John R. Liddicoat

Midline one-stage complete unifocalization and repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals ☆ ☆☆ ★ ★★ ♢ ♢♢

Traditionally patients with pulmonary atresia, ventricular septal defect, diminutive or absent central pulmonary arteries, and multiple aortopulmonary collaterals have been managed by staged procedures necessitating multiple operations. We have taken a different approach to this lesion. Between August 1992 and March 1994, ten patients aged 1.43 months to 37.34 years (median 2.08 years) at the severe end of the morphologic spectrum of this lesion underwent a one-stage complete unifocalization and repair from a midline sternotomy approach. The median Nakata index of true pulmonary arteries was 50.0 (range 0 to 103.13) and they provided vascular supply to up to nine lung segments (median 5 segments). The number of collaterals per patient ranged from two to five with a median of four. The collaterals provided vascular supply to a median of 15 lung segments per patient (range 11 to 20). Complete unifocalization was achieved in all patients with emphasis on native tissue-to-tissue connections via anastomosis of collaterals to other collaterals and to the native pulmonary arteries. In only one patient (37.34 years old) was it necessary to use a non-native conduit for peripheral pulmonary artery reconstruction. The ventricular septal defect was left open in one patient (5 years old) because of diffuse distal hypoplasia and stenosis of the pulmonary arteries and the collaterals. The postrepair peak systolic right ventricular/left ventricular pressure ratio ranged from 0.31 to 0.58 (median 0.47). There were no early deaths. Complications were bleeding necessitating reexploration in one patient, phrenic nerve palsy in three patients, and severe bronchospasm in three patients. Follow-up (median 8 months, range 2 to 19 months) was complete in all patients. One patient was reoperated on for pseudoaneurysm of the central homograft conduit and then again for stenosis of the left lower lobe collateral. After this last operation at 13 months after the initial repair she died of a preventable cardiac arrest caused by pneumothorax. The patient with open ventricular septal defect underwent balloon dilation of the unifocalized pulmonary arteries, with a current pulmonary/systemic flow ratio of 1.4 to 1.8:1, and is awaiting ventricular septal defect closure. One other patient underwent balloon dilation of the reconstructed right pulmonary artery, with a good result. All survivors (9/10) are clinically doing well. This approach establishes normal cardiovascular physiology early in life, eliminates the need for multiple systemic-pulmonary artery shunts and use of prosthetic material, and minimizes the number of operations required.(ABSTRACT TRUNCATED AT 400 WORDS)

Percutaneous mitral valve repair: A feasibility study in an ovine model of acute ischemic mitral regurgitation

Annuloplasty is the cornerstone of surgical mitral valve repair. A percutaneous transvenous catheter‐based approach for mitral valve repair was tested by placing a novel annuloplasty device in the coronary sinus of sheep with acute ischemic mitral regurgitation. Mitral regurgitation was reduced from 3–4+ to 0–1+ in all animals (P < 0.03). The annuloplasty functioned by reducing septal‐lateral mitral annular diameter (30 ± 2.1 mm preinsertion vs. 24 ± 1.7 mm postinsertion; P < 0.03). These preliminary experiments demonstrate that percutaneous mitral annuloplasty is feasible. Further study is necessary to demonstrate long‐term safety and efficacy of this novel approach. Catheter Cardiovasc Interv 2003;60:410–416.© 2003 Wiley‐Liss, Inc.

Percutaneous Mitral Valve Repair for Chronic Ischemic Mitral Regurgitation A Real-Time Three-Dimensional Echocardiographic Study in an Ovine Model

Background—Although surgical annuloplasty is the standard repair for ischemic mitral regurgitation (IMR), its application is limited by high morbidity and mortality. Using 2D and real-time 3D echocardiography in an ovine model of chronic IMR, we evaluated the geometric impact and short-term efficacy of a percutaneous transvenous catheter-based approach for mitral valve (MV) repair using a novel annuloplasty device placed in the coronary sinus. Methods and Results—Six sheep developed IMR 8 weeks after induced posterior myocardial infarction. An annuloplasty device optimized to reduce anterior-posterior (A-P) mitral annular dimension and MR was placed percutaneously in the coronary sinus. Mitral annular A-P and commissure-commissure dimensions and MV tenting area (MVTa) in 3 parallel A-P planes (medial, central, and lateral) were assessed by real-time 3D echocardiography with 3D software. The annuloplasty device reduced MR jet area from 5.4±2.6 to 1.3±0.9 cm2 (P<0.01), mitral annular A-P dimension in both systole and diastole (24.3±2.5 to 19.7±2.4 mm; P<0.03; 31.0±3.9 to 24.7±2.1 mm; P<0.001), and MVTa at mid systole in all 3 planes (153±46 to 93±24 mm2, P<0.01; 140±47 to 88±23 mm2, P<0.03; and 103±23 to 87±26 mm2, P<0.03). Conclusions—Percutaneous coronary sinus–based mitral annuloplasty reduces chronic IMR by reducing mitral annular A-P diameter and MVTa. This suggests the potential clinical application of a new nonsurgical therapeutic approach in patients with IMR.

Aortic Valve Replacement With Cryopreserved Aortic Allograft: Ten-Year Experience

OBJECTIVE Cryopreserved aortic allograft can be used for aortic valve replacement in congenital, rheumatic, degenerative, and infected native valve conditions, as well as failed prosthetic valves. This study was conducted to determine the long-term results of aortic valve replacement with cryopreserved aortic allografts. METHODS Aortic valve replacement with cryopreserved aortic allografts was performed in 117 patients from July 1985 until August 1996. All patients requiring aortic valve replacement regardless of valve disease were considered for allograft replacement; the valve was preferentially used in patients under age 55 years and in the setting of bacterial endocarditis. Four operative techniques involving cryopreserved aortic allografts were used: freehand aortic valve replacement with 120-degree rotation, freehand aortic valve replacement with intact noncoronary sinus, aortic root enlargement with intact noncoronary sinus, and total aortic root replacement. Valve function was assessed by echocardiography during the operation in 78 patients (66%) and after the operation in 77 patients (65%). RESULTS One-hundred eighteen aortic valve replacements with cryopreserved aortic allografts were performed on 117 patients; mean age was 45.6 years (range 15 to 83 years) and mean follow-up was 4.6 years (range up to 11 years). Intraoperative echocardiography disclosed no significant aortic valve incompetence. There were four operative deaths (3%) and seven late deaths; freedom from valve-related mortality at 10 years was 9:3% +/- 4.55%. New York Heart Association functional status at latest follow-up was normal in 98 (94%) patients. On postoperative echocardiography, 90% had no or trivial aortic valve incompetence. Freedom from thromboembolism at 10 years was 100% and from endocarditis, 98% +/- 2.47%. Seven (6%) patients required valve explantation, four for structural deterioration. At 10 years, freedom from reoperation for allograft-related causes was 92% +/- 3.47%. CONCLUSIONS Aortic valve replacement with cryopreserved aortic allografts can be performed with low perioperative and long-term mortality. Most patients have excellent functional status, and reoperation for valve-related causes is unusual. Aortic valve replacement with cryopreserved aortic allografts demonstrates excellent freedom from thromboembolism, endocarditis, and progressive valve incompetence.

Gene expression profile after cardiopulmonary bypass and cardioplegic arrest

OBJECTIVE This study examines the cardiac and peripheral gene expression responses to cardiopulmonary bypass and cardioplegic arrest. METHODS Atrial myocardium and skeletal muscle were harvested from 16 patients who underwent coronary artery bypass grafting before and after cardiopulmonary bypass and cardioplegic arrest. Ten sample pairs were selected for patient similarity, and oligonucleotide microarray analyses of 12,625 genes were performed using matched precardiopulmonary bypass tissues as controls. Array results were validated with Northern blotting, real-time polymerase chain reaction, in situ hybridization, and immunoblotting. Statistical analyses were nonparametric. RESULTS Median durations of cardiopulmonary bypass and cardioplegic arrest were 74 and 60 minutes, respectively. Compared with precardiopulmonary bypass, postcardiopulmonary bypass myocardial tissues revealed 480 up-regulated and 626 down-regulated genes with a threshold P value of.025 or less (signal-to-noise ratio: 3.46); skeletal muscle tissues showed 560 and 348 such genes, respectively (signal-to-noise ratio: 3.04). Up-regulated genes in cardiac tissues included inflammatory and transcription activators FOS; jun B proto-oncogene; nuclear receptor subfamily 4, group A, member 3; MYC; transcription factor-8; endothelial leukocyte adhesion molecule-1; and cysteine-rich 61; apoptotic genes nuclear receptor subfamily 4, group A, member 1 and cyclin-dependent kinase inhibitor 1A; and stress genes dual-specificity phosphatase-1, dual-specificity phosphatase-5, and B-cell translocation gene 2. Up-regulated skeletal muscle genes included interleukin 6; interleukin 8; tumor necrosis factor receptor superfamily, member 11B; nuclear receptor subfamily 4, group A, member 3; transcription factor-8; interleukin 13; jun B proto-oncogene; interleukin 1B; glycoprotein Ib, platelet, alpha polypeptide; and Ras-associated protein RAB27A. Down-regulated genes included haptoglobin and numerous immunoglobulins in the heart, and factor H-related gene 2, protein phosphatase 1, regulatory subunit 3A, and growth differentiation factor-8 in skeletal muscle. CONCLUSIONS By establishing a profile of the gene-expression responses to cardiopulmonary bypass and cardioplegia, this study allows a better understanding of their effects and provides a framework for the evaluation of new cardiac surgical modalities directly at the genome level.

Mitogen-Activated Protein Kinase Inhibition and Cardioplegia-Cardiopulmonary Bypass Reduce Coronary Myogenic Tone

Background—Cardioplegia-cardiopulmonary bypass (C/CPB) is associated with coronary microcirculatory dysfunction. Regulation of the microcirculation includes myogenic tone. Mitogen-activated protein kinases (MAPK) have been implicated in coronary vasomotor function. We hypothesized that vasomotor dysfunction of the coronary microcirculation is mediated in part by alterations in extracellular signal regulated kinase 1/2 (ERK1/2) activity following C/CPB in humans. Methods and Results—Atrial myocardium was harvested from patients (n=15) before and after blood cardioplegia and short-term reperfusion under conditions of CPB. Myogenic tone of coronary arterioles was measured by videomicroscopy. Microvessel tone was determined post-C/CPB and after PD98059, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor. MAPK phosphatase-1 (MKP-1) and activated ERK1/2 were measured by Western blot. MKP-1 gene expression was determined by Northern blot. In situ hybridization and immunohistochemistry were used to localize myocardial MKP-1 and activated ERK1/2, respectively. Myogenic tone was reduced in coronary arterioles post-C/CPB (−10.5±0.9%, P <0.01 versus control/pre-C/CPB, n=5). Myogenic tone was decreased in coronary microvessels after 30 &mgr;mol/L (n=5) and 50 &mgr;mol/L (n=5) PD98059 treatment (−11.0±0.8% and −14.6±2.0%, respectively, both P <0.01 versus control/pre-C/CPB). Myocardial levels of activated ERK1/2 were reduced post-C/CPB (0.6±0.1, post/pre-C/CPB ratio, P <0.05, n=5) while MKP-1 levels increased (4.2±0.6, post/pre-C/CPB ratio, P <0.05, n=5). Myocardial MKP-1 gene expression increased post-C/CPB (3.0±0.8, post/pre-C/CPB ratio, P <0.05, n=5). MKP-1 and activated ERK1/2 localized to coronary arterioles in myocardial sections. Conculsions—Coronary myogenic tone is dependent on ERK1/2 and decreased after C/CPB. C/CPB reduces levels of activated ERK1/2, potentially by increased levels of MKP-1. The ERK1/2 signal transduction pathway in part mediates coronary microvascular dysfunction after C/CPB in humans.

Long-term fetal outcome after fetal cardiac bypass: Fetal survival to full term and organ abnormalities

BACKGROUND Earlier work suggests that fetal cardiac bypass is technically feasible but results in significant placental dysfunction. Many of the stimuli that initiate this placental dysfunction have been identified in the past several years and these involve fetal stress, extracorporeal surfaces, priming substances (maternal blood), and flow characteristics. Fetal survival with conventional methods of bypass has been far less than optimal. A novel fetal bypass circuit requiring no priming volume was designed incorporating an in-line axial flow pump (Hemopump, Johnson & Johnson Interventional Systems, Rancho Cordova, Calif.) and was demonstrated to have a marked beneficial effect on placental function. OBJECTIVE The purpose of this study was to investigate the effect of this newly developed customized fetal bypass circuit on fetal survival and developing fetal organs. METHODS AND RESULTS Nine fetuses at 122 to 126 days of gestation were subjected to fetal cardiac bypass via a transsternal approach, with a 16F single right atrial venous cannula and a 12F arterial cannula. Normothermic cardiac bypass was continued for 30 minutes at flow rates of 320 +/- 32 ml/kg. Of the nine fetuses, one fetus was stillborn 4 days after bypass and eight (89%) were delivered alive after progressing to term gestation. One lamb died of blunt trauma 1 day after birth. All other lambs (n = 7) thrived normally, and at 1 week of age they were subjected to autopsy. No gross hemorrhagic or thromboembolic lesions were detected in the organs examined including the brain. Microscopic examination of representative sections from all organs revealed mild pleural reaction in two lambs, and in two other lambs the hepatocytes showed evidence of mild increase in glycogen content, the significance of which is unknown in relation to fetal bypass. In one fetus that was aborted there was evidence of mild to moderate neuronal loss in the cerebral cortex. CONCLUSION This study demonstrates that with improvements in fetal extracorporeal circuitry and techniques very favorable fetal outcome can be achieved. Further studies are necessary to evaluate the effects of bypass on fetal brain in an appropriate animal model. Advances in extracorporeal circuitry to suit the unique fetal physiology increase the possibility of future clinical application.

Long-term survivors of fetal cardiac bypass in lambs

The initial experience with cardiac bypass in fetal lambs resulted in early fetal death from placental insufficiency. Subsequent work in our laboratory indicated that vasoactive cyclooxygenase products were released as mediators of this response. The placental dysfunction could be blocked by the administration of indomethacin, allowing longer fetal survival. This unmasked a more subacute (but fatal) problem: fetal surgical stress resulted in diminished fetal cardiac output and progressive metabolic acidosis and contributed to the placental vasoconstriction. In acute studies, when indomethacin was given and the stress response was inhibited by the use of total spinal anesthesia, the fetus maintained normal blood gas levels, cardiac output, placental blood flow, and acid-base status for several hours after bypass. We hypothesized that beyond this point, no further fetal or placental compromise would occur and that this management technique would thus allow long-term fetal survival. With the use of total spinal anesthesia and sterile technique for long-term study, 12 fetal lambs at 120 days (80%) gestation underwent exposure, line placement, and cannulation for fetal cardiac bypass. Indomethacin was given intravenously on obtaining venous access. After 20 minutes of normothermic cardiac bypass at flow rates of 250 to 300 ml/kg/min, the fetus was weaned from bypass, the cannulas and lines were removed, the uterus and abdomen were closed, and the ewe and fetus were allowed to recover. There was one maternal death (pneumonia) and one early abortion (of twins); the remaining 10 ewes progressed to term. At term, five healthy lambs that had undergone fetal cardiac bypass were delivered (including one twin), four ewes delivered a mummified study fetus and one or two healthy siblings, and one delivered a dead term fetus. With the use of techniques that inhibit fetal stress and block placental vasoconstriction, cardiac bypass can be performed in single-gestation fetal lambs with a high degree of recovery and survival (80% in this study). The cause of the elevated abortion rate associated with twin gestation is unclear.