Consequences of chronic frequent premature atrial contractions: Association with cardiac arrhythmias and cardiac structural changes.

INTRODUCTION: Frequent premature ventricular contractions (PVCs) can cause cardiomyopathy (CM). Postextrasystolic potentiation (PESP) and irregularity have been in implicated as triggers of PVC-CM. Because both phenomena can also be found in premature atrial contractions (PACs), it is speculated that frequent PACs have similar consequences. METHODS AND RESULTS: A single-center, retrospective study included all consecutive patients undergoing a 14-day Holter monitors (November 2014 to October 2016). Patients were divided into four groups by ectopy burden group 1 (<1%) and remaining by tertiles (group 2-4). Echocardiographic and arrhythmic data were compared between PAC and PVC burdens. In addition, a translational PAC animal model was used to assess the chronic effects of frequent PACs. A total 846 patients were reviewed. In contrast to PVCs, we found no difference in left ventricular ejection fraction (LVEF), end-systolic and end-diastolic dimensions and presence of CM (LVEF <50%) between different PAC groups. Multivariate regression analysis demonstrated that only PVC burden predicted low EF (odds ratio, 1.1; confidence interval, 1.03-1.13; P = .001). While there was a weak correlation between PAC burden and supraventricular tachycardia (SVT) episodes and atrial fibrillation (AF) burden (r = 0.19; P < .001), there was no correlation between PAC burden and LVEF or CM. Finally, atrial bigeminy in our animal model did not significantly decrease LVEF after 3 months. CONCLUSION: PAC burden is associated with increased AF and SVT episodes. In contrast to a high PVC burden, a high PAC burden is not associated with CM. Our findings suggest that heart rate irregularity and/or PESP may play a minimal role in the pathophysiology of PVC-CM.

Gene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo.

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with body size has not been comprehensively studied. To address this gap in knowledge, we employed a systems approach including transcriptomics, proteomics, and measurement of in vitro and in vivo metabolic fluxes. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression according to body mass of genes related to cytosolic and mitochondrial metabolic processes, and to detoxication of oxidative damage. To determine whether flux through key metabolic pathways is ordered inversely to body size, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing C57BL/6 J mice with Sprague-Dawley rats, we demonstrate that while ordering of metabolic fluxes is not observed in in vitro cell-autonomous settings, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to other aspects of metabolism, and is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.

Vascular pathobiology of pulmonary hypertension.

Pulmonary hypertension (PH), increased blood pressure in the pulmonary arteries, is a morbid and lethal disease. PH is classified into several groups based on etiology, but pathological remodeling of the pulmonary vasculature is a common feature. Endothelial cell dysfunction and excess smooth muscle cell proliferation and migration are central to the vascular pathogenesis. In addition, other cell types, including fibroblasts, pericytes, inflammatory cells and platelets contribute as well. Herein, we briefly note most of the main cell types active in PH and for each cell type, highlight select signaling pathway(s) highly implicated in that cell type in this disease. Among others, the role of hypoxia-inducible factors, growth factors (e.g., vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-ß and bone morphogenetic protein), vasoactive molecules, NOTCH3, Kruppel-like factor 4 and forkhead box proteins are discussed. Additionally, deregulated processes of endothelial-to-mesenchymal transition, extracellular matrix remodeling and intercellular crosstalk are noted. This brief review touches upon select critical facets of PH pathobiology and aims to incite further investigation that will result in discoveries with much-needed clinical impact for this devastating disease.

Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner.

Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.

Coronary artery bypass graft markers: history, usage, and effects.

Coronary artery bypass grafting (CABG) is one of the most common procedures in the United States as many Americans suffer from coronary heart disease and undergo CABG each year. While CABG has been performed for decades, questions remain regarding the benefits graft marker placement provides for patient therapy and outcomes. Markers at the proximal graft anastomosis aim to improve the efficiency and reduce the risks of subsequent, post-coronary artery bypass grafting coronary angiography by decreasing fluoroscopy time and contrast volume used. Graft markers have been shown to reduce fluoroscopy time and contrast volume, but concerns exist regarding their potentially negative impact on patient outcomes by increasing procedural time and possibly affecting graft patency. The relationship between graft markers and graft patency has not been studied in depth, and there is little evidence to show that graft patency is determined by graft marker placement. Because of the potential benefits to patients and the limited risks, it is important to continue studying graft marker usage and their effects on long-term outcomes.

Neuroprotection against stroke and encephalopathy after cardiac surgery.

Cerebral ischemia in the perioperative period is a major risk factor for stroke, encephalopathy, and cognitive decline after cardiothoracic surgery. After coronary artery bypass grafting, both stroke and encephalopathy can result in poor patient outcomes and increased mortality. Neuroprotection aims to lessen the severity and occurrence of further injury mediated by stroke and encephalopathy and to aid the recovery of conditions already present. Several pharmacological and non-pharmacological methods of neuroprotection have been investigated in experimental studies and in animal models, and, although some have shown effectiveness in protection of the central nervous system, for most, clinical research is lacking or did not show the expected results. This review summarizes the value and need for neuroprotection in the context of cardiothoracic surgery and examines the use and effectiveness of several agents and methods with an emphasis on clinical trials and clinically relevant neuroprotectants.