Wendell S. Akers

Enhanced vascular contractility and diminished coronary artery flow in rats made hypertensive from diet-induced obesity

Objective:To determine whether obesity-induced hypertension was associated with alterations in vascular contractility and/or cardiac function.Design:Male Sprague–Dawley rats were fed either a low fat (LF; 11% kcal as fat) or a moderately high fat (MHF; 32% kcal as fat) diet for 11 weeks.Measurements:Body weight; mean arterial pressure; angiotensin peptides; mesenteric contractile response to phenylephrine (PE), potassium chloride (KCl), serotonin, angiotensin II (AngII), calcium chloride; baseline and isoproterenol-induced cardiac contractility; baseline and isoproterenol-induced coronary artery blood flow.Results:Rats fed the MHF diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups. OP rats exhibited elevations in mean arterial pressure (MAP) and elevations in systemic concentrations of angiotensin peptides. Mesenteric arteries from OP rats exhibited a greater contractile response to PE, KCl and serotonin (5-HT). Heightened responses to PE persisted in arteries from OP rats even after normalization of the response to KCl. In contrast, the response of permeabilized mesenteric arteries to a maximal concentration of calcium was similar in rats from each group. Isolated perfused hearts exhibited similar baseline and isoproterenol-induced contractility in rats from each group. However, isoproterenol was unable to increase coronary artery blood flow in hearts from OP rats.Conclusion:Enhanced vascular reactivity may contribute to obesity-induced hypertension, while reductions in coronary artery relaxation would impair the ability of the heart to respond to increased myocardial demand.

Treatment of respiratory syncytial virus pneumonia in a lung transplant recipient: case report and review of the literature.

A 61‐year‐old woman who underwent lung transplantation developed severe respiratory syncytial virus (RSV) pneumonia and experienced respiratory failure requiring mechanical ventilation. She was treated initially with aerosolized ribavirin monotherapy; RSV hyperimmune globulin was later added to her regimen. Lung transplant recipients are acutely susceptible to respiratory infections, including community‐acquired respiratory viruses. Respiratory syncytial virus is particularly difficult to treat in immunocompromised patients because of the lack of proved pharmaceutical agents and solid scientific evidence by which to guide therapy. The most important factor appears to be the early start of therapy; immunocompromised patients who develop RSV pneumonia and subsequent respiratory failure requiring mechanical ventilation have a mortality rate approaching 100%. This case report demonstrates the successful treatment of RSV pneumonia with the combination of aerosolized ribavirin and RSV hyperimmune globulin in a severely ill lung transplant recipient who required mechanical ventilation.

Recombinant Factor VIIa for Refractory Bleeding Following Orthotopic Heart Transplantation

OBJECTIVE To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation. Case Summary A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 μg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition. DISCUSSION Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients. CONCLUSIONS rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.

Effects of the angiotensin II subtype 1 receptor antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia-reperfusion.

Study Objective. To investigate the effects of the angiotensin II subtype 1 receptor (AT1R) antagonist losartan on functional recovery of isolated rat hearts undergoing global myocardial ischemia‐reperfusion compared with myocardial protective effects of ischemic preconditioning.

Successful treatment of refractory bleeding after bridging from acute to chronic left ventricular assist device support with recombinant activated factor VII.

Cardiac surgery often is associated with a significant disruption of the coagulation system, particularly in high risk patients such as those undergoing placement of ventricular assist devices. This type of severe coagulopathy can lead to life threatening bleeding that can require massive transfusions to restore hemostasis. Recently, recombinant activated factor VII (rFVlla) has been +used as an alternative to massive transfusion for the treatment of refractory bleeding in several patient populations, including cardiac surgery patients. In the case reported here, the patients risk was compounded by multiple operations in a short period of time and circulatory collapse that was initially managed with a shortterm left ventricular assist device. After multiple failed attempts at weaning the patient from circulatory assistance, he was taken back to the operating room for conversion to a chronic, implantable device. This procedure was complicated by a severe coagulopathy secondary to a myriad of factors commonly encountered after the use of cardiopulmonary bypass. The administration of rFVlla resulted in a rapid cessation of bleeding without thrombotic complications. This is the first case reported involving an acute to chronic bridge patient. Despite the anecdotal success of rFVlla, further clinical research is needed to establish both the safety and economic feasibility of this agent.

High residual platelet reactivity on standard clopidogrel maintenance dose predicts increased responsiveness to the double-standard dose in an assay-dependent manner

High residual platelet reactivity on standard clopidogrel maintenance dose predicts increased responsiveness to the double-standard dose in an assay-dependent manner -

Management of antiplatelet therapy for minimization of bleeding risk before cardiac surgery

Antiplatelet therapy is commonly administered for primary and secondary prevention of stroke, recurrent angina, myocardial infarction, and death in patients with cardiovascular disorders. It also is associated with an increased risk of bleeding. We describe the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery. In addition, we provide basic information about the mechanisms of action by which the most common antiplatelet agents inhibit platelet function. This information is integrated with results from pharmacologic studies and clinical trials. Determining the net effect in patients undergoing coronary artery bypass graft surgery requires knowledge about the pharmacokinetics, pharmacodynamics, and clinical efficacy of each drug, and an estimation of the absolute thrombotic versus hemorrhagic risk for each patient.

Effect of clonidine on cardiac norepinephrine spillover in isolated rat heart.

The purpose of this study is to determine the effect of clonidine on cardiac norepinephrine spillover utilizing an isolated rat heart preparation with attached cardiac sympathetic nerves. Following a 20-minute stabilization period, the sympathetic ganglion for each heart preparation was electrically stimulated with 10V and 2 Hz for 30 seconds (S1: 60 pulses). Heart rate, left ventricular developed pressure, and coronary perfusion pressure was allowed to return to baseline and the perfusate was randomly switched to Krebs buffer containing one of two treatments: placebo or clonidine (1 μM). After 10 minutes of treatment, the sympathetic ganglion was again electrically stimulated with 10V and 2 Hz for 30 seconds (S2: 60 pulses). The perfusate exiting the heart before, during, and after each electrical stimulation was collected for the determination of cardiac norepinephrine spillover. Clonidine administration significantly reduced cardiac norepinephrine spillover by approximately 50% (P < 0.05) and was associated with a 36% reduction in heart rate (P < 0.05). These findings provide evidence that clonidine can directly suppress NE spillover from cardiac sympathetic nerve terminals. Thus, suppression of cardiac NE by clonidine may be due to stimulation of presynaptic α2-adrenergic receptors or imidazoline subtype I receptors located on cardiac sympathetic nerve terminals. Results from our study demonstrate a reduction in cardiac NE spillover by clonidine and provide additional evidence that it can directly suppress peripheral sympathetic activity in that our results were obtained utilizing an isolated perfused heart preparation with attached cardiac sympathetic nerves devoid of any CNS input.

Presynaptic modulation of sympathetic neurotransmission in rat left ventricle slices: effect of pressure overload

Summary. The purpose of this study was to establish the rat left ventricle (LV) tissue slice system for examination of norepinephrine (NE) release from sympathetic nerve terminals. Moreover, initial experiments were performed to use the LV tissue slice system to examine differences in NE uptake and release following cardiac pressure overload induced by abdominal aortic constriction (AC). Kinetic parameters (Vmax, Km) for the specific uptake of [3H]-NE demonstrated high affinity (Km, 1.94 ± 0.83 μM) and moderate capacity uptake (Vmax, 182 ± 6 fmol/mg/weight/min). Following 10 days of pressure overload, the Vmax for [3H]-NE uptake was significantly reduced (by 46%) in LV slices from AC rats compared to sham-operated (SO) controls.In control rat LV slices preloaded with [3H]-NE, electrically evoked [3H]-overflow was calcium- and stimulus pulse number-dependent. The neuronal uptake inhibitor, desipramine (DMI), increased (by 60%) evoked [3H]-overflow from LV slices. The α2-agonist, UK14304, decreased evoked [3H]-overflow from LV slices in a concentration-dependent manner (maximal reduction of 75%). The β2-agonist, salbutamol, increased evoked [3H]-overflow from LV slices in a concentration-dependent manner (maximal increase of 200%). In separate experiments, the LV tissue slice system was used to examine the effect of pressure overload on evoked [3H]-overflow. Following 10 days of pressure overload, evoked [3H]-overflow from LV slices of AC rats was increased (by 50%) compared to SO control. Increases in evoked [3H]-overflow from LV slices of AC rats compared to SO controls remained evident in the presence of DMI. These results demonstrate the relative importance of NE release and uptake using an in vitro LV tissue slice system. Sympathetic nerve terminals innervating rat LV were demonstrated to possess functional presynaptic α2- and β2-adrenergic receptors. Finally, using this LV tissue slice system, reductions in the uptake velocity and increases in evoked NE release were demonstrated in response to acute cardiac pressure overload.

Staying in Rhythm: Management of Patients at Risk for Torsade de Pointes

This article is part two in a two-part series addressing risk factors for and management of drug-induced torsade de pointes, a potentially fatal arrhythmia that can result from severe QT-interval prolongation.