Coagulation markers predicting cardiac transplant rejection.

BACKGROUND: Acute cellular rejection in cardiac allografts is a major cause of graft loss, and is associated with activation of the coagulation system. We investigated whether plasma markers of coagulation predict the presence of allograft rejection. METHODS: A total of 132 blood specimens and endomyocardial biopsies were collected from 35 patients, between February of 1997 and May of 1998. We measured plasma prothrombin fragment 1.2 (PF1.2) and p-selectin, fibrinogen, thrombomodulin, and d-dimer. Biopsies were graded according to the International Society of Heart and Lung Transplantation system, with a range of 0 to 4. Grades 0 and 1A were grouped as "no rejection," and the higher grades as "rejection." Linear and logistic regression, accounting for longitudinal data, were the principal analytic tools. RESULTS: p-Selectin level increased progressively with increasing rejection grade (P<0.001). With multivariate analysis, both p-selectin and prothrombin fragment levels significantly predicted rejection. p-Selectin levels were predictive of prothrombin fragment levels (P<0.0001) but not of d-dimer, fibrinogen, or thrombomodulin levels. This model allowed correct prediction of rejection, based on p-selectin and prothrombin fragment values, up to 85% of the time. Dichotomizing patients by a p-selectin level of 65 ng/ml resulted in an odds of rejection of 21.4 [95% C.I. 7.1-64.7] for the patients in the high- compared with the lower risk group. CONCLUSIONS: In heart transplant recipients, p-selectin levels and PF 1.2 levels are highly predictive of organ rejection. The elevation of PF 1.2 suggests that there is systemic generation of thrombin generation. These markers may be useful for noninvasively monitoring patients for organ rejection or for after response to treatment.

Factors correlating with risk of mortality after transmyocardial revascularization.

OBJECTIVES: The purpose of this study was to determine factors correlating with the risk of postoperative mortality after transmyocardial laser revascularization (TMR). BACKGROUND: Clinical studies have indicated that TMR reduces angina by an average of two classes in patients with medically refractory symptoms not treatable by coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty. Factors which correlate with mortality after TMR, however, have not been extensively investigated. METHODS: One hundred thirty-two patients with severe angina underwent TMR as sole therapy with a CO2 laser. Age, gender, ejection fraction, prior CABG, unstable angina and the severity of coronary artery disease (graded on the basis of a newly proposed Anatomic Myocardial Perfusion index, AMP) were each determined. Each vascular territory (left anterior descending artery [LAD] left circumflex artery and posterior descending artery [PDA]) was graded as either having (AMP = 1) or not having (AMP = 0) blood flow through an unobstructed major vessel in the territory. Univariate and multivariate analysis determined which factors correlated with mortality. RESULTS: Patients with at least one AMP = 1 vascular territory (overall AMP = 1) had a 5% (4/82) postoperative mortality rate (POM), compared with 25% (12/49) with overall AMP 0 (p = 0.002). Left anterior descending artery AMP (p = 0.03) and previous CABG (p = 0.04) each correlated with the risk of POM. However, multivariate analysis indicated that no factor improved the correlation obtained with overall AMP by itself. With regard to overall mortality (Kaplan-Meier curves), univariate analysis also revealed correlations with overall AMP (p < 0.001), LAD AMP (p = 0.005), previous CABG (p = 0.003) and PDA AMP (p = 0.05) each individually correlated with mortality. Multivariate analysis indicated that overall AMP = 1, female gender and previous CABG together correlated best with lower postoperative mortality. CONCLUSIONS: Patients with good blood flow to at least one region of the heart through a native artery or a patent vascular graft have a markedly reduced risk of perioperative and longer term mortality.

Acute effects of conjugated estrogens on coronary blood flow response to acetylcholine in men.

Estrogen therapy is associated with a 50% reduction in the clinical manifestations of coronary artery disease in postmenopausal women. Attenuation of coronary vasomotor dysfunction may contribute to estrogen's cardioprotective effects. We hypothesized that conjugated estrogens, which contain several vasoactive estrogenic compounds, may favorably influence the vasomotor response to acetylcholine in men. Twenty men, 56 +/- 5 years of age, referred for clinically indicated coronary angiography, participated in this study. Acetylcholine-induced changes in coronary flow were measured by quantitative coronary angiography and intracoronary Doppler ultrasonography before and 15 minutes after intravenous administration of conjugated estrogens (0.625 mg) in 12 men and placebo in 8 men. Initial acetylcholine infusion resulted in no significant increase in coronary blood flow. However, 15 minutes after estrogen administration repeat acetylcholine infusion caused a mean 32% increase in coronary blood flow from 41 +/- 5 to 54 +/- 8 ml/min (p = 0.02). Acetylcholine-induced change in flow after estrogen was significantly different from that before estrogen (p = 0.03). Placebo administration did not affect acetylcholine-induced changes in coronary flow. Thus, intravenous conjugated estrogens favorably modulate acetylcholine-induced changes in coronary hemodynamics in men. This suggests that novel nonfeminizing estrogenic compounds may have anti-ischemic effects in men.

Long-term estrogen therapy abolishes acute estrogen-induced coronary flow augmentation in postmenopausal women.

Postmenopausal estrogen replacement therapy (ERT) may reduce the clinical manifestations of coronary heart disease by favorably modulating coronary vasoreactivity. Intravenous ethinyl estradiol acutely increases coronary flow in postmenopausal women not receiving ERT. Because several vasoactive agents induce vasomotor tolerance when administered on a long-term basis, we hypothesized that long-term ERT attenuates the acute coronary vasomotor effects of intravenous ethinyl estradiol. To test this hypothesis, coronary hemodynamics were determined before and 15 minutes after intravenous ethinyl estradiol (35 micrograms) in 10 postmenopausal women who were receiving long-term conjugated ERT (group 1) and 10 who had never received ERT (group 2). Estradiol administration in group 1 was not associated with significant changes in coronary flow or resistance. However, women in group 2 exhibited a 28.6% +/- 6.5% (p < 0.001) increase in coronary flow and a 19.9% +/- 3.5% (p = 0.008) decrease in resistance. These results demonstrate that long-term ERT significantly attenuates the response of coronary arteries to the acute vasomotor effects of a high dose of estradiol. This response may be caused by long-term estrogen-induced coronary flow augmentation or to the development of vasomotor tolerance to estrogen.

Clinical evaluation of a microsample coagulation analyzer, and comparison with existing techniques.

A new microsample coagulation analyzer (Hemochron Jr.) has recently been developed which performs a modified activated clotting time (ACT+) and an aPTT by using different reagents. The Hemochron Jr. measures the clotting time of a 5-microliter whole-blood sample by an optical detector and extrapolates the results to the activated clotting time (ACT+) or the plasma-activated partial thromboplastin time by using a validated regression analysis. We compared 124 simultaneous ACT+ and Hemochron ACTs, and 53 paired Hemochron Jr. aPTTs and hospital laboratory aPTTs, in 44 patients during coronary intervention. The Hemochron Jr. aPTT closely correlated with the lab aPTT (r = .79, P < .0001), and the test results were available much more rapidly than the lab aPTT (3.5 +/- 1.1 vs. 56.3 +/- 25.5 min, P = 0.0029). A comparison of duplicate ACT+ measurements did not identify a significant difference in the means (292 +/- 115 sec vs. 293 +/- 112 sec, P = 0.72). The ACT+ closely correlated with the Hemochron ACTs (r = .85, P < .0001). At baseline, the mean ACT+ (175 +/- 43 sec) exceeded the Hemochron ACT (144 +/- 36 sec) by 22% (P < .001). After heparin administration, the mean ACT+ (378 +/- 74 sec) exceeded the Hemochron ACT (332 +/- 65) by 12% (P < .001). The Hemochron Jr. provides a fast and reproducible methodology for measuring ACT and aPTT, using a small blood volume. Further studies are required to determine the optimal anticoagulation range when using the Hemochron Jr. during or after interventional procedures.

Coronary artery spasm in the transplanted human heart. A case report.

This report describes a patient manifesting spontaneous and catheter-induced coronary artery spasm in a transplanted, denervated heart. This diagnosis should be considered in patients undergoing posttransplant coronary angiography. Intracoronary nitroglycerin should routinely be administered prior to coronary artery injections during posttransplant angiography.

Comparison of bedside and hospital laboratory coagulation studies during and after coronary intervention.

The activated clotting time is routinely used to monitor anticoagulation during coronary intervention, whereas the hospital laboratory APTT guides pre- and postprocedure heparin therapy. An optimal coagulation test for patients undergoing percutaneous revascularization would provide a rapid and accurate assessment of anticoagulation throughout a broad range of heparin therapy. We studied the relationships of the bedside whole blood APTT, ACT, and the laboratory APTT in 166 patients undergoing coronary intervation. The whole blood APTT correlated closely with the laboratory APTT (range 18-80 sec) (r = .75), whereas the ACT and laboratory APTT had only a fair correlation (r = .42). Also, the whole blood APTT demonstrated a strong correlation with the ACT throughout the range of heparin therapy for intervention (r = .81). The diagnostic accuracy of the whole blood APTT, based on the receiver operating characteristic curve, was significantly better than that for the ACT in determining the anticoagulation status. The whole blood APTT obtained by bedside monitoring provides a rapid and accurate assessment of anticoagulation throughout the range of heparin dosing associated with coronary intervention. In situations in which an adequate assessment of residual anticoagulation is necessary, the whole blood APTT is superior to the ACT and probably should be the method of choice.

Coronary angioplasty through a new 6 French guiding catheter.

Coronary angioplasty through smaller-diameter guiding catheters using predominantly fixed-wire balloon systems has been possible, but has had some limitations. The purpose of this prospective, nonrandomized study was to investigate the results of percutaneous transluminal coronary angioplasty using a new 6F guiding catheter with over-the-wire balloon systems. Coronary angioplasty using over-the-wire balloon systems through a new 6F guiding catheter was evaluated in 79 lesions in 70 patients and then compared to randomly selected procedures using 7F guiding catheters in 70 patients performed over the same time period. Coronary angioplasty through 6F guiding catheters and over-the-wire balloons including 8 long (30-mm) and 3 perfusion balloons was successful in 94.9% of lesions and in 94% of patients. Coronary angioplasty through 7F guiding catheters was successful in 97.5% of lesions and in 97.1% of patients, respectively. Success rates between 6F and 7F guiding catheter groups were similar overall and for proximal, mid, distal, or complex (total, subtotal, or length > 10-mm) lesions. There were no failures to withdraw the deflated balloon into the 6F guiding catheter. Vessel opacification after dilatation with the guidewire across the lesion was similar between the 6F and 7F guiding catheter groups. The mean change in hematocrit for the 6F procedures (-1.4 +/- 3.7%) was significantly lower than for the 7F procedures (-3.3 +/- 3.2%, P < 0.001). Coronary angioplasty using a variety of over-the-wire balloon catheters through a new 6F guiding catheter is feasible with success rates comparable to 7F guiding catheters. Angioplasty with this 6F guiding catheter reduces procedural blood loss compared to larger-lumen guiding catheters.

Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.

BACKGROUND: Estrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endothelium-dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. METHODS AND RESULTS: Acetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35 micrograms) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 +/- 4.5% (mean +/- SEM) increase (P < .01) in coronary flow, a 15.0 +/- 3.2% decrease (P < .01) in resistance, and a 20.0 +/- 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (-33.5 +/- 12.3%, P < .01) and increase in resistance (38.9 +/- 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (-14.2 +/- 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine-induced flow, resistance, and cross-sectional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration. CONCLUSIONS: EE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and increased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.

Rapid measurements of diastolic intramyocardial vascular volume.

Rapid measurements of coronary vascular volume are necessary for a complete understanding of phasic coronary flow. Because no standard method is capable of making these measurements, we developed a method that uses digital subtraction angiography to image an intravascular contrast agent. The method is capable of measuring vascular volume in 33 ms and can be repeated three times per second. The method was first validated in phantoms. We then used this method to measure coronary vascular volume in the isolated, perfluorochemical-perfused, interventricular canine septum. The speed of the measurements allowed us, for the first time, to directly measure transients in vascular volume following sudden changes in perfusion pressure. At the steady-state and maximal vasodilation, coronary vascular volume varied from 7.5 +/- 1.2 (SE) ml/100 g at a perfusion pressure of 20 mmHg to 12.1 +/- 1.9 ml/100 g at 90 mmHg, which is similar to other reports. After a sudden change of 40 mmHg in perfusion pressure, vascular volume changed with a time constant of 3.2 +/- 0.3 (SE) s. Increasing ventricular wall stretch had no effect on either the steady-state volumes (P = 0.25) or the time constant for volume changes (P = 0.17). The fact that the time constant is longer than the cardiac cycle, yet much shorter than the time necessary to measure vascular volume using other methods, highlights the need for rapid measurements of vascular volume.

Effect of tetanic myocardial contraction on coronary pressure-flow relationships.

Cardiac contraction causes a decrease in coronary flow. Despite many studies, it is still not clear what mechanism or mechanisms are responsible for this flow decrease. The phasic nature of myocardial contraction and the complexities intrinsic to intact heart preparations make it difficult to elucidate the mechanisms. We therefore studied coronary pressure-flow relationships during steady-state (tetanic) contractions in the maximally vasodilated isolated canine interventricular septum to see whether waterfall-type behavior is present. Using ryanodine and electrical stimulation allowed the production of reproducible and reversible tetani. This preparation minimizes the difficulties associated with transmural variations and also the effects of intramyocardial capacitance. Two separate protocols were performed to delineate the pressure-flow relationships in the passive and tetanized states. The first compared diastolic and tetanized pressure-flow relationships. In the second protocol, 2,3-butanedione monoxime was added to obtain an intermediate contractile level, thus allowing the comparison of two contractile states. Both the diastolic and tetanized pressure-flow relationships were curvilinear in the low-pressure range. Linear and nonlinear fits to the data showed that the primary effect of contraction was a shift of the pressure-flow relationships to higher pressures at a given flow. This effect was graded by the level of contractility and was independent of developed stress. Although other mechanisms may also be operative, these results support the presence of waterfall behavior in the coronary vascular bed.

Fragmentation and embolization of a plastic-coated guidewire.

We report a case of fragmentation and embolization to the pulmonary artery of sheared pieces of a recently introduced hydrophilic plastic-coated guidewire. The propensity for this to occur, the lack of initial recognition, and the ability to retrieve the fragments by catheter techniques are emphasized. As these guidewires are more frequently used, physicians should be aware of this potential complication.

Brachial approach for intracoronary stent implantation: a feasibility study.

Implantation of coronary artery stents via the percutaneous femoral approach is associated with a high rate of vascular complications at the access site related to the size of the entry hole and the intense anticoagulation required to prevent stent thrombosis. Therefore we studied the feasibility of using the left brachial approach utilizing open arterial repair for implantation of coronary artery stents. Intracoronary stent implantation via the femoral approach in 24 patients (group A) was compared with implantation via the brachial approach in 16 patients (group B). Baseline lesion characteristics were similar in the two groups. All stents in group A (n = 27 stents) were successfully delivered to their target vessel. One stent in group B (n = 18 stents) could not be delivered because of an inability to engage the coronary artery from the brachial approach. There were no significant differences in the angiographic outcome between the two groups. Complications including hematomas, hemorrhage requiring blood transfusion, vascular injury requiring surgery, and pseudoaneurysm formation were significantly more common in group A than in group B (8/24 [33%] versus 1/16 [6%], respectively; p < 0.05). In addition, the length of hospital stay was significantly longer for the femoral approach than the brachial approach (9.4 vs 6.5 days, respectively; p < 0.05). Thus the left brachial approach for intracoronary stent implantation is technically feasible, safe, and associated with fewer local vascular complications and a shorter hospitalization than the femoral approach.

Coronary angioplasty using an autoperfusion balloon catheter through a 6 French guiding catheter.

Use of 6 French guiding catheters for elective percutaneous transluminal coronary angioplasty has been limited by lack of a compatible autoperfusion balloon catheter for management of complications such as acute vessel closure and large subintimal dissections. We describe the successful use of a lower profile autoperfusion balloon catheter through large internal lumen 6F guiding catheters for elective coronary angioplasty. These cases demonstrate the feasibility of the use of autoperfusion balloon catheters with 6F guiding catheters in elective, and presumably also in emergent, settings.