Alfred C. Nicolosi

Mitochondrial Sources of H2O2 Generation Play a Key Role in Flow-Mediated Dilation in Human Coronary Resistance Arteries

Abstract— We previously showed that hydrogen peroxide (H2O2) contributes to flow-induced dilation in human coronary resistance arteries (HCRAs); however, the source of this H2O2 is not known. We hypothesized that the H2O2 is derived from superoxide (O2•−) generated by mitochondrial respiration. HCRAs were dissected from right atrial appendages obtained from patients during cardiac surgery and cannulated with micropipettes. H2O2-derived radicals and O2•− were detected by electron spin resonance (ESR) using BMPO as the spin trap and by histofluorescence using hydroethidine (HE, 5 &mgr;mol/L) and dichlorodihydrofluorescein (DCFH, 5 &mgr;mol/L). Diameter changes to increases in pressure gradients (20 and 100 cm H2O) were examined in the absence and the presence of rotenone (1 &mgr;mol/L), myxothiazol (100 nmol/L), cyanide (1 &mgr;mol/L), mitochondrial complex I, III, and IV inhibitors, respectively, and apocynin (3 mmol/L), a NADPH oxidase inhibitor. At a pressure gradient of 100 cm H2O, ubisemiquinone and hydroxyl radicals were detected from effluents of vessels. Including superoxide dismutase and catalase in the perfusate reduced the ESR signals. Relative ethidium and DCFH fluorescence intensities in HCRAs exposed to flow were enhanced (1.45±0.15 and 1.57±0.12, respectively compared with no-flow) and were inhibited by rotenone (0.87±0.17 and 0.95±0.07). Videomicroscopic studies showed that rotenone and myxothiazol blocked flow-induced dilation (% max. dilation at 100 cm H2O: rotenone, 74±3% versus 3±13%; myxothiazol, 67±3% versus 28±4%; P <0.05). Neither cyanide nor apocynin altered flow-induced dilation. These results suggest that shear stress induced H2O2 formation, and flow-induced dilation is derived from O2•− originating from mitochondrial respiration.

Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial.

Levosimendan is a new myofilament calcium (Ca2+) sensitizer that increases myocardial contractility by stabilizing the Ca2+-bound conformation of troponin C. We tested the hypothesis that levosimendan enhances cardiac performance after cardiopulmonary bypass (CPB). Anesthesia was induced and maintained with midazolam, sufentanil, and vecuronium in 18 patients randomly assigned to receive levosimendan (18 or 36 microg/kg loading dose and 0.2 or 0.3 microg/kg/min infusion, respectively) or placebo 15 min before and continued for 6 h after CPB. Significant (p < 0.05) increases in heart rate (HR) and decreases in systemic vascular resistance (SVR) occurred 15 min after CPB in patients receiving placebo. Later increases in mean arterial pressure (MAP) and cardiac output (CO) and decreases in stroke volume (SV) and pulmonary vascular resistance also were observed. HR was greater in patients receiving high- but not low-dose levosimendan versus placebo immediately after CPB. MAP also was lower in patients treated with either dose of levosimendan compared with placebo after CPB. Levosimendan increased CO and decreased SVR (4.2 +/- 0.4 to 7.9 +/- 0.4 L/min and 1,150 +/- 99 to 512 +/- 42 dyn/s/cm5, respectively, 15 min after CPB; mean +/- SEM). CO and SV were higher and SVR was lower in patients receiving levosimendan versus placebo after CPB. No differences in arterial oxygenation and perioperative arrhythmias (Holter analysis) were observed between groups. The results indicate that levosimendan enhances cardiac performance after CPB in humans.

Diabetes Mellitus Impairs Vasodilation to Hypoxia in Human Coronary Arterioles Reduced Activity of ATP-Sensitive Potassium Channels

Abstract— ATP-sensitive K+ channels (KATP) contribute to vasomotor regulation in some species. It is not fully understood the extent to which KATP participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription–polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective KATP opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription–polymerase chain reaction detected mRNA expression for KATP subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90±2% versus DM(−) 96±1%, P <0.05) and hypoxia (maximum dilation, DM(+) 56±8% versus DM(−) 85±5%, P <0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to KATP opening, leading to reduced dilation to hypoxia. This reduction in KATP function could contribute to the greater cardiovascular mortality and morbidity in DM.

Perioperative Considerations in the Patient with a Left Ventricular Assist Device

Mechanical support of the cardiovascular system is facilitated by a left ventricular assist device (LVAD), which is often used as a ‘‘bridge to transplant.’’ Some patients with LVADs, because they survive for longer periods of time, will need surgery for noncardiac, nonLVAD problems. Anesthesiologists should be familiar with the unique considerations related to these patients and their devices. The three LVADs currently approved by the U.S. Food and Drug Administration for use as a ‘‘bridge to transplant’’ are the HeartMate, the Novacor, and the Thorate assist devices. They all assume the pump function of the failing left ventricle, and each is designed to drain the left ventricular blood volume into a mechanical pump, which ejects the blood into the circulation via a conduit that connects to the aorta. Each device also maintains unidirectional flow using valves in the inflow and outflow conduits that connect left ventricle to pump and pump to aorta, respectively. All three devices provide pulsatile flow. Intermittently, the blood chamber in the LVAD pump is compressed, leading to ejection of a ‘‘stroke volume’’ that is determined by the preejection chamber volume and the outflow resistance. The heart continues to beat in its own rhythm. All three pumps normally function in a ‘‘fill-to-empty’’ mode, in which the blood volume within the pump chamber is automatically emptied into the circulation each time the control unit senses that the chamber is nearly full. The HeartMate and Novacor pumps are implanted in the abdomen and are powered by a percutaneous line connected to a power source. The Thoratec is extracorporeal, and the blood conduits pass through the skin. All three devices can be powered by a battery system to provide mobility. Chronic implantation of a LVAD has a profound impact on the pathophysiology of end-stage heart failure. The LVAD restores blood pressure and cardiac output to near normal values, increases LV compliance, and decreases histopathology. Hemodynamic effects also include increases in organ perfusion and organ function and decreases in pulmonary capillary wedge pressure. LVADs lead to improved mitochondrial function and calcium-ion handling, increases in b-adrenergic responsiveness, and increases in velocity of contraction/relaxation and force/frequency. Neurohumoral effects include decreases in plasma concentrations of renin, angiotensin II, atrial natriuretic peptide, epinephrine, norepinephrine, and arginine vasopression. Implantation of an LVAD also attenuates the systemic proinflammatory response as shown by the reduction in cytokine levels. Because of these improved hemodynamics, many LVAD patients resume exercise programs and may be in better physiologic condition than other patients with heart failure, who are not receiving chronic mechanical support. The anesthesiologist must first identify the ‘‘LVAD team’’ at the institution as a resource for information about the intricacies of the device, its workings, and its management. When a patient with an LVAD presents for surgery, a reliable power supply must be secured to ensure continuous operation of the device. Even those with long-lasting, battery-powered devices should have access to or have the device converted to an alternating current power source in the operating room. The anesthesiologist should also be aware of the potential for electromagnetic interference with LVAD function by external defibrillation or electrocautery. Device settings and connections may need adjustment but should be done only with the consultation or supervision of the LVAD team. During non-LVAD surgery, hemodynamic management of the patient is important because the pump function depends on both filling volume and outflow resistance. These devices can only pump the volume delivered to them, and inadequate filling will result in decreased flow through a decrease in stroke rate. Thus, maintenance of adequate preload is vital. The devices also exhibit sensitivity to changes in afterload; hypertension should be avoided, because emptying of the LVAD is reduced by increases in arterial pressure. Attenuation of acute increases in sympathetic nervous system activity and effects on arteriolar tone produced by laryngoscopy, intubation, and surgical stimulation represents an important goal in the perioperative management of these patients. Adequate anesthetic depth Cardiovascular Anesthesia

Mortality and neurologic morbidity after repair of traumatic aortic disruption

BACKGROUND Traumatic disruption of the thoracic aorta frequently results in death before operative repair. The determinants of mortality after repair, however, are uncertain. In addition, intraoperative strategies for reducing the incidence of spinal cord injury remain controversial. METHODS The records of 45 consecutive patients undergoing repair of traumatic disruption of the thoracic aorta at a single institution during a 9-year period were reviewed in a retrospective fashion. Patient age ranged from 15 to 81 years (mean age, 33.9 years). Twenty-two patients (49%) had multiple associated injuries, and 8 (18%) had isolated aortic injuries. Nine patients (20%) experienced preoperative hypotension (systolic blood pressure of less than 90 mm Hg). Repair was performed with partial bypass in 22 patients, a heparinized shunt in 2, and no distal perfusion (clamp and sew technique) in 21. RESULTS Nine patient (20%) died after operation. Multivariate logistic regression analysis of preoperative and intraoperative variables identified advancing age and preoperative hypotension as independent predictors of operative death. The presence of associated injuries was not an independent predictor of operative death. All 4 patients with injuries proximal to the aortic isthmus died. Ten patients were excluded from analysis of spinal cord injury either because of preoperative neurologic deficit or because of death before postoperative evaluation. Six (17%) of the remaining 35 patients had development of paraplegia: 5 of the 15 patients having the clamp and sew technique, 1 of the 2 with a shunt, and 0 of the 18 patients with bypass (p < 0.05, clamp and sew versus bypass). In the clamp and sew group, patients in whom paraplegia developed had significantly longer aortic clamp times than those without neurologic injury (40.6 +/- 4.4 minutes versus 28.7 +/- 2.9 minutes, respectively; p < 0.05). CONCLUSIONS Advancing age, preoperative hypotension, and perhaps injury location are important determinants of death after repair of traumatic disruption of the thoracic aorta. Adjunctive perfusion with partial bypass should be used during repair to reduce the incidence of spinal cord injury.

Use of ECMO to Temporize Circulatory Instability During Severe Brugada Electrical Storm

We describe the use of extracorporeal membrane oxygenation to temporize circulatory instability during almost incessant ventricular fibrillation in a patient with Brugada syndrome who had electively discontinued chronic amiodarone therapy. The extracorporeal membrane oxygenation was continued for 3 days after emergent delivery of the neonate, during which time the number of ventricular fibrillation episodes and internal defibrillations markedly decreased concomitant with administration of intravenous amiodarone and verapamil. Oral anti-arrhythmic therapy was subsequently reinstituted, and the remainder of the patients hospital course was uneventful.

A novel approach to the management of tracheoinnominate artery fistula

A 75-year-old gentleman with tracheoinnominate fistula is reported. The issues regarding the surgical approach to this problem are reviewed and a creation of an aorto-axillary bypass graft described.

External Carotid Endarterectomy in the Treatment of Symptomatic Patients with Internal Carotid Artery Occlusion

In patients with internal carotid artery (ICA) occlusion, the external carotid artery (ECA) can be both a source of collateral flow and a pathway for emboli. We identified 11 patients with ICA occlusion and ipsilateral ECA stenosis who underwent ECA endarterectomy to determine its role in treating extracranial cerebrovascular disease. Follow-up ranged from 1-65 months, with a mean of 27 months. Seven of eight patients with unilateral disease remained symptom free. The eighth patient had recurrent symptoms that were subsequently diagnosed as hemi-Parkinsonism. Two of three patients with bilateral occlusive disease had developed non-hemispheric symptoms at 12 and 24 months, respectively; the third remains asymptomatic after extracranial-intracranial bypass. None of the seven patients who presented with amaurosis fugax had recurrent visual symptoms. ECA endarterectomy is a safe and effective operation in treating symptomatic patients with ICA occlusion, especially those with transient monocular blindness or unilateral occlusive disease. It is less effective in those patients who have diffuse bilateral occlusive disease.

Effects of perfusion-induced edema on diastolic stress-strain relations in intact swine papillary muscle.

The mechanism through which edema reduces left ventricular compliance has not been defined. Accordingly, diastolic properties of in situ left ventricular swine papillary muscles were studied in three groups: control (n = 6, 4 degrees to 6 degrees C), edematous (150 mOsm/L coronary perfusion, n = 6, 4 degrees to 6 degrees C), and ischemic contracture (n = 8, 28 degrees C). Lagrangian stress (sigma) and strain (epsilon) were calculated from slow stretch data and approximated by sigma = alpha(e beta epsilon-1). The natural logarithm of stress versus strain was linear over the physiologic range of 0.05 < strain < 0.40. Hypotonic perfusions (1 L x 3) progressively shifted the stress-strain relationship upward and to the left. Compared to baseline, alpha increased significantly (p < 0.05) after perfusion 3 (6.7 +/- 2.1 baseline, 12.2 +/- 6.6 perfusion 1, 12.7 +/- 3.5 perfusion 2, and 42.9 +/- 16.3 gm/cm2 perfusion 3). The constant beta did not change significantly (13.0 +/- 1.5 baseline, 13.1 +/- 1.6 perfusion 1, 13.2 +/- 1.6 perfusion 2, and 14.1 +/- 1.4 perfusion 3). Right ventricular water content increased after each perfusion (77.1% +/- 1.4% baseline, 81.6% +/- 1.3%, 84.7% +/- 1.5%, and 86.9% +/- 1.7%, p < 0.05). With ischemic contracture, alpha increased from 61.9 +/- 17.8 to 173.1 +/- 61.5 gm/cm2 (p > 0.05) and beta increased insignificantly from 6.5 +/- 0.6 to 10.6 +/- 1.8 (p = NS). In the control group all variables were unchanged after 210 minutes. We conclude that myocardial stiffness increases with myocardial edema. This may explain decreased compliance in the edematous left ventricle.

Effects of Left Heart Assist on Geometry and Function of the Interventricular Septum

BACKGROUND Right ventricular (RV) dysfunction is a common but poorly understood problem associated with mechanical left heart assist (LHA). Left ventricular unloading may affect RV function even in normal hearts by altering geometry or function of the interventricular septum, although such changes have not been well defined. Accordingly, the purposes of this study were to quantify the effects of LHA on septal geometry and function in normal swine and to assess the resultant effects on RV function. METHODS Domestic swine (50 kg, n = 10) were anesthetized and instrumented for collection of physiologic data and for open-chest LHA, which was accomplished by left atrial to subclavian artery bypass using a centrifugal pump. Both global and regional RV function data as well as two-dimensional echocardiographic data of septal geometry and function were collected at control levels and during both partial and full LHA. Short-axis echocardiographic images were obtained at the midventricular level and analyzed to quantify septal curvature (k; cm-1), systolic septal thickening (%), and systolic septal excursion (cm). RESULTS Partial LHA had no effect on either septal geometry or function. Full LHA resulted in decreased diastolic septal curvature (k = 0.10 +/- 0.07 versus 0.42 +/- 0.06 at control; p < 0.05), reduced systolic septal thickening (0.27 +/- 5.23 versus 29.32 +/- 8.61 at control; p < 0.05), and reversed leftward systolic septal excursion (-0.29 +/- 0.11 versus 0.11 +/- 0.03 at control; p < 0.05). End-diastolic septal position was shifted leftward during full LHA compared with control, but was associated with rightward systolic motion of the left ventricular mass and septum as a unit. There were no changes in global or free-wall RV function during either partial LHA or full LHA compared with control. CONCLUSIONS Left heart assist results in marked changes in both geometry and function of the interventricular septum in normal hearts. These changes, however, do not appear to be associated with changes in either global or regional RV function. Evaluation of the septum with echocardiography may be helpful in defining strategies for clinical application of this technology.