Metformin therapy and risk of cancer in patients after heart transplantation.

BACKGROUND: Diabetes mellitus (DM) and malignancy are recognized among the most common complications increasing mortality in patients after heart transplantation (HTx). Clinical trials have shown a higher risk for different types of tumours in diabetic patients. This risk is potentiated by immunosuppressive therapy in transplant patients. Biguanide metformin has been shown to exhibit anti-tumour activity and we tried to find out whether this effect is valid for heart transplant patients. METHODS: We retrospectively analysed a group of 497 patients, who undergone HTx in our centre between 1998 and 2019. The primary outcome was any malignancy during the 15-year follow-up period and patient's survival. RESULTS: Out of the 497 patients enrolled in the study, 279 (56 %) had diabetes and 52 (19 %) were treated with metformin. Fifteen-year survival in treated patients without malignancy was 93 %, the remainder for the DM patients was 56 %, with survival in non-DM patients being 74 %. Untreated diabetic patients had 4.7 times higher chance of malignancy than those on metformin (p = 0.01). Fifteen-year survival in metformin treated patients was 53 %, in other DM patients 44 %, and in non-DM patients 51 %. CONCLUSION: Our study showed a significantly lower incidence of malignancies in metformin-treated patients and slightly better overall survival (Tab. 2, Fig. 3, Ref. 19) Keywords: biguanide, heart graft, malignancy, diabetes mellitus, survival.

Association between the heart rate early after heart transplantation and the long term clinical outcomes.

BACKGROUND: A strong correlation between a lower heart rate and survival has been demonstrated in various patient populations. The optimal heart rate for heart transplant patients is still unknown. The aim of our study was to evaluate the association between an early heart rate and survival after heart transplantation. MATERIAL AND METHODS: We retrospectively analysed a group of 330 patients, who underwent heart transplantation in our institution from 1994 to 2014 and complete datasets, including 24-hour heart rate monitoring one month after the heart transplantation. Patients were divided in 2 groups: Group A (n = 278) with the average 24-hour heart rate <90 bpm, and Group B (n = 52) with ≥ 90 bpm. RESULTS: The average period of monitoring was 7.5 ± 5.3 years. No differences in baseline characteristics were observed in both groups of recipients and respective donors. One-year survival in groups A and B was 92 % and 81 %, respectively; 5-year survival was 79 % and 60 %, respectively; and 10-year survival was 66 % and 50 %, respectively (p = 0.001). CONCLUSION: Increased heart rate in the early post-transplant period was significantly associated with a poorer survival rate in patients after heart transplantation (Tab. 2, Fig. 1, Ref. 25).

Czech Registry of Monoclonal Gammopathies - Technical Solution, Data Collection and Visualisation.

BACKGROUND: The Registry of Monoclonal Gammopathies (RMG) was established by the Czech Myeloma Group in 2007. RMG is a registry designed for the collection of clinical data concerning diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies. Data on patients with monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinaemia (WM), multiple myeloma (MM) or primary AL ("amyloid light-chain") amyloidosis are collected in the registry. DATA: Nineteen Czech centres and four Slovak centres currently contribute to the registry. The registry currently contains records on more than 5,000 patients with MM, almost 3,000 patients with MGUS, 170 patients with WM and 26 patients with primary AL amyloidosis, i.e. more than 8,000 records on patients with monoclonal gammopathies altogether. RESULTS: This paper describes technology employed for the collection, storage and subsequent online visualisation of data. The CLADE-IS platform is introduced as a new system for the collection and storage of data from the registry. The form structure and functions of the new system are described for all diagnoses in general; these functions facilitate data entry to the registry and minimise the error rate in data. Publicly available online visualisations of data on patients with MGUS, WM, MM or primary AL amyloidosis from all Czech or Slovak centres are introduced, together with authenticated visualisations of data on patients with MM from selected centres. CONCLUSION: The RMG represents a data basis that makes it possible to monitor the disease course in patients with monoclonal gammopathies on the population level.Key words: Registry of Monoclonal Gammopathies - RMG - registries - monoclonal gammopathies - CLADE-IS - data visualisation - database.

Biomarkers in Immunoglobulin Light Chain Amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis - ALA) is a monoclonal gammopathy characterized by presence of aberrant plasma cells producing amyloidogenic immunoglobulin light chains. This leads to formation of amyloid fibrils in various organs and tissues, mainly in heart and kidney, and causes their dysfunction. As amyloid depositing in target organs is irreversible, there is a big effort to identify biomarker that could help to distinguish ALA from other monoclonal gammopathies in the early stages of disease, when amyloid deposits are not fatal yet. High throughput technologies bring new opportunities to modern cancer research as they enable to study disease within its complexity. Sophisticated methods such as next generation sequencing, gene expression profiling and circulating microRNA profiling are new approaches to study aberrant plasma cells from patients with light chain amyloidosis and related diseases. While generally known mutation in multiple myeloma patients (KRAS, NRAS, MYC, TP53) were not found in ALA, number of mutated genes is comparable. Transcriptome of ALA patients proves to be more similar to monoclonal gammopathy of undetermined significance patients, moreover level of circulating microRNA, that are known to correlate with heart damage, is increased in ALA patients, where heart damage in ALA typical symptom.Key words: amyloidosis - plasma cell - genome - transcriptome - microRNA.

Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry.

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.

[Overview of primary sternal closure techniques]. / Prehled metod primárního uzáveru strední sternotomie.

The aim of the overview study is to describe the currently used methods of primary median sternotomy closure in adult cardiac surgery. In the review of published literature, we draw on the data and focus on the methodology, indications, advantages, limitations, biomechanical and clinical results of the different methods in relation to the incidence of deep sternal wound complications after median sternotomy in adult cardiac surgery.Key words: sternum sternotomy adult cardiac surgery surgical procedures.

Odours stimulate neuronal activity in the dorsolateral area of the hippocampal formation during path integration.

The dorsolateral area of the hippocampal formation of birds is commonly assumed to play a central role in processing information needed for geographical positioning and homing. Previous work has interpreted odour-induced activity in this region as evidence for an 'olfactory map'. Here, we show, using c-Fos expression as a marker, that neuronal activation in the dorsolateral area of the hippocampal formation of pigeons is primarily a response to odour novelty, not to the spatial distribution of odour sources that would be necessary for an olfactory map. Pigeons exposed to odours had significantly more neurons activated in this area of the brain than pigeons exposed to filtered air with odours removed. This increased activity was observed only in response to unfamiliar odours. No change in activity was observed when pigeons were exposed to home odours. These findings are consistent with non-home odours activating non-olfactory components of the pigeon's navigation system. The pattern of neuronal activation in the triangular and dorsomedial areas of the hippocampal formation was, by contrast, consistent with the possibility that odours play a role in providing spatial information.

Relation of IL-6, IL-13 and IL-15 gene polymorphisms to the rheumatoid factors, anti-CCP and other measures of rheumatoid arthritis activity.

The aim of the study was to examine the relation between polymorphisms and serum levels of selected cytokines (IL-6, IL-13 and IL-15), production of autoantibodies and factors describing rheumatoid arthritis (RA), such as DAS28 and Total Sharp Score. A total of 156 patients with RA according to the ACR criteria, and 200 control subjects were recruited into the study. The measurements of CRP, anti-CCP, the presence of rheumatoid factors (RFs), radiographs of both hands with calculation of Total Sharp Score (TSS) and DAS28 were obtained from all patients with RA. In total, five polymorphisms in genes coding cytokines (IL-6, IL-13 and IL-15) were detected. The levels of these selected cytokines were measured in serum using ELISA method. A significant difference in allele frequencies between patients with RA and controls was observed for IL-15 -267C/T polymorphism. A higher prevalence of heterozygote variants of IL-15 polymorphisms (14035A/T and -267C/T) in the RF IgG- and RF IgA-negative subgroups was observed. Furthermore, the association of polymorphisms in gene for IL-15 with circulating level of IL-15 (14035A/T and 367G/A) and with total RF and Ig-specific RFs (-267C/T) was found. The relation of IL-15 to RFs IgA, IgM, IgG and the measure of DAS28 was proved. The frequency of the T allele of the IL-13 polymorphism -1112C/T was higher in subgroup with faster progression of the disease (TSS/month ≥ 0.1). In conclusion, we present an association of IL-15 gene polymorphisms with the RFs including subtypes (RF, IgG, IgA) underlined by the relation of increased IL-15 levels in circulation to RFs.

Incidence of cytogenetic aberrations in two B lineage subpopulations in multiple myeloma patients analyzed by combination of whole-genome profiling and FISH.

Multiple myeloma (MM) is an incurable malignant disease of the terminal developmental stage of B-lymphocytes. While genetic heterogeneity of MM is widely described, little is known about its genetic basis as well as primary damage during plasma cells (PC) development. In this study, we focused on genome-wide screening of DNA copy number changes using oligonucleotide-based array-CGH together with I-FISH of the IgH locus rearrangements in pair samples of bone marrow B-cells (CD19+) and CD138+ PC from newly diagnosed MM patients. The IgH disruption was found in 8.9% (4/45) of CD19+ samples and in 57.8% (26/45) of CD138+ samples. The genomic profiling using array-CGH identified copy number alterations (CNAs) in 10% (2/20) of CD19+ samples in regions known to be important for MM pathogenesis. In contrast, we found CNAs in 100% (16/16) of CD138+ samples. Most common chromosomal abnormalities were trisomies of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19 and 21), gain 1q, gain Xq and monosomy of chromosome 13. We did not find any correlation between incidence of CNAs in CD19+ and CD138+ cells. In conclusion, effective utilization of FISH and array-CGH can identify genetic lesions in premalignant stages leading to better understanding and characterization of MM.

[Development of immunosuppressant treatment after liver transplant]. / Vývoj imunosupresivní lécby po transplantaci jater.

The history of liver transplants extends over more than 60 years. During the first 10 years the operations were carried out only as experiments and primarily focused on designing complex surgical techniques. In the 1960s the research focused on the development of immunosuppressants and the first clinical operations were performed. However, the outcomes of these interventions were very poor. The subsequent 2 decades witnessed the development of new and very efficient immunosuppressants, significantly improving patient survival rates. The number of operations and sites performing these interventions increased. In the United States in 1983, liver transplants were recognised as a clinical treatment method for liver conditions where all conservative options had failed. In the same year the first successful liver transplant was performed in Czechoslovakia. New surgical techniques bringing significant reduction of blood loss during the operation, reduction of over  extensive grafts, splitting operations -  when one organ may be used for 2 recipients -  and collection of liver lobes from living donors resulted in a further increase in the number of transplants. The development of new immunosuppressive protocols have contributed to further improved survival rates of the patients while the majority of transplant sites achieve the longterm survival of 90%. However, the future of transplants lies in inducing the immunological tolerance of the body towards the transplanted organ with no immunosuppressive treatment administered.

[Spondyloarthritides: current perspective on diagnosis and classification]. / Spondyloartritidy: aktuální pohled na diagnostiku a klasifikaci.

Spondyloarthritides (SpA) are a heterogeneous group of chronic inflammatory diseases with common clinical features and genetic basis. They primarily affect the axial skeleton, especially the sacroiliac joint, other localizations of the affection being peripheral joints and entheses -  typical of the group of spondyloarthritides. On the basis of the predominant affection of the axial or peripheral skeleton, they can be divided, according to the current classification criteria, into axial SpA and peripheral SpA. Apart from axial and peripheral articular manifestations, many patients also display extra articular manifestations, which can thus become an important diagnostic clue and also the first symptom of the disease. The most frequent of them are anterior uveitis, inflammatory bowel diseases, and psoriasis. Also the strong binding of spondyloarthritides to the positivity of HLA B27 antigen or a family history of the disease is important information which helps in the diagnosis. Comorbidities, the most common and important of which are cardiovascular diseases or osteoporosis and its consequences in the form of fractures, are an integral part of the issue of spondyloarthritides.

[Liver transplant outcomes in Brno]. / Výsledky transplantací jater v Brne

The first liver transplant in the former Czechoslovakia took place in Brno on 2 February 1983; the patient concerned has lived for more than 30 years with a normally functioning liver and is one of the longest surviving patients after a liver transplant in Europe. The Cardiovascular and Transplantation Surgery Centre (CTSC) in Brno has experienced an increased development in the area of liver transplants since the mid  1990s. At present, about 30 patients a year undergo a transplantation, with 451 liver transplants in total as of 31 December 2012. The primary indication concerns liver cirrhosis of various etiologies, with an increasing number of cases of cirrhosis resulting from hepatitis C. Urgent liver transplants (for acute liver failure or primary dysfunction of first liver graft) amount to 11% of cases. There were 18 retransplants performed as of 31 December 2012, with 50% five year survival. The primary graft dysfunction was present in 7 patients (i.e. 1.5%). The 1 year survival rate of all patients after a liver transplant performed in CTSC is 92%, 5 year survival rate is 80%, and 10 year survival rate is 71%. Currently the parameters such as recipients age, donors age, and transplant waiting time has been statistically increasing; small recipients with a body weight below 70 kg especially have to wait for a significantly longer period of time (waiting median of 178 days). In CTSC Brno 14 combined simultaneous transplants (13 transplants of liver + kidney and one combined simultaneous transplants of liver + heart + kidney in 2005) have been performed as of 31 December 2012.

[Liver transplants in tumours and alcoholic cirrhoses]. / Transplantace jater u tumoru a alkoholických cirhóz.

The treatment of hepatocellular carcinoma requires a multidisciplinary approach; liver transplant is suitable only in the minority of strictly selected patients. The CSTC Brno applies the so  called Milan criteria. As of 31 December 2012 the CSTC Brno performed liver transplants in 16 patients with hepatocellular carcinoma in cirrhosis, with a five year survival rate of 40% and a 10 year survival after transplant of 20%. It is a paradox that the longest living (30 years) patient of CSTC Brno underwent the transplant for a large fibrolamellar hepatocellular carcinoma, which emphasises the prognostic significance of the tumour histology -  criterion taken into account for practical reasons only in some indication schemes. Liver transplant for cholangiocarcinoma is no longer being carried out in CSTC. Five patients underwent this operation in the past and the longest living one survived for four years after the transplant. Benign liver tumours (adenomatosis, cystadenoma, hemangioma with compression symptoms) are rather rare indications and transplant results are positive. Four patients were transplanted for liver carcinoid, with one patient experiencing recurrence. The most frequent compact indication for liver transplant in CSTC Brno concerns alcoholic cirrhosis (24%, 108 patients); the survival rate of these patients after transplant is very good (81% 5 year survival and 68% 10 year survival). Likewise, efforts are made to select patients with a low risk of alcohol abuse after the transplant, which is, however, not very successful. The recurrence of some kind of alcohol abuse occurred in 26% transplanted patients, while seven died of alcoholic cirrhosis of the graft.

[Heart transplantation and the subsequent treatment of AL amyloidosis]. / Transplantace srdce a následná lécba AL-amyloidózy.

UNLABELLED: Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. CASE DESCRIPTIONS: Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the λ free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 µg/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High-dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. CONCLUSION: It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments.

Diabetic Macular Edema - Diagnostics and Treatment Guidelines.

Together with diabetic retinopathy, diabetic macular edema (DME) ranks among the most common causes of severe loss of vision in working adults. Due to recent developments in imaging methods, new classification schemes of DME have been created. In addition to this, new treatment options have been introduced (new intravitreal drugs as well as treatment protocols). At the same time laser, surgical as well as combination therapy is still available. In this paper we evaluate the current knowledge about DME diagnostic and treatment options and formulate recommended guidelines for the management of DME.

Diabetic Retinopathy ­ Diagnostics and Treatment Guidelines

Diabetic retinopathy is one of the most common complications of diabetes mellitus and represents a serious health, social and economic problem. With the expected increase in the number of patients with diabetes, it is becoming the leading cause of severe vision loss in the working-age population.  The presented guidelines summarize the current knowledge about this disease in order to standardize and update the procedures for the diagnosis, classification and treatment of diabetic retinopathy.

Diabetic Retinopathy and Diabetic Macular Edema - Screening.

Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of severe visual loss in the working population. Therefore, both DR and DME have a significant socioeconomic and health impact, which taking into account the epidemiologic predictions is expected to increase.  A crucial role in the management of DR and DME (not only for individuals, but also for the population) is played by an adequate screening program. This is based on the structure and organization of the healthcare system, the latest scientific developments in diagnostics (imaging) as well as technological advancements in computing (artificial intelligence, telemedicine) and their practical use. The recommendation presented by World Health Organization is also important. This paper evaluates all these factors, including evidence-based medicine reports and experience from existing DR and DME screening programs in comparable countries. Based on an evaluation of these parameters, recommended guidelines have been formulated for screening for DR and DME in the Czech Republic, including linkage to the Czech National Screening Center and the organization of the healthcare system.

Value of PCR in surgically treated patients with staphylococcal infective endocarditis: a 4-year retrospective study.

The aim of the study was to establish a diagnostic value for broad-range polymerase chain reaction (br-PCR) and staphylococci-specific multiplex PCR (ssm-PCR) performed on surgical material from patients with staphylococcal infective endocarditis (IE). Data were analysed retrospectively from 60 patients with suspected staphylococcal IE and 59 controls who were surgically treated at three cardiosurgery centres over 4 years. Both PCR tests showed high agreement and could be aggregated. In patients with definite and rejected IE, the clinical sensitivity and specificity of PCR reached 89 and 95%, respectively. Tissue culture (TC) and PCR agreed with blood culture (BC) in 29% and 67% of IE cases. TC helped to determine aetiology in five BC negative cases while PCR aided in nine cases. Out of 52 patients with conclusive staphylococcal IE, 40 were diagnosed with S. aureus and 12 with coagulase-negative staphylococci. PCR was shown to be highly superior to TC in confirming preoperative diagnosis of IE. In addition to aid in culture negative patients, PCR helped to establish or refine aetiology in inconclusive cases. We suggest that simultaneous br-PCR and ssm-PCR performed on surgical material together with histopathology could significantly increase the performance of current Duke criteria.

[Current opinions on gout, its diagnosis and treatment]. / Soucasný pohled na dnu, její diagnostiku a lécbu.

Gout is a heterogenous group of metabolic diseases characterized by formation and deposition of sodium urate crystals in various tissues. Gouty arthritis is a rheumatic syndrome occurring in individuals with hyperuricaemia; this is an inflammatory disease of the musculoskeletal system with a presence of sodium urate crystals. Hyperuricaemia, i.e. pathologically increased levels of uric acid in the serum, represents the most important risk factor for the development of gouty arthritis. The causes of hyperuricaemia may include an increased production of uric acid and/or its reduced elimination from the body. Acute gouty arthritis is an early manifestation of gouty arthritis. When deposition of sodium urate crystals in tissues leads to a destruction of musculoskeletal system structures, this is called chronic tophaceous gouty arthritis. To treat chronic tophaceous gout, the uric acid levels must be kept below 360 µmol/l, deposits of sodium urate in tissues dissolved and their further formation prevented. Pharmacological treatment of chronic hyperuricaemia involves administration of uric acid level lowering drugs, particularly xanthine oxidase inhibitors and uricosurics. Hyperuricaemia is an important risk factor not only for the development of chronic tophaceous gout and renal impairment but some data also suggests a risk associated with cardiovascular diseases.

[Rheumatoid arthritis - an independent risk factor for cardiovascular disease]. / Revmatoidní artritida - nezávislý rizikový faktor kardiovaskulárních onemocnení

Mortality in patients with rheumatoid arthritis compared with general population is increased and approximately one-half of the premature death is due to increased cardiovascular mortality. Traditional cardiovascular risk factors only partly explain increased risk of cardiovascular disease in patients with rheumatoid arthritis. The risk of cardiovascular disease associated with rheumatoid arthritis equals that of diabetes mellitus. Rheumatoid arthritis should be regarded as a strong independent cardiovascular risk factor as diabetes mellitus. The presence of chronic inflammation implicated in pathogenesis of rheumatoid arthritis and atherosclerosis could be the key mechanism that contributes to increased cardiovascular risk. Traditional cardiovascular risk factors reduction combined with tight disease control is recommended to reduce the risk of cardiovascular disease.