Fiber technology for reliable repair of skeletal muscle.

Conventional soft-tissue reclosure methods-sutures and staples-require substantial organized-collagen content. Some tissues lack extensive intrinsic collagenous content. Wound disruption consequences range from newly closed abdominal wounds bursting open, to post-cesarean wombs splitting at delivery, to heart valves loosening. Although sutures do approach the theoretical limit of normal force transfer-cross-sectional area times compressive strength, a different paradigm-shear force transfer across the far greater surface attainable by fine fibers parallel to the potential disruptive force could exceed that theoretical limit. Capacity is now the product of frictional coefficient, existing tissue pressure, and contact area. Using a device comprising bundles of poly(ethylene terephthalate) fibers through tissue, we previously coupled muscles to devices and bones. Here we tested an analogous device for reclosing fascia-stripped abdominal wall muscles. In 28 rabbits, fascia-deprived rectus abdominus muscles were reclosed, using the experimental device or conventional sutures. Testing muscles from the 21 three-week survivors, (with closure devices retained-the usual clinical practice) demonstrated experimental failure strength which exceeded that of controls by 58%. Histologically, solid tissue elements did in-grow between fibers for an extensive tissue-prosthetic interface. Both histology and mechanical performance suggest the fiber technology presented herein surpasses conventional sutures in closure of collagen-deficient tissues.

Device-induced ventricular geometric remodeling: appraisal of critical issues.

BACKGROUND AND AIMS: Devices to therapeutically alter the shape of failing left ventricles are being developed by at least two laboratories. This review attempts to assess potential for benefit and possible negative consequences of the device concepts. METHODS AND RESULTS: Data from all known publications and scientific presentations were reviewed. Findings address four key issues: (1) Predictions, based on physical computations, of direct beneficial reduction in myocardial afterload are indeed computationally realistic and supported by effects reported experimentally. (2) Concerns that remodeling might necessitate unacceptably high epicardial contact pressure appear unfounded. Computational force modeling indicates that with optimization of contact area and contour, the expected degree of remodeling (approximately 20% effective radius reduction) might be achieved by epicardial pressures very near existing endocardial pressures, and in diastole, well below arterial perfusion pressures. Reported augmentation of systolic function suggests that there is no significant compromise of regional perfusion in acute (< or = 4 weeks) preclinical studies. (3) If intramural tangential shear stresses were sustained by local bending, detrimental tensile/compressive stresses might be introduced. However, microstructure predicts and reported evidence confirms rapid shear-stress relaxation. (4) The same reduction in wall-stress/chamber-pressure ratios that produces benefit during systole would simultaneously worsen diastolic same-volume stiffness. However, if better systolic contraction effects more complete emptying, operational volume range should become incrementally lower, at least compensating. This is supported by early published data. CONCLUSIONS: There appears to be solid computational and early experimental support for the concept of geometric ventricular remodeling. If one or more of the devices being tested should prove to be safe and effective, left ventricular geometric remodeling will be of substantial benefit in heart failure treatment.

Miniature circulatory support power transformer.

Direct power delivery to intracorporeal circulatory support devices risks infection. Electrical transformers spanning the integument (skin or mucosa) have long been attractive means of circumventing this risk. Yet all existing skin surface transformers leak substantial magnetic flux, with an intrinsic risk of battery draining cross-coupling by any nearby conductor, requiring strict control of surroundings. In a progression of designs, we have used the walls of a small pouch, surgically formed from ileum, rather than skin, as a barrier. Previously, we reported a torroidal design with complete magnetic circuits, having zero flux leakage and unmatched heat dissipation in a 2 week canine trial. This work was in three parts: (1) Devices were placed in eight dogs for 9-12 weeks to document performance of the existing design. (2) Based on these results, the device was further miniaturized. Iterative computational modeling was applied to material selection and design. Simultaneously, practical techniques for surgically constructing tiny accommodating ileal pouches were explored in cadavers, by using polymer "mock-ups" of potential designs. (3) The final design was tested by acute implantation in a live 52 kg goat and by in vitro testing of electrical transfer function. IN VIVO TRIALS: The earlier design demonstrated 97.2% AC/AC and 84.2% DC/DC efficiency with contiguous tissue warming of 0.1 degrees C. DESIGN AND PERFORMANCE: A transformer with a Square Permalloy torroidal core (6 cm3, 23 grams, both coils eight turns) was designed, by using human cadaver trials to optimize geometry. Input and output were 6 V, 12W at 9.2 kHz with AC-AC efficiency 96%. OPERATIVE PLACEMENT TRIAL: The primary coil easily fit into an isolated, vascularized, but otherwise disconnected "blind" ileal pouch < 2 cm long with a slender extension to a miniature stoma. With secondary turns, the pouch and transformer fit easily into the abdominal wall. This tiny system seems compatible with near "forgettable" power delivery allowing unprecedented freedom of environment and activity in circulatory support dependent people.

Ventricular radius reduction without resection: a computational analysis.

Reducing a dilated left ventricle's radius by wedge resection lowers wall stress, improving performance. However, compliance falls, stroke volume improvement is limited, and, later, both functional deterioration and serious dysrhythmias are frequent. These all may result from loss of circumference, loss of contractile mass, and myocardial trauma, none of which would occur in geometric remodeling. One specific technique is bimeridianal restraint, which uses two indenting bars to remodel the left ventricle (LV) as two widely communicating "lobes" of reduced radius. Computational analysis of this technique, applied to the dilated ventricular dimensions of four pretransplant patients, showed that 20% radius reduction would be accomplished by two < or =18 mm wide bars, indenting the epicardium < or =8.3 mm with < or =6.4 mm greatest outward displacement. Projected stroke volume (SV) for the subject ventricles was then modeled and compared with projections for resected ventricles. Assuming that equally improved contractile fraction will follow equal radius reduction, however that reduction is accomplished, improvement is dramatic: if postresection remodeling SV were 1.0, 1.2, or 1.5 times baseline, then postgeometric remodeling SV would be 1.36+/-0.06, 1.66+/-0.05, or 2.14+/-0.04 times baseline, respectively. These results, preservation of contractile mass and circumferential length, complete reversibility, and minimal operative trauma, warrant study of implementing mechanical designs.

Coupling of skeletal muscle to a prosthesis for circulatory support.

A durable bond between the end of skeletal muscles and prosthetic structures could, with appropriate linkage, allow circulatory support power by synchronous and/or sequential contraction of several in situ conditioned muscles. Potential advantages relative to a myoplasty wrap involve 1) less traumatic dissection, 2) efficient linear force development, 3) selectable contraction rate, 4) greater stroke work, 5) independent control of muscle pre-load and end diastolic pressure, and 6) independent control of duration of muscle tension and ejection time. However, no existing means of tissue-prosthetic bonding appears adequate. Practicality would demand that full tension bearing capacity by the bond take no longer than muscle conditioning. A prosthesis was developed to achieve those goals. As scaled for this study, it is made of 7,200-7,800 unspun, unplaited, 22 to 26 microns diameter polyester fibers swaged into four taper needles for weaving through distal muscle. The other end is formed into a polyurethane sheathed kernmantel cord for distal fixation. Devices were implanted in six 3 to 4 kg rabbits (unilateral posterior tibial tendon replacement, random side selection with contralateral dissection/closure controls), and their tensile strength was tested at 30 days. All healed well; leg movements were normal after 1 week. Limbs were frozen at -70 degrees C between death and testing. Control failure occurred at 243 +/- 94 N and experimental at 163 +/- 44 N (p = 0.065, t-test); highest estimated requirement was 17.2 N. Interface strength was adequate by 30 days. Continued investigations, addressing other questions, are warranted.

In vivo comparison of two enteric-pouch power transformers for circulatory support.

A defunctionalized ileal pouch is thin-walled (1-2 mm), well perfused (blood flow, 0.3-1.0 ml/g/min), and tactile-insensitive. If fixed within the abdominal wall and provided with a miniature stoma for primary wire entry, the heat dissipating capacity and achievable geometries could facilitate small efficient intra- to extracorporeal power transformers with virtually complete magnetic flux containment. Two transformers (A, weighing 102 gm with dual ferrite cores, intraluminal primary and extraluminal secondary each with 10 turns on its own crescentic ferrite core, 90 kHz, coupling coefficient k = 0.90-0.96; and B, 68 gm, a single flexible torroidal magnetic metallic tape core with attached 11 turn primary and free 14 turn serosal secondary, 14.7 kHz, k = 0.99) met the electrical and anatomic requirements. Each was implanted (minilaparotomy, coil-pouch fixation within abdominal musculature) in 4 dogs for 14-21 days to test the operative feasibility, electrical function, warming, and flux containment. For canine testing, wires were tunneled to a chewing-inaccessible site. Neither tissue necrosis, infection, provokable interference from contiguous metal, nor coil displacement were observed; secretions were retained in Group A pouches only. The mean power transmissions for the transformers were A: 24.90 +/- 1.50 W and B: 24.92 +/- 0.89 W, after operation for 7 days or more. The mean efficiencies were A: 75.6 +/- 0.1% total DC/DC, 96.2% coils and B: 80.4 +/- 0.1% total DC/DC, 96.2% coils. The peak skin surface magnetic fluxes for transformers A and B, both trivial at 1.7 and 1.2 G, respectively, were similar. Warming was 0.62 +/- 0.30 degrees C in Group A and 0.73 +/- 0.19 degrees C in Group B. The probability values were p < 0.5 (NS) for DC/DC efficiency and p > 0.10 (NS), for A versus B in all other areas of comparison. Observations for both were encouraging. Transformer B, with less mass, lower frequency, higher efficiency, and intrinsic invulnerability to displacement, was selected for longer term evaluation.

A physical analog of the failing left ventricle for in vitro studies of mechanical wall actuation.

Mechanical repowering of a failing heart with devices or skeletal muscle could circumvent blood-pump lining problems. Requirements are complex: indefinite support with preservation of valve competence and coronary flow, avoidance of wall coaptation, and allowance of both rapid low impedance refilling and independent left and right pressures. An accurate in vitro physical failing-heart analog could facilitate the choice and screening of surgical and engineering approaches in mock circulation experiments. Prosthetic models, transplant recipient hearts, normal animal hearts, existing in vivo animal failure models, and failing cadaver hearts all have serious limitations. One hundred and four excised porcine hearts were dilated and fixed by three iterative protocols. Geometric and passive mechanical parameters were assessed and compared with targets expected for an end-stage failing heart. For Protocol 3, Subgroup 2 (reinforcing valve support, dilatation by compliant ventricular balloon, and ethyl alcohol fixation), the left ventricular shape and capacity (ellipsoid, 201-377 ml/500 g of heart weight), passive valve function, wall flexural rigidity (Et3 range 0.101-0.331 Nm), and refilling mechanics (99 +/- 17.46 ml during 200-400 ms at < or = 10 mm Hg transmural gradient) were all within goal criteria.

Long-term ventricular wall actuation: can and should it be systematically explored?

Hearts fail because myocardial power fails. Assist, support, or replacement devices fail, at least in part, because their blood-contacting surfaces fail. Mechanical repowering of a failing heart might circumvent these difficulties by preserving a largely healthy endocardium while correcting the basic deficit, power. Any serious consideration of doing this though must confront some difficult requirements. Effective indefinite support must be coupled with preservation or restoration of valve competence, coronary flow, rapid low-impedance refilling and independent left and right pressures; the avoidance of wall coaptation; hardware that fits in the available space; and unless muscle powered, adaptability to a deliverable form of power. Despite earlier intense interest in acute mechanical devices and later empiric study of muscle wraps, little systematic methodical work has been done on elucidating and meeting these practical requirements. Concerted efforts toward developing research tools and techniques for their study and then finding mechanisms to meet them could well yield one or more effective modalities that circumvent a major obstacle to the indefinite mechanical treatment of heart failure.

Concomitant cardiac and pulmonary operation: the role of cardiopulmonary bypass.

To assess the safety and efficacy of concomitant pulmonary resection and cardiac operation requiring cardiopulmonary bypass, the records of 19 patients were reviewed. Eighteen patients (94.7%) presented with cardiac symptoms and were found to have pulmonary pathology of indeterminate etiology. Pulmonary resections were performed through a median sternotomy in all but 1 patient, who underwent posterolateral thoracotomy and right middle lobectomy after repositioning because dense adhesions prevented adequate dissection through the initial incision. A total of 24 resections were performed. Sixteen (66.7%) were performed on cardiopulmonary bypass. Six wedge resections (25.0%) were performed before bypass. Two lobectomies (8.3%) were performed after infusion of protamine sulfate. Nine patients (47.4%) had benign pathology, 7 (36.8%) had primary carcinoma, and 3 (15.8%) had metastatic disease. Bleeding complications occurred in 15.8% of patients (3/19). There was 1 perioperative death (5.3%), which was due to adult respiratory distress syndrome after intraoperative hemorrhage followed lobectomy for bullous disease. Another patient required lateral extension of the sternotomy during an episode of exsanguinating intraparenchymal pulmonary hemorrhage, which resulted in lobectomy, as well as costochondral and sternal osteomyelitis. A third patient required exploration for bleeding at the staple line. Postoperative complications occurred in 7 patients (36.8%) and were predominantly respiratory (5/7, 71.4%) (p = 0.006). The median postoperative hospitalization was 15 days. Although comparison of patients who underwent pulmonary resection during bypass with those who had resection either before heparinization or after protamine infusion showed no significant difference with respect to age, incidence of malignancy, operation performed, complications, postoperative hospitalization, or survival, this was probably due to the small number of patients in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Electric power induction through an isolated intestinal pouch.

A new transintegumental power transformer uses the walls of an isolated intestinal pouch to separate primary and secondary coils. It may surpass transcutaneous devices in heat dissipation potential and in comfort. It was acutely tested in 13 dogs. Corrections in geometry and insulation were suggested by the nine initial trials. In the remaining four animals, up to 14.1 W were delivered, incrementing over 90 to 395 min. Three pouch and two remote thermistors recorded temperature (T) at 10 min intervals. Thirty sets of data were taken at 4 W or less (Group A), 31 at 4-8 W (Group B), and 16 at more than 8 W (Group C). T elevations above reference drift were 0.096 + 0.062 degrees C, 0.468 + 0.234 degrees C, and 0.876 + 0.156 degrees C for groups A, B, and C, respectively. These were significant by t-tests (p less than 0.001 for Group A vs. B; p less than 0.05 for Group B vs. C). The concept appears to be feasible, and longer term implantation trials seem justified.

Home intravenous dobutamine therapy in patients awaiting heart transplantation.

Lack of donor availability has heightened our awareness of the need for suitable long-term management of heart failure in patients awaiting heart transplantation. Frequently patients become dependent on intravenous inotropic agents despite attempts to discontinue these agents. This can lead to prolonged hospitalizations, separation anxiety and depression in families, high hospitalization costs, and poor quality of life. Between June 1987 and April 1988 three patients awaiting heart transplantation at the University of Cincinnati Hospital were sent home while receiving constant intravenous infusion of dobutamine. All three patients had had prolonged hospitalizations and were unable to be weaned from dobutamine without clinical compromise. The patients were New York Heart Association functional class III to IV, had cardiac indices between 1.5 to 2.13 L/min/m2, cardiac output less than 4.0 L/min, pulmonary capillary wedge pressures 17 to 27 mm Hg, and left ventricular ejection fraction less than 20% in two of the patients (idiopathic cardiomyopathy), and 30% in the third patient who was awaiting retransplantation (refractory repeated acute rejections). Dobutamine was infused by means of a constant-rate portable cassette pump at 3.17 micrograms/kg/min in patient 1, 10 micrograms/kg/min in patient 2, and 5 micrograms/kg/min in patient 3. A critical care home health nursing agency was used for follow-up home care. All three patients had central lines placed before discharge from the hospital. Each patient was instructed in proper care of the central line and infusion pump and was able to demonstrate accurate technique before being discharged home. Complications were minimal and were related to central line placement. No patient required rehospitalization for complications. No wound infections were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimurine antibody formation following OKT3 therapy.

OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T lymphocytes. A major concern with OKT3 treatment in solid organ transplant recipients is the development of antimouse antibody, which may preclude retreatment with this agent. We have administered OKT3 on 215 occasions (150 renal, 34 hepatic, 26 cardiac, 5 pancreatic) in 179 patients between April 1982 and December 1988. The mean duration of treatment was 10.5 days (range, 2-22 days). Antimouse antibody data were analyzed on the most recent 133 treatment courses where the antibody status was available pretreatment. Determination of antimouse antibody production was elicited by ELISA technology at days 0, 7, 14, and 28 of OKT3 treatment. Patients were categorized according to the antibody response as follows: (a) absence of antibody; (b) low titer (1:100); or (c) high titer (greater than or equal to 1:1000). Our earlier experience has demonstrated that retreatment with OKT3 is successful in groups a and b. The development of antimurine antibodies was analyzed with regard to the following parameters: (1) The duration of OKT3 treatment; (2) treatment type (prophylactic, primary, or secondary); (3) primary treatment or retreatment; (4) concomitant immunosuppressive regimen (double or triple therapy); (5) dosage of concomitant immunosuppressive drugs; and (6) transplant organ type. The following results were obtained. (1) Duration of treatment had no effect on antibody production (11.0 days in antibody negative and 10.0 days in antibody positive). (2) There was no difference in antibody formation rates for the first treatment of OKT3 when it was used as prophylaxis (26%), primary (19%), or secondary (27%) therapy. (3) Antibody formation rate with first treatment was 29%; with retreatment, patients who were antibody negative following first treatment became positive in 28% of cases, and retreated patients who were low titer positive following first treatment converted to high titer in 57% of cases. (4) Antibody formation was higher in patients receiving double immunosuppressive therapy (36%) than in those receiving triple immunosuppressive therapy (21%) during OKT3 treatment. (5) Concomitant immunosuppression was lower in the antibody-positive group during OKT3 therapy: steroids, 61 mg/day vs. 52 mg/day; azathioprine, 89 mg/day vs. 66 mg/day; CsA, 317 mg/day vs. 186 mg/day. (6) Antibody formation rates were lower in non-renal transplants following first treatment with OKT3 (liver 17%, heart 17%, kidney 28%); this reflects the higher doses of concomitant immunosuppressive therapy used in nonrenal transplants.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunologic monitoring with Orthoclone OKT3 therapy.

Muromonab-CD3 monoclonal antibody (Orthoclone OKT3) was used 146 times in 123 transplant recipients to treat or prevent rejection. Reversal and prevention of rejection were evaluated 1 week and 1 year after OKT3 therapy. Eighty-one percent (73 of 90) of the rejection episodes in kidney transplant patients were reversed with 67% of these grafts functioning at 1 year. Eighteen of 20 (90%) rejection episodes in liver transplant recipients were reversed, as were 11 of 13 (85%) heart transplant rejection episodes. Only one of five pancreas transplant episodes were reversed. OKT3 was used prophylactically in 18 transplant recipients (13 kidney, four heart, one liver). Immunologic monitoring (lymphocyte subsets, serum OKT3 levels, and antimurine antibodies) was performed during and after OKT3 therapy. Antimurine antibody formation rate was 28% (26 of 94 patients monitored). OKT3 therapy resulted in a rapid depletion of CD3+ cells from the peripheral circulation (less than 20/mm3) and trough serum OKT3 levels of greater than 800 ng/ml by the third day of therapy in all transplant types. Twenty-three patients (14 kidney, five liver, three heart, and one pancreas) were retreated with OKT3; reversal of rejection occurred in 87% of patients (13 of 15) with no antimurine antibodies and in 83% of patients (five of six) with a low antibody titer but did not occur in the two patients with a high antibody titer. Retreatment of patients with no anti-OKT3 antibody resulted in a depletion of CD3+ cells from the peripheral blood, but it took longer than in patients treated with OKT3 for the first time. Similarly, serum OKT3 levels increased slower in retreated patients compared with first treatment. In retreatment patients with a low titer antimurine antibody, often it was necessary to increase the dose of OKT3 to achieve adequate serum OKT3 levels and to deplete CD3+ cells. Antimurine antibody developed de novo in four of the 15 antibody negative patients (27%) who were retreated. Overall, OKT3 was an effective agent in reversing and preventing rejection in solid organ transplantation with few severe side effects and a low mortality. Retreatment with OKT3 should not be considered unless the antibody status of the patient is known. Development of low titer antibodies does not preclude successful retreatment with OKT3. Alternate antirejection therapy, however, should be used in patients with high titer antimurine responses.

Successful retreatment of allograft rejection with OKT3.

OKT3 is a murine monoclonal antibody to the CD3 antigen of human T lymphocytes. The production of human antimurine antibodies after treatment with OKT3 has been perceived as a major limitation to its extended use and reuse. Treatment of 142 patients with 168 courses of OKT3 resulted in the development of antimouse antibody in 28% of the patients. Twenty-six patients (16 kidney, 6 liver, 3 heart, 1 pancreas) have been retreated with 27 courses of OKT3. Eighteen patients had no antimurine antibodies present, and the rejection reversal rate was 83% (15/18). Six patients had a low-titer antimurine antibody present, and rejection reversal occurred in 5 (83%). Rejection was not reversed in 2 patients with a high-titer antibody. Development of antimurine antibody was more frequent in renal transplant recipients (33%) than in hepatic (12%) or cardiac transplant recipients (18%). We believe that this reflects the fact that concomitant immunosuppressive therapy is more likely to be reduced during OKT3 therapy in renal transplant recipients than in hepatic or cardiac transplant recipients. Retreatment of patients with no anti-OKT3 antibody resulted in depletion of CD3+ cells from the peripheral blood, but it took longer than in patients being treated with OKT3 for the first time. Similarly, serum OKT3 levels rose more slowly in retreated patients compared to first treatment. In retreating patients with a low-titer antimurine antibody, it often was necessary to increase the dose of OKT3 in order to achieve adequate serum OKT3 levels and to deplete CD3+ cells. De novo antimurine antibody developed in 4 of the 18 (22%) antibody-negative patients who were retreated. In conclusion, retreatment with OKT3 should not be considered unless the antibody status of the patient is known. Development of low-titer antibodies does not preclude successful retreatment with OKT3; however, alternate antirejection therapy should be used in patients with high-titer antimurine responses.

Efficacy and safety of constant-rate intravenous cyclosporine infusion immediately after heart transplantation.

Oral cyclosporine therapy immediately after heart transplantation is erratic and difficult to predict. The purpose of this study was to evaluate the relative efficacy and safety of cyclosporine when administered by constant-rate infusion immediately after transplantation. Nineteen patients (17 men and two women) aged 50 years (range 25 to 61 years) who weighed 71 +/- 9 kg, participated in the study and received cyclosporine, 7 to 10 mg/hr (117 +/- 15 micrograms/kg/hr). The infusions were initially maintained for 26 +/- 5 hours (range 18 to 42 hours) without adjustments in dosage. Whole blood samples were obtained at hourly intervals for the first 8 to 12 hours and then daily throughout the 7-day study period and were analyzed by high-performance liquid chromatography. Constant-rate cyclosporine infusion resulted in therapeutic blood levels (350 to 450 ng/ml) at 6 hours. These levels remained relatively steady throughout the 7-day infusion, requiring only minimal dosage adjustments. Kidney function was not altered significantly after 7 days of intravenous cyclosporine therapy as evidenced by a mean serum creatinine level of 1.3 mg/dl before therapy and 1.4 mg/dl after therapy. There, however, was a transient rise in serum creatinine level in most patients on the second or third day after transplantation that resolved without a reduction in cyclosporine dosage. The mean endomyocardial biopsy score at 1 week after transplantation was 0.1, and only four of the patients required additional immunosuppressive therapy to treat rejection during the first 6 weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants.

The most important limitation associated with the clinical use of cyclosporine is the narrow therapeutic range between its efficacy and toxicity. Effective treatment is further complicated by significant variation in intrapatient and interpatient pharmacokinetics of the drug. We describe a practical approach to pharmacokinetic analysis that does not interfere with the cyclosporine dosage regimen or with clinical management of the patient. To optimize therapy, we individualized patient management by using noncompartmental pharmacokinetic analysis. Mean residence time (MRT) and volume of distribution at steady-state were calculated from data on concentration vs time after dose. We applied this approach to 24 kidney, 12 heart, 8 bone-marrow, 7 liver, and 5 pancreas transplants. Individualized requirements for cyclosporine dose and dosage interval can be predicted from these parameters. MRT is the most useful pharmacokinetic parameter, because it allows prediction of the optimal dosage interval.

Functional evidence in diseased human heart fibers for multiple sensitivities of the inotropic ouabain receptor Na+,K+-ATPase (NKA).

Through contributions of many investigators from our group at the University of Cincinnati Medical Center, several facts emerged. It is clear that the rat ventricle has 2 inotropic sensitivities to ouabain (Grupp et al., 1981), related to high and low affinity ouabain binding sites (Adams et al., 1982) and the presence of an appropriate abundance of alpha and alpha + catalytic subunits of NKA (Young and Lingrel, 1987). The rat atria which demonstrate only the low affinity inotropic response (Grupp et al., 1981) also show the alpha catalytic subunit in vast predominance, with little or no alpha + (Young and Lingrel, 1987). This scheme has now also been confirmed in the ferret (Ng and Akera, 1987). By analogy, we suggest that the possibility exists that in diseased hearts part of the normally prevailing alpha catalytic subunit (sensitivity in normal human fibers about 140 nM ouabain) is converted to a more sensitive alpha + catalytic subunit leading to an increase of the ouabain sensitivity to about 50 nM. There is also an earlier occurrence of toxic effects and a reduction of the number of low affinity (alpha) ouabain binding sites, resulting in a decrease of the maximally achievable contractile force effect of ouabain. This hypothesis is presently being tested in the genetics laboratory of the University of Cincinnati Medical Center where the relative abundance of the alpha, alpha + and perhaps other isoforms of the NKA are being determined in the tissues of the same hearts from which the trabeculae used in this study were obtained.