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Articles by D. R Van Wagoner
Total Records ( 5 ) for D. R Van Wagoner
  R Das , T Burke , D. R Van Wagoner and E. F. Plow
 

L-type Ca2+ channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used antihypertensive drugs that also have antiinflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends on its interaction with Plg receptors (Plg-Rs). Plg-Rs include histone 2B, -enolase, annexin 2, and p11, all proteins which lack signal sequences for cell surface export. When human or murine monocytoid cells were induced to differentiate into macrophages, their Plg binding and Plg-R expression increased by 4-fold. These changes were suppressed by pretreatment with verapamil and amlodipine. Expression of the Cav1.2 LTCC pore subunit was induced in differentiated macrophages, and siRNA against this subunit suppressed the upregulation of Plg binding and Plg-Rs. In vivo, amlodipine and verapamil suppressed peritoneal macrophage recruitment in response to thioglycollate by >60% at doses that did not affect blood pressure. In drug-treated animals, macrophages migrated into but not through the peritoneal membrane tissue and showed reduced surface expression of Plg-Rs. These findings demonstrate that Plg-R expression on macrophages is dependent on Cav1.2 LTCC subunit expression. Suppression of Plg-Rs may contribute to the antiinflammatory effects of the widely used LTCC blockers.

  O Batal , P Schoenhagen , M Shao , A. E Ayyad , D. R Van Wagoner , S. S Halliburton , P. J Tchou and M. K. Chung
  Background—

Atrial fibrillation (AF) has been linked to inflammatory factors and obesity. Epicardial fat is a source of several inflammatory mediators related to the development of coronary artery disease. We hypothesized that periatrial fat may have a similar role in the development of AF.

Methods and Results—

Left atrium (LA) epicardial fat pad thickness was measured in consecutive cardiac CT angiograms performed for coronary artery disease or AF. Patients were grouped by AF burden: no (n=73), paroxysmal (n=60), or persistent (n=36) AF. In a short-axis view at the mid LA, periatrial epicardial fat thickness was measured at the esophagus (LA-ESO), main pulmonary artery, and thoracic aorta; retrosternal fat was measured in axial view (right coronary ostium level). LA area was determined in the 4-chamber view. LA-ESO fat was thicker in patients with persistent AF versus paroxysmal AF (P=0.011) or no AF (P=0.003). LA area was larger in patients with persistent AF than paroxysmal AF (P=0.004) or without AF (P<0.001). LA-ESO was a significant predictor of AF burden even after adjusting for age, body mass index, and LA area (odds ratio, 5.30; 95% confidence interval, 1.39 to 20.24; P=0.015). A propensity score–adjusted multivariable logistic regression that included age, body mass index, LA area, and comorbidities was also performed and the relationship remained statistically significant (P=0.008).

Conclusions—

Increased posterior LA fat thickness appears to be associated with AF burden independent of age, body mass index, or LA area. Further studies are necessary to examine cause and effect, and if inflammatory, paracrine mediators explain this association.

  N Voigt , A Trausch , M Knaut , K Matschke , A Varro , D. R Van Wagoner , S Nattel , U Ravens and D. Dobrev
  Background—

Recent evidence suggests that atrial fibrillation (AF) is maintained by high-frequency reentrant sources with a left-to-right–dominant frequency gradient, particularly in patients with paroxysmal AF (pAF). Unequal left-to-right distribution of inward rectifier K+ currents has been suggested to underlie this dominant frequency gradient, but this hypothesis has never been tested in humans.

Methods and Results—

Currents were measured with whole-cell voltage-clamp in cardiomyocytes from right atrial (RA) and left (LA) atrial appendages of patients in sinus rhythm (SR) and patients with AF undergoing cardiac surgery. Western blot was used to quantify protein expression of IK1 (Kir2.1 and Kir2.3) and IK,ACh (Kir3.1 and Kir3.4) subunits. Basal current was 2-fold larger in chronic AF (cAF) versus SR patients, without RA-LA differences. In pAF, basal current was 2-fold larger in LA versus RA, indicating a left-to-right atrial gradient. In both atria, Kir2.1 expression was 2-fold greater in cAF but comparable in pAF versus SR. Kir2.3 levels were unchanged in cAF and RA-pAF but showed a 51% decrease in LA-pAF. In SR, carbachol-activated (2 µmol/L) IK,ACh was 70% larger in RA versus LA. This right-to-left atrial gradient was decreased in pAF and cAF caused by reduced IK,ACh in RA only. Similarly, in SR, Kir3.1 and Kir3.4 proteins were greater in RA versus LA and decreased in RA of pAF and cAF. Kir3.1 and Kir3.4 expression was unchanged in LA of pAF and cAF.

Conclusions—

Our results support the hypothesis that a left-to-right gradient in inward rectifier background current contributes to high-frequency sources in LA that maintain pAF. These findings have potentially important implications for development of atrial-selective therapeutic approaches.

  Y Zhang , Z. B Popovic , S Bibevski , I Fakhry , D. A Sica , D. R Van Wagoner and T. N. Mazgalev
 

Background— Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with β-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model.

Methods and Results— Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate 20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment.

Conclusions— Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF.

 
 
 
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