Skeletal muscle as the potential power source for a cardiovascular pump: assessment in vivo.

Skeletal muscle ventricles (SMVs) were constructed from canine latissimus dorsi and connected to a totally implantable mock circulation device. The SMVs, stimulated by an implantable pulse generator, pumped continuously for up to 8 weeks in free-running beagle dogs. Systolic pressures produced by the SMVs, initially of 139 +/- 7.2 mmHg and after 1 month of continuous pumping of 107 +/- 7 mmHg, were comparable to normal physiologic pressures in the adult beagles (114 +/- 21 mmHg). After 2 weeks of continuous pumping, the mean stroke work of the SMVs was 0.4 X 10(6) ergs, a performance that compares favorably with the animal's cardiac ventricles. This study shows that canine skeletal muscle which has not received prior training or electrical conditioning can perform sustained work at the high levels needed for an auxiliary cardiovascular pump. It might be possible eventually to use such muscle pumps in humans to assist the failing circulation and to provide support in children with certain types of congenital heart defects.

Detection of anti-HLA antibody by flow cytometry in patients with a left ventricular assist device is associated with early rejection following heart transplantation.

BACKGROUND: Patients with a left ventricular assist device (LVAD) as a bridge to heart transplantation (HT) often have elevated levels of panel reactive antibodies (PRA). The clinical significance of anti-human histocompatibility leukocyte antigen (HLA) antibodies detected by flow cytometry in PRA negative patients remains unclear. METHODS: Eighteen patients who underwent LVAD placement as a successful bridge to HT had standard anti-human globulin complement-dependent cytotoxicity and retrospective flow cytometry assays performed to detect class I anti-HLA antibodies. A positive flow result was defined as a fluorescent ratio of 23:1 versus a negative control. RESULTS: Six patients had anti-HLA antibodies detected by flow cytometry. Univariate analysis demonstrated more moderate-severe rejection episodes (ISHLT > or = IIIA) at 2 months (0.83+/-0.75 vs. 0; P=0.04) and a trend toward decreased time to first rejection (61+/-17 vs. 225+/-62 days; P=0.06) in these patients. No differences were observed in donor-recipient HLA mismatch or 1 year Kaplan-Meier survival between patients with or without anti-HLA antibodies. CONCLUSION: Despite a negative PRA, LVAD patients with class I anti-HLA antibodies detected by flow cytometry have a greater incidence of moderate-severe rejection in the first 2 months after HT. Flow cytometry may be a useful clinical tool in screening PRA negative LVAD patients before transplantation. Patients with positive anti-HLA antibody screening by flow cytometry may require more intensive immunosuppression in the early post-HT period.

Frequency, risk factors, and clinical outcomes of left ventricular assist device-associated ventricular thrombus.

A retrospective, transesophageal study of 51 consecutive patients receiving a left ventricular (LV) assist device (AD) over a 2-year period showed that LVAD-associated LV thrombosis (16%) was predicted by acute myocardial infarction, atrial cannulation, and postimplantation bleeding, and was associated with a fourfold increased risk of stroke compared with patients without thrombosis. LV cannulation, when using short-term LVADs, may decrease the incidence of LV thrombosis, and early transition to Heartmate-LVAD support may improve outcome.

An autologous biologic pump motor.

Latissimus dorsi skeletal muscle ventricles were constructed in six beagles. They first underwent a period of vascular delay and of electrical preconditioning over several weeks. The skeletal muscle ventricles were then connected to a totally implantable mock circulation that allowed for the chronic measurement of pressures and flows produced by the muscle. The skeletal muscle ventricles were actuated by stimulation of the motor nerve with an implanted generator that delivered brief pulse trains. The skeletal muscle ventricles pumped continuously against an afterload of 80 mm Hg with a preload of 40 to 50 mm Hg at a rate of 54 times per minute. At initiation of pumping, systolic pressure was 135 +/- 24 mm Hg and flow was 464 +/- 116 ml/min. After 2 weeks of continuous pumping, the systolic pressure was 104 +/- 1 mm Hg and continuous flow was 206 +/- 16 ml/min. Two of the skeletal muscle ventricles pumped continuously for 5 and 9 weeks, respectively. At the end of that time one was still capable of generating pressure up to 205 mm Hg and the other, 160 mm Hg. These results suggest that a chronic auxiliary skeletal muscle ventricle is a feasible approach to the treatment of end-stage cardiac failure.

Skeletal muscle ventricles in circulation. One to eleven weeks' experience.

Skeletal muscle ventricles were constructed from canine latissimus dorsi and connected to the thoracic aorta in six dogs. These ventricles were stimulated to contract synchronously during diastole. The skeletal muscle ventricles were capable of continuous stroke work when placed within the arterial circulation for several weeks. Effective synchronous diastolic counterpulsation was produced. These results demonstrate that diastolic counterpulsators can be constructed from skeletal muscle and in the future may provide a feasible therapeutic alternative for the treatment of end-stage cardiac failure.

Dynamic cardiomyoplasty: its chronic and acute effects on the failing heart.

OBJECTIVES: Dynamic cardiomyoplasty is an alternative therapy for end-stage heart failure. We investigated the mechanisms, both acute and chronic, by which a synchronously stimulated conditioned muscle wrap affects left ventricular function in a chronic canine model of dilated cardiomyopathy. METHODS: Nineteen dogs underwent rapid ventricular pacing at a rate of 215 beats/min for 4 weeks to create a model of heart failure. Eight dogs were then randomly selected to undergo cardiomyoplasty, and all dogs received 6 additional weeks of rapid ventricular pacing. The cardiomyoplasty group also received a graded muscle conditioning protocol of synchronized burst stimulation to transform the muscle wrap. All dogs were studied with pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of rapid ventricular pacing. Data in the cardiomyoplasty group were analyzed with the stimulator off, with it augmenting every beat (1:1), and with it augmenting only every other beat (1:2). RESULTS: Stimulator "of" data at 10 weeks of rapid pacing demonstrated chronic effects by enhanced ventricular function (end-systolic elastance = 1.80 after myoplasty vs 1.17 for controls, p = 0.005) and a stabilization of volumes and composite end-systolic and end-diastolic pressure-volume relations in the cardiomyoplasty group when compared with controls. Myoplasty stimulation increased apparent contractility (preload recruitable stroke work = 31.3 for stimulator "of" vs 40.6 for stimulator 1:2 assisted beats [p < 0.05] and vs 45.4 for stimulator 1:1 [p < 0.05]). CONCLUSIONS: Benefits from dynamic cardiomyoplasty are by at least two mechanisms: (1) the girdling effects of a conditioned muscle wrap, which halts the chronic remodeling of heart failure, and (2) active systolic assistance, which augments the apparent contractility of the failing heart.

Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

OBJECTIVE: Rapid ventricular pacing produces a reliable model of heart failure. Cessation after 4 weeks of rapid ventricular pacing results in rapid normalization of left ventricular function, but the left ventricle remains persistently dilated. We present novel data that show that prolonged rapid ventricular pacing (10 weeks) creates a model of chronic left ventricular dysfunction. METHODS: In 9 dogs undergoing 10 weeks of rapid ventricular pacing, left ventricular function and volumes were serially assessed by using 2-dimensional echocardiography and pressure-volume analysis for 12 weeks after cessation of pacing. RESULTS: Increased end-diastolic volume and decreased systolic and diastolic function were seen at the end of pacing. By 2 weeks of recovery from rapid ventricular pacing, end-diastolic volume and ejection fraction were partially recovered but did not improve further thereafter. Load-independent and load-sensitive indices of function obtained by pressure-volume analysis at 8 and 12 weeks of recovery confirmed a persistence of both systolic and diastolic dysfunction. In addition, left ventricular mass increased with pacing and remained elevated at 8 and 12 weeks of recovery. Four of these dogs studied at 6 months of recovery showed similar left ventricular abnormalities. CONCLUSION: Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

Early post-transplant lymphoproliferative disease following heart transplantation in the absence of lymphocytolytic induction therapy.

We report a case of post-transplant lymphoproliferative disease presenting as a disseminated polymorphous B-cell lymphoma involving the cardiac allograft 3 months following transplantation in a recipient who did not receive anti-lymphocyte induction immunosuppression. In situ hybridization for the lytic Epstein-Barr virus marker NOT I was positive within a lymphocytic infiltrate on endomyocardial biopsy. Our case is the third of early post-transplant lymphoproliferative disease (within 6 months of transplantation) involving the heart allograft in the absence of anti-lymphocyte induction immunosuppression. Post-transplant lymphoproliferative disease of the heart allograft should be considered in the presence of an atypical cardiac lymphocytic infiltrate, with possible differentiation from allograft rejection using in situ hybridization for Epstein-Barr virus.

Cortical blindness secondary to cyclosporine after orthotopic heart transplantation: a case report and review of the literature.

Cyclosporine neurotoxicity has been described after liver, kidney, and bone marrow transplantation and has been associated with a number of risk factors, including hypomagnesemia and low serum cholesterol levels. Reports in heart transplant recipients are less common. We present a patient with cortical blindness secondary to cyclosporine after orthotopic heart transplantation. The patient had confusion, focal visual field defects, and bilateral occipital lobe lesions shown on magnetic resonance imaging. Although he had significant clinical improvement with decreasing cyclosporine levels, residual computerized visual field defects and magnetic resonance imaging abnormalities were documented several months later.

Hepatitis C transmission and infection by orthotopic heart transplantation.

BACKGROUND: The transmission and clinical consequences of hepatitis C viral (HCV) infection acquired by orthotopic heart transplantation (OHT) from an HCV-infected donor to an HCV-naive recipient have not been well described. We report our experience in 5 HCV-naive patients who were transplanted with hearts from HCV-positive donors. All transplants occurred within a 1-year period. METHODS: After cardiac transplantation we retrospectively examined the recipients' clinical course, liver-associated enzymes, HCV-antibody serology, quantitative HCV RNA level, and HCV genotype. RESULTS: Five subjects with rapidly deteriorating heart failure and negative serum antibodies to HCV received an emergent OHT from a donor known to be infected with HCV. Liver-associated enzymes peaked at 2 to 6 weeks post-transplant: mean peak alanine aminotransferase was 180 U/L (normal, 9 to 52) and aspartate aminotransferase was 111 U/L (normal, 14 to 36). Liver enzymes had returned to normal limits by 6 and 12 months post-OHT. At a mean 15 months after transplantation, only 1 of 5 patients has developed antibodies to HCV, but 4 of 5 have evidence of infection, as shown by serum HCV RNA. No patient has developed evidence of liver failure. CONCLUSIONS: (1) Transmission of HCV from an HCV-positive donor to an HCV-naive recipient at the time of OHT is likely. (2) Antibodies to HCV post-OHT may remain negative for more than 1 year in these patients. (3) Hepatitis C viral RNA using polymerase chain reaction should be the test of choice for diagnosis of HCV infection post-OHT. (4) Hepatitis C viral donor hearts should be limited to critically ill patients in extremis until the long-term consequences of acquisition of HCV by an OHT recipient are known.

Use of theophylline for treatment of prolonged sinus node dysfunction in human orthotopic heart transplantation.

Sinus node dysfunction may complicate heart transplantation in over 50% of cases, leading to prolonged bradyarrhythmias in 20% of recipients. Permanent pacemaker implantation, the standard treatment for such persistent rhythm disturbances, can result in significant complications in this setting. A protocol with theophylline, a methylxanthine known to reverse the sinus node electrophysiologic abnormalities observed in transplant patients, was initiated at our institution in October 1989 to treat posttransplantation bradyarrhythmias and to reduce the need for pacemaker implantation. Patients with sinus or nodal bradycardia or sinus arrest were given theophylline orally; the drug was initiated in 15 of 38 patients (39.5%), 3 to 24 days after transplantation. Mean duration of treatment was 57.4 days (range, 20 to 105 days). Normal sinus rhythm with a rate of more than 90 beats/min was restored in 14 of 15 patients (93.3%). Permanent pacing was required in one patient. Transplant recipients before October 1989 (group 1, n = 112) were compared with subsequent transplant recipients (group 2, n = 38). These groups did not differ significantly in incidence of bradyarrhythmias or potential risk factors for posttransplantation sinus node dysfunction, though a greater preoperative use of amiodarone occurred in group 2. Permanent pacemaker requirement was significantly reduced from 16.1% in group 1 to 2.6% in group 2 (p < 0.05) with the introduction of theophylline. Theophylline is effective treatment for posttransplantation bradyarrhythmias, thereby resulting in a reduced need for pacemaker implantation.

Canine diaphragm muscle after 1 yr of continuous electrical stimulation: its potential as a myocardial substitute.

Skeletal muscle has been rendered fatigue resistant by chronic stimulation and therefore has potential as an active substitute for damaged myocardium. It is therefore important to know whether stimulation produces any deleterious effects in the long term. Hemidiaphragm muscles of four dogs were examined after chronic stimulation for 1 yr at either 2 or 4 Hz. The stimulated hemidiaphragms appeared normal on gross inspection and were still contracting vigorously. By histochemical and immunohistochemical criteria, they had acquired a uniformly type I character, in contrast to the mixed fiber type composition of the unstimulated hemidiaphragms. This transformation was also reflected in their complement of myosin isozymes. There was some enzymatic evidence of an associated shift towards aerobic pathways of energy generation. Histological examination revealed no evidence of degenerative changes. Trends, observed in the shorter term (6-8 wk), toward a decrease in fiber area and an increase in connective tissue showed no further progression at 1 yr. Thus hemidiaphragm muscle stimulated at frequencies at or above the normal heart rate does not appear to undergo adverse long-term changes that would constrain its use in a myocardial assist role.

Arterial delivery of genetically labelled skeletal myoblasts to the murine heart: long-term survival and phenotypic modification of implanted myoblasts.

The ability to replace damaged myocardial tissue with new striated muscle would constitute a major advance in the treatment of diseases that irreversibly injure cardiac muscle cells. The creation of focal grafts of skeletal muscle has been reported following the intramural injection of skeletal myoblasts into both normal and injured myocardium. The goals of this study were to determine whether skeletal myoblast-derived cells can be engrafted into the murine heart following arterial delivery. The murine heart was seeded with genetically labeled C2C12 myoblasts introduced into the arterial circulation of the heart via a transventricular injection. A transventricular injection provided access to the coronary and systemic circulations. Implanted cells were characterized using histochemical staining for beta-galactosidase, immunofluorescent staining for muscle-specific antigens, and electron microscopy. Initially the injected cells were observed entrapped in myocardial capillaries. One week after injection myoblasts were present in the myocardial interstitium and were largely absent from the myocardial capillary bed. Implanted cells underwent myogenic development, characterized by the expression of a fast-twitch skeletal muscle sarcoendoplasmic reticulum calcium ATPase (SERCA1) and formation of myofilaments. Four months following injection myoblast-derived cells began to express a slow-twitch/cardiac protein, phospholamban, that is normally not expressed by C2C12 cells in vitro. Most surprisingly, regions of close apposition between LacZ labeled cells and native cardiomyocytes contained structures that resembled desmosomes, fascia adherens junctions, and gap junctions. The cardiac gap junction protein, connexin43, was localized to some of the interfaces between implanted cells and cardiomyocytes. Collectively, these findings suggest that arterially delivered myoblasts can be engrafted into the heart, and that prolonged residence in the myocardium may alter the phenotype of these skeletal muscle-derived cells. Further studies are necessary to determine whether arterial delivery of skeletal myoblasts can be developed as treatment for myocardial dysfunction.

Mechanical circulatory support for patients with acute-fulminant myocarditis.

This report provides a review of mechanical circulatory support for patients in cardiogenic shock secondary to acute/fulminant myocarditis. Experience and outcomes with extracorporeal membrane oxygenation, left ventricular assist device support (ABIOMED, Thoratec, Thermo Cardiosystems, Novacor), and biventricular ventricular assist device support (ABIOMED, Thoratec) are described. Patients in cardiogenic shock secondary to acute myocarditis in its fulminant presentation can recover, surprisingly with normal cardiac function. An aggressive approach to the use of mechanical support is strongly justified. Survival, either by bridge to transplant or recovery, should approach 70%. Transplantation can often be avoided.

Dynamic cardiomyoplasty: at the crossroads.

BACKGROUND: Dynamic cardiomyoplasty remains a promising, but still unproven surgical treatment for patients with end-stage heart failure. Lack of a clear survival advantage and ongoing misunderstanding of its mechanism of action have hindered its acceptance as a treatment alternative for patients with end-stage heart failure. This review seeks to update current clinical results and practice of dynamic cardiomyoplasty and to present its likely mechanism of action. METHODS: The method involved a literature review. RESULTS: More than 600 patients have undergone dynamic cardioplasty since 1985. Improvement in average New York Heart Association class was noted in 80% to 85% of hospital survivors. Operative mortality has decreased from 31% in Phase I to less than 3% in the ongoing Phase III trial. Clinical work as well as recent animal work supports the hypothesis that through a combination of long-term elastic constraint and active dynamic assist, dynamic cardiomyoplasty decreases myocardial wall stress associated with the remodeling process of progressive heart failure. CONCLUSIONS: Though dynamic cardiomyoplasty can be shown to limit the remodeling process of heart failure in animal studies and some patients, its ultimate role in the treatment of heart failure will depend on the outcome of randomized, controlled studies.

Intracardiac thrombus: a risk of incomplete anticoagulation for cardiac operations.

Mitral valve replacement was performed urgently in a patient with hemorrhagic brain lesions. To decrease the risk of intracranial hemorrhage, cardiopulmonary bypass was performed using a heparin-coated perfusion system and a reduced dose of heparin. The detection of an acute intracardiac thrombus by transesophageal echocardiography during cardiopulmonary bypass exposed a potential hazard of techniques employing reduced systemic anticoagulation for cardiac operations.

New method for mechanistic studies of cardiomyoplasty: three-dimensional MRI reconstructions.

The imaging modalities used to study the mechanism of cardiomyoplasty, such as echocardiography and radionuclide scintigraphy, are seriously limited by their two-dimensional format. Radiofrequency-pulse-tagged magnetic resonance imaging was used to generate three-dimensional reconstructions of the left ventricle throughout the cardiac cycle after cardiomyoplasty. In 2 dogs that had undergone conditioned, right anterior cardiomyoplasty, wrap stimulation with alternating heartbeats was found to produce marked translation of the left ventricle in the short-axis plane, rotation around the long axis, and displacement along the long axis with net long-axis compression; there was no augmentation of radial squeeze. The findings from this study suggest that any systolic augmentation produced by the right anterior wrap is due primarily to long-axis compression. Our study demonstrates a new, more accurate technique of assessing the mechanical effects of cardiomyoplasty in three dimensions, thus permitting a more rational optimization of wrap configurations, and emphasizes the perils of using standard two-dimensional imaging modalities in this setting of exaggerated three-dimensional motion.

Mechanical circulatory support for acute heart failure.

Circulatory support devices are frequently required in postcardiotomy shock, postmyocardial infarction shock, and acute myocarditis. A panel of cardiac surgeons addressed the use of these devices in 4 patients. Cardiogenic shock after mitral valve replacement was considered best served by a left ventricular assist device (VAD) with apical rather than atrial cannulation. A left VAD should be placed first and a right VAD only if needed. Acute myocardial infarction shock was considered best treated with a left VAD with left ventricular cannulation to avoid thrombosis. If cardiac transplantation is an option, a long-term device must be considered. Young patients with acute fulminant myocarditis should be implanted with VADs in anticipation of recovery, and transplantation should be delayed. Patients with severe heart failure after coronary bypass grafting were considered best served by an extracorporal membrane oxygenation (ECMO) system or a VAD. Current postcardiotomy survival rates of postcardiotomy patients of 20% to 40% are worthwhile, but can be improved. Temporary devices such as ECMO can be changed to more long-term devices when necessary.

Triiodothyronine optimizes sheep ventriculoarterial coupling for work efficiency.

BACKGROUND: Triiodothyronine (T3) administration after cardiopulmonary bypass has been shown to significantly improve cardiac performance. The present study was undertaken to elucidate the effects of T3, when administered as an intravenous bolus, on both cardiac energetics and stroke work-oxygen utilization (EW/LVVO2) efficiency. METHODS: In both unstressed and stressed hearts, energetics were evaluated at baseline and 2 hours after intervention in an in vivo sheep preparation. In the first group (n = 5) sheep received saline vehicle. In the second group (n = 9) sheep received an intravenous bolus of 1.2 micrograms/kg of T3. In the third group (n = 7) sheep received a 2-hour intravenous infusion of dobutamine at a rate of 5 micrograms/kg/min. RESULTS: In the unstressed heart, T3 improved cardiac function at no cost in oxygen consumption by decreasing afterload and hence improved EW/LVVO2 efficiency. In contrast, dobutamine improved unstressed cardiac function by increasing contractility at the cost of increased oxygen consumption and thus decreased EW/LVVO2 efficiency. Triiodothyronine optimized ventriculoarterial coupling for efficiency, but dobutamine optimized coupling for maximal work. In the stressed heart, T3 again improved EW/LVVO2 efficiency, but dobutamine had the opposite effect. CONCLUSIONS: The bolus administration of T3 improves unstressed cardiac performance through optimization of ventriculoarterial coupling for EW/LVVO2 efficiency, primarily through vasodilation. Triiodothyronine also increases efficiency in the stressed heart. This study supports the use of T3 in cardiac operations to improve cardiac performance with no cost in oxygen consumption characteristic of inotropic agents.

Management of exsanguinating hemoptysis during cardiopulmonary bypass.

BACKGROUND: Large-volume hemoptysis during cardiopulmonary bypass is an infrequent, but life-threatening event. Rapid airway clearance and control are the primary prerequisites for successful management. METHODS: The cases of 3 patients with different sources of exsanguinating hemoptysis during cardiopulmonary bypass managed initially with rigid bronchoscopy were reviewed. RESULTS: In all patients, airway control was rapidly established and weaning from cardiopulmonary bypass CPB was accomplished. Two patients survived the operative procedure. The other patient died in the operating room of unremitting bilateral pulmonary hemorrhage. CONCLUSIONS: Major hemoptysis during cardiopulmonary bypass is best dealt with initially by rapid airway control and cessation of bypass in an expeditious manner. An algorithm for suggested management is provided. The rigid bronchoscope is the optimal tool for initial management and it should always be available. Definitive treatment is determined by the cause and the persistence of hemorrhage once these maneuvers have been performed.