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.

Arterial stiffening contributes to impairment of cerebrovascular reactivity in patients with coronary artery disease without carotid stenosis.

Impaired cerebrovascular reactivity (CVR), an important risk factor for future stroke, is affected by a presence carotid stenosis. However, in some cases CVR can be impaired in the absence of carotid stenosis due to several poorly characterized mechanisms. We hypothesized that arterial stiffening as observed in coronary heart disease (CHD) could be associated with alteration in CVR in CHD patients without carotid stenosis. The study population consisted of patients referred for coronary angiography without significant carotid stenosis (<50 %). CVR was evaluated by breath holding index (BHI) measured with transcranial color code duplex ultrasound. Arterial stiffness was assessed by pulse wave velocity (PWV) measured by the oscillometric method. The extent of coronary atherosclerosis was quantified by Gensini score (GS). Out of 186 subjects, sixty-two patients fulfilled the inclusion and exclusion criteria. BHI decreased with increasing PWV (r = -0.47, p<0.001). Decrease in BHI was significantly inversely associated with GS (r = -0.61, p<0.001). GS was associated with PWV (p<0.001). In conclusion, impaired CVR was associated with increased arterial stiffening in CHD patients in the absence of significant carotid stenosis. Thus, we speculate that increased arterial stiffness may at least partially contribute to the pathophysiology of CVR alteration in coronary artery disease.

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.

[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.

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.

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.

[Prevention of thrombembolic disease in internal medicine]. / Prevence trombembolické nemoci ve vnitrním lékarství.

Although deep vein thrombosis is often considered to be associated with recent surgery, 50-70% of symptomatic thrombembolic events occur in nonsurgical patients. Hospitalization for acute medical illness is independently associated with about eightfold increase in relative risk for venous thrombosis. Thus correct evaluation of risks for thrombembolic disease in individual inpatient and appropriate prophylaxis offers the opportunity to improve the prognosis of acutely ill patient. The most efficient and easy way of pharmacologic prophylaxis is subcutaneous administration of low molecular weight heparin. Only in minority of patients mechanical methods of prevention are sufficient. The optimal duration of thromboprohylaxis in medical patients is unknown and we have to evaluate the changing conditions in each patient.

[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.

[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.

[Takayasu's disease associated with autoimmune thyroiditis and celiac disease. Clinical course and limitations of treatment]. / Association de la maladie de Takayasu avec la thyroïdite auto-immune et la maladie coeliaque. Déroulement de la maladie et limites du traitment.

Takayasu's arteritis is a non-specific form of vasculitis involving the aorta, its main branches and pulmonary arteries. It is a rare disease in our country, contrasting with the high prevalence in Southeast Asia, Africa and South America. We discuss the course of the disease in our patient who was a young women who developed Takayasu's arteritis associated with autoimmune thyroiditis and malabsorption syndrome due to celiac sprue. Long-term immunosuppressive therapy contributed to stabilizing the associated diseases, but did not stop the progression of the vascular lesions. The main adverse outcome in our patient was the development of severe renovascular hypertension. Bilateral renal artery stenosis was treated by angioplasty with stent implantation. Based on literature reports, the association of Takayasu's disease with multiple autoimmune disorders is a rare event. However, it would appear that the arteritis was the limiting disease for prognosis in our patient.

Cardiac manifestations in Fabry disease.

Fabry disease is an X-linked recessive genetic disorder of glycosphingolipid metabolism, due to deficiency of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by the progressive intracellular lysosomal accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system. It has been reported that cardiac involvement could be the sole manifestation of the disease in some patients. Myocardial abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant cavity dilatation, the most frequent abnormal structural pattern being concentric LV hypertrophy (LVH). In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. According to our experience, systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding, representing probably the most important cause of dyspnoea in patients with Fabry disease. However, in a relatively large population of affected patients, severe diastolic dysfunction, typical of restrictive cardiomyopathy, was not found. Valvular structural abnormalities are frequent due to valvular infiltration. In several patients, hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets associated with LV outflow obstruction may aggravate the mitral valve dysfunction. We did not confirm the previously reported high prevalence of mitral valve prolapse. Valvular regurgitation seems to be relatively frequent but mostly non-significant. Electrocardiographic changes in Fabry disease are multiple and include atrioventricular (AV) conduction abnormalities (abbreviation of the P-R interval or AV blocks), signs of LVH and repolarization abnormalities. Our observations suggest that conduction defects and repolarization changes are present predominantly in subjects with LV structural abnormalities. Cardiac symptoms in patients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris (due to LVH, endothelial dysfunction and/or fixed coronary artery stenosis) and syncope (related to AV blocks or LV outflow obstruction). The extent of cardiac involvement, in particular LV mass assessment, could represent an ideal surrogate endpoint for evaluating the efficacy of specific therapies.

New insights in cardiac structural changes in patients with Fabry's disease.

BACKGROUND: Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase leading to the pathologic intracellular deposition of neutral glycosphingolipids. Although cardiac involvement is frequent, there is controversy regarding the character of the associated left ventricular (LV) changes and the severity of valvular involvement. METHODS: Clinical evaluation (disease severity scaling, laboratory tests, and echocardiography) was performed in 13 hemizygous men (mean age 39 +/- 10 years) and 17 heterozygous women (mean age 35 +/- 19 years). RESULTS: LV hypertrophy (LVH) was frequent in subjects older than 30 years, more often in men (61%) than in women (18%, P <.001). The degree of LVH was independently associated with age and the logarithm of alpha-galactosidase activity (r(2) = 0.70, P <.001). The predominant LV geometric patterns were concentric LVH and remodeling, both present in 11 subjects (36%). Three patients had an asymmetric septal hypertrophy mimicking hypertrophic cardiomyopathy. In most subjects with LVH, the systolic function was normal and severe diastolic dysfunction (restrictive pattern) was not noted. Minor structural abnormalities of the mitral valve were found in 17 subjects (57%). The aortic valve was affected in 14 patients (47%). Valvular abnormalities were frequently accompanied by regurgitation of minor to mild degree. The presence of LVH or valvular changes was associated with increased disease severity. CONCLUSIONS: Echocardiographically detectable cardiac involvement is frequent with Fabry's disease, particularly in older subjects, and more pronounced in affected hemizygous men than in heterozygous women. LVH is frequently observed but usually not associated with significant systolic or restrictive diastolic dysfunction. Concentric LVH and remodeling appear to be the major manifestations of LV structural alteration. The frequently noted valvular abnormalities were not associated with a significant degree of regurgitation. Valvular and especially LV structural changes may serve as a useful marker of disease severity.

[Thrombotic complications in patients with malignant diseases]. / Trombotické komplikace u nemocných s maligním onemocnením.

The incidence of thromboembolic disease (TED) in malignant diseases is high and is often the cause of death in these patients. The most important thrombogenic factors are changes of the coagulation system, venostasis, changes in the function and structure of the endothelium and the influence of specific anti-tumour therapy. The most frequent clinical manifestation is phlebothrombosis of the lower extremity. Diagnostic procedures in detection of thrombosis do not differ fundamentally from standard procedures (clinical examination, duplex sonography, phlebography, possibly pulmonary scintigraphy). More intensive prophylaxis of TED is necessary under certain conditions (surgical treatment, immobilization, chemotherapy). Therapeutic patterns with heparins, possibly thrombolytics, are common but subsequent anticoagulation treatment must be provided as long as the active stage of the neoplastic disease persists, in particular if the patient is treated with cytostatics. When anticoagulation treatment is contraindicated and there is a general favourable prognosis, implantation of caval filters is an adequate provision. New findings indicate the possible anti-tumourous action of low-molecular heparins, but these are only initial observations.

[Catheterization therapy of thromboembolic arterial occlusions of the lower extremities]. / Katetrizacní lécba trombembolických uzáveru tepen dolních koncetin.

Thromboembolic occlusions of peripheral arteries may threaten the vitality of extremities and sometimes patients life. Till recently the main therapeutic method was Fogarty surgical thromboembolectomy. A less invasive procedure is systemic (intravenous) and local (intraarterial) thrombolysis. All these method have, however, certain disadvantages. A new approach to the treatment for acute and subacute occlusions of peripheral arteries represents catheter thromboembolectomy, which involves the following: a) Aspiration of thromboembolic material--percutaneous thrombembolextraction (PTEE), b) Local infiltration thrombolysis where the catheter penetrates through the occlusion while simultaneously administering a fibrinolytic agent, c) PTA of residual stenosis in case of thrombotic occlusion. A combination of these methods of treatment for thromboembolic occlusions of peripheral arteries is very effective and enables to use a small amount of thrombolytic agent. The thrombosis and the underlying atherosclerotic stenosis are resolved during the same session.

[Occurrence and prognosis of silent ischemia]. / Výskyt a prognóza nemé ischémie.

The authors assessed in a group of 486 asymptomatic middle-aged men (50-60 years) the prevalence of silent myocardial ischaemia. For screening they used the exercise test on a bicycle ergometer and in men with a positive test the presence of silent ischaemia was confirmed by perfusion scintigraphy with thallium-201 or by. The prevalence of silent ischaemia was compared with the incidence of angina angiography, myocardial infarction and sudden deaths in a similar group of 1419 men followed up for 10 years in the same department. In patients with a confirmed diagnosis of silent ischaemia the prognosis was monitored, as well as possible clinical manifestations of IHD, in the course of 4-7 years of the investigation. The presence of silent ischaemia was confirmed in 32 men, i.e. 6.6%. As compared with other forms of IHD, silent ischaemia was detected almost equally frequently as myocardial infarction and as compared with angina pectoris it was observed twice as frequently. In the course of the investigation period two patients were subjected to a revascularization (CABC or PTCA). In the remaining group of 30 patients who underwent conservative treatment two patients died (sudden deaths), seven developed angina and five myocardial infarctions (incl. one clinically silent).

Does chronic nitrate therapy induce tolerance to short-acting ones?

The aim of this study was to ascertain whether long-term nitrate administration (therapy by 120 mg ISDN or 16 mg molsidomine) decreases the efficiency of administered short-acting nitrate by the mechanism of tolerance. Fourteen male patients (mean age 56 years) with stabilized angina (IIIrd degree) were included and stress test with standard workload of 75 W was performed at the beginning of the study after cessation of therapy. Subsequently, the test was repeated after administration of 2.5 mg ISDN (IsoMack spray). The period of time until maximal load increased more than twice (4.0 +/- 1.3 vs 9.1 +2- 3.3 min. mean +/- SD). Afterward, patients were treated by ISDN 120 mg (IsoMack 120) once a day or molsidomine 8 mg (Corvaton ret.) twice a day; both drugs were interchanged after the period of 6 weeks. Stress tests were repeated at the end of these therapy periods (before and after application of short-acting nitrate). During 120 mg ISDN therapy, the time until maximal load after the application of 2.5 mg ISDN increased analogously (6.2 +/- 1.8 vs 9.6 +/- 3.7 min) and similarly after molsidomin therapy (5.5 +/- 1.7 vs 10.0 +/- 4.1 min). These results indicate that stress tolerance increases after short-acting nitrate administration significantly also in patients treated by high doses of long-acting nitrates (ISDN or molsidomine). Inducing of tolerance to short-acting nitrates was not observed.