel. The risk of major bleeding event is increased and net clinical benefit is only about 0.5 % per year. Dual therapy with aspirin and prasugrel or tikagrelor is beneficial. In the second part of the review is discussed higher incidence of myocardial infarction in controlled group in the trial comparing treatment of dabigatran with warfarin. This relationship has not been resolved, however, in patients with higher risk of coronary events and indication of anticoagulant treatment with direct oral anticoagulants it is recommended to choose from xabans (apixaban and rivaroxaban).

[Pharmacogenetics in cardiovascular diseases therapy--treatment according guidelines or according the individual requirement?]. / Farmakogenetika v lécbe kardiovaskulárních chorob aneb lécba podle guidelines ci podle potreb nemocného?

In clinical practice the individual response to a drug represents a great problem. Many of us experienced a situation when the drug effect declined or drug-related toxic reaction occurred. The typical example is the variation of optimal warfarin dosage. The main cause of interindividual differences in the drug response is the polymorphism in drug resorption and elimination systems, enzymes responsible for drug biotransformation, target receptors or signal molecules. The individualized drug therapy requires physicians to be oriented in main causes of pharmacokinetic and pharmacodynamic variations and be able to predict accurately the individual drug response.

Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering?

AIMS: The DoUble-blind Atorvastatin AmLodipine (DUAAL) trial investigated whether atorvastatin decreases ischaemia by a vascular benefit, independent of low-density lipoprotein cholesterol lowering, in patients with coronary artery disease (CAD), both alone and in combination with the traditional anti-anginal therapy, amlodipine. METHODS AND RESULTS: Randomized, double-blind, parallel-group, multicountry trial (2 weeks run-in and 24 weeks active therapy) comparing three treatments: amlodipine, atorvastatin, and amlodipine + atorvastatin; in 311 patients (78% male; mean age 62 years) with stable angina (≥ 2 attacks/week), CAD history, ≥ 3 transient myocardial ischaemia (TMI) episodes, and/or ≥ 15 min ischaemia on 48 h ambulatory electrocardiographic (AECG) monitoring. Efficacy variables were change in TMI by AECG, exercise ischaemia, angina diary data, and inflammatory biomarkers at Week 26. There was a comparable, highly significant decrease in TMI with amlodipine and atorvastatin, but no additional benefit for the combination. More than 50% of patients became TMI-free in all three groups and this was accompanied by a comparable, marked reduction in angina and nitroglycerin consumption. High-sensitivity C-reactive protein fell by 40% in patients receiving atorvastatin but there was no change with amlodipine. Adverse events were comparable among groups. CONCLUSION: Atorvastatin was as potent an anti-ischaemic agent as amlodipine. Future studies of combination therapies will be instructive. CLINICAL TRIAL REGISTRATION INFORMATION: National clinical trial number: NCT00159718, protocol number A0531031 listed on http://clinicaltrials.gov/.

Destacan la utilidad del mapeo de superficie corporal en la pesquisa de la enfermedad coronaria / Myocardial ischemia screening in middle-aged and elderly men

En un estudio de prevención primaria de la enfermedad coronaria (EC), 164 varones con factores de riesgo (FR) al inicio del ensayo (1975 a 1979) se evaluaron durante el período comprendido entre 1996 y 2002 mediante un mapeo de superficie corporal (MSC). Los resultados se dividieron en dos grupos, uno con 71 varones (43.3%) con buen pronóstico (MSC normal y síndrome X) y el otro grupo con 93 sujetos (56.7%) con pronóstico desfavorable (MSC avanzado con EC moderada). Esta división hizo posible el análisis estadístico, ya que de otro modo los grupos hubieran resultado pequeños. En el análisis univariado, entre los fumadores se observó un efecto significativo del patrón de MSC sobre la EC, en comparación con los no fumadores (p = 0.002). La hipertensión sistólica (HTS) y el colesterol total no influyeron significativamente sobre el MSC. En el análisis multivariado, la probabilidad de que los fumadores presentaran un patrón de EC en el MSC fue 2.6 veces mayor en comparación con los no fumadores (p = 0.007). Los resultados del MSC se relacionaron parcialmente con la HTS (p = 0.074). Las probabilidades fueron 1.9 veces mayores en los varones con HTS > 140 mm Hg en comparación con los sujetos con presión arterial sistólica normal. No se encontraron diferencias estadísticamente significativas para el colesterol total. Los motivos de estos resultados se discuten en relación con los datos del estudio a largo plazo. Se comparan los resultados del MSC con los obtenidos en 2 pequeños ensayos sobre angina de pecho (AP) en los cuales se utilizaron electrocardiogramas.

Destacan la utilidad del mapeo de superficie corporal en la pesquisa de la enfermedad coronaria / Myocardial ischemia screening in middle-aged and elderly men

En un estudio de prevención primaria de la enfermedad coronaria (EC), 164 varones con factores de riesgo (FR) al inicio del ensayo (1975 a 1979) se evaluaron durante el período comprendido entre 1996 y 2002 mediante un mapeo de superficie corporal (MSC). Los resultados se dividieron en dos grupos, uno con 71 varones (43.3%) con buen pronóstico (MSC normal y síndrome X) y el otro grupo con 93 sujetos (56.7%) con pronóstico desfavorable (MSC avanzado con EC moderada). Esta división hizo posible el análisis estadístico, ya que de otro modo los grupos hubieran resultado pequeños. En el análisis univariado, entre los fumadores se observó un efecto significativo del patrón de MSC sobre la EC, en comparación con los no fumadores (p = 0.002). La hipertensión sistólica (HTS) y el colesterol total no influyeron significativamente sobre el MSC. En el análisis multivariado, la probabilidad de que los fumadores presentaran un patrón de EC en el MSC fue 2.6 veces mayor en comparación con los no fumadores (p = 0.007). Los resultados del MSC se relacionaron parcialmente con la HTS (p = 0.074). Las probabilidades fueron 1.9 veces mayores en los varones con HTS > 140 mm Hg en comparación con los sujetos con presión arterial sistólica normal. No se encontraron diferencias estadísticamente significativas para el colesterol total. Los motivos de estos resultados se discuten en relación con los datos del estudio a largo plazo. Se comparan los resultados del MSC con los obtenidos en 2 pequeños ensayos sobre angina de pecho (AP) en los cuales se utilizaron electrocardiogramas.(AU)

Association between cardiac energy metabolism and gain of left ventricular mass in Fabry disease.

Left ventricular (LV) hypertrophy is the hallmark of cardiac involvement in Fabry disease (FD). However, its pathogenesis is not clearly understood as pathologic substrate accumulation represents only 1-2% of the total cardiac mass. Abnormal myocardial energy metabolism has been previously demonstrated in different forms of cardiomyopathies. We hypothesized that myocardial energy status at the time of diagnosis could have a relationship to gain of LV mass in FD. In the group of 16 affected subjects, the indicators of energetic state of cardiac muscle determined by magnetic resonance spectroscopy showed significant negative correlation with annual increase in LV mass, evaluated during long-term follow-up (8 ± 3 years). Myocardial energy metabolism may therefore represent one of the mechanisms contributing to development of FD-related cardiomyopathy.

Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy.

BACKGROUND: In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized. METHODS: We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement and/or death before the initiation of enzyme replacement therapy. RESULTS: The mean rate of estimated glomerular filtration rate (eGFR) decline for patients was -2.93 for males, and -1.02 ml/min/1.73 m(2)/year for females. Prevalence and severity of proteinuria, baseline eGFR <60 ml/min/1.73 m(2) and hypertension were associated with more rapid loss of eGFR. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events (mainly arrhythmias), strokes and transient ischaemic attacks occurred in 49, 11, 6% of males, and in 35, 8, 4% of females, respectively. The mean age at death for 20 male patients was 49.9 years. CONCLUSIONS: Baseline proteinuria, reduced baseline eGFR, hypertension and male gender were associated with more rapid progression of Fabry nephropathy. The eGFR progression rate may increase with advancing nephropathy, and may differ between subgroups of patients with Fabry disease.

Right ventricular involvement in Fabry disease.

The aim of the study was to describe right ventricular (RV) structural and functional changes in Fabry disease (FD). A detailed echocardiographic examination was performed in 58 patients with proven FD (mean age 40 +/- 16 years, 24 men). RV hypertrophy (RVH) was present in 40% of affected subjects with similar prevalence in both genders. Approximately two thirds of patients with left ventricular hypertrophy (LVH) also exhibited RVH. RV dilatation was not present in any subject. RV systolic dysfunction was noted in only 1 female subject. RV diastolic dysfunction was present in 47% of 45 subjects in whom RV filling was assessed. RV diastolic dysfunction was associated with the presence of RVH. A significant correlation between RV wall thickness and age (r = 0.52, P < .001) and left ventricular mass index (r = 0.70, P < .001) was noted. RVH with normal chamber size and preserved systolic but impaired diastolic function represents a typical RV structural change in FD. Its prevalence and degree are related to the prevalence and degree of LVH and the age of the patient.

Onset and progression of the Anderson-Fabry disease related cardiomyopathy.

BACKGROUND: Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS: We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS: In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION: AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

The pharmacology of multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease.

PURPOSE: This 10-week study was conducted to determine the pharmacokinetics of varying doses of agalsidase alfa and evaluate the effect of dose and dosing frequency on plasma Gb3 levels. METHODS: Eighteen adult male Fabry patients, naive to enzyme replacement therapy, were randomized to one of five regimens: 0.1, 0.2, or 0.4 mg/kg weekly; 0.2 mg/kg every other week (the approved dose); or 0.4 mg/kg every other week. Intravenous infusion rate was 0.1 mg/kg per 20 minutes. Plasma Gb3 levels were assessed at baseline and periodically during the study. RESULTS: The mean half-life was 56-76 minutes, and the mean volume of distribution at steady state was 17%-18% of body weight, with no significant association between dose and half-life, clearance, or volume of distribution at steady state. The area under the curve was linearly proportional to the dose from 0.1 to 0.4 mg/kg. Baseline average plasma Gb3 was 9.12 +/- 2.61 nmol/mL and after 10 weeks of treatment was significantly reduced by about 50% in each group with no statistically significant differences between groups. CONCLUSIONS: Reduction of plasma Gb3 levels was independent of dose or dose frequency in the range tested. These observations, coupled with the clinical trial experience of both agalsidase alfa and agalsidase beta, indicate that the standard dose of agalsidase alfa is sufficient to maximally reduce plasma Gb3. However, because plasma Gb3 is not a validated surrogate of disease severity in Fabry disease, further clinical study will be required to determine the optimal dosing regimen for providing maximal clinical benefit.

A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population.

BACKGROUND: Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). METHODS: Large-scale screening was executed using a convenient automated enzymatic (alpha-galactosidose A, alpha-Gal A) dried blood spot on filter paper fluorescence method. RESULTS: In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma alpha-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of alpha-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. CONCLUSIONS: BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

BACKGROUND: Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. OBJECTIVE: To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. DESIGN: Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. SETTING: 41 referral centers in 9 countries. PATIENTS: 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. INTERVENTION: Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). MEASUREMENTS: The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. RESULTS: Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group. LIMITATIONS: The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event. CONCLUSIONS: Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A, and the subsequent accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Males with classical Fabry disease develop early symptoms including pain and hypohidrosis by the second decade of life reflecting disease progression in the peripheral and autonomic nervous systems. An insidious cascade of disease processes ultimately results in severe renal, cardiac, and central nervous system complications in adulthood. The late complications are the main cause of late morbidity, as well as premature mortality. Disease presentation in female heterozygotes may be as severe as in males although women may also remain asymptomatic. The recent introduction of enzyme replacement therapy to address the underlying pathophysiology of Fabry disease has focused attention on the need for comprehensive, multidisciplinary evaluation and management of the multi-organ system involvement. In anticipation of evidence-based recommendations, an international panel of physicians with expertise in Fabry disease has proposed guidelines for the recognition, evaluation, and surveillance of disease-associated morbidities, as well as therapeutic strategies, including enzyme replacement and other adjunctive therapies, to optimize patient outcomes.

Increased carotid intima-media thickness in the absence of atherosclerotic plaques in an adult population with Fabry disease.

AIM: Fabry disease is considered primarily as a progressive small vessel disease, with ischaemic degenerative lesions involving the kidneys, brain and heart. Macrovascular involvement in male patients includes an accelerated wall hypertrophy of the radial artery and a thickening of the intima-media of the common carotid artery. The aim of this study is to evaluate the prevalence and severity of carotid artery atherosclerosis in hemizygous and heterozygous patients with Fabry disease, compared with a matched control population. METHODS: The common carotid artery intima-media thickness (IMT) of 53 patients with Fabry disease (24 men, 29 women) was measured by high-definition ultrasonography, and the presence or absence of atherosclerotic plaques reported. Results were compared with those of 120 age-matched healthy individuals (83 men, 37 women). RESULTS: The common carotid artery IMT was increased to the same extent in male and female patients with Fabry disease (706+/-211 microm and 749+/-395 microm, respectively) compared with that of the control population (614+/-113 microm). In the Fabry population, IMT did not correlate with either systolic blood pressure or with renal function (plasma creatinine). In the control population, only systolic blood pressure was positively and significantly correlated with IMT. Atherosclerotic plaques in the common carotid artery were not observed in any patient with Fabry disease, whereas 34% of the control population had carotid artery plaques, as evidenced by focal non-homogeneous intima-media thickening greater than 1.2 mm. CONCLUSION: This study presents evidence of a major increase in common carotid artery IMT, both in hemizygous and heterozygous patients with Fabry disease, in the absence of focal atherosclerotic plaques. These results suggest that the conduit arteries may be protected from atherosclerosis in Fabry disease.