Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium.

Both VEGF protein and VEGF DNA in combination with an adenoviral vector have been shown to enhance collateral formation in a porcine model of chronic myocardial ischemia. We sought to determine whether direct intramyocardial injection of naked DNA encoding for VEGF could similarly improve myocardial perfusion. Initially, 23 nonischemic pigs received either 200 microg of plasmid DNA encoding beta-galactosidase (pCMVbeta, n = 11) or 500 microg of phVEGF165 (n = 12) into four separate sites in the myocardium via a small anterolateral thoracotomy incision in the fourth intercostal space. Two additional groups of pigs received an intramyocardial injection of either phVEGF165 (n = 6) or pCMVbeta (n = 7) 3 to 4 weeks after implantation of an ameroid constrictor around the left circumflex coronary artery. The injections caused no change in heart rate or blood pressure, and no ventricular arrhythmias or histologic evidence of inflammation. VEGF protein was detected by Western blot in VEGF-treated animals, with the strongest bands closest to the injection site. Plasma VEGF concentration (ELISA) increased from 3+/-2 to 27+/-13 pg/ml (p = 0.035) by day 4 after treatment. No increase in VEGF protein was noted in pCMVbeta-treated animals whereas these did stain positive for beta-Gal. Resting myocardial blood flow (colored microspheres) was significantly reduced in the ischemic versus nonischemic territory in control animals (1.07+/-0.05 versus 1.32+/-0.05; p < 0.05) but not VEGF-treated pigs (1.32+/-0.24 versus 1.13+/-0.12; p = NS). Maximal vasodilatation with adenosine significantly increased flow to the ischemic region in VEGF-treated pigs (2.16+/-0.57 versus 1.32+/-0.24; p < 0.05) but not controls (1.31+/-0.05 versus 1.17+/-0.06;p = NS). Collateral filling of the occluded circumflex artery improved in five of six VEGF-treated pigs (mean change in Rentrop score, +1.5). We conclude that direct intramyocardial transfection phVEGF165 is safe and capable of producing sufficient VEGF protein to enhance collateral formation and myocardial perfusion. This approach may offer an alternative therapy for patients with intractable myocardial ischemia not amenable to PTCA or CABG.

Catheter-based myocardial gene transfer utilizing nonfluoroscopic electromechanical left ventricular mapping.

OBJECTIVES: This study investigated the feasibility and safety of percutaneous, catheter-based myocardial gene transfer. BACKGROUND: Direct myocardial gene transfer has, to date, required direct injection via an open thoracotomy. METHODS: Electroanatomical mapping was performed to establish the site of left ventricular (LV) gene transfer. A steerable, deformable 7F catheter with a 27G needle, which can be advanced 3 to 5 mm beyond its distal tip, was then directed to previously acquired map sites, the needle was advanced, and injections were made into the LV myocardium. RESULTS: In two pigs in which methylene blue dye was injected, discretely stained LV sites were observed at necropsy in each pig, corresponding to the injection sites indicated prospectively by the endocardial map. In six pigs in which the injection catheter was used to deliver plasmid using cytomegalovirus promoter/enhancer, encoding nuclear-specific LacZ gene (pCMV-nlsLacZ) (50 microg/ml) to a single LV myocardial region, peak beta-galactosidase activity after five days (relative light units [RLU], mean 135,333+/-28,239, range = 31,508 to 192,748) was documented in the target area of myocardial injection in each pig. Percutaneous gene transfer of pCMV-nlsLacZ (50 microg/ml) was also performed in two pigs with an ameroid constrictor applied to the left circumflex coronary artery, in each pig, peak beta-galactosidase activity after five days (214,851 and 23,140 RLU) was documented at the injection site. All pigs survived until sacrifice, and no complications were observed with either the mapping or the injection procedures. CONCLUSIONS: Percutaneous myocardial gene transfer can be successfully achieved in normal and ischemic myocardium without significant morbidity or mortality. These findings establish the potential for minimally invasive cardiovascular gene transfer.

Biomembrane mimicry provides improved thromboresistance for total artificial hearts.

Thromboembolic events remain a significant issue in mechanical circulatory support. The aim of this study was to evaluate the potential benefit of surface modification in total artificial hearts (TAHs) using polymeric phospholipids (biomembrane mimicry). For this purpose, pneumatic TAHs (vacuum formed pellethane housing, hard double flap hinged inflow valves, soft trileaflet polyurethane outflow valves) had their blood-exposed surfaces either modified with polymeric phospholipids or unmodified before evaluation in bovine experiments. Orthotopic implantation of the TAHs was performed with cardiopulmonary bypass (CPB) using tip-to-tip heparin surface coated perfusion equipment and very low systemic heparinization (50 IU/kg bodyweight). After weaning from CPB and stabilizing hemodynamics, circulating heparin was neutralized with protamine (1:1). All animals were totally supported for 24 hours before elective sacrifice. No heparin was added at any time during support. Mean activated coagulation time (ACT) was 167+/-24 s at baseline before heparinization for CPB, 330+/-45 s at the end of CPB, 181+/-25 s after 1 hour of support, 180+/-31 s after 6 hours, and 185+/-28 s after 18 hours. After explantation, the TAHs perfused without anticoagulation were carefully analyzed. Atrial cuff coverage with red clot was 30+/-21% for artificial surfaces modified by biomembrane mimicry versus 100+/-0% for standard control surfaces (p<0.01). The number of macroscopic deposits found on the inflow valves was 1.33+/-0.47 for surfaces modified by biomembrane mimicry versus 3.83+/-1.86 for standard control surfaces (p<0.05). Likewise, on the outflow valves the number of macroscopic deposits was 0.00+/-0.00 for surfaces modified by biomembrane mimicry versus 1.00+/-0.81 for standard control surfaces (p<0.05). We conclude that presence and distribution of red clots and other macroscopic deposits are significantly different for artificial surfaces with biomembrane mimicry versus standard control surfaces. Application of the biomembrane mimicry concept has the potential to provide improved TAHs.

Situs inversus donor heart successfully transplanted.

Orthotopic heart transplantation was successfully performed in a 62-year-old man by use of a heart harvested from a donor with situs inversus. This procedure is a reasonable alternative when no other donor is available. The technique of this operation is described here. A month later the patient was discharged in good condition and is still doing well 1 year after the transplantation.

'No touch' technique for coronary anastomoses with arterial grafts.

We describe a simple no-touch technique for facilitating coronary anastomosis using different arterial grafts. To accomplish this technique it is necessary to make a cut near the end of the graft creating a "cuff". Holding this cuff during the anastomosis steadies the graft, which simplifies the suturing technique and facilitates precise anastomosis.

Intravascular gas transfer. Membrane surface area and sweeping gas flows are of prime importance.

Single and double hollow fiber intravascular gas exchangers were evaluated in an extracorporeal veno-venous bypass circuit (right atrium to pulmonary artery) including a tubular blood chamber (mimicking caval veins with an inner diameter of 26 mm) for evaluation of the membrane surface area/host vessel diameter gas transfer relationships. Six bovine experiments (body wt: 68 +/- 4 kg) with staged ex vivo blood flows of 1, 2, 3, and 4 L/min and a device oxygen inflow of 0, 3, and 6 L/min (0 or 3 L/min/device) were performed. Total oxygen transfer at a blood flow of 1 L/min was 33 +/- 4 ml/ min for a gas flow of 3 L/min (one device) vs 60 +/- 25 ml/ min for a gas flow of 6 L/min (two devices); at a blood flow of 2 L/min, the corresponding oxygen transfer was 46 +/- 16 ml/min for a gas flow of 3 L/min vs 95 +/- 44 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding oxygen transfer was 48 +/- 24 ml/min for a gas flow of 3 L/ min vs 92 +/- 37 ml/min for a gas flow of 6 L/min (p < 0.01 for comparison of areas under the curves). Total carbon dioxide transfer at a blood flow of 1 L/min was 47 +/- 18 ml/min for a gas flow of 3 L/min vs 104 +/- 26 ml/min for a gas flow of 6 L/min; at a blood flow of 2 L/min, the corresponding carbon dioxide transfer was 59 +/- 19 ml/min for a gas flow of 3 L/ min vs 129 +/- 39 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding carbon dioxide transfer was 60 +/- 22 ml/min for a gas flow of 3 L/min vs 116 +/- 49 ml/min for a gas flow of 6 L/min (p < 0.01). For the given setup, the blood flow/gas transfer relationship is non linear, and a plateau is achieved at a blood flow of 2.5 L/min for O2 and CO2. Doubling membrane surface area and consecutively sweeping gas flows result in doubling of gas transfers at all tested blood flows. However, increased membrane surface area and blood flow produce a higher pressure drop that in turn limits the fiber density that can be used clinically.

Aortobronchial and aortoesophageal fistulae as risk factors in surgery of descending thoracic aortic aneurysms.

OBJECTIVE: Assess outcome of patients with descending thoracic aortic aneurysms complicated by aortobronchial and aortoesophageal fistulae in comparison to patients undergoing repair of aortic aneurysms without fistulae. METHODS: In a consecutive series of 145 patients (age 60 +/- 12 years) with repair of descending thoracic and thoracoabdominal aortic aneurysms, 11 patients (8%; age 63 +/- 9; NS) primarily presented for hematemesis and/or hemoptysis. In 8/11 patients (73%) an aortobronchial fistula was identified, and 3/11 patients (27%) suffered from an aortoesophageal fistula. Five of 11 patients (45%) had undergone previous aortic surgery in the same region. RESULTS: Extent of aortic segments (range 1-8) replaced was 3.1 +/- 1.4 for all versus 2.6 +/- 0.9 for fistulae (NS). Aortic cross clamp time was 38 +/- 22 min for all versus 45 +/- 15 min for fistulae (NS). Mortality at 30 days was 18/145 (12%) for all versus 16/134 (12%) without fistulae versus 2/11 (18%) with fistulae (NS). Paraparesis and or paraplegia was observed in 11/145 (8%) for all versus 10/134 (7%) without fistulae versus 1/11 (9%) for cases with fistulae (NS). Nine additional patients died after hospital discharge, seven without fistulae and two with fistulae (days 80, and 120) bringing the 1-year mortality up to 23/134 (17%) without fistulae versus 4/11 (36%) with fistulae (NS). Further analysis shows that the 1-year mortality accounts for 1/8 patients (13%) with aorto-bronchial fistulae versus to 3/3 patients (100%) with aorto-esophageal fistulae (esophageal versus bronchial fistula: P = 0.018; esophageal versus no fistula: P = 0.006). CONCLUSIONS: Outcome of patients suffering from descending thoracic aortic aneurysms complicated by aorto-bronchial fistulae can be similar to that without fistulae, whereas for cases complicated by aorto-esophageal fistulae the prognosis seems to remain poor even after successful hospital discharge.

Successful repair of primary concomitant aortobronchial and aortoesophageal fistulas.

Combined aortobronchial and aortoesophageal fistulas developed after a rupture of a thoracoabdominal aneurysm in a 73-year-old man and were successfully repaired in a one-stage procedure. This case demonstrates that operation can be successful even in this desperate situation.

Cardiac papillary fibroelastoma excision combined with reconstructive surgery.

Three cases of cardiac papillary fibroelastomas are described. Two-dimensional echocardiography detected the tumors in the mitral valve, the cordae tendinae and in the apex of the left ventricle--a unique location. The tumor excisions were combined with bypass operation, mitral valve reconstruction, repair of cordae tendinae and Maze-procedure. The three patients are doing well after surgery.

Congenital aortopulumonary window: diagnosis, surgical technique and long-term results.

OBJECTIVE: Congenital aortopulmonary window is rare, often associated with other cardiac anomalies. Surgical repair as the only treatment should be performed before pulmonary vascular changes have developed. This study presents the long-term outcome after surgical correction for this condition. MATERIALS AND METHODS: Between 1971 and 1993, 13 patients with congenital aortopulmonary window were found. 10 had type I, 2 type II and 1 had type III. Concomitant cardiac anomalies were present in 10/13. Eleven patients were operated on at a mean age of 31.2 +/- 48.3 months (range 6 days-10 years). Thoracotomy was used in 3 and sternotomy in 9 patients. In 4/11, the aorto-pulmonary window was simply ligated, 4 had a transpulmonary approach and 1 combined with a transaortic approach. The aortopulmonary window was closed directly in 2 and with a Dacron patch in 1. Cardiopulmonary bypass was used in 6 patients. Associated anomalies in 10/11 patients. RESULTS: There was one operative death (9%): a six-day old boy with interrupted aortic arch died 6 h postoperatively due to low-cardiac output. The mean follow-up period is 8.1 +/- 7.3 years (range 2-24 years). Clinical examination, transaortic echocardiography and/or cardiac catheterization were obtained in the follow-up. There was no late death. All are in New York Heart Association (NYHA) class I. One had to be reoperated on for a recurrent shunt 29 months after ligation and one had angioplasty after 23 months for residual stenosis of the reimplanted right pulmonary artery. The actuarial survival rate is 90% after 1, 5 and 10 years. CONCLUSIONS: The surgical treatment of aortopulmonary window has a low risk, even if associated with major cardiac anomalies. Prompt operative treatment achieves excellent long-term results.

Biventricular assist using a portable driver in combination with implanted devices: preliminary experience.

Left ventricular assist systems with portable drive units are increasingly used in the clinical setting. However, such systems usually are not suitable for right ventricular support, and therefore, in the case of biventricular heart failure, they must be combined with other support devices that require additional drive consoles. As a result, most of the benefits of the wearable drive units (early mobilization and outpatient care) are lost. This present study was performed to evaluate biventricular support with implanted assist devices and a portable DC/battery-powered driver (Thoratec TLC-II). Electronic control by nonvolatile RAM accessible via RS232 interface, internal backup emergency battery, and optional manual activation are additional features of this 6 kg biventricular drive unit. In 3 bovine experiments (body weight 70 +/- 5 kg) partial cardiopulmonary bypass (CPB) was established, and two ventricular assist devices were implanted into a preperitoneal pocket on each side after connection to the right atrium and the pulmonary artery and to the left atrium and aorta, respectively. After weaning the patient from CPB, activated coagulation time (ACT) was kept at greater than 180 s, and biventricular support with the portable driver was activated. After 10 min, mean device flow stabilized at 3.5 +/- 0 L/min and remained at that level throughout the ensuing 6 h (3.5 +/- 0.3 L/min; NS). The heart rate moved from 130 +/- 13 beats per minute (bpm) at the end of CPB to 116 +/- 13 bpm after 10 min of assist (p < 0.05). Right atrial pressure moved from 11 +/- 2 mm Hg at the end of CPB to 13 +/- 3 mm Hg after 10 min of assist (not significant [NS]). Mean pulmonary artery pressure was 18 +/- mm Hg at the end of CPB and 17 +/- 5 mm Hg after 10 min of assist (NS). Left atrial pressure was 10 +/- 1 mm Hg at the end of CPB and 13 +/- 3 mm Hg after 10 min of assist (NS). Mean aortic pressure was 73 +/- 11 mm Hg at the end of CPB and 77 +/- 3 mm Hg after 10 min of assist (NS). Mixed venous oxygen saturation increased from 49 +/- 9% at the end of CPB to 58 +/- 10% after 10 min of assist (p < 0.05). The portable drive unit that was tested provides adequate power to maintain significant biventricular support with implanted right and left assist devices. The configuration of batteries tested driving two ventricles provides independence for 60 min.

Cardiac surgery for Kartagener syndrome.

Two patients (one girl, one boy) with Kartagener syndrome (situs inversus, bronchiectasis, sinusitis), despite pulmonary problems and associated congenital cardiac anomalies, were operated on at the ages of 4 years and 7 years, respectively. They had had previous palliative treatment at the age of 3 months and 1.3 years, respectively. Both postoperative periods after total correction were without significant complications. Long-term follow-up was available for 9 and 19 years, respectively, with no manifestations of heart insufficiency. Both patients are physically active, and neither requires cardiac medication. Patients with Kartagener syndrome and associated congenital cardiac anomalies can successfully undergo multiple cardiac operations with good long-term outcome.

Ivemark syndrome. A case with successful surgical intervention.

A 19-day-old boy with Ivemark syndrome (splenic agenesis associated with complex cardiac malformations and visceral abnormality) underwent palliative surgery including Glenn and hemi-Fontan procedures. Five months later the child is alive and well. We believe that early palliative surgery is worthwhile in Ivemark syndrome with a single ventricle.

Kartagener's syndrome: clinical presentation and cardiosurgical aspects.

BACKGROUND: Long-term observations in patients with Kartagener's syndrome (situs inversus, bronchiectasis, and sinusitis) are rare. The role of additional cardiac malformations and their surgical repair is not well known. METHODS: Nine patients (5 female and 4 male) with Kartagener's syndrome were identified and followed. Four patients had associated cardiac anomalies; 4 underwent total surgical repair at the ages of 4 (2 patients), 7, and 34 years. RESULTS: The postoperative period was uneventful, and these 4 patients are doing well 7 months and 2, 9, and 19 years after repair. The other patients are being treated with conservative therapy and are in relatively good condition. CONCLUSIONS: This disease can be temporarily benign when treated with antibiotics and physiotherapy. Associated cardiac anomalies seem to be quite common, and such patients need careful cardiologic follow-up. Surgical intervention can be safely performed in patients suffering from Kartagener's syndrome associated with a congenital cardiac malformation and produces good long-term results. Bilateral lung transplantation seems to be the therapy of choice in patients with respiratory insufficiency but without concomitant cardiac anomalies.

Congenital coronary fistulas in children and adults: diagnosis, surgical technique and results.

Coronary artery fistula is a very rare congenital malformation with an abnormal coronary-cameral communication that may involve any chamber and any or all coronary artery branches. We present our experience with 11 consecutive patients (mean age 16.6 years, ranging from 4 to 64 years); 9 of them were treated surgically, spontaneous closure of the fistula was observed in 1 patient and 1 patient is still under observation. Nine patients were under 17 years of age at the time of operation whereas only 2 patients were older (56 and 64 years). Fistulas originated from the right coronary artery in 4 patients and drained either into the right (n = 3) or into the left system (n = 1). In 8 patients, the origin of the coronary artery from the aorta was normal and the fistulous communications developed with the right cardiac structures only. In 2 patients, both coronary arteries were involved in the pathological drainage and 2 patients were demonstrated to have multiple drainage from the left coronary artery. Additional congenital cardiac malformations were found in 2 patients: severe tricuspid valve regurgitation in 1 and ventricular septal defect in another patient. Surgical closure of the fistula was successful in all operated patients (in 1 case treatment was possible without cardiopulmonary bypass). Simple ligation of the fistula was performed in 1 patient, intracardiac closure of the fistula was combined with different reconstructive procedures in the other patients. No hospital mortality nor severe complications occurred in this small group of patients. The mean follow-up interval was 39.4 months and all patients were in NYHA functional class I, except 1 with moderate tricuspid and mitral valve regurgitation. In the presence of symptoms of congestive heart failure, significant left-to-right shunt and arrhythmias, elective closure of coronary fistula is generally accepted, whereas the indication is more controversial in asymptomatic patients. Considering the low perioperative morbidity, we recommend surgical closure of coronary fistulas with significant shunt and/or increased coronary artery diameter.

Congenital coronary fistulas in children and adults: diagnosis, surgical technique and results.

Coronary artery fistula is a very rare congenital malformation with abnormal coronary-cameral communication that may involve any chamber and any or all coronary artery branches. We present our experience with 11 consecutive patients [mean age 16.6 years, ranging from 4 to 64 years]; 9 of them were treated surgically, spontaneous closure of the fistula was observed in one patient and one patient is still under observation. Fistulas originated from the right coronary artery in 4 patients and drained either into the right [n=3] or into the left system [n=1]. In 9 patients, the fistulas originated from the left coronary system and the fistulous communication developed with the right cardiac structures only. In 2 patients both coronary arteries were involved in the pathological drainage and 2 patients were demonstrated to have multiple drainage from the left coronary artery. Additional congenital cardiac malformations were found in 2 patients. Surgical closure of the fistula was successful in all operated patients [in one case treatment was possible without cardiopulmonary bypass]. Simple ligation of the fistula was performed in 1 patient, intracardiac closure of the fistula was combined with different reconstructive procedure in the other patients. Neither hospital mortality nor severe complications occurred. Mean follow-up interval was 39.4 months and all patients except one were in NYHA I. In presence of symptoms of congestive heart failure, significant left-to-right shunt and arrhythmias, elective closure of coronary fistula is generally accepted, whereas indication is more controversial in asymptomatic patients.

[Thrombosis-resistant heparin-coated diffusion membrane oxygenators: an experimental study]. / Die Thromboseresistenz heparinbeschichteter Diffusionsmembranoxygenatoren: eine experimentelle Untersuchung.

In the present study the thromboresistance of heparin-coated diffusion membrane oxygenators (Jostra, M 30) combined with heparin-coated venous reservoirs, tubing sets and arterial filters was investigated in six bovine experiments (70 +/- 5 kg). The perfusion with reduced systemic heparin dose (100 IE/kg) body weight) was performed with activated clotting time over 180 seconds. The perfusion began with a blood flow of 31/min and was maintained during six hours. Clotting studies including blood platelet count, activated clotting time, fibrinogen (factor I), antithrombin III and fibrinopeptid A were performed before the operation and ten minutes, two hours and five and six hours after beginning of bypass. The venous and arterial saturation remained stable during the whole investigation. After ten minutes activated clotting time dropped from 619 +/- 114s to 203 +/- 15s after six hours (p < 0.05). The antithrombin III level changed significantly from 109 +/- 11% to 95 +/- 16%. Factor 1 and fibrinopeptid A changes were not significant: from 1.6 +/- 0.3 g/1 to 1.5 +/- 0.3 g/1, and 3.0 +/- 1.4 ng/mL to 3.5 +/- 1.2 ng/mL, accordingly. There were no mechanical defects and especially no plasma leakage. Slight sediments were found only in areas of stagnant blood flow. The investigated bypass circuit with reduced systemic heparinization seems therefore particularly appropriate for long-term perfusions.

Heart transplantation with bicaval anastomoses after a maze operation.

A 49-year-old man had progressive low cardiac output syndrome after mitral valve repair combined with a maze operation. A biventricular assist device was implanted and, finally, emergency orthotopic heart transplantation was performed. The multiple incisions, especially right atrial incisions, were successfully avoided by heart transplantation with bicaval anastomoses.

Embolization of biologic glue during repair of aortic dissection.

A 72-year-old patient was operated on because of an acute type A aortic dissection with the primary entry located in the aortic arch and with retrograde involvement of the ascending aorta. Complete replacement of the aortic arch and the ascending aorta was performed after the dissected aortic layers had been readapted and sealed with gelatin-resorcin-formaldehyde biologic glue. Postoperative neurologic status was judged to be normal. The patient died 3 weeks postoperatively of septic shock. Postmortem examination of the brain revealed several small lesions, and microscopy showed very small particles of polymerized glue in the afferent vessels of ischemic cerebral and meningeal regions.