GAI - distinct genotype and phenotype characteristics in reported Slovak patients.

OBJECTIVES: The clinical, biochemical and genetic findings in two Slovak patients with glutaric aciduria type I (GAI) are presented. BACKGROUND: GAI is a rare autosomal recessive neuro-metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan. This enzymatic defect gives rise to elevated levels of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC) in body fluids. METHODS: Biochemical and molecular-genetic tests were performed. Urinary organic acids were analysed by Gas Chromatography/Mass Spectrometry (GC/MS) and the entire coding region of the GCDH gene, including flanking parts, was sequenced. RESULTS: We found the presence of typical metabolic profile and novel causal pathogenic variants in both GAI patients. CONCLUSION: We present the first report of two Slovak patients with GAI, which differed in the clinical and biochemical phenotype significantly. They were diagnosed by two distinct approaches - selective and newborn screening. Their diagnosis was complexly confirmed by biochemical and later on molecular-genetic examinations. Though we agreed with a thesis that early diagnostics might positively influenced patient's health outcome, contradictory facts should be considered. Supposed extremely low prevalence of GAI patients in the general population and/or the existence of asymptomatic individuals with a questionable benefit of the applied therapeutic intervention for them lead to doubts whether the inclusion of disease into the newborn screening programme is justified well enough (Tab. 1, Fig. 3, Ref. 41).

Frequency-domain analysis of the signal-averaged electrocardiogram in hematological malignancies survivors.

OBJECTIVES: The aim of the presented study was to evaluate the frequency-domain signal-averaged ECGs (SAECG) abnormalities in childhood and adolescence acute leukemia and lymphoma survivors treated either with or without anthracyclines (ANT) containing chemotherapy in comparison with healthy volunteers. BACKGROUND: The late development of chemotherapy-induced myocardial complications becomes an issue as the number of childhood cancer survivors is increasing. Underlying cardiac impairment may progress to serious cardiac diseases. Therefore, an early identification of myocardial injury is essential. PATIENTS AMD METHODS: Study population was divided into two treatment groups: ANT group (31 patients previously treated with ANT), and non-ANT group (32 patients who underwent chemotherapy without ANT, both more than 5 years ago). SAECG was added to routine cardiology examination in the whole population study and 32 controls. Using the frequency-domain analysis within the QRS complex a ratio (AR) of 20-50 (Hz)/0-20 (Hz) was calculated. RESULTS: AR 20-50/0-20 in SAECG was significantly higher in ANT and non-ANT groups, relative to controls (262.5 p < 0.00001 vs. 135.9 p < 0.001 vs. 74.7). The difference between both patient groups was also evident p < 0.01. CONCLUSION: Significant differences in frequency-domain SAECG parameters between patients (with or without anthracyclines) and controls might indicate the increased risk of electrical instability particularly in anthracycline-treated patients (Tab. 2, Fig. 1, Ref. 34).

Long-term cardiac effects of treatment for childhood leukemia.

Late cardiac complications in cancer survivors may develop from subclinical myocardial damage. Biochemical correlates of minimal myocardial changes can be analyzed using a commercially available rapid assay. Biomarkers are considered more sensitive markers of subclinical cardiotoxicity than conventional electrocardiographic and echocardiographic methods. The aim of this study was to determine the values of plasma N-terminal pro brain natriuretic peptide (NT-pro-BNP) and cardiac troponin T (cTnT) in asymptomatic childhood leukemia survivors after anthracycline therapy in comparison with healthy volunteers. The survivors also underwent a detailed echocardiography. Twenty six survivors of leukemia previously treated with anthracyclines with total cumulative dose 95-600 (median 221) mg/m(2) were evaluated. Analyses of cTnT and NT-proBNP from blood samples and echocardiography were performed 5-25 years after completion of therapy for childhood leukemia. Control group for biochemical analyses consisted of 22 age- and gender- matched apparently healthy volunteers. Values of NT-proBNP were significantly elevated in ANT group compared to controls (35.1 +/- 37.8 vs. 9.6 +/- 6.7 pg/ml, P<0.010). CTnT remained below the diagnostic cut-off values in both groups. All echocardiographic parameters of patients remained normal. In conclusion, differences in NT-proBNP values between patients treated with anthracyclines and healthy volunteers might signal an initial stage of anthracycline-induced myocardial damage. The potential of this biomarker to detect subclinical anthracycline-induced myocardial alterations before development of echocardiographic and clinical changes is promising.

[The risk of cardiovascular diseases induced by radiotherapy]. / Riziko vzniku kardiovaskulárnych ochorení v súvislosti s rádioterapiou.

At present the number of cancer survivors is still increasing. However, their long-term quality of life after anticancer treatment can be decreased. Radiotherapy may represent a risk for the future of some oncologic patients. The late cardiovascular effects of radiotherapy to the area of thorax, cranium and to the abdominal area are the actual multidisciplinary problem. The unique problem is mediastinal radiotherapy which may induce the development of the cardiomyopathy, constrictive pericarditis, coronary artery disease, myocardial infarction, valvular defects, arrhythmias and other complications. Exact knowledge of pathophysiological mechanisms of radiation induced cardiovascular damage after radiotherapy as well as using of new diagnostic cardiologic methods might be useful for the detection of subclinical abnormalities and their early treatment already in the asymptomatic patients.

Natriuretic peptides: biochemical markers of anthracycline cardiac toxicity?

Patients with cancer are often treated with potentially cardiotoxic chemotherapeutics. Cardiotoxicity ranges from relatively benign arrhythmias to serious conditions such as myocardial ischemia/infarction, congestive heart failure, and cardiomyopathy. In spite of different diagnostic methods, with echocardiography as a gold standard, there is an intensive search for new diagnostic tools for the early detection of myocardial abnormalities. Available data suggest that the levels of circulating cardiomarkers can monitor the extent and severity of the myocardial damage. The role of routinely used cardiomarkers is controversial and limited in this setting. Natriuretic peptides have shown promising results in assessment and monitoring of both acute and late clinical and subclinical damage of the myocardium in association with chemotherapy. This article reviews clinical studies evaluating the role of natriuretic peptides in the early diagnosis of anthracycline cardiotoxicity, and their use in the management of cancer survivors.

[Cardiotoxicity of antracycline treatment in the light of new biochemical diagnostic options]. / Kardiotoxicita antracyklínovej liecby vo svetle nových biochemických diagnostických mozností.

Oncologic patients often receive treatment which is potentially cardiotoxic. Cardiotoxic complications range from fairly mild (relatively benign arrhythmias) to life threatening conditions (ischemia/myocardial infarction, heart failure, cardiomyopathy). The toxic effect of chemotherapy drugs may impair the integrity of the sarcomere, cause the release of bioactive substances into both tissues and the circulatory system and, consequently, cause necrosis/apoptosis of myocytes. A marker of the scope and severity of damage to the myocardium can be assessed by measuring the levels of cardiac markers in the serum. Cardiologic research is currently focused on the identification of new biochemical markers with a high degree of specificity, sensitivity and predictive value that might be used in the timely detection of myocardial abnormalities. The informative value of currently measured cardiac markers (myoglobin, CK-MB mass, CK-MB, and partly CK) is insufficient. There is growing evidence of the usefulness ofnatriuretic peptides and cardiac troponins in the diagnosing and monitoring of early and late, clinical and subclinical cardiotoxiticy resulting from anti-tumour therapy. The article summarises clinical studies concerning the diagnosis and monitoring of cardiotoxicity with the use of natriuretic peptides and cardiac troponins in former oncological patients.

Cardiac troponins--biochemical markers of cardiac toxicity after cytostatic therapy.

Cardiotoxicity is a serious adverse effect of chemotherapy that encompasses a spectrum of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. The toxicity of chemotherapeutic drugs can cause loss of myocytes' sarcolemmal integrity, release of bioactive markers into the extracellular environment (tissue and circulation) and ultimately leading to the necrosis of myocytes. The extent and severity of the necrosis can be monitored by the levels of bioactive markers. Therefore current research is aimed at finding biochemical markers with absolute cardiac specificity, high sensitivity and predictive value that can be used in early detection of patients with treatment-induced myocardial damage. Routinely used biomarkers like CK, CK-MB, and myoglobin do not meet the stated criteria. Their role in early diagnosis of chemotherapy- induced myocardial toxicity is controversial and limited. However, cardiac troponins, new nonconventional markers, have shown promising results in assessment and monitoring of both, early and late, clinical and subclinical damage to myocardium after chemotherapy. The article reviews clinical studies evaluating the role of cardiac troponins in the diagnosis of cardiotoxicity and their use in the management of cancer survivors.

[Heart transplantation at the Institute of Clinical and Experimental Medicine in Prague]. / Transplantace srdce v Institutu klinické a experimentální medicíny v Praze.

In the Institute of Clinical and Experimental Medicine in Prague 101 orthotopic allotransplantations of the heart were performed in 100 patients (87 men and 13 women). The reason for transplantation were terminal stages in the first place dilated cardiomyopathies and ischaemic heart disease. 58% of the patients survive after transplantation, the mortality rate is 42%. The highest mortality is in the early postoperative period (within two weeks after operation)--21 cases (50%). The longest survival period is nine years and six months. All patients have cyclosporin immunosuppressive treatment (in combination with another drug, later with another two drugs). In the authors' group in particular incipient acute rejections are encountered, "mild" rejections are less frequent and "moderate" rejections least frequent. The patients do not reach the stage of advanced acute rejection, i.e. "severe" rejection. Acute rejections are treated as a rule with 3 g Urbason. After this treatment acute rejection improves as a rule completely after one or two weeks therapy.

Electron microscopic and light microscopic investigation of endomyocardial biopsies in the transplanted heart.

Samples from 16 endomyocardial biopsies obtained from three patients, provided cyclosporine immunosuppression, at 3-6 years since heart transplantation were examined in light and electron microscopy. In light microscopy, the endomyocardial biopsies of the patients examined within that period were free of signs of acute rejection, practically within the normal range. In electron microscopy, intercalated discs, glycogen, mitochondria, myofibrils, lipid droplets, lipofuscin granules, sarcoplasmic reticulum in myocytes and interstitial space were examined. Results of ultrastructural studies indicate that alteration of myocytes increases with time, the longer the interval since heart transplantation, the more myocytes show changes in the above structures. Irreversible changes and myelin bodies were found sporadically in myocytes that were in normal state.

[Noninvasive diagnosis of myocardial rejection using echocardiography]. / Neinvazivní diagnostika rejekce myokardu pomocí echokardiografie.

The potential of echocardiography in evaluating myocardial rejection was determined in 56 patients (8 females) following orthotopic heart transplantation. The patients' average age was 42.3 (range 18-67) years. Endomyocardial biopsy was used as the reference method. The study included a total of 254 results of biopsy: 137 specimens were free of any signs of rejection while 51 showed incipient rejection and mild rejection was found in 54 specimens. Moderate rejection was detected in 12 specimens; severe rejection was not present in any case. Echocardiography was used to determine ventricular size, wall thickness, left ventricular function, pericardial effusion, mitral and tricuspid flow and isovolumic relaxation time. Rejection has been found to be associated with ventricular wall thickening; the appearance of or an increase in pericardial effusion seems to be a relatively specific feature (a very low-sensitivity marker though); change in isovolumic relaxation time is believed to be the most sensitive marker. No relation between rejection and mitral and tricuspid flow was demonstrated. Echocardiography may alert the cardiologist to a rejection episode; isovolumic relaxation time and its alterations are the most informative features in this respect. The method may help postpone the intervals of biopsy which, however, must be performed on the slightest suspicion of rejection. Still, it cannot be regarded as a replacement for endomyocardial biopsy at the moment.

[Standardization in the evaluation of acute rejection in heart transplantation]. / Standardizace hodnocení akutní rejekce u transplantace srdce.

The author presents a review of acute rejection classifications from the point of view of histology. She examines the relationship between conventional and cyclosporin immunosuppression and the differences in clinical practice and morphology. The article includes Stanford, Texas, Hannover and Brigham's classifications. Because of the inconsistent use of classifications in endomyocardial biopsy evaluation, the Society for Heart Transplantation has developed a standard biopsy classification system also presented in the article.

[The patient after heart transplantation]. / Obraz nemocného po srdecní transplantaci.

The data of the first 100 patients undergoing heart transplantation in the period between January 1984 and May 1993 were analyzed. Of this group, 57 patients are alive. Out of the total of 43 deaths, 14 patients died from graft failure within the first postoperative days, 6 died from surgical complications, 11 from infection, 10 deaths were due to accelerated coronary atherosclerosis, and 2 patients died from tumours. Early mortality rates (within 30 days since surgery) were 37% and 17% in patients operated on between 1984-88 and between 1989-93, respectively. The health condition of heart transplant recipients is affected by side effects of immunosuppressive therapy. Forty per cent of patients re-develop systemic hypertension within the first post-transplantation year. Five years after transplantation, hypertension is detected in 60% of patients. Elevated serum creatinine levels are present in 70% of patients by the end of the first post-transplantation year. In the ensuing period, there is no progression in renal function impairment, which does not require cyclosporin withdrawal and is not associated with the development of hypertension. In the first post-transplantation year, 45% of patients are markedly obese. All patients with overweight and obesity show markedly raised levels of serum cholesterol. Another undesirable effect (mainly due to corticosteroid therapy) is the development of ulcers in 16% of patients. Heart transplantation has become an established method at the Institute for Clinical and Experimental Medicine in Prague. Despite the above pitfalls, heart transplantation substantially prolongs the life of patients and dramatically alters the quality of their life.

[Infectious complications in patients after heart transplantation]. / Infekcní komplikace nemocných po transplantaci srdce.

The incidence of infectious complications was monitored in a group of the first 100 patients undergoing orthotopic heart transplantation at the Institute for Clinical and Experimental Medicine from January 1984 through May 1993. The definition of an infectious complication was a clinically manifest infection requiring treatment. Cytomegalovirus infection and Epstein-Barr virus infection were evaluated by the development of antibody against IgM. A total of 168 infectious complications were detected in 80 patients. The infectious complications were fatal in 11 patients; hence, infections were implicated in 26% of all deaths following heart transplantation. The spectrum of infections markedly varies depending on the interval since the procedure. The most frequent infections within the 30 postoperative days are bacterial (often nosocomial) infections. In the later period (30 days onward), viral infections account for 72% of cases. Of the rarer types of infections, the pulmonary form of aspergillosis was identified in 3 cases, nocardiosis and legionellosis in one case each. Infectious complications were the main cause of deaths in the period of 1 to 4 months post-transplantation, and the spectrum and rate of complications were not different from data reported by other centres.

[Coronary disease in patients after heart transplantation]. / Koronární nemoc u pacientu po transplantaci srdce.

Coronary artery lesions are evaluated in a group of 43 patients surviving for more than 3 months after heart transplantation. An angiographic finding was obtained from 35 patients, autopsy findings were available in eight cases. Angiography demonstrated coronary artery lesions in 12 out of the 35 patients whereas autopsy findings were positive in five out of the eight post mortem examinations. Overall, lesions were found in 40% of patients at a mean follow-up interval of 3.5 years. While the finding of a coronary artery lesion was not related to the classic risk factors for atherosclerosis, an association to a previous cytomegalovirus or Epstein-Barr virus infection was demonstrated. The data suggest that infection caused by the two above viruses is an important factor in the development of vascular lesions in the heart transplant.

[Myocarditis and endomyocardial biopsy]. / Myokarditida a endomyokardiální biopsie.

In a group of endomyocardial biopsies (EMB), performed in 45 patients with the clinical diagnosis of suspect myocarditis or dilated cardiomyopathy, positive findings (including histologically suspect lesions) were made in 53.3% of first EMB. Myocarditis, particularly its focal or multifocal forms, is bound to pose a major challenge not only in clinical diagnosis but, often, also in histological diagnosis. Of paramount importance in this situation are 1) early specimen removal after the onset of clinical manifestations and before initiation of the appropriate therapy, 2) removal of a major number of specimens in a single EMB because of the potential of focal lesions.

[A fistula between the aorta and esophagus--an uncommon sequela of dissection of the thoracic aorta]. / Pístel mezi aortou a jícnem--méne bezný následek disekce hrudní aorty.

In a patient with repeated dissection of the ascendent aorta where the first episode was resolved surgically by an intraluminal prosthesis the authors describe the rare consequence of the development of a new dissection manifested by an aorto-oesophageal fistula. In the described case an inoperable episode was involved which fully confirmed the clinical validity of the pathognomic Chiari triad.

The effect of polyamines on the endothelium and vascular wall metabolism in the rat.

Administration of putrescine, a polyamine, to rats leads to endothelial injury manifesting itself by an increased number of endothelial cells circulating in blood. Moreover, putrescine affects the metabolism of the arterial wall itself, primarily by increasing the activity of phosphomonoesterases I and II and by decreasing the activities of Krebs cycle enzymes, both of which are phenomena that can be regarded as "preatherogenic" changes 5, 6, 8, 11 preceding the onset of pathological processes in the arterial wall. Putrescine significantly decreases aortic ATPase (adenylpyrophosphatase) both in the acute and chronic phases of experiment. Ultrastructural changes after 16 weeks of putrescine administration manifested themselves in increased proliferation and smooth muscle cell injury eosinophil inflitration into the adventitia. The findings support the hypothesis that high levels of PA in homocysteinemic patients and those on chronic dialysis are a common denominator accelerating atherosgenesis in these subjects.

[Complications and causes of death in heart transplantation]. / Komplikace a príciny úmrtí po transplantaci srdce.

Complications and causes of death in patients with transplanted heart were analyzed in various intervals after operation. They comprised early deaths in the first week, short-time survival until one year, and long-time survival over one year. Acute heart failure of varied nature prevailed in early deaths as well as in long-time survival. In short-time survival, there were different causes of death in addition to heart failure.

[Thromboembolic incidents in the cardiology department]. / Tromboembolické príhody na kardiologickém pracovisti.

The authors evaluate the incidence of pulmonary embolism (PE) and its impact in patients who died in the cardiological department of the Institute of Clinical and Experimental Medicine during two five-year periods (1979-1983 and 1984-1988). These two periods are compared with the period 1974-1978 in the same department. The purpose was to assess the trend of fundamental findings (number of post-mortem examinations, number of PE, number of fatal PE, source of thrombosis in PE etc.). Based on the assembled findings it may be said that the number of p.m. examinations is increasing and thus also the number of PE. There was an obvious rise of the number of women with embolic, attacks in the cardiological department. Correct clinical diagnoses are equal in all periods.