Early prediction of cardiac allograft vasculopathy and heart transplant failure.

Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.

Vascular antithrombin and clinical outcome in heart transplant patients.

A procoagulant microvasculature is associated with accelerated development of coronary artery disease (CAD) and failure in heart transplant patients. This study was performed to evaluate how changes in natural anticoagulation within cardiac allografts affect outcome. We prospectively studied 141 consecutive cardiac allograft recipients who underwent transplantation between 1988 and 1997. Serial endomyocardial biopsy specimens (6.5 +/- 0.1 biopsy specimens/patient) obtained during the first 3 months after transplantation were studied immunohistochemically to evaluate vascular antithrombin, and annual coronary angiograms (3.8 +/- 0.2 angiograms/patient) were studied to evaluate CAD. Antithrombin was present in arteries and veins, but not in capillaries, of all donor heart biopsy samples. Allografts that maintained vascular antithrombin had the best prognosis. Allografts with early and persistent loss of vascular antithrombin (n = 21) developed CAD earlier (p < 0.001), developed more severe disease (p < 0.001), showed more disease progression (p < 0.001), and failed more often (p = 0.003) and earlier (p < 0.001) than allografts retaining normal vascular antithrombin (n = 45). However, allografts that lost and recovered vascular antithrombin while developing unusual capillary antithrombin binding (n = 75) had less CAD, developed CAD later, had less severe disease and less disease progression (p < 0.01), and failed less often (p = 0.01) and later (p = 0.03) than allografts with persistent loss of vascular antithrombin. The persistent lack of a thromboresistant microvasculature increases risk of subsequent CAD and graft failure. However, recovery of vascular antithrombin and development of unusual capillary antithrombin binding improves allograft outcome.

Immunohistochemical model to predict risk for coronary artery disease and failure in heart transplant patients.

Transplant coronary artery disease is the leading cause of long-term morbidity and mortality in cardiac transplantation. We developed a model for early identification of patients who subsequently develop coronary artery disease and graft failure. Serial biopsies obtained from 141 cardiac allografts (5.5 +/- 0.1 biopsies/patient) during the first 3 months post-transplant were evaluated immunohistochemically for deposition of myocardial fibrin, depletion of arteriolar tissue plasminogen activator, presence of arterial/arteriolar endothelial activation markers, and changes in vascular antithrombin. An immunohistochemical risk score was developed with a minimum value of 0 (normal) and a maximum value of 4 (most abnormal). Scores of 0 (low risk), 0.5-3.0 (moderate risk), and 3.5-4.0 (high risk) were analyzed for association with graft failure and development, severity, and progression of coronary artery disease detected using serial coronary angiograms (3.9 +/- 0.2/patient). Allografts with high immunohistochemical risk scores in the first 3months post-transplant developed more coronary artery disease (p<0.001), developed coronary artery disease earlier (p<0.001), developed more severe disease (p<0.001), and showed more disease progression (p<0.001) than allografts with moderate or low scores. Allografts with high immunohistochemical risk scores in the first 3 months post-transplant failed more (p<0.001) and failed earlier (p<0.001) than allografts with moderate or low scores. The present study demonstrates that early changes in the microvasculature are associated with impending coronary artery disease and graft failure in cardiac allograft recipients and suggests that treatment needs to be instituted early after transplantation in order to improve outcome.

Value of serum-soluble intercellular adhesion molecule-1 for the noninvasive risk assessment of transplant coronary artery disease, posttransplant ischemic events, and cardiac graft failure.

BACKGROUND: Adhesion molecules on arterial endothelium have been implicated in spontaneous atherosclerosis and transplant coronary artery disease (CAD). We studied whether elevated serum-soluble intercellular adhesion molecule-1 (sICAM-1) during the immediate posttransplant period was a risk factor for CAD, posttransplant ischemic events, or cardiac graft failure. METHODS AND RESULTS: We initially studied serum sICAM-1 in a subset of 16 cardiac allograft recipients (5.5+/-0.7 samples per patient) to determine a cutoff point that best correlated with presence of arterial and arteriolar endothelial ICAM-1 in matching endomyocardial biopsies. The cutoff value was 308 ng/mL. Subsequently, we prospectively evaluated serum sICAM-1 in serial samples (5.3+/-0.1 per patient) obtained during the first 3 months after transplantation in a validation subset of 130 recipients and correlated early sICAM-1 levels with long-term outcome. Serum sICAM-1 >308 ng/mL correlated significantly with ICAM-1 on arterial and arteriolar endothelium (P:=0.02). Cardiac allograft recipients with serum sICAM-1 >308 ng/mL had 2.67 (95% CI, 1.28 to 5.59, P:=0.009) times greater risk of CAD and 3.63 (95% CI, 1.05 to 12.5, P:=0.04) times greater risk of graft failure. Recipients with sICAM-1 >308 ng/mL also developed more severe CAD (P:=0.009) and more ischemic events (P:=0.03) after transplantation. CONCLUSIONS: Serum sICAM-1 levels can be used to noninvasively assess risk of transplant CAD, posttransplant ischemic events, and cardiac graft failure.

The incremental risk of female sex in heart transplantation: a multiinstitutional study of peripartum cardiomyopathy and pregnancy. Cardiac Transplant Research Database Group.

BACKGROUND: Controversy remains regarding the reason females seem to be at increased risk for rejection after heart transplantation. Therefore this study was performed to define the effect of a pretransplantation diagnosis of peripartum cardiomyopathy and the effect of previous pregnancy on the outcome (incidence of rejection and death) of females after heart transplantation. METHODS: In this multiinstitutional study of 3244 adult (greater than 13 years of age) heart transplant recipients, (a) the outcome of 40 females who underwent transplantation for peripartum cardiomyopathy was compared with that of 200 females of childbearing age (13 to 45 years) who underwent transplantation for other indications and (b) the posttransplantation outcome of 543 females with a history of pregnancy was compared with that of 101 nulliparous adult females and 2562 adult males. RESULTS: The posttransplantation outcome of females with a history of peripartum cardiomyopathy was similar to that of females of childbearing age who underwent transplantation for other indications. However, parous females had a significantly shorter time to first rejection (p < 0.0001) and greater cumulative rejection than nulliparous females or males. By multivariable analysis, the risk factors for cumulative rejection at 1 year were a history of pregnancy (p < 0.0001), younger recipient age (p < 0.0001), induction therapy (p < 0.0001), and the number of human leukocyte antigen-DR mismatches (p = 0.007). CONCLUSION: Our data suggest that it is previous pregnancy, and not sex per se, that is associated with an increased frequency of rejection in females after heart transplantation.

Improved infarct-related arterial patency after high dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: results of a multicenter randomized trial of two dosage regimens.

To determine whether a weight-adjusted high dose (2 mg/kg body weight over 3 h) rapid infusion of recombinant tissue-type plasminogen activator (rt-PA) was more efficacious than a weight-adjusted standard dose (1.25 mg/kg over 3 h) in achieving reperfusion in the setting of acute myocardial infarction, 175 patients were entered into a randomized multicenter trial. Eighty-four patients were entered into the high dose group, receiving 1.2 mg/kg (10% given as a bolus injection) over 1 h, followed by 0.8 mg/kg over the next 2 h. Ninety-one patients were given 0.75 mg/kg (10% given as a bolus injection) in 1 h, followed by 0.5 mg/kg administered over the next 2 h. The median dose in the group that received 2 mg/kg dose was 145 mg, compared with 100 mg in the group that received 1.25 mg/kg. The 90 min patency rate in the group that received 2 mg/kg was 84% compared with 70% in the group that received 1.25 mg/kg (p = 0.003). Sixty-four percent of the patients in each group underwent coronary angioplasty at the time of cardiac catheterization. The infarct-related artery patency rate at the end of catheterization was 91% in the group that received 2 mg/kg compared with 83% in the group that received 1.25 mg/kg (p = 0.08). Among patients with a patent infarct-related coronary artery after catheterization, the 6 month mortality rate in the group that received 2 mg/kg was 2.9% compared with 9.8% in the group that received 1.25 mg/kg (p = 0.15). The bleeding complication rate in the two groups was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Post inferior myocardial infarction ventricular septal rupture.

Mortality from ventricular septal rupture after myocardial infarction (MI) is high. Ventricular septal rupture after inferior MI is particularly associated with a high risk because of difficulty in diagnosis and surgical approach. These three case reports show how diagnosis and correction can be expedited by emergency transportation and color-flow echo-Doppler cardiography. Prompt ventricular septal repair can provide excellent survival and rehabilitation potential.

Effect of thrombolysis (streptokinase) on left ventricular function during acute myocardial infarction.

One hundred ninety-two consecutive patients with acute myocardial infarction were enrolled in a prospective trial of coronary thrombolysis in which either intracoronary or intravenous streptokinase was administered. First-pass radionuclide ejection fraction (EF) was measured early (within 24 hours of admission) and late (10 to 14 days after admission) to assess changes in left ventricular (LV) function. In 68 patients in whom reperfusion was successful, mean EF increased from 39 +/- 11% early to 47 +/- 13% late. In 36 patients in whom reperfusion was not successful, the mean EF increase was significantly smaller (from 38 +/- 10% to 42 +/- 11%, p less than 0.025). Patients in whom reperfusion was successful were then grouped according to extent of LV functional change. The extent of EF change (delta EF) was not significantly influenced by time to lysis at intervals up to 7 hours (delta EF = 9.1 +/- 10% at 2 to 3 hours, 8.7 +/- 12% at 3 to 4 hours, 10 +/- 10% at 4 to 5 hours, and 7.0 +/- 10% at 5 to 7 hours; difference not significant [NS]), location of the infarct (delta EF = 8.9 +/- 11% for inferior and 5.7 +/- 8.0% for anterior, NS), or presence of Q waves on the initial electrocardiogram (delta EF = 8.8 +/- 11% in patients with and 7.8 +/- 9.9% in patients without Q waves). Only the initial EF was predictive of subsequent EF change.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous versus intracoronary streptokinase in acute myocardial infarction.

One hundred sixty-four consecutive patients with acute myocardial infarction were enrolled in a prospective trial of coronary thrombolysis with streptokinase (STK). The first 98 patients received intracoronary (i.c.) STK after coronary angiography and the next 66 received a high-dose rapid infusion of STK (900,000 IU) intravenously (i.v.) before angiography. First-pass radionuclide ejection fraction (EF) was performed early (within 24 hours of admission) and late (10 to 14 days after admission) to evaluate left ventricular function. In the i.v. group, 42 of 66 (64%) of infarct-related arteries were patent at the initial angiogram and 6 (9%) opened with subsequent i.c. STK. In the i.c. group, 13 of 98 (13%) of infarct-related arteries were patent at the initial angiogram and 50 of 85 (59%) opened with the i.c. STK. The i.v. and i.c. groups did not differ in time from onset of chest pain to presentation, type of infarct or underlying severity of coronary artery disease. In the i.v. group, STK was begun 67 minutes earlier than in the i.c. group. In 62 patients in whom reperfusion was successful, mean EF increased from 39 +/- 11% early to 48 +/- 13% late. In 30 in whom it was not, the mean EF increased from 36 +/- 10% to 40 +/- 12%. The increase in EF was significantly greater in patients in the reperfused group (p less than 0.03). In 18 patients who underwent reperfusion by i.v. STK, the mean EF increased 11 +/- 12%, whereas in 44 patients who had reperfusion by i.c. STK, the mean EF increased 9 +/- 10% (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)