[Measurement of natriuretic peptides in heart failure: the good laboratory and clinical practice]. / Natriureticus peptidek mérése szívelégtelen betegekben: a helyes laboratóriumi és klinikai gyakorlat.

Cardiac natriuretic peptides (BNP, NT-proBNP) play a pivotal role in cardiovascular homeostasis, mainly due to their roles in vasodilatation, natriuresis, diuresis and due to their antiproliferative properties. Proper measurement of the natriuretic peptide levels may help differentiate between respiratory and cardiac forms of dyspnea, diagnose early forms of heart failure, evaluate severity of heart failure (prognosis) and monitor the efficacy of therapy. In many countries natriuretic peptide levels are being used as one of the earliest diagnostics tools to evaluate the involvement of the heart. Current theoretical and clinical data confirm the importance of natriuretic peptides in routine healthcare. These roles are clearly described in international recommendations and guidelines. In the current review the authors discuss the problems of the measurement of natriuretic peptides in Hungary, including several aspects related to laboratory medicine, cardiology and health economy.

Cardiac allograft vasculopathy: optical coherence guided innovative treatment options with the bioresorbable vascular scaffold: proof of concept.

The aim of our work was to assess a novel interventional therapy option in cardiac allograft vasculopathy (CAV), a complex form of coronary disease presenting only in heart transplant (HTx) recipients. It is typically a rapidly progressing phenomenon, affecting the entire coronary circulation causing diffuse, severe coronary lesions and has no one unique cause. Treatment options are limited, but where eligible, palliation via percutaneous revascularization (PCI) mainly using new generation drug eluting stents (DES) is recommended. Our working group sought to assess outcomes of CAV PCI using an Absorb (Abbott Vascular, Santa Clara, CA, USA) fully bioresorbable, everolimus eluting vascular scaffold (BVS), under optical coherence tomography (OCT) guidance. Our initial, proof-of-concept case showed a late CAV, macrophage and foam-cell rich lesion, with typical asymmetric intimal hyperplasia and contralateral thin-cap fibroatheroma formation. Post-PCI OCT showed underexpansion, requiring aggressive postdilatation. Ninety-day follow-up CT angiogram identified the scaffold and displayed a patent lumen of the device. BVS use thus seems eligible in CAV, yet needs proper, meticulous implantation. Use may also delay CAV progression as lesion healing is promoted, with restoration of vasomotion and a natural increase in vascular lumen. Furthermore, the chronically present vascular irritation surrounding stent/scaffold struts may subside, as no permanent metal is present as an increased substrate for inflammation. To assess full efficacy, further studies will be needed.

Rotational atherectomy of undilatable coronary stents: stentablation, a clinical perspective and recommendation.

AIMS: Our aim was to examine procedural viability and midterm outcomes following the use of rotational atherectomy (RA) on malapposed, crippled, otherwise non-salvageable metallic stents (i.e., stentablation [SA]), and convey important procedural pointers for practitioners encountering such situations. METHODS AND RESULTS: Data on twelve SA subjects were analysed. The primary endpoint was procedural success: effective ablation of the malapposed stent and successful implantation of a new device. Major adverse cardiac events (MACE) and all-cause death at six months following the index procedure were examined as a secondary endpoint. All twelve patients underwent successful SA and novel stent implantation, with sufficient salvage of coronary anatomy (residual stenosis <30%). At six-month follow-up, however, MACE amounted to 50% and all-cause mortality to 25% in the inspected subjects. CONCLUSIONS: We found that, although feasible as an acute salvage option, SA distinctively increases post-procedural midterm MACE and mortality rates. This places emphasis on the importance of avoiding eventual SA situations, underlining the importance of ample lesion preparation prior to stent implantation.

Clinical course, prognosis, and causes of death in mixed connective tissue disease.

OBJECTIVE: To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population. METHODS: Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method. RESULTS: A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 ± 10.4 vs 41.8 ± 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-ß2-glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality. CONCLUSION: Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality.

Vitamin D insufficiency in a large MCTD population.

OBJECTIVES: The aim of the present study was to evaluate the vitamin D status in patients with mixed connective tissue disease (MCTD) and to determine which clinical symptoms, laboratory parameters and endothelial cell markers are associated with low vitamin D levels. METHODS: 125 female MCTD patients and 48 age- and sex-matched healthy controls were enrolled in the study. The clinical symptoms, autoantibodies (anti-U1-RNP, anti-cardiolipin - anti-CL and anti-endothelial cell antibody - AECA), serum cytokines (IFN-γ, IL-6, IL-12, IL-23, IL-17 and IL-10), soluble endothelial cell markers (endothelin, thrombomodulin - TM, and von Willebrand factor antigen - vWFAg) and serum lipids (total cholesterol, triglyceride, LDL-C, HDL-C, apolipoprotein A1, and apolipoprotein B) were investigated for an association with vitamin D levels by univariate and multivariate statistical analyses. RESULTS: The mean vitamin D levels were significantly lower in MCTD patients, as compared with the control group (26.16±13.50ng/ml vs. 34.92±9.64ng/ml; p<0.001). In laboratory parameters, vitamin D levels were inversely associated with serum IL-6 (p<0.001), IL-23 (p=0.011), IL-10 (p=0.033) cytokine levels, TM (p=0.001) and endothelin (p=0.033) levels. Low vitamin D levels were also significantly associated with carotid artery intima media thickness (p<0.001), fibrinogen (p=0.010), total cholesterol (p=0.042) and ApoA1 (p=0.004) levels. Among the clinical symptoms, the cardiovascular involvement showed an inverse correlation with vitamin D status in MCTD (p<0.001). CONCLUSIONS: The prevalence of vitamin D insufficiency is high in patients with MCTD. We assume that vitamin D insufficiency along with inflammatory parameters and lipid abnormalities may provoke cardiovascular events.

Alfacalcidol treatment restores derailed immune-regulation in patients with undifferentiated connective tissue disease.

Vitamin D deficiency may contribute to pathological changes in the number and function of CD4+ T helper cell subsets (CD4+Th1, CD4+Th17, CD4+CD25(bright)Foxp3-natural regulatory T cells-nTreg) in patients with undifferentiated connective tissue disease (UCTD). The aim of the present study was to evaluate, whether alfacalcidol could restore immune-regulatory changes in patients with UCTD. We assessed the optimal dose of alfacalcidol that could normalize the elevated levels of IFN-γ expressed by the CD4+Th1 cells and the IL-17 expressed by Th17 cells. Furthermore alfacalcidol decreased the Th1 and Th17 related cytokine levels, repaired the nTreg/Th7 balance, and restored the functional activity of nTreg cells. Twenty one UCTD patients with Vitamin D deficiency (<30 ng/ml) were administered with three different daily doses of alfacalcidol. Seven patients were supplemented with 0.5 µg/day, 7 patients with 1.0 µg/day, and 7 patients with 1.5 µg/day alfacalcidol treatment during 5 weeks. Our results indicated that 1.0 µg/day alfacalcidol during 5 weeks was the optimal therapeutic regime to increase the vitamin D levels, repair the nTreg/Th17 balance and raise the capacity of nTreg cells to suppress the proliferation of autologous CD4+CD25- cells. 1.5 µg daily dose alfacalcidol was not more effective than the 1.0 µg/day treatment. In this study we described that vitamin D deficiency can contribute to the complex immune-regulatory abnormalities in patients with UCTD and vitamin D substitution therapy can improve the fine balance of pro- and anti-inflammatory processes in the disease.

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease.

INTRODUCTION: The aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease. METHODS: Fifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed. RESULTS: The endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7+/-4.2% vs. 8.7+/-5.0%; P<0.001), while the percentage NMD did not differ (%NMD: 14.3+/-6.6% vs. 17.1+/-6.7%; P=0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64+/-0.13 mm vs. controls, 0.53+/-0.14 mm; P<0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5+/-2.9 vs. 5.8+/-4.8, P<0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2+/-8.1 ng/ml vs. 3.2+/-1.3 ng/ml; P<0.001) and vWFAg (224.1+/-115% vs. 89.4+/-27.1%, P<0.001) were the highest in MCTD patients with CVD. CONCLUSIONS: FMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.

Sensorineural hearing loss in patients with mixed connective tissue disease: immunological markers and cytokine levels.

OBJECTIVE: To investigate the frequency of sensorineural hearing loss (SNHL) in patients with mixed connective tissue disease (MCTD). METHODS: The study population consisted of 71 patients with MCTD (69 female; 2 male), with a mean age of 57.1 +/- 7.9 years and a mean disease duration of 14.5 +/- 8.0 years. All patients underwent audiological evaluation that included pure tone and speech audiometry. In addition, the systemic manifestations of the disease and drug therapy were recorded. All patients were tested for presence of autoantibodies. Fifty-one age-matched healthy subjects served as controls. RESULTS: SNHL was found in 33 (46.4%) of the 71 patients with MCTD. There was no correlation between SNHL and age and disease duration. An association was found between Raynaud's phenomenon (p < 0.03), secondary antiphospholipid syndrome (APS) (p < 0.05), and SNHL. MCTD patients with SNHL had higher serum levels of anti-U1RNP (p < 0.05), antiendothelial cell antibodies (p < 0.001), and IgG type anticardiolipin antibodies (p < 0.0001) than patients without SNHL. Serum levels of interferon-gamma and tumor necrosis factor-alpha were increased in MCTD patients with SNHL compared to patients without SNHL. The absolute number of natural (CD4+CD25(high)FoxP+) regulatory T cells (Treg) was lower compared to patients without SNHL. CONCLUSION: In MCTD, SNHL is a specific organ manifestation and appears frequently. We have found that pathogenic autoantibodies, decreased levels of regulatory T cells, and overexpression of proinflammatory cytokines may play a role in the pathogenesis of immune mediated inner ear disorders in MCTD.