bluuebunny/crossref_metadata_2025 huggingface dataset:
Exhaled nitric oxide as a marker for organic nitrate tolerance.
Authors: Husain M , Adrie C , Ichinose F , Kavosi M , Zapol W M
Published: June 2012

BACKGROUND

This study was designed to demonstrate the development of biochemical tolerance to organic nitrates by measuring levels of exhaled gaseous nitric oxide (NO) in lambs given intravenous (IV) nitroglycerin or sodium nitroprusside.

METHODS AND RESULTS

IV injections of nitroglycerin or sodium nitroprusside produced dose-dependent and sustained increases in the exhaled levels of nitric oxide measured by chemiluminescence in awake lambs with tracheostomies. After a 6-hour IV infusion of 25 micrograms.kg-1.min-1 nitroglycerin, peak exhaled NO levels were significantly reduced (-53.6 +/- 4.9%, mean +/- SEM, P < .001) and systemic hypotensive responses were attenuated (-52.6 +/- 5.9%, P < .001) after an IV challenge of nitroglycerin but not sodium nitroprusside. After a subsequent 12-hour nitroglycerin-free period, there was complete recovery of NO excretion in exhaled breath and a return to baseline of systemic hypotensive changes on administration of IV nitroglycerin boluses. For IV sodium nitroprusside challenges, pulmonary NO excretion and systemic hypotensive responses remained constant throughout the study. Challenges with IV nitroglycerin but not sodium nitroprusside during a 12-hour nitroglycerin-free period resulted in delayed biochemical recovery with various exhaled NO levels and systemic hypotensive responses to challenges with IV nitroglycerin.

CONCLUSIONS

Measurements of exhaled NO provide in vivo, noninvasive evidence for the development of biochemical tolerance to nitroglycerin. There was reduced NO release into exhaled gas from the pulmonary vasculature concomitant with evidence of tolerance to nitroglycerin vasodilation in the systemic circulation.
Peripheral assessment of phenylephrine-induced vasoconstriction by laser Doppler flowmetry and its potential relevance to homeostatic mechanisms.
Authors: Silverman D G , Jotkowitz A B , Freemer M , Gutter V , O'Connor T Z , Braverman I M
Published: June 2012

BACKGROUND

Cutaneous laser Doppler flowmetry enables monitoring of changes in skin perfusion by quantifying the phase shift of laser light induced by moving red blood cells under a fiberoptic probe. It thus can identify the presence of and response to a vasoconstrictive stimulus. However, aspects of the technique must be defined before it can be used with maximum effectiveness. We evaluated the responses of two different laser Doppler outputs, the concentration of moving blood cells (CMBC) and red cell flux (CMBC times cell velocity), and the responses at two sites of probe application, the finger and forearm, during systemic infusions of phenylephrine.

METHODS AND RESULTS

Eight healthy volunteers were monitored with a brachial blood pressure cuff, ECG, and laser Doppler flowmeter probes applied to the palmar surface of the fourth finger and volar forearm of the arm opposite the pressure cuff. After baseline readings were obtained, the subjects received three 10-minute intravenous infusions of phenylephrine at rates of 0.4, 0.8, and 1.6 micrograms.kg-1.min-1. The two parameters, flux and CMBC, trended similarly. Flux and CMBC at the finger declined significantly in response to each infusion (P < .05 using repeated-measures ANOVA with Duncan's multiple range test). In contrast, flux and CMBC of the forearm had highly variable responses, with an overall increase during each infusion (P < .05 for % delta of forearm versus % delta of finger readings during the 0.4 microgram.kg-1.min-1 infusion). Heart rate declined significantly during each infusion, consistent with a baroreceptor-mediated response, even though systolic and diastolic blood pressures each increased by less than 2 mm Hg during the 0.4 microgram.kg-1.min-1 infusion.

CONCLUSIONS

As expected, laser Doppler readings at the finger decreased during infusion of an alpha 1-agonist. Although, like the digital vessels, forearm vessels have the potential to constrict, the increases in forearm readings suggest that these vessels are highly susceptible to homeostatic responses. The increase in CMBC (a parameter that is sensitive primarily to local changes in vascular caliber) suggested vasodilation of the underlying vessels. The forearm vasodilation and the concomitant decline in heart rate most likely represented vagally mediated baroreceptor activity, which was altered even though blood pressure changed minimally during the 0.4 microgram.kg-1.min-1 infusion. Thus, integrated assessment of skin perfusion at the finger and forearm may provide valuable information about the direct and indirect effects of a vasoactive stimulus. The present application of laser Doppler flowmetry suggests activation of vasodilatory reflexes despite minimal changes in blood pressure.
Insulin inhibits serotonin-induced Ca2+ influx in vascular smooth muscle.
Authors: Kahn A M , Allen J C , Seidel C L , Song T
Published: June 2012

BACKGROUND

Insulin in physiological concentrations attenuates the agonist-induced intracellular Ca2+ ([Ca2+]i) transient and inhibits contraction in individual nonproliferated cultured canine femoral artery vascular smooth muscle cells (VSMCs). In the present study, we wished to define the effects of insulin on individual components of Ca2+ transport in vascular smooth muscle.

METHODS AND RESULTS

Insulin (40 microU/mL) attenuated the 5-hydroxytryptamine (5-HT, serotonin; 10(-5) mol/L)-induced [Ca2+]i transient (measured by fura 2 fluorescence) in primary confluent canine femoral artery VSMCs in the presence of extracellular Ca2+. In Ca(2+)-free media, the 5-HT-induced [Ca2+]i transient was reduced by 42% and was not affected by insulin. This finding suggested that insulin inhibits 5-HT-induced Ca2+ influx but does not affect sarcolemmal Ca2+ efflux or Ca2+ release from intracellular stores. In support of those conclusions, we found that insulin inhibited the 5-HT-induced component of Mn2+ (a Ca2+ surrogate) influx (measured by fura 2 fluorescence quenching at the Ca2+ isosbestic excitation wavelength). In addition, 5-HT stimulated the rates of 45Ca2+ efflux from intact cells (a measure of sarcolemmal Ca2+ efflux) and from saponin-permeabilized cells (a measure of Ca2+ release from intracellular stores), but insulin did not affect these rates of 45Ca2+ efflux.

CONCLUSIONS

We conclude that a physiological insulin concentration attenuates the 5-HT-induced [Ca2+]i transient in confluent primary cultured canine femoral artery VSMCs by inhibiting the 5-HT-induced component of Ca2+ influx but not by affecting sarcolemmal Ca2+ efflux or Ca2+ release from intracellular stores.
Scar remodeling and transmural deformation after infarction in the pig.
Authors: Holmes J W , Yamashita H , Waldman L K , Covell J W
Published: June 2012

BACKGROUND

Changes in stress and tissue material properties have been proposed as important mechanical factors that may influence infarct expansion and subsequent healing. Because such changes will be reflected by alterations in the finite deformation of the tissue, we examined the direction and magnitude of myocardial deformation after coronary ligation in the pig.

METHODS AND RESULTS

Gold beads were implanted in the left ventricular free wall of five pigs. After ligation of the coronary supply to the region containing the markers, we used biplane cineradiography to reconstruct the three-dimensional deformations of the myocardium during single cardiac cycles as well as the remodeling deformations that occurred over time. Deformations were studied at 1 and 3 weeks after infarction. The analysis of single cardiac cycles revealed permanent loss of systolic shortening immediately after ligation. However, significant passive systolic wall thickening (P < .001) and large shears were observed at 3 weeks in regions composed almost entirely of collagen. The analysis of remodeling deformations at 1 week revealed infarct expansion with a predominant axis that varied widely. At 3 weeks, a 30% to 60% reduction in local tissue volume was measured in the infarct region, with the principal direction of scar shrinkage nearly circumferential in all animals (range, -2 degrees to 35 degrees).

CONCLUSIONS

We conclude that infarct expansion and scar shrinkage may be controlled by different factors. In addition, we conclude that measurement of systolic wall thickening alone is not always adequate to assess postinfarction regional contractile function.
Prevention of arterial reocclusion after thrombolysis with activated protein C. Comparison with heparin in a canine model of coronary artery thrombosis.
Authors: Sakamoto T , Ogawa H , Yasue H , Oda Y , Kitajima S , Tsumoto K , Mizokami H
Published: June 2012

BACKGROUND

Reocclusion of recanalized coronary arteries often limits the efficacy of coronary thrombolytic therapy in patients with acute myocardial infarction. Activated protein C (APC) is an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the effect of APC on thrombolysis with recombinant tissue-type plasminogen activator (rTPA) was studied in a canine model of coronary artery thrombosis.

METHODS AND RESULTS

Continuous artery flow monitoring in the left anterior descending coronary artery of 30 anesthetized adult beagles was performed by a magnetic flowmeter. Localized thrombosis was produced in the left anterior descending coronary artery and administration of rTPA (alteplase, 0.45 mg/kg IV) was done for 30 minutes. The dogs were randomly assigned to receive one of the following intravenous adjunctive therapies: (1) control group (n = 10): human albumin at a rate of 0.83 mL/min; (2) APC group (n = 10): human plasma-derived APC (0.6 mg/kg) with human albumin as a vehicle at a rate of 0.83 mL/min; and (3) heparin group (n = 10): heparin (200 U/kg) with saline at a rate of 0.83 mL/min. Each adjunctive therapy was started simultaneously with rTPA and lasted for 60 minutes. Coronary recanalization occurred in all dogs of each adjunctive treatment group in 19.1 +/- 1.9 minutes (mean +/- SEM). In a 120-minute observation after the termination of rTPA, reocclusion developed in all the dogs in the control and heparin groups but in only 3 of the 10 dogs in the APC group (P < .002 versus control and heparin). Time from recanalization to reocclusion (minutes, mean +/- SEM) was prolonged in the APC group (103.2 +/- 14.2) as compared with the control (10.2 +/- 2.3, P < .001) and heparin (30.3 +/- 11.8, P < .002) groups. Activated partial thromboplastin time was prolonged similarly in each group after thrombolytic therapy. On the other hand, bleeding time was prolonged in only the heparin group after the treatment. Serious hemorrhagic side effects were not observed in all three groups.

CONCLUSIONS

APC prevents coronary artery reocclusion after recanalization with rTPA in a canine model of coronary artery thrombosis. This finding suggests that APC may be useful as an adjunctive treatment to enhance the effects of thrombolytic therapy in patients with acute myocardial infarction.
Pathogenesis of acute myocardial infarction. Novel regulatory systems of bioactive substances in the vessel wall.
Authors: Kawai C
Published: June 2012

Rupture of the lipid-rich atheromatous plaque, intraplaque hemorrhage, and intraluminal thrombus are three pathological hallmarks most commonly recognized in the infarct-related coronary artery at the site of acute myocardial infarction. Rupture of the atheromatous plaque is closely related to but does not fully explain the genesis of occlusive intracoronary thrombus formation and thus the development of acute myocardial infarction. Besides a variety of hematologic disorders, one should emphasize the role of the platelet-derived mediators that promote an environment where thrombosis and vasoconstriction occur, including TXA2, serotonin, ADP, platelet-derived growth factor, tissue factor, and the diminished availability of those natural endogenous substances that inhibit platelet aggregation, such as EDRF, tissue plasminogen activator, and PGI2. PGI2 released from vascular endothelial cells is extremely unstable. Our group provided the first evidence that HDL stabilizes PGI2 through the newly discovered function of Apo A-I, which is associated with the surface of HDL particles and identified as PGI2 stabilizing factor. Decrease in HDL-associated Apo A-I in patients with unstable angina and during the acute phase of myocardial infarction indicates that HDL plays an important role in preventing coronary atherosclerosis and intracoronary thrombus formation by stabilizing PGI2 in addition to the generally accepted biochemical property of HDL to prevent the accumulation of cholesterol by mobilizing free cholesterol from tissues or macrophages. There is also a PGI2 synthesis-stimulating factor in serum that has not yet been identified chemically. EDRF or nitric oxide provides another important regulating system in the vessel wall. Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
Associations of the HDL2 and HDL3 cholesterol subfractions with the development of ischemic heart disease in British men. The Caerphilly and Speedwell Collaborative Heart Disease Studies.
Authors: Sweetnam P M , Bolton C H , Yarnell J W , Bainton D , Baker I A , Elwood P C , Miller N E
Published: June 2012

BACKGROUND

The relative importance of HDL2 and HDL3 cholesterol as risk factors for ischemic heart disease (IHD) is still uncertain. Their associations with the incidence of IHD in the Caerphilly and Speedwell prospective studies are described.

METHODS AND RESULTS

The two studies have a common core protocol and are based on a total of 4860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell: 251 major IHD events had occurred. Lipid levels were measured on fasting samples. Different laboratories were used by the two studies. Each laboratory used ultracentrifugation to separate HDL2 and HDL3. Both subfractions were inversely associated with risk of IHD. Standardized relative odds of developing major IHD were 0.95 (95% confidence interval [CI], 0.80 to 1.14) for HDL2 cholesterol and 0.83 (95% CI, 0.68 to 1.00) for HDL3 cholesterol in Caerphilly and 0.76 (95% CI, 0.57 to 1.01) for HDL2 and 0.64 (95% CI, 0.49 to 0.83) for HDL3 in Speedwell. The association with incident IHD appeared to be stronger for HDL3 in both areas. No linear combination of the two subfractions was a better predictor of IHD than total HDL cholesterol alone.

CONCLUSIONS

In British men, both HDL2 and HDL3 cholesterol are inversely associated with the incidence of IHD. However, the prediction of the risk of IHD from total HDL cholesterol alone could not be improved upon by measurement of the two HDL subfractions. The relative value of the two HDL subfractions as predictors of risk is still unresolved. The uncertainty may be due, at least in part, to problems associated with their measurement.
Implantation by electrophysiologists of 100 consecutive cardioverter defibrillators with nonthoracotomy lead systems.
Authors: Strickberger S A , Hummel J D , Daoud E , Niebauer M , Williamson B D , Man K C , Horwood L , Schmittou A , Kalbfleisch S J , Langberg J J
Published: June 2012

BACKGROUND

Traditional lead systems for implantable cardioverter defibrillators (ICDs) require a thoracotomy for placement. Nonthoracotomy lead systems are available and are usually implanted by an electrophysiologist and a surgeon. The purpose of this study was to prospectively evaluate the safety and efficacy of ICD implantation with a nonthoracotomy lead system by electrophysiologists.

METHODS AND RESULTS

A consecutive series of 100 patients (mean age, 61 +/- 13 years, +/- SD) underwent ICD implantation with a nonthoracotomy lead system while intubated and under general anesthesia. Seventy-seven patients had coronary artery disease, 15 had idiopathic cardiomyopathy, 6 had miscellaneous heart disease, and 2 had structurally normal hearts. The mean ejection fraction was 0.29 +/- 0.13. Sixty-eight patients had suffered a cardiac arrest, and 32 had had ventricular tachycardia or syncope. All patients except 9 underwent electrophysiological testing and had failed 1 +/- 1 drug trials before ICD implantation. Three types of nonthoracotomy lead systems were used. The nonthoracotomy lead with an ICD was successfully implanted in 96 patients (96%). Of the unsuccessful implants, 1 patient did not have venous access, the passive fixation lead in 1 would not remain lodged, 1 had elevated defibrillation thresholds, and 1 developed a hemopneumothorax while venous access was being obtained. The mean defibrillation threshold was 17 +/- 6 J. The mean procedure duration was 161 +/- 57 minutes. When a subcutaneous patch was used (n = 58), the procedure duration was 189 +/- 5 minutes, and when a subcutaneous patch was not required (n = 40), the procedure lasted 123 +/- 37 minutes (P < .0001). Patients remained in the hospital 4.5 +/- 4.1 days after implantation, with no procedure-related deaths. Acute complications occurred in 10 patients; 2 had lead dislodgments, 1 with previous abdominal surgery had his abdominal cavity entered (without other complications) while the ICD pocket was being made, 1 had postoperative heart failure, 1 developed a large hematoma when anticoagulation therapy was initiated, 3 required reintubation because of excessive anesthesia, 1 developed superficial cellulitis, and 1 developed a hemopneumothorax secondary to a lacerated subclavian vein. During 6 +/- 3 months of follow-up, 2 patients developed lead fractures.

CONCLUSIONS

(1) Electrophysiologists can implant an ICD with a nonthoracotomy lead system safely and with a high success rate; (2) use of a subcutaneous patch correlates with longer procedure durations; and (3) special precautions should be taken in patients with previous abdominal surgery.
Mechanism of 'inappropriate' sinus tachycardia. Role of sympathovagal balance.
Authors: Morillo C A , Klein G J , Thakur R K , Li H , Zardini M , Yee R
Published: June 2012

BACKGROUND

"Inappropriate" sinus tachycardia (IST) is an uncommon and poorly defined atrial tachycardia characterized by inappropriate tachycardia and exaggerated acceleration of heart rate with "normal" P wave. The mechanism of this tachycardia is unknown. The purpose of the present study was to determine the role of autonomic balance in the genesis of IST.

METHODS AND RESULTS

Six female patients aged 23 to 38 years with IST and 10 age- and sex-matched control subjects were assessed with the following autonomic function tests: (1) sympathovagal balance to the sinus node assessed by calculating the LF/HF (low frequency/high frequency) ratio using power spectral analysis both in the supine position and after 10 minutes of head-up tilt to 60 degrees, (2) cardiovagal reflex assessed by cold face test (CFT), (3) beta-adrenergic sensitivity as determined by calculating isoproterenol dose-response curves and isoproterenol chronotropic dose 25 (CD25), and (4) intrinsic heart rate (IHR) assessed after autonomic blockade with atropine 0.04 mg/kg and propranolol 0.2 mg/kg administered as an intravenous bolus. No significant differences in the LF/HF ratio both in the supine position (2.8 +/- 0.3 versus 2.6 +/- 0.4) and during upright tilt (8.7 +/- 1.3 versus 8.5 +/- 0.5) were observed between control subjects and IST patients. Cardiovagal response to CFT was markedly depressed in all patients (6.3% IST patients versus 24.2% control subjects, P < .001). beta-Adrenergic hypersensitivity to isoproterenol was noted in all patients (mean CD25, 0.29 +/- 0.10 microgram IST patients versus 1.27 +/- 0.4 microgram control subjects; P < .001), and high IHR was noted in all cases. The patients were treated with high doses of beta-blockers with adequate short-term control. Radiofrequency catheter ablation of the sinus node area was performed in one drug-refractory patient.

CONCLUSIONS

These findings suggest that the mechanism leading to IST is related to a primary sinus node abnormality characterized by a high IHR, depressed efferent cardiovagal reflex, and beta-adrenergic hypersensitivity.
Mononuclear cells from dogs with acute lung allograft rejection cause contraction of pulmonary arteries.
Authors: Cale A R , Ricagna F , Wiklund L , McGregor C G , Miller V M
Published: June 2012

PURPOSE

Experiments were designed to determine whether or not leukocytes activated by acute pulmonary rejection cause contractions of isolated pulmonary arteries.

METHODS AND RESULTS

Separate suspensions of (a) polymorphonuclear cells (> 95%) and (b) mononuclear cells (85% lymphocytes/10% monocytes/5% polymorphonuclear cells), respectively, were obtained from the arterial blood of four groups of adult male mongrel dogs: unoperated dogs (controls), dogs with single-lung autotransplants, dogs with rejecting single-lung allotransplants, and unoperated dogs treated with the same immunosuppressants as allotransplanted dogs. These suspensions were added to rings of control intralobar pulmonary arteries suspended in organ chambers for measurement of isometric force. The endothelium was removed mechanically from selected rings. No significant change in basal tension of pulmonary arterial rings occurred by adding suspensions of polymorphonuclear cells from any of the four groups of dogs. Significant cell-number-dependent increases in tension occurred with suspensions of mononuclear cells from unoperated dogs, autotransplanted dogs, and unoperated, medicated dogs. These increases in tension were less in rings with compared to those without endothelium. Addition of a synthetic analogue of L-arginine abolished this difference. Suspensions of mononuclear cells from rejecting allotransplanted dogs caused significantly greater contractions in rings with endothelium than those observed with suspended cells from either unoperated, autotransplanted dogs or unoperated, medicated dogs. Addition of superoxide dismutase plus catalase or an antagonist of endothelin-A receptors (BQ-123) reduced contractions in rings with endothelium but not in those without endothelium to suspensions of mononuclear cells from rejecting allotransplanted dogs.

CONCLUSIONS

The results of this study suggest that mononuclear cells cause contraction of pulmonary arteries, which can be partially inhibited by endothelium-derived nitric oxide. However, if the mononuclear cells are activated by acute pulmonary rejection, contractions are no longer inhibited by the endothelium. Under conditions of rejection, contractions are mediated in part by oxygen radicals and endothelin(s).
Neutrophil implications in platelet deposition and vasoconstriction after deep arterial injury by angioplasty in pigs.
Authors: Merhi Y , Lacoste L L , Lam J Y
Published: June 2012

BACKGROUND

Experimental studies in vitro suggest that neutrophils can modulate platelet function and vasomotor responses. In the present study, the interactions among neutrophils, platelets, and arterial responses to injury in vivo were assessed.

METHODS AND RESULTS

The acute thrombotic and vasomotor responses of porcine carotid arteries to balloon injury in vivo were evaluated in three groups of animals: neutropenic pigs treated (n = 11) or not treated (n = 12) with aspirin and healthy untreated control pigs (n = 15). Neutropenia was achieved by treatment with cyclophosphamide (50 mg/kg, 4 days before the experiment), which decreased circulating leukocyte count by 92% and almost abolished neutrophil aggregation to N-formyl-methionyl-leucyl-phenylalanine without affecting blood platelet count, hematocrit, hemoglobin concentration, or whole blood platelet aggregation to ADP. 51Cr platelet deposition on deeply injured and uninjured arterial segments was not statistically influenced by neutrophil depletion, whereas the angiographic vasoconstrictive response at the site of endothelial injury distally was significantly reduced by 41% from 46.3 +/- 2.9% in the control group to 27.2 +/- 4.1% in the neutropenic group (P < .05). Aspirin treatment in combination with neutropenia produced a 50% reduction in whole blood platelet aggregation, resulted in a significant inhibition of platelet deposition to deeply injured arteries, and decreased vasoconstriction by 66% to 15.6 +/- 3.0% (P < .05 versus control and neutropenic).

CONCLUSIONS

Neutrophils can influence the vasoconstrictive response at the site of endothelial injury in vivo. In addition to platelets, neutrophil interaction with the injured vessel wall may be implicated in the pathophysiological response to arterial injury in vivo.
Variable participation of 5-HT1-like receptors and 5-HT2 receptors in serotonin-induced contraction of human isolated coronary arteries. 5-HT1-like receptors resemble cloned 5-HT1D beta receptors.
Authors: Kaumann A J , Frenken M , Posival H , Brown A M
Published: June 2012

BACKGROUND

Serotonin may contract human large coronary arteries through two 5-hydroxytryptamine (5-HT) receptors, 5-HT1-like and 5-HT2. These 5-HT1-like receptors resemble both cloned 5-HT1D receptor subtypes, 5-HT1D alpha and 5-HT 1D beta. Although these subtypes have similar pharmacology, 5-HT1D beta receptors appear to have lower affinity for ketanserin than 5-HT1D alpha receptors. We assessed the relative participation of 5-HT1-like and 5-HT2 receptors and attempted to identify whether vasoconstrictor 5-HT1-like receptors are 5-HT1D alpha or 5-HT1D beta.

METHODS AND RESULTS

Epicardial coronary arteries were dissected from the hearts of 29 patients (including 1 healthy (donor) undergoing heart transplant operation. Endothelium-denuded strips were set up to contract at 37 degrees C. To assess the relative contributions of 5-HT1-like and 5-HT2 receptors, we blocked the latter with ketanserin (0.1 to 1.0 mumol/L) and ketanserin-resistant receptors with methiothepin (0.1 mumol/L). Concentration-effect curves for 5-HT, in the absence and presence of ketanserin, were analyzed by using a model for two receptor subtypes. The fractional contributions of 5-HT1-like and 5-HT2 receptors to the maximum effect of 5-HT, f1 and f2, were estimated in arteries from 28 patients: f1 (0.71 +/- 0.20, mean +/- SD) was significantly larger than f2 (0.29 +/- 0.20) (P < .0001). Using [3H]-serotonin to label transfected and expressed receptors, we verified that ketanserin has lower affinity for 5-HT1D beta (pKi [-log Ki, mol/L] less than 5.0) than for 5-HT1D alpha (pKi = 7.1 +/- 0.1) receptors. A concentration of ketanserin (1 mumol/L) that would occupy more than 90% of 5-HT1D alpha receptors failed to block 5-HT-induced contractions (4 patients). The 5-HT1-like receptor stimulant sumatriptan evoked maximal contractions that matched f1 and was equipotent with 5-HT through 5-HT1-like receptors (8 patients). No systematic influence of disease, atheroma, or therapy on f1 and f2 was detected.

CONCLUSIONS

Coronary artery contractile 5-HT1-like receptors resemble cloned 5-HT1D beta receptors and predominate over 5-HT2 receptors in mediating serotonin-evoked contractions. Sumatriptan contracts coronary arteries as a full agonist through 5-HT1-like receptors.
Serum lipoproteins in African Americans and whites with non-insulin-dependent diabetes in the US population.
Authors: Cowie C C , Howard B V , Harris M I
Published: June 2012

BACKGROUND

Despite the significant role that dyslipidemia is believed to play in the development of cardiovascular disease in diabetes, most studies examining diabetic dyslipidemia in the United States have not been population based, and very little data are available for African Americans with diabetes. We used data from a national survey to compare the effect of diabetes on lipid concentrations in African-American and white men and women. In addition, we examined other factors related to lipid concentrations and controlled for these factors in our analyses.

METHODS AND RESULTS

The Second National Health and Nutrition Examination Survey included a representative sample of 4177 African Americans and whites in the US civilian noninstitutionalized population 20 to 74 years old. These persons were classified as having non-insulin-dependent diabetes mellitus (NIDDM) (n = 720) or as being nondiabetic (n = 3457) based on an oral glucose tolerance test and a medical history of diabetes. Subjects were given an interview and physical examination that included measurement of serum lipoproteins, body mass index, body fat distribution, dietary fat intake, alcohol consumption, frequency of smoking, and use of medications. By univariate analysis, a worse profile of mean cholesterol, triglycerides, and high-density lipoprotein cholesterol levels was generally apparent in NIDDM than in nondiabetic subjects, regardless of race or sex; a similar pattern was found for the prevalence of abnormal concentrations of these lipids. Lipid profiles appeared to be worse in whites with NIDDM than in African Americans. For mean total and low-density lipoprotein cholesterol, concentrations tended to be worse in women with NIDDM than in men. When other factors significantly affecting lipid levels were adjusted by multivariate analysis, we found that in all race/sex groups, total cholesterol was higher in NIDDM than in nondiabetic subjects but differences were not significant (P = 54), triglyceride concentrations were significantly higher in NIDDM subjects (P < .0001), and high-density lipoprotein cholesterol concentrations were lower in NIDDM subjects (P = .003). An interaction of diabetes with race was found for low-density lipoprotein cholesterol (P = .0001), where concentrations were substantially lower in NIDDM than in nondiabetic subjects among African Americans (P < .01) but slightly higher in NIDDM subjects among whites (P = .33). For other lipids, no differential effect of NIDDM was found by race or sex.

CONCLUSIONS

In African-American and white men and women in the United States, NIDDM is associated with a pattern of dyslipidemia that may potentiate the atherosclerotic process. Diabetic treatment should include aggressive treatment of dyslipidemia to reduce this increased risk.
Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial.
Authors: van Rij A M , Solomon C , Packer S G , Hopkins W G
Published: June 2012

BACKGROUND

The use of repeated intravenous infusions of EDTA, which has become known as "chelation therapy," has been promoted for treating intermittent claudication as well as a wide range of other disorders. Multiple reports of excellent results in large numbers of patients have encouraged the use of this regimen. The lack of well-controlled studies substantiating the benefits of this treatment has limited its use mainly to private clinics. The aim of the study was to assess the benefits of chelation therapy in patients with intermittent claudication.

METHODS AND RESULTS

A double-blind, randomized, controlled trial included 32 patients with intermittent claudication who were randomized to a treatment group (15) and a control group (17). Main outcome measures were subjective and measured walking distances and ankle/brachial pulse indices. Other outcome measures included lifestyle and subjective parameters of improvement, cardiac function, ECG, renal function, hematology, blood glucose, and lipid biochemistry. No clinically significant differences in main outcome measures between chelation therapy and placebo groups were detected up to 3 months after treatment. Measures of mood state, activities of daily living, and quality of life factors were not consistently affected by chelation therapy. An equal proportion (13%) of each group thought that they had received the active agent. The proportion of patients showing an improvement in walking distance was not significantly different between the chelation group (60%) and the control group (59%).

CONCLUSIONS

Chelation therapy has no significant beneficial effects over placebo in patients with intermittent claudication.
Age-related changes in beta-adrenergic neuroeffector systems in the human heart.
Authors: White M , Roden R , Minobe W , Khan M F , Larrabee P , Wollmering M , Port J D , Anderson F , Campbell D , Feldman A M
Published: June 2012

BACKGROUND

Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts.

METHODS AND RESULTS

Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts.

CONCLUSIONS

There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.
Decrease in myocardial ryanodine receptors and altered excitation-contraction coupling early in the development of heart failure.
Authors: Vatner D E , Sato N , Kiuchi K , Shannon R P , Vatner S F
Published: June 2012

BACKGROUND

Rapid ventricular pacing for 1 day reduced myocardial contractile function without inducing heart failure in conscious, chronically instrumented dogs. After 4 to 7 weeks of pacing, myocardial contractility was depressed further and overt signs of congestive heart failure, eg, ascites, dyspnea, and edema, were evident.

METHODS AND RESULTS

The mechanical restitution response, a physiological index of calcium release, was depressed at 1 day of rapid ventricular pacing. Postextrasystolic potentiation was also depressed by a similar amount, 14 +/- 3%, at 1 day after pacing. The response to isoproterenol 0.2 microgram/kg per minute was depressed by a significantly greater amount (P < .05), 52 +/- 7%, at 1 day after pacing. 3H-ryanodine receptor binding fell from 1013 +/- 25 to 808 +/- 42 fmol/mg after 1 day of pacing and remained depressed at similar levels (782 +/- 61 fmol/mg) at 4 to 7 weeks when heart failure was manifest. Ryanodine receptor affinity was unchanged from control values. Neither dihydropyridine binding nor affinity for 3H-PN200-110 was changed from control levels. Within 5 days after recovery from 1 day of pacing, physiological responses to isoproterenol, postextrasystolic potentiation, and mechanical restitution recovered, as did 3H-ryanodine binding density.

CONCLUSIONS

These findings suggest that the changes in excitation-contraction coupling and potentially the sarcoplasmic reticulum calcium release channel occur early in the development of heart failure and therefore may be important in the pathogenesis of the contractile abnormalities in this disease state.
Focal mechanisms underlying ventricular tachycardia during prolonged ischemic cardiomyopathy.
Authors: Pogwizd S M
Published: June 2012

BACKGROUND

The present study was performed to define the mechanisms underlying spontaneously occurring ventricular arrhythmias in the failing heart.

METHODS AND RESULTS

Three-dimensional cardiac mapping from as many as 232 intramural sites was performed in five dogs with ischemic cardiomyopathy induced by multiple intracoronary embolizations. After 5 to 10 weekly embolizations with 90-microns latex microspheres into the left anterior and circumflex coronary arteries, left ventricular ejection fraction decreased from 63 +/- 3% to 22 +/- 3%. Subsequent weekly Holter monitoring of dogs in the conscious state demonstrated frequent multiform premature ventricular complexes (PVCs) (< or = 2000/d), couplets, and runs of ventricular tachycardia (VT) (< or = 70 beats in duration and < or = 560 beats per minute) in all dogs. Three-dimensional mapping of spontaneous rhythm for 60 minutes was performed an average of 6.4 weeks after the last embolization, during which time each dog demonstrated multiform PVCs, couplets, and runs of nonsustained VT at rates comparable to those in the conscious state. Mapping was of sufficient density to define the mechanism for 31 PVCs, 45 beats of ventricular couplets, and 99 beats of VT. Sinus beats preceding PVCs (n = 36) initiated in the septum and spread rapidly with a total activation time (46 +/- 1 milliseconds) that did not differ from that of sinus beats not preceding PVCs or VT (46 +/- 2 milliseconds, n = 10, P = .69). PVCs and the first beat of couplets or VT were initiated primarily in the subendocardium by a focal mechanism, based on the lack of intervening electrical activity between the termination of the preceding (sinus) beat and initiation of the ectopic beat (225 +/- 23 milliseconds), despite the presence of multiple intervening intramural recording sites. All subsequent beats of VT also were initiated by a focal mechanism, and their total activation time (89 +/- 1 milliseconds) did not differ from that of the initiating ectopic beats (86 +/- 2 milliseconds, P = .14), despite acceleration of VT to a cycle length of 200 milliseconds. Monomorphic VT was due to repetitive focal activation of subendocardial sites. Polymorphic VT was due to sequential focal activation from multiple sites arising in the subendocardium and, at times, in the subepicardium. Comparison of mapping data with results of detailed anatomic analysis of tissue demonstrated that focal sites of initiation exhibited patchy nontransmural fibrosis. Functional conduction delay of a moderate degree was evident only when fibrosis extended transmurally.

CONCLUSIONS

Spontaneously occurring PVCs, couplets, and VT in a model of ischemic cardiomyopathy are initiated and maintained by focal mechanisms with no evidence of macroreentry. Thus, therapeutic regimens to treat or prevent VT in the presence of ischemic cardiomyopathy will likely require interruption of these focal mechanisms.
Quantification of myocardial perfusion with myocardial contrast echocardiography during left atrial injection of contrast. Implications for venous injection.
Authors: Skyba D M , Jayaweera A R , Goodman N C , Ismail S , Camarano G , Kaul S
Published: June 2012

BACKGROUND

The purpose of this study was to determine whether myocardial perfusion can be quantified with myocardial contrast echocardiography using left atrial (LA) injection of contrast.

METHODS AND RESULTS

Based on a series of in vitro and in vivo experiments, the optimal dose of sonicated albumin microbubbles injected into the LA for establishing a linear relation between video intensity and blood volume in the anterior myocardium was determined. In 10 open-chest dogs, myocardial blood flow (MBF) was augmented by increasing myocardial blood volume (MBV) with an intravenous infusion of phenylephrine HCl. In the presence of this drug, left anterior descending artery stenosis was produced, followed by release of stenosis, to change MBF within the anterior myocardium. MBV was calculated by dividing radiolabeled microsphere-derived MBF by microbubble transit rate. There was close coupling between MBF and MBV in the anterior myocardium during LA injection of contrast (y = 1.0x-0.03, SEE = 1.07, r = .92, P < .001). An excellent correlation was also noted between background-subtracted peak video intensity and MBV (y = 0.24x + 0.73, SEE = 0.36, r = .88, P < .001). On multivariate analysis, background-subtracted peak video intensity correlated best with MBV.

CONCLUSIONS

Myocardial perfusion can be quantified from time-intensity curves derived from the anterior myocardium after LA injection of contrast. Background-subtracted peak video intensity in this situation correlates closely with MBV. When MBV and MBF are closely coupled, such as during inotropic stimulation of the heart, background-subtracted peak video intensity also correlates closely with MBF. Since there are similarities in the models of LA and venous injections, these data indicate that it may be feasible to quantify myocardial perfusion with myocardial contrast echocardiography after venous injection of contrast.
Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector.
Authors: Steg P G , Feldman L J , Scoazec J Y , Tahlil O , Barry J J , Boulechfar S , Ragot T , Isner J M , Perricaudet M
Published: June 2012

BACKGROUND

Previous investigations in live animals convincingly established that arterial gene transfer, while feasible, was compromised by a low transfection efficiency. More recent studies have shown that transfection efficiency may be substantially augmented by the use of recombinant adenoviral vectors. Most in vivo transfections reported to date, however, have used direct (operative) administration of the adenoviral vector. Clinical applications of arterial gene transfer (such as prevention of restenosis), however, would require local percutaneous delivery of the transgene. The present study was designed to extend in vivo intraoperative findings to percutaneous delivery system and to assess whether gene transfer remains site specific.

METHODS AND RESULTS

A recombinant, replication-defective adenovirus modified to include an expression cassette for nucleus-targeted beta-galactosidase was introduced into rabbit iliac arteries in vivo using either a double-balloon catheter (DBC, n = 27) or a hydrogel-coated balloon catheter (HBC, n = 27). Contralateral arteries-normal, endothelium-denuded, or sham-transfected with a control adenoviral vector-served as controls. beta-Galactosidase expression was assessed by X-Gal staining. Cell-transduction efficiency was measured by morphometric analysis. Polymerase chain reaction (PCR) and histochemistry were used to detect the presence and/or expression of viral DNA in remote organs. Transgene expression was detected in all cases (46 of 46) between 3 and 14 days after transfection but was in no case detectable 28 days after transfection. In the DBC group, transgene expression was limited to endothelial cells when the endothelium was left intact and to rare medial cells (< 2.2%) when it had been removed. In contrast, HBC delivery resulted in transduction of up to 9.6% of medial smooth muscle cells (P = .0001). Optimized PCR and histochemistry failed to detect evidence of extra-arterial transfection except in a small number of cells (between 1 in 3 x 10(2) and 1 in 3 x 10(5) cells) in the livers of 2 animals in the DBC group.

CONCLUSIONS

(1) Efficient, adenovirus-mediated, arterial gene transfer to endothelial and/or smooth muscle cells is feasible by percutaneous, clinically applicable techniques. (2) Consistent transfection of medial smooth muscle cells may be achieved when the endothelial layer is abraded. (3) Medial transfection is more efficient when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the adenoviral vector via HBC results in site-specific arterial gene transfer. Very-low-level extra-arterial transfection may occur, however, when the DBC is used.
Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture.
Authors: Kaartinen M , Penttilä A , Kovanen P T
Published: June 2012

BACKGROUND

Rupture in the shoulder region of a coronary atheroma is considered to be a sequel to local extracellular matrix degradation in this highly vulnerable site. Such degradation could be triggered by mast cells, which are filled with neutral proteases and are present in coronary atheromas. However, the distribution and phenotype of mast cells within coronary atheromas have not been studied.

METHODS AND RESULTS

Specimens of normal and atherosclerotic human coronary intima from 32 autopsy cases with ages ranging from 13 to 67 years were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. Of the tryptase-containing mast cells, a variable proportion (average, 40%; range, 0% to 100%) also contained chymase. In the normal coronary intimas, mast cells amounted to 0.1% of all nucleated cells. In the fatty streaks, this proportion was higher by 9-fold, and in the cap, core, and shoulder regions of atheromas by 5-, 5-, and 10-fold, respectively. Electron and light microscopic studies of mast cells in the shoulder region of atheromas revealed degranulation of mast cells, a sign of their activation, and moreover, that the proportion of activated mast cells was much higher (85%) in this region than in the normal intima (18%).

CONCLUSIONS

The far higher proportion (50-fold) of activated mast cells in the shoulder region of atheromas supports the hypothesis that mast cells, a cell type capable of triggering matrix degradation, actively participate in the destabilization and ensuing rupture of coronary atheromas and thus may trigger an acute coronary event.