Network analysis of the structure of inter-professional knowledge exchange related to Electronic Health Record Medication Reconciliation within a Social Knowledge Networking system.

BACKGROUND: In fall 2016, a 2-year grant was secured to pilot a Social Knowledge Networking (SKN) system pertaining to Electronic Health Record (EHR) Medication Reconciliation (MedRec), to enable Augusta University Health System to progress from "limited use" of EHR MedRec technology, to "meaningful use" (MU). A total of 50 "SKN users" (practitioners), participated in discussing practice issues related to EHR MedRec, over a 1-year period. These discussions were moderated by five "SKN moderators" (senior administrators). The pilot study, completed in fall 2018, found that inter-professional knowledge exchanges on the SKN, enabled several collective learning ("aha") moments to emerge. These learning dynamics in turn, were associated with distinct improvement trends in two measures of MU of EHR MedRec technology, identified for the study. A key takeaway was that an SKN could be a valuable tool in enabling MU of EHR MedRec technology. PURPOSE: The study's key findings related to the content and dynamics of inter-professional knowledge exchange on the SKN system, and their association with trends in measures of MU of EHR MedRec technology, have been described in a separate publication. This paper seeks to describe the structure of inter-professional knowledge exchange (or the pattern of connections) related to EHR MedRec, over the 1-year SKN period. METHODS: Social network analysis (SNA) techniques were used to describe the structure of inter-professional knowledge exchange on the SKN system. RESULTS: Results revealed that three of the five SKN moderators played a strong "collective brokerage" role in facilitating inter-professional knowledge exchange related to EHR MedRec, to enable learning and practice change. Together, they played complementary roles in reinforcing best-practice assertions, providing IT system education, and synthesizing collective learning moments, to enable "champions for change" to emerge from among SKN users. CONCLUSION: Results provide insight into the structure of effective knowledge-sharing networks for enabling inter-professional learning and practice change in health care organizations.

Short-term aerobic exercise training increases postprandial pancreatic polypeptide but not peptide YY concentrations in obese individuals.

OBJECTIVE: Short-term exercise training improves glycemic control, but the effect of short-term training on postprandial satiety peptide responses or perceived satiety remains unknown. We tested the hypothesis that short-term aerobic exercise training (15 days) would alter postprandial pancreatic and gut peptide (pancreatic polypeptide (PP) and peptide YY (PYY)) responses and perceived appetite and satiety in obese individuals. SUBJECTS: Thirteen healthy obese men and women (age: 42±2 years; body mass index: 30-45 kg m(-2)). MEASUREMENTS: Subjects were studied before and after 15 days of training (walking 1 h at 70-75% VO(2peak)). On the study day, subjects consumed 1500 kcal as six meals (250 kcal: 9 g protein, 40 g carbohydrate, 6 g fat), while blood samples and satiety measurements were taken at baseline and every 20 min for 12 h. Blood was analyzed for PP, PYY, glucose and insulin levels. Appetite and satiety was assessed with a visual analog scale throughout the day. RESULTS: Incremental area under the curve (iAUC) for PP increased significantly with training (pre: 2788±753; post: 3845±830 pg ml(-1)·per min for 12 h; P<0.001), but there was no difference in the PP response to each meal. The initial PP response to the first meal increased (ΔPP(min 20-0): pre 86±25; post 140±36 pg ml(-1); P<0.05) with training. PYY iAUC showed no significant changes with training but showed a significant main effect of time across meals, with the largest response being to the first meal (P<0.005). There were no changes in satiety, glucose or insulin levels with training. CONCLUSION: Short-term exercise training increases postprandial PP concentrations in obese individuals; however, PYY levels and glycemic control remain unaffected. Both PP and PYY show meal-induced increases at all meals, but PYY has a greater response at the first meal with reduced responses at subsequent meals.

Weight-loss-associated changes in bone mineral density and bone turnover after partial weight regain with or without aerobic exercise in obese women.

BACKGROUND/OBJECTIVES: Moderate, long-term weight loss results in the loss of bone mass in overweight or obese premenopausal women. However, whether these changes persist during weight maintenance or regain remains to be determined. SUBJECTS/METHODS: Overweight or obese (body mass index: 25.8-42.5 kg/m(2)) women (n=40) with at least two risk factors for the metabolic syndrome participated in this 12-month study that examined the effects of prescribed weight loss and regain, with or without exercise, on bone turnover and on bone mineral density (BMD) in a subset of participants (n=24). During the first 6 month, participants lost ≈ 10% of their initial body weight via energy restriction and supervised aerobic exercise. Following weight loss, participants were randomly assigned to either an exercise or a no exercise treatment for the regain (+50% of weight lost) phase. A one-way (time) repeated measures one-factor analysis of variance (RMANOVA) tested the effects of weight loss on BMD and bone turnover, and a two-way RMANOVA (time, exercise) was used to examine the effects of exercise during weight regain. RESULTS: Hip (P=0.007) and lumbar spine (P=0.05) BMD decreased with weight loss, and remained reduced after weight regain with or without exercise. Likewise, the weight-loss-associated increases in osteocalcin (P<0.001) and C-terminal peptide of type I collagen (P<0.001) persisted following weight regain, independent of exercise. CONCLUSIONS: The results of the present study, which is the first to examine changes in bone mass and turnover during carefully controlled weight regain, suggest that weight-loss-induced perturbations in bone mass and turnover persist after partial weight regain, regardless of whether regular weight-bearing aerobic exercise was continued.

Effectiveness of patient safety training in equipping medical students to recognise safety hazards and propose robust interventions.

OBJECTIVES: In an effort to improve patient safety attitudes and skills among third-year medical students, two patient safety training sessions were added to their curriculum, complementing a previously implemented second-year curriculum on quality improvement, patient safety and teamwork. METHODS: Safety attitudes and skills were assessed before and after students completed the medicine clerkship training and were compared with historical controls. Students identified and reported on observed safety events, with their reports matched to event type and harm score with contemporaneous safety reports from University of Missouri's Patient Safety Network (PSN). Comparisons were assessed by five internal safety experts using criteria for report submission "worthiness", blame tone, target of blame and presence/strength of proposed solutions. RESULTS: Students completing the third-year safety booster conferences expressed statistically higher comfort levels with identifying the cause of an error than did the student control group (p<0.05). Medical students proposed safety interventions that were more robust than those suggested by event reporters regarding similar events within our health system (p<0.0001). The worthiness and blame tone of medical student reports were not statistically different than event reports in PSN. CONCLUSIONS: Completion of two 1-h patient safety booster conferences in the third year of medical school led to increased student comfort in safety event analysis. Students documented stronger resolution robustness scores, suggesting similar training should be offered to PSN reporters. Medical students represent an underutilised resource for identifying and proposing solutions for patient safety issues.

Educational quality improvement report: outcomes from a revised morbidity and mortality format that emphasised patient safety.

PROBLEM: Although Morbidity and Mortality conferences (MMC) were originally designed to promote quality care through careful analysis of adverse events, focus on individual actions or the fear of incrimination may interfere with identification of system issues contributing to the adverse outcomes. DESIGN: Pre- and post-intervention assessments of participant attitudes toward patient safety and conference redesign were performed utilizing an attitudinal survey. Participants provided a unique identifier for paired-means procedure. A list of contributing factors, recommended solutions, and targeted system improvements was maintained with ongoing progress recorded. SETTING: Department of Internal Medicine training program at University of Missouri-Columbia, an academic health care center affiliated with the University of Missouri Hospitals and Clinics and the Harry S. Truman Veteran's Administration Hospital. PARTICIPANTS: Residents and fellows from the Department of Internal Medicine residency program. EDUCATIONAL OBJECTIVES: (1) Distinguish between culture of blame/shame and patient safety culture, (2) Identify gaps in quality contributing to adverse outcomes, (3) Identify strategies to close gaps, (4) Participate in root cause analysis, demonstrating an ability to review an adverse event and recommend an action plan. STRATEGIES FOR CHANGE: An interdisciplinary team modified the internal medicine MMC to emphasize a better understanding of patient safety principles and system-based practice interventions. For each adverse event analyzed, root causes were identified, followed by discussion of system interventions that might prevent future such events. KEY MEASURES FOR IMPROVEMENT: (1) Attitudes of residents and fellows regarding patient safety, as measured on a 20 item, five-point ordinal scale (strongly disagree to strongly agree) survey, (2) System improvements generated from the Patient Safety M&M Conferences (PSMMC), and (3) Attendance at PSMMC. EFFECTS OF CHANGE: Clinical outcomes: Conference participants offered 121 system improvement recommendations; 39 suggested system interventions were pursued based upon the likelihood of achieving high impact changes. These targeted changes were assigned to department/facility representatives with 23 (59%) improvements implemented, 11 (28%) partially implemented or in progress, and five (13%) abandoned due to impracticality or redundancy. Educational outcomes: Surveys were completed by 58 residents and fellows before and after modification of conference format. Six of the 20 survey items showed significant change with four of these changes occurring in the desired direction. Eleven of the remaining 14 responses changed in the desired direction, but did not reach statistical significance. Average MMC attendance increased from 41+/-8 to 50+/-10 (p<0.03) participants. LESSONS LEARNT: The new PSMMC initiated multiple improvements in the quality of patient care without sacrificing attendance or attitudes of the residents or fellows. The new PSMMC promotes opportunities for participants to improve quality of patient care in a safe and nurturing environment.

Educational quality improvement report: outcomes from a revised morbidity and mortality format that emphasised patient safety.

PROBLEM: Although morbidity and mortality conferences (MMCs) are meant to promote quality care through careful analysis of adverse events, focus on individual actions or the fear of incrimination may interfere with identification of system issues contributing to the adverse outcomes. DESIGN: Participant attitudes before and after the intervention towards patient safety and conference redesign were assessed using an attitudinal survey. A list of contributing factors, recommended solutions and targeted system improvements was maintained with ongoing progress recorded. SETTING: Department of Internal Medicine training programme at University of Missouri-Columbia. PARTICIPANTS: Residents and fellows from the above residency programme. EDUCATIONAL OBJECTIVES: (1) Distinguish between culture of blame/shame and patient safety culture, (2) identify gaps in quality contributing to adverse outcomes (3) identify strategies to close gaps and (4) participate in root cause analysis, demonstrating an ability to review an adverse event and recommend an action plan. STRATEGIES FOR CHANGE: An interdisciplinary team modified the internal medicine MMC to emphasise a better understanding of patient safety principles and system-based practice interventions. For each adverse event analysed, root causes were identified, followed by discussion of system interventions that might prevent future such events. KEY MEASURES FOR IMPROVEMENT: (1) Attitudes of residents and fellows regarding patient safety, as measured on a 20-item, five-point ordinal scale survey, (2) system improvements generated from the patient safety MMC (PSMMC) and (3) attendance at PSMMC. EFFECTS OF CHANGE: Clinical outcomes: 121 system improvement recommendations were made and 39 were pursued on the basis of likelihood of achieving high impact changes. 23 improvements were implemented, 11 were partially implemented or in progress, and 5 were abandoned due to impracticality or redundancy. Educational outcomes: 58 residents and fellows completed surveys before and after modification of conference format. 6/20 survey items showed substantial change with four of these changes occurring in the desired direction. Eleven of the remaining 14 responses changed in the desired direction. Average MMC attendance increased from 41+/-8 to 50+/-10 participants (p<0.03). LESSONS LEARNT: The new PSMMC initiated multiple improvements in the quality of patient care without sacrificing attendance or attitudes of the residents or fellows. The new PSMMC promotes opportunities for participants to improve quality of patient care in a safe and nurturing environment.

Endothelium-derived hyperpolarizing factor in coronary microcirculation: responses to arachidonic acid.

In coronary resistance vessels, endothelium-derived hyperpolarizing factor (EDHF) plays an important role in endothelium-dependent vasodilation. EDHF has been proposed to be formed through cytochrome P-450 monooxygenase metabolism of arachidonic acid (AA). Our hypothesis was that AA-induced coronary microvascular dilation is mediated in part through a cytochrome P-450 pathway. The canine coronary microcirculation was studied in vivo (beating heart preparation) and in vitro (isolated microvessels). Nitric oxide synthase (NOS) (N(omega)-nitro-L-arginine, 100 microM) and cyclooxygenase (indomethacin, 10 microM) or cytochrome P-450 (clotrimazole, 2 microM) inhibition did not alter AA-induced dilation. However, when a Ca(2+)-activated K(+) channel channel or cytochrome P-450 antagonist was used in combination with NOS and cyclooxygenase inhibitors, AA-induced dilation was attenuated. We also show a negative feedback by NO on NOS-cyclooxygenase-resistant AA-induced dilation. We conclude that AA-induced dilation is attenuated by cytochrome P-450 inhibitors, but only when combined with inhibitors of cyclooxygenase and NOS. Therefore, redundant pathways appear to mediate the AA response in the canine coronary microcirculation.

EET homologs potently dilate coronary microvessels and activate BK(Ca) channels.

Epoxyeicosatrienoic acids (EETs) are released from endothelial cells and potently dilate small arteries by hyperpolarizing vascular myocytes. In the present study, we investigated the structural specificity of EETs in dilating canine and porcine coronary microvessels (50-140 microm ID) and activating large-conductance Ca2+-activated K+ (BK(Ca)) channels. The potencies and efficacies of EET regioisomers and enantiomers were compared with those of two EET homologs: epoxyeicosaquatraenoic acids (EEQs), which are made from eicosapentaenoic acid by the same cytochrome P-450 epoxygenase that generates EETs from arachidonic acid, and epoxydocosatetraenoic acids (EDTs), which are EETs that are two carbons longer. With EC50 values of 3-120 pM but without regio- or stereoselectivity, EETs potently dilated canine and porcine microvessels. Surprisingly, the EEQs and EDTs had comparable potencies and efficacies in dilating microvessels. Moreover, 50 nM 13,14-EDT activated the BK(Ca) channels with the same efficacy as either 11,12-EET enantiomer at 50 nM. We conclude that coronary microvessels and BK(Ca) channels possess low structural specificity for EETs and suggest that EEQs and EDTs may thereby also be endothelium-derived hyperpolarizing factors.

12-lipoxygenase in porcine coronary microcirculation: implications for coronary vasoregulation.

Noncyclooxygenase metabolites of arachidonic acid (AA) have been proposed to mediate endothelium-dependent vasodilation in the coronary microcirculation. Therefore, we examined the formation and bioactivity of AA metabolites in porcine coronary (PC) microvascular endothelial cells and microvessels, respectively. The major noncyclooxygenase metabolite produced by microvascular endothelial cells was 12(S)-hydroxyeicosatetraenoic acid (HETE), a lipoxygenase product. 12(S)-HETE release was markedly increased by pretreatment with 13(S)-hydroperoxyoctadecadienoic acid but not by the reduced congener 13(S)-hydroxyoctadecadienoic acid, suggesting oxidative upregulation of 12(S)-HETE output. 12(S)-HETE produced potent relaxation and hyperpolarization of PC microvessels (EC(50), expressed as -log[M] = 13.5 +/- 0.5). Moreover, 12(S)-HETE potently activated large-conductance Ca(2+)-activated K(+) currents in PC microvascular smooth muscle cells. In contrast, 12(S)-HETE was not a major product of conduit PC endothelial AA metabolism and did not exhibit potent bioactivity in conduit PC arteries. We suggest that, in the coronary microcirculation, 12(S)-HETE can function as a potent hyperpolarizing vasodilator that may contribute to endothelium-dependent relaxation, particularly in the setting of oxidative stress.

Impaired dilation of coronary arterioles during increases in myocardial O(2) consumption with hyperglycemia.

Previous studies showed that nitric oxide (NO) plays an important role in coronary arteriolar dilation to increases in myocardial oxygen consumption (MVO(2)). We sought to evaluate coronary microvascular responses to endothelium-dependent and to endothelium-independent vasodilators in an in vivo model. Microvascular diameters were measured using intravital microscopy in 10 normal (N) and 9 hyperglycemic (HG; 1 wk alloxan, 60 mg/kg iv) dogs during suffusion of acetylcholine (1, 10, and 100 microM) or nitroprusside (1, 10, and 100 microM) to test the effects on endothelium-dependent and -independent dilation. During administration of acetylcholine, coronary arteriolar dilation was impaired in HG, but was normal during administration of nitroprusside. To examine a physiologically important vasomotor response, 10 N and 7 HG control, 5 HG and 5 N during superoxide dismutase (SOD), and 5 HG and 4 N after SQ29,548 (SQ; thromboxane A(2)/prostaglandin H(2) receptor antagonist) dogs were studied at three levels of MVO(2): at rest, during dobutamine (DOB; 10 microg. kg(-1). min(-1) iv), and during DOB with rapid atrial pacing (RAP; 280 +/- 10 beats/min). During dobutamine, coronary arterioles dilated similarly in all groups, and the increase in MVO(2) was similar among the groups. However, during the greater metabolic stimulus (DOB+RAP), coronary arterioles in N dilated (36 +/- 4% change from diameter at rest) significantly more than HG (16 +/- 3%, P < 0.05). In HG+SQ and in HG+SOD, coronary arterioles dilated similarly to N, and greater than HG (P < 0.05). MVO(2) during DOB+RAP was similar among groups. Normal dogs treated with SOD and SQ29,548 were not different from untreated N dogs. Thus, in HG dogs, dilation of coronary arterioles is selectively impaired in response to administration of the endothelium-dependent vasodilator acetylcholine and during increases in MVO(2).

Free radicals mediate endothelial dysfunction of coronary arterioles in diabetes.

UNLABELLED: Previous studies have demonstrated that vascular responses to acetylcholine (ACh) are impaired in diabetes mellitus (DM). OBJECTIVE: Since reactive oxygen species (ROS) generation is increased in various disease states including DM, and a direct reaction between nitric oxide (NO) and superoxide anion has been demonstrated, we tested the hypothesis that inhibition of ROS will restore coronary microvascular responses to ACh in a dog model of DM (alloxan 60 mg/kg, i.v., 1 week prior to study). METHODS: Changes in coronary microvascular diameters in diabetic (blood glucose >200 mg%) and normal animals to ACh (1-100 microM, topically) in the presence and absence of superoxide dismutase and catalase were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation. RESULTS: In diabetic animals in the absence of ROS scavengers, ACh induced coronary microvascular dilation was impaired when compared to normal animals (ACh 100 microM: DM=25+/-5%; normal=64+/-13%, P<0.05). Topical application of SOD (250 U/ml) and catalase (250 U/ml) restored to normal ACh induced coronary microvascular responses in DM while having no affect in normal animals. Responses to adenosine and nitroprusside were not different between normal and diabetic groups. CONCLUSIONS: These data provide direct evidence that oxygen-derived free radicals contribute to impaired endothelium-dependent coronary arteriolar dilation in diabetic dogs in vivo.

Mechanism of coronary vasodilation to insulin and insulin-like growth factor I is dependent on vessel size.

Insulin and insulin-like growth factor I (IGF-I) influence numerous metabolic and mitogenic processes; these hormones also have vasoactive properties. This study examined mechanisms involved in insulin- and IGF-I-induced dilation in canine conduit and microvascular coronary segments. Tension of coronary artery segments was measured after constriction with PGF(2alpha). Internal diameter of coronary microvessels (resting diameter = 112.6+/-10.1 microm) was measured after endothelin constriction. Vessels were incubated in control (Krebs) solution and were treated with N(omega)-nitro-L-arginine (L-NA), indomethacin, or K(+) channel inhibitors. After constriction, cumulative doses of insulin or IGF-I (0.1-100 ng/ml) were administered. In conduit arteries, insulin produced modest maximal relaxation (32 +/- 5%) compared with IGF-I (66+/-12%). Vasodilation was attenuated by nitric oxide synthase (NOS) and cyclooxygenase inhibition and was blocked with KCl constriction. Coronary microvascular relaxation to insulin and IGF-I was not altered by L-NA, indomethacin, tetraethylammonium chloride, glibenclamide, charybdotoxin, and apamin; however, tetrabutylammonium chloride attenuated the response. In conclusion, insulin and IGF-I cause vasodilation in canine coronary conduit arteries and microvessels. In conduit vessels, NOS/cyclooxygenase pathways are involved in the vasodilation. In microvessels, relaxation to insulin and IGF-I is not mediated by NOS/cyclooxygenase pathways but rather through K(+)-dependent mechanisms.

Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation.

Cytochrome P450 epoxygenases convert arachidonic acid into 4 epoxyeicosatrienoic acid (EET) regioisomers, which were recently identified as endothelium-derived hyperpolarizing factors in coronary blood vessels. Both EETs and their dihydroxyeicosatrienoic acid (DHET) metabolites have been shown to relax conduit coronary arteries at micromolar concentrations, whereas the plasma concentrations of EETs are in the nanomolar range. However, the effects of EETs and DHETs on coronary resistance arterioles have not been examined. We administered EETs and DHETs to isolated canine coronary arterioles (diameter, 90.0+/-3.4 microm; distending pressure, 20 mm Hg) preconstricted by 30% to 60% of the resting diameter with endothelin. All 4 EET regioisomers produced potent, concentration-dependent vasodilation (EC50 values ranging from -12.7 to -10.1 log [M]) and were approximately 1000 times more potent than reported in conduit coronary arteries. The vasodilation produced by 14,15-EET was not attenuated by removal of the endothelium and indicated a direct action of 14,15-EET on microvascular smooth muscle. Likewise, 14,15-DHET, 11,12-DHET, 8,9-DHET, and the delta-lactone of 5,6-EET produced extremely potent vasodilation (EC50 values ranging from -15.8 to -13.1 log [M]). The vasodilation produced by these eicosanoids was highly potent in comparison to that produced by other vasodilators, including arachidonic acid (EC50=-7.5 log [M]). The epoxide hydrolase inhibitor, 4-phenylchalone oxide, which blocked the conversion of [3H]14,15-EET to [3H]14,15-DHET by canine coronary arteries, did not alter arteriolar dilation to 11,12-EET; thus, the potent vasodilation induced by EETs does not require formation of DHETs. In contrast, charybdotoxin (a KCa channel inhibitor) and KCl (a depolarizing agent) blocked vasodilation by 11,12-EET and 11,12-DHET. We conclude that EETs and DHETs potently dilate canine coronary arterioles via activation of KCa channels. The preferential ability of these compounds to dilate resistance blood vessels suggests that they may be important regulators of coronary circulation.

Pharmacologic activation of the human coronary microcirculation in vitro: endothelium-dependent dilation and differential responses to acetylcholine.

OBJECTIVES: In vivo studies of the human coronary resistance circulation cannot control for indirect effects of myocardial metabolism, compression, and neurohumoral influences. This study directly examined the vasodilator responses of the human coronary microcirculation to both receptor-dependent and -independent agonists. METHODS: Atrial arterioles were dissected from human right atrial appendage (103 +/- 2 microns diameter, n = 185 vessels from 145 patients) obtained at the time of cardiopulmonary bypass and left ventricular vessels from explanted human hearts (148 +/- 10 microns diameter, n = 57 vessels from 18 patients). After dissection, vessels were mounted onto pipettes in Kreb's buffer under conditions of zero flow and at a constant distending pressure of 60 mmHg. Drugs were applied extraluminally and steady state changes in diameter measured with videomicroscopy. RESULTS: After contraction by endothelin or spontaneous tone, increasing concentrations of adenosine diphosphate (ADP) produced a similar dose-dependent dilation in vessels from atria (maximum 89 +/- 4%, n = 76) and ventricles (maximum 74 +/- 9%, n = 10). The dilation to ADP was abolished by mechanical removal of the endothelium. Similar dilator responses were found to bradykinin, substance P, arachidonic acid, and the calcium ionophore A23187 in both atria and ventricle. In contrast, acetylcholine (ACh) constricted all atrial vessels (-58 +/- 3%, n = 63) regardless of patient age or underlying disease. This constriction was attenuated by denudation, but not affected by inhibition of nitric oxide synthase or cyclo-oxygenase. Microvessels isolated from human ventricle exhibited a heterogeneous response to ACh with dilation being the predominant response. CONCLUSIONS: We conclude that isolated human coronary arterioles demonstrate endothelium-dependent dilation. However, the response to acetylcholine is unique with vasoconstriction in atrial vessels and dilation in ventricular arterioles.

Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo.

In the canine coronary microcirculation, acetylcholine (ACh)-induced vasodilation of large (> or = 100 microns) epicardial arterioles (LgA), but not small (< 100 microns) epicardial arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors in vivo. We hypothesized that the ACh-induced vasodilation of SmA is mediated by a cytochrome P-450 metabolite of arachidonic acid (AA). Epicardial coronary microvascular diameters in dogs were measured at baseline and after treatment with topically applied ACh (1, 10, and 100 microM), AA (1, 5, and 10 microM), or sodium nitroprusside (SNP; 10-100 microM). Coronary microvascular diameters were compared among control dogs (group OO); dogs pretreated with N omega-nitro-L-arginine (L-NNA; 70 microM topically) (group NO); dogs pretreated with L-NNA plus clotrimazole (Clo; 1.6 microM topically) or 17-octadecynoic acid (ODYA; 2 microM topically), cytochrome P-450 monooxygenase inhibitors (groups NC and NY, respectively); dogs pretreated with Clo alone (group OC); and dogs pretreated with L-NNA plus Clo with AA as the agonist (group AA). ACh-induced vasodilation of LgA was abolished by L-NNA alone, whereas in SmA, L-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations of L-NNA plus either Clo or ODYA abolished ACh- and AA-induced dilation of SmA (100 microM ACh: NC, 3 +/- 5%; NY, 8 +/- 2%; 10 microM AA: 6 +/- 3%) but did not affect responses to SNP. These results suggest that the ACh-induced vasodilation of SmA is mediated in part by cytochrome P-450 metabolites of AA and provide the first evidence that the cytochrome P-450 pathway contributes to the regulation of coronary resistance vessels in vivo.

QT interval changes following neck dissection. A stratified prospective study.

Studies from Europe have suggested that neck dissection, especially right radical neck dissection, causes a dangerous prolongation of the QT interval. Sudden cardiac arrest due to QT prolongation has been reported following right radical neck dissection. We investigated the prevalence of QT interval prolongation following neck dissection. Electrocardiogram tracings from 45 patients who underwent different combinations of neck dissection were studied. Preoperative and postoperative tracings were interpreted by a cardiologist blinded to the patient identification of each tracing. There were 28 unilateral neck dissection patients and 17 bilateral neck dissection patients eligible for analysis. There were 7 patients in the classic right radical neck dissection group, and only 3 of these had no neck dissection on the left. Comparisons of preoperative versus postoperative corrected QT interval for all subjects did not indicate a significant change. Stratification by neck dissection type (radical, modified or selective, and carotid artery resection) or by side dissected (left, right, or both) also showed no significant differences. No malignant arrhythmias were encountered. Thus, in contrast to the European experience, our findings show no significant predictable change in the QT interval after any of the combinations of neck dissection. Head and neck surgeons should be aware of the possibility of postoperative QT interval prolongation following neck dissection, although in the absence of other risk factors it appears to be a rare occurrence.

Hyperglycemia-induced angina pectoris in a patient with diabetes mellitus.

A patient with diabetes mellitus and coronary artery disease presented with recurring episodes of worsening angina not associated with angiographic changes. Correlation with blood sugars demonstrated that angina would occur during episodes of hyperglycemia. During cardiac catheterization, coronary vascular responses including coronary flow reserve and responses to atrial pacing were measured with a Doppler flow wire before and following a glucose challenge. Coronary microvascular responses were impaired by hyperglycemia.

Myogenic constriction of human coronary arterioles.

Myogenic constriction is an important mechanism of blood flow regulation; however, it has never been demonstrated in the human coronary circulation. We examined responses of human coronary resistance vessels in vitro to changes in intraluminal pressure and evaluated the role of protein kinase C (PKC). Microvessels (passive diameter 44-227 microns) were dissected from atrial appendages obtained during cardiac surgery and studied under conditions of zero flow. In response to stepped increases in pressure, there was a graded response such that at 100 mmHg, vessels constricted to 55 +/- 4% of their passive diameter. There was an inverse relationship between vessel diameter and myogenic responsiveness. Basal tone was attenuated by inhibition of voltage-dependent calcium channels (VDCC) with diltiazem and by inhibition of PKC with calphostin C. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) enhanced basal tone. Active myogenic constriction was also impaired by calphostin C and augmented by PMA. Arterioles from patients with hypertension demonstrated enhanced myogenic constriction compared with vessels from normotensive patients (0.55 +/- 0.04 vs. 0.74 +/- 0.03; P < 0.01). These results demonstrate myogenic constriction in the human coronary microcirculation. Regulation of extracellular calcium by VDCC and intracellular calcium by PKC are important in mediating the magnitude of basal tone and myogenic responsiveness of these vessels.

Mechanism of coronary microvascular responses to metabolic stimulation.

UNLABELLED: Previous studies from our laboratory have shown that coronary microvascular dilation to increased myocardial oxygen consumption (MVO2) is greater in vessels < 100 microns. The mechanism responsible for this response is uncertain. OBJECTIVES: We tested the hypothesis that microvascular dilation to increased MVO2 is mediated by nitric oxide (NO). Since NO release may occur in response to increased shear, we also tested the hypothesis that metabolic byproducts released in response to increase in MVO2 will stimulate opening of the ATP-sensitive potassium channel. METHODS: Changes in epicardial coronary microvascular diameters were measured in 9 dogs given NG-nitro-L-arginine (LNNA; 100 microM, topically), 7 dogs given glibenclamide (10 microM, topically) and 12 control (C) dogs during increases in metabolic demand using dobutamine (DOB, 10 micrograms/kg/min, i.v.) with rapid atrial pacing (PAC, 300 bpm). Diameters of arterioles were measured using intravital microscopy coupled to stroboscopic epi-illumination. RESULTS: During the protocol, MVO2 increased to a similar degree in both experimental groups (LNNA and glibenclamide). Baseline hemodynamics and coronary microvascular diameters were similar between the two experimental groups and their respective control groups. In the presence of LNNA, coronary arteriolar (< 100 microns) dilation (% change from baseline) was impaired during the protocol (DOB: vehicle 18 +/- 5, LNNA 2 +/- 2 [P < 0.05]; DOB + RAP: vehicle 40 +/- 11, LNNA 6 +/- 2% [P < 0.05]). In contrast, glibenclamide did not impair coronary microvascular responses to increased MVO2 despite increases in MVO2. CONCLUSION: This study indicates that coronary microvascular dilation in response to increased metabolic stimulation using dobutamine in conjunction with rapid pacing is mediated through a nitric-oxide-dependent mechanism and not ATP-sensitive potassium channels. These results may have important implications in pathological disease states where nitric oxide mechanisms are impaired, such as diabetes and hypertension.

Effects of glycosylated hemoglobin on vascular responses in vitro.

UNLABELLED: Vascular responses to endothelium-dependent vasodilators are greatly impaired in vivo, while isolated blood vessels from animals with diabetes mellitus demonstrate less consistent degrees of impairment. Glycation of proteins, such as hemoglobin, has been implicated in the vascular abnormalities associated with diabetes. OBJECTIVE: The purpose of this study was to test the hypothesis that glycosylated hemoglobin is capable of reducing endothelium-dependent vasodilator responses, possibly explaining impaired dilation observed in vivo. METHODS: To test this hypothesis, the effect of glycosylated hemoglobin (GH) on vascular responses was studied in several vascular beds, including ventricular microvessels and coronary, mesenteric, femoral, and renal arteries. Coronary arterioles were isolated and mounted between two glass pipettes in a pressurized (30 cmH2O) organ chamber. Isolated artery segments were studied using a standard isometric ring technique. RESULTS: In ventricular microvessels, 10 nM nGH (non-GH) and GH both attenuated the relaxation to Ach. A lower concentration, 1 nM nGH or GH, did not alter dilation to Ach. In coronary, femoral, mesenteric and renal artery segments, endothelium-dependent responses were not altered by the presence of 10 or 100 nM nGH or GH. CONCLUSION: In coronary microvessels, and coronary, femoral, mesenteric and renal arteries, GH is not responsible for the impaired endothelial function associated with diabetes mellitus.