Background: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. Methods: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. Results: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. Conclusions: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.
Background: Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. Methods: Obese patients (n=149), hypertriglyceridemic patients (n=343), and healthy control subjects (n=84) were enrolled to assess their levels of RTN3. To explore the pathophysiological roles of RTN3 in the control of lipid metabolism, we used transgenic mice overexpressing the wild-type human RTN3 gene, the RTN3-null transgenic mouse model, and multiple Caenorhabditis legans strains for molecular characterization. The underlying mechanisms were studied with 3T3L1 cell cultures in vitro. Results: We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides. Increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with heat shock protein family A (Hsp70) member 5, and this enhanced interaction increases sterol regulatory element-binding protein 1c and AMP-activated kinase activity. Conclusions: This study provides evidence for a role of RTN3 in inducing obesity and triglyceride accumulation and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia.
BACKGROUND: Misdiagnosis of acute aortic dissection (AAD) can lead to significant morbidity and death. Soluble ST2 (sST2) is a cardiovascular injury-related biomarker. The extent to which sST2 is elevated in AAD and whether sST2 can discriminate AAD from other causes of sudden-onset severe chest pain are unknown. METHODS: We measured plasma concentrations of sST2 (R&D Systems assay) in 1360 patients, including 1027 participants in the retrospective discovery set and 333 patients with initial suspicion of AAD enrolled in the prospective validation cohort. Measures of discrimination for differentiating AAD from other causes of chest pain were calculated. RESULTS: In the acute phase, sST2 levels were higher in patients with AAD than those with either acute myocardial infarction in the first case-control discovery set within 24 hours of symptom onset or with patients with pulmonary embolism in the second discovery set (medians of 129.2 ng/mL versus 14.7 with P<0.001 for AAD versus acute myocardial infarction and 88.6 versus 9.3 with P<0.001 for AAD versus pulmonary embolism). In the prospective validation set, sST2 was most elevated in patients with AAD (median [25th, 75th percentile]: 76.4 [49.6, 130.3]) and modestly elevated in acute myocardial infarction (25.0 [15.5, 37.2]), pulmonary embolism (14.9 [10.2, 30.1]), and angina patients (21.5 [13.1, 27.6], all P< 0.001 versus AAD). The area under receiver operating characteristic curve for patients with AAD versus all control patients within 24 hours of presenting at the emergency department was 0.97 (0.95, 0.98) for sST2, 0.91 (0.88, 0.94) for D-dimer, and 0.50 (0.44, 0.56) for cardiac troponin I, respectively. At a cutoff level of 34.6 ng/mL, sST2 had a sensitivity of 99.1%, specificity of 84.9%, positive predictive value of 68.7%, negative predictive value of 99.7%, positive likelihood ratio of 6.6, and negative likelihood ratio of 0.01. CONCLUSIONS: Among patients with suspected aortic dissection in the emergency department, sST2 showed superior overall diagnostic performance to D-dimer or cardiac troponin I. Additional study is needed to determine whether sST2 might be a useful rule-out marker for AAD in the emergency room.