Fabry disease - Vascular manifestations.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by the deficient activity of alpha-galactosidase A which results in the accumulation of neutral glycosphingolipids in various tissues leading particularly to vasculopathy, cardiomyopathy, neuropathy, and chronic kidney disease. It results in substantial morbidity and premature death in affected patients. Although there are some signs and symptoms suggestive of FD including painful crisis, angiokeratomas, and corneal changes, the majority of FD complications are non-specific (left ventricular hypertrophy, conduction abnormalities, vascular spasms, proteinuria, renal insufficiency), which is why FD still remains largely underdiagnosed. The mechanism by which accumulating glycosphingolipids cause multiorgan disorder is not yet completely understood as it cannot be explained by pure substrate storage. Besides standard therapy of different medical problems in FD patients, specific enzyme replacement therapy has been introduced in the last few years.

A new strategy for the treatment of atherothrombosis - inhibition of inflammation.

Improvement in the prognosis of patients at risk of atherothrombotic events is based on three pillars - slowing down the process of atherogenesis (i.e. the development of atherosclerotic plaque), stabilizing the current atherosclerotic plaque, and reducing the risk of thrombotic occlusion in cases with unstable atherosclerotic plaque. The current prophylaxis has so far taken into consideration the adjustment of several risk factors, including dyslipidemia, arterial hypertension, smoking, and diabetes through lifestyle changes or pharmacological therapies. An essential part of prophylaxis is the anti-thrombotic strategy, especially anti-platelet therapy. Recently, a new pathway has been developed, based on reducing the activity of the inflammatory process with NLRP3 inflammasome, specifically a monoclonal antibody against interleukin 1beta (canakinumab). The efficacy and safety of this treatment, in secondary prevention, were documented in the CANTOS study. Other therapeutic procedures, including suppression of the inflammatory component of atherogenesis, are at the stage of clinical assessment.

Intravascular ultrasound assessment of coronary artery involvement in Fabry disease.

AIM: We used intravascular ultrasound (IVUS) to characterize coronary artery involvement in patients with Fabry disease (FD). METHODS: Nine FD patients (5 women) were matched to 10 control patients (5 women) chosen from our IVUS database. Standard volumetric IVUS analyses were performed along with assessment of plaque echodensity. RESULTS: Plaques in FD patients were diffuse and hypoechogenic compared with more focal and more echogenic lesions in control patients. Echogenicity of plaques was significantly lower in FD patients (median 30.7 +/- 12.9 vs 55.9 +/- 15.7, p = 0.0052, mean 37.2 +/- 15.6 vs 66.2 +/- 13.3, p = 0.0014). Diffusiveness was assessed as differences between mean and median plaque burden versus the plaque burden in each of the analysed cross-sections. These differences were lower in FD vs controls (5.8 +/- 4.8 vs 8.7 +/- 6.6, p < 0.001 for mean, and 5.8 +/- 4.9 vs 8.8 +/- 7.3, p < 0.001 for median) indicating a more diffuse involvement. The occurrence of lipid cores was significantly higher in FD patients than in controls (2.4 +/- 1.5 vs 1.0 +/- 0.94, p = 0.02). CONCLUSION: IVUS showed diffuse hypoechogenic plaques in patients with FD. The explanation may be higher lipid content in plaques and accumulation of glycosphingolipid in smooth-muscle and endothelial cells.

Natural history of the respiratory involvement in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of enzyme alpha-galactosidase A, resulting in the accumulation of glycosphingolipids within lysosomes. Pulmonary involvement in AFD has previously been documented, but until now has been studied only in a few series of patients without any longitudinal follow-up. The aim of this study was to compare spirometric changes in AFD patients with a matched control population and to follow the subsequent progression of the disease. MATERIALS AND METHODS: Fifty individuals (27 women, 23 men, mean age 40 +/- 14 years) with AFD from 14 families underwent a static spirometric examination under standard conditions. A set of indices was compared with that of the control population. Out of this cohort, 39 individuals not receiving enzyme replacement therapy were longitudinally evaluated (median follow-up time 24 months). RESULTS: A clinically significant reduction in spirometric parameters, corresponding to mild to severe airway obstruction, was observed in 26% of women and 61% of men. During the serial follow-up, a significant (p < 0.05) age-dependent reduction of predicted %FVC and %FEV1 values was observed in male patients, while the influence of age was not seen in female patients. The %FEF(25-75) values decreased by similar degrees in men and women and in older and younger patients, indicating that progressive bronchial disease affects the small airways first. CONCLUSIONS: We have demonstrated a clinically relevant age- and sex-dependent progressive pulmonary involvement in AFD patients. The effects of enzyme replacement therapy on pulmonary involvement remain to be demonstrated.

Primary prevention of coronary artery disease among middle aged men in Prague: twenty-year follow-up results.

BACKGROUND: Coronary artery disease (CAD) represents the most common cause of morbidity and mortality in the Czech Republic. The aim of this study is to analyze long-term cardiovascular diseases (CVD) mortality, identify predictors of outcome and to validate the Framingham risk function in men from the Czech Republic. DESIGN AND METHODS: A 20-year primary prevention study of atherosclerosis risk factors in 1417 men from Prague aged 38-53 years was launched in 1975 (STULONG). RESULTS: When analyzing CVD mortality, heavy smokers had hazard higher than non-smokers and light smokers (p < 0.0001); hypertensives higher than normotensives (p < 0.0001); men with hypercholesterolemia higher than those with normal cholesterol (p = 0.0432), and university-educated men lower than elementary-educated men (p = 0.0006). In 1980-1984, the age specific mortality from CVD in men from STULONG was higher (p = 0.0132) than in the Czech Republic, in 1985-1994 insignificantly lower. The Framingham risk function underestimated the absolute 10-year risk of CAD across the quintile of the risk (p < 0.0001), with 63% discrimination. CONCLUSION: In STULONG, the mortality from CVD was significantly associated with known risk factors (hypertension, smoking, hypercholesterolemia, education); the Framingham risk function underestimated the absolute 10-year risk of CAD.

[Therapy of patients with heart failure--do we owe anything to our patients?]. / Lécba chronického srdecního selhání--nedluzíme nasim nemocným nic?

In hardly any other field of treatment of a chronic disease more evident progress can be seen than in the therapy of hearth failure. Till the end of eighties of the previous century we were not able to influence the adverse development of the disease. With the critical prognosis, chronic heart disease represents more serious case than majority of tumours. In the meantime the only approach to decrease mortality has been modulation of the maladaptively activated regulatory mechanisms--the rennin, angiotensin, aldosteron axis and the sympatoadrenal system. During the previous decades we became witnesses of the development of new pharmacologic approaches aimed at the heart failure: New inotropics (e.g. lavosimendan and pomobendan) have been introduced, effects of anti-arrhythmiatics (amiodaron, dronedaron and others) and metabolically active drugs (trimetazidine, ranolazine and others) has been tested as well as methods decreasing fluid retention (aquaarretics) has been used. It is too early to conclude that such ethiopathogenetical approach can decrease mortality or morbidity. Along with the advance of new possibilities to interfere directly with the pathogenesis of the heart failure, approaches aimed at the treatment of deteriorating processes have been developing: prothrombotic state, atherogenesis or complications of anaemia.

[Primary prevention of ischemic heart disease in middle-aged men living in Prague: results of twenty-year research]. / Primární prevence ischemické choroby srdecní u muzu stredního veku v Praze: výsledky dvacetiletého sledování.

INTRODUCTION: Ischemic Heart Disease (IHD) represents the most frequent cause of mortality and morbidity in the Czech Republic. The aim of this study is to analyze long-term mortality of cardiovascular disease (CVD), identify its predictors and verify the validity of Framingham risk function for Czech patients. DESIGN AND METHODS: The twenty-year study (STULONG) of primary prevention of risk factors of atherosclerosis in 1419 men aged 38 to 53 years living in Prague was started in 1975. RESULTS: CVD mortality analysis showed a higher risk of death for heavy smokers vs. non-smokers or light smokers (p < 0.0001), hypertensive patients vs. patients with normal blood pressure (p < 0.0001), men with hypercholesterolemia vs. men with normal cholesterol level (p = 0.0432), and a lower risk for university graduates vs. men with elementary education (p = 0.0006). Between 1980 and 1984, age-specific CVD mortality rates of men from STULONG study were higher (p = 0.0132) than national CVD mortality rates; between 1985 and 1994, they were insignificantly lower. Framingham risk function underestimated absolute ten-year risk of IHD in all risk quintiles (p < 0.0001) with discrimination of 63%. CONCLUSION: CVD mortality observed within STULONG study was significantly affected by known risk factors (hypertension, smoking, hypercholesterolemia, lower education); Framingham risk function underestimated absolute ten-year risk of IHD.

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris.

The antianginal and anti-ischemic effect of isosorbide dinitrate (ISDN), 120 mg once daily, and nifedipine, 20 mg twice daily, both in slow-release formulations, were compared in 17 patients with variant angina pectoris in a randomized, double-blind trial. The design included a placebo run-in period and two 6-week crossover periods of active treatment. Mean frequency of angina decreased significantly from 43 attacks per week during the placebo period to 4 per week with ISDN and 8 with nifedipine (p less than 0.001). Sublingual nitroglycerin consumption decreased significantly from 37 tablets per week with placebo to 3 tablets per week with ISDN and 7 with nifedipine (p less than 0.001). Both drugs reduced the silent and symptomatic ST-segment deviations on ambulatory electrocardiographic recording and increased maximal exercise tolerance. Episodes of coronary spasm could be provoked, by hyperventilation, in all patients during the placebo phase but in no patient during therapy with either active drug. Thus, both ISDN and nifedipine, in their slow-release formulations, are effective in the treatment of variant angina pectoris.

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

Cardiac involvement in Fabry disease.

UNLABELLED: Fabry disease is a rare X-linked defect of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function. CONCLUSIONS: With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.

[Regulation of coronary circulation]. / Regulace koronární cirkulace.

In the submitted review the author deals with specific features of the coronary circulation, coronary reserve and importance of regulation of the tonus of the coronary arteries at their epicardiac course and the tonus at the arteriolar level. In the subsequent part the author deals systematically first with the nervous regulation incl. the basic importance of the alpha-adrenergic (vasoconstrictor) and beta-adrenergic (vaso-dilating) sympathomimetic component. He mentions also the importance of neuropeptides (neuropeptide Y and substance P). Attention is devoted to the importance of the endothelium and endothelial vasoactive substances in the control of circulation. The main representatives of substances with a vasodilatating action are the endothelial relaxation factor and prostacycline, as to vasoconstrictor substances it is endothelin, thromboxan A2 and some growth factors. The authors discuss also the mechanical component, i. e. the influence of the blood flow and viscosity on the tonus of the coronary arteries. Finally the author draws attention to the clinical importance of disorders of regulatory mechanism in atherosclerosis and some clinical entities.

[Decreasing the occurrence of arrhythmia during coronary spasm by the early administration of nitrates]. / Snízení výskytu arytmií v prubehu koronárního spazmu vcasným podáním nitrátu.

Variant angina is frequently accompanied by serious arrhythmias. The aim of our study was to verify the role of early nitrate administration in prevention of these arrhythmias. We compared arrhythmias occurrence in the course of 104 episodes of chest pain with ST elevation during which short acting nitrate was not administered (group I) and 114 episodes with administration of 2.5 mg isosorbit dinitrate (ISDN) spray (group II). Serious arrhythmias occurred in spontaneous episodes in 41 cases (39%) and in episodes with early ISDN administration in 15 cases (13%). Particular types of arrhythmias were as follows: ventricular premature beats in group I 32 and in group II only 12, supraventricular premature beats 4, resp. 3, A-V block IInd or IIIrd degree 5, resp. 1, ventricular tachycardia 5, resp. 0, junctional bradycardia 0, resp. 1. In conclusion, early administration of nitrates at the very beginning of stenocardia during coronary spasm can prevent or reduce the occurrence of serious arrhythmias.

[Comparison of isosorbide dinitrate and nifedipine in the treatment of variant angina pectoris. Randomized study]. / Srovnání isosorbid dinitrátu a nifedipinu v lécbe variantní anginy pectoris. Randomizovaná studie.

The effects of isosorbide dinitrate single dose 120 mg daily and nifedipine 20 mg twice daily were studied in 17 patients with variant angina pectoris due to coronary artery spasm. After a placebo phase the patients were randomized to treatment with either isosorbide dinitrate or nifedipine. After six weeks the patients were crossovered for another six weeks period of treatment. There was significant decrease of number of angina attacks during both treatment regimens. Using 24 hours Holter monitoring we also proved significant decrease of number of ST segment elevation or depression, either symptomatic or asymptomatic. There was increase of performed work during exercise tests after both treatment periods. The efficacy of Isoket 120 mg and Adalat Retard 2 x 20 mg daily in the treatment of patients with active variant angina pectoris was comparable in our study. 3 patients suffered untolerable headache during isosorbide dinitrate phase and had to terminate treatment after first day only.

[Diagnosis of conditions following myocardial infarct using complex analysis of electrical cardiac fields]. / Diagnostika stavu po srdecním infarktu komplexní analýzou elektrického srdecního pole.

In 22 patients with ischaemic heart disease and conditions after infarction and angina pectoris a coronarographic examination was made as well as other auxiliary examinations incl. a complex analysis of the electrical cardiac field (KAESP) (23), using a Cardiac apparatus (manufacturer ZPA Cakovice). Using the KAESP method fibroses in the heart muscle were found in all 22 patients, while a classical electrocardiogram revealed them only in 12 patients (54.5%). Post-infarction fibrous changes on the inferior cardiac wall were detected by ECG in 10 patients, KAESP revealed this localization of changes in 17 patients. The difference was particularly marked as regards localization on the anterior cardiac wall, according to ECG it was in 2 patients, according to KAESP in 17 patients. The authors investigated also on isopotential repolarization maps focal changes caused by cardiac ischaemia associated with organic affection of the appropriate coronary artery as revealed by coronarography. Identical sites were proved in 18 patients by the two methods, i. e. in 81.8%. In the discussion the authors analyse the causes which influence the accuracy of assessment of the coronary artery in KAESP. In KAESP in addition to isopotential maps also other maps were used such as isointegral, iso-areal, asynchronic potential maxima and minima, isochronic maps, maps of negative isodivergencies, profile sections etc. (20).

[Silent myocardial ischemia in outpatients being treated for hyperlipoproteinemia]. / Nemá ischémie myokardu u pacientu ambulance pro lécbu hyperlipoproteinémií.

BACKGROUND: Hyperlipoproteinaemias, in particular those associated with hypercholesterolaemia, are in a causal relationship with the development and acceleration of atherogenesis. One of the serious forms of coronary heart disease is silent myocardial ischaemia--an asymptomatic objectively confirmed ischaemic episode. The objective of the present study was to 1. assess the prevalence of this disease in subjects with hyperlipoproteinaemia and 2. to assess the optimal diagnostic procedure to detect it. METHODS AND RESULTS: The group comprises 57 subjects selected at random (23 men and 34 women) from the out-patient department for genetics and treatment of hyperlipoproteinaemias. In all subjects an ergometric loading test was made and 24-hour ambulatory ECG monitoring. Suspected silent myocardial ischaemia (i.e. positive results of the two examinations) was confirmed by load scintigraphy of the heart muscle. Silent myocardial ischaemia was proved in 3 of 23 examined men (13%) and in 4 of 34 women (11.8%). CONCLUSIONS: Prevalence of silent myocardial ischaemia is significantly higher in high risk subjects--with hyperlipoproteinaemia than in the general asymptomatic population. The best screening test for its detection is a loading test and ambulatory ECG monitoring, supplemented by loading scintigraphy of the heart muscle.

[Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family]. / Pitevní diagnóza Fabryho nemoci u heterozygotky, vedoucí k rozpoznání nediagnostikované manifestní nemoci v rodine.

The authors detected on necropsy in a 63-year-old woman with the clinical diagnosis of hypertension, atherosclerosis of the coronary and peripheral arteries, thromboembolism into the cerebral circulation and impaired cardiac conductivity lysosomal storage identified by histochemical and electronoptic analyses along with lipid chromatography as Fabry's disease. The stored lipids were neutral glycosphingolipids of the globo series globotriaosylceramide) and of the gala- series (galabiosylceramide) which accumulated as a result of deficient activity of the degrading enzyme alpha galactosidase A. Marked accumulation of these specific lipids was found in cardiomyocytes, in smooth muscles (of the media in arteries of the heart, kidneys, liver, spleen, lungs) in podocytes and mesangial cells of renal glomeruli, in epithelia of Henle's loop and in the distal tubules. In the vascular endothelium the storage was at the borderline of detectability. Accumulation did not lead to detectable organ disorders with the exception of the heart where it participated, no doubt, significantly in the cardiocyte hypertrophy. Examination of relatives revealed in the proband's son (age 41 years) a combination of renal, cardiac and skin changes typical for Fabry's disease which, however was not clinically diagnosed. The diagnosis was confirmed by proving of alpha-galactosidase A deficiency in the peripheral leucocytes and point mutation L293X in the VIth exon of the appropriate gene. In a granddaughter (age 15 years) biochemical and molecular genetic methods revealed the heterozygous state of Fabry's disease in preclinical stage.

[Calcium channel blockers in the treatment of ischemic heart disease]. / Blokátory kalciového kanálu v lécbe ischemické choroby srdecní.

After a brief review of the pathophysiological properties of calcium channel blockers on the ischaemic heart muscle the author deals with the therapeutic effect of blockers on coronary spasms and at the same time on vasodilatation of arteries in the systemic circulation. Their effect is manifested also by the favourable action on the arteriosclerotic process proper, the clinically significant retardation of atherogenesis, stabilization of atherosclerotic plaques. The author pays special attention to the new calcium channel blocker-amlodipine which as to its pharmacokinetic properties is superior to all hitherto used types of blockers.

[New trends in pharmacotherapy of cardiovascular diseases]. / Nové trendy farmakoterapie kardiovaskulárních chorob.

There has not been a year that would not have brought something new, often upheaval in the field of cardiovascular pharmacotherapy during last decades. This overview addresses the perspectives that may be expected in the treatment of cardiovascular diseases in the coming years. As for the field of dyslipidemy treatment there are some new options of blocking cholesterol resorption at the enterocyte level opening up in the field of dyslipidemy treatment (e.g. brush border transport system inhibitors, inhibitors of esterification or bind to apolipoprotein), further big revolution may be foreseen in the field of the stimulation of peroxysomal receptors controlling the lipids and glycides metabolism. It is also the field of antithrombotic drugs where we encounter the series of innovative approaches as the inhibitors of receptors facilitating the thrombocyte adhesion, new direct thrombin inhibitors or tissue factor blockers. There is no significant advance in the field of arrhythmias pharmacology, that field is completely posessed by electro-impulse therapy and ablative methods. On the contrary, great perspectives may be foreseen in the field of heart failure therapy. Along with the new methods moderating hyperactivated regulation mechanisms (e.g. renin or vasopeptidases inhibitors) promising is the field of the new inotropics active without increasing the supply of calcium (calcium sensitizers, the stimulators of sarcoplasmatic calcium ATPase). In the field of diuretics there may be expected the introduction of adiuretin blockers (akvaretics). Finally the last promising field is represented by the drugs intervening the metabolism of non-cellular matrix which are expected primarily to have a positive influence on the ventricle remodellation.

[Modern cardiac pacing. II. Rate responsive pacemakers: clinical experience]. / Moderní kardiostimulace. II. Stimulátory s frekvencní odpovedí: klincké zkusenosti.

Rate responsive cardiac pacemakers adapting their pacing frequency according to physical effort are able to solve not only a bradycardia, but a chronotropic incompetence too. 23 rate responsive pulse generators, implanted in 1987-1991 in our center, simulated the physiological conditions and in this way they significantly improved both working capacity in bicycle stress test (p < 0.0001) and well-being in comparison with ordinary demand pacers. The incidence of complications did not exceed that in simple common pacemakers, but the rate adaptive ones were expensive and their programming was time consuming. In all three rate adaptive principles used their non-specific response revealed some imperfection of sensor driven devices. In addition, both in QT and in respiratory dependent systems their pretty proportional frequency response was delayed, while the irregular pacing rate in body activity sensor was not very proportionate to the physical exercise. The non-specific sensor response may be reduced by a combination of biologic sensors.

[Cardiac manifestation of Fabry's disease: current knowledge]. / Kardiální manifestace Fabryho choroby: soucasné znalosti.

Fabry's disease is a rare lysosomal storage disease caused by the X-linked defect of the enzyme alpha-galactosidase A leading to the intracellular accumulation of glycosphingolipids in various organs and tissues. Cardiac involvement is frequent and, in individuals with some residual enzyme activity, may be the sole manifestation of the disease. Hemizygous men are generally more seriously affected than heterozygous women. The dominant cardiac manifestations include myocardial hypertrophy of the left ventricle, which, in some patients, mimics hypertrophic cardiomypathy. Left ventricular systolic function is usually preserved, on the other hand mild to moderate diastolic dysfunction is regularly detected. Valvular abnormalities are frequently noted. However, hemodynamically significant lesions are rare. Conduction system involvement leads initially to the shortening of atrioventricular conduction, in later stages, with a progression of the disease, antrioventricular blocks and various forms of supraventricular and ventricular arrhythmias appear. Myocardial ischemia in Fabry disease has in most cases a functional origin due to endothelial dysfunction of coronary arteries and also due to the increase oxygen demand of hypertrophied myocardium. The results of so far performed studies with enzyme replacement therapy are promising in preventing further deterioration and even improving function of affected organs.