ABSTRACT
AIM: Diastolic dysfunction is a common problem in patients with obesity, hypertension, diabetes, or coronary artery disease. The purpose of this study was to evaluate the association of left ventricular diastolic dysfunction with an abnormal coronary artery calcium score (CAC score). METHODS: This study considered a cohort of patients ≥ 18 years of age with normal ejection fraction who were admitted to the hospital with chest pain. All patients underwent regadenoson myocardial perfusion stress imaging and had no evidence of ischemia or infarction. Patients then underwent cardiac CT for measurement of CAC score. Patients were excluded if they had prior history of coronary artery disease, ECG findings diagnostic of an acute coronary syndrome, an elevated troponin level, or hemodynamic instability. RESULTS: A total of 114 patients were included and 52 (45.6%) patients had echocardiographic evidence of diastolic dysfunction. Patients with diastolic dysfunction were more likely to have an abnormal calcium score (79.6% vs 20%; OR 15.10, 95% CI 5.70 to 43.85; p ï¼ 0.001). In multivariable analysis, the presence of diastolic dysfunction on echocardiogram was significantly associated with an abnormal calcium score (OR 13.82, 95% CI 5.57 to 37.37; p ï¼ 0.001) after adjusting for Framingham Risk Score or clinical risk factors (age, gender, diabetes mellitus, dyslipidemia, and obesity; OR 19.06,95% CI 4.66 to 107.97; p ï¼ 0.001). CONCLUSIONS: Our study demonstrates that left ventricular diastolic dysfunction is associated with an abnormal CAC score even after adjusting for Framingham Risk Score or clinical risk factors. Patients without known coronary artery disease that present with chest pain and have normal perfusion imaging with evidence of abnormal diastolic function on echocardiogram may warrant more thorough evaluation for coronary atherosclerotic disease with CAC score assessment.
Subject(s)
Calcinosis/blood , Coronary Artery Disease/pathology , Diastole , Heart Ventricles/physiopathology , Ventricular Dysfunction, Left/pathology , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/pathology , Adult , Aged , Area Under Curve , Calcium/metabolism , Cohort Studies , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Coronary Vessels/pathology , Echocardiography , Female , Humans , Male , Middle Aged , Multidetector Computed Tomography , ROC Curve , Risk Factors , Sensitivity and Specificity , Tomography, X-Ray Computed , Troponin/blood , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/diagnostic imagingABSTRACT
The idea that serotonergic synaptic transmission plays an essential role in the control of mood and the pharmacotherapy of anxiety and depression is one of the cornerstones of modern biological psychiatry. As a result, there is intense interest in understanding the mechanisms controlling the activity of serotonin-synthesizing (serotonergic) neurons. One of the oldest and most durable ideas emerging from this work is that serotonergic neurons are capable of autonomously regulating their own basal firing rate. Serotonergic neurons express on their surface 5-HT1A receptors (autoreceptors) that, when activated, induce the opening of potassium channels that hyperpolarize and thereby inhibit cell firing. Activity-dependent release of serotonin within serotonergic nuclei is thought to activate these autoreceptors, thus completing an autoinhibitory feedback loop. This concept, which was originally proposed in the 1970s, has proven to be enormously fruitful and has guided the interpretation of a broad range of clinical and preclinical work. Yet, remarkably, electrophysiological studies seeking to directly demonstrate this phenomenon, especially in in vitro brain slices, have produced mixed results. Here, we critically review this work with a focus on electrophysiological studies, which directly assess neuronal activity. We also highlight recent work suggesting that 5-HT1A receptor-mediated autoinhibition may play other roles in the control of firing besides acting as a feedback regulator for the pacemaker-like firing rate of serotonergic neurons.
Subject(s)
Action Potentials/physiology , Neural Inhibition/physiology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonergic Neurons/physiology , Animals , Dorsal Raphe Nucleus/physiologyABSTRACT
Deubiquitinating enzymes (DUBs) are proteases that control the post-translational modification of proteins by ubiquitin and in turn regulate diverse cellular pathways. Despite a growing understanding of DUB biology at the structural and molecular level, little is known about the physiological importance of most DUBs. Here, we systematically identify DUBs encoded by the genome of Drosophila melanogaster and examine their physiological importance in vivo. Through domain analyses we uncovered 41 Drosophila DUBs, most of which have human orthologues. Systematic knockdown of the vast majority of DUBs throughout the fly or in specific cell types had dramatic consequences for Drosophila development, adult motility or longevity. Specific DUB subclasses proved to be particularly necessary during development, while others were important in adults. Several DUBs were indispensable in neurons or glial cells during developmental stages; knockdown of others perturbed the homeostasis of ubiquitinated proteins in adult flies, or had adverse effects on wing positioning as a result of neuronal requirements. We demonstrate the physiological significance of the DUB family of enzymes in intact animals, find that there is little functional redundancy among members of this family of proteases, and provide insight for future investigations to understand DUB biology at the molecular, cellular and organismal levels.
