Multiple clinical profiles of families with the short QT syndrome.

Aims: Short QT syndrome (SQTS) is a rare cardiac channelopathy characterized by a shortened corrected QT (QTc)-interval that can lead to ventricular arrhythmias and sudden cardiac death. The aim of this study was to investigate the clinical phenotypes and long-term outcomes of three families harbouring genetic mutations associated with the SQTS. Methods and results: Clinical data included medical history, physical examination, 12-lead ECG, 24-h Holter-ECG, and transthoracic echocardiography from three index patients and their first-degree relatives. Next generation clinical exome sequencing and genetic cascade screening were performed in index patients and their relatives, respectively. Two index patients experienced malignant ventricular arrhythmias and one patient suffered from arrhythmogenic syncope during a median follow-up period of 8 years. They all had genetic mutations associated with the SQTS. Two mutations were found in the KCNH2 gene, and one in the CACNA2D gene. One patient had an additional SCN10A variant. Alive and mutation-positive family members had short QTc-intervals, but no further phenotypic manifestations. None of the mutation-negative family members had an abnormal ECG or any symptoms. In all patients with shortened QTc-intervals, the QTc-interval had a low long-term variability and QTc shortening always remained detectable by 12-lead ECG. Conclusion: This study shows the variety of phenotypic manifestations in different families with SQTS. It further emphasizes the importance of a 12-lead ECG for early diagnosis, and the utility of next generation sequencing for the identification of mutations associated with the SQTS.

Individualized antithrombotic therapy.

UNLABELLED: Clot formation in the circulation is a physiological mechanism preventing bleeding at sites of loss of vascular integrity. Clot formation may also occur intravascularly under pathological conditions, e.g. leading to myocardial infarction, stroke, and critical limb ischaemia. Clot formation involves activation of the coagulation cascade and of platelets eventually leading to an occlusive clot. In the venous circulation, clots are rich in erythrocytes and fibrin, while in the arterial circulation platelets predominate. Accordingly, drugs have been developed to interfere with the activation of the coagulation and/or platelets. As several coagulation factors such as factor VII, VIIII, X and thrombin (factor II) are vitamin K-dependent, drugs interfering with the effects of the vitamin (VKAs), i.e. warfarin, marcoumar or sintrom have been used for decades to prevent thromboembolism and embolic stroke. With the advent of selective inhibitors of factor X (apixaban, edoxaban and rivaroxaban) or factor II (dabigratan) the therapeutic spectrum of anti-thrombotic therapy has been expanded. On the other hand, platelet inhibitors such as aspirin and thienopyridines, i.e. clopidogrel, prasugrel, and ticagrelor have extensively been used to treat arterial disease in the coronary, cerebrovascular and peripheral circulation. Individualized antithrombotic therapy considers (1) characteristics of the disease and (2) those of the patient. Such a decision tree first separates "arterial" and "venous" thrombi. For the prevention of arterial thrombi that occur in acute myocardial infarction and certain forms of stroke and critical limb ischemia, platelet inhibitors are indicated. The first line drug is aspirin which interferes with thromboxane A2 (TXA2) formation and partially inhibits platelet activation. In patients receiving a stent or in acute coronary syndromes (ACS), the combination of aspirin with a thienopyridine is indicated. On the other hand, patients with venous clots should be treated with anticoagulants interfering with the activation of the coagulation cascade. While the longest experiences exist with vitamin K antagonists, the novel oral anticoagulants (NOACs) are at least as effective, but associated with less intracerebral and life-threatening bleeding. VKAs remain the treatment of choice in patients receiving artificial heart valves or with renal failure (in general a GFR of 30 ml/min/KG or less). In the remaining patients, current evidence suggests that NOACs should be preferred. The NOACs are well documented in patients with thromboembolism and atrial fibrillation. Whether patients with an acute ACS should receive dual antiplatelet drugs plus a low dose NOAC is a matter of debate, although conceptually it is an attractive concept. In patients after stent implantation with atrial fibrillation, in which a triple therapy with dual antiplatelet drugs and an anticoagulant is indicated, bleeding is an issue. Recent data suggest that administering a thienopyridine plus warfarin (or possibly a NOAC), while at the same time skipping aspirin may be an alternative to avoid severe bleeding and to maintain antithrombotic efficacy. CONCLUSION: An extensive therapeutic arsenal to interfere with clot formation requires an individualized approach considering the disease condition and co-morbidities of the patient, the anticoagulants' and patient characteristics. This review builds on and extends previous publications of the authors on this topic.

[Risk-adapted anticoagulation in atrial fibrillation in Germany, Austria and Switzerland - an analysis from the PREFER-in-AF study]. / Risikoadaptierte Antikoagulation zur Schlaganfallprävention bei Vorhofflimmern in Deutschland, Österreich und der Schweiz.

BACKGROUND: The management of patients with atrial fibrillation (AF) has substantially improved in recent years, among others due to the introduction of new risk scores for the stratification of patients, as well as the availability of the non-vitamin K oral antagonists (NOAC). The PREFER-in-AF study aimed to document the management of AF patients with particular focus on stroke prevention on the basis of anticoagulants. METHODS AND RESULTS: In Germany, Austria and Switzerland a total of 1771 patients were enrolled between January 2012 and January 2013 (mean age 71.9 ±â€…9.2 years; 63 % males).At inclusion, the mean time since AF diagnosis was 4.8 ±â€…5.3 years. Paroxysmal AF was present in 30.7 %, persistent in 11 %, long standing persistent in 4.7 % and permanent AF in 53.3 % of the patients. 25.1 % of the Patients were in sinus rhythm. Mean CHA2DS2-VASc Score was 3.7 ±â€…1.8 points (0 points in 3.0 %, 1 point in 7.1 %, ≥ 2 points in 89.9 %).For the prevention of thromboembolic events 68.1 % of patients received vitamin K antagonists (VKA, mainly phenprocoumon), 11.6 % received a NOAC (mainly rivaroxaban or dabigatran), 7.6 % an antiplatelet agent, and 7.7 % a combination of VKA plus an antiplatelet agent. 5.0 % of patients did not receive any anticoagulant. During the 12 months prior to inclusion, interruption of VKA therapy due to an interventions was reported in 29.7 %. In the group of patients with known INR values and available CHA2DS2-VASc score, 75.1 % were adequately controlled (defined as at least 2 of 3 INR values in the range of 2.0-3.0).Bleeding propensity or bleedings in patient history were reported for 5.1 % of the patients, hospitalizations due to major bleeding events in the past 12 months for 1.9 %. Possible risk factors associated with anticoagulation were present in 76.7 %. Mean HAS-BLED score was 2.1 ±â€…1.1 points. CONCLUSION: The rates of AF patients who received oral anticoagulation were about 90 % and substantially higher compared to previous observational studies. NAOCs were administered to 11.7 % of patients.

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.

BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

Vitamin K antagonists. Ready to be replaced?

For the last decades, anticoagulation for stroke prevention in atrial fibrillation (AF) as well as for the prophylaxis and long-term treatment of venous thromboembolism has been entirely based on vitamin K antagonists (VKA). Although very effective under optimal conditions, long-term treatment with these drugs is flawed by the fact that the time in the therapeutic range frequently is suboptimal due to biological factors, drug interactions and compliance. The direct thrombin inhibitor dabigatran, as well as the direct FXa inhibitors rivaroxaban and apixaban provide more consistent anticoagulation and have proven their efficacy and safety against VKAs in several large scale randomized clinical trials for stroke prevention in atrial fibrillation as well as for the treatment and prevention of venous thromboembolism. In view of these convincing data and other advantages such as the lack of mandatory monitoring and only few drug interactions, VKAs will most likely be replaced in a majority of patients for these indications. Based on the most recent trial evidence, the current review discusses the role of VKA treatment and that of the novel anticoagulants.

Histamine differentially interacts with tumor necrosis factor-alpha and thrombin in endothelial tissue factor induction: the role of c-Jun NH2-terminal kinase.

BACKGROUND: Histamine plays an important role in vascular disease. Tissue factor (TF) expression is induced in vascular inflammation and acute coronary syndromes. OBJECTIVES: This study examined the effect of histamine on tumor necrosis factor-alpha- (TNF-alpha-) vs. thrombin-induced endothelial TF expression. METHODS AND RESULTS: Histamine (10(-8)-10(-5) mol L-1), TNF-alpha (5 ng mL-1), and thrombin (1 U mL-1) induced TF expression in human endothelial cells. Although TF expression by TNF-alpha and thrombin was identical, histamine augmented TNF-alpha-induced expression 7.0-fold, but thrombin-induced expression only 2.6-fold. Similar responses occurred with TF activity. The H1-receptor antagonist mepyramine abrogated these effects. Differential augmentation by histamine was also observed at the mRNA level. Histamine-induced p38 activation preceded a weak second activation to both TNF-alpha and thrombin. Histamine-induced c-Jun NH2-terminal kinase (JNK) activation was followed by a strong second activation to TNF-alpha, and less to thrombin. Selective inhibition of this second JNK activation by SP600125 reduced TF induction to histamine plus TNF-alpha by 67%, but to histamine plus thrombin by only 32%. Histamine augmented TNF-alpha- and thrombin-induced vascular cell adhesion molecule 1 (VCAM-1) expression to a similar extent. Consistent with this observation, VCAM-1 induction to TNF-alpha and thrombin was mediated by p38, but not by JNK. CONCLUSIONS: Histamine differentially augments TNF-alpha- vs. thrombin-induced TF expression and activity, which is mediated by the H1-receptor, occurs at the mRNA level, and is related to differential JNK activation.