Reinforcing the evidence of oligoclonal bands as a prognostic factor in patients with Multiple sclerosis.

The prognostic value of oligoclonal bands in the cerebrospinal fluid of Multiple Sclerosis (MS) patients is controversial. While several studies have demonstrated a worse disease course in OCB positive patients, others did not reproduce these findings. We evaluated the prognostic significance of OCB retrospectively based on clinical records of OCB status upon diagnosis and severity outcomes including the MS Severity Score, Progression Index and regional involvement in Magnetic Resonance Imaging. OCB positive patients had a higher median MSSS and PI, and a greater proportion of spinal cord involvement. These findings provide further evidence of the prognostic importance of OCB in MS patients.

Pulsatile flow in patients with a novel nonpulsatile implantable ventricular assist device.

BACKGROUND: Ventricular assist devices (VADs) are an accepted therapy for patients with end-stage heart failure. The implantable devices that are available produce a pulsatile flow and are very large. In 6 patients, beginning in November 1998, we started to use the continuous-flow implantable DeBakey VAD device, which weighs 93 g. To detect the flow in peripheral vessels, we measured transcranial Doppler signals in patients after implantation. METHODS AND RESULTS: Transcranial Doppler studies were performed with the MULTI-DOP X4 device with two 2-MHz probes (for the middle cranial arteries) in 4 patients for up to 12 weeks twice weekly after implantation. The blood velocity was measured, and the pulsation index (PI) calculated. The measured pump flow and rotations per minute were registered. The preoperative echocardiographic assessment values were compared with those acquired 6 weeks after implantation. The PI increased continually in all patients after VAD implantation, left ventricular (LV) ejection fraction did not improve, but right ventricular (RV) ejection fraction after implantation improved compared with preoperative values. The LV end-diastolic diameter after implantation decreased between 11% and 46% intraindividually. There was no correlation between PI and blood pressure or, except in 1 patient, between PI and blood flow through the VAD. CONCLUSIONS: The DeBakey VAD unloads the LV, which leads to a decrease in LV end-diastolic LV diameter and to the restoration of RV function. The unloaded LV and partially recovered RV provide a nearly physiological pulsatile flow despite the continuous flow of the VAD. Pulsatility is independent of peripheral vascular resistance. The first clinical experience with the DeBakey VAD was positive and has resulted in its continued use.

First clinical experience with the DeBakey VAD continuous-axial-flow pump for bridge to transplantation.

BACKGROUND: A shortage of donor organs and increased numbers of deaths of patients on the waiting list for cardiac transplantation make mechanical circulatory support for a bridge to transplantation a standard clinical procedure. Continuous-flow rotary blood pumps offer exciting new perspectives. METHODS AND RESULTS: Two male patients (ages 44 and 65 years) suffering from end-stage left heart failure were implanted with a DeBakey VAD axial-flow pump for use as a bridge to transplant. In the initial postoperative period, the mean pump flow was 3.9+/-0.5 L/min, which equals a mean cardiac index (CI) of 2.3+/-0.2 L. min(-1). m(-2). In both patients, the early postoperative phase was characterized by a completely nonpulsatile flow profile. However, with the recovery of heart function 8 to 12 days after implantation, increasing pulse pressures became evident, and net flow rose to 4.5+/-0.6 L/min, causing an increase of mean CI up to 2.7+/-0.2 L. min(-1). m(-2). Patients were mobilized and put through regular physical training. Hemolysis stayed in the physiological range and increased only slightly from 2. 1+/-0.8 mg/dL before surgery to 3.3+/-1.8 mg/dL 6 weeks after implantation. CONCLUSIONS: The first clinical implants of the DeBakey VAD axial-flow pump have demonstrated the device to be a promising measure of bridge-to-transplant mechanical support.

Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support : A potential mechanism for cardiac recovery.

BACKGROUND: An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-alpha is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-alpha expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-alpha expression in human failing myocardium. METHODS AND RESULTS: Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-alpha, and quantitative analysis of the stained area was performed. We found that TNF-alpha content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-alpha content were found in patients who were successfully weaned off the LVAD who did not require transplantation. CONCLUSIONS: These data show for the first time that chronic mechanical circulatory assistance decreases TNF-alpha content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.

Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

Relation of the contractile reserve of hibernating myocardium to myocardial structure in humans.

BACKGROUND: Although dobutamine echocardiography (DE) is widely used to assess myocardial viability in humans, little is known about the relation between contractile reserve and myocardial structure. METHODS AND RESULTS: We evaluated 20 patients with coronary disease (64+/-13 years old, ejection fraction 28+/-7.5%) with DE (up to 40 micrograms . kg(-1). min(-1)), rest-redistribution (201)Tl single photon emission CT, and quantitative angiography before bypass surgery. During surgery, patients underwent transmural myocardial biopsies (n=37) guided by transesophageal echocardiography to determine the extent of interstitial fibrosis and intracellular and interstitial proteins by histopathology and immunohistochemistry. Among the 37 segments biopsied, 16 recovered function as assessed 2 to 3 months later. Segments with postoperative functional recovery had more wall thickening at low-dose DE (28% versus 3%, P<0.001), higher thallium uptake (69% versus 48%, P=0.03), and less interstitial fibrosis (2% versus 28%, P<0.001). Quantitative angiographic parameters did not predict recovery of function. Segments with DE viability (contractile reserve and/or ischemia) had less fibrosis (2.7% versus 28%, P<0.001), less vimentin and fibronectin (both P<0.01), more glycogen (P=0.016), and higher thallium uptake (64% versus 35.5%, P<0.05) than those without viability. Viable segments by both DE and thallium had less fibrosis (1%) than those viable by 1 of the 2 techniques (9%) or not viable by both (28%, P=0.005). Thickening at low-dose DE correlated well with the extent of interstitial fibrosis (r=-0.83, P<0.01). CONCLUSIONS: Contractile reserve during DE correlates inversely with the extent of interstitial fibrosis and the amount of fibronectin and vimentin and directly with rest-redistribution thallium uptake.

Delayed recovery of severely "stunned" myocardium with the support of a left ventricular assist device after coronary artery bypass graft surgery.

A 53 year old man underwent repeat coronary artery bypass graft surgery after presenting with unstable angina. Because of intraoperative ischemia, the patient developed profound left ventricular dysfunction requiring placement of a left ventricular assist device and intraaortic balloon pump and catecholamine infusion. Serial radionuclide ventriculograms documented delayed recovery of the severely stunned myocardium with mechanical and pharmacologic support.

An accurate, nontraumatic ultrasonic method to monitor myocardial wall thickening in patients undergoing cardiac surgery.

Measurement of systolic wall thickening by sonomicrometry provides an accurate index of regional left ventricular function, but the trauma of crystal insertion limits its widespread clinical use. The first clinical application of a 10 MHz ultrasonic Doppler probe that can be either sutured or applied by suction to the epicardium and can measure wall thickening at any depth of the left ventricular wall is described. In 18 dogs, measurements obtained with the suction probe correlated well (r = 0.97) with those of a previously validated sutured probe. To assess clinical feasibility, the probe was applied to the epicardium of patients undergoing coronary bypass surgery. Good quality wall thickening signals were obtained with no complications. Transmural left ventricular thickening fraction before bypass surgery was 34 +/- 3% (mean value +/- SE) at the mid-ventricular lateral wall, 33 +/- 4% at the anterior basal wall and 26 +/- 4% at the mid-ventricular posterior wall. Right ventricular thickening fraction averaged 25 +/- 3%. Endocardial thickening fraction tended to exceed epicardial thickening fraction, although the difference attained statistical significance (p less than 0.05) only at the anterior basal wall. On average, thickening fraction during the immediate postoperative period remained unchanged compared with the preoperative values, but a marked individual variability was observed, with 7 of 15 patients exhibiting a decrease and 8 an increase. Exteriorization of the wires attached to the sutured probe allowed continuous in situ monitoring of wall thickening in the postoperative period and subsequent removal of the probe. In six patients the crystal was left in place for 48 to 72 h after surgery and then removed without complications; good wall thickening signals were obtained for the entire period during which the probe was implanted. Thus, the Doppler probe is an accurate, atraumatic method for measuring right and left ventricular regional function. Transmural, endocardial and epicardial function can be mapped at various sites during surgery, and post-operatively one can monitor serial changes of regional function and assess the effects of cardioplegia and other therapeutic interventions. This technique should be useful for both investigative and clinical purposes.

Lymphocyte subset populations in bronchiolitis obliterans after heart-lung transplantation.

The long-term success of heart-lung transplantation is limited by the development of bronchiolitis obliterans, possibly as a form of chronic lung allograft rejection. In the present study, we have characterized by immunohistochemical staining the lymphocytes infiltrating the lesions of bronchiolitis obliterans in one patient following heart-lung transplantation. The finding that the preponderant cells expressed the CD8 (putative cytotoxic/suppressor) marker lends support to the notion that chronic rejection is at least one mechanism for the development of bronchiolotis obliterans following heart-lung transplantation.

Dynamics of soluble interleukin-2 receptor levels immediately after heart transplantation. Attenuation of increase by OKT3 therapy.

Quantification of T cell activation after cardiac transplant by measuring serum soluble interleukin 2 receptor levels daily may give insight into immunologic dynamics after cardiac allograft implantation. It was our hypothesis that this protein would demonstrate a characteristic rise after heart transplant not related to severe rejection that was distinct from a control group, and that this increase could be attenuated with OKT3 therapy. We measured soluble interleukin 2 receptor levels daily for two weeks in 26 patients undergoing orthotopic cardiac transplantation (19 receiving triple therapy immunosuppression with cyclosporine, azathioprine, and prednisone, and 7 with OKT3 added days 1 through 5). Interleukin-2 receptor levels for transplant patients were compared with 15 control subjects (14 undergoing bypass surgery and one valve replacement). Mean soluble interleukin-2 receptor level for the entire two-week period was higher for transplants versus controls; 839 +/- 31 U/ml vs. 504 +/- 20 U/ml (mean +/- SEM; P less than .05). Patients receiving OKT3 had a lower level (670 +/- 39 U/ml) than those not (902 +/- 36 U/ml, P less than .05) despite the fact that mean biopsy scores for the observation period were not significantly different. No significant rejection or infection episodes occurred in any patient. These results describe, for the first time, sequential changes in soluble interleukin 2 receptor levels early after heart transplant and demonstrate that the characteristic early rise can be attenuated with short-term OKT3 administration.

Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation.

Successful cardiac transplantation requires suppression of rejection, and endomyocardial biopsy is generally used to quantify this and guide immunotherapy. Biopsy, however, is an invasive, costly, cardiac catheterization with repetition limited. Since rejection requires lymphocyte activation, an alternative method of assessing rejection dynamics might be ELISA determination of soluble interleukin-2 receptor (sIL-2R) levels since induction of the interleukin-2 ligand and its receptor is required. Reports suggest that sIL-2R levels rise during kidney, liver, and heart-lung allograft rejection and heart recipients have an adverse prognosis if sIL-2R is elevated postoperatively. It is unclear, however, if serial measurements or single determinations are sufficient or if change from a baseline assessment is important. The purpose of this study was to determine if an isolated sIL-2R level after heart transplant predicted endomyocardial biopsy score at that moment. To do this, we prospectively followed 60 consecutive patients after orthotopic heart transplant and correlated 479 endomyocardial biopsy scores (McAllister scale 0-10) with matched sIL-2R levels. Regression analysis demonstrated minimal relationship between sIL-2R level and biopsy score (r =.11, r2 =.01, P=.009). When the maximum sIL-2R level for each individual patient was compared with the matched biopsy score, regression analysis revealed r=.04, r2=.001, P=.8. Likewise, when all biopsy scores and sIL-2R levels for each patient were meaned, analysis showed r=.14, r2=.02, P=.26. Thus in heart transplant patients, there is poor correlation between an isolated biopsy score and matched sIL-2R level. However, when mean +/- SEM sIL-2R was determined for severe rejection (score 7-10) and compared with sIL-2R for all other grades, it was significantly higher (1600 +/- 257 vs. 423 +/- 57 U/ml; P=.012). Still, the sensitivity, specificity, and predictive value of an sIL-2R level above 1000 U/ml predicting severe rejection was only 52%, 63%, and 8%. It would be difficult, therefore, to use a single sIL-2R determination after heart transplant to foretell the endomyocadial biopsy score. Serial measurements or quantification of a change in sIL-2R level from baseline might be more predictive of rejection severity.

Functional assessment of the total artificial heart by blood-pool radionuclide angiography.

Blood-pool radionuclide angiography was used to image a patient with a Jarvik 7-(70) total artificial heart. Excellent delineation of the chambers was achieved, allowing assessment of the total artificial heart pumping function. Estimation of the left ventricular volumes, cardiac output, and filling rates by radionuclide angiography corresponded closely with those simultaneously obtained from the total artificial heart driving lines. Radionuclide angiography affords the unique possibility to assess the function of the artificial heart noninvasively.

Blood-pool radionuclide angiography in patients with a Novacor left ventricular assist device.

Blood-pool radionuclide angiography was used to investigate the left ventricular function in eight patients who received a Novacor assist device as a bridge-to-cardiac transplantation. Studies were performed during maximal and minimal tolerated assist device flows. The left ventricular ejection fraction, volumes, cardiac output, and the pump ejection fraction were computer-assessed. All patients had severe left ventricular dilation and hypokinesis before insertion of the assist device, with a mean ejection fraction of 18% +/- 4% which improved to 44% +/- 18% (p less than 0.01) during maximal assist device flows, but fell to 25% +/- 15% (p less than 0.01) during minimal flows. The ventricular volumes became normal at maximal assist device flow but increased significantly (p less than 0.05) during minimal flow. The pump was well visualized and had an ejection fraction of 82% +/- 7%. These data indicate that this assist device effectively unloads the left ventricle. The deterioration in ejection fraction following decrease in assist device flow is in keeping with the dependency of these patients on the device to sustain adequate hemodynamics.

Treatment of symptomatic peripheral atherosclerotic disease with a rotational atherectomy device.

Narrowings 70 to 90% in diameter in 3 iliac, 4 superficial femoral and 2 popliteal arteries were crossed and atherectomized successfully in 6 patients using the Squibb Rotablator under angiographic guidance during surgical bypass procedures on these arteries. The Rotablator consists of a 1.25 to 4.5 mm diameter oblong burr with tiny diamond blades mounted on a flexible shaft, which tracks over a spring-tip guidewire and rotates at speeds greater than 120,000 rpm. All stenoses were reduced to less than or equal to 50% of the normal luminal diameter. No significant complications occurred. Of the 6 patients having the atherectomy procedure, 5 were reevaluated by duplex Doppler measurements 1.5 to 5.5 (mean 3.5) months after atherectomy and found to be patient with only mild residual flow disturbance. Repeat follow-up by angiography after a mean of 5.2 months, however, showed only 3 (37%) of the atherectomized segments in 3 patients to still be patent. All were symptomatically improved. Of the effluent particles analyzed, 90% were less than 8 microns in size, while only 5% reached 250 microns. With improvements in technique, the largest particles were 150 to 180 microns, constituting only 1.4% of effluent debris. Samples of the effluent from 2 patients were injected in vivo into the left coronary system of 2 pigs. There were no acute hemodynamic or electrocardiographic complications or pathologic evidence of muscle necrosis or vascular thrombosis 18 to 48 hours later. These preliminary results with respect to feasibility and safety of the Rotablator are promising.

Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant.

Obstructive coronary artery vasculopathy can be a major problem after cardiac transplant. The use of noninvasive tests to detect coronary artery vasculopathy was studied in 73 consecutive patients after heart transplant. Angiographically or autopsy-proved coronary artery disease was noted in 19 consecutive patients (26%) followed prospectively for 2.5 +/- 1.3 years (mean +/- standard deviation). Patients underwent yearly surveillance echocardiographic, rest/exercise-gated wall motion, oral dipyridamole thallium, ambulatory electrocardiographic monitor and angiographic studies. Positive test results were defined by decrease in ejection fraction, wall motion abnormality, failure to increase ejection fraction, lack of systolic blood pressure increase, and ischemic ST changes at maximal exercise (or on ambulatory monitor). Wall motion abnormalities and depressed ejection fraction on echocardiography were also abnormal studies as were fixed or reversible perfusion defects on thallium scan. Angiograms were considered positive when 50% luminal narrowing was observed and autopsy coronary artery vasculopathy was defined as cross-sectional coronary obstruction greater than or equal to 70%. No procedure that was examined proved to be a sensitive noninvasive detector of heart transplant coronary artery vasculopathy. All except ambulatory electrocardiographic monitoring had positive predictive values less than 50%. Interestingly, of the techniques evaluated, echocardiography was most sensitive (53%). The poor predictive ability of noninvasive testing in this population may be due to the fact that these tests are designed to detect effects of ischemia rather than coronary obstruction alone. Use of these particular noninvasive modalities routinely after heart transplant to detect coronary artery vasculopathy should be reconsidered because of their low sensitivity and predictive value when used as a surveillance screen.

Fortuitous rupture of aortic aneurysm: a catastrophic event affording time for surgical cure.

The rupture of an aortic aneurysm is generally a fatal event, but occasionally the rupture will occur into an adjacent vascular structure, thereby preventing exsanguination and affording temporary survival. Three cases are presented illustrating the fortuitous nature of the rupture of an aortic aneurysm into a vascular structure. The first patient had an atherosclerotic abdominal aortic aneurysm that ruptured into the inferior vena cava and was successfully repaired. The second case demonstrates the formation of a fistula from the aorta to the left pulmonary artery in a patient with a syphilitic thoracic aortic aneurysm. In the third patient a dissecting aneurysm of the aortic root that communicated with the right ventricle after coronary bypass surgery was successfully repaired. Rarely, aortic aneurysms will rupture fortuitously into vascular capacitance structures. These three cases emphasize the need for early accurate diagnosis and the institution of appropriate surgical measures.

Platelet aggregation: effects of cardiopulmonary bypass.

This study was designed to determine whether reduction in platelet aggregate microembolization during the first 30 minutes of cardiopulmonary bypass is due to thrombocytopenia or to decreased ability of platelets to aggregate. The total volume of platelet aggregates induced in blood by adenosine diphosphate (ADP) was measured with a Coulter counter. The volume of platelets in blood was calculated by multiplying hemocytometry platelet counts by the mean platelet volume. Immediately before cardiopulmonary bypass, the total volume of aggregates induced in blood by ADP (2muM) was reduced when compared to normal donors because of (1) a slight fall in the volume of platelets, and (2) reduction in the percentage by volume of platelets which aggregated. After 30 minutes on bypass, the volume of both platelets and aggregates fell, but a greater percentage of platelets aggregated. This indicates that reduction of platelet aggregate formation during cardiopulmonary bypass is due to thrombocytopenia. It also suggests that anesthesia, surgical trauma and heparinization alter platelet reactivity more than cardiopulmonary bypass.

Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation.

Thirty-two recipients of single, double, or heart-lung transplantation followed-up for at least 3 months posttransplant were retrospectively reviewed to assess the frequency, predictors, and risk factors associated with the development of bronchiolitis obliterans (BO). A clinical definition for the diagnosis of BO was made using the following criteria: persistent and progressive decline in FEF25-75, associated with normal results of cytologic and microbiologic studies for significant pathogens in bronchoalveolar lavage fluid, with a normal chest radiograph. This was correlated with histologic diagnosis and patient outcome. Sixteen (50%) of the patients developed BO, and this was associated with a 56% mortality. All but 1 patient with histologic BO had a clinical diagnosis of BO made (often months) prior to diagnostic biopsy. No patients with normal histologic findings had a clinical diagnosis of BO. More than 3 episodes of histologically documented acute rejections in any 12-month period were eventually associated with a 100% incidence of BO. Cytomegalovirus occurred with greater frequency in patients with BO, and in most cases, preceded or occurred concomitantly with the diagnosis of acute rejection or BO.

Outcome of the native lung after single lung transplant. Multiorgan Transplant Group.

Twenty-one long-term survivors of single lung transplant since 1987 have been followed from 7 to 81 months. Posttransplant complications unique to the native lung and their impact on patient outcome are reported. In 7 of 21 recipients of single lung transplant, clinical complications in the native lung developed, including infection, pulmonary infarction, and severe ventilation-perfusion mismatching. Impact on the patient has ranged from little effect (prolongation of hospital or ICU stay) to recurrent severe infections, the need for surgical intervention, and a possible contribution to the recurrence of original disease--giant cell interstitial pneumonitis. The remaining native lung can be a source of significant complications following single lung transplant. Pretransplant diagnoses other than uncomplicated idiopathic pulmonary fibrosis seem to be most frequently associated with compromise of function or risk of infection arising from the native lung.

Semiquantitative measurement of cytomegalovirus DNA in lung and heart-lung transplant patients by in vitro DNA amplification.

We report the cases of two lung transplant recipients (one heart-lung and one single lung) who eventually developed cytomegalovirus (CMV) pneumonitis after documentation of increasing CMV DNA titers in sequential bronchoalveolar lavage (BAL) specimens by polymerase chain reaction (PCR) amplification. To our knowledge, this is the first report that semiquantitation of PCR-amplified DNA can detect an increase in CMV DNA titer in BAL specimens prior to the onset of clinical symptoms or detection of infection by traditional techniques in lung transplant patients. The results obtained in these two cases suggest that DNA titer measurement on sequential BAL samples may differentiate latency from active viral replication and, thus, provide an opportunity for clinical intervention before the development of overt clinical symptoms.