Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease.

Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M1 - M5, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype-selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.

Robustness, variability, phase dependence, and longevity of individual synaptic input effects on spike timing during fluctuating synaptic backgrounds: a modeling study of globus pallidus neuron phase response properties.

A neuron's phase response curve (PRC) shows how inputs arriving at different times during the spike cycle differentially affect the timing of subsequent spikes. Using a full morphological model of a globus pallidus (GP) neuron, we previously demonstrated that dendritic conductances shape the PRC in a spike frequency-dependent manner, suggesting different functional roles of perisomatic and distal dendritic synapses in the control of patterned network activity. In the present study we extend this analysis to examine the impact of physiologically realistic high conductance states on somatic and dendritic PRCs and the time course of spike train perturbations. First, we found that average somatic and dendritic PRCs preserved their shapes and spike frequency dependence when the model was driven by spatially-distributed, stochastic conductance inputs rather than tonic somatic current. However, responses to inputs during specific synaptic backgrounds often deviated substantially from the average PRC. Therefore, we analyzed the interactions of PRC stimuli with transient fluctuations in the synaptic background on a trial-by-trial basis. We found that the variability in responses to PRC stimuli and the incidence of stimulus-evoked added or skipped spikes were stimulus-phase-dependent and reflected the profile of the average PRC, suggesting commonality in the underlying mechanisms. Clear differences in the relation between the phase of input and variability of spike response between dendritic and somatic inputs indicate that these regions generally represent distinct dynamical subsystems of synaptic integration with respect to influencing the stability of spike time attractors generated by the overall synaptic conductance.

Beating heart surgery reduces mortality in the reoperative bypass patient.

BACKGROUND: Reoperative coronary artery bypass grafting (redo-CABG) has an increased operative morbidity and mortality compared to patients undergoing primary revascularization. In an effort to reduce the hazards of reoperative CABG, we commenced revascularizing selected patients without cardiopulmonary bypass (CPB) as an alternative to conventional approaches. METHODS: From January 1998 to Dec. 2000, 432 patients underwent reoperative CABG, 153 patients (35%) without the aid of CPB. Treatment groups were compared by means of univariate analysis for preoperative risk factors and postoperative complications. Predicted risk and risk-adjusted mortality were determined by the Society of Thoracic Surgeons risk algorithm. RESULTS: There was a significant difference in the preoperative predicted risk scores between the two treatment groups (off pump 6.5% vs. on pump 5.4%, p=0.0343). There was a significant difference in the off pump observed mortality (2.61%) versus the on pump group (9.68%, p=0.0065). Decreased morbidity in the off pump group was evidenced by a reduced need for blood products (25% vs. 67%, p<0.0001), and the incidence of prolonged ventilation (4% vs. 14%, p=0.0032). The off pump group also had shorter hospital stays (6.2 +/- 5.96 days vs. 8.0 +/- 7.82, p=0.0091). No significant differences between the two groups were seen in the prevalence of perioperative myocardial infarction, stroke, renal failure, or reoperation for bleeding. CONCLUSION: Bypass grafting without CPB significantly decreases mortality and morbidity in selected reoperative patients, and should be considered a viable alternative to conventional approaches.

Initial prospective multicenter clinical trial of robotically-assisted coronary artery bypass grafting.

BACKGROUND: This multicenter prospective trial was designed to assess the safety and efficacy of using a robotically-assisted microsurgical system to create endoscopic coronary anastomoses. METHODS: . Thirty-two patients scheduled for elective primary coronary surgery underwent endoscopic anastomosis of the left internal thoracic artery (LITA) to the left anterior descending (LAD) artery. Three thoracic ports (two for instruments and one for a camera) were placed, and a robotic system was used to perform the LITA-LAD graft. Conventional techniques were used to perform the other grafts. Thirty-one patients underwent median sternotomy and 1 patient underwent a limited anterior thoracotomy. RESULTS: . Graft flow was measured in the operating room and averaged 37 +/- 19 mL/min. Mean anastomosis time was 24 +/- 9 minutes. There were three intraoperative revisions (9%). Two were for inadequate flow and one for an inadvertent injury. Each of these grafts was successfully revised by hand. There were no technical failures of the robotic system. Average postoperative length of stay was 5.5 +/- 2.7 days. There were three reoperations for bleeding, but none of these were related to the LAD anastomosis. Two months following the operation, selective angiography revealed a graft patency of 93%. The patients have been followed for 16 +/- 4 months. CONCLUSIONS: This initial prospective multicenter trial documents the feasibility of robotically-assisted coronary bypass grafting. Further trials are warranted to establish the safety and efficacy of this new technology.

Influence of diabetes on mortality and morbidity: off-pump coronary artery bypass grafting versus coronary artery bypass grafting with cardiopulmonary bypass.

BACKGROUND: Myocardial revascularization in diabetic patients is challenging with no established optimum treatment strategy. We reviewed our coronary artery bypass grafting experience to determine the impact of eliminating cardiopulmonary bypass on outcomes in diabetic patients relative to nondiabetic patients. METHODS: From January 1995 through December 1999, 9,965 patients, of whom 2,891 (29%) had diabetes, underwent isolated coronary artery bypass grafting. Diabetic and nondiabetic patients were further divided into groups on the basis of cardiopulmonary bypass use. Twelve percent (346 of 2,891) of diabetic patients and 12% (829 of 7,074) of nondiabetic patients underwent coronary artery bypass grafting without cardiopulmonary bypass; the remainder had coronary artery bypass grafting with cardiopulmonary bypass. Nineteen preoperative variables were compared among treatment groups by univariate analysis. RESULTS: Patients undergoing coronary artery bypass grafting without cardiopulmonary bypass compared with those having coronary artery bypass grafting with cardiopulmonary bypass had higher mean predicted mortalities (diabetic, 3.96% versus 3.72%, p = 0.83; nondiabetic, 3.03% versus 2.86%, p = 0.79). In nondiabetic patients, coronary artery bypass grafting without cardiopulmonary bypass provides an actual and risk-adjusted survival advantage over coronary artery bypass grafting with cardiopulmonary bypass (1.81% versus 3.44%, p = 0.0127; risk-adjusted mortality, 1.79% versus 3.61%, p = 0.007). This survival benefit of coronary artery bypass grafting without cardiopulmonary bypass was not seen in diabetic patients (2.89% versus 3.69%, p = 0.452; risk-adjusted mortality, 2.19% versus 2.98%, p = 0.42). Diabetic patients undergoing coronary artery bypass grafting without cardiopulmonary bypass had fewer complications, including decreased blood product use (34.39% versus 58.4%, p = 0.001), and reduced incidence of prolonged ventilation (6.94% versus 12.10%, p = 0.005), atrial fibrillation (15.90% versus 23.26%, p = 0.002), and renal failure requiring dialysis (0.87% versus 2.75%, p = 0.036). CONCLUSIONS: The survival advantage in nondiabetic patients treated with coronary artery bypass grafting without cardiopulmonary bypass is not apparent in diabetic patients. Coronary artery bypass grafting without cardiopulmonary bypass in diabetic patients is nevertheless associated with a significant reduction in morbidity.

Off-pump bypass grafting is safe in patients with left main coronary disease.

BACKGROUND: Because of a concern about the ability to tolerate beating heart grafting, patients with left main coronary artery stenosis have been excluded from off-pump bypass. We reviewed our experience with off-pump coronary artery bypass grafting for patients with left main coronary artery disease. METHODS: Eight hundred twenty-three patients underwent bypass grafting for left main coronary artery disease from January 1998 to October 1999. One hundred patients were revascularized without the use of cardiopulmonary bypass and compared with a contemporaneous cohort of 723 patients who underwent grafting with the aid of cardiopulmonary bypass. All patients had multivessel grafting performed through a sternotomy. RESULTS: There was one death (1%) in the group undergoing off-pump grafting as compared with a 30-day mortality of 4.7% (p = 0.059) in the on-pump group. Univariate analysis established that patients revascularized without cardiopulmonary bypass were significantly less likely to require postoperative inotropic support (23% versus 62%, p < 0.001) and transfusion (35% versus 67%, p < 0.001). Logistic regression analysis revealed that cardiopulmonary bypass was an independent risk factor for mortality (odds ratio, 7.3; 95% confidence interval, 1.34 to 138.4). CONCLUSIONS: Coronary artery bypass grafting using off-pump techniques are safe and effective in left main coronary artery disease.

Analysis of hemodynamic changes during beating heart surgical procedures.

BACKGROUND: Coronary artery bypass grafting on the beating heart causes significant hemodynamic compromise during displacement of the heart. The precise mechanisms causing altered hemodynamics have not been clearly understood. The purpose of this study was to define the hemodynamic changes caused by displacing the heart in patients undergoing beating heart surgical procedures. METHODS: Forty-four patients (35 men, 9 women; mean age, 64.5 +/- 9.6 years) underwent off-pump coronary artery bypass grafting. The hemodynamic variables were collected before and after positioning the heart for anastomosis of the left anterior descending, circumflex, and posterior descending coronary arteries. RESULTS: There was a significant increase in right ventricular end-diastolic pressure during positioning for all vessels, and in left ventricular end-diastolic pressure during positioning for the left anterior descending and circumflex coronary arteries. Positioning for the circumflex artery showed the largest increase of left and right ventricular end-diastolic pressure, resulting in the greatest hemodynamic compromise. CONCLUSIONS: In the clinical setting of diseased human hearts, there is a biventricular contribution to altered hemodynamics. The increase of right ventricular end-diastolic pressure in all positions suggests that the major cause of hemodynamic changes is disturbed diastolic filling of the right ventricle, especially by direct ventricular compression.

A review of 1,582 consecutive Octopus off-pump coronary bypass patients.

BACKGROUND: Off-pump coronary bypass may provide a safer form of surgical revascularization by avoiding the unwanted complications of cardiopulmonary bypass, particularly in the increasingly complex patients being referred for operation. This study reviews the entire experience of the Medtronic Octopus System (Medtronic, Minneapolis, MN) for beating heart bypass from 7 surgeons. Demographics, operative procedures, early outcomes, and trends in usage were examined. METHODS: Patients were selected for off-pump procedures by the individual surgeons. Data were entered prospectively into locally maintained databases and then collected for collation and analysis. RESULTS: A total of 1,582 consecutive Octopus patients were entered, representing the entire Octopus experience of each surgeon. Proportions of off-pump procedures relative to standard bypass increased over time, as did the percentage of patients receiving three or more grafts, 24.6% in 1997 and 55.9% in 1999. A total of 3,653 anastomoses were performed, 1,905 to the left anterior descending system, 837 to the circumflex distribution, and 911 to the right coronary territory. Morbidity was low. Few patients required conversion to cardiopulmonary bypass (2.6%; 0.2% urgently). Permanent stroke occurred in 0.6% and myocardial infarction in 1.2%. Operative mortality was 1%. CONCLUSIONS: Octopus off-pump bypass was demonstrated to be a safe procedure with widening applicability. With experience surgeons tend to apply the system to increasing proportions of their patients and are able to revascularize all coronary territories.

Endothelial cell seeding of latissimus dorsi muscle pouches.

The transformation of skeletal muscle tissue into a fatigue-resistant, autologous blood pump is being explored as an attempt to aid the failing heart. One of the options is to generate a pouch underneath the latissimus dorsi muscle, to connect an electrically conditioned muscle pouch to the circulation, and to use it as an autologous, contractile cardiac assist device. However, the potential of thrombus formation on the blood contacting surface, which is composed of fibrous material, might thwart the clinical usefulness of such skeletal muscle ventricles. We hypothesized that the thrombogenicity of these pouches could be reduced by lining their luminal surfaces with autologous endothelial cells. As a first step, we examined the feasibility of this approach under resting, nonbeating conditions. Using a multistage operative procedure, we isolated microvascular endothelial cells from canine adipose tissue and, after culturing these cells in the laboratory, seeded the autologous cells into preformed latissimus dorsi pouches in six mongrel dogs. Four to six weeks later the dogs were sacrificed and the ultrastructure of the pouches was examined by light and electron microscopy and by fluorescence techniques. The micrographs confirmed that the surfaces of seeded pouches, but not of the untreated controls, are lined with a continuous monolayer of functional endothelial cells, as assessed by the presence of several endothelial cell-specific markers. Current studies are under way to assess the thrombogenicity of these endothelialized skeletal muscle pouches.

Zollinger-Ellison syndrome associated with persistently normal fasting serum gastrin concentrations.

A 63-year-old man with a 2-year history of upper gastrointestinal ulcers was found to have the Zollinger-Ellison syndrome. Despite histologic verification of gastrinoma, several fasting serum gastrin concentrations were normal. However, in response to intravenous secretin infusion, a paradoxical increase in serum gastrin levels indicative of gastrinoma was seen. Although serum gastrin concentrations in patients with suspected gastrinoma may be persistently normal, provocative testing may be necessary to establish the diagnosis of the Zollinger-Ellison syndrome.

Influence of aortic stenosis on the hemodynamic importance of coronary artery narrowing in dogs without left ventricular hypertrophy.

Coronary hemodynamic effects of controlled left ventricular outflow obstruction stimulating aortic valve stenosis were studied in 20 open-chest dogs, with and without graded coronary artery diameter narrowing. Aortic stenosis was regulated so that a mean left ventricular-aortic pressure gradient of 46 +/- 20 mm Hg (mean +/- standard deviation) was created as both heart rate and stroke volume were unchanged. In addition, during aortic stenosis, mean aortic pressure (105 +/- 17 to 84 +/- 15 mm Hg, p less than 0.05) and diastolic pressure time index/systolic pressure time index ratio (1.2 +/- 0.3 to 0.6 +/- 0.2, p less than 0.05) decreased and end-diastolic left ventricular pressure (7 +/- 4 to 14 +/- 6 mm Hg, p less than 0.05) increased. With no coronary narrowing, mean coronary flow increased during aortic stenosis (53 +/- 23 to 62 +/- 23 ml/min) as the percentage of diastolic flow increased (83 +/- 6 to 89 +/- 4) and endocardial/epicardial ratio decreased (1.14 +/- 0.16 to 0.95 +/- 0.24) (all p less than 0.05). Peak reactive hyperemic flow also decreased (168 +/- 85 to 125 +/- 73 ml/min, p less than 0.05). This value with no coronary narrowing was similar to peak hyperemic flow with 60% narrowing without aortic stenosis. With 90% coronary narrowing, mean coronary flow decreased with or without aortic stenosis. Transmural flow distribution also decreased but was lower during aortic stenosis (0.86 +/- 0.19 to 0.61 +/- 0.25, respectively; p less than 0.05). These data suggest that although mean coronary flow is increased during aortic stenosis, endocardial flow may be limited, and coronary reserve exposed during reactive hyperemia appears decreased. When a coronary artery is narrowed, aortic stenosis has an even more important hemodynamic influence on the coronary circulation.