Postoperative course of S-100B protein and neuron-specific enolase in patients after implantation of continuous and pulsatile flow LVADs.

BACKGROUND: In the early post-operative period after implantation of a continuous flow left ventricular assist device (LVAD) a non-pulsatile flow occurs. We compared the post-operative time-courses of protein S-100B (S100B) and neuron-specific enolase (NSE) as biochemical markers of brain injury in patients after implantation of a continuous flow LVAD and patients receiving a pulsatile flow LVAD. METHODS: Since 1998 the continuous flow DeBakey VAD has been implanted in 8 patients at our institution. For comparison purposes, a group of 7 consecutive patients in whom a pulsatile Novacor N100 LVAD was implanted were investigated. In both groups cardiopulmonary bypass (CPB) with cardiotomy suction was used. S100B and NSE were measured in serum pre-operatively, 4 hours after CPB, and on days 1, 3, 7, and 14 after implantation of the LVAD. A neurologic examination was performed pre-operatively and post-operatively on days 3 and 14. RESULTS: No differences were found between groups in pre-operative characteristics. The analysis of variance with repeated measurements for S-100B and NSE showed significant time effects (p = 0.004, p = 0.009, respectively) but no group effects (p = 0.06, p = 0.26, respectively) and no interaction between groups and time (p = 0.12, p = 0.48, respectively). The pre-operative serum level of S100B was significantly higher (p = 0.03) in the DeBakey VAD group. The pre-operative serum level of NSE was similar in the 2 groups (p = 0.7). In both groups there was a significant increase of S100B and NSE immediately after surgery (S100B: p = 0.006, p = 0.019; NSE: p = 0.01, p = 0.001). The values returned to pre-operative levels in the DeBakey VAD group on day 1 after implantation and in the Novacor group for S100B on day 3 and NSE on day 1. Post-operatively the mean values of S100B and NSE in the DeBakey VAD group compared with the Novacor group were significantly elevated only on day 3 (p = 0.005, p = 0.023).No neurologic complications were noted in patients with a continuous flow LVAD, whereas in the pulsatile LVAD group 2 patients presented neurologic abnormalities during the study period. CONCLUSIONS: The similar course of biochemical markers of brain damage in both groups may indicate that the non-pulsatile flow in the early post-operative period does not lead to increased brain injury or permeability of the brain blood barrier.Elevated levels of S100B and NSE in the post-operative period can be used as diagnostic markers of brain injury in patients after implantation of both types of LVAD.

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.

New strategies for the management of acute decompensated heart failure.

Acute heart failure in adults is the unfolding of heart failure in minutes, hours or a few days. Low output heart failure describes a form of heart failure in which the heart pumps blood at a rate at rest or with exertion that is below the physiological range and the metabolizing tissues extract their required oxygen from blood at a lower rate, causing a proportionately smaller oxygen amount remaining in the blood. Therefore, a widened arterial-venous oxygen difference occurs. High output heart failure is characterized by pumping blood with a rate above the physiological range at rest or during exertion, resulting in an arterial-venous oxygen difference, which is normal or low. This may be caused by peripheral vasodilatation during sepsis or thyrotoxicosis, blood shunting, or reduced blood oxygen content/viscosity (Fig. 1). The differentiation between low output heart failure versus high output heart failure is of highest importance for the choice of therapy and therefore the information and the monitoring of the systemic vascular resistance. Patients who present with acute heart failure suffer from a severe complication of different cardiac disorders. Most often they have an acute injury that affects their myocardial performance (eg, myocardial infarction) or valvular/chamber integrity (mitral regurgitation, ventricular septal rupture), which leads to an acute rise in left-ventricular filling pressures resulting in pulmonary edema.

Transcranial detection of microembolic signals in patients with a novel nonpulsatile implantable LVAD.

Mechanical ventricular assist devices (VAD) have become an accepted therapy for the support of patients in severe heart failure. With the devices presently available, the incidence of thromboembolic complications is high. Since November 1998, we have used the DeBakey VAD (MicroMed, Inc., Woodlands, TX). To detect the effect of this VAD on the appearance of microthrombi or bubbles from cavitation, we measured Microembolic Signals (MES) with transcranial Doppler in patients after the implantation of the DeBakey VAD. Transcranial Doppler studies were performed with the MULTI-DOP X4 device with two 2 MHz probes (for the left and right middle cranial arteries [MCA]) in five patients preoperatively and during 10 weeks after VAD implantation. Both MCAs were monitored simultaneously for 60 minutes in 10 sessions in each patient. The detection and analysis of MES was performed in accordance with the technique and criteria described by the international consensus group. No MES were noted during the study period in four patients. In one patient with preoperatively noted MES the prevalence of MES postoperatively was 50%. The high speed rotating impeller of the DeBakey VAD did not produce any detectable microthrombi or bubbles from cavitation effects.

Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device.

The implantation of a ventricular assist device (VAD) is associated with a stimulation of the inflammatory system. We compared changes in the inflammatory response after implantation of a pulsatile Novacor left (L) VAD and the axial flow MicroMed DeBakey VAD. Six consecutive patients after implantation of a Novacor LVAD (NC) and six patients after implantation of a MicroMed DeBakey VAD (MD) were included in the investigation. Patients received LVADs for medically non treatable end-stage heart failure. Tumor necrosis factor alpha (TNF), C3a, C5a, interleukin 6 (IL-6), and neutrophil elastase were measured twice a week over a period of 3 months after implantation of the device. All tests were performed with an enzyme-linked immunosorbent assay. There was no significant difference in the clinical course of the two groups. All inflammatory parameters were elevated in both groups during the entire period of the investigation. There was no difference in TNF, polynuclear leukocyte elastase, or C3a levels between the two groups; however, IL-6 (NC: 23.6+/-37.6 pg/ml vs. MD: 63+/-114 pg/ml, p < 0.001) and C5a (NC: 708+/-352 microg/L vs. MD: 1,745+/-1,305 microg/L, p < 0.001) were increased significantly more in patients following implantation of the axial flow MicroMed DeBakey VAD. Compared with the pulsatile Novacor device, the implantation of the axial flow MicroMed DeBakey LVAD seems to be associated with an increased stimulation of one part of the inflammatory system. Further investigations are necessary for evaluation of the pathophysiologic mechanism and clinical implications of these findings.

Complications common to ventricular assist device support are rare with 90 days of DeBakey VAD support in calves.

The DeBakey VAD is a miniaturized, electromagnetically driven axial flow pump intended for long-term ventricular assist. Safety and performance data from six calves implanted with the complete DeBakey VAD system are reported elsewhere; here we describe complications and necropsy findings for these same six animals, all of which survived 90 days. The study was conducted according to a uniform protocol, which included anticoagulation and antibiotic prophylaxis. Clinical complications tracked included bleeding, cardiovascular abnormalities (e.g., arrhythmias, tachycardia unrelated to pain, bradycardia), hemolysis, hepatic dysfunction, renal dysfunction, thromboembolism (neurologic or peripheral), or infection. Each adverse event was retrospectively categorized with regard to severity (mild, moderate, severe) and relationship to device. Clinical findings were confirmed by necropsy. There was no evidence of systemic infection, thromboembolism, hemolysis, or renal or hepatic dysfunction in these six animals during the study period. A single adverse event was noted in each of two of the calves. Both events were considered mild according to the predefined criteria. Bleeding related to the surgical implantation procedure and requiring reoperation occurred in one animal. The other animal had evidence of a superficial infection at the exit site of the cables on the left lateral thoracic wall; the infection did not extend into the thoracic cavity. Chronic, healed small renal infarct scars were present in several animals. Mild valvular endocardiosis was observed in two calves and mild fibroelastosis was present in the endocardium at the site of the inflow cannula in three calves; however, these lesions were not considered clinically significant. No other gross or histologic abnormalities were noted at necropsy. In conclusion, calves implanted with the complete DeBakey VAD for 90 days demonstrated few complications and had no significant necropsy findings. Complications common to ventricular assist device (VAD) support (i.e., hemolysis, infection, bleeding, thromboembolism) were rare during long-term support (90 days) with the DeBakey VAD.

Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support.

BACKGROUND: The cellular and structural changes that occur during long-term ventricular unloading leading to cardiac recovery are poorly understood. However, we have previously demonstrated that left ventricular assist device (LVAD) support leads to a significant decrease in intracardiac tumor necrosis factor-alpha (TNF-alpha), a protein capable of producing hypertrophy and fibrosis. METHODS: To further define the beneficial effects of long-term ventricular unloading on cardiac function, we determined the effect of mechanical circulatory support on fibrosis and hypertrophy in paired myocardial samples of 18 patients with end-stage cardiomyopathy obtained at the time of LVAD implantation and removal. RESULTS: We determined total collagen as well as collagen I and III by a semiquantitative analysis of positive immune-stained areas in pre- and post-LVAD myocardial samples. We found that total collagen content was reduced by 72% (p < 0.001), whereas collagen I content decreased by 66% (p < 0.001) and collagen III content was reduced by 62% (p < 0.001). Next, we determined myocyte size by direct analysis of cellular dimensions utilizing a computerized edge detection system in pre- and post-LVAD myocardial samples. We found that myocyte size decreased in all patients studied for an average reduction of 26% (33.1 +/- 1.32 to 24.4 +/- 1.64 microm, p < 0.001). CONCLUSION: These data demonstrate that long-term mechanical circulatory support significantly reduces collagen content and decreases myocyte size. We suggest that the reduction of fibrosis and hypertrophy observed may in part contribute to the recovery of cardiac function associated with long-term mechanical circulatory support.

Clinical experience with the MicroMed DeBakey ventricular assist device.

BACKGROUND: The MicroMed DeBakey ventricular assist device (VAD) (MicroMed Technology, Inc, Houston, TX) is the first long-term axial flow circulatory assist device to be introduced into clinical trials as a bridge to transplantation. Clinical trials began in Europe in November 1998 and in the United States in June 2000. METHODS: To qualify for the study, the patients must be listed for cardiac transplantation and must have demonstrated profound cardiac failure. There were no exclusions to the MicroMed DeBakey VAD implant other than those patients who would typically be excluded from cardiac transplantation. RESULTS: As of September 2000, 51 patients have been implanted with the MicroMed DeBakey VAD. A detailed evaluation of the first 32 patients has been completed. With current data, the probability of survival at 30 days after VAD implant is 81%. CONCLUSIONS: The clinical trial demonstrated that the MicroMed DeBakey VAD is capable of providing adequate circulatory support in patients with severe heart failure, sufficient to recover and return to normal activities while awaiting a heart transplantation. Much has been learned about the function of the device and its continuous flow in humans.

Turbine blood pumps.

After years of development and preclinical testing, clinical trials of the MicroMed DeBakey VAD began in November 1998 in Europe and in June 2000 in the United States. As of August 2000, 44 patients in Europe and 3 patients in the United States have undergone implantation with the MicroMed DeBakey VAD. In conclusion, data from the European clinical trial of the MicroMed DeBakey VAD support the safety and performance of the device. Results show that the device provides adequate left ventricular and circulatory support in patients with end-stage heart failure without unduly jeopardizing patient safety. Moreover, the device provides advantages not inherent to commercially available pulsatile devices: (1) miniature size, enabling implantation in smaller patients; (2) ease of implantation; (3) reduced surgical bleeding; and (4) a low incidence of postoperative infections, often a limiting factor with other devices. The MicroMed DeBakey VAD European clinical trial is the first demonstration of the compatibility of continuous blood flow with adequate tissue perfusion and overall maintenance of life for up to 4.5 months. This initial experience with the MicroMed DeBakey VAD suggests that the pump can provide circulatory support to bridge patients to cardiac transplantation and may provide an improved quality of life for the patient with end-stage heart failure.

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.

Alterations in coagulation after implantation of a pulsatile Novacor LVAD and the axial flow MicroMed DeBakey LVAD.

BACKGROUND: The MicroMed DeBakey left ventricular assist device (LVAD) is a chamber and valveless axial flow blood pump. We investigated parameters of the coagulation system in patients after implantation of the axial flow LVAD and patients following implantation of a pulsatile Novacor LVAD. METHODS: Six consecutive patients of both groups were investigated over a period of 6 weeks after implantation. beta-Thromboglobulin, platelet factor 4, factor XIIa, thrombin/antithrombin complexes, plasmin/alpha2-antiplasmin complexes, and D-Dimer levels were measured. RESULTS: With the exception of the plasmin/alpha2-antiplasmin levels in the Novacor group, all parameters were elevated in both groups. The levels of beta-thromboglobulin, platelet factor 4, factor XIIa, and plasmin/alpha2-antiplasmin were significantly increased in the axial flow LVAD group. CONCLUSIONS: The axial flow LVAD strongly influences the systems of contact activation and fibrinolysis. The elevation of platelet proteins appears to follow platelet damage. Although no thromboembolic events were observed in both groups, elevation of thrombin/antithrombin complexes provides convincing evidence of an increased activation of the coagulation system and the concomitant risk for the development of thromboembolism.

Development and clinical application of the MicroMed DeBakey VAD.

A miniaturized axial flow pump to provide left ventricular assistance has been developed. Such a device has the potential to address limitations of the larger pulsatile devices. Clinical trials of the MicroMed DeBakey VAD (ventricular assist device) began in Europe in November 1998. As of December 1, 1999, 18 patients have been implanted with the MicroMed DeBakey VAD. Hemodynamic evaluations along with blood chemistry analysis were recorded routinely. Exercise tolerance was observed. In most patients, end-organ function has improved and has not deteriorated in any patient. Patients have been able to perform normal low-level activity and have tolerated positional changes without evidence of postural hemodynamic changes. Select patients have taken supervised out-of-hospital excursions. This initial clinical experience with the MicroMed DeBakey VAD suggests that the miniaturized axial flow pump can provide ventricular support to bridge patients to cardiac transplant and may provide an improved quality of life for the end-stage heart failure recipient.

Cardiac transplantation: the final therapeutic option for the treatment of heart failure.

End-stage heart failure is still associated with a decrease in quality and prognosis of life. Cardiac transplantation remains the final extraordinary therapeutic option for the treatment of truly irreversible end-stage heart failure in all age groups. The selection process of candidates and the acceptance of patients with relative contra-indications is characterized by the experience and skills of an interdisciplinary transplant team, which should have access to different mechanical circulatory support systems for short-term or long-term use: bridging to transplant as well as for recovery.

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.

The implications for cardiac recovery of left ventricular assist device support on myocardial collagen content.

BACKGROUND: To define the beneficial cellular changes that occur with chronic ventricular unloading, we determined the effect of left ventricular assist device (LVAD) placement on myocardial fibrosis. METHODS: We obtained paired myocardial samples (before and after LVAD implantation) from 10 patients (aged 43 to 64 years) with end-stage cardiomyopathy. We first determined regional collagen expression of an explanted heart by a computerized semiquantitative analysis of positive picro-sirius red stained areas. RESULTS: We found that there was no statistically significant difference in collagen content between regions of the failed heart studied. Next we determined collagen content in these paired myocardial biopsies pre- and post-LVAD implantation. All 10 patients had significant reductions in collagen content after LVAD placement with a mean reduction of 82% (percent of tissue area stained decreased from 32% +/- 4% to 4% +/- 0.8%, P < 0.001). CONCLUSION: In summary, these data demonstrate that chronic mechanical circulatory support significantly reduces fibrosis in the failing myocardium.

[The DeBakey VAD axial flow pump: first clinical experience with a new generation of implantable, nonpulsatile blood pumps for long-term support prior to transplantation]. / Die DeBakey VAD-Axialpumpe: Erste klinische Erfahrungen mit einer neuen Generation von implantierbaren, nonpulsatilen Blutpumpen als Langzeit-Uberbrückung bis zur Transplantation.

Because of the high frequency of acute hemodynamic deterioration in patients awaiting cardiac transplantation, mechanical techniques of circulatory support to bridge the period until transplantation have become a standard clinical procedure. Continuous-flow rotary blood pumps offer exciting new perspectives in terms of ventricular assistance and/or as a total cardiac substitute. A DeBakey VAD axial flow pump was implanted in two male patients (aged 44 and 65 years, respectively) suffering from end-stage left heart failure. In the initial postoperative period the mean flow rate of the pump was 3.9 +/- 0.5 l/min. In both patients, the early postoperative phase was characterised by a completely non-pulsatile flow profile. Two weeks after implantation and partial recovery of the natural left ventricle, increasing pulse pressures became evident and net flow increased to 4.5 +/- 0.6 l/min. Patients were mobilised and made to under-go regular physical training. Hemolysis produced by the pump was low while free haemoglobin stayed in physiological ranges, increasing only slightly from 2.1 +/- 0.8 mg/dl preoperatively to 3.0 +/- 1.5 mg/dl ten weeks after implantation. One patient was successfully transplanted on day 74 after implantation of the DeBakey VAD while the second patient is, after 110 days of pumping, still waiting for transplantation. This first experience concerning clinical implantation of the DeBakey VAD axial flow pump showed that the device is promising as a means of providing mechanical support to bridge the period until cardiac transplantation.