Faculty Bibliography

Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, 'upstream therapy') only prevent a part of this burden of disease. New treatment modalities are therefore currently under evaluation in clinical trials. Given the multifold clinical consequences of AF, controlled trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these 'requirements' for outcome assessment in AF trials, further outcome parameters are described in each outcome domain. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF

Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, 'upstream therapy') only prevent a part of this burden of disease. Several new treatment modalities are therefore under evaluation in controlled trials. Given the multifold clinical consequences of AF, trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these 'requirements' for outcome assessment in AF trials, further, more detailed outcome parameters are described. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF

BACKGROUND: Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. METHODS AND RESULTS: We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg . kg(-1) . d(-1)). We classified the mutations as sensitive to Mex (P1332L, R1626P; >/=10% of QTc shortening and QTc <500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na(+) current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na(+) current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. CONCLUSIONS: We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3

Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are generally better tolerated than conventional antipsychotics since most do not cause debilitating extrapyramidal symptoms. They are associated though with an array of cardiovascular adverse events that may affect morbid-mortality of schizophrenic patients. Orthostatic hypotension, electrocardiographic changes and metabolic syndrome (MS) are the main cardiovascular effects of atypical antipsychotics. They contribute to the overall disease burden associated with schizophrenia even though the benefit risk of such treatments still is highly favourable.We aim to review the main cardiovascular side effects of new atypical oral antipsychotics, the pharmacological mechanisms involved, and to which drugs they are particularly attributed