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1.  ABCC9 is a Novel Brugada and Early Repolarization Syndrome Susceptibility Gene 
International journal of cardiology  2014;171(3):431-442.
Background
Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K+ channel (IK-ATP), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS.
Methods and Results
Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS, inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5±2 mM to 13.4±5 μM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by −18.0mV (p<0.01) and increased late INa from 0.14% to 2.01% of peak INa (p<0.01).
Conclusion
Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in IK-ATP when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
doi:10.1016/j.ijcard.2013.12.084
PMCID: PMC3947869  PMID: 24439875
Mutation; ATP-Sensitive Potassium Channel; Sodium Channel; Sudden Cardiac Death; J Wave Syndromes
2.  Diagnostic and prognostic utility of soluble CD 14 subtype (presepsin) for severe sepsis and septic shock during the first week of intensive care treatment 
Critical Care  2014;18(5):507.
Introduction
The aim of this study was to evaluate the diagnostic and prognostic value of presepsin in patients with severe sepsis and septic shock during the first week of ICU treatment.
Methods
In total, 116 patients with suspected severe sepsis or septic shock were included during the first 24 hours of ICU treatment. Blood samples for biomarker measurements of presepsin, procalcitonin (PCT), interleukin 6 (IL-6), C reactive protein (CRP) and white blood cells (WBC) were drawn at days 1, 3 and 8. All patients were followed up for six months. Biomarkers were tested for diagnosis of sepsis, severe sepsis, septic shock and for prognosis of 30-days and 6-months all-cause mortality at days 1, 3 and 8. Diagnostic and prognostic utilities were tested by determining diagnostic cutoff levels, goodness criteria, C-statistics and multivariable Cox regression models.
Results
Presepsin increased significantly from the lowest to most severe sepsis groups at days 1, 3 and 8 (test for linear trend P <0.03). Presepsin levels revealed valuable diagnostic capacity to diagnose severe sepsis and septic shock at days 1, 3 and 8 (range of diagnostic area under the curves (AUC) 0.72 to 0.84, P = 0.0001) compared to IL-6, PCT, CRP and WBC. Goodness criteria for diagnosis of sepsis severity were analyzed (≥sepsis, cutoff = 530 pg/ml; ≥severe sepsis, cutoff = 600 pg/ml; ≥septic shock, cutoff = 700 pg/ml; P <0.03). Presepsin levels revealed significant prognostic value for 30 days and 6 months all-cause mortality (presepsin: range of AUC 0.64 to 0.71, P <0.02). Patients with presepsin levels of the 4th quartile were 5 to 7 times more likely to die after six months than patients with lower levels. The prognostic value for all-cause mortality of presepsin was comparable to that of IL-6 and better than that of PCT, CRP or WBC.
Conclusions
In patients with suspected severe sepsis and septic shock, precipices reveals valuable diagnostic capacity to differentiate sepsis severity compared to PCT, IL-6, CRP, WBC. Additionally, presepsin and IL-6 reveal prognostic value with respect to 30 days and 6 months all-cause mortality throughout the first week of ICU treatment.
Trial registration
ClinicalTrials.gov NCT01535534. Registered 14 February 2012.
doi:10.1186/s13054-014-0507-z
PMCID: PMC4174283  PMID: 25190134
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3.  Right Ventricular Function Quantification in Takotsubo Cardiomyopathy Using Two-Dimensional Strain Echocardiography 
PLoS ONE  2014;9(8):e103717.
Aims
This study sought to characterize global and regional right ventricular (RV) myocardial function in patients with Takotsubo cardiomyopathy (TC) using 2D strain imaging.
Methods
We compared various parameters of RV and left ventricular (LV) systolic function between 2 groups of consecutive patients with TC at initial presentation and upon follow-up. Group 1 had RV involvement and group 2 did not have RV involvement.
Results
At initial presentation, RV peak systolic longitudinal strain (RVPSS) and RV fractional area change (RVFAC) were significantly lower in group 1 (−13.2±8.6% vs. −21.8±5.4%, p = 0.001; 30.7±9.3% vs. 43.5±6.3%, p = 0.001) and improved significantly upon follow-up. Tricuspid annular plane systolic excursion (TAPSE) did not differ significantly at initial presentation between both groups (14.8±4.1 mm vs. 17.9±3.5 mm, p = 0.050). Differences in regional systolic RV strain were only observed in the mid and apical segments. LV ejection fraction (LVEF) and LV global strain were significantly lower in group 1 (36±8% vs. 46±10%, p = 0.006 and −5.5±4.8% vs. −10.2±6.2%, p = 0.040) at initial presentation. None of the parameters were significantly different between the 2 groups upon follow-up. A RVPSS cut-off value of >−19.1% had a sensitivity of 85% and a specificity of 71% to discriminate between the 2 groups.
Conclusion
In TC, RVFAC, RVPSS, LVEF and LV global strain differed significantly between patients with and without RV dysfunction, whereas TAPSE did not. 2 D strain imaging was feasible for the assessment of RV dysfunction in TC and could discriminate between patients with and without RV involvement in a clinically meaningful way.
doi:10.1371/journal.pone.0103717
PMCID: PMC4121208  PMID: 25089702
4.  Position paper on the importance of psychosocial factors in cardiology: Update 2013 
GMS German Medical Science  2014;12:Doc09.
Background: The rapid progress of psychosomatic research in cardiology and also the increasing impact of psychosocial issues in the clinical daily routine have prompted the Clinical Commission of the German Heart Society (DGK) to agree to an update of the first state of the art paper on this issue which was originally released in 2008.
Methods: The circle of experts was increased, general aspects were implemented and the state of the art was updated. Particular emphasis was dedicated to coronary heart diseases (CHD), heart rhythm diseases and heart failure because to date the evidence-based clinical knowledge is most advanced in these particular areas. Differences between men and women and over the life span were considered in the recommendations as were influences of cognitive capability and the interactive and synergistic impact of classical somatic risk factors on the affective comorbidity in heart disease patients.
Results: A IA recommendation (recommendation grade I and evidence grade A) was given for the need to consider psychosocial risk factors in the estimation of coronary risks as etiological and prognostic risk factors. Furthermore, for the recommendation to routinely integrate psychosocial patient management into the care of heart surgery patients because in these patients, comorbid affective disorders (e.g. depression, anxiety and post-traumatic stress disorder) are highly prevalent and often have a malignant prognosis. A IB recommendation was given for the treatment of psychosocial risk factors aiming to prevent the onset of CHD, particularly if the psychosocial risk factor is harmful in itself (e.g. depression) or constrains the treatment of the somatic risk factors. Patients with acute and chronic CHD should be offered anti-depressive medication if these patients suffer from medium to severe states of depression and in this case medication with selective reuptake inhibitors should be given. In the long-term course of treatment with implanted cardioverter defibrillators (ICDs) a subjective health technology assessment is warranted. In particular, the likelihood of affective comorbidities and the onset of psychological crises should be carefully considered.
Conclusions: The present state of the art paper presents an update of current empirical evidence in psychocardiology. The paper provides evidence-based recommendations for the integration of psychosocial factors into cardiological practice and highlights areas of high priority. The evidence for estimating the efficiency for psychotherapeutic and psychopharmacological interventions has increased substantially since the first release of the policy document but is, however, still weak. There remains an urgent need to establish curricula for physician competence in psychodiagnosis, communication and referral to ensure that current psychocardiac knowledge is translated into the daily routine.
doi:10.3205/000194
PMCID: PMC4012565  PMID: 24808816
depression; anxiety; post-traumatic stress disorder; psychotherapy; psychopharmacology
5.  Impact of Shocks on Mortality in Patients with Ischemic or Dilated Cardiomyopathy and Defibrillators Implanted for Primary Prevention 
PLoS ONE  2013;8(5):e63911.
Background
Emerging interest is seen in the paradox of defibrillator shocks for ventricular tachyarrhythmia and increased mortality risk. Particularly in patients with dilated cardiomyopathy (DCM), the prognostic importance of shocks is unclear. The purpose of this study was to compare the outcome after shocks in patients with ischemic cardiomyopathy (ICM) or DCM and defibrillators (ICD) implanted for primary prevention.
Methods and Results
Data of 561 patients were analyzed (mean age 68.6±10.6 years, mean left ventricular ejection fraction 28.6±7.3%). During a median follow-up of 49.3 months, occurrence of device therapies and all-cause mortality were recorded. 74 out of 561 patients (13.2%) experienced ≥1 appropriate and 51 out of 561 patients (9.1%) ≥1 inappropriate shock. All-cause mortality was 24.2% (136 out of 561 subjects). Appropriate shock was associated with a trend to higher mortality in the overall patient population (HR 1.48, 95% CI 0.96–2.28, log rank p = 0.072). The effect was significant in ICM patients (HR 1.61, 95% CI 1.00–2.59, log rank p = 0.049) but not in DCM patients (HR 1.03, 95% CI 0.36–2.96, log rank p = 0.96). Appropriate shocks occurring before the median follow-up revealed a much stronger impact on mortality (HR for the overall patient population 2.12, 95% CI 1.24–3.63, p = 0.005). The effect was driven by ICM patients (HR 2.48, 95% CI 1.41–4.37, p = 0.001), as appropriate shocks again did not influence survival of DCM patients (HR 0.63, 95% CI 0.083–4.75, p = 0.65). Appropriate shocks occurring after the median follow-up and inappropriate shocks occurring at any time revealed no impact on survival in any of the groups (p = ns).
Conclusion
Appropriate shocks are associated with reduced survival in patients with ICM but not in patients with DCM and ICDs implanted for primary prevention. Furthermore, the negative effect of appropriate shocks on survival in ICM patients is only evident within the first 4 years after device implantation.
doi:10.1371/journal.pone.0063911
PMCID: PMC3651165  PMID: 23675514
6.  A Novel Rare Variant in SCN1Bb Linked to Brugada Syndrome and SIDS by Combined Modulation of Nav1.5 and Kv4.3 Channel Currents 
Heart Rhythm  2011;9(5):760-769.
BACKGROUND
Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes.
OBJECTIVE
To identify and characterize variations in SCN1Bb associated with Brugada (BrS) and sudden infant death syndromes (SIDS).
METHODS AND RESULTS
Patient 1 was a 44-y/o male with an ajmaline-induced Type-1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-y/o female displaying a coved-type BrS ECG who developed cardiac arrest during fever. Patient 3 was a 4-m/o female SIDS case. All known exons and intron borders of BrS and SIDS susceptibility genes were amplified and sequenced in both directions. A R214Q variant was detected in exon 3A of SCN1Bb (Navβ1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp and co-immunoprecipitation techniques. Co-expression of SCN5A/WT+SCN1Bb/R214Q resulted in peak sodium channel current (INa) 56.5% smaller compared to SCN5A/WT+SCN1Bb/WT ( n=11–12, p<0.05 ). Co-expression of KCND3/WT+SCN1Bb/R214Q induced a Kv4.3 current (Ito) 70.6% greater compared with KCND3/WT+SCN1Bb/WT(n=10–11, p<0.01). Co-immunoprecipitation indicated structural association between Navβ1B and Nav1.5 and Kv4.3.
CONCLUSION
Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for Brugada or SIDS phenotypes via a combined loss of function of INa and gain of function of Ito.
doi:10.1016/j.hrthm.2011.12.006
PMCID: PMC3334446  PMID: 22155597
Brugada Syndrome; Sudden Infant Death Syndrome; Arrhythmias; SCN1Bb; Sodium; Potassium
7.  Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide 
BACKGROUND
The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear.
OBJECTIVE
Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies.
METHODS
Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and Tpeak-Tend intervals were analyzed before and during rufinamide treatment.
RESULTS
The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). Tpeak-Tend intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed.
CONCLUSION
QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations nothwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.
doi:10.1016/j.hrthm.2012.01.006
PMCID: PMC3482382  PMID: 22245794
Drug-induced QT-interval shortening; Short QT syndrome; SUDEP; sudden cardiac death; Proarrhythmia; Rufinamide
8.  Molecular Genetic and Functional Association of Brugada and Early Repolarization Syndromes with S422L Missense Mutation in KCNJ8 
Heart Rhythm  2011;9(4):548-555.
Background
ATP-sensitive potassium (KATP) cardiac channels consist of inward rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9).
Objective
To examine the association of mutations in KCNJ8 with Brugada (BrS) and early repolarization (ERS) syndromes and elucidate the mechanism underlying the gain of function of KATP channel current (IK-ATP).
Methods
Direct sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch clamp methods were used to study mutated channels expressed in TSA201 cells.
Results
The same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS proband, but was absent in 430 alleles from ethnically-matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole cell patch clamp studies showed a two-fold gain of function of glibenclamide-sensitive IK-ATP when KCNJ8-S422L was co-expressed with SUR2A-wild type. Inside-out patch clamp evaluation yielded a significantly greater IC50 for ATP in the mutant channels (785.5±2 vs. 38.4±3 µM, n=5; p<0.01) pointing to incomplete closing of the KATP channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/QTc intervals, likely due to their effect to induce an increase in ICa-L.
Conclusion
Our results support the hypothesis that KCNJ8 is a susceptibility gene for Brugada and early repolarization syndromes and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in IK-ATP is due to reduced sensitivity to intracellular ATP.
doi:10.1016/j.hrthm.2011.10.035
PMCID: PMC3288170  PMID: 22056721
Cardiac Arrhythmias; Sudden Cardiac Death; Genetics; Hotspot mutation; Electrophysiology; J wave syndrome; ATP-sensitive potassium channel
9.  The Relationship between the Severity of Coronary Artery Disease and Epicardial Adipose Tissue Depends on The Left Ventricular Function 
PLoS ONE  2012;7(11):e48330.
Background
Epicardial adipose tissue (EAT) is an active metabolic and endocrine organ. Previous studies focusing mainly on patients with preserved left ventricular function (LVF) could show a correlation between increased amounts of EAT and the extent and activity of coronary artery disease (CAD). However, to date, there are no data available about the relationship between EAT and the severity of CAD with respect to the whole spectrum of LVF impairment. Therefore, we evaluated this relationship in patients with CAD.
Methods
250 patients with CAD and 50 healthy controls underwent CMR examination to assess EAT. The severity of CAD was defined using the angiographic Gensini score (GSS).
Results
The GSS ranged from 2–364. Linear regression analysis revealed a significant correlation between EAT and GSS (r = 0.177, p = 0.01). Patients with mild (GSS≤10) and moderate CAD (GSS>10−≤40) showed comparable EAT to healthy controls. However, in patients with severe CAD (GSS>40) EAT was significantly reduced (p<0.0001) compared to healthy controls. Interestingly, patients with the same GSS revealed different EAT depending on the left ventricular function (LVF). Patients with preserved LVF (LVF≥50%) showed more EAT mass compared to those with reduced LVF (LVF<50%) regardless of the GSS. In patients with preserved LVF and mild CAD, EAT was comparable to healthy controls (61.8±19.4 g vs. 62.9±14.4 g, p = 0.8). In patients with moderate CAD, EAT rose significantly to 83.1±24.9 g (p = 0.01) and started to decline to 66.4±23.6 g in patients with severe CAD (p = 0.03). Contrary, in CAD patients with reduced LVF, EAT was already significantly reduced in patients with mild CAD as compared to healthy controls (p = 0.001) and showed a stepwise decline with increasing CAD severity.
Conclusion
The relationship between EAT and the severity of CAD depends on LVF. These findings emphasize the multifactorial interaction between EAT and the severity of CAD.
doi:10.1371/journal.pone.0048330
PMCID: PMC3487764  PMID: 23133630
10.  Alterations of leptin in the course of inflammation and severe sepsis 
BMC Infectious Diseases  2012;12:217.
Background
The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.
Methods
In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).
Results
Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).
Conclusions
Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.
doi:10.1186/1471-2334-12-217
PMCID: PMC3462137  PMID: 22973876
Adipocytes; Drotrecogin alpha (activated); Leptin; mRNA; Sepsis; Supernatants
11.  Effects of ethanol on the properties of platelets and endothelial cells in model experiments 
World Journal of Cardiology  2012;4(6):201-205.
AIM: To investigate effects of ethanol on activity markers of atherosclerosis in an in vitro endothelial cell model.
METHODS: After 24 h incubation with ethanol (0.0095%), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide, and were then incubated in direct contact with activated platelets. Following this incubation, the expression of CD40L and CD62P on platelets, and the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), urokinase plasminogen activator receptor (uPAR), and membrane-type 1 matrix metalloproteinase (MT1-MMP) on endothelial cells were measured by flow cytometry.
RESULTS: The increased expression of VCAM-1 and uPAR on endothelial cells by proinflammatory stimulation with activated platelets was significantly reduced through pre-incubation with ethanol (P < 0.05). Furthermore, platelets in direct contact with ethanol and with endothelial cells pre-incubated in ethanol showed a significant reduction in their CD40L expression (P < 0.05). Ethanol had no significant effect on ICAM-1 and MT1-MMP expression on endothelial cells.
CONCLUSION: Ethanol directly attenuates platelet activation and has significant endothelial cell-mediated effects on selected markers of atherosclerosis in vitro. These findings underline possible protective effects of ethanol on atherosclerosis.
doi:10.4330/wjc.v4.i6.201
PMCID: PMC3386310  PMID: 22761973
Platelets; Endothelial cells; Ethanol; Inflammation; Atherosclerosis
12.  Cellular Imaging of Human Atherosclerotic Lesions by Intravascular Electric Impedance Spectroscopy 
PLoS ONE  2012;7(4):e35405.
Background
Newer techniques are required to identify atherosclerotic lesions that are prone to rupture. Electric impedance spectroscopy (EIS) is able to provide information about the cellular composition of biological tissue. The present study was performed to determine the influence of inflammatory processes in type Va (lipid core, thick fibrous cap) and Vc (abundant fibrous connective tissue while lipid is minimal or even absent) human atherosclerotic lesions on the electrical impedance of these lesions measured by EIS.
Methods and Results
EIS was performed on 1 aortic and 3 femoral human arteries at 25 spots with visually heavy plaque burden. Severely calcified lesions were excluded from analysis. A highly flexible micro-electrode mounted onto a balloon catheter was placed on marked regions to measure impedance values at 100 kHz. After paraffin embedding, visible marked cross sections (n = 21) were processed. Assessment of lesion types was performed by Movats staining. Immunostaining for CD31 (marker of neovascularisation), CD36 (scavenger cells) and MMP-3 (matrix metalloproteinase-3) was performed. The amount of positive cells was assessed semi-quantitatively. 15 type Va lesions and 6 type Vc lesions were identified. Lesions containing abundant CD36-, CD31- and MMP-3-positive staining revealed significantly higher impedance values compared to lesions with marginal or without positive staining (CD36+455±50 Ω vs. CD36- 346±53 Ω, p = 0.001; CD31+436±43 Ω vs. CD31- 340±55 Ω, p = 0.001; MMP-3+ 400±68 Ω vs. MMP-3- 323±33 Ω, p = 0.03).
Conclusions
Atherosclerotic lesions with abundant neovascularisation (CD31), many scavenger receptor class B expressing cells (CD36) or high amount of MMP-3 immunoreactivity reveal significantly higher impedance values compared to lesions with marginal or no detection of immunoreactivity. Findings suggest that inflammatory processes in vulnerable plaques affect the impedance of atherosclerotic lesions and might therefore be detected by EIS.
doi:10.1371/journal.pone.0035405
PMCID: PMC3324547  PMID: 22509411
13.  Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death 
BACKGROUND
L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death.
OBJECTIVE
The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing.
METHODS/RESULTS
Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval.
CONCLUSION
The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Cav genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.
doi:10.1016/j.hrthm.2010.08.026
PMCID: PMC2999985  PMID: 20817017
Arrhythmia; Calcium; Electrophysiology; Genetics; Ion channels
14.  Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2 
Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4–V6 and LQT1 morphology in leads V1–V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current–voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared to WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = −53.1 ± 1.13 mV and −60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.
doi:10.1139/y10-094
PMCID: PMC3076201  PMID: 21164565
genetics; arrhythmias; electrophysiology; HERG
15.  Incidence and Severity of Coronary Artery Disease in Patients with Atrial Fibrillation Undergoing First-Time Coronary Angiography 
PLoS ONE  2011;6(9):e24964.
Background
In standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular risk factors (CRF) has increased and modern treatment strategies (“pill in the pocket”) are only applicable to patients without structural heart disease. The aim of this study was to investigate the incidence and severity of CAD in patients with AF.
Methods
From January 2005 until December 2009, we included 261 consecutive patients admitted to hospital with paroxysmal, persistent or permanent AF in this prospective study. All patients underwent coronary angiography and the Framingham risk score (FRS) was calculated. Patients with previously diagnosed or previously excluded CAD were excluded.
Results
The overall incidence of CAD in patients presenting with AF was 34%; in patients >70 years, the incidence of CAD was 41%. The incidence of patients undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was 21%. Patients with CAD were older (73±8 years vs 68±10 years, p = 0.001), had significantly more frequent hypercholesterolemia (60% vs 30%, p<0.001), were more frequent smokers (26% vs 13%, p = 0.017) and suffered from angina more often (37% vs 2%, p<0.001). There was a significant linear trend among the FRS categories in percentage and the prevalence of CAD and PCI/CABG (p<0.0001).
Conclusions
The overall incidence of CAD in patients presenting with AF was relatively high at 34%; the incidence of PCI/CABG was 21%. Based upon increasing CRF in the western world, we recommend a careful investigation respecting the FRS to either definitely exclude or establish an early diagnosis of CAD – which could contribute to an early and safe therapeutic strategy considering type Ic antiarrhythmics and oral anticoagulation.
doi:10.1371/journal.pone.0024964
PMCID: PMC3177852  PMID: 21957469
16.  Capsule Endoscopy in a Patient with an Implanted CCM System and an Implantable Defibrillator 
Case Reports in Cardiology  2011;2011:275659.
Wireless video capsule endoscopy (CE) is a modern diagnostic tool. Because of its use of digital radiofrequency, it is still relatively contraindicated in patients with implanted cardiac devices. We report the case of a patient with an Optimizer III system delivering cardiac contractility modulating signals (CCM) for heart failure therapy and an implantable cardioverter defibrillator (ICD) who underwent CE. No interferences between the devices were found.
doi:10.1155/2011/275659
PMCID: PMC4008400  PMID: 24940511
17.  Expansion of the Multi-Link Frontier™ Coronary Bifurcation Stent: Micro-Computed Tomographic Assessment in Human Autopsy and Porcine Heart Samples 
PLoS ONE  2011;6(7):e21778.
Background
Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the expansion of the Multi-Link (ML) Frontier™ stent in human and porcine coronary arteries to provide the cardiologist with useful in-vitro information for stent implantation and selection.
Methodology/Principal Findings
Nine ML Frontier™ stents were implanted in seven human autopsy heart samples with known coronary artery disease and five ML Frontier™ stents were implanted in five porcine hearts. Proximal, distal and side branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L) were assessed by micro-computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart samples than in porcine heart samples (3.54±0.47 mm vs. 4.04±0.22 mm, p = 0.048; 10.00±2.42 mm2 vs. 12.84±1.38 mm2, p = 0.034, respectively) and than those given by the manufacturer (3.54±0.47 mm vs. 4.03 mm, p = 0.014). L was smaller in human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.66±1.30 mm vs. 17.30±0.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.66±1.30 mm vs. 18 mm, p = 0.015).
Conclusions/Significance
Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a contribution to the development of these devices. The proximal diameter and proximal area of the stent system were considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary optimize) stent expansion.
doi:10.1371/journal.pone.0021778
PMCID: PMC3140974  PMID: 21814552
18.  Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism 
Critical Care  2011;15(1):R23.
Introduction
There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin.
Methods
In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 μg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6.
Results
Initial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 μg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment.
Conclusions
In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation.
Trial registration
ClinicalTrials.gov: NCT00191724
doi:10.1186/cc9968
PMCID: PMC3222057  PMID: 21241489
19.  Drugs and Brugada syndrome patients: review of the literature, recommendations and an up-to-date website (www.brugadadrugs.org) 
Background:
Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death at a relatively young age. Importantly, many drugs have been reported to induce the characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.
Objective:
To review the literature on the use of drugs in Brugada syndrome patients, to make recommendations based on the literature and expert opinion regarding drug safety, and to ensure worldwide online and up-to-date availability of this information to all physicians who treat Brugada syndrome patients.
Methods:
We have performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation to each drug, and initiated a website (www.brugadadrugs.org).
Results:
The literature search yielded 506 reports to be considered. Drugs were categorized to one of four categories: 1) drugs to be avoided (n=18), 2) drugs preferably avoided (n=23), 3) antiarrhythmic drugs (n=4) and 4) diagnostic drugs (n=4). Level of evidence for most associations was C (only consensus opinion of experts, case studies, or standard-of-care) as there are no randomized studies and few non-randomized studies in Brugada syndrome patients.
Conclusions:
Many drugs have been associated with adverse events in Brugada syndrome patients. We have initiated a website (www.brugadadrugs.org) to ensure worldwide availability on safe drug use in Brugada syndrome patients.
doi:10.1016/j.hrthm.2009.07.002
PMCID: PMC2779019  PMID: 19716089
20.  Epicardial adipose tissue in patients with heart failure 
Purpose
The aim of this study was to evaluate the extent of epicardial adipose tissue (EAT) and its relationship with left ventricular (LV) parameters assessed by cardiovascular magnetic resonance (CMR) in patients with congestive heart failure (CHF) and healthy controls.
Background
EAT is the true visceral fat deposited around the heart which generates various bioactive molecules. Previous studies found that EAT is related to left ventricular mass (LVM) in healthy subjects. Further studies showed a constant EAT to myocardial mass ratio in normal, ischemic and hypertrophied hearts.
Methods
CMR was performed in 66 patients with CHF due to ischemic cardiomyopathy (ICM), or dilated cardiomyopathy (DCM) and 32 healthy controls. Ventricular volumes, dimensions and LV function were assessed. The amount of EAT was determined volumetrically and expressed as mass indexed to body surface area. Additionally, the EAT/LVM and the EAT/left ventricular remodelling index (LVRI) ratios were calculated.
Results
Patients with CHF had less indexed EAT mass than controls (22 ± 5 g/m2 versus 34 ± 4 g/m2, p < 0.0001). In the subgroup analysis there were no significant differences in indexed EAT mass between patients with ICM and DCM (21 ± 4 g/m2 versus 23 ± 6 g/m2, p = 0.14). Linear regression analysis showed that with increasing LV end-diastolic diameter (LV-EDD) (r = 0.42, p = 0.0004) and LV end-diastolic mass (LV-EDM) (r = 0.59, p < 0.0001), there was a significantly increased amount of EAT in patients with CHF. However, the ratio of EAT mass/LV-EDM was significantly reduced in patients with CHF compared to healthy controls (0.54 ± 0.1 versus 0.21 ± 0.1, p < 0.0001). In CHF patients higher indexed EAT/LVRI-ratios in CHF patients correlated best with a reduced LV-EF (r = 0.49, p < 0.0001).
Conclusion
Patients with CHF revealed significantly reduced amounts of EAT. An increase in LVM is significantly related to an increase in EAT in both patients with CHF and controls. However, different from previous reports the EAT/LVEDM-ratio in patients with CHF was significantly reduced compared to healthy controls. Furthermore, the LV function correlated best with the indexed EAT/LVRI ratio in CHF patients. Metabolic abnormalities and/or anatomic alterations due to disturbed cardiac function and geometry seem to play a key role and are a possible explanation for these findings.
doi:10.1186/1532-429X-12-40
PMCID: PMC2914772  PMID: 20624277
21.  Extent of late gadolinium enhancement detected by cardiovascular magnetic resonance correlates with the inducibility of ventricular tachyarrhythmia in hypertrophic cardiomyopathy 
Background
Myocardial fibrosis is frequently identified in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to investigate the role of myocardial fibrosis detected by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) as a potential arrhythmogenic substrate in HCM. We hypothesized that the extent of LGE might be associated with the inducibility of ventricular tachyarrhythmias (VT) during programmed ventricular stimulation (PVS).
Methods
We evaluated retrospectively LGE CMR of 76 consecutive HCM patients, of which 43 presented with one or more risk factors for sudden cardiac death (SCD) and were therefore clinically classified as high-risk patients. Of these 43 patients, 38 additionally underwent an electrophysiological testing (EP). CMR indices and the extent of LGE, given as the % of LV mass with LGE were correlated with the presence of risk factors for SCD and the results of EP.
Results
High-risk patients had a significant higher prevalence of LGE than low-risk patients (29/43 [67%] versus 14/33 [47%]; p = 0.03). Also the % of LV mass with LGE was significantly higher in high-risk patients than in low-risk patients (14% versus 3%, p = 0.001, respectively). Of the 38 high- risk patients, 12 had inducible VT during EP. LV function, volumes and mass were comparable in patients with and without inducible VT. However, the % of LV mass with LGE was significantly higher in patients with inducible VT compared to those without (22% versus 10%, p = 0.03). The prevalence of LGE was, however, comparable between HCM patients with and those without inducible VT (10/12 [83%] versus 15/26 [58%]; p = 0.12). In the univariate analysis the % of LV mass with LGE and the septal wall thickness were significantly associated with the high-risk group (p = 0.001 and 0.004, respectively). Multivariate analysis demonstrated that the extent of LGE was the only independent predictor of the risk group (p = 0.03).
Conclusions
The extent of LGE in HCM patients correlated with risk factors of SCD and the likelihood of inducible VT. Furthermore, LGE extent was the only independent predictor of the risk group. This supports the hypothesis that the extent of fibrosis may serve as potential arrhythmogenic substrate for the occurrence of VT, especially in patients with clinical risk factors for SCD.
doi:10.1186/1532-429X-12-30
PMCID: PMC2887438  PMID: 20492668
22.  Matrix metalloproteinases and their inhibitors: promising novel biomarkers in severe sepsis? 
Critical Care  2009;13(6):1006.
The multicenter study conducted by Lorente and coworkers published in the previous issue of Critical Care demonstrates that matrix metalloproteinase (MMP)-9 and MMP-10 and their inhibitor tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are promising novel biomarkers to predict severity and outcome of sepsis. In recent years MMPs have emerged as biomarkers in a variety of diseases, such as sepsis, coronary artery disease, cancer, heart failure, chronic lung disease and rheumatoid arthritis. MMPs constitute a family of proteinases that are expressed during developmental, physiological, and pathophysiological processes, for example as a response to infection. Excessive inflammation following infection may cause tissue damage, and MMPs are implicated in causing this immunopathology. The activity of MMPs is regulated by secretion of specific inhibitors (TIMPs). Studies using MMP inhibitors and MMP knockout mice indicate that MMPs play an essential role in infection and in the host response to infection. The measurement of MMP-9 and MMP-10 and their inhibitor TIMP-1 in the intensive care setting could be an attractive noninvasive tool for determination of outcome of septic patients.
doi:10.1186/cc8156
PMCID: PMC2811909  PMID: 20017890
23.  CMR findings in patients with hypertrophic cardiomyopathy and atrial fibrillation 
Objectives
We sought to evaluate the relation between atrial fibrillation (AF) and the extent of myocardial scarring together with left ventricular (LV) and atrial parameters assessed by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM).
Background
AF is the most common arrhythmia in HCM. Myocardial scarring is also identified frequently in HCM. However, the impact of myocardial scarring assessed by LGE CMR on the presence of AF has not been evaluated yet.
Methods
87 HCM patients underwent LGE CMR, echocardiography and regular ECG recordings. LV function, volumes, myocardial thickness, left atrial (LA) volume and the extent of LGE, were assessed using CMR and correlated to AF. Additionally, the presence of diastolic dysfunction and mitral regurgitation were obtained by echocardiography and also correlated to AF.
Results
Episodes of AF were documented in 37 patients (42%). Indexed LV volumes and mass were comparable between HCM patients with and without AF. However, indexed LA volume was significantly higher in HCM patients with AF than in HCM patients without AF (68 ± 24 ml·m-2 versus 46 ± 18 ml·m-2, p = 0.0002, respectively). The mean extent of LGE was higher in HCM patients with AF than those without AF (12.4 ± 14.5% versus 6.0 ± 8.6%, p = 0.02). When adjusting for age, gender and LV mass, LGE and indexed LA volume significantly correlated to AF (r = 0.34, p = 0.02 and r = 0.42, p < 0.001 respectively). By echocardiographic examination, LV diastolic dysfunction was evident in 35 (40%) patients. Mitral regurgitation greater than II was observed in 12 patients (14%). Multivariate analysis demonstrated that LA volume and presence of diastolic dysfunction were the only independent determinant of AF in HCM patients (p = 0.006, p = 0.01 respectively). Receiver operating characteristic curve analysis indicated good predictive performance of LA volume and LGE (AUC = 0.74 and 0.64 respectively) with respect to AF.
Conclusion
HCM patients with AF display significantly more LGE than HCM patients without AF. However, the extent of LGE is inferior to the LA size for predicting AF prevalence. LA dilation is the strongest determinant of AF in HCM patients, and is related to the extent of LGE in the LV, irrespective of LV mass.
doi:10.1186/1532-429X-11-34
PMCID: PMC2749835  PMID: 19740409
25.  Electromechanical coupling in patients with the short QT syndrome: Further insights into the mechanoelectrical hypothesis of the U wave 
BACKGROUND
Patients with a short QT syndrome (SQTS) are at risk of sudden cardiac death (SCD). It is not known whether abbreviation of cardiac repolarization alters mechanical function in SQTS. Controversies persist regarding whether the U wave is a purely electrical or mechanoelectrical phenomenon.
OBJECTIVE
The present study uses echocardiographic measurements to discriminate between the hypotheses for the origin of the U wave.
METHODS
Diagnostic work-up including echocardiography and electrocardiogram was performed in 5 SQTS patients (39 ± 19 years old) from 2 unrelated families with a history of SCD and 5 age-matched and gender-matched control subjects.
RESULTS
QT intervals were 268 ± 18 ms (QTc 285 ± 28 ms) in SQTS versus 386 ± 20 ms (QTc 420 ± l 22 ms) in control subjects (P < .005). In SQTS patients, the end of the T wave preceded aortic valve closure by 111 ± 30 ms versus −12 ± 11 ms in control subjects (P < .005). The interval from aortic valve closure to the beginning of the U wave was 8 ± 4 ms in patients and 15 ± 11 ms in control subjects (P = .25). Thus, the inscription of the U wave in SQTS patients coincided with aortic valve closure and isovolumic relaxation, supporting the hypothesis that the U wave is related to mechanical stretch.
CONCLUSION
Our data show for the first time a significant dissociation between the ventricular repolarization and the end of mechanical systole in SQTS patients. Coincidence of the U wave with termination of mechanical systole provides support for the mechanoelectrical hypothesis for the origin of the U wave.
doi:10.1016/j.hrthm.2007.100.015
PMCID: PMC2366900  PMID: 18242547
Short QT syndrome; Sudden cardiac death; Electromechanical dissociation; Isovolumic relaxation; U wave

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