O. H. Frazier

Transmyocardial laser revascularization: Clinical experience with twelve-month follow-up

We are investigating a new technique for myocardial revascularization in which an 800 W carbon dioxide laser is used to drill 1 mm diameter channels into a beating heart after left thoracotomy. Clotting occludes the channels on the subepicardium, and in the long-term setting, blood from the left ventricular cavity flows through these channels to perfuse the ischemic subendocardium. To test the efficacy of this technique in a preliminary clinical trial, we used it as sole therapy for 21 consecutive patients. All patients had hibernating myocardium, reduced coronary flow reserve, or both, had distal diffuse coronary artery disease, and had angina refractory to normal therapy. Eight patients were excluded from follow-up because of death (n=5), rerevascularization (n=2), or diaphragmatic paralysis resulting in postoperative respiratory incapacity (n=1). In the remaining 13 patients available for follow-up, the mean angina class (Canadian Cardiovascular Society) was 3.7 +/- 0.4 before operation and 1.8 +/- 0.6 12 months after operation (p < 0.01). Mean resting left ventricular ejection fraction was 48% +/- 10% before operation and 50% +/- 8% at 12-month follow-up. At 12 months, resting mean subendocardial/subepicardial perfusion ratio had increased by 20% +/- 9% in septal regions treated by laser but decreased by 2% +/- 5% in untreated regions (n=11, p <.001). These results suggest that revascularization by this laser technique positively affects subregional myocardial perfusion and may result in clinical benefits for patients with reversible myocardial ischemia. Studies to date have not demonstrated significant changes in global and regional ventricular contractile function.

Myocardial Revascularization With Laser Preliminary Findings

BACKGROUND We assessed the transmyocardial laser revascularization (TMLR) as sole therapy in patients with symptomatic coronary artery disease refractory to interventional or medical treatment. METHODS AND RESULTS Thirty-one patients were evaluated with positron emission tomography (PET), dobutamine echocardiography, 201Tl single-photon emission computed tomography (201Tl-SPECT), and multigated acquisition radionuclide ventriculography (MUGA). TMLR was performed in 21 patients who had demonstrable ischemia in viable myocardium. The mean Canadian Cardiovascular Society (CCS) angina class was 3.70 +/- 0.7 (4 patients with unstable angina). Untreated septal segments were used as controls. At 3 months, (n = 15 patients), the mean CCS angina class was to 2.43 +/- 0.9 (P < .05). On dobutamine echocardiography, the mean resting wall motion score index was improved by 16% in lased segments (P < .03 vs control), and mean LVEF at peak stress increased by 19% (P = NS vs baseline). On 201Tl-SPECT, perfusion of lased and nonlased segments did not change. On PET, the mean ratio of subendocardial to subepicardial perfusion (SEn/SEp) increased 14% over baseline (P < .001 vs control). At 6 months (n = 15 patients), the mean CCS angina class was 1.7 +/- 0.8 (P < .05). The mean resting wall motion score index was up by 13% in lased segments (P < .05 vs control). Resting LVEF was unchanged. Stress LVEF increased 21% (P = NS vs baseline). Myocardial perfusion remained unchanged by 201Tl-SPECT. On PET, 36% of the lased segments were better, and 25% were worse compared with baseline. The resting SEn/SEp by PET was up 21% (P < .001 vs control). All deaths (two perioperative and three late) occurred in patients with preoperative congestive heart failure. Two patients required repeat revascularization of new coronary lesions. CONCLUSIONS These results suggest that TMLR improves anginal status, relative endocardial perfusion, and cardiac function in patients who do not have preoperative congestive heart failure.

The effect of coronary bypass on the outcome of peripheral vascular operations in 1093 patients

One of the greatest risks in peripheral vascular operations is the presence of significant coronary artery disease. To assess the proper timing and demonstrate a possible protective effect of coronary artery bypass (CAB), 1093 patients who underwent one or more peripheral vascular operations in addition to CAB from 1976 through 1984 were analyzed. During that same period, 24,441 patients underwent CAB procedures, and 8530 patients underwent major vascular operations. Carotid endarterectomy (493 patients), abdominal aneurysm resection (130 patients), renal artery bypass (12 patients), aortofemoral bypass (77 patients), femoral-popliteal-tibial bypass (190 patients), and combined vascular procedures (191 patients) were included. The patients were divided into three groups according to severity of disease, which determined timing of the procedure. Group I (255 patients) underwent simultaneous CAB and peripheral vascular operation because of unstable coronary artery disease and severe vascular disease. The early mortality rate for group I was 4% (10 patients). Seven of the 10 deaths were cardiac. In group II, 279 patients had CAB and peripheral vascular operation during the same hospital admission with the same operative mortality rate (4%, 10 patients). Six deaths were from cardiac causes, three from neurologic causes, and one from hemorrhage. In group III, 559 patients underwent CAB first, then peripheral vascular operation during a separate hospital admission. There were no cardiac-related deaths and only one neurologic-related death (operative mortality rate, 0.2%). These data demonstrate the protective effect of CAB in patients who undergo elective vascular surgery. The increased risk in patients undergoing simultaneous or same admission procedures was related to the severity of the vascular and coronary artery disease and not to the combined operations. Operative complications were not increased by performing simultaneous or same admission procedures.

Effects of perfusion mode on regional and global organ blood flow in a neonatal piglet model

BACKGROUND Organ injury (brain, kidney, and heart) has been reported in up to 30% of pediatric open heart surgery patients after conventional hypothermic non-pulsatile cardiopulmonary bypass (CPB) support with or without deep hypothermic circulatory arrest (DHCA). The effects of pulsatile (with a Food and Drug Administration approved modified roller pump) versus non-pulsatile perfusion on regional and global cerebral, renal, and myocardial blood flow were investigated during and after CPB with 60 minutes of DHCA in a neonatal piglet model. METHODS Piglets, mean weight 3 kg, were used in both pulsatile (n = 7) and non-pulsatile (n = 7) groups. After initiation of CPB, all animals were subjected to hypothermia for 25 minutes, reducing the rectal temperatures to 18 degrees C, 60 minutes of DHCA followed by 10 minutes of cold reperfusion and 40 minutes of rewarming with a pump flow of 150 mL/kg/min. During cooling and rewarming, alpha-stat acid-base management was used. Differently labeled radioactive microspheres were injected pre-CPB, on normothermic CPB, pre-DHCA, post-DHCA, and after CPB to measure the regional and global cerebral, renal, and myocardial blood flows. RESULTS Global cerebral blood flow was significantly higher in the pulsatile group compared to the non-pulsatile group at normothermic CPB (100.4 +/- 6.3 mL/100 gm/min versus 70.2 +/- 8.1 mL/100 gm/min, p < 0.05) and pre-DHCA (77.2 +/- 5.2 mL/100 gm/min versus 56.1 +/- 6.7 mL/100 gm/min, p < 0.05). Blood flow in cerebellum, basal ganglia, brain stem, and right and left cerebral hemispheres had an identical pattern with the global cerebral blood flow. Renal blood flow appeared higher in the pulsatile group compared to the non-pulsatile group during CPB, but the results were statistically significant only at post-CPB (94.8 +/- 9 mL/100 gm/min versus 22.5 +/- 22 mL/100 gm/min, p < 0.05). Pulsatile flow better maintained the myocardial blood flow compared to the non-pulsatile flow after CPB (316.6 +/- 45.5 mL/100 gm/min versus 188.2 +/- 19.5 mL/100 gm/min, p < 0.05). CONCLUSIONS Pulsatile perfusion provides superior vital organ blood flow compared to non-pulsatile perfusion in this model.

Pulsatile and nonpulsatile flows can be quantified in terms of energy equivalent pressure during cardiopulmonary bypass for direct comparisons.

The purpose of this study was to quantify and compare pulsatile and nonpulsatile pressure and flow waveforms in terms of energy equivalent pressure (EEP) during cardiopulmonary bypass in a neonatal piglet model. EEP is the ratio of the area under the hemodynamic power curve and the flow curve. Piglets, mean weight of 3 kg, were used in physiologic pulsatile pump (n = 7), pulsatile roller pump (n = 6), and nonpulsatile roller pump (n = 7) groups. Data (waveforms of the femoral artery pressure, pump flow, and preaortic cannula extracorporeal circuit pressure) were collected during normothermic cardiopulmonary bypass at 35 degrees C (15 minutes on-pump), before deep hypothermic circulatory arrest (pre-DHCA) at 18 degrees C, and after cold reperfusion and rewarming (post-DHCA) at 36 degrees C. The pump flow rate was 150 ml/kg/min in all three groups. During pulsatile perfusion, the pump rate was 150 bpm in both pulsatile groups. Although there was no difference in mean pressures in all groups, EEP and the percentage increase of pressure (from mean pressure to EEP) of mean arterial pressure and preaortic cannula extracorporeal circuit pressure were higher with pulsatile perfusion compared with nonpulsatile perfusion (p < 0.001). In particular, the physiologic pulsatile pump group produced significantly higher hemodynamic energy compared with the other groups (p < 0.001). These results suggest that pulsatile and nonpulsatile flows can be quantified in terms of EEP for direct comparisons, and pulsatile flow generates higher energy, which may be beneficial for vital organ perfusion during cardiopulmonary bypass.

Valve failure with the Ionescu-Shiley bovine pericardial bioprosthesis: Analysis of 2680 patients

Early reports on the excellent hemodynamic function and low thromboembolic rates of the Ionescu-Shiley bovine pericardial bioprosthetic valve (BPV) encouraged us to use it as our choice for valve replacement in 2680 patients from 1978 through 1983. Analysis of these patients at 5-year follow-up (mean 21.6 months) demonstrated the following important trends. Despite anticoagulation therapy in 48%, thromboembolism occurred in 88 patients for a linearized rate of 1.87% emboli per patient-year and was not time-related. The highest incidence of thromboembolism was in mitral valve replacement (MVR) (2.76% per patient-year). The actuarial freedom from reoperation resulting from valve failure at 5 years was 82% in aortic valve replacement (AVR), 87.1% in MVR, and 92.6% in AVR/MVR. The most distressing causes for reoperation were valve calcification (33 patients, 0.68% per patient-year) and leaflet disruption (11 patients, 0.23% per patient-year). Valve calcification was related to age, small valve size, and AVR position and increased with time, especially at the 4- to 5-year intervals. In patients under 30 years of age, calcification occurred in 18.7% at a mean time of 40.8 months in AVR and in 8.2% at 44 months in MVR, for an overall rate of 11.6%. Over the age of 30 years, it occurred in 14 patients (0.6%) at a mean time of 44 months. Leaflet disruption was not related to age and occurred later in AVR (50 to 58 months) than MVR (1.5 to 61 months). Events increased with time (mean range 37 to 58 months). Because of calcification and leaflet disruption, valve failure causing reoperation has increased significantly at the 4- to 5-year intervals even when valve replacement in patients under 30 years of age is excluded. If this trend continues, the valve failure rate will be exceedingly high on further follow-up. Thus we have limited the use of the BPV to a selected group of patients in whom valve longevity is less important than effective orifice size, thromboembolic rate, and freedom from anticoagulation.

Infectious complications associated with ventricular assist systems.

Infectious complications during support with a ventricular assist system (VAS) can cause severe morbidity and mortality, affecting nearly one-half of all VAS recipients. Because of the lack of a uniform definition of infection, the incidence of this complication is hard to determine accurately. It is approximately 50% for patients being supported by an implantable VAS as a bridge to heart transplantation and 28% for patients supported by an external, short-term VAS. Infections can be classified according to the involvement or noninvolvement of the implanted device and according to the severity of the infection. Severe infections involving the implanted device may preclude heart transplantation for some patients, but numerous patients with milder infections have undergone successful transplantation. Numerous factors predispose VAS patients to infection. Postoperative bleeding necessitating re-operation is an important contributing factor. Endotracheal tubes, intravascular catheters, and other indwelling tubes necessary for the care of postsurgical patients are also common routes of contamination. Control of infection may be improved with new VAS designs, antibiotic impregnated drivelines, and innovative therapies such as antibiotic beads. The next generation of VASs should be inherently less susceptible to infection because of their smaller size, reduced thrombogenicity, and better flow characteristics. In addition to more effective antibiotics, improved VAS designs that incorporate transcutaneous energy transmission systems may reduce infectious complications and allow safe, long-term VAS support.

The implications for cardiac recovery of left ventricular assist device support on myocardial collagen content.

BACKGROUND To define the beneficial cellular changes that occur with chronic ventricular unloading, we determined the effect of left ventricular assist device (LVAD) placement on myocardial fibrosis. METHODS We obtained paired myocardial samples (before and after LVAD implantation) from 10 patients (aged 43 to 64 years) with end-stage cardiomyopathy. We first determined regional collagen expression of an explanted heart by a computerized semiquantitative analysis of positive picro-sirius red stained areas. RESULTS We found that there was no statistically significant difference in collagen content between regions of the failed heart studied. Next we determined collagen content in these paired myocardial biopsies pre- and post-LVAD implantation. All 10 patients had significant reductions in collagen content after LVAD placement with a mean reduction of 82% (percent of tissue area stained decreased from 32% +/- 4% to 4% +/- 0.8%, P < 0.001). CONCLUSION In summary, these data demonstrate that chronic mechanical circulatory support significantly reduces fibrosis in the failing myocardium.

The effect of prolonged left ventricular support on myocardial histopathology in patients with end-stage cardiomyopathy

To determine the histopathologic effect of prolonged (> 30 days) left ventricular unloading on the myocardium, the authors studied myocardial tissue specimens from eight men (mean age, 40.8 years) with end-stage cardiomyopathy (six idiopathic, two ischemic) who were supported with the HeartMate (Thermo Cardiosystems, Inc., Woburn, MA) left ventricular assist device (LVAD) as a bridge to cardiac transplantation. The average length of support was 79.6 days (range, 31-136 days). Before left ventricular support was instituted, transthoracic echocardiography revealed that all patients had significantly dilated left ventricular cavities (average left ventricular diastolic dimension, 7.2 cm). Tissue specimens from the core of the left ventricular apex, which is removed at the time of LVAD implantation, were compared through pathologic examination with specimens from the explanted hearts at the time of cardiac transplantation. Apical core specimens from all patients exhibited extensive areas of attenuated myocardial fibers, combined with wavy patterns in some areas. In these regions, the nuclei of the cardiac myocytes from idiopathic cardiomyopathy specimens were neither pyknotic nor disappearing, as was noted in an infarcted area of a specimen from one patient with ischemic cardiomyopathy. At the time of heart transplantation, myocardial tissue specimens from the explanted hearts had a significant decrease or disappearance of stretched fibers. There was also a slight increase in interstitial replacement fibrosis, as well as an increase in the diameter of the myocardial fibers. These findings appear to correlate with the clinical impression of improved native ventricular function and with radiographic findings and decreased chamber size during prolonged ventricular support.

Exacerbation of cyclosporine toxicity by concomitant administration of erythromycin.

Cyclosporine (CsA), an immunosuppressive drug widely used in clinical organ transplantation, causes a variety of side effects, including parenchymal complications of nephrotoxicity and hepatotoxicity. Erythromycin ethinylsuccinate (EES), a macrolide antibiotic frequently administered to transplant patients afflicted with pneumonias caused by Mycoplasma pneumoniae and Legionella pneumophila, markedly potentiated parenchymal drug toxicity in nine (three renal and six cardiac) CsA-treated allograft recipients. The mean and median blood urea nitrogen (BUN), creatinine, and total bilirubin increased upon initiation of EES treatment: in the renal recipients from 27, 1.7, and 0.5 mg/dl, respectively, before, to a mean and median of 81/101, 8.3/3.9, and 2.1/1.2 mg/dl during, and to 72/22, 1.9/1.7, and 0.6/0.5 mg/dl after cessation of EES treatment. The median serum radioimmunoassay (RIA)-determined CsA trough value of 147 ng/ml prior, rose to a zenith of 1125 ng/ml during, EES therapy. In the six cardiac recipients, the mean and median BUN, creatinine, and total bilirubin of 51/45, 1.5/1.3, 1.2/1.3 mg/dl, respectively, before, rose to 100/91, 3.7/3.6, and 2.3/2.1 mg/dl during, and fell to 49/44, 1.8/2.1, and 1.0/0.8 mg/dl after, cessation of EES. The mean serum CsA trough value of 185 ng/ml rose to 815 ng/ml during EES administration. Since EES and CsA are both metabolized by the hepatic cytochrome P450 mixed-function oxidase system, simultaneous use of these two drugs may decrease CsA metabolism, with consequent elevation of blood levels and induction of CsA toxicity. Therefore, blood level monitoring and careful regulation of CsA dose are necessary, in order to achieve the safe use of EES in transplant recipients.