Arthur A. Bert

Decellularization reduces calcification while improving both durability and 1-year functional results of pulmonary homograft valves in juvenile sheep

OBJECTIVE The juvenile sheep functional valve chronic implant calcification model was used to compare long-term calcification rates, functional performance, and durability for 3 types of right ventricular outflow tract implants: classically cryopreserved homografts and 2 decellularized pulmonary valved conduits. METHODS Fifteen juvenile sheep were randomly assigned to one of 3 study arms and underwent pulmonary valve replacement. The arms included the following: (1) cryopreserved ovine pulmonary valves; (2) cryopreserved, decellularized, saline (1 degrees C-10 degrees C)-stored ovine pulmonary valves; and (3) cryopreserved, decellularized, glycerolized (-80 degrees C) stored ovine pulmonary valves. Animal growth, serial echocardiographic results (with valve performance assessment), dimensions, and tissue-specific calcification measurements were compared with pre-explant angiographic analysis and right ventricular outflow tract pressure measurements, cardiac magnetic resonance imaging, specimen radiographic analysis, gross explant pathology, and histopathology. Parametric and nonparametric statistical analysis were performed. RESULTS All but 2 study animals receiving implants thrived postoperatively, with similar growth rates, explant valve dimensions, ventricular functions, cardiac output, and indices during the study. As determined by means of echocardiographic analysis, 3 animals in arm 1 (and one in arm 2) had leaflet dysfunction. Valve regurgitation was recognized in 1 survivor each from both arms 1 and 2. Although 1 arm 1 animal died with calcified subacute bacterial endocarditis, and the other 4 had leaflet and conduit wall calcification by the time of death, no arm 2 or arm 3 animals demonstrated leaflet calcium, and no arm 3 and only 1 arm 2 animals had calcium in the conduit wall over the entire year, as determined with any measurement method. All cryopreserved conduit walls had calcium by 20 weeks, whereas only 1 of 10 decellularized conduits (arms 2 plus 3) had wall calcium. CONCLUSION Cryopreserved-decellularized-glycerolized valves retained normal valve function, with absent leaflet and minimal wall calcifications 1 year postoperatively, as opposed to classically cryopreserved allografts. These results might be predictive of the prolonged durability and functionality of a cryopreserved-decellularized-glycerolized allograft valve.

Stroke during coronary artery bypass grafting using hypothermic versus normothermic perfusion

Does the abandonment of hypothermic perfusion during cardiopulmonary bypass compromise cerebral protection and thus lead to a higher incidence of stroke? From 1987 to June 1993, 2,585 consecutive patients underwent myocardial revascularization using warm-body (perfusion at 37 degrees C), cold-heart (cold cardioplegic arrest) surgical technique and were followed for new overt neurologic deficits. Perfusion pressure was maintained between 50 and 70 mm Hg, and hematocrit was kept around 20%. There were 25 operative deaths (1%) in this normothermic group, and new neurologic deficits developed after operation in 25 patients (1%). These results were compared retrospectively with those in 1,605 patients who underwent myocardial revascularization between 1980 and 1986 with moderate hypothermic (25 degrees to 30 degrees C) perfusion, the same surgical team, and similar operative techniques. The normothermic group included more elderly patients, more patients with left ventricular dysfunction and unstable angina, and more frequent use of an internal mammary artery conduit. Neurologic complication rates were 1% and 1.3% for the normothermic and hypothermic perfusion groups, respectively. Risk factors for stroke that were identified included age greater than 70 years, severity of aortic arch atherosclerosis, and severe hypotension in the perioperative period. Thus, in a large clinical series, the incidence of overt neurologic injuries was found to be no higher with normothermic perfusion than with hypothermic perfusion.

Performance and Morphology of Decellularized Pulmonary Valves Implanted in Juvenile Sheep

BACKGROUND Because of cryopreserved heart valve-mediated immune responses, decellularized allograft valves are an attractive option in children and young adults. The objective of this study was to investigate the performance and morphologic features of decellularized pulmonary valves implanted in the right ventricular outflow tract of juvenile sheep. METHODS Right ventricular outflow tract reconstructions in juvenile sheep (160±9 days) using cryopreserved pulmonary allografts (n=6), porcine aortic root bioprostheses (n=4), or detergent/enzyme-decellularized pulmonary allografts (n=8) were performed. Valve performance (echocardiography) and morphologic features (gross, radiographic, and histologic examination) were evaluated 20 weeks after implantation. RESULTS Decellularization reduced DNA in valve cusps by 99.3%. Bioprosthetic valves had the largest peak and mean gradients versus decellularized valves (p=0.03; p<0.001) and cryopreserved valves (p=0.01; p=0.001), which were similar (p=0.45; p=0.40). Regurgitation was minimal and similar for all groups (p=0.16). No cusp calcification was observed in any valve type. Arterial wall calcification was present in cryopreserved and bioprosthetic grafts but not in decellularized valves. No autologous recellularization or inflammation occurred in bioprostheses, whereas cellularity progressively decreased in cryopreserved grafts. Autologous recellularization was present in decellularized arterial walls and variably extending into the cusps. CONCLUSIONS Cryopreserved and decellularized graft hemodynamic performance was comparable. Autologous recellularization of the decellularized pulmonary arterial wall was consistently observed, with variable cusp recellularization. As demonstrated in this study, decellularized allograft valves have the potential for autologous recellularization.

Nineteen-Millimeter Aortic St. Jude Medical Heart Valve Prosthesis: Up to Sixteen Years’ Follow-up

UNLABELLED BACKGROUND; Prosthetic valve replacement in a small aortic root without annulus enlargement raises concern about its long-term benefits. METHODS Between July 1979 and June 1994, 104 (18%) of 593 patients underwent aortic valve replacement using the 19-mm St. Jude Medical heart valve prosthesis. There were 93 women and 11 men, with a mean age of 66.2 +/- 10.6 years. Forty-four patients (42%) were 70 or more years old. The mean body surface area was 1.61 +/- 0.16 m2 (range, 1.2 to 2.1 m2). Forty-nine patients (47%) underwent concomitant procedures; 23 patients (22%) required coronary artery bypass grafts and 25 patients (24%), mitral valve replacement. Ninety-eight patients (94%) presented in New York Heart Association class III and IV. RESULTS The operative mortality was 7.6% (8 patients). Follow-up was 100% with a mean of 5.48 +/- 3.73 years (range, 1 to 16 years) and a total of 708 patient-years. There were 18 late deaths, with a mortality of 2.5% patient-years. The incidence of thromboembolism was 0.4% patient-years (3 patients) and anticoagulant-related morbidity was 0.85% patient-years (6 patients). Long-term survival in the two groups with a body surface area of less than 1.7 m2 and 1.7 m2 or more was not statistically different (p = 0.30). The univariate analysis with body surface area as a predictor of mortality showed that a larger body surface area had no effect on the long-term mortality (chi2 p value = 0.36). Survival for 5 and 10 years with the 95% confidence interval was 80.6% +/- 8.3% and 61.6% +/- 15%. Freedom from thromboembolism was 96.3% +/- 4.2% and anticoagulant-related hemorrhage was 91.8% +/- 6.8% at the end of 16 years. Cox proportional hazards model, with time-dependent covariates, showed that events of thromboembolism, anticoagulant-related hemorrhage, and myocardial infarction during follow-up increased the risk of late death (risk ratio, 9.5, 10.3, and 32.8, respectively). The age at operation was an independent risk factor, with decreased survival with age 70 or more years (p = 0.0002). However, body surface area (p = 0.97) and concomitant cardiac procedures (p = 0.86) were not statistically significant predictors of death. CONCLUSIONS The long-term performance of the 19-mm St. Jude Medical heart valve prosthesis in the small aortic root is satisfactory irrespective of the body surface area, and it is a viable alternative for such patients.

St. Jude medical cardiac valves in small aortic roots: Follow-up to sixteen years ☆ ☆☆

Prosthetic aortic valve replacement in the small aortic root raises concerns of its long-term effects. Between 1978 and 1994, 270 patients received only small aortic prostheses (< or = 21 mm). There were 117 men (43.3%) and 153 women (56.7%) with a mean age of 64.3 +/- 11.6 years (range 19 to 87 years). The body surface areas ranged from 1.2 to 2.26 m2 (mean 1.71 +/- 0.27 m2). Ninety-one percent of patients had New York Heart Association class III or IV symptoms and 33% underwent concomitant coronary artery bypass grafting. The operative mortality rate was 3.3% (9 deaths) and follow-up (100%) extended from 1 to 16 years (mean 6.2 +/- 3.9 years) with cumulative survival of 1676 patient-years. There were 55 late deaths (3.28% per patient-year). The linearized rates of morbidity reported as percent per patient-year were as follows: structural failure, 0%; paravalvular leak, 0.12%; prosthetic endocarditis, 0.24%; anticoagulant-related morbidity, 1.24%; and thromboembolism, 1.10%. In 89% of the survivors New York Heart Association functional performance had improved to class II or I. The actuarial survival with 95% confidence intervals at 5, 10, and 16 years was 86.9% (82.5%, 91.3%), 68.6% (60.6%, 76.6%), and 53.6% (36.6%, 70.6%), respectively. Freedom from late valve-related events (95% confidence intervals) at 10 and 16 years was as follows: thromboembolism, 91.2% (86.6%, 95.8%) and 78.3% (62.6%, 94%); anticoagulant-related morbidity, 89.1% (83.8%, 94.4%) and 81.0% (65.1%, 96.9%); and prosthetic endocarditis, 98.8% (97.5%, 100%) and 98.8% (97.5%, 100%), respectively. Multivariate analysis revealed age at operation, myocardial infarction, and endocarditis affected the long-term survival. The risk of sudden death irrespective of body surface area and valve size was not statistically different. Thus the long-term performance of the St. Jude Medical valve in small aortic roots is satisfactory.

Monitoring End-tidal Carbon Dioxide During Weaning from Cardiopulmonary Bypass in Patients Without Significant Lung Disease

End-tidal carbon dioxide tension (Petco2) changes with fluctuations in cardiac output (CO). We compared Petco2 to pulmonary artery blood flow (PAQt) during weaning from cardiopulmonary bypass (CPB) in normothermic patients without significant pulmonary disease. Fifteen consecutive adult cardiac surgical patients were prospectively studied during and shortly after weaning from CPB. Before separation from CPB, Petco2 and PAQt were measured, the latter by transesophageal Doppler echocardiography. At the time of measurements patients were normothermic, and ventilated at 6 breaths/min with tidal volumes of 10 mL/kg. After separation from CPB, thermodilution cardiac output (TDCO) was measured in addition to PAQt and Petco2. Regression and bias analyses were used to compare Petco2, PAQt, and TDCO. Seventy measurements were recorded; 31 before separation from CPB and 39 after separation from CPB. A good correlation was seen between PAQt and Petco2 (r = 0.88) and between TDCO and PAQt (r = 0.93; mean bias 0.03 L/min; sd 0.52 L/min). The regression analysis of PAQt on Petco2 showed greater variability at Petco2 levels > 34 mm Hg (n = 22; r = 0.14). Increases in Petco2 plateaued at this level, although PAQt continued to increase. When Petco2 was more than 30 mm Hg, all PAQt and TDCO values were >4.0 L/min (>2.0 L/min/m2). When Petco2 exceeded 34 mm Hg, all values of PAQt, and 28/29 values of TDCO were more than 5 L/min (>2.5 L/min/m2). One patient had TDCO of 4.69 L/min (2.39 L/min/m2). In normothermic patients without significant pulmonary disease, Petco2 is a useful index of PAQt during separation from CPB. Under the clinical settings in this study, a Petco2 greater than 30 mm Hg was invariably associated with a CO more than 4.0 L/min or a cardiac index >2.0 L/min/m2. Implications In normothermic patients without pulmonary disease, acute changes in Petco2 during separation from cardiopulmonary bypass were reflective of changes in pulmonary artery blood flow. Specific Petco2 values were predictive of cardiac output values under the clinical conditions of the study.

Inotropes Improve Right Heart Function in Patients Undergoing Aortic Valve Replacement for Aortic Stenosis

The administration of inotropes after aortic valve replacement (AVR) for aortic stenosis (AS) is controversial. Issues include the risk of left ventricular (LV) systolic outflow obstruction (LVOTO) and the proper treatment of diastolic dysfunction for patients in whom LV systolic function is often preserved and subsequently improved. In this study, we assessed the hemodynamic benefits of inotropes for patients undergoing AVR for AS. Thirty-four patients were prospectively randomized to one of three groups: epinephrine, milrinone, or placebo. Hemodynamic and echocardiographic data were obtained before and immediately after cardiopulmonary bypass (CPB). Data were also obtained before and after increases in ventricular preload to assess the effects of inotropes on diastolic function. The use of inotropes was associated with significantly larger increases in right ventricular (RV) (placebo, 0.5%; epinephrine, +9%; milrinone, +8%; P < 0.01) and LV (placebo, +7%; epinephrine, +18%; milrinone, +20%; P = 0.07) ejection fractions (EF) and cardiac output after CPB. Changes in cardiac output and index were more strongly correlated with changes in RVEF (r = 0.56, P < 0.01; r = 0.47, P < 0.01, respectively) than with LVEF (r = 0.22, r = 0.08). Of all patients receiving epinephrine or milrinone, only one (1 of 22) had a decrease in RVEF, whereas 6 of 12 patients receiving placebo had a reduction in RVEF from pre-CPB to post-CPB. Correspondingly, for LVEF, 1 of 22 patients receiving inotropes had a decrease in LVEF, whereas 3 of 12 placebo patients had a reduction in LVEF from pre-CPB to post-CPB. No patient had evidence of LVOTO. Inotropes improved hemodynamics after AVR for AS. This was attributable more to improved RV function than to changes in LV function. Although there were no changes in diastolic function, it is possible that this study did not allow significant timing to observe benefits of inotropes on diastolic function in this setting.

Perioperative paraplegia and multiorgan failure from heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia and thrombosis syndrome is a rare but devastating complication. We report a patient with heparin-induced thrombocytopenia in whom heparin-induced thrombocytopenia and thrombosis syndrome developed after a cardiac operation, complicated by acute thrombosis of the aorta followed by renal failure, paralysis, and ischemic necrosis of the lower extremities. The literature suggests aspirin, dipyridamole, and iloprost as effective prophylactic agents for perioperative heparin-induced thrombocytopenia and thrombosis syndrome. This unfortunate complication underscores the importance of close platelet count monitoring in all preoperative patients undergoing prolonged heparin therapy.

Aortic valve replacement (AVR) : influence of age on operative morbidity and mortality

Retrospective analysis of 306 patients following aortic valve replacement (AVR) was carried out between 1985-89. Patients were divided into two groups: group 1 patients were less than 70 years of age and group 2 were greater than 70 years of age. The multivariant analysis of risk factors showed the only increased risk for surgery was the NYHA class IV in either group. There was no overall difference in morbidity and mortality. The actuarial survival rate for group 2 patients was 95% at 1 year and 75% at 5 years. This was not different when compared for death in age- and sex-matched controls from the general population. AVR in the elderly is safe, the long-term result is good and it remains the treatment of choice unless there is an absolute contraindication.

Bioengineered human and allogeneic pulmonary valve conduits chronically implanted orthotopically in baboons: Hemodynamic performance and immunologic consequences

OBJECTIVE This study assesses in a baboon model the hemodynamics and human leukocyte antigen immunogenicity of chronically implanted bioengineered (decellularized with collagen conditioning treatments) human and baboon heart valve scaffolds. METHODS Fourteen baboons underwent pulmonary valve replacement, 8 with decellularized and conditioned (bioengineered) pulmonary valves derived from allogeneic (N = 3) or xenogeneic (human) (N = 5) hearts; for comparison, 6 baboons received clinically relevant reference cryopreserved or porcine valved conduits. Panel-reactive serum antibodies (human leukocyte antigen class I and II), complement fixing antibodies (C1q binding), and C-reactive protein titers were measured serially until elective sacrifice at 10 or 26 weeks. Serial transesophageal echocardiograms measured valve function and geometry. Differences were analyzed with Kruskal-Wallis and Wilcoxon rank-sum tests. RESULTS All animals survived and thrived, exhibiting excellent immediate implanted valve function by transesophageal echocardiograms. Over time, reference valves developed a smaller effective orifice area index (median, 0.84 cm(2)/m(2); range, 1.22 cm(2)/m(2)), whereas all bioengineered valves remained normal (effective orifice area index median, 2.45 cm(2)/m(2); range, 1.35 cm(2)/m(2); P = .005). None of the bioengineered valves developed elevated peak transvalvular gradients: 5.5 (6.0) mm Hg versus 12.5 (23.0) mm Hg (P = .003). Cryopreserved valves provoked the most intense antibody responses. Two of 5 human bioengineered and 2 of 3 baboon bioengineered valves did not provoke any class I antibodies. Bioengineered human (but not baboon) scaffolds provoked class II antibodies. C1q(+) antibodies developed in 4 recipients. CONCLUSIONS Valve dysfunction correlated with markers for more intense inflammatory provocation. The tested bioengineering methods reduced antigenicity of both human and baboon valves. Bioengineered replacement valves from both species were hemodynamically equivalent to native valves.