13-cis-retinoic acid v placebo in myelodysplasia.
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Humans↗
Biomedical subjects
R E Clark
Publications and source records attributed to R E Clark.
Ventricular aneurysms and other lesions produced by the struts of bioprosthetic valves implanted in sheep.
Damage to the posterolateral wall of the left ventricle was found in eight of approximately 700 sheep undergoing mitral valvular replacement as part of animal model studies of bioprosthetic valves. The damage consisted of left ventricular aneurysms in five animals, subacute rupture of the left ventricle in one, acute left ventricular laceration in one, and endocardial scarring in one. Six of the eight bioprostheses were bovine pericardial valves, including five low-profile valves and one standard valve; of the two porcine bioprostheses, one was intentionally oversized and the other was a low-profile supra-annular valve. In each of these animals the damage appeared to have been caused by contact between the most posterior strut of the bioprosthesis and the left ventricular wall.
Animals↗
Early and late healing responses of normal canine artery to excimer laser irradiation.
Acute in vitro histologic studies have shown that the pulsed xenon chloride excimer laser causes precise microablation without the surrounding thermal tissue injury associated with frequently used continuous-wave lasers such as the argon, carbon dioxide, and neodymium:yttrium aluminum garnet lasers. However, the in vivo healing response of artery wall to excimer laser injury is not known. Accordingly, a xenon chloride excimer laser (308 nm, 40 nsec pulse width, 39 mJ/mm2/pulse) was transmitted via a 600 micron fused silica fiber to create 420 craters of varying depths (30 to 270 micron) in 21 normal canine femoral and carotid arteries. At 2 hours, 2 days, 10 days, and 42 days after excimer laser ablation, the artery segments were perfusion fixed in situ and analyzed by light, scanning, and transmission electron microscopy. At 2 hours, craters were covered by a carpet of platelets and entrapped red blood cells. Fibrin and exposed collagen fibers were seen at the crater base. There was a sharp demarcation of the crater-artery wall interface without lateral laser tissue injury. At 2 days, adherent platelets persisted with thrombus covering the base of the craters. Early healing responses were present, consisting of polymorphonucleated leukocytes and new endothelial cells, which extended over the crater rims. At 10 days, no thrombi were seen, and healing continued with almost complete reendothelialization. Macrophages, fibroblasts, fibrin, and entrapped red blood cells were present below the reendothelialized surface. At 42 days, healing was complete with obliteration of the craters by fibrointimal ingrowth. The surface was completely covered by a smooth monolayer of axially aligned endothelial cells. There were no aneurysms or surface hyperplastic responses. These favorable healing responses in normal canine arteries suggest that pulsed lasers with high tissue absorption coefficients, such as the xenon chloride excimer laser, may be suitable energy sources for clinical laser angioplasty procedures. However, further studies in atherosclerotic animals are required before human clinical responses can be accurately predicted.
Animals↗
Primary myelodysplastic syndrome and cancer.
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Adolescent↗
Effect of 13-cis-retinoic acid on survival of patients with myelodysplastic syndrome.
A randomised therapeutic trial of 13-cis-retinoic acid was carried out in 70 patients with myelodysplastic syndrome having 5% or fewer marrow blast cells. Among non-sideroblastic patients the 1-year survival in the treated group was 77%, compared with 36% in the control group. There were too few deaths among patients with sideroblastic anaemia to allow any effect of therapy on survival to be evaluated.
Adult↗
Intrinsic failure of Hancock mitral bioprostheses: 10- to 15-year experience.
Hancock porcine bioprostheses have been implanted in the mitral position at the National Institutes of Health since July, 1970. Eight models (330, 330A, 330B, 330C, 332, 340, 341, and 342) were used during a 54-month period ending December, 1974, and 100 consecutive surviving patients were evaluated for subsequent bioprosthetic valve failure and prosthesis-related complications by annual clinic examinations and serial hemodynamic studies. Actuarial patient survival was 76 +/- 4%, 51 +/- 5%, and 30 +/- 6% after 5, 10, and 15 years, respectively. Intrinsic valve failure, defined as structural degeneration of bioprosthetic tissue or stent geometry alteration or both, in the absence of prior infection, occurred in 23 patients. The linear occurrence rate of bioprosthetic valve failure was 0.2%, 5%, and 15% per patient-year, and it affected 1 patient, 14 patients, and 8 patients at sequential 5-year milestones. The actuarial freedom from valve failure was 99 +/- 1%, 75 +/- 6%, 58 +/- 8%, and 40 +/- 12% after 5, 10, 12, and 14 years, respectively. The valve durability of early Hancock bioprostheses (models 330 through 341; N = 39) was not appreciably different from that of the current model 342 valves (N = 61). However, an increased incidence of intrinsic valve failure was observed for the first polypropylene-stented valve type (model 330) compared with the currently available model 342 valve (8/16, 50%, versus 12/61, 20%; p = 0.034). The yearly occurrence rate of prosthesis-related complications remained constant, but the rate of intrinsic valve failure increased in a progressive, nonlinear fashion. The high intrinsic failure rate of the Hancock porcine bioprosthesis after 10 to 12 years has moderated our initial enthusiasm for this valve in the mitral position, and has resulted in more frequent implantations of mechanical valve substitutes at this institution.
Actuarial Analysis↗
Operation for hypertrophic subaortic stenosis in the aged.
To determine if operative palliation of idiopathic hypertrophic subaortic stenosis (IHSS) is worthwhile in the elderly, hemodynamic, cardiac conduction, symptomatological, functional, and survival data were examined in 52 patients (39 women) 65 years old and older (mean age, 69 years; range, 65 to 81 years) who had a left ventricular myotomy and myectomy (LVMM) (Morrow procedure) alone or with concomitant operations. Seventy-four percent of all operative survivors underwent catheterization an average of 6 months postoperatively. The mean follow-up was 54 months (range, 5 to 120 months). The population was divided for analyses into those with coronary artery disease (CAD) (N = 11,21%) and those without (N = 41). The peak resting left ventricular outflow tract gradient was reduced from 65 +/- 16 mm Hg to 3 +/- 1 mm Hg (p less than 0.01) in the group with CAD and from 95 +/- 13 mm Hg to 17 +/- 9 mm Hg (p less than 0.001) in the group without CAD. Significant reductions in peak gradients in response to provocation also occurred in both groups. New conduction abnormalities occurred in 72% of survivors, 85% of whom showed improvement in regard to symptoms. The overall average New York Heart Association Functional Class was 3.2 +/- 0.1 preoperatively and at latest follow-up, 1.9 +/- 0.1 (p less than 0.001). The hospital mortality for LVMM alone in the absence of CAD was 8% with a 5-year actuarial survival of 75 +/- 8%. LVMM in the presence of CAD resulted in an operative mortality of 27% (N = 3); all deaths were related to an acquired ventricular septal defect.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
A randomized trial of 13-cis retinoic acid with or without cytosine arabinoside in patients with the myelodysplastic syndrome.
Ninety-eight consecutive patients with myelodysplastic syndrome were randomized to a treated or a control group, both receiving conventional supportive therapy. The treated group were given 13-cis-retinoic acid 20 mg/d if marrow blasts were less than or equal to 5% or cytosine arabinoside 10 mg/d subcutaneously on 6 d/week if marrow blasts were 6-30%, to which retinoic acid was added after 12 weeks. Serum levels of the drugs in the treated group were similar to those that would produce inhibition of CFU-GM growth in vitro. In patients in the low blast group receiving retinoic acid, myeloid surface antigens reverted from an abnormal to a normal pattern. Log rank analysis carried out after 25 months showed no significant difference in survival between the treated and control group, either in the total patient population or in the high and low blast groups considered separately. However, analysis of 39 non-sideroblastic patients with less than or equal to 5% blasts showed an increase in survival in the treated group.
Adult↗
The effect of cytosine arabinoside on CFU-GM from patients with myelodysplastic syndrome.
CFU-GM clonal growth was examined in bone marrow from patients with myelodysplastic syndrome (MDS) in the presence of Ara-C at 10(-8) M and 4 X 10(-8) M and the response compared to the effect on progenitors from normal subjects. Seventy-three percent of marrow cultures from patients with MDS showed colony growth below the 95% confidence limits for normal subjects in the presence of 10(-8) M Ara-C. At 4 X 10(-8) M Ara-C 43% of marrow cultures had subnormal colony growth. These results suggest that CFU-GM from patients with MDS may have a greater than normal sensitivity to Ara-C.
Bone Marrow Cells↗
Myeloid surface antigen abnormalities in myelodysplasia: relation to prognosis and modification by 13-cis retinoic acid.
The relation between prognosis and lineage specific surface antigen expression on peripheral blood granulocytes and monocytes was studied using monoclonal antibodies and flow cytometry in 37 patients with myelodysplastic syndromes (MDS). Abnormalities in antigen expression were summarised as a score, and cases were divided into low (few abnormalities) and high (many abnormalities) groups. Survival was significantly worse in the "high" group (logrank chi 2 = 5.793, p = 0.016), this group having a median survival of 31 weeks, compared with more than 67 weeks in the "low" group. No correlations were found between the score and any of the following: peripheral blood platelet and granulocyte count; FAB subtype; bone marrow blast cells and sideroblast count, or erythroid and myeloid progenitor growth. Antigen expression was also studied in six further cases of MDS before and after six weeks of treatment with 13-cis retinoic acid (CRA), 20 mg given orally, and a comparison was made with six untreated patients studied before and after a similar time interval. In the treated group 58% of initially abnormal measurements reverted to normal, compared with 24% in the untreated group. Five of the six treated patients showed a decrease in the score, whereas only two of the six improved in the untreated group. The data indicate that myeloid antigen expression is a useful indicator of prognosis in MDS, and that antigen expression may be affected by treatment.
Adult↗
Circulatory support for right ventricular dysfunction.
New modes of circulatory support for right ventricular dysfunction have recently been described. The present study compared the effectiveness of pulmonary artery balloon counterpulsation with a right ventricular assist device for support of surgically induced right ventricular dysfunction. Right ventricular hypertrophy was created in 16 neonatal lambs by pulmonary artery banding. Right ventricular dysfunction was produced in all animals by performing a right ventriculotomy and maintaining the pulmonary artery band. Four unassisted animals developed severe acute right heart failure and died. Six sheep had pulmonary artery balloon counterpulsation with a Dacron graft anastomosed to the proximal pulmonary artery as a reservoir for a 40 ml intra-aortic balloon after the onset of heart failure. The remaining six sheep had a pneumatically activated ventricular assist device inserted between the proximal pulmonary artery and the right ventricular apex. Periods of circulatory support with the balloon pump and the assist device on and off were compared. Decreases in right atrial pressure were observed with both balloon counterpulsation and right ventricular assistance: 14 +/- 1 to 11 +/- 1 mm Hg, p less than 0.0001, versus 19 +/- 2 to 12 +/- 2 mm Hg, p less than 0.0002, respectively. Cardiac output increased with both balloon counterpulsation and ventricular assistance: 1.45 +/- 0.16 to 2.03 +/- 0.13 L/min, p less than 0.001, versus 0.72 +/- 0.15 to 2.24 +/- 0.23 L/min, p less than 0.0002, respectively. Aortic systolic pressure increased in both support groups: 78 +/- 7 to 99 +/- 6 mm Hg, p less than 0.0004, versus 53 +/- 9 to 85 +/- 9 mm Hg, p less than 0.0001, respectively. Ventricular assistance produced greater changes in the right atrial pressure (39% +/- 6% versus 17% +/- 3%, p less than 0.01), cardiac output (153% +/- 39% versus 54% +/- 11%, p less than 0.05), and aortic systolic pressure (85% +/- 13% versus 39% +/- 9%, p less than 0.01). The insertion of a right ventricular assist device caused a significant increment in right ventricular dysfunction. These data, obtained with the devices in place but not operating, showed significantly increased right atrial and right ventricular end-diastolic pressures and approximately 50% less cardiac output than with the pulmonary artery balloon counterpulsation system. The results demonstrate that both modes of circulatory support were effective in reversing surgically induced right ventricular failure.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Tricuspid regurgitation in patients with acquired, chronic, pure mitral regurgitation. I. Prevalence, diagnosis, and comparison of preoperative clinical and hemodynamic features in patients with and without tricuspid regurgitation.
Most reports of clinical experiences with palliation of acquired tricuspid regurgitation have failed to address the issue of coexisting disease of the mitral or aortic valve, or both. To accurately determine the natural history and the effect of operative interventions, we studied patients with chronic, pure mitral regurgitation who had surgical treatment at the National Heart, Lung, and Blood Institute from 1968 to 1984. Forty-seven patients fulfilled the criteria of a documented history of mitral regurgitation for more than 1.5 years, minimal mitral diastolic gradient, severe mitral regurgitation by angiography, and no prior mitral or tricuspid operative procedure. Twenty-five of the 47 patients (53%) had evidence of tricuspid regurgitation. No statistical differences in age, sex, mean duration of symptoms of congestive heart failure, or functional class were found between those patients with and those without tricuspid regurgitation. However, patients with symptoms of congestive heart failure for more than 6 years were more likely to have tricuspid regurgitation. This increased prevalence also correlated with higher elevations of left ventricular end-diastolic, systolic pulmonary artery, and mean right atrial pressures. The severity of tricuspid regurgitation estimated preoperatively did not correlate statistically with that determined by digital palpation, although the presence of tricuspid regurgitation was reliably confirmed. These data demonstrate that tricuspid regurgitation is frequently present in patients with chronic, pure mitral regurgitation and is associated with prolonged symptoms of congestive heart failure and significant alterations in right heart dynamics.
Blood Pressure↗
Tricuspid regurgitation in patients with acquired, chronic, pure mitral regurgitation. II. Nonoperative management, tricuspid valve annuloplasty, and tricuspid valve replacement.
The incidence, preoperative and intraoperative diagnosis, methods, and the clinical and hemodynamic features of patients with and without tricuspid regurgitation associated with chronic mitral regurgitation were presented in Part I. This study (Part II) compares the early and late results in patients with chronic, pure mitral regurgitation undergoing isolated mitral valve replacement, mitral replacement and tricuspid valve annuloplasty, and mitral and tricuspid valve replacement. The mean follow-up interval was 6 years. Those with the longest duration of symptoms (18 years) required tricuspid and mitral valve replacement (11 patients), whereas those with the shortest duration (8.1 years) had only mitral replacement (22 patients). Eight patients had minimal tricuspid regurgitation by digital palpitation, with no procedure performed, and six had tricuspid valve annuloplasty, only one of whom received a ring support. Operative mortality rate was similar in all groups (13% to 18%). All but two of the surviving patients improved by at least one New York Heart Association functional class, and no statistically significant differences were found between preoperative and postoperative hemodynamic data. There were no statistically significant differences in survival at 1, 5, or 8 years (85%, 70%, and 60%, respectively) for patients with or without TR. Only two of the surviving five patients who underwent tricuspid valve annuloplasty were alive 3 years after operation, whereas 70% to 80% of those with mitral replacement or mitral and tricuspid replacement were alive after the same time interval. It is not clear whether or not the pathogenesis of tricuspid regurgitation resulting from mitral regurgitation is different from that of tricuspid regurgitation resulting from mitral stenosis. It is our contention that whether tricuspid regurgitation arises because of anatomic destruction of the tricuspid valve or because of right ventricular dilatation with tricuspid annular enlargement, the underlying mitral valve lesion may determine the preoperative and postoperative courses of these patients. Therefore, when tricuspid valve disease is being evaluated, we urge that patients be categorized by the nature of their underlying mitral or aortic valve lesions.
Adult↗
Continuous measurement of intramyocardial pH: relative importance of hypothermia and cardioplegic perfusion pressure and temperature.
The continuous measurement of intramyocardial pH was used to follow the progression of ischemia and permit correlation to functional recovery. Adequacy of myocardial preservation following 38 degrees C or 25 degrees C global ischemia alone or with the administration of one or two doses of 38 degrees C, 25 degrees C, or 1 degree C crystalloid cardioplegia at aortic root perfusion pressures of 90 mm Hg or 130 mm Hg was assessed. A new miniature myocardial transducer incorporating fiberoptic technology and dual pH and temperature-sensing capability was placed into the left ventricular free wall and septum of 44 sheep undergoing ischemic arrest during cardiopulmonary bypass. All groups underwent global ischemia until myocardial pH was 6.8. An intramyocardial pH level of 6.8 reliably correlated to similar levels of functional recovery in each group. Aortic root perfusion pressure of 130 mm Hg provided enhanced myocardial protection by increasing the total ischemic time (5 to 10 minutes) with one (p less than 0.01) or two (p less than 0.001) doses of cardioplegic solution until a given functional level of recovery was attained. Aortic root perfusion pressure of 90 mm Hg provided no added benefit in total ischemic time, rate of change of pH, or degree of recovery of function. Hypothermic (25 degrees C) global ischemia alone enhanced myocardial protection by providing increased time (p less than 0.01) until a given functional level of recovery was attained with a slower rate of change of pH (p less than 0.01) compared with normothermic (38 degrees C) global ischemia alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Valve replacement in narrow aortic roots: serial hemodynamics and long-term clinical outcome.
No long-term data are available that correlate clinical outcome with serial hemodynamic studies for small-diameter (17-mm or 19-mm) aortic prostheses implanted without enlargement of the annulus. After insertion of these valves without annuloplasty, 52 patients underwent resting catheterization and were followed up at the Surgery Clinic of the National Heart, Lung, and Blood Institute for 295 patient-years (mean, 5.7 years per patient). At similar flow rates, peak systolic gradients across 17-mm Björk-Shiley aortic prostheses (N = 6) tended to exceed those of the 19-mm Björk-Shiley model (N = 38); these gradients averaged 30 +/- 6 mm Hg (mean +/- standard error of the mean) and 20 +/- 2 mm Hg, respectively (p = .053). Those patients with 19-mm Hancock (N = 4) and St. Jude Medical valves (N = 4) were studied, and the lowest prosthetic gradients were found with the St. Jude Medical prosthesis (mean, 3 +/- 2 mm Hg). Aortic gradient was independent of flow for 17-mm but not for 19-mm Björk-Shiley valves. There was no difference in calculated effective orifice area with respect to valve size. Effective orifice area and prosthetic gradients were stable during intervals of 2 to 12 years in 10 patients who underwent additional catheterizations. No association was found between prosthetic gradients, flows, or calculated orifice areas and early or late functional class. Actuarial survival was 86 +/- 5% at 5 years, 83 +/- 5% at 8 years, 71 +/- 9% at 10 years, and 60 +/- 12% at 12 years of complete follow-up. It is concluded that small aortic prostheses provide acceptable palliation for long periods and that resting hemodynamic studies have a limited predictive value for long-term prognosis.
Adult↗
Continuous measurement of intramyocardial pH: correlation to functional recovery following normothermic and hypothermic global ischemia.
The continuous measurement of intramyocardial pH was used to follow the progression of ischemia and was correlated to the recovery of left ventricular function following normothermic (38 degrees C) and hypothermic (25 degrees C) global ischemia. New miniature myocardial transducers, which incorporate fiberoptic technology and dual pH- and temperature-sensing capability, were placed into the left ventricular free wall and septum of 52 sheep undergoing cardiopulmonary bypass. Left ventricular stroke work as a function of mean left atrial pressure curves were generated before and after cardiopulmonary bypass by volume loading with whole blood. Functional recovery was determined by the ratio of the integrals of the preischemic and postischemic function curves. Control sheep (N = 11) did not undergo ischemia. Three groups (N = 41) underwent aortic cross-clamping until pH reached 7.0, 6.8, or 6.6. The preischemic myocardial pH averaged 7.42 +/- 0.01. Following both normothermic and hypothermic global ischemia, no significant difference was demonstrated in recovery of function between control (pH 7.4) and pH 7.0 groups at either temperature. However, recovery of function of the pH 6.8 and pH 6.6 groups was significantly decreased (p less than 0.01) versus control and pH 7.0 groups at both temperatures. No significant difference in recovery of function was demonstrated at any pH level when normothermic versus hypothermic groups were compared. However, hypothermia provided increased time (p less than 0.001) before each level of function was reached with a slower rate of change of pH (p less than 0.01) compared with the corresponding same pH group in sheep undergoing normothermic (38 degrees C) cardiopulmonary bypass.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Left ventricular outflow tract obstruction following mitral valve replacement: effect of strut height and orientation.
The influence of strut position and strut height of Ionescu-Shiley bovine pericardial valves on the degree of left ventricular outflow tract (LVOT) obstruction was studied following mitral valve replacement (MVR) in hypertrophied left ventricles. Left ventricular hypertrophy was created in 6 lambs by constrictive banding of the descending thoracic aorta at 2 weeks of age. MVR was accomplished seven months later utilizing cardiopulmonary bypass and hypothermic cardioplegic arrest. Each animal underwent three consecutive valve replacements with 25-mm bovine pericardial valves randomly inserted in each of the following manners: (1) standard-profile valve with orientation of the struts out of the LVOT; (2) standard-profile valve with a strut oriented into the LVOT; and (3) low-strut profile investigational valve with a strut oriented into the LVOT. Gradients across the LVOT were measured after MVR and then following administration of isoproterenol hydrochloride (0.05 micrograms per kilogram of body weight per minute). No gradient was created with the struts oriented out of the LVOT with or without isoproterenol administration. When a strut was oriented into the LVOT without isoproterenol, the gradients were comparable with the standard- and low-profile valves (7 +/- 2 mm Hg versus 6 +/- 4 mm Hg, respectively). With isoproterenol, however, a significant difference in gradients between the standard- and low-profile valves (65 +/- 20 mm Hg versus 22 +/- 14 mm Hg, respectively) was observed when a strut was oriented into the LVOT. The results show that LVOT obstruction following MVR was related to the orientation of the strut of the bioprosthetic valve, and this obstruction was diminished with a decreased strut height of the Ionescu-Shiley prosthesis.
Animals↗
Myocardial protective effect of amiodarone in hypertrophied hearts during global ischemia.
The effect of amiodarone on the ischemic-reperfusion injury was tested in an isolated working preparation, using hypertrophied rat heart at 37 degrees C. Constant filling and afterload pressures and similar heart rates were used. Hearts from spontaneously hypertensive rats (N = 78) had thirty minutes of ischemia. Each received a 12-ml injection, by aortic root infusion, of amiodarone in normal saline or of normal saline alone at 37 degrees C at the onset of ischemia. Heart rate, aortic output, coronary sinus output, atrial pressure, and aortic pressure were recorded before and after global ischemia under steady-state conditions. Dose-response studies were performed at concentrations of 0.01 to 1.0 mg/ml. At every dose administered, amiodarone was found to significantly ameliorate the deleterious effects of global ischemia. The maximal benefit of amiodarone (70 +/- 4.6% recovery of function [mean +/- standard error of the mean], p less than 0.01) was found to be 0.25 mg (0.021 mg/ml), or 0.11 mg/g wet heart weight. Improvement in survival (return of aortic output and heart rate following ischemia) with all doses of amiodarone was statistically significant (p less than 0.002). Decreased recovery of function following global ischemia when doses were greater than 0.25 mg may have been secondary to the known negative inotropic effects of the drug. The mechanisms for the protective effects of amiodarone may be coronary vasodilatation, antiarrhythmic stabilization, or inhibition of calcium flux at the slow channel.
Amiodarone↗