AIMS:The international-normalized-ratio (INR) is typically used to monitor patients on warfarin or related oral anticoagulant therapy. The aim of our study was to investigate the association of the INR with mortality in coronary artery disease (CAD) patients not on oral anticoagulant therapy.METHODS AND RESULTS:Between 1997 to 2000 the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study enrolled 3316 patients of German ancestry that had been referred for coronary angiography. We excluded patients on coumarin therapy (n = 222) and patients with an INR more than 5 standard deviations (SD) away from the mean (n = 30). During a median follow-up of 9.9 years, 884 patients died, 547 patients from cardiovascular causes. After adjustment for cardiovascular risk factors the INR was associated with all-cause mortality in all patients and the CAD positive group with HRs (95% CI) of 1.14(1.07-1.21) and 1.16(1.09-1.23) per 1-SD increase, respectively. Adjustment for NT-proBNP rendered the association insignificant.CONCLUSION:In LURIC, the INR was positively associated with mortality in patients with prevalent CAD not on oral anticoagulant therapy as well as in patients without CAD. Adjustment for NT-proBNP abolished the association suggesting clinical or subclinical heart failure strongly contributing to increased INR and higher mortality.

Objectives: The genetic origin of thoracic aortic aneurysm (TAA) is well known since 20% of all TAA-patients show a positive family history with co-segregation of causative mutations with disease. Currently, molecular screening of established disease genes discovers the causative mutation only in 20% of familial TAA-patients. Therefore testing is initiated only in a small proportion of patients. A large proportion of TAA-patients will die due to complications of aortic aneurysms. For these patients premature aortic repair is a powerful strategy to prevent acute dissection. To date, the diameter of the dilated aorta is used to decide on surgical intervention. In a German TAA-family we want to demonstrate the usefulness of molecular genetic analysis and mutation detection as an additional and more powerful tool in the assessment of the need for preventive aortic repair.

With the implementation of high-throughput sequencing protocols, the exhaustive scanning of known and candidate disease genes has become a feasible approach to genetic testing of patients with cardiomyopathy. A primary objective of the present study was to assess the performance characteristics of a 46-gene next-generation sequencing (NGS) assay that targets well-established cardiomyopathy genes. A total of 25 samples were analyzed. Twelve of those had previously been sequenced using resequencing arrays and served as reference samples for the assessment of the assay's performance characteristics. The remaining 13 samples were derived from consecutive patients. Both the analytical sensitivity and the specificity of the assay were 100% and the percentage of low-coverage bases was 0.4%, at an average read depth of 210×. In order to assess the diagnostic yield of the test, 13 consecutive samples representing cases of Dilated (n = 7), Hypertrophic (n = 4) and Left Ventricular Non-Compaction Cardiomyopathy (n = 2), were subjected to the 46-gene NGS assay. Including predicted pathogenic variants in the gene TTN, a total of 22 variants (11 novel) were detected in 10 patients, with a clear preponderance of variants of unknown pathogenicity (class 3 variants, 21/22, 95%). Of the seven DCM cases, two were digenic, involving variants in the genes MYH7 and RBM20 in one case and in DSP and TTN in the other case. Three other patients carried single TTN variants predicted to be pathogenic. Of the four HCM patients, one was trigenic (LAMA4, PKP2 and TTN) and three were digenic (DSP and TTN, MYH7 and NEXN, NEXN and TTN, respectively). As to LVNC, one of the two patients had one variant in the gene ABCC9 and two predicted pathogenic variants in the gene TTN. Strikingly, out of the thirteen investigated cases, only a single case exhibited a likely pathogenic or pathogenic variant justifying a positive test report. The percentage of inconclusive cases thus amounted to 69%. Three cases were devoid of any relevant variant. Two of these "negative" cases were subsequently taken to initially evaluate the use of an alternative NGS assay addressing 4813 genes previously implicated in genetic diseases (the so-called clinical exome). Although showing similar sensitivity and specificity values, the coverage of the 46 established cardiomyopathy genes was less efficient (low-coverage bases: 5%). In a case of DCM, the assay revealed a disruptive variant in the gene encoding the adrenoreceptor beta 2 (ADRB2), a protein implicated in signal transduction and energy metabolism in the heart. In conclusion, the 46 gene assay is applicable to routine genetic diagnostics of cardiomyopathy. The test detects many variants of unknown pathogenicity which need to be followed-up in order to gain benefit for the patients and their families. Samples devoid of any relevant variant may be subjected to a clinical exome assay, in order to identify interesting novel candidate genes.

Introduction: The recently launched TruSight ONE panel comprises 4812 genes and is meant to enable a one-for-all-mendelian-diseases genetic test.

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.

Aim: Chronic heart failure (CHF) is currently one of the most prevalent cardiac diseases. The present analysis sought to estimate the one-year disease-related resource use and associated management costs of patients with CHF differentiated according to patients with preserved (HFpEF) and reduced ejection fraction (HFrEF). This differentiation could be used to describe patients as having systolic heart failure (HFrEF) and diastolic heart failure (HFpEF). Today, there is still paucity of data concerning cost of illness in heart failure according to these subgroups. Subject and Methods: 4,714 individuals with heart failure (mean age 64.5 years ± 13.2, 31.2% female, NYHA I-IV) were included from the German Competence Network Heart Failure. Patients with an ejection fraction (EF) of less than 50% were assigned to the HFrEF group (n = 3.530, mean age 63.7 years ± 13.2, 23.8% female, NYHA I-IV), whereas those with an EF≥50% constituted the HFpEF group (mean age 66.8 years ± 13.0, 53.3% female, NYHA I-IV). Disease-related resource use was assessed with regard to outpatient contacts to physicians, hospitalizations, rehabilitation stays, and drug utilization for a period of 12 months. Costs refer to the year 2011. Results: During one year, the entire patient population had on average 5.3 contacts to the general practitioner, 1.8 contacts to cardiologists and 0.7 hospital stays per year. The analysis showed that patients with HFrEF had a significant higher resource use compared to patients with HFpEF: The HFrEF group consulted the general practitioner with 6.1 contacts significantly more often in comparison to patients with HFpEF, who had on average 2.9 contacts to the GP (p < 0.001). A similar result was also seen in cardiologist contacts: the mean number of contacts was 2.2 in the HFrEF group and 0.7 in the HFpEF group (p < 0.001). In addition, the mean number of hospital stays was 0.9 for patients with HFrEF and 0.3 for patients with HFpEF (p < 0.001). Overall disease-related care costs per patient were calculated at 2,845 € per year, while the costs of the HFrEF group were 3.373 € and 1.271 € in the HFpEF group (p < 0.001). The largest component of total costs in the HFrEF group related to hospitalizations (2,481 €, 74%), while costs of rehabilitation (344 €, 10%), outpatient contacts (279 €, 8%), and medication (268 €, 8%) were considerably lower. The percentage distribution was nearly the same in the two subgroups of patients with HFrEF and HFpEF. Therefore, hospital admissions accounted for 74% of the total costs with 941 € in the HFpEF group, too. Costs for rehabilitation stays were 116 € (9% of the total costs) in the HFpEF group, while 9% of the total costs related to outpatient contacts (111 €), and 8% to drug utilization with 104 €. Conclusion: The present analysis demonstrates a high disease-related resource use of heart failure care. In particular, patients with reduced ejection fraction require increased resources compared to patients with preserved ejection fraction. Inpatient resources are the largest component in heart failure care, irrespective of underlying HFrEF or HFpEF. Hence, improved treatment strategies need to be developed to optimize care thus reducing hospitalization rates.

Thoracic aortic aneurysm and dissection is associated with increasing mortality rate that may occur as part of a syndrome or as an isolated familial condition. Several genes have been implicated in causing TAAD, though an appropriate genetic test for their parallel testing is not yet available. Herein, we describe the novel 117-kb “MFSTAAD chip” that may help to understand the genetic basis of TAAD. A custom duplicate resequencing assay was developed to cover eight genes previously described in TAAD; FBN1, TGFBR1&2, COL3A1, MYH11, ACTA2, SLC2A10 and NOTCH1. GSEQ and SeqC software were used for data analysis. The analytical sensitivity of the assay was validated by the recognition of 182 known mutations (153 point mutations, 21 deletions, 7 insertions and 1 duplication) and a cohort of 28 patients were selected to determine the mutation yield, whereby 18 of them were previously negative for mutations in the genes FBN1 and TGFBR2. The assay had significantly higher sensitivity for point mutations (100%) and the largest deletion of 16 bp was detectable through a decline in the hybridization strength. The overall analytical sensitivity was 85%. Mutation testing of 28 unrelated TAAD patients revealed 4 known and 6 possibly pathogenic mutations with a mutation yield of 32%. The MFSTAAD chip is an alternative tool to next-generation sequencing that allows parallel analysis of several genes on a single platform. Refinements in the probe design and data analysis software will increase the analytical sensitivity of insertions and deletions making this assay even more applicable for clinical testing.

analyzed by resource use and costs Janine Biermann , Till Neumann ⁎, Christiane E. Angermann , Raimund Erbel , Bernhard Maisch , David Pittrow , Vera Regitz-Zagrosek , Thomas Scheffold , Rolf Wachter , Gotz Gelbrich , Jurgen Wasem , Anja Neumann b and on behalf of the German Competence Network Heart Failure a Clinic of Cardiology, University Hospital Essen, Germany b Institute for Health Care Management and Research, University of Duisburg-Essen, Essen, Germany c Department of Internal Medicine I and Comprehensive Heart Failure Center, University Hospital Wurzburg, Germany d Department of Internal Medicine, Cardiology, University Hospital Giessen and Marburg, Marburg, Germany e Department for Clinical Pharmacology, Medical Faculty, Carl Gustav Carus, Technical University of Dresden, Germany f Department of Cardiovascular Diseases in Women, Charite University Medicine, Berlin, Germany g Institute for Heart and Circulation Research, University of Witten/Herdecke, Dortmund, Germany h Department of Cardiology and Pneumology, Georg-August University Gottingen, Germany i Clinical Trial Centre Leipzig, University of Leipzig, Germany

Systolic chronic heart failure (CHF) is currently one of the most prevalent cardiac diseases. The present analysis sought to estimate the 1-year disease-related resource use and associated management costs of patients with CHF.

Background: High sensitive troponin T (hsTnT) and heart fatty acid binding protein (hFABP) are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF). We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF).Methods: We analyzed hsTnT, hFABP and N-terminal brain natriuretic peptide in 130 patients comprising 49 HFnEF patients, 51 patients with asymptomatic left ventricular diastolic dysfunction (LVDD), and 30 controls with normal diastolic function. Patients were classified to have HFnEF when the diagnostic criteria as recommended by the European Society of Cardiology were met.Results: Levels of hs TnT and hFABP were significantly higher in patients with asymptomatic LVDD and HFnEF (both p < 0.001) compared to controls. The hsTnT levels were 5.6 [0.0-9.8] pg/ml in LVDD vs. 8.5 [3.9-17.5] pg/ml in HFnEF vs. < 0.03 [< 0.03-6.4] pg/ml in controls; hFABP levels were 3029 [2533-3761] pg/ml in LVDD vs. 3669 [2918-4839] pg/ml in HFnEF vs. 2361 [1860-3081] pg/ml in controls. Furthermore, hsTnT and hFABP levels were higher in subjects with HFnEF compared to LVDD (p = 0.015 and p = 0.022).Conclusion: In HFnEF patients, hsTnT and hFABP are elevated independent of coronary artery disease, suggesting that ongoing myocardial damage plays a critical role in the pathophysiology. A combination of biomarkers and echocardiographic parameters might improve diagnostic accuracy and risk stratification of patients with HFnEF.

FUNDAMENTO: O fator de diferenciação de crescimento-15 ou GDF-15, uma citocina de resposta ao estresse relacionada ao fator transformador de crescimento beta (TGF-ß), está elevado e independentemente relacionado à prognóstico adverso na insuficiência cardíaca sistólica. OBJETIVO: O objetivo do presente estudo é investigar os níveis plasmáticos de GDF-15 em pacientes com disfunção diastólica pré-clínica ou insuficiência cardíaca com fração de ejeção normal (ICFEN). MÉTODOS: Avaliamos 119 pacientes com fração de ejeção (FE) normal, encaminhados à angiografia coronariana eletiva, dos quais 75 (63%) tinham doença arterial coronariana (DAC). Os indivíduos foram classificados como tendo disfunção diastólica ventricular esquerda leve (DDVE grau I, n = 61), ICFEN (DDVE grau II ou III, n = 38) ou função diastólica normal (controles, n = 20). Em um subgrupo de 20 indivíduos, alterações no débito cardíaco (DC) foram medidas através de reinalação de gás inerte (Innocor®) em resposta a um teste hemodinâmico ortostático. RESULTADOS: Os níveis de GDF-15 na ICFEN [mediana 1,08, variação interquartil (0,88-1,30) ng/ml] eram significantemente mais altos do que nos controles [0,60 (0,50-0,71) ng/ml, p = 0,003] e em pacientes com DDVE grau I [0,78 (0,62-1,04) ng/ml, p < 0.001]. Além disso, os níveis de GDF-15 estavam significantemente elevados em pacientes com DDVE grau I, em comparação aos controles (p = 0,003). Adicionalmente, GDF-15 estava correlacionado com os marcadores ecocardiográficos de disfunção diastólica e estava correlacionado com a magnitude da resposta do CO à alteração na posição do corpo de ereta para supina (r = -0,67, p = 0,005). CONCLUSÃO: Os níveis de GDF-15 estão elevados em indivíduos com ICFEN e podem diferenciar função diastólica normal de DDVE. Além disso, os níveis de GDF-15 estão associados com uma redução na resposta do DC no teste hemodinâmico ortostático.

BACKGROUND:High sensitive troponin T (hsTnT) and heart fatty acid binding protein (hFABP) are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF). We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF).METHODS:We analyzed hsTnT, hFABP and N-terminal brain natriuretic peptide in 130 patients comprising 49 HFnEF patients, 51 patients with asymptomatic left ventricular diastolic dysfunction (LVDD), and 30 controls with normal diastolic function. Patients were classified to have HFnEF when the diagnostic criteria as recommended by the European Society of Cardiology were met.RESULTS:Levels of hs TnT and hFABP were significantly higher in patients with asymptomatic LVDD and HFnEF (both p < 0.001) compared to controls. The hsTnT levels were 5.6 [0.0-9.8] pg/ml in LVDD vs. 8.5 [3.9-17.5] pg/ml in HFnEF vs. <0.03 [< 0.03-6.4] pg/ml in controls; hFABP levels were 3029 [2533-3761] pg/ml in LVDD vs. 3669 [2918-4839] pg/ml in HFnEF vs. 2361 [1860-3081] pg/ml in controls. Furthermore, hsTnT and hFABP levels were higher in subjects with HFnEF compared to LVDD (p = 0.015 and p = 0.022).CONCLUSION:In HFnEF patients, hsTnT and hFABP are elevated independent of coronary artery disease, suggesting that ongoing myocardial damage plays a critical role in the pathophysiology. A combination of biomarkers and echocardiographic parameters might improve diagnostic accuracy and risk stratification of patients with HFnEF.

BACKGROUND:Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far. METHODS AND RESULTS:The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r(2)) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF. CONCLUSION:The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.

BACKGROUNDIn patients with aortic stenosis (AS), increased afterload induces changes in left ventricular (LV) geometry to preserve a normal ejection fraction (EF). Nevertheless, myocardial dysfunction may occur in spite of a normal EF. Global longitudinal strain (GLS) analysis can detect subtle contractile dysfunction at a pre-clinical stage. The aim of our study was to assess LV function deteriorations with GLS analysis and the association with geometric changes in patients with AS and normal EF.METHODSForty four patients with moderate to severe AS and 40 controls were enrolled. All patients underwent echocardiography, including two-dimensional strain imaging. The relative wall thickness and LV muscle mass measurements were performed with magnetic resonance imaging and patients were subdivided into four groups: Group 1 with normal LV, Group 2 with concentric remodeling, Group 3 with eccentric hypertrophy, and Group 4 with concentric hypertrophy.RESULTSThe total group of patients with AS showed a GLS of -15.3 ± 3.6% while the control group reached -18.9 ± 3.2% (p < 0.001). GLS was lower in the hypertrophy Groups 3 and 4 compared to Groups 1 and 2 (12.9 ± 3.4% vs 17.2 ± 2.5%, p < 0.05, respectively). Splitting the patients into Groups 1 to 4, the GLS was -17.2 ± 2.4%, -17.2 ± 2.7%, -12.4 ± 3.8% and -13.1 ± 3.3, respectively (p = 0.002).CONCLUSIONSIn subjects with AS, lower GLS is related to LV hypertrophy, but not to the presence of concentric remodeling. Assessment of GLS can identify subtle contractile dysfunction independent of a preserved EF, and might be useful in identifying patients at high risk for the transition from compensatory to pathological remodeling. (Cardiol J 2011; 18, 2: 151-156).

Background/objectivesGuidelines recommend screening all patients with cardiovascular disease by oral glucose tolerance test (OGTT). Due to its time-consuming protocol, costs and overall inconvenience performance of OGTT is limited in cardiological routine. Thus, we aimed to identify easily available parameters that could help to reduce the numbers of OGTT needed.MethodsOGTTs (n=1215) were performed in all patients without known type 2 diabetes mellitus (T2DM) that were submitted to the heart center Wuppertal with known or suspected coronary artery disease for an elective coronary angiography from January to October 2007.Results31.4% had normal glucose tolerance; prediabetes was present in 50.7%, whereas 17.9% were newly diagnosed with T2DM. Thus, 998 OGTTs did not result in the new diagnosis of so far undiagnosed T2DM. Multiple logistic regression and receiver operated characteristic analyses demonstrated that fasting blood glucose (FBG)≥90mg/dl and age≥55years were predictive for so far undiagnosed T2DM. Considering these two parameters 81.1% (=sensitivity) of so far undiagnosed T2DM patients would have been identified (specificity=63.4%) and the number of OGTTs could have been reduced from 1215 to 541.ConclusionsAbout 70% of patients were newly diagnosed with impaired glucose metabolism. FBG≥90mg/dl and age≥55years were predictive for so far undiagnosed T2DM and OGTTs could be reduced by 55.5%. This should alleviate the implementation of the current guidelines in daily cardiological practice.

High sensitive troponin T (hsTnT) and heart fatty acid binding protein (hFABP) are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF). We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF).

AimsHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding β‐myosin heavy chain (MYH7) or cardiac myosin‐binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype‐to‐phenotype correlations.Methods and resultsCoding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array‐based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame‐shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin‐binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype‐to‐phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM.ConclusionA large clinical‐genetic study has unravelled novel genotype‐to‐phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.