Alan G Rose

Aortic valve pathophysiology during left ventricular assist device support

The increased applicability and excellent results with left ventricular assist devices (LVADs) have revolutionized the available treatment options for patients with advanced heart failure. Pre-existing valve abnormalities are common in this population, and subsequent development of valve abnormalities after LVAD placement is also often noted. Although native mitral and tricuspid valve disease is more common in heart failure patients before LVAD placement, aortic valves are much more likely to generate abnormal pathophysiology in the LVAD patient during as well as after LVAD placement. The aim of this comprehensive review is to review aortic valve function in LVAD patients and highlight the consideration of pre-existing valve disease on patient treatment at the time of LVAD implant. The basis for structural changes leading to valve pathophysiology during and after LVAD placement will be described, providing a basis for improved clinical understanding and new strategies to prevent these conditions.

Partial aortic valve fusion induced by left ventricular assist device

BACKGROUND Left ventricular assist devices (LVADs) may be used (1) as a bridging device to cardiac transplantation, (2) for permanent replacement of left ventricular function, and (3) as a bridge to recovery of ventricular function, for example, in recoverable myocardial disease. In this third group of patients, it is important that the LVAD does not produce changes in the heart that will have a deleterious effect on cardiac function once the device is removed. Furthermore, if the LVAD fails, survival depends on optimal function of the diseased heart. METHODS All hearts with LVADs encountered as surgical specimens following heart transplantation or at autopsy at the Fairview-University of Minnesota Medical Center during the 5-month period August 1998 to January 1999 were examined for native valvular heart disease. The nature and extent of commissural fusion was noted and measured. Light microscopy was performed on any valve lesions. RESULTS Four of 6 patients with HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) LVADs showed evidence of commissural fusion (acquired aortic stenosis). In 1 patient, this condition was caused by an organizing thrombus uniting a 14-mm length of the commissural region of the right coronary and noncoronary cusps of the aortic valve. Fibrous commissural fusion due to totally organized thrombus in the other 3 patients affected one aortic commissure (2 patients, 2 mm and 4 mm, respectively) and two commissures (1 patient, 2 mm and 5 mm). Partial cuspal fusion in each case was due to permanent closure of the native aortic valve induced by the LVADs operating in its automatic setting. Mean length of commissural fusion was 5.4 mm (range, 2 to 14 mm; standard deviation [SDI = +/-5.0 mm). Mean duration of implantation of the six LVADs was 180.3 days (range, 26 to 689 days; SD = +/-253.8 days). The LVADs of the 3 patients with fibrous fusion of the commissures had been implanted for an average of 252.3 days (range, 26 to 689 days; SD = +/-378.2 days). CONCLUSIONS Normal function of the LVAD produces permanent closure of the native aortic valve. Stasis on the ventricular aspect of the aortic valve, combined with a low level of anticoagulation, favors thrombosis at this site. Thrombus organization leads to aortic stenosis of variable severity. This previously unsuspected complication was not detected clinically in any of our patients. Aortic stenosis may hold serious implications for patients in whom the LVAD acts as a bridge to recovery or in those in whom the LVAD fails. Prevention may be achieved by intermittently reducing LVAD pumping action. A built-in venting cycle would be of value in long-term implants. Thrombi on the aortic valve may also predispose patients to infective endocarditis, because bloodstream infection is common in patients with LVADs.

Pulmonary Complications After Bone Marrow Transplantation An Autopsy Study From a Large Transplantation Center

CONTEXT Bone marrow transplantation (BMT) is used to treat various malignant and nonmalignant disorders. Pulmonary complications are some of the most common causes of mortality in BMT recipients. Poor general health and bleeding tendency frequently preclude the use of definitive diagnostic tests, such as open lung biopsy, in these patients. OBJECTIVE To identify pulmonary complications after BMT and their role as the cause of death (COD). DESIGN The autopsy and bronchoalveolar lavage (BAL) slides and microbiology studies of BMT recipients from a 7-year period were reviewed. RESULTS Pulmonary complications were identified in 40 (80%) of the 50 cases. The most common complications were diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH). Pulmonary complications were the sole or 1 of multiple CODs in 37 cases (74%). All complications were more common in allogeneic BMT recipients. In 19 (51%) of the 37 cases in which pulmonary complications contributed to the death, cultures were negative. Both DAD and DAH, complications commonly reported in the early post-BMT period, were seen more than 100 days after BMT in 33% and 12% of cases, respectively. Five (83%) of 6 cases of invasive pulmonary aspergillosis diagnosed at autopsy were negative for fungi ante mortem (by BAL and cultures). CONCLUSIONS Pulmonary complications are a significant COD in BMT recipients, many of which, especially the fungal infections, are difficult to diagnose ante mortem. The etiology of DAD and DAH is likely to be multifactorial, and these complications are not limited to the early posttransplantation period. Autopsy examination is important in determining the COD in BMT recipients.

Venular thrombosis is the key event in the pathogenesis of antibody-mediated cardiac rejection.

Abstract: A review of the histopathologic features of serial biopsies and excised grafts of 117 experimental and clinical cardiac allografts and xenografts revealed a common sequence in the development of histopathologic changes in grafts showing antibody‐mediated (hyperacute and acute vascular) rejection. Based on these observations, we propose the new concept that thrombosis of cardiac veins and venules is the initial key event in antibody‐mediated rejection. This is followed by the development of congestion in the subtended venules and capillaries accompanied by interfascicular and, later, intermyocyte edema. Subsequently, focal or diffuse interstitial hemorrhage affecting the subendocardium, extending sometimes to involve the inner half of the ventricular myocardium, is observed. Antibody‐mediated rejection therefore appears to be analogous to incomplete venous infarction of the heart. The observed histopathology (in which venular thrombosis plays a key role) favors a thrombogenic basis for the classical features of antibody‐mediated rejection, namely edema, vascular thrombi and interstitial hemorrhage. A key role for venular thrombosis would explain the non‐uniform distribution of the changes and may suggest new ways of preventing antibody‐mediated xenograft rejection.

Total left ventricular outflow tract obstruction due to left ventricular assist device–induced sub-aortic thrombosis in 2 patients with aortic valve bioprosthesis

This report describes 2 patients with an aortic bioprosthesis. Both patients developed total thrombotic occlusion of the sub-aortic left ventricular outflow tract consequent to insertion of a left ventricular assist device (LVAD). Replacing a mechanical valve with a bioprosthesis in patients receiving a left ventricular assist device offers no additional protection against thrombosis of the aortic prosthesis. Pericardial patching below the aortic prosthesis at the time of LVAD implantation may be performed, but will significantly impede or prohibit the native ventricle from ejecting blood and demonstrating any degree of recovery.

Failure to detect Chlamydia pneumoniae in senile calcific aortic stenosis or calcified congenital bicuspid aortic valve by immunofluorescence, polymerase chain reaction and electron microscopy

INTRODUCTION Chlamydia pneumoniae has been identified in arterial atherosclerosis. Aortic valves affected by senile calcific aortic stenosis (SCAS) or calcification of a congenital bicuspid valve (CCBAV) may have interior environments similar to atherosclerosis. This study aimed to detect C. pneumoniae within either SCAS or CCBAV. METHODS 60 valves showing either SCAS (n=36) or CCABV (n=22) and control valves (n=2) were studied for the presence of C. pneumoniae by the following three techniques: (1) indirect immunofluorescence (IF) was performed on 36 SCAS valves, 22 CCBAV valves and 2 control aortic valves using a HEp-2 cell line infected with C. pneumoniae as a positive control. Negative controls comprised duplicate slides of the same valves with omission of the primary antibody step. A section of human stomach was also used as a negative control. A semiquantitative scoring method was used to grade positive IF staining. (2) Polymerase chain reaction (PCR) was performed on 30 SCAS valves, 20 CCBAV valves and 1 control valve using C. pneumoniae as a positive control and negative controls comprised a Ureaplasma sp. and human DNA from peripheral blood mononuclear cells. (3) Electron microscopy (EM) was performed upon 13 SCAS, 8 CCBAV and 2 control valves. RESULTS All three methods failed to detect the presence of C. pneumoniae in any of the 60 aortic valves examined. False positive IF staining was encountered in 81% of test valves and in 76% of negative control valve sections (positive in calcified material due to nonspecific binding of FITC-conjugated secondary antibody). No staining was observed in the negative control stomach sections. CONCLUSIONS This study failed to detect C. pneumoniae within aortic valves showing SCAS or CCBAV. Studies using IF alone to detect C. pneumoniae in calcified tissues should be interpreted with caution, since nonspecific binding of FITC-conjugated secondary antibody by calcium in the cusps may be misinterpreted as evidence of Chlamydia. The use of appropriate controls and ancillary methods for the identification of C. pneumoniae are important in this regard.

Understanding the pathogenesis and the pathology of hyperacute cardiac rejection.

The terminology of hyperacute rejection (HAR) has become outmoded and confusing due both to advances that have been made in delaying its onset and due to a proliferation of synonyms for the same pathologic process. Until such time as antibody-mediated xenograft rejection can be classified by the type of causative antibody, it is recommended that the term hyperacute rejection be applied to antibody-mediated rejection with classical HAR occurring within 24 h. Delayed HAR is the same pathologic process encountered after 24 h. Recognition of the key role that venous thrombosis plays in the pathogenesis of HAR allows the microscopist to intelligently interpret biopsies from various portions of a transplanted organ according to the pathologic effects of the obstructed venous drainage of the organ. Particularly in the heart, HAR often shows different pathologic features in the inner compared to the outer myocardium. Once xenografting becomes feasible, it will be possible to apply a grading system of HAR in clinical practice.

Left ventricular assist device support for medically unresponsive pulmonary hypertension from left ventricular failure.

BACKGROUND. Severe pulmonary hypertension (PHT) from end-stage left ventricular (LV) failure that is unresponsive to medical therapy is an absolute contraindication for orthotopic heart transplantation. Pulmonary venous congestion has been shown to be an important determinant of systolic PHT. We hypothesized that left ventricular assist device (LVAD) bridge therapy to heart transplant may reverse pulmonary venous congestion, and thus allows these patients to become suitable transplant candidates. METHODS: We identified 3 patients with end-stage ischemic cardiomyopathy who had severe PHT which was unresponsive to medical therapy, including prostaglandins, nitroprusside, milrinone, and dobutamine. LVAD implantation was performed with the intention to improve PHT and bridge them to heart transplantation. RESULTS: All 3 patients had severe LV dysfunction (ejection fraction 15-20%). Lung biopsies at the time of LVAD implantation showed evidence of reversible pulmonary hypertensive changes (grade I to early grade III) in the pulmonary vasculature. Following LVAD implantation, all patients responded favorably with significant reduction in pulmonary hypertension. CONCLUSION: LVAD support improves pulmonary venous congestion, thus lowering the severe medically unresponsive PHT secondary to LV failure. This permits orthotopic heart transplantation in patients who otherwise would have been unsuitable candidates. Pre-LVAD vs. Post-LVAD Hemodynamic Data

Acquired supravalvar aortic stenosis following heart transplantation: Report of 2 cases

We report 2 cases of acquired supravalvar aortic stenosis (SVAS) complicating orthotopic cardiac transplantation that contributed to the post-operative death of both patients. In the first patient the stenosis resulted from kinking of a too-long graft aortic component that was rendered into a fixed deformity by healed mediastinitis and constrictive pericarditis. Supra-aortic stenosis in the second patient occurred at a site of multiple aortic cannulations that was surrounded by dense fibrosis. Acquired SVAS contributed to the death of the first patient (who had graft arteriopathy) and was the proximate cause of death in the second patient. Specific echocardiography of the ascending aorta, which is not routinely performed, may detect SAVS.

An investigation of the immunosuppressive effects of niridazole and metronidazole in rat and baboon heterotopic cardiac allograft models.

Niridazole alone (at 50 mg/kg/day) and particularly in combination with azathioprine and prednisolone showed potent immunosuppressive activity, far surpassing that produced by conventional agents, in the rat heterotopic cardiac allograft model. Benzoylmetronidazole or metronidazole (at 50 mg/kg/day) either alone or in combination with azathioprine and prednisolone demonstrated little immunosuppressive activity. The potent immunosuppression obtained with niridazole in the rat could not be reproduced in the baboon heterotopic cardiac allograft model in the doses used; niridazole at 50 mg/kg/day seems to be toxic in this animal.