Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease. METHODS: Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months. RESULTS: For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001). CONCLUSIONS: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators.

BACKGROUND: The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis. METHODS AND RESULTS: A total of 11 590 patients with unstable angina or non-ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, P=0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, P=0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, P=0.03), but the rate of non-Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, P=0.005). There were no increases in clinically serious adverse events. CONCLUSIONS: No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.

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.

Relation of donor age and preexisting coronary artery disease on angiography and intracoronary ultrasound to later development of accelerated allograft coronary artery disease.

OBJECTIVES: This study assessed the influence of donor age and preexisting donor coronary disease on the later development of allograft coronary artery disease, ischemic events and overall survival. BACKGROUND: The increasing demand for heart donors has led to a tendency to liberalize age criteria for donor acceptability. METHODS: A total of 233 consecutive heart transplant recipients who had baseline, early postoperative and follow-up coronary angiograms, as well as a subset of 47 patients with baseline intracoronary ultrasound imaging recordings, were analyzed (mean 3.8 years of follow-up). Patients were subclassified according to the presence of donor coronary artery disease on the baseline angiogram and stratified at age 40 years. RESULTS: patients without evidence of preexisting coronary artery disease on a baseline angiogram (n = 219) were significantly less likely to develop new disease than the 14 patients with preexisting coronary artery disease (p = 0.002). Although older donors exhibited earlier coronary artery disease than younger donors at 3 years of follow-up, there was no difference by 5 years (p = 0.25). There was no difference in survival or probability of developing ischemic events between the groups. Baseline ultrasound imaging revealed substantial disease in 7 of 9 older donated hearts, and in only 7 of 38 younger donated hearts (p = 0.002). Preexisting coronary artery disease, nonuse of calcium channel blocking agents, older donor age, posttransplantation cytomegalovirus infection, elevated very low density lipoprotein levels and previous ischemic heart disease in the recipient were significant predictors of allograft coronary artery disease. CONCLUSIONS: Heart donors with angiographic evidence of preexisting coronary artery disease and older donors are more likely to develop new allograft coronary artery disease by 3 years. However, there is no difference in survival or freedom from ischemic events between younger and older donors at a mean follow-up of 3.8 years.

Role of compensatory enlargement and shrinkage in transplant coronary artery disease. Serial intravascular ultrasound study.

BACKGROUND: Compensatory enlargement of the vessel wall has been described in the early stages of native atherosclerosis. Whether compensatory enlargement plays a role in transplant coronary artery disease is not known. The objective of this study was to determine, by use of serial intravascular ultrasound (IVUS), whether compensatory dilation occurs in transplant coronary artery disease over time. METHODS AND RESULTS: Seventy-five heart transplant recipients with 151 matched coronary segments were selected for the presence of intimal disease progression as detected by serial IVUS examinations 1 to 3 years apart. Intimal disease progression was defined as a > 10% increase in intimal area (IA). IVUS catheter location in follow-up studies was verified angiographically in relation to branch vessels. Luminal area (LA) and total vessel area (TA) were measured at each site. Intimal area (IA = TA-LA) was calculated. Changes in IA (delta IA) and TA (delta TA) between baseline and follow-up IVUS were compared: delta IA, 2.9 +/- 0.2 mm2: delta TA, 2.7 +/- 0.4 mm2. A remodeling index (RI) was defined as RI = delta TA/delta IA. Three subgroups could be distinguished: over compensation (RI > I), partial compensation (RI 0 to 1), and no compensation or shrinkage (RI < or = 0). Seventy-four segments (49%) showed overcompensation, 44 (29%) showed partial compensation, and 33 (22%) showed no compensation or shrinkage. CONCLUSIONS: In this study, serial IVUS shows that early after cardiac transplantation, a large proportion of the coronary segments with progression of intimal thickening have compensatory dilation of the vessel wall. However, a substantial number of coronary segments (22%) show no compensatory dilation or shrinkage. The progressive luminal narrowing in transplant patients may be due in part to vessel shrinkage or the lack of compensatory dilation over time.

Prediction of angiographic disease by intracoronary ultrasonographic findings in heart transplant recipients.

BACKGROUND: Intracoronary ultrasonography has proven to be a more sensitive test than angiography for the detection of intimal thickening in transplant recipients. However, the prognostic significance of the intimal thickening detected by intracoronary ultrasonography has not been proven. METHOD: During a 1-year period, 70 transplant recipients without angiographically apparent coronary artery disease underwent intracoronary ultrasonography examination. For each intracoronary ultrasonography study an intimal index, defined as the ratio of the plaque area to the area within the media, was measured for the most diseased segment imaged. The subsequent annual follow-up angiograms of these 70 patients were reviewed for the development of visually apparent coronary artery disease. The time since transplantation for the 70 patients without angiographically apparent coronary artery disease ranged from 1 to 15 years, with a mean of 4.2 years an median of 3.9 years. Mean duration of angiographic follow-up was 2.0 years (range 1 to 3 years). RESULTS: Angiographically apparent coronary artery disease developed on follow-up angiograms in 13 of the 70 patients, with a mean time to development of 1.5 years. Four of 46 patients (9%) with an intimal index < 0.3 subsequently had angiographically apparent coronary artery disease, whereas of 25 patients (36%) with an intimal index > or = 0.3 subsequently had angiographically apparent coronary artery disease. Odds ratio for future angiographically apparent coronary artery disease between patients with an intimal index > or = and intimal index < 0.3 was 5.9 (p < 0.01 by Fisher's Exact test). In a subgroup of 22 patients more than 5 years after transplantation at the time of intracoronary ultrasonography, 12 had an intimal index < 0.3 and 10 had an intimal index > or = 0.3. In this subgroup none of the 12 patients with an intimal index < 0.3 had angiographically apparent coronary artery disease and only 1 of the 10 with an intimal index > or = 0.3 had angiographically apparent coronary artery disease (difference not significant). CONCLUSIONS: The presence of moderate to severe intimal thickening by intracoronary ultrasonography is predictive of the future development of angiographically apparent coronary artery disease among patients more than 1 year and less than 5 years after transplantation. This same degree of intimal thickening may not carry the same prognostic significance among patients greater than 5 years after transplantation without the development of angiographically apparent coronary artery disease.

Early development of accelerated graft coronary artery disease: risk factors and course.

OBJECTIVES: This study assessed the time of first appearance of angiographic graft coronary artery disease in relation to clinical and laboratory variables and clinical events in heart transplant recipients. BACKGROUND: Graft coronary artery disease is the main factor limiting long-term survival after heart transplantation, and it is important to understand its natural history. METHODS: One hundred thirty-nine consecutive patients who developed angiographic coronary artery disease after heart transplantation were classified according to early (< or = 2 years) versus late (> 2 years) posttransplantation initial detection of coronary artery disease. These subgroups were analyzed for differences in clinical and laboratory demographics, incidence of progression to ischemic events and incidence of antecedent cytomegalovirus infection. RESULTS: The early-onset group (64 patients) had more rapid progression to ischemic events than the late-onset group (75 patients), with 59% of the late group and only 35% of the early group free from ischemic events by 5 years after initial detection (p = 0.02), but there were no significantly correlated clinical or laboratory predictors of ischemic events. The early group had a significantly higher incidence of antecedent cytomegalovirus infection. CONCLUSIONS: We conclude that 1) accelerated graft coronary artery disease develops at variable times after heart transplantation; 2) the early appearance of graft coronary artery disease may be a marker of intrinsically more aggressive disease; 3) cytomegalovirus infection is associated with earlier onset of graft coronary artery disease. Patients with early development of graft coronary artery disease should potentially be given priority for interventional strategies as they are developed.

Overexpression and mutations of p53 in metastatic malignant melanomas.

Alterations of the p53 tumor suppressor gene are the most frequent genetic abnormalities in human malignancies, but the role of p53 in the etiology of malignant melanomas is unclear. Fifty unselected malignant melanomas were analyzed for p53 overexpression by immunohistochemistry using 3 monoclonal antibodies (MAbs). Fifteen tumors (29.4%) showed positive staining with at least 2 different antibodies. In the first 20 consecutive tumors exons 5-9 and adjacent splice sites of the p53 gene were analyzed by genomic sequencing. There were 4 mutations in 20 metastatic melanomas. Three of 4 mutations were C:G-->T:A transitions. A search of our database of p53 mutations revealed that out of 8 p53 mutations reported by others, 4 are C:G-->T:A transitions at dipyrimidine sites, and one is a tandem CC-->TT mutation. This mutational pattern is comparable with the pattern of p53 mutations in squamous cell and basal cell carcinomas of the skin and is related to exposure to ultraviolet B (UV-B) wavelength radiation. Taken together with a predominance of UV-induced mutations in the CDKN2/ p16 gene demonstrated in melanoma cell lines, our data support a role of sunlight exposure in the etiology of malignant melanoma. The low frequency of p53 mutants in melanomas compared with other types of skin cancers suggests that although mutations in this gene are likely to be involved in the development of some malignant melanomas, they do not play as large a role as in squamous and basal cell carcinomas of the skin.

Analysis of deaths in patients awaiting heart transplantation: impact on patient selection criteria.

OBJECTIVE: To analyse the clinical characteristics of patients who died on the Stanford heart transplant waiting list and to develop a method for risk stratifying status 2 patients (outpatients). METHODS: Data were reviewed from all patients over 18 years, excluding retransplants, who were accepted for heart transplantation over an eight year period from 1986 to 1994. RESULTS: 548 patients were accepted for heart transplantation; 53 died on the waiting list, and 52 survived on the waiting list for over one year. On multivariate analysis only peak oxygen consumption (peak VO2: 11.7 (SD 2.7) v 15.1 (5.2) ml/kg/min, P = 0.02) and cardiac output (3.97 (1.03) v 4.79 (1.06) litres/min, P = 0.04) were found to be independent prognostic risk factors. Peak VO2 and cardiac index (CI) were then analysed in the last 141 consecutive patients accepted for cardiac transplantation. All deaths and 88% of the deteriorations to status 1 on the waiting list occurred in patients with either a CI < 2.0 or a VO2 < 12. In those with a CI < 2.0 and a VO2 < 12, 38% died or deteriorated to status 1 in the first year on the waiting list. Patients with CI > or = 2.0 and a VO2 > or = 12 all survived throughout follow up. Using a Cox's proportional hazards model with CI and peak VO2 as covariates, tables were constructed predicting the chance of surviving for (a) 60 days and (b) 1 year on the waiting list. CONCLUSIONS: These data provide a basis for risk stratification of status 2 patients on the heart transplant waiting list.

Transplant candidates with severe left ventricular dysfunction managed with medical treatment: characteristics and survival.

OBJECTIVES: This study sought to assess the clinical characteristics and survival of patients with symptomatic heart failure who were referred as potential heart transplant candidates, but were selected for medical management. BACKGROUND: Patients with severe left ventricular dysfunction referred for heart transplantation may be considered too well to be placed immediately on an active waiting transplant list. The clinical characteristics of this patient group and their survival have not been well defined. These patients represent a unique group that are characterized by comparatively low age and freedom from significant comorbid conditions. METHODS: We studied 116 consecutive patients with symptomatic heart failure, severe left ventricular dysfunction (left ventricular ejection fraction 20 +/- 7% [mean +/- SD]) and duration of symptoms >1 month referred for heart transplantation, who were acceptable candidates for the procedure but who were not listed for transplantation because of relative clinical stability. These patients were followed up closely on optimal medical therapy. A variety of baseline clinical, hemodynamic and exercise variables were assessed to define this patient group and used to predict cardiac death and requirement later for heart transplantation. RESULTS: During a mean follow-up period of 25.0 +/- 14.8 months (follow-up 99% complete), there were eight cardiac deaths (7%) (seven sudden, one acute myocardial infarction). Only nine patients (8%) were listed for heart transplantation. Actuarial 1- and 4-year cardiac survival rates were 98 +/- 1% and 84 +/- 7% (mean +/- SE), respectively, and freedom from listing for transplantation was 95 +/- 2% and 84 +/- 7% (mean +/- SE), respectively. Patients were mainly in New York Heart Association functional class II or III and had a preserved cardiac index (2.4 liters/min.m2), pulmonary capillary wedge pressure of 16 +/- 9 mm Hg (mean +/- SD) and maximal oxygen consumption of 17.4 +/- 4.3 ml/min per kg (mean +/- SD). By logistic regression analysis, there was no predictor for cardiac death. Longer duration of heart failure (p = 0.013) and mean pulmonary artery (p < 0.05) and pulmonary systolic (p = 0.014) and diastolic (p < 0.05) pressures correlated significantly with listing for heart transplantation by univariate logistic regression. By multivariate logistic regression, only pulmonary artery systolic pressure (p < 0.004) and duration of heart failure (p < 0.015) remained as predictors for need for later transplantation. CONCLUSIONS: In the current treatment era, prognosis is favorable in a definable group of transplant candidates despite severe left ventricular dysfunction. This patient group can be identified after intensive medical therapy by stable symptoms, a relatively high maximal oxygen uptake at peak exercise and a preserved cardiac output.

Coronary artery intimal thickening in the transplanted heart. An in vivo intracoronary untrasound study of immunologic and metabolic risk factors.

This study examined the hypothesis that immunologic factors are the major correlates of coronary artery intimal thickening and luminal stenosis. The study population included 116 adult heart transplant recipients with a mean age of 44.7 +/- 12.0 years (89 men and 27 women) undergoing annual coronary angiography and intracoronary ultrasound 3.4 +/- 2.7 (range, 1.0-14.6) years after transplantation. Mean intimal thickness was obtained from several distinct sites along the left anterior descending and/or left circumflex coronary artery by intracoronary ultrasound. Coronary artery stenosis defined by angiography was classified as mild (< 30% luminal stenosis), moderate (> or = 30-70% luminal stenosis), or severe (> 70% luminal stenosis or diffuse pruning of distal vessels). Prevalence of any transplant coronary artery disease (TxCAD) was 85% by intracoronary ultrasound and 15% by angiography. By multiple regression analysis, only average fasting plasma triglyceride level (P < 0.006) and average weight (P < 0.007) were significantly correlated with severity of intimal thickening (R = 0.54, P < 0.0001). Donor age (P < 0.006) and average fasting plasma triglyceride level (P < 0.009) were significantly correlated with stenosis by angiography. Correlation of multiple immunologic and metabolic factors with intimal thickness by univariate analysis suggests a multifactorial etiology for TxCAD. Among the multiple univariate correlates of TxCAD, higher fasting plasma triglyceride levels and body weight are the only independent correlates of TxCAD. The absence of acute rejection as an independent predictor of intimal thickening suggests that mechanisms beyond those mediating typical cellular rejection should be targeted for advancing our understanding of Tx-CAD.

Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation.

BACKGROUND: Although intracoronary ultrasound (ICUS) has been validated for the early detection of transplant coronary artery disease (TxCAD), the prognostic importance of findings detected by this new imaging technique is unknown. METHODS AND RESULTS: This study examined the relation of clinical outcome in 145 heart transplant recipients (mean age, 45.1 +/- 11.1 years) with the amount of intimal thickness measured by ICUS during routine annual coronary angiography 1 to 10 years (mean, 3.1 +/- 2.2 years) after transplantation. From published autopsy data, a mean intimal thickness of > 0.3 mm was considered significant. During a mean follow-up time of 48.2 +/- 10.2 months, 23 deaths (12 cardiac) occurred, and 6 patients required retransplantation. Angiographic TxCAD developed in 22 of 125 patients (17.6%) in the subgroup with normal angiograms at the time of ICUS and a follow-up annual angiographic study. In the total population and the subgroup, mean intimal thicknesses of > 0.3 and < or = 0.3 mm, respectively, were associated with significantly inferior 4-year actuarial overall survival (73% versus 96%, P = .005; 72% versus 92%, P = .05), cardiac survival (79% versus 96%, P = .005; 80% versus 98%, P = .04), and freedom from cardiac death and retransplantation (74% versus 98%, P < .0001; 70% versus 96%, P = .001). In addition, ICUS predicted freedom from development of subsequent angiographic TxCAD in the subgroup that was initially normal (26% versus 72%, P = .02). A mean intimal thickness by ICUS of > 0.3 mm was associated with inferior clinical outcome regardless of the presence of angiographic TxCAD and predicted the development of subsequent angiographic TxCAD. Despite significantly longer duration after transplantation, higher rejection incidence, and lower average daily cyclosporine dose, none of these covariates were independent risk factors for outcome. CONCLUSIONS: These findings confirm the prognostic importance of mean intimal thickening of > 0.3 mm in heart transplant recipients and suggest that these patients should be candidates for early interventional strategies.

Influence of preexistent donor coronary artery disease on the progression of transplant vasculopathy. An intravascular ultrasound study.

BACKGROUND: Transplant vasculopathy (TxCAD) limits longterm survival of allograft recipients. The possibility that preexistent donor coronary disease (PEDD) might accelerate this process is of concern. The serial progression of sites with and without PEDD as assessed by intravascular ultrasonic imaging is explored in this study. METHODS AND RESULTS: Thirty patients with baseline intravascular imaging within 3 weeks of cardiac transplantation who had at least one annual follow-up study were included in this study. Vessel luminal area (LA), total area (TA), intimal index (II = TA - LA/TA), mean intimal thickness (MIT), and Stanford classification were expressed for each image site and for each patient at each study. Progression of sites and of patients with and without PEDD on the baseline study was compared. Patients with PEDD (n = 9) still had significantly more intimal disease than those without PEDD (n = 21) at the first follow-up study (MIT = 0.35 +/- 0.13 versus 0.13 +/- 0.11 mm; II = 0.29 +/- 0.11 versus 0.11 +/- 0.1; class = 3.7 +/- 0.5 versus 2.2 +/- 0.94; P < .001 for all comparisons). However, the increase in intimal thickness during the 1- year interval was not significantly different between the two groups. In 4 patients in whom both types of sites were present, no difference in progression was found. Data were similar for patients and sites studied over > 1 year. CONCLUSIONS: PEDD does not accelerate the progression of TxCAD within the first few years after cardiac transplantation. The pathophysiology of TxCAD is most likely immune mediated and does not seem to be accelerated by native coronary artery disease.

Calcium blockers and atherosclerosis: lessons from the Stanford Transplant Coronary Artery Disease/Diltiazem Trial.

Accelerated coronary artery disease (TxCAD) in the long term heart transplant patient remains the major limitation to long term survival, with approximately 50% of patients developing an angiographic event of TxCAD by five years post-transplant. This accelerated vasculopathic process is believed to be due to chronic immune injury to the endothelium with coronary intimal proliferation developing rapidly. Subsequent lipid deposition develops in these proliferated areas, leading to a diffuse progressive occlusive CAD which can be seen on serial coronary arteriography as a progressive luminal narrowing. Based on multiple annual studies demonstrating a protective effect of calcium blockers in diet- or injury-induced vascular disease in animals, the authors undertook a randomized trial of diltiazem versus no calcium blocker begun early after heart transplantation in 1986. Serial quantitative coronary arteriographic measurements have demonstrated no significant change in the diltiazem group versus a decrease in mean coronary lumen diameter, from 2.41 +/- 0.27 to 2.19 +/- 0.28 mm, in the no calcium blocker group. These differences persisted at two and three years of follow-up. Freedom from CAD based on qualitative angiographic data confirmed this protective effect of diltiazem. These observations are supported by other reported retrospective studies of calcium blockers post-heart transplantation and in non-TxCAD. Therefore, calcium blockers appear to prevent the early coronary intimal proliferation in response to chronic immune injury, as well as the later lipid deposition. The cardiac transplant patient may serve as a useful model for study of antiatherosclerotic agents in humans.

Correlation of donor characteristics with transplant coronary artery disease as assessed by intracoronary ultrasound and coronary angiography.

The mechanisms responsible for transplant coronary artery disease (CAD) and its predisposing factors remain incompletely understood. The influence of donor characteristics as predisposing factors has not been studied systematically. We examined the correlation of donor demographic, clinical, and immunologic parameters with transplant CAD assessed by both intracoronary ultrasound (ICUS) and coronary angiography in 116 heart transplant recipients (age 44.7 +/- 12.0 years) studied 3.4 years (range 1.0 to 14.6) after transplantation. Quantitative ultrasound data were obtained by calculating mean intimal thickness from several distinct coronary sites. Coronary angiograms were categorized visually as normal or showing any transplant CAD. By multivariate regression analysis, donor undersize of > 20% of recipient weight (p < 0.02) and duration after transplantation (p < 0.005) were independently correlated with the amount of ICUS intimal thickness (r = 0.36, p = 0.0007), and older donor age with angiographic evidence for the disease (r = 0.34, p < 0.006). In a subgroup analysis of the 39 patients studied 1 year after transplantation, white donor race (p < 0.05), fewer human leukocyte antigen-DR mismatches (p < 0.002), shorter ischemic time (p < 0.04), and donor smoking history (p < 0.02) were independent predictors for severity of ICUS intimal thickening (r = 0.92, p = 0.0009); higher donor age (p < 0.006) and higher arterial partial pressure of oxygen (p < 0.003) were independent predictors for angiographic disease (r = 0.67, p < 0.002). In conclusion, donor characteristics may contribute to the probably multifactorial pathogenesis of transplant CAD.

Giant cell myocarditis.

BACKGROUND: Giant cell myocarditis is a rare and frequently fatal disorder of unknown origin that is defined histopathologically as diffuse myocardial necrosis with multinucleated giant cells in the absence of sarcoidlike granulomata. The clinical and pathologic features of lymphocytic myocarditis have been described in several recent publications, but the features of idiopathic giant cell myocarditis have not been adequately addressed. METHODS AND RESULTS: We describe five patients with idiopathic giant cell myocarditis who were seen at Stanford University over the past 10 years. In each case the onset was subacute congestive heart failure. After diagnosis each patient received immunosuppressive therapy and was evaluated for heart transplantation. Progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly, two of progressive heart failure and one of sudden cause. Two patients underwent orthotopic heart transplantation and are currently alive, one with disease recurrence. Pathologic studies, including endomyocardial biopsy and evaluation of postmortem or explanted material at transplantation were reviewed. The pathologic studies provided additional support that the giant cells derive from a monocytic/histiocytic lineage. Segmental wall motion abnormalities suggest giant cell myocarditis can be a focal, as well as diffuse process at certain stages of its course. This experience is compared with published cases and implications for diagnosis and treatment are discussed. CONCLUSIONS: In view of the uniformly fatal nature of the disease, heart transplantation should be a serious consideration, and the patients evaluated once the diagnosis is established. Triple-drug immunosuppressive therapy should be considered at the time of diagnosis.