Homozygous deletion of the p16INK4A gene occurs more frequently in CD2+ than in CD2+ T-cell acute lymphoblastic leukemia

Right ventricular assist devices are an important part of the armamentarium of cardiac surgeons for the treatment of right-sided circulatory failure after cardiac transplantation or insertion of a left ventricular assist device. However, right ventricular assist device insertion can be technically challenging in the setting of pulmonary hypertension because of a number of concomitant anatomic and physiologic phenomena. We present a technique for the insertion of the right ventricular assist device outflow cannula that is easier and faster to insert, and safer to explant, especially if cardiopulmonary bypass is to be avoided.     

Transient normalization of systolic and diastolic function after support with a left ventricular assist device in a patient with dilated cardiomyopathy

A 19-year-old man who had fulminant heart failure caused by an idiopathic dilated cardiomyopathy was supported with a left ventricular assist device for 183 days as a bridge to heart transplantation. At the time of intended transplantation it was noted that the patient's heart had returned to normal size, had a normal ejection fraction, and was able to maintain normal pressures and flows. In view of the apparent recovery of cardiac properties, the left ventricular assist device was explanted and the transplantation was not performed. However, the heart dilated, ejection fraction worsened, and the patient died of heart failure exacerbated acutely by a systemic viral illness. Although such recovery of systolic function is uncommon, as use of the left ventricular assist devices becomes more widespread other physicians might encounter similar findings and, in this regard, they might find our experience useful as they contemplate their treatment options.     

Epitope mapping of monoclonal antibodies against 4-aminobenzoate hydroxylase from Agaricus bisporus

BACKGROUND: Left ventricular assist devices have been reported previously to reverse ventricular remodeling in patients with dilated cardiomyopathy. In patients with prolonged mechanical support, structural failure of the left ventricular assist device inflow valve can cause regurgitation into the left ventricle, which may affect adversely this process. METHODS: Left ventricular end-diastolic pressure-volume relation of hearts explanted from 8 patients with left ventricular assist device and 8 control subjects with idiopathic cardiomyopathy was determined ex vivo at the time of transplantation. RESULTS: Duration of mechanical support ranged from 210 to 276 days (mean +/- standard deviation = 283 +/- 76 days) in 3 patients with inflow valve regurgitation versus 100 to 155 days (132 +/- 22 days) in 5 patients without (p = 0.005). The end-diastolic pressure-volume relation of all hearts supported mechanically was shifted to the left toward normal controls. This effect was markedly attenuated in patients with inflow valve regurgitation. CONCLUSIONS: Mechanical assistance can cause reverse remodeling in patients with dilated cardiomyopathy as evidenced by the shift in the end-diastolic pressure-volume relation curve to the left. Inflow valve failure, associated with prolonged support, can attenuate changes in left ventricular structure and dimension. Ineffective pressure and volume unloading may explain these observations.     

Mechanical circulatory support for post cardiotomy cardiogenic shock in infants

Eleven infants weighing 2.3 to 7.8 kg underwent mechanical circulatory support for post cardiotomy cardiogenic shock. Initiated pre-operatively in two patients, extracorporeal membrane oxygenation was used in a total of eight patients aged 6 days to 3 months in association with repair of cyanotic congenital heart disease with increased pulmonary blood flow or with a right sided obstructive lesion. Ventricular assist devices were used in three other patients: a centrifugal left ventricular assist device in Patient 1 (10 months, 5.7 kg) after repair of the anomalous left coronary artery, and a pneumatic biventricular assist device (stroke volume 12 ml) in Patient 2 (6 months, 7.0 kg) for cardiac arrest after closure of ventricular septal defect and in Patient 3 (10 months, 7.8 kg) for post transplant graft failure. Duration of extracorporeal membrane oxygenation duration ranged from 26 to 192 hr (mean, 88 hr). Three patients were weaned from extracorporeal membrane oxygenation and two survived. Two others were separated from extracorporeal membrane oxygenation because of bleeding, but both subsequently died. Patient 1 was weaned from the left ventricular assist device after 192 hr and discharged from the hospital. Support was discontinued after 45 hr in Patient 2 who exhibited irreversible brain damage. Patient 3 was weaned from a biventricular assist device after 174 hr, but suffered recurrent graft failure. Our results show that an appropriate circulatory support system should be selected according to the cardiac anatomy in infants.     

An intracorporeal (abdominal) left ventricular assist device. Initial clinical trials

We have initiated clinical trials with an intracorporeal (abdominal) partial artificial heart and ten preterminal postcardiotomy patients have been studied. During profound left ventricular failure, the device captures the entire cardiac output from the apex of the left ventricle at low pressures (20 to 40 mm Hg) and ejects (at 80 to 150 mm Hg) into the infrarenal abdominal aorta; the biological aortic valve opens only intermittently and the entire systemic circulation is pump generated. The device is six to ten times more effective than intra-aortic balloon pumping in man and has maintained systemic perfusion during clinical asystole and ventricular fibrillation. We have documented that the profoundly depressed postcardiotomy left ventricle, initially incapable of ejection, can recover during total left ventricular unloading with the abdominal left ventricular assist device support over a seven-day period.     

Evaluation of a pulsatile pediatric ventricular assist device in an acute right heart failure model

BACKGROUND: The development of pulsatile ventricular assist devices for children has been limited mainly by size constraints. The purpose of this study was to evaluate the MEDOS trileaflet-valved, pulsatile, pediatric right ventricular assist device (stroke volume = 9 mL) in a neonatal lamb model of acute right ventricular failure. METHODS: Right ventricular failure was induced in ten 3-week-old lambs (8.6 kg) by right ventriculotomy and disruption of the tricuspid valve. Control group 1 (n = 5) had no mechanical support whereas experimental group 2 (n = 5) had right ventricular assist device support for 6 hours. The following hemodynamic parameters were measured in all animals: heart rate and right atrial, pulmonary arterial, left atrial, and systemic arterial pressures. Cardiac output was measured by an electromagnetic flow probe placed on the pulmonary artery. RESULTS: All results are expressed as mean +/- standard deviation and analyzed by Student's t test. A p value less than 0.05 was considered statistically significant. Base-line measurements were not significantly different between groups and included systemic arterial pressure, 80.6 +/- 12.7 mm Hg; right atrial pressure, 4.6 +/- 1.6 mm Hg; mean pulmonary arterial pressure, 15.6 +/- 4.2 mm Hg; left atrial pressure, 4.8 +/- 0.8 mm Hg; and cardiac output, 1.4 +/- 0.2 L/min. Right ventricular injury produced hemodynamics compatible with right ventricular failure in both groups: mean systemic arterial pressure, 38.8 +/- 10.4 mm Hg; right atrial pressure, 16.8 +/- 2.3 mm Hg; left atrial pressure, 1.4 +/- 0.5 mm Hg; and cardiac output, 0.6 +/- 0.1 L/min. All group 1 animals died at a mean of 71.4 +/- 9.4 minutes after the operation. All group 2 animals survived the duration of study. Hemodynamic parameters were recorded at 2, 4, and 6 hours on and off pump, and were significantly improved at all time points: mean systemic arterial pressure, 68.0 +/- 13.0 mm Hg; right atrial pressure, 8.2 +/- 2.3 mm Hg; left atrial pressure, 6.4 +/- 2.1 mm Hg; and cardiac output, 1.0 +/- 0.2 L/min. CONCLUSIONS: The results demonstrate the successful creation of a right ventricular failure model and its salvage by a miniaturized, pulsatile right ventricular assist device. The small size of this device makes its use possible even in small neonates.     

Mixed endo-exo ultrastructural morphology of some beta cells in adult porcine pancreas

Life-threatening, recurrent ventricular tachycardia developed in a 54-year-old heart transplant candidate with ischemic cardiomyopathy. The episodes of ventricular tachycardia were refractory to aggressive medical management and implantable cardiac defibrillator placement. A Heartmate left ventricular assist device was implanted, in combination with isolated right coronary artery bypass grafting, which abolished any further episode of ventricular tachycardia. The patient successfully underwent cardiac transplantation 79 days later.     

Platelet glycoprotein IIb/IIIa inhibitor attenuates complement activation during in vitro ventricular assist circulation

Complement activity and platelet glycoprotein (GP) IIb/IIIa dysfunction have been demonstrated during in vitro ventricular assist device circulation. Platelets contain C1 serine protease inhibitor (C1 INH) in secretory granules, which normally regulates complement. Complement activity may result from a loss of platelet regulation on complement during ventricular assist device circulation as platelets lose viability. The purpose of this study was to assess the ability of a platelet GP IIb/IIIa receptor inhibitor to attenuate ventricular assist device associated complement activation during in vitro ventricular assisted circulation. Eight in vitro nonpulsatile centrifugal ventricular assist device circuits were simulated for 4 days using 450 ml fresh human whole blood. Cardiac index, temperature, pH, PO2, PCO2, Ca, glucose, and activated clotting time were maintained at physiologic levels. Levels of C1 INH and C3a were measured with and without a reversible glycoprotein IIb/IIIa inhibitor (MK-383). Concentrations of C1 INH increase on exposure to ventricular assist device, and decrease to a plateau within 12 hr. The decrease in circulating unbound C1 INH was attenuated with pre treatment with MK-383. Concentrations of C3a increase 34 fold within 4 hr of exposure to a ventricular assist device with and 22 fold without pre treatment with MK-383. These findings suggest that protection of the platelet GP IIb/IIIa complex delays complement activation during in vitro ventricular assist device circulation.     

Circulatory support with a left-heart assist device after intracardiac operation: design concepts and management techniques

A simple left-heart assist device was developed to reduce left ventricular preload while simultaneously increasing total systemic blood flow. It consists of special cannulas connected to a simple extracorporeal tubing loop and roller pump, designed to permit bypass of as much as 5 liters of blood per minute from left atrium to ascending aorta. Employed in 15 patients with advanced heart disease who were in low cardiac output following repair, the system was proven effective. An asset of the device is the ability to subsequently separate the patient from the device without need to reenter the thorax or abdomen.     

Analytic processing elicits right ear superiority in monaurally presented speech

Experiments were designed to assess the performance of an intracorporeal (abdominal) left ventricular assist device (ALVAD) in the presence of induced tachycardias, multiple premature ventricular contractions (PVC's), and ventricular fibrillation in calves. Performance criteria were the degree of left ventricular unloading and the per cent cardiac output assumed by the ALVAD. During synchronous pumping, left ventricular unloading was complete and the entire cardiac output was captured by the device. During induced tachycardias up to rates of 120 beats per minute, these degrees of performance were maintained. At rates in excess of 120 beats per minute, performance declined due to decreased biologic stroke volumes and prosthetic filling times. In the presence of induced PVC's, performance during synchronous pumping decreased because of erratic R-wave sensing. Left ventricular unloading was complete but irregular, and the total cardiac output was captured. When asynchronous pumping was utilized, mean left ventricular systolic pressures increased, but total cardiac output was still captured. During induced ventricular fibrillation, ALVAD actuation maintained cardiac outputs equal to control values for periods up to 5 1/2 hours. These experiments indicate that, during normal sinus rhythm, synchronous pumping is optimal; asynchronous pumping is optimal during complex dysrhythmias; and either can be utilized to support the circulation with varying degrees of left ventricular unloading.     

Overcoming right ventricular failure with left ventricular assist devices

BACKGROUND: Right ventricular failure can lead to circulatory collapse while on left ventricular assist device support. By shunting blood from the femoral vein to the left ventricular assist device, cardiac output can be increased, but arterial oxygen saturation will decrease. METHODS: To determine the effects on O2 delivery, a model was developed on the basis of O2 uptake in the lungs and whole body O2 consumption. An equation was derived that related cardiac output, pulmonary venous O2 saturation, O2 consumption, and the ratio of shunt-to-systemic blood flow to systemic O2 delivery. RESULTS: When total cardiac output increases, the shunt will increase systemic O2 delivery while decreasing arterial O2 saturation and leaving systemic venous O2 saturation unaltered. When total output does not increase, the shunt will decrease systemic O2 delivery, arterial O2 saturation, and systemic venous O2 saturation. CONCLUSIONS: The analysis suggests that measuring systemic venous oxygen saturation may be a useful way to monitor patient safety. A decrease in systemic venous O2 saturation when creating the shunt implies an inadequate increase in cardiac output.     

Hemodynamic and physiologic changes during support with an implantable left ventricular assist device

To evaluate hemodynamic effectiveness and physiologic changes on the HeartMate 1000 IP left ventricular assist device (Thermo Cardiosystems, Inc., Woburn, Mass.), we studied 25 patients undergoing bridge to heart transplantation (35 to 63 years old, mean 50 years). All were receiving inotropic agents before left ventricular assist device implantation, 21 (84%) were supported with a balloon pump, and 7 (28%) were supported by extracorporeal membrane oxygenation. Six patients died, primarily of right ventricular dysfunction and multiple organ failure. Nineteen (76%) were rehabilitated, received a donor heart, and were discharged (100% survival after transplantation). Pretransplantation duration of support averaged 76 days (22 to 153 days). No thromboembolic events occurred in more than 1500 patient-days of support with only antiplatelet medications. Significant hemodynamic improvement was measured (before implantation to before explantation) in cardiac index (1.7 +/- 0.3 to 3.1 +/- 0.8 L/min per square meter; p < 0.001), left atrial pressure (23.7 +/- 7 to 9 +/- 7.5 mm Hg; p < 0.001), pulmonary artery pressure, pulmonary vascular resistance, and right ventricular volumes and ejection fraction. Both creatinine and blood urea nitrogen levels were significantly higher before implantation in patients who died while receiving support. Renal and liver function returned to normal before transplantation. We conclude that support with the HeartMate device improved hemodynamic and subsystem function before transplantation. Long-term support with the HeartMate device has a low risk of thromboemboli and makes a clinical trial of a portable HeartMate device a realistic alternative to medical therapy.     

Pulmonary hypertension is not a risk factor for RVAD use and death after left ventricular assist system support

Unlike transplantation candidates, patients with pulmonary hypertension (PHTN) and a high transpulmonary gradient do not appear to be at increased risk for right ventricular dysfunction after left ventricular assist system implant. To verify this observation, we reviewed 63 patients supported with the HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left ventricular assist system. Patients were divided into two groups: patients with PHTN (47 patients) had mean pulmonary artery pressure > 30 mm Hg and/or pulmonary vascular resistance > 4 Wood units, and the remainder of patients did not have PHTN (16 patients). Both groups were similar in age (mean, 51 years), gender distribution (% men, 83% vs 94%, not significant), and number of patients with ischemic cardiomyopathy (72% vs 69%, not significant). More patients in the group without PHTN required extracorporeal membrane oxygenation support (38% vs 12%, p = .06). Right ventricular assist device support was instituted in five (11%) patients with PHTN and four (25%) patients without PHTN. A significantly larger number of patients without PHTN died while on support (14% vs 44%, p = .01). Survival after transplantation in both groups was > 90%. Patients with PHTN have higher transpulmonary gradient, show a significant decrease in pulmonary pressure after left ventricular assist system implantation, and have a higher transplantation rate compared to patients without PHTN. A larger patient cohort is needed to determine if the absence of PHTN is a risk factor for RVAD need and poor outcome after LVAS support.     

Exercise performance and chronotropic response in heart failure patients with implantable left ventricular assist devices

During metabolic stress testing, 9 of 20 patients with left ventricular assist devices exhibited a lag in peak device rate by < or = 85% of peak native heart rate (group I), with peak device rates of 118 +/- 9 beats/min compared with group II, in which peak device rate nearly equaled peak native rates. Peak systolic blood pressure was significantly greater in group II than group I, but there was no significant difference in peak oxygen consumption, anaerobic threshold, or peak flows.     

Analysis of right ventricular function during bypass of the left side of the heart by afterload alterations in both normal and failing hearts

This study investigated the mechanism of right ventricular failure during bypass of the left side of the heart by precisely assessing right ventricular function with use of a conductance catheter. Bypass of the left side of the heart was established with a centrifugal pump in 10 mongrel dogs weighing 11 to 19 kg. Right ventricular function during left heart bypass was evaluated by two parameters that were both derived from measurement of relative change in right ventricular volume by the conductance catheter technique. One parameter was the right ventricular end-systolic pressure-volume relationship as a load-independent index, and the other was the peak right ventricular pressure-right ventricular stroke volume relationship as a "force-velocity relationship." These parameters were measured in both normal and failing hearts while afterload was increased by bilateral intrapulmonary balloon inflation. Moreover, changes in these relationships were observed by varying assist ratios of left heart bypass from 0% to 100%. Failing heart models were induced by normothermic aortic clamping for 20 minutes. The right ventricular end-systolic pressure-volume relationship in normal hearts did not change, irrespective of the assist ratio of left heart bypass, whereas that in failing hearts decreased from 4.25 +/- 1.41 mm Hg/ml without bypass of the left side of the heart to 3.53 +/- 1.30 mm Hg/ml after 100% assist of left heart bypass (p < 0.05). In the peak right ventricular pressure-right ventricular stroke volume relationship, right ventricular stroke volume was almost constant in normal hearts when afterload was increased regardless of the assist ratio of left heart bypass. Moreover, right ventricular stroke volume was maintained at a higher level during bypass of the left side of the heart compared with that without left heart bypass. However, that slope of the relationship in failing hearts was inversely linear and became significantly steeper after 100% assist of bypass of the left side of the heart compared with that without left heart bypass (-0.131 +/- 0.042 versus -0.051 +/- 0.038, p < 0.005). Therefore ++these two slopes of the relationship intersected at a point that was considered the critical point of afterload during bypass of the left side of the heart. In other words, right ventricular stroke volume was decreased by 100% left heart bypass above the critical point of afterload. In conclusion, this study demonstrates not only that bypass of the left side of the heart results in an increase in right ventricular stroke volume in both normal and failing hearts at the physiologic range of afterload, but also that right ventricular function against higher afterload is impaired by 100% assist of bypass of the left side of the heart in failing hearts.     

Determinants of clinical results of mechanical circulatory support for ventricular failure after cardiotomy

To clarify determinants of clinical results of circulatory support for ventricular failure after cardiotomy, we examined 53 patients (33 men and 20 women) who underwent circulatory support for post operative heart failure from 1984 to October 1995. Their ages ranged from 22 to 74 years (mean, 51 years). In 53 patients, 32 had valvular, 19 had ischemic, and 2 had congenital heart disease. After operation, 21 patients underwent venoarterial bypass, 20 underwent biventricular bypass, and 8 underwent left ventricular bypass. The remaining 4 patients received a pulsatile left ventricular assist device. Weaning and discharge rates of the patients by type of support were 52.4% and 28.6% with venoarterial bypass, 75.0% and 55.0% with biventricular bypass, 87.5% and 37.5% with left ventricular bypass, and 75.0% and 50.0% with left ventricular assist device, respectively. The results of this series (67.9% weaning rate and 41.5% discharge rate) were acceptable. Peri-operative variables before and during circulatory support were analyzed multivariately by logistic regression analysis. Selected independent determinants (odds ratio) of significant difference (p < .05) were type of support (7.547) for non weaning and pre support cardiogenic shock (17.246), and type of support (8.780) and support duration (1.487) for mortality. These results suggest that early application before profound shock and appropriate selection of type of support might be key factors in successful circulatory support for ventricular failure occurring after cardiotomy.     

Induction of ventricular collapse by an axial flow blood pump

An important consideration for clinical application of rotary blood pump based ventricular assist is the avoidance of ventricular collapse due to excessive operating speed. Because healthy animals do not typically demonstrate this phenomenon, it is difficult to evaluate control algorithms for avoiding suction in vivo. An acute hemodynamic study was thus conducted to determine the conditions under which suction could be induced. A 70 kg calf was implanted with an axial flow assist device (Nimbus/UoP IVAS; Nimbus Inc., Rancho Cordova, CA) cannulated from the left ventricular apex to ascending aorta. On initiation of pump operation, several vasoactive interventions were performed to alter preload, afterload, and contractility of the left ventricle. Initially, dobutamine increased contractility and heart rate ([HR] = 139; baseline = 70), but ventricular collapse was not achievable, even at the maximal pump speed of 15,000 rpm. Norepinephrine decreased HR (HR = 60), increased contractility, and increased systemic vascular resistance ([SVR] = 24; baseline = 15), resulting in ventricular collapse at a pump speed of 14,000 rpm. Isoproterenol (beta agonist) increased HR (HR = 103) and decreased SVR (SVR = 12), but ventricular collapse was not achieved. Inferior vena cava occlusion reduced preload, and ventricular collapse was achieved at speeds as low as 11,000 rpm. Esmolol (beta1 antagonist) decreased HR (HR = 55) and contractility, and ventricular collapse was achieved at 11,500 rpm. Episodes of ventricular collapse were characterized initially by the pump output exceeding the venous return and the aortic valve remaining closed throughout the cardiac cycle. If continued, the mitral valve would remain open throughout the cardiac cycle. Using these unique states of the mitral and aortic valves, the onset of ventricular collapse could reliably be identified. It is hoped that the ability to detect the onset of ventricular collapse, rather than the event itself, will assist in the development and the evaluation of control algorithms for rotary ventricular assist devices.     

Spectroscopic study of Y210C lambda-repressor: implications for cooperative interaction

The development of a percutaneous artificial internal organ system requires a reliable biocompatible connection between the external environment and the inside of the human body. Such is necessary for the success of a permanent left ventricular assist device. However, the search for a satisfactory interface at the epidermal level has proven to be difficult. Carbon has been proposed for this application, but its texture does not typically promote ingrowth from surrounding tissue. We have therefore employed a new processing method to produce a fine trabecularized carbon implant. The method for preparing the implant involves infiltrating low temperature pyrolytic carbon into the surface of a carbon core which is wrapped with carbon fabric. This results in a tightly woven porous structure of carbon (carbon fiber diameter: 35-50 microm, maximal pore size >200 microm) with gradually increasing porosity from 15-75%. We implanted test samples percutaneously in a calf for in vivo histological evaluation. Thirty days after implantation epidermal downgrowth was minimal. Microscopic analysis revealed that a thin fibrous capsule surrounded the implant, and mature connective tissue with accompanying blood vessels filled the pores of the fine trabecularized carbon layer. From these results we suggest that fine trabecularized carbon is ideally suited for a percutaneous device system in a permanent left ventricular assist device.     

Use of a rate-limited ultrafiltration circuit with centrifugal ventricular assist

Renal insufficiency and pulmonary edema are frequently observed in patients who require centrifugal ventricular assist for postcardiotomy ventricular failure. We describe a technique of using a rate-limited ultrafiltration device in parallel with the assist device circuit to remove excess intravascular volume.     

Importance of pre-treatment radiation absorbed dose estimation for radioimmunotherapy of non-Hodgkin''s lymphoma

We have been developing a new type of centrifugal pump for long-term use. The magnetically suspended centrifugal pump (MSCP) contains no shaft and seal so that long life expectancy is predicted. Paracorporeal left ventricular (LV) assist circulation between the left atrium and the descending aorta was instituted using sheep. The flow rates ranged from 2.5-5.5 L/min. The sheep that lived the longest (46 days) died of an embolism as a result of the thrombus in the pump. No thrombus formation was observed in other pumps. Plasma free hemoglobin levels ranged from 9 to 18 mg/dl, which led to the conclusion that the hemolysis level remained within an acceptable range. Two driving modes were compared. The slope of the pressure-flow relationship plot under a constant motor current mode was steeper than that under a constant rotational speed mode, and thus, the flow fluctuation decreased. In conclusion, the MSCP is durable for more than a month at the current stage of development and is a promising device for long-term ventricular assist.