Pharmacogenetic distinction of the Croatian population from the European average.

AIM: To compare the Croatian and European population in terms of allele frequencies of clinically relevant polymorphisms in drug absorption, distribution, metabolism, and excretion (ADME) genes. METHODS: In 429 Croatian participants, we genotyped 27 loci in 20 ADME genes. The obtained frequencies were merged with the published frequencies for the Croatian population by sample size weighting. The study sample obtained in this way was compared with the average data for the European population from the gnomAD database. RESULTS: Variant allele frequencies in the Croatian population were higher in three and lower in two polymorphisms (Benjamini-Hochberg-corrected P values: 0.0027 for CYP2B6*4 rs2279343, CYP2C9*2 rs1799853, and VKORC1 rs9923231; 0.0297 for GSTP1 rs1695; 0.0455 for CYP2A6 rs1801272) compared with the European population. The most marked difference was observed for CYP2B6*4 (9.3% in Europe vs 24.3% in Croatia). The most clinically relevant findings were higher variant allele frequencies in two polymorphisms related to lower warfarin requirements: VKORC1*2 (34.9% in Europe vs 40.1% in Croatia) and CYP2C9*2 (12.3% in Europe vs 14.7% in Croatia). This indicates that three-quarters of Croatian people have at least one variant allele at these loci. Variants in genes GSTP1 and CYP2A6 were significantly less frequently observed in Croatia. CONCLUSIONS: Croatian population has a higher bleeding and over-anticoagulation risk, which is why we recommend the prescription of lower doses of anticoagulation drugs such as warfarin and acenocoumarol. Lower phenytoin, and higher bupropion and efavirenz doses are also recommended in the Croatian population.

Atrial fibrillation-related stroke in women: Evidence and inequalities in epidemiology, mechanisms, clinical presentation, and management.

BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and one of the major causes of stroke, heart failure, sudden death, and cardiovascular morbidity. Despite substantial advances in (interventional) rhythm control treatment during the last decade, anticoagulation for stroke prevention remains a major component of AF treatment. HYPOTHESIS: There are important sex-specific differences in AF-related stroke, resulting from sex-specific mechanisms and therapeutic differences. METHODS: This review summarizes available data on sex differences in risk assessment and prevention of stroke and highlights current knowledge gaps in AF-related stroke mechanisms, prevention and management that warrant further research. RESULTS: Increased thrombotic risk in women is multifactorial, involving hormonal changes after menopause, structural, endocrine and lifestyle/social factors and their interactions. It is clear from randomized studies that women benefit from anticoagulant treatment and that their bleeding risk is similar to men. Women should therefore receive equivalent treatment to men, based on the validated criteria for anticoagulation therapy. However, women are not represented equally in the large randomized studies and sex-related information in many fields is lacking. CONCLUSIONS: Female sex is an established risk factor for stroke in AF patients. The evidence for sex-specific differences in stroke risk assessment and stroke prevention is accumulating. However, the underlying biological mechanisms remain incompletely understood and further studies are required in order to decrease AF-related morbidity and mortality.

Increasing age does not affect time to appropriate therapy in primary prevention ICD/CRT-D: a competing risks analysis.

Aims: To evaluate the impact of age on the clinical outcomes in a primary prevention implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) population. Methods and Results: A retrospective, multicentre analysis of patients aged 60 years and over with primary prevention ICD/CRT-D devices implanted between 1 January 2006 and 1 November 2014 was performed. Survival to follow-up with no therapy (T1), death prior to follow-up with no therapy (T2), delivery of appropriate therapy with survival to follow-up (T3), and delivery of appropriate therapy with death prior to follow-up (T4) were measured. In total, 424 patients were eligible for inclusion in the analysis, mean follow-up of 32.6 months during which time 44 patients (10.1%) received appropriate therapy. The sub-hazard ratio (SHR) for the cumulative incidence of appropriate therapy (T3) according to age at implant was 1.00 (P = 0.851; 95% CI 0.96­1.04). The SHR for cumulative incidence of death (T2) according to age at implant was 1.06 (P < 0.001; 95% CI 1.03­1.01). Age at implant, ischaemic aetiology, baseline haemoglobin, and the presence of diabetes mellitus were predictors of all-cause mortality. Conclusion: Age has no impact on the time to appropriate therapy, but risk of death prior to therapy increases by 6% for every year increment. As the ICD population ages, the proportion who die without receiving appropriate therapy increases due to competing risks. Characterizing competing risks predictive of death independent of ICD indication would focus therapy on those with potential to benefit and reduce unnecessary exposure to ICD-related morbidity.

Expression of secreted frizzled-related protein 1 and 3, T-cell factor 1 and lymphoid enhancer factor 1 in clear cell renal cell carcinoma.

Frequency and mortality of renal cell carcinoma (RCC) are increasing for decades. However, the molecular background of RCC tumorigenesis is still poorly understood. In current study we investigated the expression of TCF/LEF and SFRP family members (SFRP1 and SFRP3) to gain a better understanding of biological signaling pathways responsible for epidemiology and clinical parameters of clear cell RCC (cRCC). Thirty-six pairs of paraffin-embedded clear cRCC and adjacent nontumoral tissues samples using immunohistochemistry (IHC) were analyzed and compared with corresponding clinicopathological parameters. Immunohistochemistry indicated statistically significant decreased SFRP3 expression in tumor tissues but no consistency in SFRP1 expression in analyzed normal and tumor tissue. The TCF1 expression level was significantly weaker in normal tissue compared to tumor samples while LEF1 protein levels were significantly weaker in tumor tissue. To our knowledge, this is the first report on analysis of the expression of transcription factors TCF1 and LEF1 in clear cell renal cell carcinoma and their comparison with Wnt signal pathway antagonists belonging to SFRP family.

Age trends in prevalence of cardiovascular risk factors in Roma minority population of Croatia.

The Roma (Gypsy) are the largest European minority population characterized by poverty, social exclusion as well as by numerous life-style and cultural specificities, which all could have an adverse impact on their cardiovascular health. This study assesses the prevalence of cardiovascular diseases (CVD) risk factors in community-based sample of 430 adult Roma, living in rural area of Croatia, by providing the actual and age-adjusted estimates using the European standard population. The most prominent classical CVD risk phenotypes (blood pressure, obesity, smoking, glucose and lipid profile) were selected, and the standard risk cut-offs were applied. The study has shown that compared to general population of Croatia, the Roma population bears a high CVD risk factors load related to smoking and high glucose level. The CVD risk factors prevalence in Roma also showed important sex and age patterns, the most imposing of which are the findings of higher prevalence of CVD risks in women (especially obesity and triglyceride levels) and the trend of higher body mass index (BMI) level in younger age group (18-34 years) which both stand in contrast to the trends characterizing the general population of Croatia. These findings are complemented by the trend of decreased risk in the oldest age group (65+ years) for all investigated CVD risk factors (with exception of triglycerides level) compared to the 50-64 age group. We conclude that the age and sex CVD risks pattern point to the health transition of this rural Roma population. As we expect the proportion of CVD in the Roma minority of Croatia to increase in the future along with further modernization of their lifestyle, the CVD prevention measures in this population are urgent and should be primarily targeted at women and at the younger segment of this population.

Combined endocardial and epicardial catheter ablation in arrhythmogenic right ventricular dysplasia incorporating scar dechanneling technique.

BACKGROUND: Ventricular tachycardia (VT) ablation in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has a low success rate. A more extensive epicardial (Epi) arrhythmogenic substrate could explain the low efficacy. We report the results of combined endocardial (Endo) and Epi VT ablation and conducting channel (CC) elimination. METHODS AND RESULTS: Eleven consecutive patients with ARVD/C were included in the study. A high-density 3D Endo (321±93 sites mapped) and Epi (302±158 sites mapped) electroanatomical voltage map was obtained during sinus rhythm to define scar areas (<1.5 mV) and CCs inside the scars, between scars, or between the tricuspid annulus and a scar. The end point of the ablation procedure was the elimination of all identified CCs (scar dechanneling) and the abolition of all inducible VTs. The mean procedure and fluoroscopy time were 177±63 minutes and 20±8 minutes, respectively. Epi scar area was larger in all cases (26±18 versus 94±45 cm(2), P<0.01). The combined Endo and Epi VT ablation eliminated all clinical and induced VTs, and the addition of scar dechanneling resulted in noninducibility in all cases. Seven patients continued on sotalol. During a median follow-up of 11 months (6-24 months), only 1 (9%) patient had a VT recurrence. There was a single major bleeding event that did not preclude a successful procedure. CONCLUSIONS: Combined Endo and Epi mapping reveals a wider Epi VT substrate in patients with ARVD/C with clinical VTs. As a first-line therapy, combined Endo and Epi VT ablation incorporating scar dechanneling achieves a very good short- and midterm success rate.

Integration of 3D electroanatomic maps and magnetic resonance scar characterization into the navigation system to guide ventricular tachycardia ablation.

BACKGROUND: Scar heterogeneity identified with contrast-enhanced cardiac magnetic resonance (CE-CMR) has been related to its arrhythmogenic potential by using different algorithms. The purpose of the study was to identify the algorithm that best fits with the electroanatomic voltage maps (EAM) to guide ventricular tachycardia (VT) ablation. METHODS AND RESULTS: Three-dimensional scar reconstructions from preprocedural CE-CMR study at 3T were obtained and compared with EAMs of 10 ischemic patients submitted for a VT ablation. Three-dimensional scar reconstructions were created for the core (3D-CORE) and border zone (3D-BZ), applying cutoff values of 50%, 60%, and 70% of the maximum pixel signal intensity to discriminate between core and BZ. The left ventricular cavity from CE-CMR (3D-LV) was merged with the EAM, and the 3D-CORE and 3D-BZ were compared with the corresponding EAM areas defined with standard cutoff voltage values. The best match was obtained when a cutoff value of 60% of the maximum pixel signal intensity was used, both for core (r(2)=0.827; P<0.001) and BZ (r(2)=0.511; P=0.020), identifying 69% of conducting channels (CC) observed in the EAM. Matching improved when only the subendocardial half of the wall was segmented (CORE: r(2)=0.808; P<0.001 and BZ: r(2)=0.485; P=0.025), identifying 81% of CC. When comparing the location of each bipolar voltage intracardiac electrogram with respect to the 3D CE-CMR-derived structures, a Cohen κ coefficient of 0.70 was obtained. CONCLUSIONS: Scar characterization by means of high resolution CE-CMR resembles that of EAM and can be integrated into the CARTO system to guide VT ablation.

E2 allele of the apolipoprotein E gene polymorphism is predictive for obesity status in Roma minority population of Croatia.

BACKGROUND AND AIMS: The Roma (Gypsies) are a transnational minority, founder population characterized by unique genetic background modeled by culturally determined endogamy. The present study explores whether the widely found cardiovascular diseases (CVD) risk effects of ACE I/D, APOE (ε2, ε3, ε4), eNOS-VNTR and LEP G2548A polymorphisms can be replicated in this specific population. METHODS AND RESULTS: The community-based study was carried on 208 adult Bayash Roma living in rural settlements of eastern and northern Croatia. Risk effect of four CVD candidate polymorphisms are related to the most prominent classical CVD risk phenotypes: obesity indicators (body mass index and waist circumference), hypertension and hyperlipidemia (triglycerides, HDL and LDL cholesterol). For all of them the standard risk cut-offs were applied. The extent to which the phenotypic status is related to genotype was assessed by logistic regression analysis. The strongest associations were found for ε2 allele of the APOE as a predictor of waist circumference (OR 3.301; 95%CI 1.254-8.688; p = 0.016) as well as for BMI (OR 3.547; 95%CI 1.471-8.557; p = 0.005). It is notable that ε3 allele of APOE gene turned out to be a protective genetic factor determining low lipid levels. CONCLUSION: The strength of the relation and the similarity of the results obtained for both tested indicators of obesity provide firm evidence that APOE plays an important role in obesity development in the Roma population.

[Pleural mesothelioma--case report]. / Mezoteliom pleure--prikaz bolesnika.

Pleural mesothelioma is a rare neoplasm with the incidence of 1-2 per million people. The incidence is higher in male population (10-30/million), whereas the incidence in female population is 2 per million. It occurs predominantly at older age (65+ years). The most common clinical manifestation of pleural mesothelioma is pleural effusion with dyspnea, which makes it a diagnostic problem since many cardiac diseases can have the same presentation. We report a case of pleural mesothelioma in an 80-year-old woman that presented with dyspnea and pleural effusion, which was at first considered as a sign of heart failure. Clinical presentation also included metabolic disorders and deep vein thrombosis, and the patient's epidemiologic history was negative, so diagnostic procedures including pleurocentesis were directed towards detection of the possible malignant disease. Cytologic analysis followed by biopsy pointed to the diagnosis of pleural mesothelioma. Persistent pleural effusions that do not coincide with cardiac disease, especially if accompanied by metabolic disorders and paraneoplastic syndromes, require additional diagnostic workup to identify the etiology of pleural effusion.

Entrapment of the circular mapping catheter in the mitral valve in two patients undergoing atrial fibrillation ablation.

The circular catheter is a useful tool to guide and test pulmonary vein (PV) isolation in atrial fibrillation ablation. However, its shape may facilitate entrapment in cardiac structures. We describe the entrapment of a circular mapping catheter within the mitral valve apparatus after transseptal catheterization and mapping of the left atrium and PVs in two of our patients.

Defibrillation threshold decrease with the supradiaphragmatic extracardiac implantable cardioverter-defibrillator implantation technique.

Despite advances in implantable cardioverter-defibrillator (ICD) technology, the optimal ICD implantation technique for pediatric patients has not yet been established. One increasingly used option is totally extracardiac implantation. However, concern exists about the high defibrillation threshold (DFT) at the moment of implantation or during follow-up. We report the case of a 3-year-old boy with repetitive syncopal idiopathic ventricular tachycardia episodes treated with ICD implantation using the extracardiac technique. Changing device position from abdominal to a supradiaphragmatic, solved unsafe elevated discharge impedance and DFT during follow-up.

Traditional CVD risk factors and socio-economic deprivation in Roma minority population of Croatia.

Researches into health inequalities consistently show disadvantages in health status, morbidity and mortality for various ethnic minority groups. Current knowledge about prevention of cardiovascular diseases (CVD) mainly derives from studies carried out in populations of European origin while the evidences involving Roma population are scarce. Roma, an ethnic minority of northern Indian origin, live in many countries throughout the world and are well known for preserved traditions and resistance to assimilation. They are most often marginalized economically, spatially, politically and in terms of culture. In order to assess the health status and health-related lifestyle attributes, a multidisciplinary anthropological and epidemiological community-based study was carried out including a total of 423 members of the Bayash Roma minority population living in two regions of Croatia (144 men and 279 women, aged 18-84 yrs). Hypertension (HT) was found in 24.8% Bayash Roma (21.5% men and 26.5% women) using standard diagnostic criteria (i.e. BP > or = 140/90 mm Hg or taking antihypertensive therapy). The prevalence increases from 5.9% in the age group 18-34 yrs; 35.0% in the age group 35-64 yrs, and 51.4% in the age group 65+ yrs. The prevalence of hypertension in the Bayash Roma is almost half of the magnitude of what is usually reported for the general population of Croatia. It is also lower when compared with other European populations and this finding is not due to comparatively younger average age of the Bayash sample. The significant association of hypertension with age and BMI was confirmed in this study and the importance of non-traditional SES-related CVD risk factors was highlighted. Smoking is a part of traditional Roma life-style and with 70% of smokers almost the entire population is equally exposed to this risk factor in their family environment. Since homogenously distributed, this risk factor did not show to be a significant predictor of hypertension. The extent to which hypertension is influenced by traditional CVD risk factors as well as by some SES indicators was also assessed using a forward stepwise method of the multivariate logistic analysis. Each risk factor was explored as quantitative variable as well as qualitative one using various cut-offs. The best model showed to be the one having age and BMI presented as quantitative variables and sex, region, smoking status, income and schooling years as categorical ones; with cut-off 3 for number of income sources and 8 for the number of schooling years. In spite of the low prevalence of hypertension, the presented results are showing that Bayash Roma are bearing a high CVD risk factors load. We expect that with westernization of their life-style and along with increase of the economic power, the proportion of CVD in population of Bayash Roma will also increase. Therefore, it is important to recognize the need for early cardiovascular disease risk factors prevention in this minority population.

Abnormal systolic blood pressure during treadmill test and brachial artery flow-mediated vasodilatation impairment.

The aim of the study was to assess the relationship between systolic blood pressure during maximal treadmill test (SBP9mtt)) and flow-mediated vasodilation (FMD). Abnormal rise of SBP(mtt) is the phenomenon more frequent in hypertensive persons but it could be found in normotensive subjects too. 199 subjects referred to treadmill test were enrolled in the study. Four groups were formed: hypertensives with abnormal SBP(mtt) (group A), hypertensives with normal SBP(mtt) (group B), normotensives with abnormal SBP(mtt) (group C) and normotensives with normal SBP(mtt) (group D). Rise of SBP(mtt) above 200 mmHg was considered abnormal reaction. Simple linear regression analysis showed significant inverse relationship between SBP(mtt) and FMD (F = 20.2036, p < 0.001, R2 = 0.0956). Mean FMD index was worst in hypertensive subjects with abnormal SBP(mtt) (group A), followed by normotensives with abnormal SBP(mtt) (group C), hypertensives with normal SBP(mtt) (group B) and the best was in normotensives with normal SBP(mtt) (3.56 +/- 5.17, 4.19 +/- 5.14, 6.81 +/- 8.43 and 10.92 +/- 7.48%, respectively). In multivariate regression analysis FMD showed significant association with abnormal SBP(mtt) (p < 0.001) along with brachial artery diameter (p < 0.001), male gender (p < 0.001), but not with hypertension (p = 0.073), BMI (p = 0.137) and total cholesterol (p = 0.23) (coefficients: -0.26, -0.40, -0.27, -0.13, -0.11 and -0.07, respectively). There was a significant inverse relationship between SBP(mtt) and FMD. An impairment of FMD exists in normotensive subjects with abnormal SBP(mtt). In hypertensives with abnormal SBP(mtt) an additional impairment of FMD exists when compared to hypertensives with normal SBP(mtt). Abnormal SBP(mtt) should be taken into account in global cardiovascular risk assessment.