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BackgroundNumerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilatation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy of ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.Methods and ResultsIn separate studies, three Ang II receptor antagonists, including AT1-selective (L-158,809), balanced AT1/AT2(L-163,082), and AT2-selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg·kg−1·d−1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg·kg−1·d−1), L-163,082 (1 mg·kg−1·d−1), or L-164,282 (1.5 mg·kg−1·d−1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12,P=.75, andP=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty.ConclusionsThese findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Background Experiments were designed to define cardiac function in dogs with single lung allografts during acute rejection of the allografted lung. Methods and Results Left lungs were either autotransplanted (n=4) or allotransplanted (n=8) in adult male mongrel dogs. All allotransplanted animals were maintained on triple-drug immunosuppression (cyclosporine, azathioprine, and steroids) for 5 days after the operation. In 4 allotransplanted animals, treatment was discontinued, allowing the animals to reject (usually after a further 3 days; rejecting group); 4 other allotransplanted animals were maintained on immunosuppression for an additional 3 days (immunosuppressed group). Another group of dogs were not operated on but were maintained on the same immunosuppression as the rejecting group (controls). All experimental animals underwent fast computed tomographic scanning with measurement of left ventricular pressure and calculation of ventricular chamber volumes, cross-sectional areas of coronary arteries, myocardial perfusion, and intramyocardial blood volume. Neither cardiac output, left ventricular mass, left ventricular pressure, nor myocardial oxygen consumption was altered during acute rejection of lung allografts. However, left ventricular contractility (systolic elastance, E max ) and ejection fraction were depressed to approximately one half ( P <.05) in acutely rejecting animals compared with other groups. The cross-sectional area of the coronary arteries was less in autotransplanted and allotransplanted treated animals than in animals that were not operated on. Cross-sectional area of the coronary arteries was decreased by an additional 30% in the rejecting group ( P <.05). Conclusions The results of this study indicate that acute rejection of a single lung allograft decreases cardiac performance and reduces diameter of coronary arteries in the recipient. Alterations of circulating humoral factors and activated leukocytes may contribute to these changes.

Background —Our goal was to test sympathetic and cardiovagal baroreflex sensitivity and the transduction of sympathetic traffic into vascular resistance during the early follicular (EF) and midluteal (ML) phases of the menstrual cycle. Methods and Results —Sympathetic baroreflex sensitivity was assessed by lowering and raising blood pressure with intravenous bolus doses of sodium nitroprusside and phenylephrine. It was defined as the slope relating muscle sympathetic nerve activity (MSNA; determined by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. Vascular transduction was evaluated during ischemic handgrip exercise and postexercise ischemia, and it was defined as the slope relating MSNA and calf vascular resistance (determined by plethysmography). Resting MSNA (EF, 1170±151 U/min; ML, 2252±251 U/min; P <0.001) and plasma norepinephrine levels (EF, 240±21 pg/mL; ML, 294±25 pg/mL; P =0.025) were significantly higher in the ML than in the EF phase. Furthermore, sympathetic baroreflex sensitivity was greater during the ML than the EF phase in every subject (MSNA/diastolic blood pressure slopes: EF, −4.15; FL, −5.42; P =0.005). No significant differences in cardiovagal baroreflex sensitivity or vascular transduction were observed. Conclusions —The present study suggests that the hormonal fluctuations that occur during the normal menstrual cycle may alter sympathetic outflow but not the transduction of sympathetic activity into vascular resistance.

Background —In a previous randomized trial, the 12F laser sheath removed pacing leads via the implant vein more successfully than traditional mechanical tools alone. Two larger sizes of laser sheath, the 14F and 16F models, were developed to extract defibrillator leads and large-diameter pacing leads implanted for the chronic. These devices use pulsed ultraviolet laser light to core though fibrotic tissue grown over the lead body to free the lead from the vasculature. A mandatory prospective registry studied the safety and effectiveness profiles of the larger laser sheaths vis-à-vis the 12F laser sheath. Methods and Results —In this study, 863 patients underwent extraction of 1285 leads at 52 sites. Patients treated with the 14F device tended to have older leads than the 12F population; the 16F population, which comprised mostly defibrillator patients, were younger, had younger leads, and were more often male than the 12F population. Clinical success (extracting the entire lead or the lead body minus the distal electrode) was observed in 91% to 92% of cases for all device sizes. The overall complication rate was 3.6%, with 0.8% perioperative mortality. Incidence of complications was independent of laser sheath size. Conclusions —The 14F and 16F laser sheaths offer an extraction option for larger long-term transvenous pacemaker and defibrillator leads that is as safe and effective as the 12F laser sheath.

Background —Cardiogenic shock is usually considered a sequela of ST-segment elevation myocardial infarction. There are limited prospective data on the incidence and significance of shock in non−ST-segment elevation patients. This study assessed the incidence and outcomes of cardiogenic shock developing after enrollment among patients with and without ST-segment elevation in the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-IIb trial. Methods and Results —Among 12 084 patients in GUSTO-IIb who did not present with cardiogenic shock, 4092 (34%) had and 7991 (66%) did not have ST-segment elevation on the enrollment ECG. Cardiogenic shock developed in 4.2% of ST-segment elevation patients compared with 2.5% of patients without ST-segment elevation (odds ratio, 0.581; 95% CI, 0.472 to 0.715; P <0.001). Shock developed significantly later among patients without ST-segment elevation. There were significant differences in baseline characteristics between shock patients with and without ST-segment elevation: Patients without ST-segment elevation were older, more frequently had diabetes mellitus and 3-vessel disease, but had less TIMI grade 0 flow at angiography. Regardless of the initial ECG, mortality was high: 63% among patients with ST-segment elevation and 73% in those without ST-segment elevation. Conclusions —Cardiogenic shock occurs in the setting of acute ischemic syndromes regardless of whether ST-segment elevation is present. The incidence, patient characteristics, timing, clinical course, and angiographic findings differ between the 2 groups. Mortality from cardiogenic shock is similarly high among patients with and without ST-segment elevation.

Background —The physiological stress suffered by patients with heart failure results in an increased production of cortisol and a shift in the leukocyte differential toward a decreased percentage of lymphocytes (%L). The purpose of this study was to determine the prognostic significance of a low %L in advanced heart failure. Methods and Results —Patients evaluated in our cardiac transplantation clinic between April 1988 and July 1995 were retrospectively reviewed (n=263). Fifty-two patients were excluded because they had recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. In the remaining 211 patients, we used Cox proportional hazards analysis to examine the association between survival and transplant-free survival with baseline variables. Univariate analysis showed a significant association between time to death and %L ( P =.004), New York Heart Association (NYHA) class ( P =.002), and maximal oxygen uptake ( P =.05). Univariate analysis of the end point of survival free from transplantation yielded similar results. One- and 4-year survival rates for patients with a low %L (<20.3%) were 78% and 34% compared with 90% and 73% for those with a normal %L. Multivariate analysis showed NYHA class ( P <.008) and %L ( P <.01) were independent predictors of survival and survival free from cardiac transplantation. Conclusions The relative lymphocyte concentration is an inexpensive, readily available, simple prognostic marker in patients with symptomatic heart failure who do not have recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. It could be incorporated into clinical models to predict patient outcome and to aid in the selection of patients for cardiac transplantation.

Background Respiratory variation of ≥25% in mitral E velocity is a characteristic Doppler echocardiographic feature in constrictive pericarditis. However, a subset of patients with constriction do not exhibit the typical respiratory change, most likely because of marked increase in the left atrial pressure, and preload reduction may unmask the respiratory variation. Methods and Results In 12 patients with surgically confirmed constrictive pericarditis who had <25% respiratory variation in mitral E velocity during an initial preoperative examination, the Doppler study was repeated after an attempt to decrease left ventricular filling pressure. At baseline, mean mitral E velocity was similar after inspiration and expiration (0.81±0.24 and 0.84±0.21 m/s, respectively). On repeat Doppler examination, with the patient in a head-up tilt or sitting position, the decrease in mitral E velocity with inspiration (0.61±0.13 m/s) was significant ( P <.004), whereas it did not change significantly with expiration. The mean percent respiratory change in E velocity was 5±7% at baseline and 32±28% with preload reduction. Eight (75%) of the 12 patients developed respiratory variation of ≥25%. Conclusions When the respiratory variation in Doppler mitral E velocity is blunted or absent during the evaluation of suspected constrictive pericarditis, repeat Doppler recording of mitral flow velocities after maneuvers to decrease preload is recommended to unmask the characteristic respiratory variation in mitral E velocity.

Background Conventional cardiac catheterization criteria for the diagnosis of constrictive pericarditis (CP) rely on equalization of intracardiac pressures and have many recognized limitations. Recently, Doppler echocardiographic methods have been used to examine dynamic respiratory changes of increased ventricular interdependence and dissociation of intrathoracic and intracardiac pressures for the diagnosis of CP. These pathophysiological features may be best delineated by cardiac catheterization. Therefore, we studied the accuracy of these dynamic respiratory changes in left ventricular and right ventricular pressure for the diagnosis of CP at cardiac catheterization. Methods and Results High-fidelity manometric catheters and respirometry were used to study 36 patients: 15 patients with surgically proven CP (group 1) and 21 patients with other causes of heart failure (group 2). Conventional cardiac catheterization variables used to establish the diagnosis of CP lacked sensitivity and specificity and failed to distinguish between these groups. However, the finding of discordance between right ventricular and left ventricular pressures during inspiration, a sign of increased ventricular interdependence, accurately distinguished patients in group 1 from those in group 2 ( P <.05). Conclusions Examination of dynamic respiratory changes indicating increased ventricular interdependence may be helpful in the diagnosis of CP in the cardiac catheterization laboratory.

Object Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population. Methods Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5–220 months). Results Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression–free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression. Conclusions Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.

Background— Alterations at the level of the coronary circulation with aging may play an important role in the evolution of age-associated changes in left ventricular (LV) fibrosis and function. However these age-associated changes in the coronary vasculature remain poorly defined primarily due to the lack of high resolution imaging technologies. The current study was designed to utilize cardiac micro–computed tomography (micro-CT) technology as a novel imaging strategy, to define the 3-dimensional coronary circulation in the young and aged heart and its relationship to LV fibrosis and function. Methods and Results— Young (2 months old; n=10) and aged (20 months old; n=10) Fischer rats underwent cardiac micro-CT imaging as well as echocardiography, blood pressure, and fibrosis analysis. Importantly, when indexed to LV mass, which increased with age, the total and intramyocardial vessel volumes were lower, whereas the epicardial vessel volume, with and without indexing to LV mass, was significantly higher in the aged hearts compared with the young hearts. Moreover, the aged hearts had a significantly lower percentage of intramyocardial vessel volume and a significantly higher percentage of epicardial vessel volume, when normalized to the total vessel volume, compared with the young hearts. Further, the aged hearts had significant LV fibrosis and mild LV dysfunction compared with the young hearts. Conclusions— This micro-CT imaging study reports the reduction in normalized intramyocardial vessel volume within the aged heart, in association with increased epicardial vessel volume, in the setting of increased LV fibrosis, and mild LV dysfunction.