Edward B. Stinson

Effect of Intrathoracic Pressure on Left Ventricular Performance

Left ventricular dysfunction is common in respiratory-distress syndrome, asthma and obstructive lung disease. To understand the contribution of intrathoracic pressure to this problem, we studied the effects of Valsalva and Müller maneuvers on left ventricular function in eight patients. Implantation of intramyocardial markers permitted beat-by-beat measurement of the velocity of fiber shortening (VCF) and left ventricular volume. During the Müller maneuver, VCF and ejection fraction decreased despite an increase in left ventricular volume and a decline in arterial pressure. In addition, when arterial pressure was corrected for changes in intrapleural pressure during either maneuver it correlated better with left ventricular end-systolic volumes than did uncorrected arterial pressures. These findings suggest that negative intrathoracic pressure affects left ventricular function by increasing left ventricular transmural pressures and thus afterload. We conclude that large intrathoracic-pressure changes, such as those that occur in acute pulmonary disease, can influence cardiac performance.

Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease.

: We report our initial experience with three patients who received heart-lung transplants. The primary immunosuppressive agent used was cyclosporin A, although conventional drugs were also administered. In the first patient, a 45-year-old woman with primary pulmonary hypertension, acute rejection of the transplant was diagnosed 10 and 25 days after surgery but was treated successfully; this patient still had normal exercise tolerance 10 months late. The second patient, a 30-year-old man, underwent transplantation for Eisenmengers syndrome due to atrial and ventricular septal defects. His graft was not rejected, and his condition was markedly improved eight months after surgery. The third patient, a 29-year-old woman with transposition of the great vessels and associated defects, died four days postoperatively of renal, hepatic, and pulmonary complications. We attribute our success to experience with heart-lung transplantation in primates, to the use of cyclosporin A, and to the anatomic and physiologic advantages of combined heart-lung replacement. We hope that such transplants may ultimately provide an improved outlook for selected terminally ill patients with pulmonary vascular disease and certain other intractable cardiopulmonary disorders.

Sensitivity and Specificity of Echocardiographic Diagnosis of Pericardial Effusion

In order to evaluate the reliability and sensitivity of echocardiograms for detecting and quantitating pericardial effusion, 41 patients had echocardiograms on the day prior to cardiac operation. A fluid trap was used to aspirate the pericardium at operation. Thirty-nine of 41 patients had echocardiograms of diagnostic quality. In 25 patients, the echocardiogram was negative for pericardial effusion, with 0-16 ml identified at operation. In 13 patients, the echocardiogram was positive for pericardial effusion, with 15-775 ml aspirated at operation. A transition of patterns of relative posterior epicardial-pericardial movement was noted as the pericardial fluid volume increased. More than 15 ml was always found when a posterior echo-free space persisted throughout the cardiac cycle between a flat pericardium relative to the epicardium. In the presence of such a posterior echo-free space, a large anterior echo-free space made a moderately large pericardial effusion likely. In the absence of this diagnostic posterior echo-free space, an anterior echo-free space had no diagnostic significance, as it was found in 11 patients with less than 16 ml of pericardial effusion. A small posterior echo-free space persisting throughout the cardiac cycle between pericardial and epicardial echoes demonstrating virtually identical movements was found in two patients without any surgical evidence for pericardial effusion, but with evidence of adhesive fibrocalcific pericardial disease. A method of estimating pericardial volume is proposed, which uses the difference between the cubed diameters at the end-diastole of the pericardium and epicardium.

A Controlled Trial of Ganciclovir to Prevent Cytomegalovirus Disease after Heart Transplantation

BACKGROUND Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. METHODS This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. RESULTS Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. CONCLUSIONS The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

A Preliminary Study of Diltiazem in the Prevention of Coronary Artery Disease in Heart-Transplant Recipients

BACKGROUND Accelerated coronary artery disease is a major cause of late morbidity and mortality among heart-transplant recipients. Because calcium-channel blockers can suppress diet-induced atherosclerosis in laboratory animals, we assessed the efficacy of diltiazem in preventing coronary artery disease in transplanted hearts. METHODS Consecutive eligible cardiac-transplant recipients were randomly assigned to receive diltiazem (n = 52) or no calcium-channel blocker (n = 54). Coronary angiograms obtained early after cardiac transplantation and annually thereafter were used for the visual assessment of the extent of coronary artery disease. The average diameters of identical coronary artery segments were measured on the angiograms obtained at base line and at the first and second follow-up examinations. RESULTS In the 57 patients who had all three angiograms, the average coronary artery diameter (+/- SD) 0.27 decreased in the group that received no calcium-channel blocker from 2.41 +/- 0.27 mm at base line to 2.19 +/- 0.28 mm at one year, and to 2.22 +/- 0.26 mm at two years (P < 0.001 for both years). The average diameter in the diltiazem group changed little from the base-line value of 2.32 +/- 0.22 mm (2.32 +/- 0.27 mm at one year and 2.36 +/- 0.22 mm at two years). The average change in the diameter of the segment differed significantly between the two treatment groups (P < 0.001), and the estimated effect of treatment changed only negligibly after adjustment for other relevant clinical variables. New angiographic evidence of coronary artery disease developed in 14 patients not given calcium-channel blockers, as compared with 5 diltiazem-treated patients (P = 0.082). Coronary stenoses greater than 50 percent of the luminal diameter developed in seven patients not given calcium-channel blockers, as compared with two patients given diltiazem; death due to coronary artery disease or retransplantation occurred in five patients in the group that did not receive calcium-channel blockers and none of those who received diltiazem. CONCLUSIONS Our preliminary results suggest that diltiazem can prevent the usual reduction in the diameter of the coronary artery in cardiac-transplant recipients, but further follow-up will be required to determine whether diltiazem can decrease the long-term incidence of symptomatic coronary artery disease.

Mortality in Patients with Implanted Automatic Defibrillators

Fifty-two patients who survived several arrhythmic cardiac arrests had implantation of an automatic defibrillator along with additional cardiovascular surgery as indicated. The mean follow-up was 14.4 months and the longest was 3 years. In the hospital, the implanted devices identified and reverted 82 episodes of spontaneous and 81 of 99 episodes of induced malignant tachyarrhythmias. There were 62 automatic resuscitations in 17 patients outside the hospital. Twelve patients died; four of the deaths were not witnessed. These deaths represent a 22.9% total and 8.5% sudden-death 1-year mortality rate. Because the expected 1-year mortality in patients without the automatic defibrillator was calculated to be 48%, there was an estimated 52% decrease in anticipated total deaths. The automatic implantable defibrillator can identify and correct potentially lethal ventricular tachyarrhythmias, leading to a substantial increase in 1-year survival in properly selected high-risk patients.

Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis A Post Hoc Analysis of a Randomized, Placebo-Controlled Study

BACKGROUND Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Transplant coronary artery disease: Histopathologic correlations with angiographic morphology

Accelerated coronary artery disease is a major cause of morbidity and mortality among cardiac transplant recipients. Ten patients who died or underwent retransplantation within 2 months of coronary angiography had direct correlation of angiographic (normal discrete lesions, diffuse concentric narrowing) with histologic appearance of coronary arteries. Of the 26 angiographically normal segments, 73% showed mild to moderate fibrous intimal thickening by light microscopy. The remainder had intermediate lesions or atheromatous plaques. Discrete stenoses usually corresponded to lipid-rich intermediate or atheromatous disease. In contrast, angiographically diffuse, concentrically narrowed lesions usually were areas of severe fibrous intimal thickening. Fresh or organizing thrombus was most often associated with discrete lesions and accounted for all complete occlusions. Histologic and angiographic comparisons of the degree of luminal narrowing showed generally good correlation for high grade stenoses. Lesions graded as having less than 25% diameter narrowing were often underestimated angiographically as compared with histologic determinations. Transplant coronary artery disease has a heterogeneous histologic and angiographic appearance, with angiographic underestimation of disease in some patients.

Infectious Complications in Heart Transplant Recipients Receiving Cyclosporine and Corticosteroids

The rate of infectious complications differed significantly in two groups of heart transplant recipients who received different immunosuppressive regimens. Compared with patients who received conventional immunosuppression, patients treated with cyclosporine had a lower rate of infectious complications, and the contribution of infection to observed mortality was lower. Herpes simplex virus caused less morbidity and there were fewer active cytomegalovirus infections in seropositive recipients treated with cyclosporine. The incidence of bacterial pulmonary infections and associated bacteremia also decreased impressively. A decrease in nocardial infections was offset by a rise in those due to Legionella species. The frequency of aspergillosis was decreased by 54% in the cyclosporine-treated group, but half of these infections disseminated beyond the lung and such dissemination was always fatal. Infections with Pneumocystis carinii were significantly less common with cyclosporine-based immunosuppression. Screening serologic tests for toxoplasma should be done routinely and consideration given to prophylaxis in heart transplant recipients at high risk.

Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center.

A total of 1073 infectious episodes (IEs) that occurred in 620 consecutive heart transplantation patients at Stanford Medical Center between 16 December 1980 and 30 June 1996 were reviewed. Infectious complications were a major cause of morbidity and mortality, second only to rejection as the cause of early deaths and the most common cause of late deaths. Of the IEs, 468 (43.6%) were caused by bacteria, 447 (41.7%) by viruses, 109 (10.2%) by fungi, 43 (4.0%) by Pneumocystis carinii, and 6 (0.6%) by protozoa. The largest number of IEs occurred in the lungs (301 [28.1%]). A significant reduction in the incidence of IEs and a delay in presentation after transplantation were observed; these were most likely related to the introduction of new chemoprophylactic regimens during the study period and prevention of significant disease caused by cytomegalovirus.