Prediction of clinical irrelevance of PK differences in atorvastatin using PK/PD models derived from literature-based meta-analyses.

To support the development of a fixed-dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature-based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non-clinically significant change of <1.2% absolute difference in the percentage lowering of low-density-lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose-response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.

Preoperative risk factors for right ventricular failure after implantable left ventricular assist device insertion.

BACKGROUND: Implantable left ventricular assist device (LVAD) insertion complicated by early right ventricular (RV) failure has a poor prognosis and is generally unpredictable. METHODS: To determine preoperative risk factors for perioperative RV failure after LVAD insertion, patient characteristics and preoperative hemodynamics were analyzed in 100 patients with the HeartMate LVAD (Thermo Cardiosystems, Inc, Woburn, MA) at the Cleveland Clinic. RESULTS: RV assist device support was required for 11 patients (RVAD group). RVAD use was significantly higher in younger patients, female patients, smaller patients, and myocarditis patients. There was no significant difference in the cardiac index, RV ejection fraction, or right atrial pressure between the two groups preoperatively. The preoperative mean pulmonary arterial pressure (PAP) and RV stroke work index (RV SWI) were significantly lower in the RVAD group (p = 0.015 and p = 0.011, respectively). Survival to transplant was poor in the RVAD group (27%) and was 83% in the no-RVAD group. CONCLUSIONS: The need for perioperative RVAD support was low, only 11%. Preoperative low PAP and low RV SWI were significant risk factors for RVAD use.

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.

One hundred patients with the HeartMate left ventricular assist device: evolving concepts and technology.

BACKGROUND: Implantable left ventricular assist devices are common as a bridge to transplantation but are just reaching their goal as an alternative to transplantation. METHODS: From December 1991 until December 1996, 97 left ventricular assist devices were implanted as a bridge to transplantation, one as an alternative to transplantation, and two as a bridge to recovery. Included were 64 pneumatic devices and 36 electric devices. Most patients (69%) had ischemic cardiomyopathy and most (53%) had had previous cardiac surgery. Preoperative circulatory support (extracorporeal membrane oxygenation) was used in 25. RESULTS: Perioperative insertion of a right ventricular assist device was unusual (11%). The mean duration of support with a left ventricular assist device (bridge to transplantation) was 70 +/- 41 days (up to 206 days). Survival to transplantation was 76%. Cause of death included multiple organ failure (n = 13), perioperative stroke (n = 5), device failure (n = 5), and controller disconnect (n = 1). Significant risk factors for death included (1) preoperative need for ventilator or extracorporeal membrane oxygenation, (2) elevated blood urea nitrogen, creatinine, or bilirubin, and (3) low pulmonary artery pressures. Risks after insertion of the left ventricular assist device were reoperation for bleeding, support with a right ventricular assist device, dialysis, or device failure. Catastrophic failure of the device occurred 14 times in 12 patients and was treated by emergency pump exchange in six instances. Only two device-related thromboembolic episodes were detected. Positive blood cultures were found in 59% of patients, driveline infection in 28%, and pump infection in 11%. CONCLUSIONS: The HeartMate device provided excellent hemodynamic support with low device-related thromboembolic events. Infection and reliability of the device contributed to the high cost of therapy. These areas need to be improved for the left ventricular assist device to attain its goal as a viable alternative to transplantation.

Early results with partial left ventriculectomy.

OBJECTIVE: We sought to determine the role of partial left ventriculectomy in patients with dilated cardiomyopathy. METHODS: Since May 1996 we have performed partial left ventriculectomy in 53 patients, primarily (94%) in heart transplant candidates. The mean age of the patients was 53 years (range 17 to 72 years); 60% were in class IV and 40% in class III. Preoperatively, 51 patients were thought to have idiopathic dilated cardiomyopathy, one familial cardiomyopathy, and one valvular cardiomyopathy. As our experience accrued we increased the extent of left ventriculectomy and more complex mitral valve repairs. For two patients mitral valve replacement was performed. For 51 patients the anterior and posterior mitral valve leaflets were approximated (Alfieri repair); 47 patients also had ring posterior annuloplasty. In 27 patients (51%) one or both papillary muscles were divided, additional left ventricular wall was resected, and the papillary muscle heads were reimplanted. RESULTS: Echocardiography showed a significant decrease in left ventricular dimensions after resection (8.3 cm to 5.8 cm), reduction in mitral regurgitation (2.8+ to 0), and increase in forward ejection fraction (15.7% to 32.7%). Cardiac index did not increase significantly (2.2 to 2.4 L/min per square meter). Eight patients (15%) required a perioperative left ventricular assist device; one died and was the only perioperative mortality (1.9%). At 11 months, actuarial survival was 87% and freedom from relisting for transplantation was 72%. CONCLUSIONS: Improved selection criteria are necessary to avoid early failures, and much more follow-up and analyses of data are mandatory. However, the operation may become a biologic bridge, or even alternative, to transplantation.

Factors influencing HLA sensitization in implantable LVAD recipients.

BACKGROUND: Patients bridged to transplantation (TX) with the implantable left ventricular assist device (LVAD) may be at increased risk for the development of panel-reactive antibodies (PRA) during support. METHODS: To investigate that, we evaluated 60 patients who received the HeartMate LVAD at our institution, of whom 53 had PRA results available for analysis. T lymphocyte PRA levels were examined before LVAD, at the peak PRA level during LVAD support (PEAK), and just before TX. A PRA level more than 10% was considered indicative of sensitization against HLA antigens. RESULTS: The only factor that had a significant effect on PRA levels before LVAD was patient's sex (1.3% for men versus 7.4% for women; p = 0.005). During LVAD support, peak PRA levels increased significantly and the sex-associated differences were no longer evident (33.3% men, 34.3% women; not significant). At the time of TX, PRAs decreased to 10.9% (men) and 7.0% (women) (not significant). We examined the influence of blood products received before TX on PRA levels. Patients who received less than the median number of total units (median). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (median: 46.9%; p = 0.03). Patients who received blood that was leukocyte-depleted tended to have lower TX PRA levels (2.9%) compared with those who did not (13.9%, p = 0.18). Forty-two patients were successfully bridged to TX, with three early and two late deaths after TX. Whereas 39 patients received transplants without intervention, 3 were treated by plasmapheresis with a 77% reduction in their HLA antibody levels at TX as measured by flow cytometry. CONCLUSIONS: Patients with the implantable LVAD are at significant risk for the development of anti-HLA antibodies during support. Although this sensitization is often transient, intervention using plasmapheresis may be useful for some patients.

Permanent mechanical circulatory support with an implantable left ventricular assist device.

A 67-year-old man had end-stage ischemic cardiomyopathy. He had had two previous coronary bypass operations and a previous left ventricular aneurysmectomy. In December 1995 he underwent vented-electric HeartMate LVAD insertion as an alternative to transplantation. He was discharged from the hospital 13 days after the operation, and 5 months postoperatively he had returned to New York Heart Association functional class II.

Does successful bridging with the implantable left ventricular assist device affect cardiac transplantation outcome?

OBJECTIVES: We sought to determine whether cardiac transplant recipients who required a bridge to transplantation with an implantable left ventricular assist device had a different outcome than patients who underwent transplantation without such a bridge. METHODS: A retrospective study of 256 cardiac transplants from 1992 to 1996 included 53 patients who received the HeartMate left ventricular assist device and 203 patients who had no left ventricular assist device support. RESULTS: Left ventricular assist device transplants increased from 8% of all transplants in 1992 (n = 63) to 32% in 1995 (n = 65) and 43% in 1996 (n = 14 year to date). Patients with and without left ventricular assist device had similar age and sex distributions. Left ventricular assist device recipients were larger (body surface area 1.96 vs 1.86 m2, p = 0.004). They were more likely to have ischemic cardiomyopathy (70% vs 45%, p = 0.001) and type O blood group (51% vs 34%, p = 0.06). All patients with left ventricular assist device and 42% of those without had undergone previous cardiac operations by the time of transplantation (mean number per patient 1.5 vs 0.3, p < 0.001). More patients in the left ventricular assist device group had anti-HLA antibodies before transplantation (T-cell panel reactive antibody level > 10% in 66% of left ventricular assist device group vs 15% of control group, p < 0.0001). Waiting time was longer for the left ventricular assist device than for patients in status I without a left ventricular assist device (median 88 vs 37 days, p = 0.002). There was no difference in length of posttransplantation hospital stay (median 15 days for each) or operative mortality (3.8% vs 4.4%). Mean follow-up averaged 22 months. No significant difference was found in Kaplan-Meier survival estimates. One-year survival was 94% in the left ventricular assist device group and 88% in the control group (difference not significant). Comparison of posttransplantation events showed no significant difference in actuarial rates of cytomegalovirus infection (20% vs 17%) or vascular rejection (15% vs 12%) at 1 year of follow-up. Similar percentages of patients were free from cellular rejection at 1 year of follow-up (12% vs 22%, p = 0.36). CONCLUSIONS: Left ventricular assist device support intensified the donor shortage by including recipients who otherwise would not have survived to transplantation. Bridging affected transplant demographics, favoring patients who are larger, have ischemic cardiomyopathy, have had multiple blood transfusions and complex cardiac operations, and are HLA sensitized. Successfully bridged patients wait longer for a transplant than do UNOS status I patients without such a bridge, but they have similar posttransplantation hospital stay, operative mortality, and survival to those of patients not requiring left ventricular assist device support.

Prediction of right ventricular dysfunction after left ventricular assist device implantation.

BACKGROUND: Right ventricular dysfunction (RVD) significantly affects mortality and morbidity after left ventricular assist device (LVAD) implantation, and its occurrence often is unpredictable. The aim of the present study was to identify predictors of RVD after LVAD implantation. METHODS AND RESULTS: We studied right ventricular (RV) hemodynamics in 28 patients before and after LVAD implantation with a rapid-response thermistor pulmonary artery catheter. Measurements included mean right atrial pressure (RAP), mean pulmonary arterial pressure (PAP), cardiac index, transpulmonary gradient (TPG), pulmonary vascular resistance (PVR), RV end-diastolic and end-systolic volume indexes (EDVI and ESVI, respectively), and RV ejection fraction (RVEF). We regarded patients who had RAP > or = 15 mm Hg at LVAD explantation (n = 8) or who required an RV assist device (n = 3) as the RVD group (n = 11). The other patients were categorized as the RV nondysfunctional group (RVN, n = 17). Before LVAD implantation, the RVD group had larger RV volumes (200 +/- 107 versus 125 +/- 46 mL/m2 for EDVI; 177 +/- 109 versus 104 +/- 48 mL/m2 for ESVI) and higher preload (23 +/- 6 versus 17 +/- 6 mm Hg for RAP) and afterload (20 +/- 9 versus 13 +/- 6 mm Hg for TPG; 5.9 +/- 3.0 versus 3.8 +/- 2.0 Wood units for PVR) than the RVN group (P < .05 for all). RVEF and PAP did not differ significantly. LVAD implantation remarkably improved RV hemodynamics in both groups, decreasing RV volumes, preload, and afterload and increasing RVEF in all patients, but post-LVAD PAP tended to be higher in the RVD group. Multivariate logistic regression analysis revealed that RAP and TPG before LVAD implantation and an acute decrease (delta) in PAP by LVAD were significant predictors of RVD (P < .05). The sensitivity for predicting RVD by a combination of at least two of these three predictors (RAP > or = 20 mm Hg, TPG > or = 16 mm Hg, and delta PAP < or = 10 mm Hg) was 82%, and the specificity was 88%. CONCLUSIONS: Dilated right ventricle with increased RV preload and afterload predisposes to RVD after LVAD implantation. Not only baseline parameters but also the immediate hemodynamic response to the LVAD are predictive, and a combination of these parameters may be useful in predictions of the occurrence of RVD after LVAD implantation.

Anatomic fitting studies of a total artificial heart in heart transplant recipients. Critical dimensions and prediction of fit.

Anatomic fitting studies of the Cleveland Clinic-Nimbus total artificial heart were performed in 33 patients undergoing heart transplantation. The pump fit in the pericardial space in 20 men (80%) and 4 women (50%). There was no significant difference between the Fit and Non-Fit groups in external chest dimensions. Among 42 intrathoracic dimensions, the distance from the center of the mitral valve to the diaphragm (Fit: 5.6 +/- 2.2 cm, Non-Fit: 3.6 +/- 0.4 cm, p < 0.00001) and the distance from the caudal end of the pulmonary valve to the diaphragm (Fit: 9.4 +/- 1.6 cm, Non-Fit: 6.3 +/- 0.8 cm, p < 0.0001) were the most critical. To predict anatomic fit, an index (A x B x C) was obtained from chest X-ray measurements (A, the craniocaudal distance from the dorsal region of the 8th left rib to the left diaphragm; B, the maximum left chest width; and C, the maximum anteroposterior sternum-vertebrae dimension). The pump fit in 88.5% of the patients with an index above 1200 cm3, whereas it fit in only 14.3% of the patients with an index below 1200 cm3 (p < 0.001). This index was an easily obtainable, good predictor of anatomic fit.

Extended cardiac support with a portable left ventricular assist system in the home.

Since 1986, the HeartMate left ventricular assist system (LVAS) has been widely used as a bridge to transplantation. Recently, a multicenter study was undertaken to evaluate the safety of allowing patients supported by the vented electric (VE) LVAS to await transplantation at home. Eligible patients progressed from 1 day to 3 day passes, then were discharged from the hospital. Twenty-nine patients at four centers were evaluated for incidence of adverse events and change in quality of life. Mean time of support was 193.7 +/- 138 days (range, 35-504 days). Patients spent a total of 2,922 days at home: 344 1 day passes and 150 3 day passes were issued; 21 patients were discharged from the hospital. There were 15 readmissions to the hospital: 9 for medical reasons and 6 for device related problems. Patients were able to resolve numerous technical problems at home. No deaths occurred outside of the hospital. Two patients returned to full-time employment, and all patients resumed an active lifestyle. Although adverse events occurred, the results of this study appear to demonstrate that patients may safely await transplantation at home while supported by a HeartMate VE-LVAS.

Age related outcome after implantable left ventricular assist system support.

To examine the relationship between age and outcome after implantable left ventricular assist system support, the authors investigated the results of 223 patients from 17 centers who were supported with a HeartMate (Thermo Cardiosystems, Inc., Woburn, MA) pneumatic left ventricular assist system between 1986 and 1994. In addition, the authors examined a single center's experience with 67 patients between 1992 and 1996. Ages are separated by decile and ranged from 10 to 69 years. Men dominated all age groups, averaging 82% of the total (range, 64-91%). Viral, idiopathic, and post partum cardiomyopathies were the indication for support in 88% of the patients younger than 39 years of age. Ischemic cardiomyopathy was the cause of myocardial failure in the majority of patients older than 40 years of age (40-49 years, 54%; 50-59 years, 57%; and 60-69 years, 67%). Patients aged 40-59 accounted for 64% of the patients supported, and had the best outcomes both on support and after transplantation. Survival to transplantation was not significantly different among the groups, although the patients older than 60 and younger than 69 years of age had higher mortalities on support, most commonly from cardiac failure. At the Cleveland Clinic Foundation, the survival to transplantation and survival to discharge were indistinguishable between age groups. Age does not appear to be significant risk factor for outcome after implantable left ventricular assist system support. These results predict acceptable mortality for patients supported who are older than the age of 60.

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.

Implantable LVAD infections: implications for permanent use of the device.

BACKGROUND: Infection in implantable left ventricular assist device (LVAD) patients is common and has serious implications regarding permanent use of the LVAD. METHODS: Thirty-three patients had HeartMate LVAD insertion as a bridge to heart transplantation. The mean length of hospital stay was 8 days before LVAD insertion. Before insertion 6 patients (18%) had positive pulmonary cultures and 5 patients (15%) had bacteremia. RESULTS: During LVAD support 18 patients (55%) had bloodstream infection. Of 24 patients (73%) successfully bridged to transplantation, 12 (50%) had positive blood cultures including Staphylococcus species (n = 9), Candida (n = 3), Pseudomonas (n = 2), and Enterococcus (n = 2). Infectious complications encountered in this series included driveline infection requiring surgical revision, septic embolus, "cleared" device infection, "suppressed" device infection, and LVAD infection treated by device removal in 1 patient and device exchange in another. CONCLUSIONS: Infection in implantable LVAD patients is common, especially in patients in whom multiple organ failure develops, requiring prolonged stay in the intensive care unit. Strategies are needed to prevent these infections in recipients of the permanent LVADs because treatment of an established infection is difficult and expensive.

Screening scale predicts patients successfully receiving long-term implantable left ventricular assist devices.

BACKGROUND: Although use of long-term implantable left ventricular assist devices (LVAD) is becoming more popular, further reduction of the mortality rate accompanying device insertion through improved patient selection would make this alternative even more appealing. We sought to develop a scoring system that was based on criteria obtainable at the time of evaluation and predictive of successful early outcome and simple to apply. METHODS AND RESULTS: Patients (n = 56) undergoing LVAD insertion between 1990 and 1994 were screened for easily obtainable preoperative risk factors. To test the association between survival and each risk factor, a chi 2 analysis was performed, and relative risks were estimated. Oliguria, ventilator dependence, elevated central venous pressure, elevated prothrombin time, and reoperation stats had low probability values and high estimated relative risks. On the basis of these relations, a risk factor-selection scale (RFSS) (range, 0 to 10) was developed by computing appropriate weights for each risk factor. The distribution of patients for each scale score reveal that with RFSS > or = 5, most device recipients will die (P < .001). The average RFSS (+/- SD) of survivors (n = 42) was 2.45 +/- 1.73 compared with 5.43 +/- 2.85 in nonsurvivors (n = 14) (P < .0001). Univariate logistical regression was also significant (score statistic, 16.2; df = 1; P = .001). CONCLUSIONS: The RFSS is simple, easy to apply, and statistically valid. Physicians could use the scale as a starting point in discussing the suitability for LVAD implantation in a specific patient and as a basis for comparing patient outcomes.

Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure.

BACKGROUND: The HeartMate left ventricular assist device has been successfully used as a bridge to cardiac transplantation. Because many patients exhibit marked clinical improvement in their heart failure after HeartMate implantation, we studied the physiological effect of this device on the neurohormonal axis. METHODS AND RESULTS: In 13 patients awaiting transplant (mean cardiac index, 1.7 +/- 0.3 L.min-1.m-2) who underwent HeartMate implantation, venous atrial natriuretic peptide, epinephrine, norepinephrine, plasma renin activity, angiotensin, and arginine vasopressin were measured immediately before insertion and at explant/transplantation. Mean time to explant was 86 +/- 40 days. All patients were taken off inotropic medications within 1 month. Mean cardiac index on support before explant was 3.1 +/- 0.9 L.min-1.m-2. Plasma renin activity decreased from 57 +/- 56 ng.mL-1.h-1 at baseline (before insertion) to 3 +/- 3 ng.mL-1.h-1 at explant (mean percent change, 92%; P < .001). Angiotensin II level decreased from 237 +/- 398 U/L at baseline to 14 +/- 14 U/L at explant (mean percent change, 73%; P < .001). Plasma epinephrine level fell from 6800 +/- 1323 pg/mL at baseline to 46 +/- 46 pg/mL at explant (mean percent change, 86%; P < .001). Norepinephrine level decreased from 2953 +/- 1457 pg/mL at baseline to 518 +/- 290 pg/mL at explant (mean percent change, 79%; P < .001). Atrial natriuretic peptide fell from baseline values of 227 +/- 196 to 168 +/- 40 pg/mL at explant (mean percent change, -49%; P = 519); and arginine vasopressin level decreased from 6 +/- 6 pg/mL at baseline to 0.8 +/- 0.5 pg/mL (mean percent change, 69%; P = .002). CONCLUSIONS: We provide data supporting that the neurohormonal axis markedly improves after HeartMate implantation, providing biochemical confirmation of the improvement in hemodynamic status.

The role of the registered nurse-first assistant in the implantable left ventricular assist device program.

Successful support of patients using the implantable left ventricular assist device requires sustained and coordinated efforts by physicians and medical personnel. The authors describe the role of their registered nurse-first assistant (RNFA) as it has evolved through caring for 43 implantable pneumatic left ventricular assist device patients and 8 vented-electric left ventricular assist system patients during a 3 year period. Intraoperatively, the RNFA is responsible for pump assembly, including pre sealing all grafts and connecting areas of the pump using a combination of cryoprecipitate and thrombin. The RNFA assists with pump insertion during surgery. At device explantation, the RNFA dismantles the pump according to the FDA protocol for disassembly. Post operatively, the RNFA assesses and maintains patient hemodynamic stability and intervenes to manage hemodynamic and mechanical problems. Of the 51 patients, 13 are still on support, 9 died before transplantation (17.6%), and post transplant survival is 96.0%. In conclusion, an active left ventricular assist device program requires skilled personnel to manage complex problems and contributes to a successful patient outcome.

Hemostatic profiles of HeartMate ventricular assist device recipients.

Candidates for ventricular assist devices often have hepatic dysfunction and concomitant coagulation abnormalities. Factors II, V, VII, XI, plasminogen, fibrinopeptide A (FpA), and D-dimers were measured in 19 HeartMate (ThermoCardiosystems, Inc., Woburn, MA) patients before device implantation; at 6 hr, 24 hr, and 2 weeks postimplantation; and before explantation. Ten patients had entry hepatic dysfunction (total bilirubin > 2 mg/dl; aspartate and alanine aminotransferases > 60 U/L); nine had normal hepatic function. All except one patient received perioperative aprotinin; all received only aspirin and dipyridamole after surgery. At preimplant, both patient groups had subnormal factor II, V, VII, XI, and plasminogen with elevated FpA and D-dimer. By 2 weeks postimplant, these factor levels had normalized, except for FpA and D-dimer levels, which suggest ongoing remodeling of fibrin deposits on the device surfaces. No statistically significant differences in the assayed hemostatic markers were observed between the two patient groups. Clinically, 15/19 (79%) patients survived to cardiac transplantation; 3/19 (16%) patients required reoperation for early bleeding. All three had low factor VII and XI; two of three also had hepatic dysfunction and subnormal levels of factor II and V. Most patients with entry hepatic dysfunction improve after device implantation; all four deaths were in patients with persistent hepatic dysfunction despite circulatory support.

Late reconstruction of the midfoot and tarsometatarsal region after trauma.

The management of painful arthritis and deformity after trauma to the midfoot starts with careful assessment by physical examination and appropriate investigation to identify the affected joints. Conservative treatment may be very effective and includes the use of NSAIDs, custom insoles with arch support, and a rocker-bottom sole with extended steel shank with or without a SACH heel. If this treatment fails, usually a year after the injury, then arthrodesis of all the symptomatic joints with restoration of the arch and alignment of the weight-bearing surface is the recommended treatment. The long-term results of these fusions may be compromised by the subsequent development of arthritis in adjacent joints.

Structural and left ventricular histologic changes after implantable LVAD insertion.

Long-term support on the implantable left ventricular assist device (LVAD) produces structural changes in the recipient's heart. To assess the possibility of heart "recovery" we reviewed the records of 19 HeartMate LVAD recipients to determine structural and left ventricular histologic changes during LVAD support. Intraoperative transesophageal echocardiographic studies were performed in the operating room before LVAD insertion, immediately after LVAD insertion, and at explantation and heart transplantation (mean duration of support, 76 +/- 34 days). The initiation of LVAD pumping led to an immediate decrease (p < 0.001) in left ventricular dimensions, which were not significantly different by the time of device explantation. Left ventricular fractional shortening did not significantly improve during LVAD support (0.07 +/- 0.03 before LVAD; 0.11 +/- 0.10 immediately after LVAD; 0.11 +/- 0.11 before explantation). Histologic specimens showed a significant reduction in the number of wavy fibers, and contraction band necrosis (p < 0.01), both markers of acute myocyte damage. However, myocardial fibrosis increased (p < 0.05). Myocyte diameter increased slightly (p = 0.07). We conclude that implantable LVAD support is associated with immediate changes in ventricular structure. Histologic markers of acute myocyte damage improve, but fibrosis increases. Because the structural changes occur immediately, they do not indicate "recovery" of left ventricular function, but merely changes in loading conditions.