Pharmacokinetics and pharmacodynamics of intravenous diltiazem in patients with atrial fibrillation or atrial flutter. Diltiazem, a calcium channel blocker, has been shown to be safe and effective in the treatment of patients in atrial fibrillation and/or atrial flutter. However, there have been no pharmacokinetic/pharmacodynamic studies of diltiazem in these patients. The pharmacokinetics and pharmacodynamics of intravenous diltiazem were determined in 32 patients with atrial fibrillation or atrial flutter (mean +/- SD age, 66 +/- 7 years; mean baseline heart rate, 131 +/- 10 beats per minute) after 20 mg or 20 mg followed by 25-mg bolus doses and a 10 and 15 mg/hr infusion for 24 hours. After the 10 and 15 mg/hr infusions of diltiazem, mean +/- SD elimination half-life was 6.8 +/- 1.8 and 6.9 +/- 1.5 hours, volume of distribution was 411 +/- 151.8 and 299 +/- 70.8 I, and systemic clearance was 42 +/- 12.4 and 31 +/- 8.3 l/hr, respectively. Percentages of the plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem to diltiazem were < 15% and < 10%, respectively. Thirty of 32 patients maintained response throughout the 24-hour infusion of diltiazem. Using a sigmoidal Emax pharmacodynamic model, a strong relation (mean +/- SD r2, 0.78 +/- 0.2) was observed between plasma diltiazem concentration and percent heart rate reduction. Mean +/- SD Emax (maximum percent reduction in heart rate from baseline) and EC50 (plasma diltiazem concentration that achieves half Emax) were 52 +/- 17% and 110 +/- 84 ng/ml, respectively. The model predicts that mean plasma diltiazem concentration of 79, 172, and 294 ng/ml are required to produce a 20%, 30%, and 40% reduction in heart rate, respectively. A relation between plasma diltiazem concentration and percent change in systolic blood pressure (SBP) or diastolic blood pressure (DBP) from baseline was not observed (mean +/- SD r2, SBP/DBP: 0.35 +/- 0.24/0.36 +/- 0.2). There were no untoward side effects observed. First, the pharmacokinetics of diltiazem in patients with atrial fibrillation or atrial flutter is nonlinear with an apparent dose-dependent decrease in systemic clearance with increasing infusion rate. Second, using a sigmoidal Emax model, there is a strong relation between plasma diltiazem concentration and percent heart rate reduction. Third, the plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem are low and are not expected to contribute significantly to the pharmacodynamics of intravenous diltiazem in these patients.


Dynamic intraventricular obstruction during dobutamine stress echocardiography. A new observation. The implications of hypotension occurring during dobutamine stress echocardiography have not been elucidated. We observed in some patients that hyperdynamic left ventricular function developed during dobutamine stress echocardiography and hypothesized that intracavitary obstruction was occurring and might account for hypotension in some patients. Fifty-seven consecutive patients undergoing dobutamine stress echocardiography underwent pulsed-wave and continuous-wave Doppler examination of the left ventricular cavity at rest and at peak dobutamine infusion. The development of an intraventricular gradient with dobutamine stress was defined as a late-peaking left ventricular Doppler velocity profile that exceeded basal velocity by at least 1 m/sec. During dobutamine stress testing, left ventricular outflow velocity or intracavitary velocity increased in all patients. Obstruction occurred in 12 patients (21%, group 1). Group 2 was the remaining 45 patients. Peak velocities in group 1 ranged from 2.0 to 5.0 m/sec (mean, 3.5 m/sec), and the mean increase from velocity at rest was 2.3 m/sec. The mean change in systolic blood pressure was significantly lower in patients in group 1 (-15 versus 4 mm Hg, p = 0.02). When the 18 patients with an ischemic response to stress testing (evidenced by new or worsening wall motion abnormalities) were excluded from analysis, systolic blood pressure response was still significantly different for the two groups (-19 versus 2 mm Hg, p = 0.03). Dynamic left ventricular obstruction is a new observation; it may develop frequently in patients undergoing dobutamine stress echocardiography. Obstruction rather than ischemia may explain a decrease in blood pressure during dobutamine stress echocardiography.


Real-time NMR beam-directed velocity mapping. V-mode NMR. Currently available noninvasive techniques for measuring blood flow velocities are constrained by limited view orientations (Doppler ultrasound) or limited time resolution (magnetic resonance imaging, MRI). We describe an MRI technique for measuring flow velocities in real time at arbitrary orientations within a cylindrical volume or "beam": V-mode nuclear magnetic resonance (NMR). The technique was implemented on a standard 1.5-T clinical NMR imager with no special hardware and was tested on phantoms and human volunteers. The beam can be fired at rates up to 60 times per second, allowing measurements on a time scale that is appropriate for ungated cardiac studies. In phantoms, steady flow velocities were measured with the beam aligned along the direction of flow, and the measured velocities correlated well with the actual velocities (r > 0.99). The radial distribution of velocities in phantoms under constant flow conditions was also determined. In humans, flow of blood in the descending aortas of normal and aortic insufficiency subjects was measured. Distinctive backflow of blood because of aortic insufficiency was readily apparent. The V-mode NMR technique is capable of acquiring clinically relevant real-time blood flow information from any desired angle of view with no attenuation at bone or air-tissue interfaces.


Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease. Diabetic subjects have a high incidence of cardiovascular accidents, with an altered circadian distribution. Abnormalities in the circadian rhythm of autonomic tone may be responsible for this altered temporal onset of cardiovascular disease. To assess circadian changes of sympathovagal balance in diabetes, we performed 24-hour power spectral analysis of RR interval fluctuations in 54 diabetic subjects (age, 44 +/- 2 years) with either normal autonomic function or mild to severe autonomic neuropathy and in 54 age-matched control subjects. The power in the low-frequency (LF, 0.03-0.15 Hz) and high-frequency (HF, 0.18-0.40 Hz) bands was considered an index of relative sympathetic and vagal activity, respectively. Diabetic subjects with autonomic abnormalities showed a reduction in LF compared with control subjects (5.95 +/- 0.12 In-msec2 versus 6.73 +/- 0.11, p < 0.001) and an even greater reduction in LF, particularly during the night and the first hours after awakening (5.11 +/- 0.18 In-msec2 versus 6.52 +/- 0.14, p < 0.001). Day-night rhythm in sympathovagal balance was reduced or absent in diabetic subjects compared with control subjects. Diabetic subjects with or without signs of autonomic neuropathy have a decreased vagal activity (and hence a relatively higher sympathetic activity) during night hours and at the same time of the day, during which a higher frequency of cardiovascular accidents has been reported. These observations may provide insight into the increased cardiac risk of diabetic patients, particularly if autonomic neuropathy is present.


Abnormal neuroendocrine responses during exercise in heart transplant recipients. Osmotic and neural factors stimulate neuroendocrine activity during exercise. In contrast to excitatory mechanisms, afferent information from cardiac mechanoreceptors inhibits integrative centers in the hypothalamus and medula oblongata, which serves to buffer neuroendocrine activity. Orthotopic cardiac transplantation results in the loss of afferent information from cardiac mechanoreceptors. Thus, transplantation possibly results in exaggerated neuroendocrine responses when patients are physically active. We measured the neuroendocrine response to moderate and strenuous exercise performed at the same relative intensity in 11 heart transplant recipients (50 +/- 14 years old) 18 +/- 12 months after transplantation and 11 control subjects matched with respect to sex, age, and body size. Plasma levels of norepinephrine, vasopressin, renin activity, atrial natriuretic peptide, angiotensin II, and aldosterone were measured at rest, during a maximal graded exercise test, and during submaximal exercise at 40% and 70% of peak power output on a cycle ergometer (W). Plasma renin activity and atrial natriuretic peptide were elevated at rest in heart transplant recipients (p < or = 0.05). Heart rate (%HRmax reserve), rating of perceived exertion, and reductions in plasma volume (% delta from rest) at the conclusion of the three exercise conditions did not differ between heart transplant recipients and control (p > or = 0.05). Relative changes in neuroendocrine hormones were similar (p > or = 0.05) in heart transplant recipients and control during exercise at 40% of peak power output. Relative changes in plasma norepinephrine, vasopressin, atrial natriuretic peptide, and plasma renin activity were greater (p < or = 0.05) in heart transplant recipients during exercise at 70% of peak power output and the graded exercise test. We interpret these data as a possible indication of ablation of cardiac mechanoreceptor afferents and unopposed neuroendocrine stimulation in heart transplant recipients. Furthermore, chronic neuroendocrine hyperactivity is likely in ambulatory heart transplant recipients. Although cyclosporine nephrotoxicity is implicated in the development of hypertension, our data suggest that chronic neuroendocrine hyperactivity, which alters renal volume regulation, also contributes to the incidence and severity of hypertension in heart transplant recipients.


Radiofrequency catheter ablation of left lateral accessory pathways via the coronary sinus. The purpose of this study was to describe a new technique for catheter ablation of left lateral accessory pathways (APs) by radiofrequency energy applied at the epicardium through the coronary sinus wall using a unipolar configuration. In an overall group of 212 patients with left lateral APs, multiple endocardial ablation attempts of the AP were unsuccessful in eight patients. The mean +/- SD cumulative duration of previous attempts was 12 +/- 9 hours, using DC shocks and/or radiofrequency energy applied both at the atrial and/or ventricular AP insertions. Epicardial AP insertion was determined by bipolar and unipolar unfiltered distal electrograms by scanning the coronary sinus with a steerable 6F or 7F catheter with a 4-mm distal electrode. The local atrial to ventricular electrogram amplitude ratio was 0.3-1.6. At the ablation site, the catheter tip was slightly deflected toward the annulus to increase both the ventricular component of electrograms and contact with the epicardium. In four patients, epicardial electrogram timings were earlier than endocardial ones. The AP was ablated in seven of the eight patients with 20-30 W applied for 10-60 seconds. No complications occurred except a marked nonspecific pain during radiofrequency energy application; however, the catheter remained adherent to the coronary sinus wall, and its withdrawal was performed during a new radiofrequency application to decrease the risk of coronary sinus rupture. After ablation, echocardiograms, coronary artery angiograms, and levophase coronary sinus angiograms showed no abnormality in all patients except two who had a probable mural thrombus in the coronary sinus. AP conduction remained abolished for 1-10 months of follow-up in seven patients. Radiofrequency catheter ablation of left lateral APs can be achieved effectively and relatively safely via the mid or distal coronary sinus when endocardial approaches are unsuccessful.


Temperature monitoring during radiofrequency catheter ablation of accessory pathways. Animal studies have suggested that the temperature of the electrode-tissue interface during radiofrequency catheter ablation accurately predicts lesion size. The purpose of the current study was to evaluate the utility of continuous temperature monitoring during radiofrequency catheter ablation in patients with Wolff-Parkinson-White syndrome. Twenty patients with manifest preexcitation were included in the study. The ablation catheter was positioned on the ventricular side of the mitral annulus for left-sided accessory pathways and on the atrial side of the tricuspid annulus for right-sided and septal accessory pathways. A thermistor imbedded in the distal electrode of the ablation catheter allowed continuous temperature monitoring during each energy application. To define the relation between power and temperature, radiofrequency current was applied several times at each site using outputs of 20, 30, 40, and 50 W. The accessory pathways were successfully ablated in each of the 20 patients. Because of marked variability in the efficiency of heating between sites, power output did not predict temperature. However, at any given site, there was a positive dose-response relation between power and temperature. Radiofrequency energy applications on the atrial side of the tricuspid annulus produced lower temperatures than did applications on the ventricular side of the mitral annulus (49 +/- 7 versus 60 +/- 16 degrees C, p = 0.0001). Transient block in the accessory pathways occurred at a mean of 50 +/- 8 degrees C, whereas permanent block was seen at a mean of 62 +/- 15 degrees C (p = 0.0001). Less than half of the applications at outputs < or = 40 W produced temperatures adequate to interrupt accessory pathway conduction. An abrupt rise in impedance caused by coagulum formation occurred only at temperatures between 95 and 100 degrees C. Temperature monitoring may facilitate radiofrequency catheter ablation of accessory pathways. By adjusting power output to ensure that adequate but not excessive temperatures have been achieved, a rise in impedance can be avoided and the total number of energy applications and procedure duration may be reduced.


Identification of patients with coronary disease at high risk for loss of employment. A prospective validation study. Work disability is common in patients with coronary artery disease and adversely affects both economic well-being and quality of life. The purpose of this study was to construct a model to predict premature departure from the work force of patients with coronary disease and to validate this model prospectively in an independent cohort of patients. We enrolled 1,252 coronary disease patients referred for diagnostic cardiac catheterization who were less than age 65, employed, and without prior coronary angioplasty or coronary bypass surgery. Medical, functional, psychological, economic, and job-related variables were measured at the time of baseline diagnostic cardiac catheterization, and all patients were followed for 1 year. Three hundred twelve patients underwent percutaneous transluminal coronary angioplasty (PTCA) within 60 days of catheterization, and 449 had coronary artery bypass graft surgery (CABG) within 60 days of catheterization. The remaining 491 patients were treated with initial medical therapy. Logistic regression was used to develop a multivariable model for predicting 1-year work status in the training sample patients (872 patients enrolled between March 1986 and February 1989). This model was then validated in the independent prospective test sample (380 patients enrolled between March 1989 and June 1990). Eight factors were independent predictors of departure from the work force: lower initial functional status (as assessed by the Duke Activity Status Index), followed by older age, black race, presence of congestive heart failure, lower education level, presence of extracardiac vascular disease, poorer psychological status, and lower job classification. Standard clinical variables provided only 20% of the total predictive information available from the model about follow-up work outcomes, whereas functional measures provided 27%, and demographic and socioeconomic measures provided 45%. In the test sample, the area under the receiver operating characteristic curve for the model predictions was 0.74, compared with 0.80 in the training sample, and model predictions agreed well with observed prevalences of return to work. After adjustment for baseline imbalances, there was no significant difference in 1-year return-to-work rates among the patients receiving initial PTCA or CABG therapy versus initial medical therapy. Patients with coronary disease who are at high risk for premature departure from the work force can be accurately identified from a combination of medical and nonmedical risk factors. The model developed in this study provides a tool to identify patients at high risk for premature loss from the work force. Such patients may benefit from special multidimensional intervention programs designed to preserve work status. Our data show that revascularization with either PTCA or CABG is not, by itself, sufficient to accomplish this goal.


Tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in women stratified by age. Activated platelets have been implicated in both acute thrombus formation and atherogenesis. Because smoking is a risk factor for cardiovascular disease in men and women and male smokers have biochemical evidence of increased platelet activation, we found it of interest to study whether smoking augments platelet activity in women as well. Data on smoking habits and a urinary sample were obtained from 125 healthy female nonsmokers and an equal number of smokers, stratified by age in five groups from 18 to 59 years old. Urinary samples were analyzed with gas chromatography/mass spectrometry for the 2,3-dinormetabolites of thromboxane A2 (Tx-M), reflecting platelet activity, and prostacyclin (PGI-M), representing platelet/vessel wall interaction. Urinary Tx-M in smokers was higher than in nonsmokers (p < 0.001), increasing with the number of cigarettes smoked per day and with age. In nonsmokers, there was no difference in Tx-M between the age groups. Urinary PGI-M in smokers was higher than that in nonsmokers (p < 0.001) and decreased with age in nonsmokers but not in smokers. There was no difference in Tx-M between previous smokers and lifelong nonsmokers. The elevated Tx-M in women who smoke cigarettes indicates an increased platelet activity that is dependent on smoking intensity. In parallel, PGI-M is augmented, suggesting that platelet/vessel wall interaction is stimulated. Quitting smoking is an effective means to restore platelet function. We propose that the observed increase in platelet activity in women who smoke cigarettes may be related to subsequent development of cardiovascular disease and that quitting smoking should be considered a high-priority medical target also in this sex.


Clinical outcomes after the arterial switch operation for transposition. Patient, support, procedural, and institutional risk factors. Congenital Heart Surgeons Society. As the probability increases that the arterial switch operation is optimal treatment for transposition, detailed information about outcomes and the circumstances in which they are suboptimal becomes important. A multi-institutional prospective study with annual detailed follow-up included 513 neonates with simple transposition or transposition and ventricular septal defect entering for diagnosis and treatment at < 15 days of age and undergoing an arterial switch repair. The 1-month and 1- and 5-year survivals were 84%, 82%, and 82%, respectively. The hazard function for death had a rapidly declining single phase that approached zero by 12 months after surgery. Among the eight patients who died > or = 3 months after the operation, four had severe ventricular dysfunction, probably related to imperfect coronary arterial transfer. Coexisting single ventricular septal defect was not a risk factor for death. Origin of the left main coronary artery or only the left anterior descending or the circumflex artery from the right posterior sinus (sinus 2) was a risk factor that was even stronger when an intramural course was present; multiplicity of ventricular septal defects was a risk factor. Longer global myocardial ischemic time and total circulatory arrest time were risk factors. Certain institutions were shown to be risk factors for death; the results in some improved with increasing experience, in some they did not, and in some they worsened. Good early and intermediate-term clinical outcomes can be obtained in neonates with simple transposition and transposition and ventricular septal defect by use of the arterial switch operation. Certain coronary artery patterns and certain institutions lessen the goodness of outcome.


Diagnosis and management of right ventricle-dependent coronary circulation in pulmonary atresia with intact ventricular septum. Coronary artery anomalies including 1) right ventricle (RV)-to-coronary artery fistulas, 2) coronary artery stenoses, and 3) coronary occlusions occur in patients with pulmonary atresia with intact ventricular septum (PA-IVS). In some, a large part of the coronary blood supply may depend on the RV. This RV-dependent coronary circulation may determine survival after right ventricular decompression (RVD): RVD may cause RV "steal" in the presence of fistulas alone and ischemia, coronary isolation, or myocardial infarction in the presence of coronary stenoses. Eighty-two patients with PA-IVS who presented between January 1979 and January 1990 were reviewed; 26 (32%) had RV-to-coronary artery fistulas. Of these 26, 23 had adequate preoperative coronary angiograms for analysis. RVD was achieved in 16. Seven of 16 had fistulas only; each survived RVD. Six of 16 had stenosis of a single coronary artery [left anterior descending coronary artery (LAD), four; right coronary artery (RCA), two]; four of six survived RVD. Three of 16 had stenoses and/or occlusion of both the RCA and LAD; all three died shortly after RVD of acute left ventricular dysfunction. 1) Potential RV steal alone does not preclude successful RVD. 2) Fistulas with stenoses to a single coronary artery may not preclude successful RVD. 3) RVD appears to be contraindicated in the presence of stenoses and/or occlusion involving both the right and left coronary systems. Nonsurvival after RVD seems to depend on the amount of the left ventricular myocardium at risk, i.e., that which is distal to coronary artery stenoses, especially when involvement of both coronary arteries limits effective collateralization. Precise definition of coronary arterial anatomy is mandatory in neonates with PA-IVS.


Dehydroepiandrosterone sulfate, incidence of myocardial infarction, and extent of atherosclerosis in men. Antiatherogenic effects of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have been suspected for more than 30 years, yet the available evidence to support or refute such effects in humans is inconclusive. The hypothesis has not been adequately tested in large-scale epidemiological studies. The present study used a cohort of men initially free of clinically detectable coronary heart disease, stroke, and cancer to compare DHEAS levels measured in sera obtained in 1968-1971 between 238 cases who had definite coronary heart disease during the subsequent 18 years and 476 age-matched controls who survived the follow-up period and remained free of clinically detectable coronary heart disease. In a separate study, the relation of DHEAS levels to extent of atherosclerosis was examined among 82 cohort men who died during the follow-up period and had protocol autopsies. Age-adjusted DHEAS levels were lower among fatal cases of coronary heart disease than among controls (94.7 versus 106.9 micrograms/dl, respectively; p < 0.05). After adjustment for eight coronary risk factors, the odds ratio for fatal coronary heart disease comparing a 100-micrograms/dl difference in DHEAS level was 0.46 (95% confidence intervals, 0.19-1.07). In contrast, age-adjusted DHEAS levels did not significantly differ between nonfatal cases of myocardial infarction and controls (107.2 versus 106.9 micrograms/dl, respectively). Furthermore, DHEAS levels were not related to extent of atherosclerosis at autopsy. These findings do not support a role of DHEAS in the development of nonfatal myocardial infarction or the progression of atherosclerosis. The association of DHEAS with fatal coronary heart disease and possibly with death from all causes merits further investigation. These findings suggest continued skepticism that DHEAS has an important role in coronary disease etiology or prevention.


Effect of chronic subcutaneous or intramural administration of heparin on femoral artery restenosis after balloon angioplasty in hypercholesterolemic rabbits. A quantitative angiographic and histopathological study. Heparin is known to have antithrombotic, anticoagulant, and antiproliferative effects. We hypothesized that chronic subcutaneous and/or direct intramural administration of heparin would reduce restenosis and inhibit plaque growth after balloon angioplasty. Focal atherosclerosis was induced bilaterally in the femoral arteries of 59 rabbits by air desiccation intimal injury and a 2% cholesterol diet. After angioplasty, the rabbits were assigned to one of four treatment groups. Control arteries (n = 21) received no additional heparin. A second group of 20 arteries was treated with a porous balloon that delivered heparin (1,500 units) directly into the arterial wall. A third group (n = 29) received subcutaneous heparin (350 units.kg-1.day-1) for 28 days, and a fourth group (n = 23) was treated with subcutaneous and intramural heparin. Quantitative angiography showed a modest reduction in restenosis (defined as the change in minimal luminal diameter from immediately after angioplasty to 28 days) with subcutaneous heparin compared with control arteries (0.32 +/- 0.18 versus 0.58 +/- 0.34 mm, p < 0.01); however, luminal diameter was not improved at 28 days compared with before angioplasty. Intramural delivery of heparin by the porous balloon catheter was confirmed by use of fluoresceinated heparin in one animal. Angiographic restenosis was not reduced in arteries treated with intramural heparin versus controls (0.61 +/- 0.54 versus 0.58 +/- 0.34 mm, p = NS). Blinded planimetric analysis of histological sections showed no differences in luminal cross-sectional area narrowing by atherosclerotic plaque, in plaque area, or in plaque/media ratio at 28 days among the four treatment groups. Chronic subcutaneous heparin after balloon angioplasty results in a modest reduction in angiographic restenosis in this model; however, the absolute luminal diameter is not improved compared with before angioplasty, and plaque area and percent luminal narrowing by plaque were not different among the four treatment groups. Heparin can be delivered into an atherosclerotic plaque by a porous balloon, but this treatment does not reduce restenosis after angioplasty in this model.


Spatial and temporal linking of epicardial activation directions during ventricular fibrillation in dogs. Evidence for underlying organization. It remains controversial as to whether electrical activation during ventricular fibrillation (VF) is organized. To detect the presence of organization in VF, the direction of epicardial activation (EA) at multiple sites was examined by using vector mapping. If VF is not a random process, EA direction at a given site should be related to adjacent sites and prior beats. Thirteen dogs with healing myocardial infarction (MI) and four dogs without MI had VF induced by programmed stimulation. Using a plaque electrode array with a 2.5-mm interelectrode distance, 91 vector loops were created for each "beat" of VF. Direction of maximum EA was determined at each site for the first 10 consecutive beats of VF and for 10 consecutive beats recorded 5 seconds after VF was established. Spatial and temporal linking of EA directions was evaluated by the ability of activation direction at a given site to be predicted by activation directions at eight adjacent sites for the index beat and at eight adjacent sites and the site of interest for the preceding beat using stepwise linear regression. The strength of the model as reflected by the correlation coefficient (r) indicated the degree of linking. We determined 1) changes in the degree of linking over time during a given episode of VF (using a paired-difference t test), 2) differences in the degree of linking between the anterior and posterolateral walls in animals with (n = 4) and without (n = 4) MI (using two-way ANOVA), and 3) the effect of repeated inductions (n = 10) on the degree of linking (using one-way ANOVA with repeated measures). During 57 episodes of VF, r for each model ranged from 0.64 to 0.88 during the transition to VF to 0.39-0.78 during established VF (p < 0.0001 for the difference). The presence of MI, the site of recording, and repeated inductions did not affect the degree of linking. For each episode, spatial linking was more prominent than temporal linking. Electrical activation during VF is organized. The degree of linking of EA directions during VF is not affected by the presence of MI, the site of recording, or repeated inductions of VF. During the first 5 seconds of VF, the degree of linking decreases.


Serotonin selectively aggravates subendocardial ischemia distal to a coronary artery stenosis during exercise. The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischemia. Because serotonin possesses both vasodilator and vasoconstrictor properties, we examined its effect in the coronary circulation distal to an arterial stenosis that resulted in myocardial hypoperfusion during exercise. Seven chronically instrumented dogs were studied during treadmill exercise in the presence of a stenosis that reduced distal left circumflex coronary artery perfusion pressure to 42 +/- 1 mm Hg. Myocardial blood flow was assessed with radioactive microspheres during exercise before and during intracoronary infusion of 0.4 and 2.0 micrograms/kg-1.min-1 serotonin. The stenosis was adjusted to maintain distal coronary pressure constant during control exercise and with the two doses of serotonin. In seven dogs, the effect of serotonin (2.0 micrograms/kg-1.min-1) was also studied during exercise with normal arterial inflow. During control exercise, the stenosis decreased mean myocardial blood flow to 45% of flow in the normally perfused region. This decrease was most pronounced in the subendocardium (endocardial/epicardial ratio 0.36 +/- 0.06 versus 1.46 +/- 0.14 in the control region; p < 0.01). With no change in pressure distal to the stenosis, serotonin decreased subendocardial flow from 0.51 +/- 0.09 ml/min-1.g-1 to 0.41 +/- 0.12 (p < 0.05) and then to 0.35 +/- 0.08 ml/min-1.g-1 (p < 0.05) and tended to increase subepicardial flow from 1.47 +/- 0.17 to 1.91 +/- 0.23 and 1.85 +/- 0.21 ml/min-1.g-1 (p = 0.08) during infusions of 0.5 and 2.0 micrograms/kg-1.min-1, respectively, with no change in total arterial inflow. In contrast, in the absence of a stenosis, serotonin (2.0 micrograms/kg-1.min-1) increased subendocardial flow from 2.43 +/- 0.25 to 3.73 +/- 0.25 ml/min-1.g-1 (p < 0.01) and subepicardial flow from 1.88 +/- 0.20 to 5.29 +/- 0.38 ml/min-1.g-1 (p < 0.01). During normal arterial inflow, serotonin dilated coronary resistance vessels and increased flow to all myocardial layers. During hypoperfusion, a vasodilator response was still present in the subepicardium, but vasoconstriction was then observed in the subendocardium. Our data suggest that serotonin constricts the intramural penetrating arteries, thereby selectively increasing resistance to subendocardial blood flow.


Vascular injury and time course of smooth muscle cell proliferation after experimental holmium laser angioplasty. In vitro experiments have shown that holmium laser energy can effectively ablate even calcified plaque in human arterial vessels. Because high-energy densities from holmium lasers can easily be transmitted through quartz fibers, this solid-state laser has been suggested as an alternative intraluminal treatment of atherosclerotic plaque. To develop an intimal plaque, 35 New Zealand White rabbits underwent electrical stimulation of their right carotid artery for 28 days. Subsequently, in 25 rabbits, holmium laser angioplasty (wavelength, 2.12 microns; pulse duration, 150 microseconds; energy density, 350 mJ/mm2) was performed. To study the morphological results, the vessels were excised after 7, 14, 28, and 42 days. Cross sections were analyzed in regard to laser-specific injury. Staining of alpha-actin was used to identify smooth muscle cells (SMCs). After bromodeoxyuridine labeling, the extent of proliferation (number of cells undergoing DNA synthesis) was determined by using a monoclonal antibody. Holmium laser ablation resulted in an initial decrease of the numbers of intimal cell layers in the early group (7 days after treatment: 5 +/- 1 cell layers with 76 +/- 39 microns; control: 13 +/- 3 cell layers with 144 +/- 44 microns). Quantification of SMCs undergoing DNA synthesis in the intima (control: 51 +/- 19 cells/mm2) showed a significant increase of labeled cells after 7 (216 +/- 74 cells/mm2, p = 0.003) and 14 days (281 +/- 139 cells/mm2, p = 0.011). Integrity of the internal elastic lamina was disrupted in all animals after intervention. Seven and 14 days after treatment, a considerable reduction of medial cell nuclei was found in 10 of 12 animals. SMC proliferation in the medial layer was increased within the first 2 weeks after laser ablation (168 +/- 113 cells/mm2; control: 8 +/- 4 cells/mm2; p = 0.023). Six weeks after holmium laser angioplasty, SMC proliferation had returned to control levels in the intima and remained increased in the medial layer. This proliferative response resulted in a significant increase of intimal thickening within 6 weeks after laser ablation (30 +/- 6 cell layers, 375 +/- 97 microns resp.; p = 0.001 each). Holmium laser treatment leads to considerable vessel wall injury and results in SMC proliferation in the intimal and medial layer with a maximum of proliferative activity within the first 2 weeks. Subsequently, this results in considerable intimal and medial hyperplasia within 6 weeks after treatment.


Percutaneous polymeric stents in porcine coronary arteries. Initial experience with polyethylene terephthalate stents. To test the feasibility of percutaneous deployment of intracoronary polymeric stents, a prototype polyethylene terephthalate (PET) stent and a catheter-based delivery system were developed. Polymeric stents were deployed in the coronary arteries of 11 Yucatan swine: six stents were placed in the left anterior descending coronary artery, four stents were placed in the circumflex artery, and one stent was placed in the right coronary artery. Stent deployment was achieved by withdrawal of an outer delivery sheath, thus allowing the PET stent to self-expand to a preformed configuration. Two animals died during surgery, one during stent placement and the other several hours after implantation due to intracoronary thrombus formation. Two animals were electively sacrificed within 24 hours of stent implant to examine the adequacy of stent deployment within the coronary vessel. The remaining seven animals survived until the termination of the study 4-6 weeks later. Light microscopic examination of the stented vessels showed an extensive neointimal proliferative response with vessel occlusion in all animals who survived initial stent placement. There were two distinct types of histological responses to the PET stent--a chronic foreign body inflammatory response around the stent tines and a neointimal proliferative response in the center of the occluded vessel lumen. The histological response seen in the central area of the vessel was morphologically similar to that seen in patients with restenosis after successful percutaneous transluminal coronary angioplasty, whereas the morphological response seen at the periphery of the stent tine was similar to that exhibited by a chronic foreign body reaction and was not typical of that seen in a restenosis lesion. A ventricular aneurysm also developed in the area of myocardium that was previously supplied by the occluded vessel. This study demonstrates that percutaneous deployment of polymeric stents in the coronary arteries is technically feasible. The use of PET polymer was associated with an intense proliferative neointimal response that resulted in complete vessel occlusion. Histological examination of the stented segments of the vessel revealed no evidence that dissection of the vessel wall had occurred at the time of initial stent deployment. Although the PET polymer was of similar quality to that used in the manufacture of balloon angioplasty catheters, a toxic chemical or contaminant effect cannot be completely excluded as the stimulus to intimal proliferation. This finding may have relevance to the selection of materials for use as intravascular devices.


Changes in pericardial pressure during the perinatal period. To determine how the tissues that surround the heart affect diastolic and systolic function during the perinatal period, we studied the pressure-diameter relation of the left ventricle in partially delivered fetal lambs. We anesthetized (1.5-2.0% halothane, balance O2) and ventilated six pregnant ewes (142-144 days of gestation) and then partially delivered each lamb by cesarean section. Each lamb was instrumented to record left ventricular anteroposterior diameters (endocardial ultrasonic transducers), pericardial pressure (liquid-containing balloon), and left ventricular pressure (transducer-tipped catheter). Left ventricular pressure-diameter relations were recorded under three conditions: initially, with a closed chest and closed pericardium (before ventilation); second, after interruption of the umbilical circulation and 1 hour of ventilation; and finally, when the lungs and the pericardium were retracted from the heart. Pericardial pressure (recorded at a common diameter, i.e., the maximal end-diastolic diameter recorded before ventilation) decreased by 48% after 1 hour of ventilation (p < 0.05). After ventilation, left ventricular anteroposterior diameters were 4-5% greater (p < 0.05) at each end-diastolic pressure compared (12.5, 15.0, 17.5, and 20 mm Hg). Thus, ventilation appeared to increase left ventricular diastolic compliance. Contractility also appeared to increase after ventilation when evaluated using ventricular stroke work as a function of end-diastolic pressure as preload. When we used a more appropriate measure of preload (i.e., transmural end-diastolic pressure), ventilation did not change left ventricular diastolic compliance or contractility. Thus, left ventricular systolic function increased because of an increase in preload. The tissues surrounding the fetal heart significantly augment pericardial pressure and limit left ventricular preload. The initiation of ventilation reduces pericardial pressure, increases left ventricular preload, and increases left ventricular systolic function. At birth, a decrease in pericardial pressure and the resulting increase in preload may help increase left ventricular output through the Frank-Starling mechanism.


Assignment of patients into the classification of cardiomyopathies. The original classifications of the cardiomyopathies based on anatomic criteria from radiographic and necropsy studies, as well as hemodynamic criteria from clinical and catheterization data, have been supplemented in recent years by information from noninvasive techniques. Echocardiography, radionuclide methods, and ambulatory ECG, in particular, have facilitated the ethical screening of family members and those less symptomatic than patients on whom the original classification was based. These powerful methods show a broad spectrum of anatomy and ventricular physiology along the natural history of and within the traditional categories of the cardiomyopathies. They also provide data on the effect of ventricular loading conditions affecting a range of diastolic filling patterns. This review has attempted to point out the areas of overlap among and/or controversy about the categories that have led us to a feeling of frustration when trying to neatly classify individual patients. The addition of filling patterns from Doppler echocardiography and nuclear angiography to the standard methods has been reviewed and hopefully will lend more perspective to the range of physiology seen in these conditions. The categories of cardiomyopathy should not be seen as excluding patients with the newly recognized variations in anatomy and ventricular filling patterns. Rather, the classification provides a framework on which to build and expand our understanding of these important conditions.


Outcome of Stanford type B acute aortic dissection. The optimal timing of surgery in patients with Stanford type B aortic dissection remains controversial. This report reviews retrospectively early and long-term outcomes of patients with Stanford type B acute aortic dissections at our institute. From April 1979 through January 1991, 75 patients were diagnosed with Stanford type B aortic dissection, and 58 of them were hospitalized within 2 weeks from onset. They were treated initially as follows: emergent surgery was performed in 13 patients for rupture or impending rupture, and the remaining 45 were treated medically. In the former group, nine patients (69%) died; in the latter, eight (18%) needed surgery because of enlargement or rupture of the aneurysm in the follow-up period, and only one of these (13%) died. Of the other 37 patients treated medically, three (8%) died within 2 weeks and seven died (19%) in the chronic phase, four of them from rupture. Among 42 discharged patients initially treated medically, rupture occurred in 11.9% (five of 42). In acute-phase cases, surgical mortality is so high that medical treatment is preferable unless there are major complications. However, even in patients who had undergone successful initial medical treatment, expansion of the aneurysm, requiring surgery, often occurred. If careful observation reveals any sign of expansion, because elective surgery can be performed at low risk, it should be considered as soon as possible before a rupture develops.


Modified Fontan procedure in patients less than 4 years of age. Initial experience with the modified Fontan procedure in patients < 4 years of age has met with variable success, with early reports showing a high mortality. More recently, improved results with the modified Fontan procedure in younger patients have been achieved. Important advantages of an early Fontan include protection of the pulmonary vascular bed and preservation of ventricular function by reduction in ventricular volume overload and chronic hypoxemia. From 1982 through May 1991, 90 patients < 4 years of age underwent a modified Fontan procedure. The average age was 29 months (range, 7-48 months), and 30 patients were < 2 years of age. Diagnoses included tricuspid atresia in 36, single ventricle in 45, pulmonary atresia intact septum in seven, and hypoplastic left heart syndrome in two patients. An adjustable ASD was placed in 21. Early mortality was 8.9% (eight of 90), which is only slightly higher than our overall Fontan early mortality of 7.4% in 242 patients. The early mortality in the 30 patients < 2 years of age was 6.7% (two of 30). In a mean follow-up of 38 months (range, 7-89 months), there have been three late deaths (3.7%), and one patient has undergone cardiac transplantation. Early Fontan should be undertaken in patients > 6 months old who present with increasing cyanosis provided good hemodynamics are present. A modified Fontan procedure can be performed safely with good clinical results in patients < 4 years old.


Late functional status of survivors of the Fontan procedure performed during the 1970s. During the 1970s (1973-1979), 41 patients with tricuspid atresia and 25 patients with double-inlet left ventricle had a Fontan procedure performed at the Mayo Clinic. In the tricuspid atresia group, there were seven hospital deaths and six late deaths, leaving 28 survivors 11-16 years after surgery. In the double-inlet left ventricle group, there were six hospital deaths and six late deaths, leaving 13 survivors 11-13 years after surgery. The present status of 38 of the 41 long-term survivors was recently (September 1990) determined. Of these 38 patients contacted, 34 felt they were in excellent or good condition, three considered themselves in fair condition, and one was in poor condition. Nineteen of the 38 (50%) were receiving no cardiovascular medications. Twenty-eight (76%) were employed full-time or were full-time students with three others working part-time. Only four patients (11%) felt physically incapable of working or attending school. Seven patients have graduated from college since their Fontan procedure with three others presently enrolled. Present occupations include architect, lawyer, industrial manager with a master's degree, policeman, truck driver, horseback riding instructor, and artist. Nine patients are married, and one woman tolerated a pregnancy without difficulty. The most troublesome late problems requiring medical therapy were atrial dysrhythmia in seven patients (18%) and protein-losing enteropathy in two patients (5%). Surgical mortality of the Fontan procedure for tricuspid atresia and double-inlet left ventricle is now less than 10%, and that, plus these late results, justify continued application of this operation in patients with these lesions.


Total extracardiac right heart bypass.

Total extracardiac right heart bypass. Total cavopulmonary connection has been proposed as a rational alternative to atriopulmonary connection for complex Fontan operations. In addition to fluid dynamic advantages proposed by de Leval, total right heart bypass may address an emerging important issue after repair of single ventricle: late atrial arrhythmias. The purpose of this study is to document the postoperative hemodynamic findings in 22 consecutive patients who received a total extracardiac right heart bypass with an inferior vena cava-to-pulmonary artery extracardiac Dacron conduit with a modified Glenn anastomosis (superior vena cava-to-pulmonary artery anastomosis). Twenty-eight patients with complex congenital heart disease underwent this surgical procedure. One patient died (early mortality, 3.5%). Mean follow-up was 13.9 months. Postoperative cardiac catheterization and echo Doppler studies were performed in 22 of the 27 survivors. In 18 of 22 patients, hemodynamic data were satisfactory; a preferential direction of caval flows to both lungs was observed. Echo Doppler assessments show that forward cavopulmonary flow appears as a predominant early diastolic event, in contrast to what occurs in atriopulmonary connections. This hemodynamic model emphasizes the possible role of the diastolic ventricular performance (as a "suction pump") in Fontan circulation. Early postoperative atrial arrhythmias were observed in two of the survivors. The technical advantages and the hemodynamic benefits of this form of right heart bypass are encouraging. Although the use of artificial material in this procedure is extensive, none of the survivors showed thromboembolic complications or peel formations with narrowing and/or obstruction. Further investigations during a longer follow-up are needed to confirm the early and intermediate results, especially the reduction of late atrial arrhythmias.


Factors associated with choreoathetosis after cardiopulmonary bypass in children with congenital heart disease. Choreoathetosis (CHO) after congenital heart surgery has been described since 1960. Risk factors and patient outcome have not been well defined. As our complexity of cases increased and management of pH on cardiopulmonary bypass (CPB) evolved, we noted the appearance of CHO among patients beginning in 1986. We reviewed the hospital course and follow-up of all 19 affected children, including eight younger patients (median age, 4.3 months) who developed a mild transient form of CHO, all of whom survived and had complete resolution of CHO; seven of these eight patients had deep hypothermic circulatory arrest (DHCA). Eleven older patients (median age, 16.8 months) developed severe persistent CHO; 11 had DHCA, 10 were cyanotic, seven had anatomic pulmonary atresia, and three others were physiologically analogous with a systemic to pulmonary artery shunt-dependent circulation. Five of six patients who had pertinent preoperative angiography had systemic to pulmonary collateral vessels arising from the head and neck arteries. Mortality in severe patients was 36% (four of 11); the seven survivors showed improvement, but only one had a normal neurological examination after 60 months of follow-up. When severe CHO patients were compared with 17 age- and diagnosis-matched patients without neurological complications, no differences were found in CPB or DHCA times, arterial blood gases, or hematocrits. Time from onset of CPB to onset of DHCA (time to shutoff) was shorter in the severe persistent CHO group than for comparison patients (22 +/- 7 versus 40 +/- 29 minutes, p = 0.053). Factors that may be associated with the development of severe persistent CHO include 1) age beyond early infancy, 2) cyanotic heart disease with systemic to pulmonary collaterals, particularly those arising from the head and neck vessels, and 3) the duration of the cooling period used in conjunction with deep hypothermic circulatory arrest. We advocate earlier reparative surgery, precise preoperative diagnosis and preoperative or intraoperative control of systemic to pulmonary artery collaterals, and further study of pH effects during CPB on development of CHO.


High-frequency jet ventilation for respiratory failure after congenital heart surgery. Extracorporeal membrane oxygenation (ECMO) is considered when respiratory failure (RF) persists despite increasing conventional mechanical ventilation (CMV). High-frequency jet ventilation (HFJV) can improve ventilation with comparable mean airway pressure (PAW) to that found on CMV. This study was undertaken to determine whether HFJV is an effective treatment and alternative to ECMO for RF after congenital heart surgery. HFJV was instituted in nine patients ranging in age from 6 days to 3.3 years with congenital heart disease meeting pulmonary criteria for ECMO. Indications for HFJV were pulmonary hypertension (six), adult-type respiratory distress syndrome (two), and pneumonitis (one). Seven patients (77%) were placed on HFJV within 24 hours of operation, and two patients required HFJV 2 weeks after operation. HFJV resulted in resolution of RF in eight of nine patients (89%). After 1 hour of HFJV, the arterial pH increased from 7.40 +/- 0.1 to 7.56 +/- 0.1 (p < 0.05) and the PaCO2 decreased from 44 +/- 15 to 29 +/- 12 mm Hg (p < 0.05). During HFJV there was no change in PaO2, although the FIO2 decreased from 0.99 +/- 0.0 to 0.73 +/- 0.2 (p < 0.05). There was no change in PAW, peak inspiratory pressures, positive end-expiratory pressures, heart rate, or mean arterial blood pressure during HFJV when compared with CMV. Mean duration of HFJV was 43 hours. Four patients were extubated and discharged from the hospital. Two patients were extubated but died from sepsis. Two patients had resolution of RF, but one died at reoperation and one from multisystem organ failure. The patient who failed HFJV therapy was placed on ECMO and died. This study suggests that HFJV improves ventilation and is an alternative to ECMO in patients with RF after surgery for congenital heart disease.


Surgical management of late right ventricular failure after Mustard or Senning repair. Information on surgical management and outcome in patients who develop symptomatic right ventricular failure after prior Mustard or Senning operations is limited. From March 1987 to March 1991, 10 patients 3.6-23.5 years old (median, 7.0 years) with transposition of the great arteries and prior Mustard (six patients) or Senning (four patients) repairs (performed at ages 2 months to 5 years; median, 6 months) underwent surgical intervention for symptomatic right ventricular failure. In five of 10 patients, anatomic correction with either an arterial switch operation (three patients) or a pulmonary artery-to-aorta anastomosis and right ventricle-to-pulmonary artery conduit (two patients) was performed. Before anatomic correction in these five patients, four of five patients had a pulmonary artery band to prepare the left ventricle. The interval between preparation and correction ranged from 8 days to 12 months (median, 2 months). One patient died after an arterial switch operation. In the remaining five patients, coexisting left ventricular dysfunction precluded anatomic correction; all five patients survived cardiac transplantation. Survival for the entire group of 10 patients is 90%, and the median postoperative hospital stay was 17 days. During follow-up (12-62 months; median, 27 months), there were no deaths. Neoaortic insufficiency after anatomic correction was common (mild in one patient, moderate in two patients, and severe in one patient who required aortic valve replacement 4 months after surgery). In the transplantation group, one patient developed lymphoma 3 months after transplantation but is currently in remission after reduction of immunosuppression. In patients who develop late right ventricular failure after Mustard or Senning repair, surgical intervention with either anatomic correction or cardiac transplantation can be done with acceptable morbidity and low mortality. Neoaortic valve insufficiency demands close follow-up after anatomic correction.


Failure of cryopreserved homograft valved conduits in the pulmonary circulation. This study evaluates our experience with the cryopreserved homograft valved conduit used for reconstruction of the pulmonary circulation in patients with congenital heart disease. Between July 1, 1985, and December 31, 1990, 219 patients had cryopreserved homograft extracardiac valved conduits placed in the pulmonary circuit. Average age at operation was 7.2 years. Of these, 132 patients had a pulmonary homograft, and 87 had an aortic homograft. Twenty-four patients (11%) died in hospital. Hospital survivors (n = 195) have been followed an average of 29.8 months (SD, +/- 18.4 months). Fourteen patients died during follow-up, almost all related to the complexity of their original cardiac malformation. Thirty-two patients (15%) have required reoperation for conduit-related problems. Actuarial freedom from conduit reoperation is 55 +/- 12% at 5 years. The most common indication for reoperation was calcific stenosis (n = 27). Other indications for reoperation were pseudoaneurysm (n = 2), conduit infection (n = 2), and pulmonary insufficiency (n = 1). Reoperation rate for patients with aortic homografts (16 of 87) compared with that for pulmonary homografts (16 of 132) was not significantly different by the actuarial method. Long-term function of cryopreserved homograft valved conduits in the pulmonary circulation is disappointing.


Surgical connections from ventricle to pulmonary artery. Comparison of four types of valved implants. Four types of valved conduits used to correct venous ventricle to pulmonary artery (V-PA) discontinuity were compared. Four hundred fifty-seven patients with congenital heart defects requiring a V-PA connection during the past 25 years were reviewed. Age at implant varied from 1 day to 64 years (mean, 9.1 years). Four types of valved prostheses were used: 1) homograft conduit (HC, n = 178), 2) valved Dacron conduit (VDC, n = 126), 3) polystan conduit (PC, n = 47), and 4) orthotopic pulmonary valve implant (PVI, n = 106). There were 83 early deaths (18.2%) and 34 late deaths (8.5%). Follow-up ranged from 1 month to 22 years (mean, 3.5 years). One hundred eight conduit replacements were performed in 93 patients (21%). The overall patient survival was 73 +/- 2.3%, 67 +/- 3.2%, and 56 +/- 6.8% at 5, 10, and 15 years, respectively. Factors predictive of patient survival were diagnosis (p < 0.001) and valve size (p < 0.001). Age at operation (p < 0.001) and type of valve (p < 0.001) were the only risk factors for valve survival. At 5 years, survival of PVI (89 +/- 5%) and VDC (89 +/- 4%) was significantly better than survival of HC (46 +/- 13%) or PC (57 +/- 9%). Patients who survived the initial construction of a V-PA conduit had a reasonable long-term survival. A PVI was the most durable prosthesis. A Dacron porcine-valved conduit had significantly better durability than either a cryopreserved homograft or a PC.


Partial biventricular repair of pulmonary atresia with intact ventricular septum. Use of an adjustable atrial septal defect. Repair of pulmonary atresia with intact ventricular septum (PA-IVS) is one of the more challenging problems in congenital heart surgery. The hypertrophied but hypoplastic right ventricle is suddenly presented with an increased volume load as the right-to-left shunt is abolished by closure of the atrial septal defect (ASD) as part of definitive repair. We have proposed that a restrictive, adjustable ASD that allows a controlled right-to-left shunt may prevent excessive venous hypertension and allow adequate left-sided filling after biventricular repair of PA-IVS. From 1982 through 1991, 39 patients presented for definitive repair of PA-IVS. Nineteen of these patients were thought to be suitable candidates for biventricular repair, and the other 20 underwent a modified Fontan procedure. An adjustable ASD was used in 12 of the 19 patients undergoing biventricular repair. Mean age was 24 months (age range, 5-66 months). Two patients had their ASD snared closed in the operating room after coming off bypass. In the other 10 patients, closure of the ASD could not be tolerated at the time of surgery as evidenced by elevation of right atrial pressures by > 15 mm Hg and decreased blood pressure when closure was attempted. Seven patients had their open ASDs closed by the snare device, and one patient had his ASD narrowed in the early postoperative period. One patient underwent delayed closure 16 months after surgery. There was one hospital death. The snare-controlled adjustable ASD allows partial biventricular repair of PA-IVS, reducing the risk of low cardiac output and severe venous hypertension in the postoperative period.


Left ventricular mechanics and myocyte function after correction of experimental chronic mitral regurgitation by combined mitral valve replacement and preservation of the native mitral valve apparatus. Contractile function improves after correction of experimental mitral regurgitation, but ejection performance becomes depressed when mitral valve replacement involves chordal transection. A role for chordal transection in producing the depressed ejection performance was suspected but uncertain. Therefore, in this study, we tested two specific hypotheses: 1) that contractile function would improve and, in conjunction with chordal preservation, would allow for preserved ejection performance and 2) that improved left ventricular contractile function after surgery would be reflected in the function of myocytes isolated from the affected left ventricles. We examined ventricular contractile function and ejection performance and isolated myocyte function after correction of experimental mitral regurgitation (chordal rupture) with mitral valve replacement that involved chordal preservation. After 3 months of chronic mitral regurgitation, the average regurgitant fraction of seven dogs was 0.77 +/- 0.04. End-diastolic volume had increased from 79 +/- 5 to 132 +/- 10 cm3 (p < 0.05). At that time, all indexes of left ventricular contractile function were depressed. Three months after mitral valve replacement with chordal preservation, end-diastolic volume fell to 100 +/- 4 cm3 (p < 0.05). At this time, all indexes of contractile function had returned to normal. End-systolic stress and ejection fraction after mitral valve replacement were similar to their baseline levels. Viscosity-velocity curves (analogous to force-velocity curves) of myocytes isolated from the affected left ventricles were similar to those of myocytes isolated from normal left ventricles. We conclude that mitral valve replacement with chordal preservation allows ventricular contractile function to return to normal. Normal global ventricular function, in turn, is associated with normal function of the individual myocytes that compose the left ventricular chamber. Further, chordal preservation allowed for loading and ejection performance to return to premorbid levels.


Aortoventriculoplasty in infants and children. When aortic valve replacement is required in infants or small children with complex left ventricular outflow tract obstruction (LVOTO) or aortic incompetence (AI), the diameter of the annulus may limit the size of the prosthesis that can be safely inserted, and aortoventriculoplasty (AVP) may be required. To assess the results of this procedure in the pediatric age group, we reviewed our results in 19 patients who underwent AVP from May 1986 to April 1991. Patient age ranged from 1 day to 18 years (mean, 5.9 years), with six patients < 2 years of age and 13 patients younger than 5 years. Operative indications included complex LVOTO after aortic valvotomy and/or subaortic resection (six), severe AI after valvotomy or aortic valve replacement (four), severe AI with bacterial endocarditis (one), truncus arteriosus with truncal insufficiency (three), failure of an apical-aortic conduit (three), and combined aortic stenosis and mitral stenosis (two). In all patients, valve insertion was performed after patch enlargement of the annulus and septum. Associated procedures included coronary artery reimplantation in five patients and mitral valve replacement in two. Mechanical valve prostheses were used in 15 patients and allografts in four. There were three hospital deaths (16%; 70% confidence limit, 9-26%), two in patients with severe pulmonary vascular disease, and no late deaths. Actuarial survival was 84 +/- 8% at 1 month and beyond (mean follow-up, 2.5 years). Complications have included complete heart block (one), residual ventricular septal defect (one), and early postoperative peripheral embolus (one). No late thromboembolic events have occurred. No patient has clinical or echocardiographic evidence of significant residual LVOTO or AI. These data indicate that AVP may be performed at low risk and that it is an effective procedure for complex LVOTO or AI in infants and small children.


Preoperative risk factors that predict hospital length of stay in coronary artery bypass patients > 60 years old. The ability to predict prolonged length of stay (LOS) is essential to control escalating hospital costs. Operative mortality is a poor predictor of LOS; morbidity as defined by hospitalization for > 14 days after coronary artery bypass graft surgery (CABG), appears to be responsible for increasing costs. The purpose of this study was to measure preoperative predictive indicators of increased LOS with an eventual plan to offer alternative cost-benefit therapeutic options. Nine hundred twenty-four consecutive patients (age, 60-86 years) undergoing CABG were retrospectively studied by means of the Cox proportional hazards model. Seventeen variables, excluding death, were analyzed and quantified as to importance, and point totals were calculated for each patient. Scores were 12 for congestive heart failure and intra-aortic balloon assist device; 10, creatinine > 2; 6, intra-aortic balloon assist device only; 5, congestive heart failure only; 3, obesity; 6, age > 75 years; 3, age 70-75 years; and 2, 65-69 years. Increasing index score directly correlated with an exponential increase in LOS. These data substantiate the hypothesis that a mathematical model can predict LOS in CABG patients and may offer rational alternative strategies in delivering cost-effective health care.


Interaction of age and preoperative risk factors in predicting operative mortality for coronary bypass surgery. Models for predicting operative mortality for coronary bypass surgery assume that preoperative risk factors affect mortality to the same extent in all patients groups. To determine whether certain preoperative risk factors disproportionately increase operative mortality in the elderly, 663 consecutive elderly patients (age 75 years or older) and 1,464 younger patients (age 65 or younger) undergoing isolated coronary bypass surgery between 1982 and 1990 were studied. Hospital mortality was significantly greater in the elderly patients than in younger patients (7.5% versus 1.8%; relative risk, 4.5). Univariate analysis identified age, prior coronary artery bypass grafting, congestive heart failure, left main disease, New York Heart Association functional class, hypertension, prior myocardial infarction (MI), and preoperative atrial fibrillation as associated with mortality. Multivariate analysis was then used to construct a model to describe the risk of operative mortality in terms of selected risk factors. However, comparison of observed mortality rates with those predicted by the model revealed problems with the model's goodness of fit. Further testing revealed that young patients without prior MI had a mortality rate lower by an order of magnitude than either younger patients with prior MI or elderly patient groups with and without MI. Two separate models were therefore constructed stratifying by the presence of prior MI. This resulted in a significant improvement in the fit of the models to the observed data. These results suggest that the impact of risk factors on the elderly may be significantly different from the effect of these risk factors on younger patients. Models for predicting outcome after bypass surgery should be tested for potential interactions between age and risk factors.


Survival analysis of octogenarian patients with coronary artery disease managed by elective coronary artery bypass surgery versus conventional medical treatment. In view of the increasing age of the U.S. population, the use of coronary artery bypass surgery in the management of the elderly patients with coronary artery disease needs to be better defined. To evaluate the effects of medical and surgical therapy on octogenarian patients with coronary artery disease in our institution, we retrospectively reviewed 177 consecutive octogenarians who underwent cardiac catheterization over a 5-year period. Sixty-five of these patients were found to have significant coronary artery disease without severe valvular disease. Elective coronary artery bypass surgery was performed in 36 patients, whereas 29 patients were continued on maximization of medical therapy and not referred to the surgical service. Left ventricular ejection fractions (LVEF) were similar for the two groups, whereas the surgical patients had slightly higher average number of diseased coronary vessels and slightly higher levels of angina. Univariate survival analysis of 20 variables, including the choice of medical versus surgical treatment and the associated conditions, was performed by Mantel-Cox testing of the paired Kaplan-Meier product limit survival curves stratified by the subgroups of each variable. The variables found to be significant were then included in a multivariate survival analysis using the Cox proportional hazards regression model. The treatment choice, LVEF, level of angina, and presence of any aortic and/or mitral valvular disease at the time of cardiac catheterization were found to be independent prognostic indicators of survival in the follow-up period of 26 +/- 16 months. The 3-year probability of survival rates for the surgical patients and medical patients were 77.4% and 55.2%, respectively (p = 0.0294). The New York Heart Association functional class of the surgical group decreased significantly from a mean preoperative level of 3.4 +/- 0.5 to a mean level of 1.2 +/- 0.6 at the follow-up interview (p < 0.01), whereas it did not significantly change for the medical group from a baseline mean level of 2.8 +/- 1.3 to a mean follow-up level of 2.5 +/- 1.0. We conclude that coronary artery bypass surgery provided improved long-term survival and functional benefit compared with conventional medical treatment in a small group of octogenarian patients in our institution.


Observational comparison of event-free survival with medical and surgical therapy in patients with coronary artery disease. 20 years of follow-up. The purpose of this study was to describe the long-term event-free survival patterns of patients with significant coronary artery disease treated medically versus patterns of those treated surgically and to evaluate the factors associated with improved event-free survival. We studied the results of 5,824 patients undergoing medical and surgical therapy for ischemic heart disease from 1969 to 1984, with follow-up to 1991. Events considered for this evaluation were nonfatal myocardial infarction or cardiovascular death. The Cox proportional hazards model was used to determine factors differentially affecting surgical event-free survival. The survival benefits previously reported for bypass surgery in this population were largely preserved when event-free survival was examined. The two factors associated with significant event-free survival benefits for surgically treated patients were more severe coronary artery disease and a more recent surgery data. Patients with more severe coronary obstruction had a greater relative improvement with surgery in event-free survival than did patients with less severe anatomic disease. Event-free survival with surgery progressively improved over the period of the study and, by 1984, was significantly better than medical therapy for most patient subgroups. Patients with poor prognosis because of risk factors such as older age, severe angina, or left ventricular dysfunction had a risk reduction with surgery proportional to their overall risk under medical therapy. Higher-risk patients with more severe disease (due to either coronary disease or other risk factors and age) should be considered for coronary revascularization because it is in these patients that coronary artery bypass graft surgery has the greatest impact in reducing future cardiovascular events.


Differences in vasomotor control between human gastroepiploic and left internal mammary artery. Internal mammary artery grafts have a greater long-term patency rate than do saphenous vein grafts. This has in part been attributed to the difference in endothelial function of arterial and venous vessels. The use of the gastroepiploic artery in coronary artery bypass grafting has become popular recently because of its similarity to internal mammary artery. In this study, we compared the endothelial responses of gastroepiploic and left internal mammary arteries to vasoactive substances. Gastroepiploic and left internal mammary arteries were obtained during surgery from patients undergoing elective coronary artery bypass surgery. Vascular rings of both graft types were studied in organ bath experiments. Relaxation responses to metacholine and sodium nitrite were similar in rings of both arteries. In contrast, bradykinin induced potent relaxations in rings of the gastroepiploic artery but not in rings of the left internal mammary artery. Furthermore, there was a inverse correlation of maximal metacholine-induced relaxations with increasing age. The resemblance of relaxations induced by metacholine and sodium nitrite in both gastroepiploic and left internal mammary arteries suggests a similar activation and behavior of the L-arginine pathway in both arteries. The difference in bradykinin-induced relaxations may reflect a prostaglandin metabolism in the gastroepiploic artery different from that in the left internal mammary artery. Furthermore, maximal metacholine-induced relaxation in rings of the left internal mammary artery shows an age dependency that was not observed in rings of the gastroepiploic artery.


Vasomotor response to ergometrine and nitrates of saphenous vein grafts, internal mammary artery grafts, and grafted coronary arteries late after bypass surgery. In vitro studies have shown that the vasomotor response of internal mammary artery to vasoactive agents differs from that of saphenous vein. To assess whether the response in vivo to methylergometrine and to nitrates differs in saphenous vein grafts, internal mammary artery grafts, and coronary arteries, 25 patients were studied more than 6 months (range, 6-96 months) after surgery. Angiograms of saphenous vein grafts (n = 11) or mammary artery grafts (n = 14) were obtained in basal conditions, after intravenous infusion of 0.4 mg methylergometrine, and after intragraft infusion of 1 mg isosorbide dinitrate. Computerized quantitative angiography was used to assess the changes in luminal diameter of the bypass graft and of the grafted coronary artery (n = 11). Methylergometrine reduced the diameter of saphenous vein grafts by 6.9 +/- 7.4%, from 3.26 +/- 0.71 to 3.05 +/- 0.76 mm (p < 0.01), and that of grafted coronary arteries by 9.3 +/- 7.2% (NS compared with saphenous vein grafts), from 2.08 +/- 0.49 to 1.89 +/- 0.49 mm (p < 0.005). The diameter of internal mammary artery grafts did not change significantly, from 3.27 +/- 0.42 to 3.25 +/- 0.44 mm (-0.3 +/- 5.1%, p < 0.02 compared with saphenous vein grafts and p < 0.002 compared with coronary arteries). After isosorbide dinitrate, the diameter of both grafted coronary arteries and mammary artery grafts increased significantly (respectively to 2.46 +/- 0.62 mm and 3.44 +/- 0.43 mm), the vasodilatation being greater (p < 0.002) in coronary arteries (+17.8 +/- 9.8% in proportion to basal diameter, p < 0.001) than in mammary grafts (+5.5 +/- 3.3%, p < 0.001). The diameter of saphenous vein grafts returned to control values (3.28 +/- 0.70 mm, NS compared with basal); the changes in luminal diameter after nitrates (+0.7 +/- 3.1%, NS) were significantly smaller than for mammary artery grafts (p < 0.01) and for grafted coronary arteries (p < 0.001). Unlike internal mammary artery grafts, saphenous vein grafts constrict in response to methylergometrine and do not dilate in response to nitrates. These differences in vasomotor response could reflect heterogeneity in the sensitivity of vascular smooth muscle to these agents or differences in the basal level of vasomotor tone.


Physiological and pharmacological responses of arterial graft flow after coronary artery bypass grafting measured with an implantable ultrasonic Doppler miniprobe. The present study was designed to investigate physiological and pharmacological responses of the arterial graft flow measured by the directly implanted ultrasonic pulsed Doppler miniprobe after coronary artery bypass grafting (CABG). Our original 5-MHz, 5-mm-diameter, Doppler mini-flow probe catheter, which has four silicone brims in front to facilitate its fixation onto the graft without direct suture, was attached onto internal thoracic artery (ITA) and gastroepiploic artery (GEA) grafts during CABG in 10 patients. Approximately 2 weeks postoperatively, when the patient's condition was quite stable without medication, changes of flow velocity in those grafts induced by catecholamine, exercise, taking meals, and coronary vasodilating drugs were measured. Dobutamine significantly increased both ITA and GEA graft flow velocity (p < 0.01), whereas dopamine had no distinct positive effect. Upon the patient taking meals, the GEA graft showed an 83% increase of the flow velocity (p < 0.05), whereas the ITA graft showed no significant change. Walking exercise for 6 minutes increased both grafts' flow velocity up to two times that of control values (p < 0.01). Oral intake of coronary vasodilating drugs showed no significant effect. After the investigation was completed, the probe was removed easily at bedside without difficulty. Using this implantable Doppler miniprobe, postoperative function in the individual coronary bypass graft under various conditions was effectively investigated.


Modeling distribution of donor hearts to maximize early candidate survival. Priority for cardiac transplantation should reflect the relative waiting list mortality and operative mortality of outpatient candidates and critical candidates. To determine how to distribute donor hearts for maximal overall survival, a Markov model of eight states was constructed from current statistics for outpatient sudden death, deterioration to critical status, operative mortality for outpatients, and operative mortality for critical candidates. Because the fraction of hearts offered to critical candidates varied, expected survival at 1 year was calculated. To determine the factors most critical in determining priority policy, current conditions were then varied over a fourfold range. Priority for critical candidates maximized overall candidate survival (with and without transplantation), increasing 1-year survival to 78% compared with 66% if hearts were offered only to outpatients. The benefit of giving priority to critical patients persisted when current group mortality rates were individually halved or doubled because these rates were still small compared with the 100% expected mortality of critical patients without transplantation. If the outpatient sudden death rate and the operative mortality for critical patients were doubled simultaneously, however, there was a slight negative impact on survival if critical candidates received priority. Regardless of changes in subgroup outcomes, the distribution of donor hearts had a relatively modest impact on survival because of the large excess of candidates. Critical candidates for transplantation should continue to receive priority even if their operative mortality increases above current levels. However, postoperative outcomes must be assessed in relation to changing pretransplantation risks. Distribution of donor hearts will be most beneficial when it is possible to identify the waiting patients at greatest risk for sudden death and deterioration without transplantation.


Effects of dynamic cardiomyoplasty on regional wall motion, ejection fraction, and geometry of left ventricle. Dynamic cardiomyoplasty may provide functional and hemodynamic improvement in patients with heart failure. The purpose of this study was to investigate the effects of cardiomyoplasty on global ejection fraction, regional wall motion, and geometry of the left ventricle. These parameters were determined in 10 patients submitted to cardiomyoplasty for treatment of refractory heart failure by left ventricular (LV) angiography. The studies were performed before and 16.5 +/- 4.8 months after cardiomyoplasty with the myostimulator turned on. They were repeated 24 +/- 1 hours with the myostimulator turned off in eight patients. LV ejection fractions were determined by the area-length method, and the centerline method was used for assessment of regional wall motion. LV geometry was studied by LV major-to-minor axis ratio and sphericity index. A LV ejection fraction improvement from 15 +/- 8% to 30.9 +/- 8.3% (p < 0.01) was demonstrated with the myostimulator turned on after cardiomyoplasty. The values with the myostimulator turned off were 23 +/- 13%, remaining higher than the values observed before surgery (p < 0.05). Regional wall motion analysis showed an improvement in all studied regions. Regarding the LV shape, the left ventricle became markedly more spheric in the diastole. Dynamic cardiomyoplasty may improve LV function in selected patients. The analysis of LV wall motion corroborated these results, and these changes were associated with modifications in the LV geometry.


Rejection after cardiac transplantation. A time-related risk factor analysis. The determinants of early and repeated episodes of acute rejection after cardiac transplantation remain elusive. To gain insight into this phenomenon, a multivariate analysis for repeated events was applied to 229 patients receiving 249 transplanted hearts between 1981 and July 1, 1991 (595 rejection episodes). The mean frequency of rejection per patient after initial cardiac transplantation was 1.2 at 3 months, 1.8 at 1 year, and 2.8 at 5 years. The pattern of rejection was characterized by an early period of higher risk (greatest during the first month) followed by a low constant risk that continued throughout the period of follow-up (maximum, 9.5 years). By multivariate analysis, risk factors were identified for the likelihood of subsequent rejection after a previous rejection episode (or time of transplantation). Triple-drug immunosuppression plus induction therapy yielded a higher risk of early subsequent rejection compared with other baseline immunotherapy protocols, but it also provided the greatest freedom (95%) from rejection-related death during the first year. Risk factors in the constant phase of hazard included younger age at transplant, female donor and/or recipient, longer donor ischemic time, greater HLA donor-recipient mismatch, and an increased number of previous rejection episodes. Immunologic and other patient-specific characteristics as well as rejection history predict the likelihood of future rejection events. The value of any antirejection protocol must be evaluated both in terms of rejection episodes and rejection-related deaths. Future analyses may identify specific high- and low-risk patient subsets for rejection, which may provide a more rational basis for altering the amount of chronic immunosuppressive therapy.


Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report. Photopheresis is a technique in which reinfusion of mononuclear cells exposed to UV-A light ex vivo after in vivo treatment with 8-methoxypsoralen initiates host-immunosuppressive responses. To determine if photopheresis safely reverses International Society for Heart and Lung Transplantation (ISHLT) rejection grades 2, 3A, and 3B without hemodynamic compromise, 16 heart transplant patients with ISHLT rejection grades 2, 3A, and 3B were randomized to photopheresis or corticosteroid therapy. The average number of mononuclear cells treated with each photopheresis procedure was 9.8 +/- 9.1 x 10(9) (mean +/- SD). Photopheresis and corticosteroids reversed eight of nine and seven of seven episodes of rejection, respectively. The median time from initiation of treatment to rejection reversal was 25 days (range, 6-67 days) in the photopheresis group and 17 days (range, 8-33 days) in the corticosteroid group. Hemodynamics were normal before either treatment and did not change after reversal of rejection. No adverse reactions occurred with photopheresis, and all patients in either treatment group are alive. These preliminary, short-term results in prospectively randomized patients indicate that photopheresis may be as effective as corticosteroids for treating ISHLT rejection grades 2, 3A, and 3B. The apparently low toxicity and potential efficacy of photopheresis warrant further analysis of its role in the prevention and treatment of heart transplant rejection.


Imaging of pulmonary artery and vein anastomoses by transesophageal echocardiography after lung transplantation. In patients after isolated lung transplantation, the postoperative course may be complicated by dysfunction of the pulmonary artery and vein anastomoses. Pulmonary artery and vein anastomoses in 11 transplanted lungs (four left, four right, and three bilateral lungs) in 10 patients were studied 1 day to 11 months after operation by transesophageal echocardiography (TEE). All 14 pulmonary vein anastomoses, all seven right (100%) and five of seven (71%) left pulmonary artery anastomoses could be visualized by TEE. Thrombosis of a left pulmonary vein anastomosis could be identified by TEE and successfully treated by thrombolysis. TEE detected a significant stenosis in one right and one left pulmonary artery anastomosis; anastomoses dysfunction were confirmed by cardiac catheterization and pulmonary angiography and successfully treated by surgical correction in both cases. Function and morphology of pulmonary artery and vein anastomoses in patients after isolated lung transplantation can reliably be assessed by TEE. In patients with suspected dysfunction of an anastomosis, TEE may be considered the diagnostic technique of choice.


Doppler examination of superior vena caval flow for the detection of acute cardiac rejection. Doppler echocardiographic studies have previously documented abnormalities of mitral flow during acute rejection similar to those seen in patients with "restrictive" physiology. As central venous flow is known to be abnormal in such patients, it was proposed that examination of superior vena caval flow with Doppler echocardiography might be useful for the detection of acute cardiac rejection. Thirty orthotopic cardiac transplant patients, 15 of whom had acute cardiac rejection diagnosed by endomyocardial biopsy, were studied within 36 hours of biopsy. Superior vena caval Doppler flow velocities as well as mitral and tricuspid flow velocities were recorded using a Hewlett-Packard Sonos 500/1000 echocardiograph system. Examinations were performed blinded to the biopsy result. Mitral and tricuspid peak early flow velocities in the nonrejector group were similar to those seen in normal subjects (mitral, 70 +/- 5 cm/sec; tricuspid midexpiratory apnea, 50 +/- 11 cm/sec). Superior vena caval flow was abnormal with 13 of 15 patients demonstrating a biphasic pattern of forward flow with dominant diastolic flow. In the 15 patients with acute cardiac rejection, both mitral and tricuspid flow velocities developed a "restrictive"-type pattern with increased peak early flow velocities (mitral, 89 +/- 24 cm/sec; tricuspid midexpiratory apnea, 63 +/- 19 cm/sec; p < or = 0.05 versus nonrejectors) and decreased mitral early flow-velocity deceleration times (rejectors, 97 +/- 26 msec; nonrejectors, 144 +/- 41 msec; p < or = 0.05). The pattern of superior vena caval flow became markedly abnormal with a virtually complete loss of forward systolic flow (rejectors, 4.4 +/- 6.6 cm/sec; nonrejectors, 26.1 +/- 8.8 cm/sec at midexpiratory apnea; p < or = 0.0001). In 10 of 15 patients, systolic forward flow was absent. If acute rejection was defined as forward systolic flow < or = 17 cm/sec, then sensitivity was 100%, specificity was 80%, and predictive accuracy was 90%. During acute cardiac rejection, forward systolic superior vena caval flow is markedly diminished compared with nonrejectors. This is accompanied by other Doppler echocardiographic features consistent with the development of "restrictive" physiology. It is postulated that the loss of forward systolic flow in the superior vena cava is due to diminished long-axis shortening of the right ventricle associated with acute cardiac rejection.


Rigid ring fixation of the mitral annulus does not impair left ventricular systolic function in the normal canine heart. Previous studies suggest that rigid fixation of the mitral annulus with an annuloplasty ring may impair left ventricular (LV) systolic performance. We used load-insensitive indexes of global and regional LV contractile mechanics to test the hypothesis that rigid fixation of the mitral annulus alters LV systolic function. Global and regional LV systolic mechanics were compared in 10 dogs during two mitral annular conditions: rigidly fixed and freely mobile. Carpentier-Edwards annuloplasty rings (20-24 mm) were inserted using a special buttressing suture technique that permitted alternate cinching of the ring down onto the annulus and subsequent removal away from the annulus. Aortic flow was measured with an electromagnetic flow probe, LV pressure by a micromanometer, and LV wall thickness and three near-orthogonal LV endocardial chamber dimensions using piezoelectric crystals during four sequential ring conditions: 1) down, 2) away, 3) down, and 4) away. The following parameters were analyzed during each ring condition to assess global LV systolic function: end-systolic chamber elastance (end-systolic pressure-volume relation), fiber elastance (end-systolic stress-volume relation), preload recruitable stroke work, and myocardial stress-strain relation. Additionally, regional LV systolic performance was assessed using the end-systolic pressure-diameter relation and a regional analog of preload recruitable stroke work. No significant differences in any of these measurements of LV systolic mechanics were observed between the two mitral annular conditions. Rigid fixation of the mitral annulus alters neither global nor regional LV systolic function in anesthetized, open-chest dogs with normal ventricles.


Clinical significance of mild rejection of the cardiac allograft. The clinical status of heart transplant patients during mild rejection (lymphocytic infiltrate without myocyte necrosis) has not been previously reported. This study examined the frequency and outcome of mild rejection associated with allograft dysfunction sufficient in magnitude to be evident on clinical exam (two or more abnormal findings) and/or two-dimensional echocardiography. The study population consisted of 59 patients, 50 men and nine women 14-61 years old (mean, 1.7 +/- 0.8 years) with a mean follow-up of 1.7 +/- 0.8 years after transplant. All were receiving cyclosporine, azathioprine, and prednisone. A total of 108 episodes of mild rejection were detected (frequency, 1.8 episodes per patient). Detailed records of clinical findings were available for 94 episodes. Thirty-five (37%) of these 94 mild rejections were associated with allograft dysfunction: hypotension, n = 4; elevated jugular venous pressure, n = 14; S3, n = 13; rales, n = 10; sinus rate > or = 110 beats per minute, n = 25; atrial fibrillation, n = 5; bradycardia < 60, n = 1; and systolic dysfunction on echo, n = 14. Treatment with high-dose steroids was clinically indicated in eight mild rejection episodes (9%) with allograft dysfunction. Of the remaining 86 untreated episodes, eight (30%) of 27 with allograft dysfunction versus six (10%) of 53 without allograft dysfunction progressed to moderate rejection on subsequent biopsy (chi 2 = 5.15, p = 0.02). Episodes with allograft dysfunction occurred earlier than those without dysfunction (15.4 +/- 2.8 weeks versus 34.4 +/- 5.5 weeks, p = 0.01) when baseline immunosuppression was higher. Our findings indicate that 1) mild rejection is frequently associated with cardiac allograft dysfunction; 2) nine percent of mild rejection episodes may be accompanied by severe allograft dysfunction or arrhythmias, requiring aggressive treatment; 3) mild rejection associated with allograft dysfunction occurs earlier than that without allograft rejection; 4) untreated, mild rejection episodes with allograft dysfunction progress to moderate rejection more frequently than those without allograft dysfunction. These episodes require increased surveillance for progression.


Ventricular volume growth after cardiac transplantation in infants and children. Intermediate-term survival after pediatric cardiac transplantation continues to improve. However, little is known about cardiac function and especially ventricular growth in young patients after cardiac transplantation. The purpose of this study was to evaluate serially the hemodynamics, left ventricular (LV) volume, and ventricular function after cardiac transplantation in infants and children. Indications for cardiac transplantation were dilated cardiomyopathy (eight patients), hypoplastic left heart syndrome (six patients), and postoperative structural congenital heart disease (three patients). The age at time of transplant ranged from 7 days to 15 years (median, 3.5 years). The mean follow-up was 30.3 months (range, 13-46 months). Serial annual cardiac catheterizations were performed 1 year (17), 2 years (15), and 3 years (seven) after transplant. Measurements included right and left heart pressures, cardiac index, and LV volume and ejection fraction (Lange). Cumulative results (expressed as mean +/- SD) were pulmonary artery pressure, 14.9 +/- 3.2 mm Hg; LV end-diastolic pressure, 7.7 +/- 2.6 mm Hg; cardiac index, 3.5 +/- 0.52 l/min.m-2; and pulmonary vascular resistance, 2.02 +/- 0.76 units/m2. LV end-diastolic volume increased as patients grew, so that left ventricular end-diastolic volume remained 90 +/- 14% of that predicted for body surface area. The ejection fraction was 99 +/- 6% of that predicted. There was no evidence of chronic rejection by endomyocardial biopsy. No accelerated coronary artery atherosclerosis was identified. Serial studies in these young patients demonstrate normal hemodynamics and LV function after cardiac transplantation. Cardiac transplantation is associated with normal LV volume growth despite immunosuppression and denervation.


The implantable defibrillator: an electronic bridge to cardiac transplantation. Sudden cardiac death (SCD) is common among patients awaiting heart transplantation. Medical management of SCD may fail due to lack of efficacy or adverse side effects. The implantable cardioverter-defibrillator (ICD) may extend patient survival until a donor heart is available. We reviewed 16 patients listed for transplantation between November 1988 and October 1991 who underwent ICD implantation for ventricular arrhythmias refractory to medical management. Mean age was 51.4 +/- 11.4 years (range, 19-66 years), mean ejection fraction was 15.4 +/- 3.0% (range, 10-21%), and underlying cardiomyopathy was ischemic (12 patients), valvular (one patient), or dilated (three patients). There was no mortality from ICD insertion. Fourteen patients were discharged before transplantation, and two patients remained in the hospital until transplantation. Twelve patients underwent transplantation after a mean of 155.7 +/- 113.7 days (range, 3-319) on the transplant list. The ICD delivered shocks for tachyarrhythmia associated with near syncope in 15 of 16 patients. ICD shocks numbered > 10 in five patients, 5-9 in three patients, and 1-4 in seven patients. There was no morbidity or mortality attributed to patch electrode removal. We conclude that the ICD can be implanted with minimal morbidity in transplant candidates, allowing the patients to be ambulatory and to leave the hospital while awaiting heart transplantation. In patients at risk of SCD, the ICD is an effective electronic bridge to transplantation.


Detrimental effects of temperature on the efficacy of the University of Wisconsin solution when used for cardioplegia at moderate hypothermia. Comparison with the St. Thomas Hospital solution at 4 degrees C and 20 degrees C. We have previously reported the superior protective properties of the University of Wisconsin (UW) solution compared with the St. Thomas solution (ST) in the rat heart subjected to the deep hypothermia (4 degrees C), thus demonstrating its possible use in cardiac transplantation. We thought it was important to evaluate the potential of the UW solution as a cardioplegic solution under the moderately hypothermic (20 degrees C) conditions of routine intraoperative myocardial protection. Isolated rat hearts were subjected to 60 minutes of ischemia at 4 degrees C or 30 (or 60) minutes of ischemia at 20 degrees C with UW, ST, and ST plus 100 mM K (ST + 100) solutions. Coronary flow, mechanical function, endothelial function, and ultrastructure were observed. Mean time (seconds) to infuse 10 ml of cardioplegic solution under constant pressure, a measure of coronary vascular resistance at 4 degrees C and 20 degrees C, respectively, for each solution were ST, 69.2 +/- 6.9 and 64.7 +/- 3.8; UW, 142.2 +/- 8.8 and 187.2 +/- 10.0 (p < 0.01); and ST + 100, 78.2 +/- 8.0 and 176 +/- 8.1 (p < 0.001). Mean recovery values of cardiac output (expressed as percentage of its preischemic value) after 60 minutes of ischemia at 4 degrees C were ST, 95.5 +/- 2.1%; UW, 93.0 +/- 2.4%; and ST + 100, 96.5 +/- 1.5%. After 30 minutes of ischemia at 20 degrees C, values were ST, 88.0 +/- 1.3%; UW, 72.2 +/- 3.6% (p < 0.005 versus ST); and ST + 100, 53.3 +/- 1.8% (p < 0.001 versus ST). The efficacies of UW and severely hyperkalemic cardioplegic solutions are affected by the degree of hypothermia under which they are used. Under moderate hypothermia (20 degrees C), severe hyperkalemia induces a marked increase in coronary vascular resistance that is associated with impaired myocardial protection. These studies discourage the use of UW for routine intraoperative cardioplegic arrest where the degree of hypothermia cannot be readily controlled. The ST solution does not share this constraint.


In vitro assessment of the effects of glucose added to the University of Wisconsin solution on myocyte preservation. University of Wisconsin solution (UWS) has been successfully used for liver transplantation and may be beneficial for hypothermic cardiac storage. The addition of glucose may enhance myocardial preservation. Cultured human ventricular myocytes (eight dishes per group) were stored at 0 degree C for 12 hours in either unmodified UWS or UWS with glucose (1, 3, 10, 30, or 100 mmol/l). Cells were assayed for protein by spectrofluorometry and adenine nucleotides by high performance liquid chromatography after storage. Protein recovery, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and total adenine nucleotides (ATP+ADP+AMP) were all depleted after storage (p < 0.0001 by ANOVA). Protein recovery (p < 0.005), ATP (p < 0.05), and ADP (p < 0.05) were increased with glucose administration compared with unmodified UWS. Improvement was maximal using 30 mmol/l (protein, 0 mmol/l = 0.48 +/- 0.14 and 30 mmol/l = 0.65 +/- 0.11 mg per dish; ATP, 0 mmol/l = 3.08 +/- 0.63 and 30 mmol/l = 4.32 +/- 0.90 nmol/mg protein; ADP, 0 mmol/l = 3.76 +/- 0.80 and 30 mmol/l = 4.63 +/- 0.38 nmol/mg protein, mean +/- SD). Total adenine nucleotides tended to increase at any glucose concentration (p = 0.07 by ANOVA) and were significantly better with 30 mmol/l glucose (0 mmol/l = 7.61 +/- 1.58 and 30 mmol/l = 9.62 +/- 1.08 nmol/mg protein). Increasing the glucose concentration from 0 to 30 mmol/l improved adenine nucleotide and cellular protein preservation in this in vitro assessment.