Systemic inflammatory response in cardiac allograft vasculopathy: high-sensitive C-reactive protein is associated with progressive luminal obstruction.

BACKGROUND: Response to immunologic and nonimmunologic injury has been reported to initiate the development of cardiac allograft vasculopathy (CAVD). Although histopathologic examinations reveal signs of focal inflammation, little is known about the systemic inflammatory response in this accelerated coronary syndrome. METHODS AND RESULTS: Therefore, we investigated high-sensitive C-reactive protein (CRP) in a large cohort of heart transplant (HTX) recipients (n=102, 90 male, mean age 45.2+/-11.5 years, 6.1+/-3.3 years after HTX) in correlation with a progression of luminal obstruction as assessed by serial coronary angiography (defined as an increase of focal stenosis >/=30% or detection of a new lesion) after a mean interval of 1.8+/-1.0 years. Patients with signs of an acute rejection or infection were excluded. In the entire group, CRP levels ranged from 0.2 to 12.7 mg/L (mean 2.6+/-2.7 mg/L). Patients with progressive CAVD (n=35) presented with significantly higher levels of CRP (4.1+/-3.3 mg/L) than did those with a nonprogressive course (n=67) (1.8+/-1.9 mg/L, P:=0.001). These observations were independent of the initial indication for HTX (atherosclerotic disorder versus cardiomyopathy, P:=0.18) and the severity of CAVD at baseline examination (P:=0.12). CONCLUSIONS: Progressive cardiac allograft vasculopathy is accompanied by a systemic inflammatory reaction, which gives further insight into the pathogenesis of this coronary syndrome and may well serve as an indicator for patients at risk.

Volumetric remodeling of the proximal left coronary artery: early versus late after heart transplantation.

OBJECTIVES: The aim of this study was to characterize progression of cardiac allograft vasculopathy (CAV) with special respect to coronary artery geometry. BACKGROUND: As previously shown by intravascular ultrasound (IVUS), CAV is characterized by a multifocal intimal hyperplasia. Little is known, however, about vascular remodeling processes influencing vessel geometry and luminal narrowing. METHODS: In 30 heart transplant recipients serial IVUS studies were performed at baseline (BL) and after a mean follow-up period of 12.5+/-2.5 months. Changes in plaque, lumen and vessel volume were assessed in the proximal left anterior descending artery. Pattern of remodeling was analyzed in patients "early" (n = 15, BL study 1.4+/-0.7 months after heart transplantation [HTX]) compared with "late" after HTX (n = 15, BL 46.1+/-29.1 months). RESULTS: Plaque volume was found to increase by a mean of 23.8+/-25.9 mm3, not significantly different within and beyond the 1st year after HTX. Significant differences, however, were observed in changes in vessel volume with a mean decrease of -52.8+/-70.9 mm3 in the early group, whereas late follow-up group presented with an enlargement of 32.3+/-46.0 mm3. Based on these changes, lumen volume decreased by -73.2+/-69.8 mm3 early, in contrast to a slight increase of 5.2+/-32.6 mm3 in the late group. CONCLUSIONS: Progression of CAV is a complex process, modified by changes in the vascular geometry. Especially within the 1st year after HTX, luminal loss is influenced not only by an increase in plaque area but by a decrease in total vessel volume as well.

Retrograde coronary venous contrast echocardiography: assessment of shunting and delineation of regional myocardium in the normal and ischemic canine heart.

Coronary venous injections of sonicated Renografin-76 were performed in seven closed chest dogs during two-dimensional echocardiography to study the ability of this new technique to opacify regional myocardium before and after occlusion of the left anterior descending coronary artery. The balloon of a 4F double lumen catheter was inflated in the great cardiac vein for each contrast injection to prevent backflow through the coronary sinus into the right atrium. Retrograde injections before coronary artery occlusion generally resulted in patchy myocardial contrast uptake. Injections after coronary occlusion always resulted in confluent and transmural myocardial opacification which occupied 42.8 +/- 8.6% (range 26 to 54) (mean +/- standard deviation) of the myocardial circumference. Retrograde opacification always extended into adjacent myocardium beyond the ischemic zone, which was assessed in echocardiograms with antegrade contrast injections into the left main coronary artery and which measured 30 +/- 6.3% of the ventricular circumference. Shunting from the coronary venous system to cardiac chambers was evaluated in a parasternal four chamber view and was graded on a scale of 0 to 4+. Contrast appearance was equally intense in the right atrium and right ventricle (3.5 +/- 0.6+, range 2+ to 4+), less intense in the left ventricular cavity (1.5 +/- 0.6+, range 1+ to 3+) and absent in the left atrium. Postmortem anatomic validation with retrograde great cardiac vein injections of indocyanine green corroborated and in vivo contrast appearance in chambers. Retrograde coronary venous contrast echocardiography appears capable of providing in vivo information about the extent and location of myocardial zones that can be reached by retrograde infusions of therapeutic agents and about the ability of these agents to reach ischemic myocardium. In addition, this new method allows for in vivo evaluation of shunts between coronary veins and cardiac chambers, which may influence the efficacy of retrograde interventions.

Impaired coronary dilator responses to substance P and impaired flow-dependent dilator responses in heart transplant patients with graft vasculopathy.

OBJECTIVES: Because pathologic mechanisms for transplant vasculopathy are still uncertain, we tested the hypothesis that endothelial function, in terms of the release of endothelium-derived relaxing factor (EDRF), is impaired in patients with evidence of angiographic transplant vasculopathy. BACKGROUND: The long-term prognosis after heart transplantation is mainly determined by the development of transplant vasculopathy. METHODS: The study included 23 patients undergoing diagnostic cardiac catheterization approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of transplant vasculopathy. Coronary flow velocity (by intravascular Doppler echocardiography) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary bolus injections (1 ml) of the endothelium-dependent dilator substance P (20 pmol) and the endothelium-independent dilators nitroglycerin (0.1 mg) and papaverine (8 mg). Substances were injected through the lumen of the Doppler catheter, which was placed into the midportion of the left anterior descending artery. RESULTS: Increases in blood flow velocity in response to substance P were significantly less in patients with than in patients without evidence of transplant vasculopathy. In addition, flow-mediated dilation of epicardial coronary arteries in response to papaverine was abolished in patients with such evidence. Vasodilation of epicardial coronary arteries in response to nitroglycerin and increases in flow velocity in response to papaverine were similar in both groups. CONCLUSIONS: These results suggest that transplant vasculopathy in heart transplant patients is associated with endothelial dysfunction (that is, impaired EDRF-mediated vasodilation). Furthermore, responsiveness of epicardial arteries to increased flow appears to be abolished in patients with evidence of transplant vasculopathy. These abnormal vascular functions may contribute to the pathogenesis of transplant vasculopathy and its vascular complications.

Impact of vascular branching sites on focal progression of allograft vasculopathy in transplanted hearts.

BACKGROUND: Cardiac allograft vascular disease (CAVD) represents one of the most accelerated progressing coronary syndromes in the human heart. A variety of risk factors have been identified over recent years; however, little is known about the influence of physical forces. As a model for differences in focal blood flow dynamics, we analyzed progression of intimal hyperplasia at vascular bifurcational sites using intravascular ultrasound (IVUS). METHODS: The most diseased vascular sites ("worst sites") in 59 coronary arteries were assessed (30 MHz, motorized pull back) in 25 consecutive heart transplant recipients at baseline (52.8+/-15.3 days postoperatively) and after 1 year of follow up (360.5+/-24.9 days). Progression of intimal hyperplasia was compared between branching and non-branching lesions as well as in focal relation to the position of the flow divider. RESULTS: A total of 41 (69.5%) worst sites were identified at branching locations. Progression of intimal hyperplasia was found to be significantly more severe at bifurcational sites with an increase in plaque area by 1.5+/-1.8 mm(2) in branching versus 0.4+/-0.6 mm(2) in non-branching lesions (P=0.015). The highest rate in focal progression was found at the opposite site of the flow divider with an increase in maximal intimal thickness by 0.3+/-0.23 mm (180 degrees ) as compared to 0.11+/-0.15 mm (90 degrees, P<0.001) and 0.15+/-0.15 mm (P=0.014) at 270 degrees. CONCLUSIONS: Using serial intravascular ultrasound examinations, vascular branching sites could be identified to be predisposing locations not only for a donor related arteriosclerosis, but also for progression of intimal hyperplasia within transplanted hearts. The highest regional increase in intimal thickness was found at the outer wall of the flow divider, suggesting focal shear or wall stress to be involved in pathogenesis.

Impact of chronic infection with chlamydia pneumoniae on incidence of cardiac allograft vasculopathy.

Chronic infection with Chlamydia pneumoniae (CP) is associated with development of coronary disease. However, little information exists concerning CP infection and impact on posttransplant cardiac allograft vasculopathy (CAV). A total of 202 patients were investigated 5.5+/-3.1 years after cardiac transplantation (46.5+/-11.0 years; 169 male, 33 female). Assessment of CAV was performed by annual coronary angiograms. Chlamydia serology (IgG/IgA) was performed using micro-immunofluorescence. Statistics comprised analysis of variance and Kaplan-Meier analysis. A total of 152 patients were CAV positive. Elevated titers were present in 45% (IgG) and 72.8% (IgA) of patients. Generally, serostatus was not associated with development of CAV when evaluated over the total postoperative interval. However, after month 14 there was a significant trend toward lower actuarial freedom from CAV in patients with elevated IgA titers. CP seems not to play a significant role in the development of CAV early after heart transplantation but might be a predicting risk factor after the first postoperative year.

Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms.

BACKGROUND: Recently, homocysteine (HCY) levels have been suggested to be a risk factor in cardiac allograft vascular disease (CAVD). As plasma levels are partially under genetic control, we investigated the influence of the methylenetetrahydrofolate reductase (MTHFR) polymorphism on HCY levels and development of CAVD in heart transplant (HTX) recipients. METHODS: Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography. RESULTS: Actuarial freedom from CAVD did not differ significantly between the genotypes. However, patients positive for CAVD presented with higher HCY levels than CAVD-negative individuals (21.0+/-9.4 vs. 18.2+/-6.6 micromol/L, P=0.046). CONCLUSIONS: There is some evidence that plasma HCY might be involved in development of CAVD. However, polymorphism of the MTHFR gene could not be shown to be related to severity of allograft vascular disease.

Impact of plaque burden on compensatory enlargement of coronary arteries in cardiac allograft vasculopathy. Working Group on Cardiac Allograft Vasculopathy.

Using intravascular ultrasound, we demonstrated plaque-induced compensatory enlargement of coronary arteries in cardiac allograft vasculopathy. Besides intimal hyperplasia, adaptive remodeling processes of vessel and luminal geometry have physiologic and prognostic importance.

Usefulness of increased myocardial cyclic adenosine 3',5'-monophosphate content as a sign of rejection after cardiac transplantation.

Cardiac allograft rejection represents a series of cellular and molecular events triggered by the recognition of the graft by the host immune system. One of the second messenger systems involved in mitogenic mechanisms is the cyclic adenosine 3',5'-monophosphate (cAMP)-coupled signaling system. The aim of this preliminary study was to evaluate whether rejection after cardiac transplantation is accompanied by changes in the expression of cAMP. Myocardial cAMP content was determined by radioimmunoassay in endomyocardial biopsy specimens taken during routine follow-up after cardiac transplantation with or without cellular and/or vascular (i.e., coronary vasculopathy) rejection, respectively. Analysis of the different subgroups of patients showed that patients without any signs of rejection (no vasculopathy, no cellular rejection) had the lowest myocardial cAMP content (1.41 +/- 0.12 pmol/mg wet weight). Patients with either cellular or vascular rejection had significantly higher myocardial cAMP levels (2.25 +/- 0.29 and 2.24 +/- 0.59 pmol/mg wet weight, respectively, p < 0.05). Patients with both cellular rejection and coronary vasculopathy had the highest cAMP levels (5.95 +/- 1.6 pmol/mg wet weight; p < 0.001). We speculate that cAMP may play a functional role in mediating rejection induced by mitogenic factors activated after cardiac transplantation, suggesting a possible "cross-talk" between different cellular signaling pathways.

Multidrug resistance in heart transplant patients: a preliminary communication on a possible mechanism of therapy-resistant rejection.

Multidrug resistance refers to a complex cellular phenotype, the hallmark of which is cross-resistance to multiple drugs, for example, chemotherapeutic agents, that are unrelated to the selecting agent in structure, cellular target, and mode of action. The expression of this multidrug resistance is connected with the overexpression of P-glycoprotein. By applying the method of immunocytochemical assay, we have demonstrated the appearance of the multidrug-resistant phenotype (P-glycoprotein+ cells, multidrug-resistant cells) in mononuclear cells of the peripheral blood from 32/49 patients receiving triple-drug (azathioprine, steroids, cyclosporine) immunosuppressive therapy after heart transplantation. In the group of patients showing not only the presence of cells with multidrug-resistant phenotype in the peripheral blood, but also a significant increase in the number of these cells during the interval of observation (0 to 767 days)-16/32/49 cases--a significantly increased incidence of acute rejection episodes could be demonstrated. This supports the hypothesis of a possible existence of a therapy-resistant form of acute rejection, with an involvement of mechanisms of multidrug-resistance playing a role in its causal development.

ACE-gene polymorphism is associated with the development of allograft vascular disease in heart transplant recipients.

BACKGROUND: Cardiac allograft vascular disease is (CAVD) the most important cause of death following heart transplantation (HTX). Although in the past, researchers focused predominantly on mechanisms of endothelial injury, the possible role of recipient-related and genetically determined factors has not been studied in detail. METHODS: Stimulated by recent observations in native coronary artery disease, we analyzed the potential impact of angiotensin-converting enzyme (ACE) polymorphism (insertion/deletion [I/D], intron 16) on development and progression of CAVD. We characterized genotype in 146 patients 1 to 12 years after HTX (121 men; mean age, 46.2+/-11.3 years; observation period, 6.1+/-3.8 years) and correlated genotype to the onset and progression of CAVD, defined as luminal obstruction > 50%. RESULTS: We found allelic frequencies to be 28.8% (n = 42) for ACE-DD, 49.3% (n = 72) for ACE-DI, and 21.9% (n = 32) for ACE-II. Differences in actuarial freedom from vasculopathy were significant 6 years after transplantation, with 84.6% for ACE-II compared with 54.4% for ACE-DD. We observed intermediate results for ACE-DI genotype (77.3%, p = 0.015). CONCLUSIONS: In this large cohort study, we demonstrated a close relationship between the recipient-related ACE-D genotype and development of advanced CAVD. These observations suggest that gene-environment interactions might be clinically important in coronary vasculopathy after HTX.

Plasma thromboxane B2 as an early marker of acute graft rejection after heart transplantation: preliminary report.

Six patients undergoing heart transplantation were followed up by serial endomyocardial biopsies to detect signs of graft rejection and the plasma level of thromboxane B2 was measured at the same time. During the operative procedure and concomitant with histologic signs of acute graft rejection, the plasma level of thromboxane B2 significantly increased. After immunosuppressive treatment with steroids and either antithymocyte globulin or monoclonal antibody, regression of the histologic signs of rejection and a significant fall in the level of thromboxane B2 were documented. We conclude that the plasma level of thromboxane B2 may be useful as an early marker of acute graft rejection after heart transplantation.

Some aspects of changed histopathologic appearance of acute rejection in cardiac allografts after prophylactic application of OKT3.

The histopathologic findings of therapy-requiring acute rejection in the cardiac allograft observed in endomyocardial biopsy specimens taken from patients under prophylactic administration of OKT3 show certain differences in comparison with the classic description of acute rejection. These differences are characterized above all by a distinctly reduced cellularity of the infiltrates, with a relative decrease of T cells, as well as edema and retrogressive changes, up to necroses of myocytes with marked fragmentation; some patients also have increased vascular reactions. Furthermore, an earlier occurrence of and an increased frequency of changes corresponding to the so-called lymphoma-like lesions ("Quilty" effect) were observed in patients who received immunosuppressive prophylaxis with OKT3. The changed histopathologic findings of therapy-requiring acute rejection under prophylactic application of OKT3 may, to a certain extent, explain the discrepant results reported by different transplant groups with respect to the frequency of rejection episodes and the time when the first episode of therapy-requiring rejection occurs after heart transplantation.

Preventive treatment of coronary vasculopathy in heart transplantation by inhibition of smooth muscle cell proliferation with angiopeptin.

BACKGROUND: The underlying mechanism of accelerated coronary vasculopathy in cardiac allografts still remains unclear. Our hypothesis was that inhibition of smooth muscle cell proliferation with the somatostatine analogue Angiopeptin may reduce vasculopathy. METHODS: Fifty-four patients received Angiopeptin injections (1500 micrograms x three times daily subcutaneously) for 21 days after the operation and three additional injections with every rejection treatment. Angiography was performed yearly, and data were compared with a matched historic control group. RESULTS: Actuarial survival was 85% at 1 year and 80% at 2 years, comparable with our results in general (80%/77%). Forty-six long-term survivors could be followed by coronary angiography. At 1 year, vasculopathy was assessed in nine patients (17%). Of the 18 patients investigated at 2 years thus far, an additional three patients were found to have vasculopathy. In the control group vasculopathy was comparable, being 13% after 1 year and 20% after 2 years. A significantly lower incidence of rejections and lower creatinine values were found in the study group within the entire observation period (p < 0.05). CONCLUSIONS: We conclude that Angiopeptin treatment appears to be safe without significant side effects; it may reduce the number of acute rejections, at least during the first year after heart transplantation. However, the results of the 2-year follow-up in the remaining patients would have to be included in assessing the effect of Angiopeptin. Long-term follow-up will be necessary to decide whether Angiopeptin will be helpful in reducing the incidence of transplant vasculopathy.

Steal phenomenon caused by a parallel branch of the internal mammary artery.

We report on a patient with postoperative mammary artery steal resulting from a parallel branch of the vessel as well as from a patent first left intercostal artery, both of which had not been divided. The patient was cured of angina pectoris after embolization of both vessels.

Systemic recombinant tissue plasminogen activator lysis for left atrial thrombus formation after single-lung retransplantation.

This report describes a recipient of single-lung transplantation surviving extraordinary complications: (1) early graft failure mandating retransplantation; (2) left atrial thrombus formation, which resolved by recombinant tissue plasminogen activator lysis; (3) and development of a "locked-in-syndrome." Possible underlying mechanisms are discussed.

Nisoldipine versus isosorbide dinitrate in coronary heart disease: results of a double-masked study.

The efficacy and tolerability of a twice-daily dose of 5 mg of nisoldipine versus 40 mg of sustained-release isosorbide dinitrate (ISDN) were compared in a randomized, double-masked study in 91 patients. During the 21-day treatment period, the mean time taken during bicycle ergometry to the appearance of an ST segment depression of at least 0.1 mV compared with the resting value increased from 287 +/- 129 seconds to 391 +/- 150 seconds in the nisoldipine group and from 254 +/- 140 seconds to 350 +/- 191 seconds in the ISDN group. The mean value at the end of treatment calculated by using analysis of covariance was 383 seconds in both groups. The difference between the two treatment groups was not statistically significant. The mean ST segment depression at individually maximal workload decreased from 0.19 +/- 0.07 mV to 0.12 +/- 0.08 mV in the nisoldipine group and from 0.18 +/- 0.07 mV to 0.14 +/- 0.08 mV in the ISDN group. The mean total duration of exercise increased from 420 +/- 161 seconds to 497 +/- 140 seconds in the nisoldipine group and from 425 +/- 167 seconds to 456 +/- 168 seconds in the ISDN group. In the nisoldipine group, 9 patients reported 12 adverse events that were considered to be possibly or probably related to the test medication; in the ISDN group, 13 patients reported 26 adverse events. Although the anti-ischemic effect of the two treatments was comparable, nisoldipine was descriptively superior to ISDN in terms of tolerability.

Prediction of the onset of atrial fibrillation after cardiac surgery using the monophasic action potential.

OBJECTIVE: To show that the monophasic action potential (MAP) recorded continuously from human epicardium may be used to predict the imminent onset of atrial fibrillation or flutter (AF) following surgery, thus allowing prophylactic treatment to be started. PATIENTS: 22 patients (14 male, 8 female; mean (SD) age 64 (12) years) undergoing aortic valve replacement. SETTING: Tertiary referral centre. METHODS: Over a mean observation period of 8 (2.7) days (range 4 to 14), nine episodes of AF were seen in six patients. Before AF, specific and significant alterations of the MAP morphology were observed. In seven of nine episodes the MAP shortened (25 (4)% 60 minutes before AF), developed a triangular shape, and the plateau amplitude decreased from 5.3 (1.2) to 2 (0.2) mV. In the two remaining episodes the beat to beat variability of cycle length and MAP duration at 90% repolarisation (MAPd90) increased significantly from 24 (7) ms and 12 (8) ms (24 hours before AF) to 137 (27) ms and 56 (11) ms (30 minutes before AF) respectively. AF was successfully treated by the administration of sotalol in three cases and by a combination of verapamil and digoxin in a further four. Previously observed changes of MAPd90 and MAP morphology regressed after conversion to sinus rhythm. CONCLUSIONS: The continuous and intermediate term recording of the MAP from atrial epicardium appears to be a valid tool for detecting imminent AF after cardiac surgery with a high sensitivity (99%) and specificity (88%). Optimised antiarrhythmic treatment may thus be given selectively for prophylaxis.

Acute influence of beta-adrenergic antagonists on left ventricular diastolic function: contrasting results after administration of celiprolol and metoprolol.

Various beta-adrenergic receptor antagonists have different effects on myocardial function. A clinical study was performed in 30 patients with symptomatic coronary artery disease and systemic hypertension to compare the effects of single intravenous doses of 0.15 mg/kg celiprolol (n = 16) (third generation beta-blocking agent) and metoprolol (n = 14) (second generation) on left ventricular diastolic function. Parameters derived from pressure, volume, flow, time intervals and their combination were used to characterise diastolic function. After celiprolol administration, parameters of diastolic myocardial function improve (dp/dtip-; relaxation time constant T1, peak filling rate PFR; first-third filling rate FF1/3 or diastolic wall stress-time integral Sigdiasc) or remain unchanged. In contrast, after metoprolol administration parameters of diastolic function seem to be deteriorated (dp/dtip-, T1; Sigdiasc). This indicates an improvement in myocardial relaxation and filling under the influence of celiprolol but not under metoprolol. The left shift of the pressure-volume loops after celiprolol (n = 13), in contrast to metoprolol, supports this interpretation. Celiprolol did not show any deterioration of diastolic function in patients with coronary heart disease and arterial hypertension under these acute conditions.

The inferior epigastric artery for coronary bypass grafting. Functional assessment and clinical results.

The use of the internal thoracic artery (ITA) for coronary bypass grafting (CBG) has resulted in superior long-term function. Other autologous arteries have been investigated also, but the role of the inferior epigastric artery (IEA) for CBG has not yet been defined. From March 91 to August 92, IEA grafts were used in 50 male patients aged 30-68 years/mean 54.9) combined with 1 (n = 40) or 2 (n = 8) ITA grafts. Pedicled grafts were dissected (length: 8.5-16.5, 13.1 cm) but left in situ covered by sponges soaked with papaverine solution until going on bypass. There was no mechanical or pharmacological intraluminal manipulation. Distal free flow (in situ) was 41.8 ml/min (16-95 ml/min). A total of 146 grafts were constructed (2.9/patient), including free IEA-CBG performed to the LAD (n = 28) or its diagonal branches (n = 22). The operative mortality was 2.0%, there were no sternal wound complications but superficial abdominal infections in 5 patients. Recatheterization (1-6 months postoperatively) revealed an 82.6% patency rate (19/23) in IEA, compared to 100% in ITA, grafts. In vitro stimulation of arterial segments by endothelium- or muscular-dependent relaxation revealed a response (% of the maximum) of 92.4% in IEA and 74.6% in ITA to acethylcholine, while the response to nitroglycerin was 92.7% and 98.6%, respectively. Our clinical results would support the concept of combining IEA and ITA for arterial revascularization in CBG. Inferior epigastric artery grafts should provide adequate blood flow and good long-term patency due to preservation of their endothelial function.