bluuebunny/crossref_metadata_2025 huggingface dataset:
Low molecular weight heparin in prevention of restenosis after angioplasty. Results of Enoxaparin Restenosis (ERA) Trial.
Authors: Faxon D P , Spiro T E , Minor S , Coté G , Douglas J , Gottlieb R , Califf R , Dorosti K , Topol E , Gordon J B
Published: June 2012

BACKGROUND

Heparin, an anticoagulant, possesses antiproliferative effects and has been shown to reduce neointimal proliferation and restenosis following vascular injury in experimental studies.

METHODS AND RESULTS

The primary aim of this double-blind multicenter study was to determine if 40 mg Enoxaparin, a low molecular weight heparin, administered subcutaneously once daily for 1 month after successful angioplasty would reduce the incidence of restenosis. Four hundred fifty-eight patients were randomized at nine clinical centers (231 to placebo and 227 to Enoxaparin). The primary end point was angiographic or clinical restenosis. Angiographic restenosis was defined as a loss of 50% of the initial gain as measured by quantitative coronary angiography (QCA) at a core laboratory. In the absence of QCA, clinical evidence of restenosis was defined as death, myocardial infarction, repeat revascularization, or worsening angina. Using the intention-to-treat analysis for all patients, restenosis occurred in 51% of the placebo group and 52% of the Enoxaparin group (relative risk, 1.07, P = .625). Likewise, no difference in restenosis was evident when the change in minimal lumen diameter or other angiographic definitions of restenosis were used. Adverse clinical events were infrequent and did not differ between the groups with the exception of minor bleeding complications, which were more common in the Enoxaparin group.

CONCLUSIONS

Enoxaparin (40 mg/d SC for 1 month) following successful angioplasty did not reduce the incidence of angiographic restenosis or the occurrence of clinical events over 6 months. The treatment was well tolerated, although in-hospital minor bleeding was more common with active treatment.
Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary hypertension secondary to congenital heart defects.
Authors: Brook M M , Fineman J R , Bolinger A M , Wong A F , Heymann M A , Soifer S J
Published: June 2012

BACKGROUND

Pulmonary hypertension results in increased morbidity and mortality in children after surgical repair of congenital heart defects. Various vasodilators have been unsuccessful in providing preferential pulmonary vasodilation in these patients. Identification of a more preferential pulmonary vasodilator would improve the assessment, management, and outcome of these children. To determine whether ATP-MgCl2 is a preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects, ATP-MgCl2 was administered during routine cardiac catheterization, and the effects were compared with tolazoline. In addition, ATP-MgCl2 was infused intravenously during episodes of postoperative pulmonary hypertension.

METHODS AND RESULTS

During cardiac catheterization in 28 children, the effect of ATP-MgCl2 on the pulmonary artery pressure (PAP) and pulmonary vascular resistance index (Rp) was compared with tolazoline. ATP-MgCl2 (0.1 mg of ATP per kilogram per minute) decreased mean PAP by 24% (P < .05) and Rp by 47% (P < .05) without changing mean systemic arterial pressure or systemic vascular resistance. These effects were comparable to those of tolazoline (1 mg/kg). ATP-MgCl2 produced no significant side effects; tolazoline caused tachycardia, nausea, and vomiting. After cardiac surgery in 7 patients, ATP-MgCl2 decreased PAP by 14% (P < .05) and systemic arterial pressure by 6% (P < .05) and eliminated pulmonary hypertensive crises in 3 of 3 patients.

CONCLUSIONS

ATP-MgCl2 is a safe, effective, and preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects. It is useful for evaluating pulmonary vasoreactivity during cardiac catheterization and for treating pulmonary hypertension after cardiac surgery.
Rapid two-stage arterial switch operation. Evaluation of left ventricular systolic mechanics late after an acute pressure overload stimulus in infancy.
Authors: Boutin C , Wernovsky G , Sanders S P , Jonas R A , Castaneda A R , Colan S D
Published: June 2012

BACKGROUND

Banding of the pulmonary artery to induce left ventricular (LV) hypertrophy followed by arterial switch operation (ASO) within 2 weeks has been performed when a primary ASO was considered high risk because of inadequate LV hypertrophy.

METHODS AND RESULTS

Potential adverse myocardial effects of the two-stage procedure were examined by comparing outcome in 18 patients after a rapid two-stage ASO with 33 patients after a primary ASO. Regional wall motion was assessed. Echocardiographic and noninvasive pressure data were combined to obtain LV dimension, wall thickness, mass, fractional shortening, rate-corrected mean velocity of shortening, and end-systolic wall stress. Afterload-adjusted velocity of shortening was obtained as a load-independent index of contractility. In the two-stage ASO group, the magnitude and rate of hypertrophy after pulmonary artery banding were measured serially. No wall motion abnormalities were seen in either group. Systolic dysfunction due to higher afterload and lower contractility was observed in the two-stage ASO group. Contractility below the limits of normal was seen in 25% of two-stage ASO compared with 3% of primary ASO; however, symptomatic or progressive LV dysfunction was not observed. There was a significant inverse relation between the peak rate of hypertrophy immediately after banding and contractility at late exam. Lower ejection fraction before and early after pulmonary artery banding correlated with depressed contractility on late examination.

CONCLUSIONS

Myocardial contractility is lower after the two-stage ASO than after a primary repair. Severe or progressive dysfunction was not seen. A very high peak rate of hypertrophy and severe LV dysfunction after banding predict a greater reduction in late contractility.
Inhalation of steady-state sidestream smoke from one cigarette promotes arteriosclerotic plaque development.
Authors: Penn A , Chen L C , Snyder C A
Published: June 2012

BACKGROUND

A number of epidemiologic studies have suggested that every year environmental tobacco smoke (second-hand smoke) is responsible for tens of thousands of deaths, mostly from heart disease, in the United States. Environmental tobacco smoke is composed mainly (80% to 85%) of aged and diluted sidestream smoke. The remainder is exhaled mainstream smoke. Among the thousands of compounds that have been identified in environmental tobacco smoke are a number of carcinogens, including polynuclear aromatic hydrocarbon carcinogens, such as benzo(a)pyrene. We have demonstrated previously that a number of carcinogens, including benzo(a)pyrene, promote plaque development after injection into cockerels. There have been almost no studies showing a direct stimulatory effect of environmental tobacco smoke on plaque development. Recently we demonstrated that cockerels exposed to sidestream smoke for approximately 0.4% of their projected lifespan exhibited accelerated development of arteriosclerotic plaques. In that study, cockerels in specially designed inhalation chambers were exposed to the steady-state sidestream smoke from 5 cigarettes for 6 h/d for 16 weeks. This level of exposure is high but environmentally plausible. Statistically significant increases in plaque size were demonstrated in the smoke-exposed cockerels.

METHODS AND RESULTS

In the present study, exposure levels were decreased by a factor of 5. Thirty cockerels were exposed to the steady-state sidestream smoke from 1 cigarette for 6 hours per day for 16 weeks. The smoke was mixed with filtered air. Ten control cockerels were exposed to filtered air only. Levels of smoke surrogates, including carbon monoxide and total suspended particulates, were measured three times a day. Again, there was a statistically significant increase in plaque size in the smoke-exposed cockerels. To place these studies within a context of environmental relevance, levels of carbon monoxide were measured independently over 1 to 3 hours in four bars where there was heavy smoking. Measured carbon monoxide levels were as high or higher in the bars than they were in the exposure chambers during the 1-cigarette sidestream-smoke study.

CONCLUSIONS

Experimental exposure to secondhand smoke at levels equal to or even below those routinely encountered by people in smoke-filled environments is sufficient to promote arteriosclerotic plaque development.
Efferent sympathetic and vagal innervation of the canine right ventricle.
Authors: Ito M , Zipes D P
Published: June 2012

BACKGROUND

The functional pathways of efferent sympathetic and vagal innervation to the right ventricle (RV) might be important in a variety of disease states that involve the RV wall. The purpose of this study was to investigate those pathways.

METHODS AND RESULTS

We determined the effects of phenol and endocardial radiofrequency ablation applied to the RV anterolateral wall and outflow tract on effective refractory period (EPR) shortening during bilateral ansae subclaviae stimulation and ERP lengthening during bilateral vagal stimulation. We found that efferent sympathetic axons to the RV are located in the superficial subepicardium and that lateral sites receive sympathetic innervation predominantly from the lateral margin of the RV near the AV groove. Medial sites close to the left anterior descending coronary artery (LAD) receive sympathetic innervation from both the right lateral atrioventricular (AV) groove and regions near the LAD. At the RV outflow tract, some sympathetic fibers are located intramurally. Efferent vagal fibers are located at the RV surface within 10 mm of the right lateral AV groove; they penetrate intramurally and reach to the medial sites of the RV anterior wall. Other vagal fibers originate near the LAD and are intramural. Vagal fibers to the RV outflow tract are located intramurally either from the lateral side (close to the right coronary artery) or medial side (close to the LAD).

CONCLUSIONS

Efferent vagal and sympathetic innervation of the right ventricle resembles that of the left ventricle. A major difference is that efferent sympathetic fibers to the right ventricular outflow tract are located not only in the subepicardium but in the subendocardium as well.
Long-term outcome for 120 Japanese patients with Takayasu's disease. Clinical and statistical analyses of related prognostic factors.
Authors: Ishikawa K , Maetani S
Published: June 2012

BACKGROUND

Patients with Takayasu's disease, a chronic inflammatory arteriopathy of unknown cause, have variable clinical courses, and predictors of the long-term outcome are not well understood. We studied prognostic factors of this disease, based on follow-up results, and a new prognostic classification was proposed.

METHODS AND RESULTS

Life-table methods and Cox regression analyses were applied to clinical data on 120 patients who had been prospectively followed for a median of 13 years (range, 1 month to 34 years). The overall survival rate at 15 years after the diagnosis was 82.9% and remained the same for the remainder of the follow-up period. Univariate Cox analyses revealed that of the six dichotomous variables evaluated at diagnosis, four were statistically significant predictors, including complications (Takayasu's retinopathy, hypertension, aortic regurgitation, and aneurysm), pattern of the past clinical course, age of the patient, and calendar year of diagnosis. Thus, the 15-year survival was 66.3% versus 96.4% for patients with and without a major complication, 67.9% versus 92.9% for patients with and without a progressive course, 58.3% versus 92.7% for age > 35 years and < or = 35 years, and 79.9% versus 96.5% for patients diagnosed in 1957 through 1975 and in 1976 through 1990, respectively. The delay in diagnosis and the erythrocyte sedimentation rate (ESR) were of marginal significance. The multivariate Cox analysis showed that only two of the above variables were statistically independent predictors, ie, the major complication and the progressive course. In addition to these two factors, ESR was the third predictor, if the Cox stepwise elimination procedure was performed. These three predictors used in various combinations made a total of 1822 classifications theoretically feasible. Of these, a three-stage classification was selected as the best one, based on the Akaike information criterion. The presence of both major complication and progressive course (stage 3) was the worst prognostic indicator (43% survival at 15 years). In contrast, no patient died who had neither of these manifestations or who had a progressive course but an elevated ESR as well (stage 1).

CONCLUSIONS

The long-term outcome for patients with Takayasu's disease seems best predicted by two major prognostic factors, ie, complications and the pattern of the past clinical course, as well as by ESR. Aggressive medical and surgical treatment may be considered for patients with a major complication and a progressive course (stage 3).
Measurement of regional elastic properties of the human aorta. A new application of transesophageal echocardiography with automated border detection and calibrated subclavian pulse tracings.
Authors: Lang R M , Cholley B P , Korcarz C , Marcus R H , Shroff S G
Published: June 2012

BACKGROUND

Evaluation of regional aortic elastic properties in humans has been hampered by the need for invasive techniques to access instantaneous aortic pressure, wall thickness, and cross-sectional area or diameter. In this study, a new noninvasive method is presented for quantification of regional aortic elastic properties.

METHODS AND RESULTS

Twenty-five patients were studied during transesophageal echocardiographic procedures. Measurements of instantaneous aortic cross-sectional area were obtained with an automated border detection algorithm applied to short-axis transesophageal two-dimensional echocardiographic images of the proximal descending thoracic aorta. Instantaneous aortic wall thickness was derived from combined two-dimensional targeted M-mode end-diastolic wall thickness and instantaneous aortic area measurements. Instantaneous aortic pressures were estimated from calibrated subclavian pulse tracings recorded simultaneously. Data were digitized to generate aortic area-pressure loops. Regional aortic mechanical properties were quantified in terms of compliance per unit length (C is the slope of the area-pressure regression), aortic midwall radius (Rm), and incremental elastic modulus of the aortic wall (Einc). To assess the independent effect of age, Rm and Einc values were compared at a common level of aortic midwall stress (0.666 x 10(6) dynes/cm2). Mean values (+/- SD) for C, Rm, and Einc were 0.01 +/- 0.004 cm2/mm Hg, 1.14 +/- 0.17 cm, and 7.059 +/- 4.091 x 10(6) dynes/cm2, respectively. An inverse linear correlation was found between aortic compliance per unit length and age (r = -.68, P < .0007). Incremental elastic modulus was related to age (r = +.80, P < .00003) in a nonlinear fashion such that it increased sharply after the age of 60 years. Finally, midwall radius was less tightly correlated with age (r = +.45, P < .05). Values for C, Rm, and Einc as well as the age dependency of these properties are similar to those reported previously when invasive techniques were used.

CONCLUSIONS

This methodology constitutes a new tool to improve the clinical evaluation of regional aortic elastic properties in multiple disease states.
Inhibition of platelet deposition and lysis of intracoronary thrombus during balloon angioplasty using urokinase-coated hydrogel balloons.
Authors: Mitchel J F , Azrin M A , Fram D B , Hong M K , Wong S C , Barry J J , Bow L M , Curley T M , Kiernan F J , Waters D D
Published: June 2012

BACKGROUND

Conventional balloon angioplasty of intracoronary thrombus is associated with a high incidence of abrupt closure, distal embolization, and no-reflow phenomenon. The purpose of this study was to assess a new technique for treating intracoronary thrombus consisting of the local delivery of urokinase directly to the angioplasty site with urokinase-coated hydrogel balloons.

METHODS AND RESULTS

We assessed local urokinase delivery using hydrogel balloons in four protocols. First, we evaluated the pharmacokinetics of urokinase delivery in vitro using 125I-labeled urokinase to measure drug loading onto hydrogel balloons, drug retention by the hydrogel polymer during blood exposure, and drug transfer from the balloon surface to the arterial wall during balloon dilatation. Second, we measured 125I-urokinase washoff from the hydrogel balloon in the intact circulation and intramural drug delivery during in vivo balloon angioplasty in 10 anesthetized New Zealand rabbits. Third, we assessed the effect of local urokinase delivery on 111In-labeled platelet deposition after balloon angioplasty in vivo in 13 porcine carotid or iliac arteries dilated with urokinase-coated balloons and compared them with contralateral control arteries dilated with saline-coated balloons. Finally, we determined the clinical efficacy of urokinase-coated balloons in 15 patients with intracoronary thrombus, including 7 who demonstrated abrupt thrombotic closure after conventional angioplasty. Between 241 and 1509 U urokinase could be loaded onto hydrogel balloons ranging in size from 2 to 8 mm. In vitro and in vivo studies demonstrated that hydrogel balloons absorbed significantly more urokinase and demonstrated less drug wash-off than nonhydrogel balloons (P < .01). Similarly, both in vitro and in vivo studies demonstrated urokinase transfer from the hydrogel to the arterial wall during balloon angioplasty, with greater intramural drug deposition with larger balloons (P < .01). Local urokinase delivery after in vivo porcine angioplasty decreased 111In-labeled platelet deposition by 47% compared with contralateral control vessels (P = .03). Use of urokinase-coated balloons in patients with intracoronary thrombus resulted in thrombus dissolution and reversal of abrupt closure in all cases, without evidence of distal embolization.

CONCLUSIONS

With the use of hydrogel-coated balloons, urokinase can be delivered locally to an angioplasty site. This technique decreases platelet deposition after in vivo balloon angioplasty and is efficacious in treating intracoronary thrombus in patients, including those with abrupt thrombotic closure.
Treatment of myocardial infarction in the United States (1990 to 1993). Observations from the National Registry of Myocardial Infarction.
Authors: Rogers W J , Bowlby L J , Chandra N C , French W J , Gore J M , Lambrew C T , Rubison R M , Tiefenbrunn A J , Weaver W D
Published: June 2012

BACKGROUND

Multiple clinical trials have provided guidelines for the treatment of myocardial infarction, but there is little documentation as to how consistently their recommendations are being implemented in clinical practice.

METHODS AND RESULTS

Demographic, procedural, and outcome data from patients with acute myocardial infarction were collected at 1073 US hospitals collaborating in the National Registry of Myocardial Infarction during 1990 through 1993. Registry hospitals composed 14.4% of all US hospitals and were more likely to have a coronary care unit and invasive cardiac facilities than nonregistry US hospitals. Among 240,989 patients with myocardial infarction enrolled, 84,477 (35.1%) received thrombolytic therapy. Thrombolytic recipients were younger, more likely to be male, presented sooner after onset of symptoms, and were more likely to have localizing ECG changes. Among the 60,430 patients treated with recombinant tissue-type plasminogen activator (rTPA), 23.2% received it in the coronary care unit rather than in the emergency department. Elapsed time from hospital presentation to starting rTPA averaged 99 minutes (median, 57 minutes). Among patients receiving thrombolytic therapy, concomitant pharmacotherapy included intravenous heparin (96.9%), aspirin (84.0%), intravenous nitroglycerin (76.0%), oral beta-blockers (36.3%), calcium channel blockers (29.5%), and intravenous beta-blockers (17.4%). Invasive procedures in thrombolytic recipients included coronary arteriography (70.7%), angioplasty (30.3%), and bypass surgery (13.3%). Trend analyses from 1990 to 1993 suggest that the time from hospital evaluation to initiating thrombolytic therapy is shortening, usage of aspirin and beta-blockers is increasing, and usage of calcium channel blockers is decreasing.

CONCLUSIONS

This large registry experience suggests that management of myocardial infarction in the United States does not yet conform to many of the recent clinical trial recommendations. Thrombolytic therapy is underused, particularly in the elderly and late presenters. Although emerging trends toward more appropriate treatment are evident, hospital delay time in initiating thrombolytic therapy remains long, aspirin and beta-blockers appear to be underused, and calcium channel blockers and invasive procedures appear to be overused.
Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation.
Authors: Matsuno H , Stassen J M , Vermylen J , Deckmyn H
Published: June 2012

BACKGROUND

RGD-containing peptides are able to prevent binding of ligands to certain integrins such as alpha IIb beta 3 (glycoprotein IIb/IIIa) and alpha v beta 3 and as such are inhibitors for platelet aggregation and smooth muscle cell migration, both of which are involved in neointima formation.

METHODS AND RESULTS

Hamster carotid arteries were damaged, and neointima formation was determined at different time points. G4120, a cyclic RGD-containing peptide, was administered continuously intravenously by an implanted osmotic pump. Neointima formation was inhibited dose dependently. The inhibition was strongest when treatment was started before the vascular injury and continued for the full observation period. Treatment started after the damage and maintained until neointima assessment or started before and stopped earlier was less effective.

CONCLUSIONS

Inhibition of integrin function by an RGD-containing peptide results in reduction of the development of a neointima. This effect is due both to an early event, which could be due to inhibition of secretion of PDGF by the platelets with blocked alpha IIb beta 3, and to a late event, possibly by interference with smooth muscle cell alpha v beta 3.
Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study.
Authors: Kawachi I , Sparrow D , Vokonas P S , Weiss S T
Published: June 2012

BACKGROUND

Several studies have suggested an increased risk of fatal coronary heart disease (CHD) among patients with panic disorder, phobic anxiety, and other anxiety disorders. We prospectively examined this association in the Normative Aging Study.

METHODS AND RESULTS

An anxiety symptoms scale was constructed out of five items from the Cornell Medical Index, which was administered to the cohort at baseline. During 32 years of follow-up, we observed 402 cases of incident coronary heart disease (137 cases of nonfatal myocardial infarction, 134 cases of angina pectoris, and 131 cases of fatal CHD: made up of 26 cases of sudden cardiac death and 105 cases of nonsudden death). A nested case-control design (involving 1869 control subjects who remained free of diagnosed CHD) was used to assess the association between anxiety and risk of CHD. Compared with men reporting no symptoms of anxiety, men reporting two or more anxiety symptoms had elevated risks of fatal CHD (age-adjusted odds ratio [OR] = 3.20, 95% confidence interval [CI]: 1.27 to 8.09), and sudden death (age-adjusted OR = 5.73, 95% CI: 1.26 to 26.1). The multivariate OR after adjusting for a range of potential confounding variables was 1.94 (95% CI: 0.70-5.41) for fatal CHD and 4.46 (95% CI: 0.92-21.6) for sudden death. No excess risks were found for nonfatal myocardial infarction or angina.

CONCLUSIONS

These data suggest an association between anxiety and fatal coronary heart disease, in particular, sudden cardiac death.
Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction.
Authors: Ellis S G , da Silva E R , Heyndrickx G , Talley J D , Cernigliaro C , Steg G , Spaulding C , Nobuyoshi M , Erbel R , Vassanelli C
Published: June 2012

BACKGROUND

When used in the setting of acute myocardial infarction, intravenous thrombolytic agents fail to achieve early infarct artery patency in 15% to 50% of patients. We tested the hypothesis that immediate balloon angioplasty applied to patients with failed early reperfusion would improve left ventricular function and clinical outcome at 30 days compared with conservative management alone.

METHODS AND RESULTS

One hundred fifty-one patients with first anterior wall infarction treated with any accepted intravenous thrombolytic regimen and angiographically demonstrated to have an occluded infarct vessel within 8 hours of chest pain onset were randomized to aspirin, heparin, and coronary vasodilators (conservative therapy) or to this therapy and balloon angioplasty supplemented by further thrombolytic therapy as needed. Left ventricular function was assessed using multiple-gated equilibrium radionuclide technique to determine ejection fraction, and adverse clinical outcome was assessed evaluating death, ventricular tachycardia, and class III or IV heart failure at 30 days. Seventy-three patients were randomized to conservative therapy and 78 to angioplasty. The two groups were well balanced for patient age (59 +/- 11 years), sex (82% were male), and time to randomization (4.5 +/- 1.9 hours). Angioplasty was technically successful in 72 of 78 randomized patients (92%). Two patients randomized to conservative therapy crossed over to angioplasty within 72 hours. Resting 30-day ejection fraction was 40 +/- 11% in the angioplasty group and 39 +/- 12% in the conservative group (P = .49), but ejection fraction with exercise was 43 +/- 15% and 38 +/- 13% for the angioplasty and conservatively treated groups, respectively (P = .04). Adverse clinical outcomes included death in 5% and 10% (P = .18), severe heart failure in 1% and 7% (P = .11), and either death or severe heart failure in 6% and 17% (P = .05) of the angioplasty and conservatively managed groups, respectively.

CONCLUSIONS

When applied to patients with first anterior infarction, rescue angioplasty appears to be useful in the prevention of death or severe heart failure, with improvement in exercise, but not resting, ejection fraction. This strategy deserves further study and highlights the potential advantage of early mechanical restoration of infarct vessel patency when thrombolytic therapy has failed.
Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise.
Authors: Fleg J L , Schulman S , O'Connor F , Becker L C , Gerstenblith G , Clulow J F , Renlund D G , Lakatta E G
Published: June 2012

The cardiovascular response to beta-adrenergic stimulation is markedly blunted with advancing age, and this blunting may underlie some of the prominent age-associated changes in the hemodynamic profile during dynamic exercise. To examine this hypothesis, we administered the nonselective beta-adrenergic receptor blocker propranolol (0.15 mg/kg IV) to 25 healthy normotensive men ages 28 to 72 years from the Baltimore Longitudinal Study of Aging (BLSA) immediately before maximal upright cycle ergometry with 99mTc gated cardiac blood pool scintigraphy. Their hemodynamic responses to exercise were compared with those of 70 age-matched healthy unmedicated male BLSA control subjects. The maximal cycle work rate achieved was similar in propranolol-treated men (158 +/- 32 W) and control subjects (148 +/- 32 W) and declined similarly with age in both groups. Hemodynamics at seated rest were not age-related in either group; however, propranolol-treated men had lower heart rates (HR), systolic blood pressure (SBP), ejection fraction, and cardiac index than control subjects but higher end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) by covariance analysis. At maximal effort, several striking age-drug interactions were evident: Propranolol caused a greater reduction in HR and greater increases in EDVI and stroke volume index (SVI) in younger than in older men. Hence, at maximal work rate, HR declined less with age in the propranolol group (0.46 versus 1.09 beats per minute per year, P < .05 by covariance analysis); EDVI and SVI decreased with age (0.27 and 0.48 mL/m2 per year, respectively) after propranolol compared with increases of 0.47 and 0.16 mL/m2 per year in control subjects, respectively, each P < or = .05 by covariance analysis. The left ventricular contractility index, SBP/ESVI, at exhaustion was reduced by propranolol to a greater extent in younger than older men. Thus, acute beta-adrenergic blockade reverses the age-associated ventricular dilation at end diastole and end systole observed during upright cycle exercise and blunts the decline in maximal HR and myocardial contractility. These data suggest that the age-associated declines in maximal HR and left ventricular contractility during vigorous exercise are manifestations of reduced beta-adrenergic responsivity with advancing age which is partially offset by exercise-induced ventricular dilation.
Use of Hirulog in the prevention of venous thrombosis after major hip or knee surgery.
Authors: Ginsberg J S , Nurmohamed M T , Gent M , MacKinnon B , Sicurella J , Brill-Edwards P , Levine M N , Panju A A , Powers P , Stevens P
Published: June 2012

BACKGROUND

The study objective was to determine whether Hirulog, a direct thrombin inhibitor, has potential efficacy and safety in the prevention of deep vein thrombosis (DVT) in orthopedic patients. A phase 2 open-label, dose-escalating design was used to study 222 unselected patients undergoing major hip or knee surgery in tertiary-care, university-affiliated hospitals.

METHODS AND RESULTS

Subcutaneous Hirulog was initiated postoperatively. Patients were evaluated for bleeding and symptomatic pulmonary embolism, and mandatory bilateral venography was performed before discharge. Dose escalations were made on the basis of observed rates of bleeding and venous thrombosis. There were five dosage regimens used: 0.3 mg/kg every 12 hours, 0.6 mg/kg every 12 hours, 1.0 mg/kg every 12 hours for 3 days followed by 0.6 mg/kg every 12 hours for up to 11 days, 1.0 mg/kg every 12 hours, and 1.0 mg/kg every 8 hours. One hundred seventy-seven patients who had technically adequate bilateral venography or objectively documented pulmonary embolism were included in the primary analysis of efficacy. The highest dosage regimen (1.0 mg/kg every 8 hours) provided the lowest rates of total DVT (17%) and proximal DVT (2%), both of which were significantly lower (P = .010 and P = .023, respectively) than the pooled rates of total (43%) and proximal (20%) DVT seen with the first four regimens. Bleeding rates were low (< 5%) with all regimens.

CONCLUSIONS

This study demonstrates that 1.0 mg/kg Hirulog every 8 hours started postoperatively is potentially efficacious and safe for the prevention of DVT after major hip or knee surgery.
Thrombolytic effects of recombinant fibrolase or APSAC in a canine model of carotid artery thrombosis.
Authors: Markland F S , Friedrichs G S , Pewitt S R , Lucchesi B R
Published: June 2012

BACKGROUND

Thrombolytic agents used clinically rely on the activation of plasminogen to plasmin. Plasmin possesses multiple actions including increasing thrombin activity and activation of platelets. Thus, after successful thrombolytic therapy, arterial hyperactivity and reocclusion may be the result of a predominant plasmin-induced thrombogenic action at the site of the residual thrombus. Fibrolase, a direct-acting fibrinolytic enzyme from southern copperhead snake venom, induces rapid clot lysis in vitro. Fibrolase does not rely on plasminogen activation or any other bloodborne components for activity and is not inhibited by any of the rapidly acting serine proteinase inhibitors in blood.

METHODS AND RESULTS

We investigated the efficacy of fibrolase to lyse an occlusive thrombus formed in the carotid artery of the anesthetized dog. Electrolytic injury was initiated in both the right and left carotid arteries. Thirty minutes after both arteries were occluded, each vessel was infused with either fibrolase (4 mg/kg over 5 minutes) or physiological saline (over 5 minutes). In two separate groups of dogs, anisoylated plasminogen streptokinase activator complex (APSAC) (0.1 U/kg) was infused into the occluded vessel. In the artery infused with fibrolase, five of five dogs exhibited patency within 6 +/- 1 minutes of the infusion (P < .05 versus vehicle-treated artery; Fisher's exact test). In the contralateral carotid artery that received vehicle, the occlusion was maintained throughout the experimental protocol. APSAC alone lysed the thrombus in each vessel within 17 +/- 3 minutes. Five minutes after the end of fibrolase administration and in one of the groups administered APSAC, a glycoprotein (GP)IIb/IIIa antibody, 7E3 (0.8 mg/kg IV), was administered to prevent reocclusion of the patent artery. After 7E3 administration, the vessel treated with fibrolase remained patent in four of five dogs, and six of six APSAC-treated vessels were patent for the remainder of the observation period (2 hours).

CONCLUSIONS

These studies demonstrate that local administration of fibrolase lyses a carotid arterial thrombus rapidly without excessive hemorrhage or hemodynamic compromise. The enzyme in combination with antiplatelet therapy (7E3) offers a unique mechanism for clot dissolution and may prove useful as a clinically efficacious alternative to presently used thrombolytic agents or may act in a synergistic manner with plasminogen activators.
Acute effects of nitrates on exercise testing in patients with syndrome X. Clinical and pathophysiological implications.
Authors: Lanza G A , Manzoli A , Bia E , Crea F , Maseri A
Published: June 2012

BACKGROUND

Sublingual nitrates are much more effective in relieving angina pectoris in patients with coronary artery disease than in patients with syndrome X, but it is not known whether their effect on exercise tolerance is also different in these two groups of patients.

METHODS AND RESULTS

Treadmill exercise testing was performed before and after administration of sublingual isosorbide dinitrate (ISDN, 5 mg) in 18 patients with syndrome X (effort angina and normal coronaries, group X) and in 33 patients with documented coronary artery disease (group C). As a selection criterion, all patients had ST-segment depression > or = 1 mm on the control exercise test. Compared with the control test, the main differences in the two groups observed during the exercise test after administration of ISDN were (1) heart rate at 1-mm ST-segment depression was higher (126 +/- 25 versus 104 +/- 15 beats per minute [bpm], P < .01) in group C, whereas it was not different (125 +/- 15 versus 126 +/- 16 beats per minute) in group X; (2) the rate-pressure product at 1-mm ST-segment depression, the time to 1-mm ST-segment depression, and the exercise duration were significantly improved in group C (P < .01 for all) but were worsened in group X (18,047 +/- 4159 versus 20,535 +/- 4507 bpm . mm Hg, P = .014; 268 +/- 312 versus 429 +/- 214 seconds, P < .01; 494 +/- 279 versus 622 +/- 194 seconds, P = .013, respectively); (3) a normalization of the ECG (no ST-segment depression) was obtained in 10 patients (30%) of group C but in only 1 (5%) of group X (P < .01); (4) angina was prevented in 10 of 19 patients of group C but in no patient of group X (P < .01).

CONCLUSIONS

In patients presenting with anginal chest pain, the effects of sublingual nitrates on exercise testing appear to be clinically useful to distinguish patients with coronary artery stenoses from patients with syndrome X. Indeed, worsening of exercise tolerance is highly predictive of normal coronary arteries. Furthermore, the failure of nitrates to improve exercise tolerance in patients with syndrome X suggests that a deficiency in coronary prearteriolar nitric oxide production is unlikely to play a key role in the pathophysiology of the syndrome.
Different effects of strenuous exercise and moderate exercise on platelet function in men.
Authors: Wang J S , Jen C J , Kung H C , Lin L J , Hsiue T R , Chen H I
Published: June 2012

BACKGROUND

Platelets play an important role in the pathogenesis of cardiovascular diseases. It is also noticed that on one hand, regular exercise can reduce the risk of cardiovascular diseases, and on the other hand, vigorous exercise provokes sudden cardiac death. We therefore hypothesize that various intensities of exercise may affect platelet function differently.

METHODS AND RESULTS

Strenuous and moderate exercise (about 50% to 55% of peak oxygen consumption, VO2peak) on a bicycle ergometer in 10 sedentary and 10 physically active healthy young men was executed on two separate occasions. Blood samples were collected before and immediately after exercise. A newly designed tapered parallel plate chamber was used to assess platelet adhesiveness. Platelet aggregation induced by ADP was evaluated by the percentage of reduction in single platelet count. beta-Thromboglobulin (beta-TG) and platelet factor 4 (PF4) were measured by ELISA. In addition, a similar study on 5 patients with stable angina were also conducted. Our results showed that (1) in the sedentary healthy group, platelet adhesiveness and aggregation were increased by strenuous exercise and depressed by moderate exercise; (2) in the active healthy group, platelet adhesiveness and aggregation were enhanced by severe exercise, whereas only aggregation was decreased by moderate exercise; (3) in the patients with stable angina, platelet adhesiveness and aggregation were enhanced by strenuous exercise and adhesiveness was suppressed by moderate exercise; (4) the degree of hemoconcentration induced by acute exercise tended to be related to the severity of exercise in all subjects; and (5) although severe exercise elevated beta-TG and PF4, there were no significant changes in beta-TG, PF4, and the ratio of beta-TG to PF4 in healthy subjects after exercise.

CONCLUSIONS

It is concluded that platelet adhesiveness and aggregability may be sensitized by strenuous exercise in both healthy subjects and patients with stable angina. In contrast, platelet function can be suppressed significantly by moderate exercise in the healthy and tends to be depressed in patients with stable angina. The former may increase the risk of cardiac arrest and the latter may protect us from cardiovascular diseases. In addition, the effects of acute exercise tend to be more pronounced in the sedentary than in the active.
Timing and velocity of ejection as major determinants of end-systolic pressure in isolated rabbit hearts.
Authors: Ezzaher A , el Ouazzani T , Crozatier B
Published: June 2012

BACKGROUND

Systolic shortening is known to produce muscle deactivation. The present study was designed to analyze whether the velocity and the timing of ejection play a role on end-systolic pressure-volume relations (ESPVR).

METHODS AND RESULTS

In isolated rabbit hearts, left ventricular pressure and volume were recorded and digitized, and left ventricular volume was controlled by a servosystem (4-millisecond cycles) to alter the timing of ejection. A significant deficit in end-systolic pressure was observed when ejection was late in systole with respect to earlier ejection. This was associated with a significantly reduced end-systolic elastance. End-systolic pressure of beats with slow ejection was intermediate between that of the beats with early ejection and that of beats with late ejection with a significantly increased end-systolic volume compared with beats with early rapid ejection. The same results were obtained with hypertrophied hearts (abdominal aortic stenosis). Pressure-volume loop areas were significantly increased in beats with slow ejections and with rapid delayed ejections versus early rapid ejections. No change in the positive peak of dP/dt was observed when the timing and the velocity of ejection were modified.

CONCLUSIONS

ESPVR is modified by the ejection profile, with a decreased end-systolic pressure and an increased pressure-volume loop area related to the velocity and the amount of shortening during the end-systolic phase. These indices of ventricular function thus must be used with caution when the timing of ejection is altered, and the end-diastolic volume-peak dP/dt relation may be a better index of ventricular function.
Effect of ventilation on resuscitation in an animal model of cardiac arrest.
Authors: Idris A H , Becker L B , Fuerst R S , Wenzel V , Rush W J , Melker R J , Orban D J
Published: June 2012

BACKGROUND

The need for ventilation during the initial management of cardiac arrest is an important public health problem that is being debated. The present study was designed to determine whether ventilation affects return of spontaneous circulation from cardiac arrest in a swine model with an interval of untreated ventricular fibrillation of 6 minutes, as reported in witnessed out-of-hospital human cardiac arrest.

METHODS AND RESULTS

Twenty-four animals were randomly assigned to two groups: one that received ventilation during the first 10 minutes of chest compression and one that did not. Coronary perfusion pressure and minute ventilation were continuously recorded. Arterial and mixed venous blood gases were measured at intervals. Return of spontaneous circulation was defined prospectively as an aortic systolic blood pressure of > 80 mm Hg for > 5 minutes and was the primary outcome variable. All animals were anesthetized, paralyzed, and intubated. Ventricular fibrillation was induced and persisted for 6 minutes without chest compression, followed by mechanical chest compression for 10 minutes and then attempted defibrillation. Animals without return of spontaneous circulation were given epinephrine, ventilation, and chest compression for an additional 3 minutes. Defibrillation was again attempted, and animals were assessed for return of spontaneous circulation. There were no significant differences between the two groups in baseline prearrest mean cardiac index, coronary perfusion pressure, or arterial and mixed venous blood gases. However, after 9 minutes of chest compression, significant differences were noted between the ventilated and nonventilated groups. The nonventilated group had significantly (P < .05) lower mean arterial PO2 (38 +/- 17 mm Hg compared with 216 +/- 104 mm Hg) and higher PCO2 (62 +/- 16 mm Hg compared with 35 +/- 8 mm Hg), lower mixed venous PO2 (15 +/- 7 mm Hg compared with 60 +/- 7 mm Hg). Nine of 12 (75%) of the ventilated animals, and only 1 of 12 (8%) of the nonventilated animals had return of spontaneous circulation after cardiac arrest (P < .002).

CONCLUSIONS

In this animal model of cardiac arrest, ventilation was important for resuscitation. The importance of ventilation could be related to the prolonged duration of untreated ventricular fibrillation and the significantly greater hypoxia and hypercarbic acidosis found in the nonventilated animals.
Formation of the Tricuspid Valve in the Human Heart
Authors: Lamers Wouter H. , Virágh Szabolcs , Wessels Andy , Moorman Antoon F.M. , Anderson Robert H.
Published: June 2012

Background
Some of the problems concerning the origin of the inlet component of the definitive right ventricle were resolved in a previous study in which we showed it to be derived exclusively from the embryonic right ventricle. Questions remain, however, concerning the relative contributions of endocardial cushion tissue and myocardium to the definitive valvar apparatus guarding the right atrioventricular orifice and the origin of the valvar leaflets.

Methods and Results
The formation of the tricuspid valve was studied by scanning electron microscopic and immunohistochemical techniques. Concurrent with the development of the right atrioventricular connection, a myocardial ridge forms at the boundary between the atrioventricular canal and the embryonic right ventricle. It grows to become a myocardial gully that funnels atrial blood beneath the lesser curvature of the initial heart tube toward the middle of the right ventricle. Fenestrations in the floor of the gully create an additional inferior opening in the funnel, transforming its initial anterior rim into the septomarginal trabeculation. The septum formed by the fusion of the endocardial ridges of the outflow tract becomes myocardialized in its inferior portion to form, in part, the outlet septum and, in part, the supraventricular crest. The smooth atrial surface of the tricuspid valvar leaflets develops from endocardial cushion tissue. The leaflets become freely movable, however, only after delamination of the tension apparatus within the myocardium. The inferior and septal leaflets derive from the gully and the ventricular septum, their delamination being a single, continuous process. The anterosuperior leaflet forms by delamination from the developing supraventricular crest.

Conclusions
The leaflets of the tricuspid valve develop equally from the endocardial cushion tissues and the myocardium. The myocardium contributing to the valve comes from two sources, the tricuspid gully complex and the developing supraventricular crest. These findings facilitate the understanding of several congenital malformations.
Tetrahydrobiopterin and Dysfunction of Endothelial Nitric Oxide Synthase in Coronary Arteries
Authors: Cosentino Francesco , Katusic Zvonimir S.
Published: June 2012

Background
The
l
-arginine/nitric oxide pathway plays a key role in the regulation of arterial tone. Biosynthesis of nitric oxide requires activation of nitric oxide synthase in the presence of tetrahydrobiopterin as a cofactor. Biochemical studies demonstrated that activation of purified nitric oxide synthase at suboptimal concentrations of tetrahydrobiopterin leads to production of hydrogen peroxide. The present experiments were designed to determine whether in coronary arteries inhibition of tetrahydrobiopterin synthesis may favor nitric oxide synthase–catalyzed production of hydrogen peroxide.

Methods and Results
Primary branches of canine left anterior descending artery were incubated for 6 hours in minimum essential medium in the presence or in the absence of the tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP; 10
−2
mol/L). Arterial rings were suspended for isometric tension recording. Production of cGMP was measured by radioimmunoassay. Experiments were performed in the presence of indomethacin (10
−5
mol/L). During contractions to the thromboxane A
2
/prostaglandin H
2
receptor agonist U46619 (10
−7
mol/L), calcium ionophore A23187 (10
−9
to 10
−6
mol/L) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor,
N
G
-nitro-
l
-arginine methyl ester (3×10
−4
mol/L), significantly inhibited these relaxations. In DAHP-treated arteries, relaxations to A23187 and its stimulating effect on cGMP production were significantly reduced in the presence of catalase (1200 U/mL). By contrast, catalase did not exert any effect in rings incubated in the absence of DAHP. Furthermore, the inhibitory effect of catalase on A23187-induced relaxations was abolished when coronary arteries were incubated in the presence of DAHP plus a liposoluble analogue of tetrahydrobiopterin, 6-methyltetrahydropterin (10
−4
mol/L).

Conclusions
The present study suggests that hydrogen peroxide may be a mediator of endothelium-dependent relaxations in coronary arteries depleted of tetrahydrobiopterin. This initially compensatory response, triggered by a dysfunctional nitric oxide synthase, may represent an important mechanism underlying oxidative vascular injury.