Diagnostic and prognostic value of serial dobutamine stress echocardiography for noninvasive assessment of cardiac allograft vasculopathy: a comparison with coronary angiography and intravascular ultrasound.

BACKGROUND: Routine methods for surveillance of cardiac allograft vasculopathy (CAV) are coronary angiography and intravascular ultrasound (IVUS). This study analyzed the diagnostic and prognostic value of dobutamine stress echocardiography (DSE) for noninvasive assessment of CAV. METHODS AND RESULTS: In 109 heart transplant recipients, 333 DSEs were compared with 285 coronary angiograms and 199 IVUS analyses. Studies were repeated after 1, 2, 3, 4, and >/=5 years in 88, 74, 37, 18, and 7 patients, respectively. Resting 2D echocardiography detected CAV defined by IVUS and angiography with a sensitivity of 57% (specificity 88%). DSE increased the sensitivity to 72% (P=0.002). M-mode analysis increased the sensitivity of 2D rest and stress analysis (P=0.001, 0.004). Cardiac events occurred after 1.9% of normal stress tests by 2D analysis (combined 2D and M-mode: 0%), compared with 6.3% (3.8%) of normal resting studies. Worsening of serial DSE indicated an increased risk of events compared with no deterioration (relative risk 7.26, P=0.0014). Serial deterioration detected by stress only was associated with a higher risk of events than changes evident from resting studies (relative risk 3.06, P=0.0374). CONCLUSIONS: DSE identifies patients at risk for events and facilitates monitoring of CAV. A normal DSE predicts an uneventful clinical course and justifies postponement of invasive studies. The prognostic value of DSE is comparable to that of IVUS and angiography.

Rapid cardiovascular action of aldosterone in man.

Rapid nongenomic in vitro effects of aldosterone have been demonstrated recently in cultured vascular smooth muscle and endothelial cells. But there is, as yet, little evidence for corresponding in vivo effects. The present study thus investigates the rapid nongenomic effects of aldosterone on human cardiovascular function. In a double-blind placebo-controlled randomized parallel trial on 17 patients with suspected coronary heart disease, the effect of 1 mg aldosterone iv on cardiovascular function was assessed during cardiac catheterization. Hemodynamic parameters (such as heart rate, left ventricular and atrial pressures, arterial pressures, vascular resistances, and cardiac output) were measured before and 3 and 10 min after administration of aldosterone or placebo. Significant changes were found for systemic vascular resistance, cardiac output, and cardiac index, compared with the placebo group (Wilcoxon test, P < 0.02-0.05). The effect of aldosterone dissipated within 10 min. The results are in line with the in vitro data cited above and consistent with earlier findings on acute cardiovascular effects of aldosterone, which have now been confirmed and extended by contemporary techniques. The hypotheses of rapid nongenomic in vivo effects of aldosterone are further substantiated by this study.

Predictors of reduced coronary flow reserve in heart transplant recipients without angiographically significant coronary artery disease.

BACKGROUND: Determination of coronary flow reserve (CFR) is increasingly used to assess the functional significance of cardiac allograft vasculopathy. Although the relation between CFR and angiographically defined vasculopathy has been studied extensively, little is known about other factors determining CFR in heart transplant recipients without significant lesions by coronary angiography. METHODS: Sixty consecutive patients were studied 0.5 to 148 months after heart transplantation with intracoronary Doppler and intravascular ultrasound. An endothelium-independent CFR< or =2.5 was defined as abnormal. Stepwise logistic regression analysis was used to identify factors (demographic data of donor and recipient, lipid profile, epicardial vessel morphology by intravascular ultrasound, left ventricular hypertrophy, acute rejection episodes, and hemodynamics) potentially associated with a reduced CFR. RESULTS: Only the presence of left ventricular hypertrophy (48% vs. 14%, P=0.007 and P=0.023, bivariate and multivariate analysis, respectively) and higher donor ages (41+/-12 vs. 29+/-11 years, P=0.002 and P=0.013, bivariate and multivariate analysis, respectively) showed an independent association with an abnormal flow reserve. CFR in patients with left ventricular hypertrophy was reduced due to higher baseline flow velocities (27+/-11 vs. 20+/-6 cm/sec, P=0.004). Furthermore, resting flow velocity increased as a function of donor age (r=0.264, P=0.047), while hyperemic flow velocity was not different. Other patient characteristics and hemodynamics did not affect CFR. CONCLUSION: The presence of left ventricular hypertrophy and higher donor ages independently contribute to a reduced CFR in patients after heart transplantation. This reduction in CFR is due to elevated baseline flow velocities rather than to a change in hyperemic flow velocities. These findings should be taken into account for the interpretation of reduced CFR values obtained by intracoronary Doppler in heart transplant recipients without angiographically overt coronary lesions.

Dobutamine stress echocardiography for noninvasive diagnosis of cardiac allograft vasculopathy: a comparison with angiography and intravascular ultrasound.

This study was performed to assess the value of dobutamine stress echocardiography for noninvasive diagnosis of cardiac allograft vasculopathy (CAV) compared with coronary angiography and intravascular ultrasound (IVUS) in 50 consecutive orthotopic heart transplant recipients. In 46 of 50 patients, a technically adequate echocardiogram could be obtained. Using a 16-segment model, a total of 675 segments were analyzed. At rest, wall motion abnormalities were found in 61 of 675 (9.0%) left ventricular segments in 15 of 46 patients. At maximal dobutamine stress, 103 of 675 segments (15.3%) had wall motion abnormalities (25 of 46 patients). Based on IVUS and angiographic findings, patients were allocated to 2 groups. Group I (n=18) had absent or only mild intimal hyperplasia (mean IVUS grade < or = 3.0 on a 6-grade scale). Group II (n=28) had moderate to severe intimal hyperplasia (mean grade > 3.0 with or without angiographic evidence of CAV. The prevalence of wall motion abnormalities was significantly higher in group II than in group I, both at rest (50 of 415 vs 11 of 270 coronary segments in 13 of 28 vs 2 of 18 patients) and during maximal stress (88 of 415 vs 15 of 270 coronary segments in 22 of 28 vs 3 of 18 patients). Quantitative M-mode echocardiography demonstrated decreased wall thickening in group II versus group I patients at maximal dobutamine dosage in the septum (48 +/- 18% vs 61 +/- 17%; p < 0.01) as well as in the left ventricular posterior wall (77 +/- 21% vs 96 +/- 21%; p <0.005). Regional myocardial dysfunction as assessed by dobutamine stress echocardiography was associated with IVUS evidence of moderate to severe intimal hyperplasia. Dobutamine stress echocardiography appears to be a feasible noninvasive method for detection of CAV in heart transplant recipients, which may reduce the need for routine coronary angiography.

Adult human cardiomyocytes coexpress vimentin and Ki67 in heart transplant rejection and in dilated cardiomyopathy.

BACKGROUND: The aim of this study was to investigate whether adult human cardiomyocytes may reexpress vimentin and whether this is linked to cellular activation. METHODS: Myocardial samples of 81 heart transplant recipients (n=183) and patients with dilated cardiomyopathy (n=10) were investigated by immunohistochemistry with the use of the marker molecule vimentin, the muscle-specific protein desmin, and Ki67, a marker for cell activation. RESULTS: Vimentin protein expression in cardiomyocytes was found in 28 samples of transplant recipients and 5 myocardial samples of patients with dilated cardiomyopathy. Coexpression of vimentin and Ki67 was found in 52 of 340 vimentin-positive cardiomyocytes. CONCLUSIONS: We suggest that the vimentin/Ki67 coexpression indicates cell activation processes as the result of different growth stimuli.

Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound.

BACKGROUND: Coronary angiography is still the routine screening method for cardiac allograft vasculopathy in most transplant centers. This study was designed to analyze functional and morphologic changes in heart transplant recipients with normal angiographic findings. METHODS: Dobutamine stress echocardiography and intracoronary ultrasound were obtained in 56 patients with a normal coronary angiogram 41+/-31 months after heart transplantation. Intracoronary Doppler flow velocity measurements before and after intracoronary adenosine administration were performed in 34 of 56 patients. Any regional wall motion abnormalities detected by stress echocardiography were regarded as abnormal. By quantitative intracoronary ultrasound analysis using a 6-grade scale, a mean grade of all coronary segments >3.0 was defined as significant intimal hyperplasia. RESULTS: Only 17 patients (30%) showed both a normal dobutamine stress echocardiogram and absence of significant intimal hyperplasia by intravascularultrasound. Abnormal findings were observed in 39 patients (70%): both by dobutamine stress echocardiography and intravascular ultrasound in 22 patients, by intravascular ultrasound alone in 11 patients, and by dobutamine stress echocardiography alone in 6 patients. Coronary flow velocity reserve did not discriminate between patients with normal or abnormal intravascular ultrasound or dobutamine stress echocardiographic findings. CONCLUSIONS: Only a minority of heart transplant patients with a normal coronary angiogram is free of pathological changes, when assessed by intravascular ultrasound and dobutamine stress echocardiography. Coronary flow velocity reserve does not seem useful to further characterize these patients.

Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies.

BACKGROUND: There are no well-established diagnostic criteria to detect humoral rejection in organ transplantation. The value of commonly used markers in immunohistochemistry, such as C1q, C3c, IgG, IgM and fibrinogen, is questioned by some groups. Complement fragment C4d is a more stable marker of complement activation as it is covalently bound to graft capillaries. C4d has been shown to identify clinically relevant, but otherwise undetectable humoral anti-graft reactions in human kidney transplants. METHODS: Immunohistochemical techniques were used to evaluate 155 endomyocardial biopsies from 56 heart transplant recipients less than 3 months post transplantation for the presence of capillary C4d staining. In a subset of patients, C4d staining was compared with C1q, C3c, IgM and fibrin staining and was correlated with clinical outcome. RESULTS: Within 3 months 9 of 56 patients died. Five of these nonsurvivors had prominent C4d staining (p < .05), whereas C1q, C3c and IgM showed no correlation with clinical outcome. Presence of fibrin correlated with clinical outcome and C4d staining (p < .05). CONCLUSIONS: The capillary deposition of complement split product C4d in human endomyocardial biopsies was significantly associated with graft loss. Determination of fibrin deposition may yield additional information to establish a diagnosis of humoral rejection. The immunohistochemical assessment of capillary deposition of C4d and fibrin appears to be an appropriate tool for the identification of patients, who may require additional or alternative immunosuppressive therapy targeted against the humoral immune system.

Intravenous Albunex during transesophageal echocardiography: quantitative assessment by videodensitometry and integrated backscatter analysis from unprocessed radiofrequency signals.

This study investigates the comparative sensitivity of video and radiofrequency imaging to detect changes of the myocardial acoustic properties after intravenous Albunex. Thirty-six patients received Albunex, 0.08 and 0.22 ml/kg intravenously, during transesophageal imaging of the ventricular short axis. Analysis of video images was performed in all patients and of radiofrequency data in 20 patients. Although myocardial videointensity remained unchanged, 57% of the myocardial backscatter plots demonstrated significant contrast enhancement. The study demonstrates that intravenous Albunex is capable of myocardial contrast enhancement and proves the diagnostic superiority of radiofrequency compared with video imaging. Ultrasonic radiofrequency imaging may provide a technical basis for future noninvasive assessment of myocardial perfusion.

Transpulmonary contrast echocardiography: effects on delineation of endocardial border, assessment of wall motion and interobserver variability in stress echocardiograms of limited image quality.

BACKGROUND: A major limitation of stress echocardiography remains poor image quality. OBJECTIVE: To investigate the effects of transpulmonary contrast echocardiography (TCE) with BY 963 on endocardial border delineation, detectability of wall motion abnormalities and interobserver variability at rest and during dobutamine stress echocardiography (DSE) in subjects with technically limited baseline echocardiograms. METHODS: BY 963 was administered intravenously to 36 patients (5 ml for parasternal LAX/SAX, 10 ml for apical four-chamber/two-chamber view) both at rest and at peak stress during DSE. Two observers applied a delineation score (0, endocardial border not visible; 1 border poorly visible; and 2, border clearly visible) to 12 wall segments in the parasternal and 10 in the apical views both before and after administration of BY 963. A 16-segment wall-motion score was used. RESULTS: In parasternal views, the delineation score was not improved by TCE. In the apical views, TCE significantly increased the delineation score (from 14.1 +/- 5.4 to 20.7 +/- 4.2 at rest and from 14.6 +/- 5.7 to 21.7 +/- 4.1 under stress, both P< 0.01). For 18 of 25 patients with coronary artery disease (> or = 70% stenosis) results of DSE were positive before TCE, whereas results were positive for 21 patients during TCE. For 10 of 11 patients without coronary artery disease, results of DSE were negative both before and during TCE. For the apical delineation score, interobserver variability was decreased significantly by TCE (from 19.5 +/- 19.6 to 8.2 +/- 15.6% at rest and from 20.2 +/- 19.6 to 3.3 +/- 11.4% at peak stress, both P< 0.01). CONCLUSIONS: TCE enhances endocardial border delineation in apical views at rest and during DSE, resulting in a decrease of interobserver variability and an improvement in assessment of wall motion. Use of TCE, at least how it was applied in this investigation, seems not to be indicated for parasternal projections.

Stress echocardiography for assessment of cardiac allograft vasculopathy.

Invasive methods as coronary angiography and intravascular ultrasound (IVUS) are still the routine tools for diagnosis of cardiac allograft vasculopathy (CAV). Nevertheless, invasive tests are expensive and not free of risk. Dobutamine stress echocardiography (DSE) emerged as a useful noninvasive tool for assessment of cardiac allograft vasculopathy (CAV). In our study, echocardiographic wall motion abnormalities (WMA) at rest had a sensitivity of 57% (specificity 88%) to detect CAV defined by IVUS and angiography, which was significantly (p < 0.0001) improved to 72% (specificity 88%) by stress testing. Additional M-mode analysis of systolic wall thickening improved the sensitivity of the resting echocardiogram to 72% (specificity 85%), the combined M-mode and 2D-analysis during stress had a sensitivity of 85% (p < 0.0001; specificity 82%). DSE was also useful to predict prognosis: 1.9% of patients with normal, but 27.3% of patients with abnormal 2D-DSE developed cardiac events (heart failure, infarction, death, re-HTX, PTCA) between annual studies (p < 0.0002). No change in serial DSE studies was associated with a low event rate (4%), compared to serial DSE deterioration (29%, p < 0.0014). Based on our experience, we postpone invasive studies for 12-24 months, if DSE is normal or remains unchanged in serial studies. Angiography is used in patients with abnormal or deteriorating DSE. In conclusion, noninvasive DSE provides useful diagnostic and prognostic information. It appears safe to use DSE as a first step of CAV monitoring.

[Effect of enalapril, furosemide and verapamil on cyclosporin concentration in whole blood]. / Einfluss von Enalapril, Furosemid und Verapamil auf die Ciclosporin-Konzentration im Vollblut.

Introduction of ciclosporin A into immunosuppressive therapy is considered a major progress in improving results of organ transplantation. Clinical use of ciclosporin, however, is limited by a low therapeutic index and toxic side effects. Therefore, interactions of ciclosporin with other drugs are clinically important. In our study, we used enalapril, furosemide and verapamil for treatment of arterial hypertension in cardiac transplant recipients and investigated the influence of these drugs on ciclosporin whole blood trough levels. The antihypertensive regimen used in this study normalized blood pressure in each of the 25 patients. Enalapril and furosemide did not influence ciclosporin levels. Adding verapamil, however, resulted in a significant increase of ciclosporin levels, whereas cessation of the drug in one patient treated with verapamil only lowered ciclosporin levels. Thus, when verapamil is introduced or discontinued in patients on ciclosporin, close monitoring of ciclosporin levels and dosage adjustment are necessary. Besides its specific effects verapamil allows reduction of ciclosporin dosage necessary to maintain unaltered levels, which is important regarding cost of therapy. In general, use of any drug with unknown influence on ciclosporin levels requires careful monitoring, even if information exists on other substances of the same group of drugs in this respect. This is especially indicated in drugs known to influence the hepatic cytochrome P450 enzyme system.

Sulfadiazine therapy for toxoplasmosis in heart transplant recipients decreases cyclosporine concentration.

Toxoplasmosis may cause serious problems after organ transplantation. For treatment of active infection, pyrimethamine combined with a sulfonamide is recommended. During oral sulfadiazine therapy, a significant decrease in cyclosporine concentrations was observed in three heart transplant recipients. This interaction has not been reported previously.

[Infectious endocarditis following orthotopic heart transplantation]. / Infektiöse Endokarditis nach orthotoper Herztransplantation.

Infection remains a major problem in the early phase after heart transplantation. Immunosuppressive therapy is the most important predisposing factor. It may also reactivate preexisting latent endogenous infections. Unspecific symptoms and a chronic clinical course, as described in this report, may suggest infective endocarditis of the cardiac allograft. From this case, we do not suggest a general antibiotic prophylaxis for heart transplant recipients; however, special precaution should be considered in heart transplant patients with a history of endocarditis.

[Immunogenic hyperthyroidism with hyperdynamic heart failure and early cirrhotic transformation of the liver]. / Immunogene Hyperthyreose mit hyperdynamischem Herzversagen und beginnendem zirrhotischem Umbau der Leber.

HISTORY AND CLINICAL FINDINGS: A 58-year-old woman was admitted because of jaundice, ascites and marked oedema. For three years she had suffered from nervousness, decreasing fitness and weight loss, which had been assumed as due to chronic alcoholism. Liver biopsy revealed extensive fibrosis, in part with early cirrhotic transformation. This was followed by cardiac failure with atrial fibrillation (ventricular rate 140/min) and marked pleural effusions. The thyroid was diffusely enlarged and there were signs of exophthalmos. INVESTIGATIONS: Bilirubin concentration was 3 mg/dl, lactate dehydrogenase activity was 310 U/l, cholesterase 1.3 kU/l and the prothrombin test was 21%. The TSH level was 0.01 microU/ml while the free thyroxine level was 4.7 ng/dl and that of free triiodothyronine 13.5 pg/ml. Chest radiograph revealed cardiomegaly, bilateral peripheral pulmonary congestion and pleural effusions to midfield. Right heart catheterization excluded pulmonary hypertension; cardiac output was 10l/min. The thyroid was enlarged on ultrasound and diffusely echopoor, as in immune thyroid disease. TREATMENT AND COURSE: Cardiac failure regressed and thyroid function normalized within ten days on propranolol, 4 x 40 mg and thiamazole 3 x 40 mg daily intravenously. Subtotal thyroidectomy was performed three weeks later with subsequent thyroid hormone substitution. Liver functions were normal six months later and ultrasound showed no signs of cirrhotic change and the ascites had resolved. CONCLUSION: Hyperthyroidism is frequently associated with changes in liver functions. In extreme cases, high-output cardiac failure may occur, with liver congestion and clinical as well as histological changes like those in liver cirrhosis.

Conversion of atrial fibrillation to sinus rhythm: a possible side effect of transesophageal echocardiography.

Transesophageal echocardiography (TEE) is accepted as the procedure of choice for the diagnosis of intracardiac sources of systemic embolism. A case report is presented on a 74-year-old patient with atrial fibrillation referred for TEE evaluation after an acute embolic event. During TEE, atrial fibrillation converted to sinus rhythm. Although TEE is a very safe method, which is performed in increasing numbers of patients, this is the first reported case of conversion of atrial fibrillation to sinus rhythm during the procedure. We suggest that no restriction should be imposed on the use of TEE in patients with atrial fibrillation, as the small risk associated with conversion of atrial fibrillation is outweighed by the potential diagnostic benefits.

Cardiac function during graded bicycle exercise: Doppler-echocardiographic findings in normal subjects and heart transplant recipients.

Orthotopic heart transplantation results in altered atrial anatomy and denervation of the donor heart. To assess the impact of these sequelae on left ventricular filling and systolic performance, 16 heart transplant recipients and 10 normal controls were evaluated by Doppler echocardiography at rest and during graded bicycle exercise. Global and regional systolic ventricular allograft function was normal at rest and during exercise. Resting Doppler profiles demonstrated diminished atrial contribution to ventricular filling in transplant recipients. The response to dynamic exercise was different in both groups; controls increased heart rate, while mitral time-velocity integral was unchanged. Heart transplant recipients, in contrast, showed a blunted heart rate response and increased time-velocity integral. Atrial contribution to ventricular filling was not augmented during exercise as in normal controls. Alterations in transmitral flow profiles in heart transplant recipients do not necessarily reflect ventricular myocardial damage, but may be related to impaired atrial function.