[Anaemia in chronic heart failure]. / Anémie pri chronickém srdecním selhání.

Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study.

Effect of short-term maximal exercise on BNP plasma levels in healthy individuals.

Many studies documented the relationship between elevated plasma concentrations of natriuretic peptides and cardiovascular diseases, especially heart failure. However, it is still uncertain whether physical exercise leads to a significant release of natriuretic peptide in healthy subjects. The aim of this study was to determine the effect of maximal physical activity on plasma BNP concentrations in healthy individuals within 3 hours after the short-term exercise. BNP plasma concentrations were measured in 15 healthy volunteers before, immediately after as well as 1 hour and 3 hours after bicycle spiroergometry. Maximal workload and exercise capacity were assessed in watts, watt-seconds, metabolic equivalents and VO(2max). Mean BNP plasma levels before, immediately after, 1 hour and 3 hours post-exercise were 19.4+/-2.5; 30.6+/-4.7; 17.9+/-2.5 and 18.7+/-3.1 pg/ml, respectively. The increase of BNP concentrations immediately after exercise was statistically significant (p=0.0017) compared to baseline values. We did not find any correlation between the post-exercise increase of BNP levels and age, body mass index, maximal workload or exercise capacity. In conclusion, short-term maximal physical exercise in healthy individuals led to a fast and transient rise of plasma BNP concentrations, which remained well within normal range and far below the cut-off value for heart failure (100 pg/ml).

[Will the therapy of chronic heart failure be guided by plasma levels of natriuretic peptides?]. / Budeme lécit srdecní selhání podle plazmatické koncentrace natriuretických peptidu?

Natriuretic peptides, especially BNP and NT-proBNP became useful tool for both, the diagnostics and the estimation of prognosis in chronic heart failure. As the plasma levels of natriuretic peptides copy changes in clinical status, an attractive hypothesis was formed saying that BNP/NT-proBNP guided therapy could have better clinical outcomes than therapy guided by patients' clinical status (symptoms). In past few years this hypothesis was tested in several randomized controlled clinical trials (STARS-BNP, TIME-CHF, PRIMA). However, results of these trials are very controversial. There are preliminary results of clinical trial OPTIMA referred in this paper, too. This one-centre study was performed at the authors' institution. Altogether 52 patients with chronic heart failure were randomized to one of the above mentioned treatment strategies. The rate of cardiovascular events was lower in the patients in whom the treatment was guided by BNP values compared to the patients in whom the treatment was guided by their clinical status. However, the difference was not statistically significant.

[To treat or not to treat with statins patients with chronic heart failure?]. / Lécit, ci nelécit nemocné s chronickým srdecním selháním statiny?

Two clinical trials--CORONA and GISSI-HF--have been conducted to resolve uncertainties about the effects of statins in patients with chronic heart failure and justified suspicions that treatment with statins in these patients might be detrimental. The CORONA trial researched the effects of 10 mg rosuvastatin compared to placebo on the incidence of serious cardiovascular events in 5,011 patients with systolic heart failure of ischemic aetiology, above 60 years of age and in the NYHA functional class II-IV. Even though rosuvastatin reduced the mean LDL-cholesterol plasma concentrations by 45.0% (p < 0.001) and high-sensitivity C-reactive protein (hsCRP) concentrations by 37.1% (p < 0.001), the incidence of cardiovascular events was not importantly affected (HR = 0.92; p = 0.12). Rosuvastatin had no effect on overall mortality. The treatment resulted only in a reduction of the number of hospitalizations for cardiovascular causes (p < 0.001). The GISSI-HF trial involved 4,574 patients with chronic heart failure irrespective of aetiology and the ejection fraction value randomised to take either 10 mg of rosuvastatin or placebo. The results were almost identical. Rosuvastatin had no effect on the incidence of the primary end-point--the sum of cardiovascular mortality and hospitalizations (HR = 1.01; p = 0.903). The overall mortality was not affected either. Administration of rosuvastatin in both studies was safe, the number of adverse events, including myopathies and renal failure, was no different from placebo. However, recent results from the CORONA trial subtrials have suggested that important interactions exist in patients with chronic heart failure between the effects of rosuvastatin and natriuretic peptide and hsCRP plasma concentrations. Rosuvastatin provides clinical benefit in patients with relatively low concentrations of natriuretic peptides, i.e. relatively well-controlled, while it has no clinical effect in patients with high natriuretic peptide concentrations. Similarly, rosuvastatin provides clinical benefit in patients with high hsCRP but has no effect in patients with normal hsCRP (< 2 mg/l).

Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure.

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.

[Recurrent peripheral arterial embolism from metastatic lung choriocarcinoma]. / Opakované embolizace do periferních tepen z plicní metastázy choriokarcinomu.

A case of patient with choriocarcinoma, most likely of ovarian origin, with lung metastasis is presented. The disease manifested by recurrent embolism into peripheral arteries. Publications on this topic are reviewed.

Impact of essential hypertension and primary aldosteronism on plasma brain natriuretic peptide concentration.

INTRODUCTION: Brain natriuretic peptide (BNP) has important role in the diagnosis and management of heart failure. Data on the impact of blood pressure (BP) on BNP are controversial. In primary aldosteronism (PA), BNP production can be affected by both hypertension and specific endocrine mechanisms. This study was aimed at investigating the impact of hypertension and hyperaldosteronism on plasma BNP levels. METHODS: Plasma BNP concentration, casual and 24-h BP and echocardiographic indices were assessed in 40 patients with moderate to severe essential hypertension (EH), 40 BP-matched patients with PA, and 40 age- and sex-matched healthy controls. RESULTS: BNP levels in PA and EH groups did not differ significantly and were higher compared with those in controls [median and interquartile range 26 (13-48) pg/ml, p = 0.01, and 23 (9-32) pg/ml, n.s., vs 14 (6-26) pg/ml in controls]. Remarkably elevated BNP was observed only in three PA and two EH patients, all having significant left ventricular (LV) hypertrophy. BNP levels in PA and EH groups correlated weakly with casual and 24-h BP, interventricular septal thickness and LV mass index (LVMI). Diastolic BP and LVMI were identified as the strongest independent determinants of BNP (p = 0.002 and p = 0.01, respectively). CONCLUSIONS: Both PA and EH patients had modest and mutually comparable elevation of BNP, which was independently determined by diastolic BP and LVMI. Both subtypes of PA (aldosterone-producing adenoma and bilateral adrenal hyperplasia) had similar effect on BNP production. Specific impact of hyperaldosteronism on BNP was not confirmed.

[Recommendations for the treatment of tobacco dependence]. / Doporucení pro lécbu závislosti na tabáku.

This first Czech version of guidelines formulated by the working group of mentioned medical associations is based on current literature and international guidelines. They are aimed mainly on clinical medicine and on incorporation of this treatment into the health care system according to WHO recommendations. They should serve to the treatment of tobacco dependence at any level: during any contact with the smoking patient (short intervention), in specialised centres or for the health care providers or health system itself.

[Heart failure--epidemic of the 21st century]. / Srdecní selhání--epidemie 21. století.

Number of patients with chronic heart failure is increasing in all developed countries. The reasons are both, the improving prevention and treatment of deadly cardiovascular diseases, like acute myocardial infarction or stroke, and the increasing life expectancy. The cardiovascular mortality has declined by 30% and the average life expectancy has increased by 4 years also in the Czech Republic during the last 15 years. The prevalence of heart failure is about 1.5% in a general population, which means that there is about 150,000 patients in the Czech Republic. The annual incidence is about 0.4%, which means that there is about 40,000 new patients in the Czech Republic every year. The prevalence is increasing with age significantly. With respect to the ageing of the population it is expected that number of heart failure patients will be increasing. Based on the results of big clinical trials the treatment of heart failure has changed significantly. ACE inhibitors and beta-blockers became the first choice treatment improving not only symptoms but also mortality. In spite of all the progress in pharmacotherapy the prognosis of heart failure is still bad. Over 40% of patients will die within 4 years after making the diagnosis of heart failure and one-year mortality of patients with advanced heart failure (NYHA class IV) is over 50%. Therefore, a research of new therapeutic possibilities is still continuing. At present, a clinical significance of different devices, like biventricular cardiac pacemakers (cardiac resynchronization therapy) or implantable cardioverter/defibrillators in heart failure treatment is studied. A gene and cell therapy represents a great hope for heart failure treatment in future.

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial--FAT).

OBJECTIVE: It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS: 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS: We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS: Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

Anti-ischaemic efficacy and tolerability of trimetazidine administered to patients with angina pectoris: results of three studies.

Several clinical studies have compared the anti-ischaemic properties of trimetazidine used as monotherapy with those of standard anti-anginal therapy. In the treatment of uncontrolled angina pectoris, the addition of a metabolic agent such as trimetazidine to existing therapy with a haemodynamic agent would appear to confer advantages over the addition of a second haemodynamic agent. Here we report the results of three studies conducted in Poland, the Czech Republic and Hungary that provide additional evidence for the beneficial effects of combining trimetazidine with a conventional haemodynamic agent such as beta-blockers, long-acting nitrate or calcium channel blockers. This combination provided significant benefits in terms of improved exercise capacity and decreased number of angina attacks along with a good tolerability profile.

Regression of acromegalic left ventricular hypertrophy after lanreotide (a slow-release somatostatin analog).

A group of 13 acromegalic patients was treated with lanreotide for 18 months and followed-up echocardiographically; these patients showed significant correlations between the decrease of both growth hormone (GH) and insulin-like growth factor-1 and the decrease of left ventricular mass index. This documents a regression of left ventricular hypertrophy in acromegaly after lanreotide treatment, the degree of which is dependent on the magnitude of the decrease of GH and insulin-like growth factor-1 serum levels.

Quantitation of individual molecular species of phosphatidylcholines by reversed-phase high-performance liquid chromatography with fluorometric detection.

The multiplicity of phosphatidylcholines is caused by the presence of different pairs of fatty acids in their individual molecular species and at least 27 miscellaneous fatty acids were identified in phosphatidylcholines in the serum of healthy individuals by combined gas-liquid chromatography and mass spectrometry in our present experiments. A method is described for the separation and quantitation of molecular species of phosphatidylcholine in human serum. Total phosphatidylcholine is isolated from lipids extracted from the serum with chloroform-methanol (2:1) by reversed-phase liquid-liquid extraction and subjected to reversed-phase high-performance liquid chromatography with a discontinuous descending gradient of water. Separation is monitored by fluorometry (340/460 nm) and absorption at 205 nm, if required. Up to 25 different molecular species of phosphatidylcholine may be quantified with a satisfactory reproducibility (+/-5-8%). Data on the distribution of individual molecular species in phosphatidylcholine of 53 normal serums are presented. The method may be used for quantitation of these phospholipids also in other biological materials (cell lines, leukemic cells from patients), and on a micropreparative scale to isolate individual compounds. The speed of separation as well as a satisfactory reproducibility are its principal advantages.

Valsartan and atenolol in patients with severe essential hypertension.

The aim of this study was to evaluate the efficacy and tolerability of valsartan, a new angiotensin II receptor antagonist, versus atenolol in the treatment of severe primary hypertension. A total of 103 adult out-patients were randomised to receive either valsartan 160 mg or atenolol 100 mg once daily for 6 weeks. If necessary, additional blood pressure (BP) control could be provided as add-on therapy. Both valsartan and atenolol decreased mean sitting diastolic BP (DBP) and mean sitting systolic BP (SBP): least squares mean change from baseline in DBP; valsartan, -20.0 mm Hg; atenolol, -20.4 mm Hg: in SBP; valsartan, -30.0 mm Hg; atenolol, -25.5 mm Hg. There was no statistically significant difference between the treatment groups. Add-on hydrochlorothiazide (HCTZ) 25 mg was required by 97.2% of patients receiving atenolol and 83.6% of patients receiving valsartan; additional verapamil SR 240 mg was also required by 58.3% of patients receiving atenolol and 64.2% receiving valsartan. Valsartan was well tolerated, with a comparable incidence of treatment-related adverse experiences in both groups. In conclusion valsartan 160 mg is as well tolerated and effective as atenolol 100 mg in lowering BP in severely hypertensive patients.

Alterations of phosphatidylcholine concentrations in the serum of patients with mammary cancer.

As determined by reversed-phase liquid-solid extraction, concentration of total phosphatidylcholines in the serum of 53 patients with mammary cancer was significantly (P<0.003) increased to 2.24 +/- 0.59 mg/ml when compared with the normal value of 1.86 +/- 0.36 mg/ml. In 31 fractions of their individual molecular species separated by high-performance liquid chromatography there was a shift to compounds composed of longer fatty acids that were significantly more abundant than in normal serum. The concentration of fractions containing stearic, oleic, linoleic, eicosatrienoic, arachidonic and docosahexaenoic acid as well as traces of C17 acids was 2-5 fold enhanced. On the other hand, molecular species containing palmitic acid combined with palmitoleic, oleic linoleic, arachidonic and further poly-unsaturated fatty acids are considerably decreased in cancer serum. All these atypical phosphatidylcholines are apparently specific products of tumor cells and are released into the blood stream. The possibility of using these alterations of phospholipid metabolism for the follow-up of cancer patients is further investigated.

Isolation and quantitation of phosphatidylcholine by reversed-phase liquid-liquid extraction.

A simple and rapid method is described for the determination of total phosphatidylcholines in serum. Extracts of lipids are applied to octadecyl silica cartridges and phosphatidylcholines are eluted by methanol-acetonitrile mixtures containing choline. Quantitation of these compounds is performed by colorimetry of their complexes with erythrosin B. The method is sensitive down to approximately 10 microg, exhibits good reproducibility and may be used as a preliminary step for the separation of individual molecular species of phosphatidylcholines by high-performance liquid chromatography.