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Aims: Increased serum prolactin (PRL) concentrations have been associated with adverse cardiovascular risk profiles, but the relation between PRL and mortality risk is unknown., Methods and Results: We evaluated 3929 individuals (1946 men and 1983 women) aged 20-81 (mean 50.3 years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (sex-specific tertiles) serum PRL concentrations with all-cause and cause-specific mortality were analysed separately for men and women by age- and multivariable-adjusted Cox regression models. During a median follow-up period of 10.1 years (38 231 person-years), 419 deaths (10.7%), 132 cardiovascular deaths (3.4%), and 152 cancer deaths (3.9%) were observed. After multivariable adjustment, we observed a positive association of PRL with all-cause mortality in men and women [hazard ratio (HR) per SD increase: 1.17, 95% confidence interval (CI): 1.07-1.29 and HR: 1.22, 95% CI: 1.03-1.46, respectively]. Similarly, individuals with PRL concentrations in the highest tertile (when compared with lowest PRL tertile) experienced the highest mortality risk (men: HR, 1.75; 95% CI, 1.32-2.32; women: HR, 1.66; 95% CI, 1.08-2.56), with a significant trend across PRL tertiles (P- for trend <0.05). Cause-specific mortality analyses yielded similar associations for cardiovascular death in both sexes, but for cancer death only in men., Conclusion: This is the first study to report an independent positive association of PRL concentrations with all-cause and cardiovascular mortality. Further studies are required to confirm our findings and to elucidate the potential role of PRL as a useful biomarker of cardiovascular risk and mortality assessment.

Aim: To investigate molecular phenotypes of myocardial B19V-infection to determine the role of B19V in myocarditis and dilated cardiomyopathy (DCM)., Methods: Endomyocardial biopsies (EMBs) from 498 B19V-positive patients with myocarditis and DCM were analyzed using molecular methods and functional experiments. EMBs were obtained from the University Hospitals of Greifswald and Tuebingen and additionally from 36 German cardiology centers. Control tissues were obtained at autopsy from 34 victims of accidents, crime or suicide. Identification of mononuclear cell infiltrates in EMBs was performed using immunohistological staining. Anti-B19V-IgM and anti-B19V-IgG were analyzed by enzyme-linked immunosorbent assay (ELISA). B19V viral loads were determined using in-house quantitative real-time polymerase chain reaction (PCR). For B19V-genotyping a new B19V-genotype-specific restriction fragment length polymorphism (RFLP)-PCR was established. B19V-genotyping was verified by direct DNA-sequencing and sequences were aligned using BLAST and BioEdit software. B19V P6-promoter and HHV6-U94-transactivator constructs were generated for cell culture experiments. Transfection experiments were conducted using human endothelial cells 1. Luciferase reporter assays were performed to determine B19V-replication activity. Statistical analysis and graphical representation were calculated using SPSS and Prism5 software., Results: The prevalence of B19V was significantly more likely to be associated with inflammatory cardiomyopathy (iCMP) compared to uninflamed DCM (59.6% vs 35.3%) (P < 0.0001). The detection of B19V-mRNA replication intermediates proved that replication of B19V was present. RFLP-PCR assays showed that B19V-genotype 1 (57.4%) and B19V-genotype 2 (36.7%) were the most prevalent viral genotypes. B19V-genotype 2 was observed more frequently in EMBs with iCMP (65.0%) compared to DCM (35%) (P = 0.049). Although there was no significant difference in gender-specific B19V-loads, women were more frequently infected with B19V-genotype 2 (44.6%) than men (36.0%) (P = 0.0448). Coinfection with B19V and other cardiotropic viruses was found in 19.2% of tissue samples and was associated with higher B19V viral load compared to B19V-monoinfected tissue (P = 0.0012). The most frequent coinfecting virus was human herpes virus 6 (HHV6, 16.5%). B19V-coinfection with HHV6 showed higher B19V-loads compared to B19V-monoinfected EMBs (P = 0.0033), suggesting that HHV6 had transactivated B19V. In vitro experiments confirmed a 2.4-fold increased B19V P6-promoter activity by the HHV6 U94-transactivator., Conclusion: The finding of significantly increased B19V loads in patients with histologically proven cardiac inflammation suggests a crucial role of B19V-genotypes and reactivation of B19V-infection by HHV6-coinfection in B19V-associated iCMP. Our findings suggest that B19V-infection of the human heart can be a causative event for the development of an endothelial cell-mediated inflammatory disease and that this is related to both viral load and genotype.

Background: Currently, many methods for quantitation of coronary collateral function are based on intracoronary pressure measurements distal of an occluded balloon, which do not fully account for the dynamic nature of collateral flow. Therefore, a flow-based parameter of coronary collateral function based upon principles of thermodilution was evaluated., Methods: In 26 patients with a high-grade coronary artery stenosis, intracoronary hemodynamics were analyzed by the RadiAnalyzer system (St Jude Medical), including fractional flow reserve (FFR), index of microcirculatory resistance (IMR), and the pressure-based collateral flow index (CFI) during balloon occlusion and hyperemia (intravenous adenosine). Moreover, immediately after an intracoronary bolus of room-temperature saline, the balloon was occluded and the intracoronary temperature distal to the balloon was analyzed over time. The slope of the temperature-time curve was calculated after logarithmic transformation as an index of collateral blood flow (CBFI)., Results: The coefficient of variation between two measurements of CBFI amounted to 11 ± 2%. In patients with CFI ≥0.25, CBFI amounted to 0.55 ± 0.09, whereas in those with CFI <0.25, CBFI was 0.37 ± 0.03. CBFI correlated significantly with CFI (r = 0.65; P<.001). Interestingly, in the subgroup with IMR below the median (<14.2 mm Hg · s), the slope of the linear regression for CBFI vs CFI was steeper than in individuals with higher IMR, which indicates more effective collateral flow for any given intracoronary pressure distal to the occluded balloon in the group with lower microvascular resistance., Conclusions: This novel index might be useful as a flow-based index of collateral function, and should be evaluated in further studies.

Auto-antibodies against cardiac proteins have been described in patients with dilated cardiomyopathy. Antibodies against the C-terminal part of KChIP2 (anti-KChIP2 [C-12]) enhance cell death of rat cardiomyocytes. The underlying mechanisms are not fully understood. Therefore, we wanted to explore the mechanisms responsible for anti-KChIP2-mediated cell death. Rat cardiomyocytes were treated with anti-KChIP2 (C-12). KChIP2 RNA and protein expressions, nuclear NF-κB, mitochondrial membrane potential Δψm, caspase-3 and -9 activities, necrotic and apoptotic cells, total Ca(2+) and K(+) concentrations, and the effects on L-type Ca(2+) channels were quantified. Anti-KChIP2 (C-12) induced nuclear translocation of NF-κB. Anti-KChIP2 (C-12)-treatment for 2 h significantly reduced KChIP2 mRNA and protein expression. Anti-KChIP2 (C-12) induced nuclear translocation of NF-κB after 1 h. After 6 h, Δψm and caspase-3 and -9 activities were not significantly changed. After 24 h, anti-KChIP2 (C-12)-treated cells were 75 ± 3% necrotic, 2 ± 1% apoptotic, and 13 ± 2% viable. Eighty-six ± 1% of experimental buffer-treated cells were viable. Anti-KChIP2 (C-12) induced significant increases in total Ca(2+) (plus 11 ± 2%) and K(+) (plus 18 ± 2%) concentrations after 5 min. Anti-KChIP2 (C-12) resulted in an increased Ca(2+) influx through L-type Ca(2+) channels. In conclusion, our results suggest that anti-KChIP2 (C-12) enhances cell death of rat cardiomyocytes probably due to necrosis., (© 2013 Wiley Periodicals, Inc.)

Objectives: Our goal was to validate an educational 90-min minicourse in lower-irradiating cardiac invasive techniques., Background: Despite comprehensive radiation safety programs, patient radiation exposure in invasive cardiology remains considerable., Methods: Before and at a median period of 3.7 months after the minicourse at 32 German cardiac centers, 177 interventionalists consistently documented radiation parameters for 10 coronary angiographies: dose area product (DAP), radiographic and fluoroscopic fractions, fluoroscopy time, and number of radiographic frames and runs., Results: A total of 154 cardiologists attended the minicourse and achieved significant (p < 0.001) decrease in patients' median overall DAP (-48.4%), from baseline 26.5 to 13.7 Gy × cm(2). They reduced fluoroscopy times (-20.8%), radiographic runs (-9.1%), frames/run (-18.6%) and frames (-29.6%), and both radiographic DAP/frame (-27.4%) and fluoroscopic DAP/s (-39.3%), which indicate improved collimation, reduced-irradiation angulations, or adequate image quality. Dose-related parameters for the remaining 23 invited cardiologists unable to attend the workshop did not change significantly in univariate comparison. Multilevel analysis (p < 0.001) confirmed the efficacy of the minicourse itself (-14.7 Gy × cm(2)) and revealed higher DAP for increasing body mass index (+1.5 Gy × cm(2) per kg/m(2)), male sex (+5.8 Gy × cm(2)), age (+1.5 Gy × cm(2)/decade), and-owing to different settings during image acquisition-for advanced flat-panel detector systems (+9.0 Gy × cm(2)) versus older, traditional image intensifier systems., Conclusions: Despite significant required training in radiation safety for all interventional cardiologists, the presented additional 90-min minicourse significantly reduced patient dose., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk., Background: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored., Methods: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases)., Results: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements., Conclusions: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM., Methods and Results: Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors., Conclusion: The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Aiming at a speed up of the re-endothelialization process of biodegradable endovascular implants, novel approaches for the functionalization of poly(l-lactide) (PLLA) with anti-CD34 antibodies were established. We propose a three-step process involving PLLA surface activation with functional amino groups, attachment of a protein repelling peptide spacer, and covalent random or site-selective immobilization of the antibodies. Obtainable antibody surface densities and antigen binding capacities were thoroughly evaluated by means of enzyme-linked immunosorbent assay. Results indicate that a lower amount of anchoring sites on the antibody favors high coupling efficiency, while localization of the anchoring sites, facing the antigen binding moiety, strongly enhances the antigen capture capacity of the support. Besides minimization of physisorption and cell adhesion exemplarily shown with bovine serum albumin, avidin, and human umbilical vein endothelial cells, respectively, the inclusion of the protein-repelling spacer strengthened this effect, yielding antigen capture capacities exceeding values so far reported in literature. In contrast, the number of amino groups on the PLLA surfaces, which is indeed highly dependent on the applied activation procedure, does not seem to influence antibody coupling efficiency and antigen capture capacity considerably. This allows the choice of surface activation treatment, plasma or wet-chemical, regarding other processing parameters as for instance sterilizability or favored modification depth., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM., Methods and Results: Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R(2)=0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions., Conclusions: Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.

Background: Previous studies suggested an impaired endothelial function in patients with diabetes. However, the validity of this finding may be limited by the lack of adequate adjustment for further cardiovascular confounders. We assessed endothelial function as measured by flow-mediated dilation (FMD) of the brachial artery in patients with either type 1 or type 2 diabetes in comparison with non-diabetic controls., Methods: The study population comprised 1487 subjects including 122 subjects with type 2 diabetes, aged 25 to 85, from the population-based Study of Health in Pomerania, and 65 outpatients, aged 23 to 75, with type 1 diabetes. FMD measurements were performed using standardized ultrasound techniques. Subjects with type 1 and type 2 diabetes were matched 1:4 to healthy controls using propensity score matching., Results: Neither type 1 diabetes (β = 0.142; SE = 0.568, p = 0.803) nor type 2 diabetes (β = 0.107; SE = 0.340, p = 0.752) were significantly associated with FMD in comparison with their non-diabetic controls after adjustment for major cardiovascular confounders like age, gender, body mass index, smoking status, hypertension, antihypertensive medication, LDL and HDL cholesterol levels., Conclusions: In this population-based study comparing adjusted FMD values of diabetic individuals with adequately matched controls, propensity score analyses revealed no association between diabetes and endothelial function. Since these findings are in discordance with the majority of previous reports, we suggest performing similar analyses using data from other population-based studies.

This study aimed to assess the potential association of periodontal diseases with lung volumes and airflow limitation in a general adult population. Based on a representative population sample of the Study of Health in Pomerania (SHIP), 1463 subjects aged 25-86 years were included. Periodontal status was assessed by clinical attachment loss (CAL), probing depth and number of missing teeth. Lung function was measured using spirometry, body plethysmography and diffusing capacity of the lung for carbon monoxide. Linear regression models using fractional polynomials were used to assess associations between periodontal disease and lung function. Fibrinogen and high-sensitivity C-reactive protein (hs-CRP) were evaluated as potential intermediate factors. After full adjustment for potential confounders mean CAL was significantly associated with variables of mobile dynamic and static lung volumes, airflow limitation and hyperinflation (p<0.05). Including fibrinogen and hs-CRP did not change coefficients of mean CAL; associations remained statistically significant. Mean CAL was not associated with total lung capacity and diffusing capacity of the lung for carbon monoxide. Associations were confirmed for mean probing depth, extent measures of CAL/probing depth and number of missing teeth. Periodontal disease was significantly associated with reduced lung volumes and airflow limitation in this general adult population sample. Systemic inflammation did not provide a mechanism linking both diseases.

Objective: Data mining represents an alternative approach to identify new predictors of multifactorial diseases. This work aimed at building an accurate predictive model for incident hypertension using data mining procedures., Methods: The primary study population consisted of 1605 normotensive individuals aged 20-79 years with 5-year follow-up from the population-based study, that is the Study of Health in Pomerania (SHIP). The initial set was randomly split into a training and a testing set. We used a probabilistic graphical model applying a Bayesian network to create a predictive model for incident hypertension and compared the predictive performance with the established Framingham risk score for hypertension. Finally, the model was validated in 2887 participants from INTER99, a Danish community-based intervention study., Results: In the training set of SHIP data, the Bayesian network used a small subset of relevant baseline features including age, mean arterial pressure, rs16998073, serum glucose and urinary albumin concentrations. Furthermore, we detected relevant interactions between age and serum glucose as well as between rs16998073 and urinary albumin concentrations [area under the receiver operating characteristic (AUC 0.76)]. The model was confirmed in the SHIP validation set (AUC 0.78) and externally replicated in INTER99 (AUC 0.77). Compared to the established Framingham risk score for hypertension, the predictive performance of the new model was similar in the SHIP validation set and moderately better in INTER99., Conclusion: Data mining procedures identified a predictive model for incident hypertension, which included innovative and easy-to-measure variables. The findings promise great applicability in screening settings and clinical practice.

According to the current WHO classification of cardiomyopathies, myocarditis is an inflammatory disease of the myocardium and is diagnosed by endomyocardial biopsy using established histological, immunological and immunohistochemical criteria; it may be idiopathic, infectious or autoimmune and may heal or lead to dilated cardiomyopathy (DCM). DCM is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic, viral and/or immune. The diagnosis of DCM requires exclusion of known, specific causes of heart failure, including coronary artery disease. On endomyocardial biopsy, there is myocyte loss, compensatory hypertrophy, fibrous tissue and immunohistochemical findings consistent with chronic inflammation (myocarditis) in 30-40 % of cases. In a patient subset, myocarditis and DCM represent the acute and chronic stages of an inflammatory disease of the myocardium, which can be viral, post-infectious immune or primarily organ-specific autoimmune. Here, we review the clinical presentation, etiopathogenetic diagnostic criteria, and management of immune-mediated and autoimmune myocarditis.

Background: The effects of smoking on central aortic pressures and the age-related increase in left ventricular mass (LVM) are largely unknown. We studied the relationship between smoking, arterial distensibility, central aortic pressures and left ventricular mass in two population-based studies., Methods: Data was obtained from two German population-based studies (KORA and SHIP, participants' ages 25-84 years). We identified 114 normotensive current smokers and 185 normotensive all-time non-smokers in KORA as well as 400 and 588 such individuals in SHIP. Echocardiographic LVM was obtained at baseline (T0) and follow-up after ten years (T1) in KORA and at follow-up (T1) in SHIP. Additionally, pulse-wave analysis-based central aortic pressure and augmentation index (AIx) were measured at T1 in KORA., Results: Cross-sectional analysis, using KORA T0 and SHIP T1, revealed in both studies a higher covariate-adjusted LVM and left ventricular mass index (LVMI) in smokers as compared with non-smokers. Moreover, in the KORA T1 examination, the smokers demonstrated a more pronounced increase, relative to baseline, of LVM (+13.5%) and LVMI (+13.4%) compared to non-smokers (+8.59% and +8.65%; p=0.036 and 0.042, respectively). Additionally, at KORA T1 smokers had a higher central systolic blood pressure and higher AIx than non-smokers (p=0.012 and p=0.001, respectively)., Conclusions: The difference in central aortic pressure due to enhanced and more prolonged wave reflection may explain our finding of a further pronounced increase in left ventricular wall thickness and mass over time in smokers., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Atrial fibrillation (AF) is characterized by electrical and structural remodeling of the atria with atrial fibrosis being one hallmark. Angiotensin II (AngII) is a major contributing factor and blockage of its type I receptor (AT1R) prevents remodeling to some extent. Here we explored the effects of the AT1R antagonist irbesartan on global gene expression and profibrotic signaling pathways after induction of rapid atrial pacing (RAP) in vivo in pigs., Methods and Results: Microarray-based RNA profiling was used to screen left atrial (LA) tissue specimens for differences in atrial gene expression in a model of acute RAP. RAP caused an overall expression profile that reflected AngII-induced ROS production, tissue remodeling, and energy depletion. Of special note, the mRNA levels of EDN1, SGK1, and CTGF encoding pro-endothelin, stress- and glucocorticoid activated kinase-1, and of connective tissue growth factor were identified to be significantly increased after 7h of rapid pacing. These specific expression changes were additionally validated by RT-qPCR or immunoblot analyses in LA, RA, and partly in LV samples. All RAP-induced differential gene expression patterns were partially attenuated in the presence of irbesartan. Similar results were obtained after RAP of HL-1 cardiomyocytes in vitro. Furthermore, exogenously added endothelin-1 (ET1) induced CTGF expression concomitant to the transcriptional activation of SGK1 in HL-1 cells., Conclusions: RAP provokes substantial changes in atrial and ventricular myocardial gene expression that could be partly reversed by irbesartan. ET1 contributes to AF-dependent atrial fibrosis by synergistic activity with AngII to stimulate SGK1 expression and enhance phosphorylation of the SGK1 protein which, in turn, induces CTGF. The latter has been consistently associated with tissue fibrosis. These findings suggest ETR antagonists as being beneficial in AF treatment., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Multiple sclerosis (MS) starting in childhood and adolescence poses a challenge for diagnosis and management of the disease. The aim of the present study was to assess the characteristics of early onset MS in Brazilian patients. Methods Retrospective data collection from specialized MS units. Results From 20 MS units in 11 Brazilian states, 117 cases of MS starting before the age of 18 years were collected. These patients had an average of 10 years of disease duration, still typically with low disability and one relapse every 2.5 years. The mean age for disease onset was 13.7 years. Conclusion The present study introduces a large series of Brazilian cases of pediatric MS. Although some patients presented a very severe form of MS, on the whole the group of patients with MS starting in childhood or adolescence presented a relatively mild form of this disease in Brazil.

Less than a hundred cases of pregnancies in women with neuromyelitis optica (NMO) have been published in the world. The aim of the present study was to add the Brazilian experience to this subject. Cases of women with NMO who became pregnant, or who developed NMO soon after pregnancy, were included. Retrospective analysis of medical data from these patients was carried out by the neurologist responsible for the case. Seventeen cases of pregnancies (16 full-term pregnancies, one miscarriage) were identified. The relapse rate of demyelinating events in the first trimester after pregnancy was significantly higher than at any other time. Disability progression was significantly worse 1 year after delivery. Pregnancy negatively influenced the disease course of NMO in these women. These results are similar to those of other authors, although the total number of cases so far described is still small. Obstetricians must be aware of the potential complications of a pregnancy in a woman who has NMO.

Background: The impact of white blood cell count (WBCc) on the outcome of patients with non-ischemic left ventricular (LV) dysfunction is unknown. In the present study we investigated the influence of WBCc on mortality and cardiac inflammation in patients with reduced LV systolic function in the absence of ischemic or valvular etiology., Methods and Results: We included 381 patients with reduced left ventricular (LV) ejection fraction (LVEF ≤ 45%) quantified by two-dimensional echocardiography. Coronary artery disease and valvular diseases were excluded by angiography and echo, respectively, in all patients. WBCc was quantified routinely upon first hospital admission. In 291 patients, endomyocardial biopsies from the right ventricle were performed upon first hospital admission for assessment of cardiac inflammation. Follow-up was up to 5.5 years (median 2.93 [1.7;4.0]). Information on vital status of patients was obtained from official resident data files. WBCc >11 Gpt/l was associated with significantly increased mortality in patients with severe LV dilation (end-diastolic diameter (LVEDD) >70 mm quantified by echocardiography) in comparison to patients showing WBCc ≤ 11 Gpt/l (41.7% vs 13.6%, p=0.02). Multivariable Cox regression analysis showed that WBCc predicts mortality independently of other cardiovascular risk factors and LVEF (hazard ratio 1.14; p=0.04). Doses of heart failure medication did not differ significantly in patients with LVEDD >70 mm and WBCc >11 Gpt/l when compared to LVEDD >70 mm and WBCc ≤ 11 Gpt/l (percent of maximum doses: ß-blockers p=0.51, ACE inhibitors p=0.56, AT1 antagonists p=0.77, aldosterone antagonists p=0.35). WBCc including its subpopulations (monocytes, lymphocytes and granulocytes) did not show a significant correlation with cardiac amounts of CD3(+)-lymphocytes (r=0.02, p=0.78) or CD68(+)-macrophages (r=1.0, p=0.09) (n=291)., Conclusion: WBCc at first hospital admission predicts long term-mortality in patients with dilated cardiomyopathy independently of cardiovascular risk factors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular disease in the general population and in patients with chronic kidney disease. The objective of this study was to investigate the association of estimated glomerular filtration rate (eGFR) with left ventricular mass index (LVMI), LVH and left ventricular geometry. A question of clinical relevance is whether estimated glomerular filtration rate based on cystatin C (eGFRcystatinC) is a better marker for cardiovascular risk than estimated glomerular filtration rate based on creatinine (eGFRcreatinine)., Methods: The study sample included 2830 individuals from the population-based Study of Health in Pomerania (SHIP). LVH was defined as echocardiographic LVMI >48 g/m(2.7) in men and >44 g/m(2.7) in women. Kidney function, as assessed by eGFR, was determined from established equations: the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and a cystatin-based multivariable equation., Results: We found an inverse association between eGFR and LVMI. This association was stronger in models with eGFRcystatinC than in models with eGFRcreatinine. Subjects with moderately-to-severely decreased kidney function (defined as eGFR 15-<60 mL/min per 1.73 m(2)) had higher odds for abnormal geometric patterns of the left ventricle than subjects with normal eGFR when eGFRcystatinC was used., Conclusions: The findings suggest that eGFRcystatinC is superior to eGFRcreatinine for assessing the risk of cardiovascular disease., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess whether the month of birth in different latitudes of South America might influence the presence or severity of multiple sclerosis (MS) later in life., Methods: Neurologists in four South American countries working at MS units collected data on their patients' month of birth, gender, age, and disease progression., Results: Analysis of data from 1207 MS patients and 1207 control subjects did not show any significant variation in the month of birth regarding the prevalence of MS in four latitude bands (0-10; 11-20; 21-30; and 31-40 degrees). There was no relationship between the month of birth and the severity of disease in each latitude band., Conclusion: The results from this study show that MS patients born to mothers who were pregnant at different Southern latitudes do not follow the seasonal pattern observed at high Northern latitudes.

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

Background: Besides their prognostic impact blood pressure and peak heart rate are widely used endpoint parameters for incremental exercise tests. Reference equations and ranges on both are sparse., Objective: This study aims to describe prediction equations and reference ranges for systolic and diastolic blood pressure as well as for peak heart rate assessed during a symptom limited incremental exercise test based on a population based study--the Study of Health in Pomerania., Design: For this purpose, 1708 individuals aged 25-85 years underwent cardiopulmonary exercise testing., Results: After exclusion of subjects with cardiopulmonary diseases and antihypertensive medications regression analyses revealed age, sex and body mass index as statistically significant interfering factors. In accordance, prediction equations and reference ranges for blood pressure and peak heart rate with respect to sex, age and BMI have been established., Conclusion: This study provides a reliable set of prediction equations for blood pressure and heart rate values at peak exercise, assessed in a general population over a wide age range., (Copyright © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Purpose: To validate the long-term efficacy of a 90-min. educational mini-course in less-irradiating cardiac interventional techniques., Materials and Methods: Before, two months after, and two years after the mini-course (periods I, II, and III), we analyzed the following radiation dose parameters for ten coronary angiographies (CA), performed by each of 7 cardiologists: total dose-area product (DAP), radiographic and fluoroscopic DAP fractions, number of radiographic frames and runs, and fluoroscopy time., Results: The median patient DAP for periods I, II and III was 31.4, 15.8 and 8.5 Gy × cm2, respectively. The long-term effect was related to shorter median fluoroscopy times (180, 172, and 120 s), shorter (57, 52, and 45) and fewer (12, 12, and 10) radiographic runs, consistent collimation and restriction to an adequate image quality. Both radiographic DAP/frame (28.7, 17.0, and 18.4 mGy × cm2) and fluoroscopic DAP/second (45.7, 24.2, and 10.0 mGy × cm2) decreased significantly. The multivariate linear regression analysis confirmed the increasing efficacy of the mini-course itself (-44.6 and -60.7%), and revealed a decreasing influence of the interventionalist's experience (-8.6% and -4.9% per 1,000 CAs, lifelong performed until the mini-course). The number of CAs performed after the mini-course did not influence the long-term DAP results., Conclusion: The presented educational mini-course allows a significant, long-lasting, and apparently ongoing reduction of patient radiation exposure due to CA. A self-surveillant documentation of relevant radiation parameters is well suited to monitor and improve each operator's individual long-term radiation-reducing efforts., (© Georg Thieme Verlag KG Stuttgart · New York.)

Unlabelled: The cellular uptake of oxidized low density lipoprotein (LDL) is mediated through the oxidized LDL receptor-1, LOX-1. We investigated whether circulating factors link LOX-1 expression in endothelial cells and impaired endothelium-dependent vasoreactivity (EDVR) as functional indicator of atherogenesis. EDVR was measured as flow-mediated dilation (FMD) of the brachial artery in 27 patients with a known history of cardiovascular disease. Human umbilical vein endothelial cells (HUVEC) were incubated with bradykinin or prostacyclin in the presence of tumour necrosis factor-alpha (TNF-α) or with serum of each patient for four hours. Total mRNA and protein extracts were analysed for LOX-1 and eNOS expression relative to the expression in medium-treated cells and corrected for GAPDH expression., Results: Prostacyclin and bradykinin did not modulate LOX-1 basal expression but were able to prevent significantly the up-regulation of LOX-1 expression by TNF-α, in HUVEC in vitro. Impaired EDVR was associated significantly with reduced endothelial nitric oxide synthase (eNOS) protein expression in HUVEC (r=0.788, P<0.001), diabetes (P=0.024), and smoking status (yes/no, P=0.047). In contrast, no such association was established with LOX-1 mRNA (r=0.292, P=0.138) or with LOX-1 protein expression in HUVEC (r=0.201, P=0.312)., Conclusions: Using a combination of in vitro experiments with in vivo measurements, we found no evidence that endothelial LOX-1 expression and EDVR mediated through circulating factors were associated.

Background: Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction., Methods and Results: Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min(-1)·m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m(-2); 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s(-1)·cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s(-1)·cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups., Conclusions: Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.

Background: A.BY/SnJ mice are used to study pathological alterations in the heart due to enteroviral infections. Since age is a well-known factor influencing the susceptibility of mice to infection, response to stress and manifestation of cardiovascular diseases, the myocardial proteome of A.BY/SnJ mice aged 1 and 4 months was comparatively studied using two dimensional-differential in-gel electrophoresis (2D-DIGE) and liquid chromatography tandem mass spectrometry (LC-MS/MS)., Results: Complementary analyses by 2D-DIGE and gel-free LC-MS/MS revealed 96 distinct proteins displaying age associated alterations in their levels. Proteins related to protein transport, and transport chain, lipid metabolism and fatty acid transport showed significant changes in 4 months old mouse hearts compared to juvenile hearts. Proteins involved in lipid metabolism and transport were identified at significantly higher levels in older mice and dysregulation of proteins of the respiratory transport chain were observed., Conclusion: The current proteomics study discloses age dependent changes occurring in the hearts already in young mice of the strain A.BY/SnJ. Besides alterations in protein transport, we provide evidence that a decrease of ATP synthase in murine hearts starts already in the first months of life, leading to well-known low expression levels manifested in old mice thereby raising the possibility of reduced energy supply. In the first few months of murine life this seems to be compensated by an increased lipid metabolism. The functional alterations described should be considered during experimental setups in disease related studies.

Exercise capacity and survival of patients with IPF is potentially impaired by pulmonary hypertension. This study aims to investigate diagnostic and prognostic properties of gas exchange during exercise and lung function in IPF patients with or without pulmonary hypertension. In a multicentre setting, patients with IPF underwent right heart catheterization, cardiopulmonary exercise and lung function testing during their initial evaluation. Mortality follow up was evaluated. Seventy-three of 135 patients [82 males; median age of 64 (56; 72 years)] with IPF had pulmonary hypertension as assessed by right heart catheterization [median mean pulmonary arterial pressure 34 (27; 43) mmHg]. The presence of pulmonary hypertension was best predicted by gas exchange efficiency for carbon dioxide (cut off ≥152% predicted; area under the curve 0.94) and peak oxygen uptake (≤56% predicted; 0.83), followed by diffusing capacity. Resting lung volumes did not predict pulmonary hypertension. Survival was best predicted by the presence of pulmonary hypertension, followed by peak oxygen uptake [HR 0.96 (0.93; 0.98)]. Pulmonary hypertension in IPF patients is best predicted by gas exchange efficiency during exercise and peak oxygen uptake. In addition to invasively measured pulmonary arterial pressure, oxygen uptake at peak exercise predicts survival in this patient population.

Background and Aims: Besides exercise intolerance, the assessment of ventilatory and perfusion adequacy allows additional insights in the disease pathophysiology in many cardiovascular or pulmonary diseases. Valid measurements of dead space/tidal volume ratios (VD/VT), arterial (a') - end-tidal (et) carbon dioxide (CO2) and oxygen (O2) pressure differences (p(a'-et)CO2) and (p(et-a')O2), and alveolar (A)-a' O2 pressure differences (p(A-a')O2) require using blood samples in addition to gas exchange analyses on a breath-by-breath-basis. Smoking and nutritional status are also important factors in defining disorders. Using a large healthy population we considered the impact of these factors to develop useful prediction equations., Methods and Results: Incremental cycle exercise protocols were applied to apparently healthy volunteer adults who did not have structural heart disease or echocardiographic or lung function pathologies. Age, height, weight, and smoking were analysed for their influence on the target parameters in each gender. Reference values were determined by regression analyses. The final study sample consisted of 476 volunteers (190 female), aged 25-85 years. Smoking significantly influences p(A-a')O2 and p(a'-et)CO2 at rest and peak exercise, and VD/VT during exercise. Obesity influences upper limits of VD/VT, p(a'-et)CO2 and p(et-a')O2 at rest as well as p(A-a')O2 and p(et-a')O2 at exercise. Reference equations for never-smokers as well as for apparently healthy smokers considering influencing factors are given., Conclusion: Gender, age, height, weight, and smoking significantly influence gas exchange. Considering all of these factors this study provides a comprehensive set of reference equations derived from a large number of participants of a population-based study., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The primary goals of personalized medicine are to optimize diagnostic and treatment strategies by tailoring them to the specific characteristics of an individual patient. In this Review, we summarize basic concepts and methods of personalizing cardiovascular medicine. In-depth characterization of study participants and patients in general practice using standardized methods is a pivotal component of study design in personalized medicine. Standardization and quality assurance of clinical data are similarly important, but in daily practice imprecise definitions of clinical variables can reduce power and introduce bias, which limits the validity of the data obtained as well as their potential clinical applicability. Changes in statistical methods with personalized medicine include a shift from dichotomous outcomes towards continuously measured variables, predictive modelling, and individualized medical decisions, subgroup analyses, and data-mining strategies. A variety of approaches to personalized medicine exist in cardiovascular research and clinical practice that might have the potential to individualize diagnostic and therapeutic procedures. For some of the emerging methods, such as data mining, the most-efficient way to use these tools is not yet fully understood. In addition, the predictive models-although promising-are far from mature, and are likely to be greatly improved by using available large-scale data sets.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Dilated cardiomyopathy (DCM) is one of the main causes for heart failure in younger adults. Although genetic disposition and exposition to toxic substances are known causes for this disease in about one third of the patients, the origin of DCM remains largely unclear. In a substantial number of these patients, autoantibodies against cardiac epitopes have been detected and are suspected to play a pivotal role in the onset and progression of the disease. The importance of cardiac autoantibodies is underlined by a hemodynamic improvement observed in DCM patients after elimination of autoantibodies by immunoadsorption. A variety of specific antigens have already been identified and antibodies against these targets may be detected by immunoassays. However, these assays cannot discriminate between stimulating (and therefore functionally effective) and blocking autoantibodies. There is increasing evidence that this distinction is crucial. It can also be assumed that the targets for a number of cardiotropic antibodies are still unidentified and therefore cannot be detected by immunoassays. Therefore, we established a method for the detection of functionally active cardiotropic antibodies, independent of their respective antigen. The background for the method is the high homology usually observed for functional regions of cardiac proteins in between mammals. This suggests that cardiac antibodies directed against human antigens will cross-react with non-human target cells, which allows testing of IgG from DCM patients on adult rat cardiomyocytes. Our method consists of 3 steps: first, IgG is isolated from patient plasma using sepharose coupled anti-IgG antibodies obtained from immunoadsorption columns (PlasmaSelect, Teterow, Germany). Second, adult cardiomyocytes are isolated by collagenase perfusion in a Langendorff perfusion apparatus using a protocol modified from previous works. The obtained cardiomyocytes are attached to laminin-coated chambered coverglasses and stained with Fura-2, a calcium-selective fluorescent dye which can be easily brought into the cell to observe intracellular calcium (Ca(2+)) contents. In the last step, the effect of patient IgG on the cell shortening and Ca(2+) transients of field stimulated cardiomyocytes is monitored online using a commercial myocyte calcium and contractility monitoring system (IonOptix, Milton, MA, USA) connected to a standard inverse fluorescent microscope.

Aims: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG., Methods and Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only., Conclusion: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.

Aims: Autoantibodies against second extracellular loops of β(1)-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function., Methods and Results: IgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β(1)-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed., Conclusions: (i) Autoantibodies trigger conformation changes in the β(1)-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels.

An early response to high arterial pressure is the development of cardiac hypertrophy. Functional and transcriptional regulation of ion channels and Ca(2+) handling proteins are involved in this process but the relative contribution of each is unclear. In this study, we investigated the expression of genes involved in action potential generation and Ca(2+) homeostasis of cardiomyocytes in hypertensive cyp1a1ren-2 transgenic rats. In this model, the transgene prorenin was induced by indole-3-carbinol for 2 weeks allowing the induction of hypertension. Electrophysiological recordings from cardiomyocytes of hypertensive rats revealed a slight increase in membrane capacitance consistent with cellular hypertrophy. L-type calcium current density was reduced by 30%. Left ventricles of hypertensive rats showed a significant increase in transcript and protein levels of the cation channel TRPC6 and FK506-binding protein, whereas levels of SERCA2 and voltage-dependent potassium channels K(v)4.2 and K(v)4.3 were found to be decreased. Further, a marked nuclear localization of the transcription factors GATA4 and NFATC4 was observed in cardiac tissue of hypertensive rats. The cyp1a1ren-2 transgenic rat thus appears to be a valid model to investigate early changes in cardiac hypertrophy. This study points to roles for TRPC6, FK506BP, SERCA2, K(v)4.2, and K(v)4.3 in the development of cardiac hypertrophy.

Background and Objective: Women with multiple sclerosis (MS) who intend to get pregnant are often advised to discontinue disease modifying therapy (DMT) prior to conception. This recommendation is not based on medical evidence and may interfere with disease control by immunomodulatory drugs. The present study was designed to help discuss the effect of DMT for MS on pregnancy and on disease course., Patients and Methods: Retrospective data from 152 pregnancies of 132 women with MS were collected by the physician in charge of the case. All data were entered into a specific file for qualitative and quantitative statistical analysis., Results: From the total group of patients, 89 pregnancies occurred without any exposure to MS drugs, while 61 pregnancies occurred with at least eight weeks of exposure to MS immunomodulatory drugs. The rate of obstetric and neonatal complications was similar in both groups, except for the newborn weight and height which was smaller for mothers receiving medications. Mothers' post-delivery relapse rate and EDSS scores in the follow-up period were significantly higher in the absence of treatment., Conclusion: It is possible that, with further such supportive data, international guidelines on MS treatment in young women who intend to get pregnant may need to be revised., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: The aim of this exploratory, cross-sectional study was to evaluate pain in sickle cell disease patients and aspects related to primary healthcare., Methods: Data were obtained through home interviews. The assessment instruments (body diagram, Numerical Pain Scale, McGill Pain Questionnaire) collected information on the underlying disease and on pain. Data were analyzed using the Statistical Package for Social Sciences program for Windows. Associations between the subgroups of sickle cell disease patients (hemoglobin SS, hemoglobin SC, sickle β-thalassemia and others) and pain were analyzed using contingency tables and non-parametric tests of association (classic chi-square, Fisher's and Kruskal-Wallis) with a level of 5% (p-value < 0.05) being set for the rejection of the null hypothesis., Results: Forty-seven over 18-year-old patients with sickle cell disease were evaluated. Most were black (78.7%) and female (59.6%) and the mean age was 30.1 years. The average number of bouts of pain annually was 7.02; pain was predominantly reported by individuals with sickle cell anemia (hemoglobin SS). The intensity of pain (Numeric Pain Scale) was 5.5 and the quantitative index (McGill) was 35.9. This study also shows that patients presented a high frequency of moderately painful crises in their own homes., Conclusion: According to these facts, it is essential that pain related to sickle cell disease is properly identified, quantified, characterized and treated at the three levels of healthcare. In primary healthcare, accurate measurement of pain combined with better care may decrease acute painful episodes and consequently minimize tissue damage, thus improving the patient's overall health.

Background and Objective: The assessment of static lung volumes and airway resistance is a frequently performed diagnostic procedure and considered as an important tool in medical surveillance to detect pulmonary diseases. The objectives of the study are to establish reference equations for body plethysmographic parameters in a representative adult population across a wide age range and to compare the normative values from this sample with previous ones., Methods: Body plethysmography was applied in 1809 participants (885 males) of a cross-sectional, population-based survey (Study of Health in Pomerania). Individuals with cardiopulmonary disorders and/or a pack-year smoking history >10 years and participants with a body mass index >30 kg/m(2) were excluded. In total, 686 healthy individuals (275 males) aged 25-85 years were assessed., Results: Prediction equations for both genders were established by quantile regression analysis taking into account the influence of age, height and weight., Conclusions: The study provides a novel set of prediction equations for static lung volumes and airway resistance obtained using body plethysmography. Compared with our findings, existing equations underestimated some normal values. The results emphasize the need for up-to-date reference equations., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

The interpretation of gas exchange measured by cardiopulmonary exercise testing (CPET) depends on reliable reference values. Within the population based Study of Health in Pomerania (SHIP) CPET was assessed in 1706 volunteers. The assessment based on symptom limited exercise tests on a bicycle in a sitting position according to a modified Jones protocol. CPET was embedded in an extensive examination program. After the exclusion of active smokers and volunteers with evidence of cardiopulmonary and musculoskeletal disorders the reference population comprised 616 healthy subjects (333 women) aged 25 to 85 years. Reference equations including upper and/or lower limits based on quantile regression were assessed. All values were corrected for the most important influencing factors.This study provides reference equations for gas exchange and exercise capacity assessed within a population in Germany., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Across the industrialized world, men experience an earlier onset of cardiovascular disease (CVD) and a life expectancy 5 to 10 years shorter than women. Low total testosterone (TT) concentrations in men have been suggested as a novel CVD risk factor, but its contribution to this gender gap is less well studied., Methods: We used data of 4152 individuals (2113 women and 2039 men) aged 20 to 79 years from the longitudinal population-based cohort Study of Health in Pomerania, Germany. Multivariable Poisson and Cox proportional hazard regression models were used to investigate the risk of incident cardiovascular morbidity (5-year examination follow-up), as well as all-cause and CVD mortality (10-year follow-up) between men and women. Additionally, the added risk attributable to low TT in men (<10th percentile) was assessed., Results: Compared with women, men were uniformly at higher risk of incident cardiovascular morbidity, including overweight, hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. Men were also at increased all-cause mortality (hazard ratio = 2.05; 95% CI, 1.61-2.60) and 10-year CVD risk compared with women. In subgroup analyses, men with low TT showed the highest 10-year CVD and mortality risk compared with both men with higher TT and women. TT was also negatively associated with cardiovascular risk as defined by the Framingham risk score (P < 0.001), after multivariable adjustment., Conclusions: Analyzing a large population-based sample, we observed that men have a generally higher risk of incident cardiovascular morbidity and mortality. Furthermore, men with low TT concentrations were identified as high-risk individuals with regard to 10-year CVD and mortality risk., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Psoriasis has been associated with cardiovascular diseases, but its relationship to markers of subclinical atherosclerosis has not been fully elucidated. The aim of the study is to analyze the association of psoriasis with common carotid artery intima-media thickness (CCA-IMT) and plaque prevalence of the carotid arteries., Methods: Data of 1987 men and women aged 25-88 years from the population-based Study of Health in Pomerania (SHIP) in north-eastern Germany were used. Cross-sectional associations of psoriasis with IMT and carotid plaque prevalence were analyzed using linear and logistic regression models adjusted for relevant confounders (age, sex, smoking, alcohol consumption, waist circumference, physical activity, systolic blood pressure, anti-hypertensive medication, acetylsalicylic acid, HbA(1c), total/HDL cholesterol ratio, lipid-lowering medication)., Results: Psoriasis was associated with mean CCA-IMT, but not with carotid plaque prevalence. Comparisons between subjects with and without psoriasis showed an adjusted mean difference of the CCA-IMT of 0.016 mm (95% confidence interval [CI]: 0.004 mm-0.028 mm, p < 0.01) and an odds ratio for plaque prevalence of 1.12 (95% CI: 0.85-1.47) after adjusting for confounders., Conclusion: Our findings suggest that psoriasis is associated with increased carotid mean IMT and might therefore contribute to the atherosclerotic process and subsequent cardiovascular events., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Resident cardiac progenitor cells have emerged as a potential source of adult stem cells for regeneration of damaged myocardium. Sca-1 cells, expressing Stem cell antigen-1 as a cell surface marker, are multipotent cells that were shown to differentiate into different cell types i.e. cardiomyocytes. Previous studies have reported that Sca-1 positive cells are able to home to the injured heart. However, the mechanism of improving cardiac function is still unclear. In the current study, we have profiled the proteome and transcriptome of Sca-1 positive cells in comparison with other endogenous heart cell types to unravel the molecular phenotype of the progenitor cells. Among the 861 proteins identified with high confidence in total, 331 non-redundant proteins were overrepresented in Sca-1 positive cells. Highly abundant candidates were mostly associated with cell growth and proliferation, cell migration and cytoskeletal organization. Transcriptional profiling disclosed significant expression of surface antigens such as CD31, CD36, CD38, CD66a, CD102, and CD202B. Growth factors like KITL, JAG2, PDGFB and VEGFC showed a higher expression in Sca-1 progenitor cells than in Sca-1 negative cells. Selective candidates were validated by Western blotting. These global findings provide a basis for the study of their capability to participate in the cardiac regeneration process., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Objectives: This is an exploratory, descriptive and transversal study aiming to determine the prevalence, characterization, location, and measurement and discuss pharmacological analgesic measures for acute pain management in five inpatient wards of a university hospital., Method: We enrolled 856 subjects in the study, of whom 272 were in pain at the time. Information related to pain was obtained using a bedside structured interview. Numeric pain scale and body diagram were used., Results: Analgesia was assessed through medical records. The overall prevalence of pain was 31.8%, with severe pain in 44.2% and mean of 6.6 on numeric pain scale. The main reason was trauma and the most common site the abdomen. The most widely used analgesic was dipyrone (76.1%) with/without combination. Strong opioid was prescribed to 4.4%. For 27.5% there was no improvement., Conclusion: We conclude that pain is highly prevalent, poorly evaluated, undertreated, with inappropriate use of analgesics., (Copyright © 2012 Elsevier Editora Ltda. All rights reserved.)

The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.

Aims: Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD., Methods and Results: This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) ≤40% and mean pulmonary arterial pressure (PAP(mean)) ≥25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAP(mean), while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase., Conclusion: The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454.

Objective: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects., Methods: Data were obtained from the first follow-ups of the population-based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC., Results: The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects., Conclusions: A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.

Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the β-adrenergic (β-adrenoceptor) and M2 muscarinic receptor. β(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of β(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human β(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Background: Previous experimental and patient-based studies suggest that prolactin (PRL) and its 16 kDa fragment influence cardiovascular phenotypes by modulating angiogenesis. The association between serum PRL and cardiac remodeling in the general population is unknown., Methods: We evaluated 804 individuals (441 women) from the population-based Study of Health in Pomerania, aged ≥ 45 years, with available baseline serum PRL who underwent serial echocardiography at baseline and five-year follow-up. Left ventricular mass (LVM) was calculated and left ventricular hypertrophy (LVH) defined by sex-specific distributions of LVM. LV geometry was defined on the basis of relative wall thickness (RWT) and LVH. Sex-specific multivariable regression analyses were performed relating PRL (independent variable modelled as a continuous variable and as sex-specific quartiles) to change in LVM, RWT, and to incident LVH and abnormal geometry., Results: Baseline PRL concentrations were inversely associated with LVM change in men, but not in women (β per 10% decrease in PRL: 0.37; 95% CI, 0.13-0.60 in men and -0.02; 95% CI, -0.21 to 0.17 in women, respectively). In men, baseline PRL concentrations were also inversely associated with incident LVH [first vs. fourth PRL quartile: relative risk (RR) 2.26 (95% CI, 1.20-4.24)] and altered LV geometry on follow-up [RR for incident concentric hypertrophy per 10% decrease in PRL: 1.20 (95% CI, 1.06-1.37)]. None of the longitudinal associations were observed in women., Conclusion: We observed inverse associations of PRL with LVM change, incident LVH, and altered LV geometry in men, but not in women. Additional studies are warranted to confirm our findings and to elucidate the mechanisms underlying these sex-specific associations., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)