Deletion of the lmna gene induces growth delay and serum biochemical changes in C57BL/6 mice.

The A-type lamin deficient mouse line (Lmna (-/-) ) has become one of the most frequently used models for providing insights into many different aspects of A-type lamin function. To elucidate the function of Lmna in the growth and metabolism of mice, tissue growth and blood biochemistry were monitored in Lmna-deficient mice, heterozygous (Lmna (+/-) ) and wide-type (Lmna (+) (/) (+) ) backcrossed to C57BL/6 background. At 4 weeks after birth, the weight of various organs of the Lmna (-/-), Lmna (+/-) and Lmna (+) (/) (+) mice was measured. A panel of biochemical analyses consisting of 15 serological tests was examined. The results showed that Lmna deficient mice had significantly decreased body weight and increased the ratio of organ to body weight in most of tissues. Compared with Lmna (+) (/) (+) and Lmna (+/-) mice, Lmna (-/-) mice exhibited lower levels of ALP (alkaline phosphatase), Chol (cholesterol), CR (creatinine), GLU (glucose), HDL (high-density lipoprotein cholesterol) and higher levels of ALT (alanine aminotransferase) (p<0.05). Lmna (-/-) mice displayed higher AST (aspartate aminotransferase) values and lower LDL (lowdensity lipoprotein cholesterol), CK-MB (creatine kinase-MB) levels than Lmna (+) (/) (+) mice (p<0.05). There were no significant differences among the three groups of mice with respect to BUN (blood urea nitrogen), CK (creatine kinase), Cyc C (cystatin C), TP (total protein), TG (triacylglycerols) and UA (uric acid) levels (p>0.05). These changes of serological parameters may provide an experimental basis for the elucidation of Lmna gene functions.

Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis.

BACKGROUND: Tacrolimus and cyclosporine are the 2 major immunosuppressants for lung transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this meta-analysis of randomized controlled trials (RCTs) was to compare the beneficial and harmful effects of tacrolimus and cyclosporine as the primary immunosuppressant for lung transplant recipients. METHODS: We conducted searches of electronic databases and manual bibliographies. We performed a meta-analysis of all RCTs comparing tacrolimus with cyclosporine as primary immunosuppression for lung transplant recipients. Extracted, pooled data for mortality, acute rejection, withdrawals, and adverse events were analyzed using Mantel-Haenszel tests with a random effects model. RESULTS: Three RCTs including 297 patients were assessed in this study. Mortality at 1 year or more was comparable between lung recipients treated with tacrolimus and cyclosporine (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.42-2.10; P = .88). Tacrolimus-treated patients experienced fewer incidences of acute rejection (MD = -0.14; 95% CI, -0.28 to -0.01; P = .04). Pooled analysis showed a trend toward a lower risk of bronchiolitis obliterans syndrome (BOS) among tacrolimus-treated patients, although it did not reach significances (OR, 0.53; 95% CI, 0.25-1.12; P = .10). Fewer patients stopped tacrolimus than cyclosporine (OR, 0.12; 95% CI, 0.03-0.48; P = .003). The rate of new-onset diabetes was higher among the tacrolimus group (OR, 3.69; 95% CI, 1.17-11.62; P = .03). The incidence of hypertension and renal dysfunction were comparable in these 2 groups (OR, 0.24; 95% CI, 0.03-1.70; P = .15; and OR, 1.67; 95% CI, 0.70-3.96; P = .25, respectively). There was a trend toward lower risk of malignancy in tacrolimus-treated patients, although it did not reach significance either (OR, 0.19; 95% CI, 0.03-1.13; P = .07). The incidence of infection was comparable in these 2 groups (MD = -0.29, 95% CI, -0.68 to 0.11; P = .16). CONCLUSION: Using tacrolimus as primary immunosuppressant for lung transplant recipient resulted in comparable survival and reduction in acute rejection episodes when compared with cyclosporine.

Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation.

BACKGROUND: Clinical reports on humoral rejection after heart transplantation showed that these episodes were often more severe than those mediated through T lymphocytes and that the patient's prognosis was significantly worsened. METHODS: To evaluate the impact of plasmapheresis on the course of humoral rejection with hemodynamic compromise (HRHC) episodes, we retrospectively investigated the records of 1,108 heart transplant patients. All patients received triple-drug immunosuppression (cyclosporine a, azathioprine, prednisone) and cytolytic antibodies for induction. Between April 1986 and December 1990, HRHC episodes were treated with cortisone boli and cytolytic antibodies for at least 3 days (Group A). Between January 1991 and April 1999, HRHC episodes were treated with cortisone boli, cytolytic antibodies, and plasmapheresis for at least 3 days (Group B). All patients who survived their first HRHC episode received cyclophosphamide instead of azathioprine as maintenance immunosuppression. RESULTS: Altogether we observed 29 HRHC episodes. In 11 cases, no therapy could be administered or the therapy regimen did not correspond to either Protocol A or B. In the remaining 18 HRHC episodes, 7 episodes in 7 patients were treated without plasmapheresis (Group A), but only 2 patients survived, whereas in 11 HRHC episodes in 6 patients, therapy included plasmapheresis (Group B) and all patients survived (p = 0.002). Four of 6 patients who received cyclophosphamide after their first HRHC episode experienced at least 1 further HRHC episode. CONCLUSIONS: Plasmapheresis seems to improve outcomes in HRHC. However, cyclophosphamide as a maintenance immunosuppressive drug failed to prevent further humoral rejection episodes.

Midterm follow-up of patients who underwent removal of a left ventricular assist device after cardiac recovery from end-stage dilated cardiomyopathy.

OBJECTIVE: Cardiac recovery in end-stage idiopathic dilated cardiomyopathy recently occurred after temporary support with a left ventricular assist device. We report the case histories of patients who underwent removal of the device more than 4 years ago. METHODS: Since June 1994, 23 patients with end-stage idiopathic dilated cardiomyopathy who were supported by a left ventricular assist device or biventricular assist device for 1 to 26 months (mean, 6 months) underwent removal of the device after complete or extensive cardiac recovery, as revealed by echocardiography. RESULTS: Seven patients (group A) had recurrent cardiac failure after 4 to 24 months. Transplantation was performed in 6 patients, and one died while on the waiting list. Three patients died of noncardiac causes within a period of 4 months and 3 days after removal of the assist device. Stable cardiac recovery occurred in 13 patients (group B) for 3 to 49 months (mean, 23 months). At the time of implantation, there were no significant differences between the groups with regard to age, hemodynamics, left ventricular ejection fraction, left ventricular internal diameter in diastole, and autoantibody levels. The increase of ejection fraction and the decrease of left ventricular internal diameter in diastole after 2 months were highly significant. The patients in group A had longer histories of heart failure and first cardiac symptoms and duration of assist when compared with group B. Group B demonstrated a quicker cardiac recovery on the assist device, and thus support was shorter. Also, the degree of recovery at assist device explantation was more complete in group B. The age at the time of device placement was the only influencing factor for duration on the assist device. The probability of recurrence of heart failure was influenced by the duration of heart failure. CONCLUSIONS: In selected patients with idiopathic dilated cardiomyopathy, lasting recovery can be achieved after unloading with a left ventricular assist device. Lasting cardiac recovery seems to be related to functional normalization and a more rapid recovery during the unloading period.

Complicated chronic pancreatitis causing mycotic aortic aneurysm: in situ replacement with a cryopreserved aortic allograft.

Mycotic aortic aneurysm, which resulted from infected pancreatic pseudocysts with retroperitoneal abscess, developed in a patient with chronic pancreatitis. The aorta was approached through median laparotomy. Necrotic material was debrided from the pancreatic pseudocysts, and the mycotic aneurysm was resected. The aorta was replaced in situ with a cryopreserved aortic allograft. This report discusses the rare complication of pancreatic pseudocysts, which affect the infrarenal abdominal aorta and cause a large mycotic aneurysm. This case suggests that the use of cryopreserved allografts is promising for in situ reconstruction, even in a grossly infected field.

Cellular allograft rejection affecting the donor aorta after combined heart-lung transplantation.

BACKGROUND: Infectious pseudoaneurysms of the ascending aorta are a recognized major complication after heart-lung transplantation. METHOD: This report describes an unusual and previously unreported complication, that of cellular allograft rejection, which caused a pseudoaneurysm of the donor's ascending aorta in a patient who underwent combined heart-lung transplantation. Repair was performed by primary suture after mobilization of the aortic segments. RESULT: On histological examination the resected aneurysm showed evidence of proliferative vasculitis with perivascular infiltration of the vasa vasorum by mononuclear cells. The mononuclear cells were identified as CD4+ and CD8+ by immunohistological staining. CONCLUSIONS: This report shows that cellular allograft rejection may affect the donor aorta after heart-lung transplantation and may result in pseudoaneurysm formation, even under triple-drug immunosuppression after ABO-compatible allograft transplantation.

Children may survive severe myocarditis with prolonged use of biventricular assist devices.

The outcome of acute myocarditis with cardiogenic shock is poor. In some children in whom aggressive medical treatment fails, artificial replacement of heart function may offer lifesaving support until the myocardium has recovered. Four previously healthy children (three boys aged 4, 6, and 1 years; one girl aged 5) developed acute myocarditis with ventricular failure and multiorgan dysfunction caused by low cardiac output. Biventricular assist devices (BVAD) were implanted for prolonged support. In three children cardiac function improved and after up to 21 days mechanical support could be withdrawn. They had full recovery of heart function. In the fourth patient there was no myocardial recovery after a period of 20 days. He underwent orthotopic heart transplantation with an uneventful postoperative course. Prolonged circulatory support with BVAD is an effective method for bridging until cardiac recovery or transplantation in children.

A modified repair technique for tricuspid incompetence in Ebstein's anomaly.

OBJECTIVE: A modified technique for tricuspid valve repair in Ebstein's anomaly restructures the valve mechanism at the level of the true tricuspid anulus by using the most mobile leaflet for valve closure without plication of the atrialized chamber. Midterm results of this therapeutic approach for patients with Ebstein's anomaly and tricuspid valve incompetence are reported. METHODS: Between October 1988 and April 1997, the incompetent tricuspid valve was repaired with our technique in 19 patients (12 female, 7 male; 2 to 54 years, mean 21 years). The indication for operation was congestive heart failure of various degrees in all patients. Tricuspid incompetence was grade II in two patients, grade III in 14, and grade IV in three. Associated congenital malformations were simultaneously repaired (interatrial communication in 18, ventricular septal defect in two, pulmonary stenosis in two, mitral valve prolapse in one). Follow-up ranged between 10 and 103 months (median 28 months) and was complete for all patients. RESULTS: There were no operative deaths. One patient with active endocarditis and pulmonary abscess died 2 months after the operation of recurrent sepsis; there were no late deaths. During follow-up, New York Heart Association functional class improved from 2.8 before the operation to 1.9 without recurrent cyanosis, and tricuspid incompetence decreased from a mean grade of 3.1 to one of 0.9, without any echocardiographic deterioration of the tricuspid valve function or right ventricular dilation. CONCLUSIONS: Our technique allows tricuspid valve repair in patients with Ebstein's anomaly, even in cases usually reserved for primary valve replacement, without late functional deterioration.

Dynamic change in the left ventricular base with or without a rigid mitral valve prosthesis.

To evaluate the narrowing of the left ventricular outflow tract (LVOT) during systole caused by a rigid mitral prosthesis, the geometric relationship between the prosthesis (or the mitral annulus) and the left ventricular base (LVB) was studied in five patients with mechanical mitral valve prostheses and eight normal subjects. The images of the mitral valve annulus (MVA) and the LVOT orifice reconstructed in three dimensions were projected on the plane of the LV base. Calculating the areas of these projected images (i.e., those for MVA [Sm], LVOT orifice [So], the LVB [Sb; Sb = Sm + So]), the MVA-LVB ratio (Sm/Sb) was determined. In the normal subject, the MVA-LVB ratio was nearly constant during systole (59 +/- 5% at 0 msec and 62 +/- 7% at 300 msec, respectively), whereas in the patients with prostheses, the ratio increased from 61 +/- 4% (0 msec) to 69 +/- 4% (300 msec). The increase in MVA-LVB ratio reduces the proportionate share of LVOT orifice in relation to the total LVB. The ideal mitral valve prosthesis should be flexible at the annulus to attain good performance in LVB dynamics.

Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Implantation of mechanical cardiac support systems (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. We report of long-term effects of ventricular unloading on cardiac function, humoral anti-beta1-adrenoceptor autoantibodies (A-beta1-AABs), and myocardial fibrosis. METHODS AND RESULTS: Seventeen patients in New York Heart Association functional class IV with nonischemic IDC received MCSS. All had a cardiac index of < 1.6 L x min(-1) x m(-2) of body surface area, a left ventricular ejection fraction (LVEF) of <16%, and a left ventricular internal diameter in diastole (LVIDd) of >68 mm and tested positive for A-beta1-AABs. Echocardiographic evaluation, serum tests for A-beta1-AABs, and histological assessment of myocardial fibrosis were performed before and after MCSS implantation. The mean support duration was 230+/-201 days. Six patients died, four were transplanted, and two are still on MCSS. Five patients with significant cardiac recovery (mean LVIDd, 54+/-2.3 mm; LVEF, 47+/-3.7%) were weaned after 160 to 794 days and are now device free for 51 to 592 days. A-beta1-AABs disappeared gradually during MCSS without increase after weaning; cardiac function and volume density of fibrosis remained normal. Nine patients' cardiac function hardly improved during ventricular unloading. CONCLUSIONS: Cardiac function can be normalized in selected patients with end-stage IDC by MCSS. The degree of preoperative myocardial fibrosis may be an indicator for outcome; A-beta1-AABs can be used to monitor myocyte recovery. Weaning from MCSS offers an alternative to cardiac transplantation in certain patients.

[Temporary mechanical left heart support. Recovery of heart function in patients with end-stage idiopathic dilated cardiomyopathy]. / Temporäre mechanische Linksherzentlastung. Erholung der Herzfunktion bei Patienten mit idiopathischer dilatativer Kardiomyopathie im Endstadium.

BACKGROUND: Implantation of a mechanical cardiac support system (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. Our experience now includes 13 patients who have been "weaned" from MCSS and we report about the overall results of this treatment as well as the effects of ventricular unloading on cardiac function, anti-beta 1-adrenoceptor-autoantibody (A-beta 1-AAB) level and the degree of myocardial fibrosis. METHODS: 13 patients with non-ischemic IDC who had been admitted here in cardiogenic shock (CI < 1.61.min-1.m2, left ventricular ejection fraction [LVEF] < 16% and left ventricular internal diameter in diastole [LVIDd] > 68 mm) and who all tested positive for A-beta 1-AABs were implanted with an uni-(12 patients) or a biventricular (1 patient) mechanical assist device. Echocardiographic evaluation and A-beta 1-AAB-level-monitoring was routinely performed after implantation and explantation of the MCSS and the degree of myocardial fibrosis was assessed at the time of implantation and after explantation. RESULTS: During a mean duration of mechanical support of 236 +/- 201 days (range: 30 to 794 days), LV-EF improved to a mean of 46% and LVIDd decreased to a mean value of 56 mm in these 13 patients. A-beta 1-AABs decreased and disappeared 11.7 weeks after implantation of the device and did not reincrease thereafter. The highly pathologic degree of fibrosis at the time of implantation diminished to normal values about 1 year after explantation. One patient died of anesthesiologic complications and another patient shortly presented with a new episode of cardiac insufficiency 6 months after explantation. He was implanted again with an univentricular assist device was successfully transplanted 3 weeks later. Mean observation period of the remaining 11 patients now amounts to 12.6 +/- 9.77 (range: 3 to 26) months after explantation of the device--as of May, 31, 1997--with a cumulative observation period of 139 patient months. CONCLUSION: Temporary implantation of a MCSS may normalize cardiac function in selected patients with IDC. The striking degree of myocardial fibrosis can reduce to normal values after explantation of the device. A-beta 1-AABs disappear during ventricular unloading and do not increase thereafter. "Weaning" from mechanical device may constitute an alternative treatment to cardiac transplantation in selected patients.

[Combined surgical-interventional procedure in congenital heart defects with postoperative, left ventricular dysfunction]. / Kombiniertes operativ-interventionelles Vorgehen bei angeborenen Herzfehlern mit postoperativer, linksventrikulärer Dysfunktion.

Creation of a communication between the left and right atrium to decompress the left ventricle can be life-saving after corrective surgery in some patients with congenital heart disease and small left ventricle. After adaptation of the left ventricle, surgical closure of this anastomosis becomes mandatory. We report four patients (2.9 to 8.2 kg) where non-surgical, transcatheter-closure was performed in the first year of life using the Rashkind-PDA-Occluder System (USCI). In a newborn with d-transposition of the great arteries (2.9 kg), in a patient with atrial septal defect (5.1 kg), and in a patient with tetralogy of Fallot with atrial septal defect (4.9 kg) atrial septal defects were not completely closed during correction because of left-ventricular dysfunction. Five to 12 days postoperatively transcatheter closure was performed utilizing the 8F-Rashkind-PDA-Occluder System in the first two patients (2.9 kg and 4.9 kg) and by use of the 11F-Rashkind-PDA-Occluder System in the third patient (4.9 kg). In the patient with supracardiac total anomalous pulmonary venous drainage via a vertical vein, the vertical vein was not closed during surgical correction at the age of 2 months. Transcatheter closure was performed 6 months later using the 11F-Rashkind-PDA-Occluder-System. It is concluded that small, defined atrial septal defects can be closed, even in newborns, using the Rashkind-PDA-Occluder System (USCI) and, furthermore, that large vessels, even without luminal narrowing can be occluded completely. Thus, this combined "surgical-interventional approach" is not limited by age and could reduce the risk of surgical correction in patients with congenital heart disease and small left ventricle.