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Background: Revision of the Task Force diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) has increased their sensitivity for the diagnosis of early and familial forms of the disease. The epsilon wave is a major diagnostic criterion in the context of ARVC/D, which, however, remains not quantifiable and therefore may leave room for substantial subjective interpretation.Objective: The purpose of this study was to assess interobserver agreement in epsilon wave definition and epsilon wave importance for ARVC/D diagnosis.Methods: Electrocardiographic (ECG) tracings depicting leads V1, V2, and V3 collected from individuals evaluated for ARVC/D (n = 30) were given to panel members who were asked to respond to the question whether ECG patterns meet epsilon wave definition outlined by the Task Force diagnostic criteria. The prevalence and importance of epsilon waves for ARVC/D diagnosis were assessed in a pooled data set of patients with definite ARVC/D from European and American registries (n = 815).Results: The number of ECG patterns identified as epsilon waves varied from 5 to 18 per reviewer (median 13 per reviewer). A unanimous agreement was reached for only 10 cases (33%), 2 of which qualified as epsilon waves and 8 as non-epsilon waves by all panel members. From a pooled data set, 106 patients reportedly had epsilon waves (13%). In 105 of 106 patients with epsilon waves (99%), exclusion of epsilon waves from the diagnostic score would not affect the "definite" diagnostic category.Conclusion: Interobserver variability in the assessment of epsilon waves is high; however, the impact of epsilon waves on ARVC/D diagnosis is negligibly low. The results urge to exercise caution in the assessment of epsilon waves, especially in patients who would not otherwise meet diagnostic criteria. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disease accounting for ventricular tachycardia and sudden death in the young and arising from areas of fibrofatty replacement of predominantly right ventricular myocardium. That some patients manifest life-threatening ventricular tachycardia in the absence of substantial myocardial replacement suggests that gap junction remodeling might be acting synergistically to ventricular remodeling to promote arrhythmogenesis. Hence, we sought to verify gap junction composition and distribution by analyzing the expression and occurrence of specific gap junction proteins (connexins [Cxs]) in patients with ARVC. Right ventricular endomyocardial biopsy specimens were taken from 16 patients with definite ARVC (age 48 - 16 years) and analyzed for Cx40, Cx43, and Cx45 messenger ribonucleic acid expression (relative to glyceraldehyde-3-phosphate-dehydrogenase messenger ribonucleic acid expression). The results were compared to those obtained from nondiseased donor hearts (n [ 6; age 32 - 11 years). The patients with ARVC showed a significant reduction in the messenger ribonucleic acid expression of Cx40 (p <0.0001) and Cx45 (p <0.0001) compared to that of the controls. The expression of Cx43 was similar in patients with ARVC and controls (p [ 0.098). Mutations in plakophilin-2 were identified in 7 of 16 patients (25%). The Cx expression levels were comparable between the mutation carriers and noncarriers (p [ NS). In conclusion, ARVC features alterations in the expression of Cxs and their distribution at cardiac intercalated discs. Apart from the deposition of extracellular matrix, the potential loss of gap junctions and shift in the composition of gap junctional Cxs in the ventricular conduction system might further contribute to the development of ventricular arrhythmias in patients with ARVC. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that cardiac sarcoidosis (CS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) can manifest very similarly. Objective: To investigate whether there are significant demographic and electrophysiological differences between patients with CS and ARVC. Methods: We prospectively compared patients with proven CS or ARVC who underwent radiofrequency catheter ablation of ventricular tachycardias by using 3-dimensional electroanatomical mapping. Furthermore, we evaluated whether the diagnostic criteria for ARVC would have excluded ARVC in patients with CS. Results: Eighteen patients (13 men; mean age 44.9 years) were included. All 18 patients had mild to moderately reduced right ventricular ejection fraction. Patients with cardiac sarcoidosis (n = 8) had a significantly lower mean left ventricular ejection fraction (35.6±19.3 vs 60.6±9.4; P = .002). Patients with CS had a significantly wider QRS (0.146 vs 0.110s; P = .004). Five of 8 (63%) patients with CS fulfilled the diagnostic ARVC criteria. Ventricular tachycardias (VTs) with a left bundle branch block pattern were documented in all but one patient (with CS). Programmed ventricular stimulation induced an average of 3.7 different monomorphic VTs in patients with CS vs 1.8 in patients with ARVC (P = .01). VT significantly more often originated in the apical region of the right ventricle in CS vs ARVC (P = .001), with no other predilection sites. Ablation success and other electrophysiological parameters were not different. Conclusions: The current diagnostic ARVC guidelines do not reliably exclude patients with CS. Clinical and electrophysiological parameters that were characteristic of CS in our patients include reduced left ventricular ejection fraction, a significantly wider QRS, right-sided apical VT, and more inducible forms of monomorphic VT. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present study was to assess the feasibility and safety of target-directed sampling of right ventricular (RV) endomyocardial biopsies (EMB) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Background: EMB is an integral part of the diagnostic evaluation of ARVC. Due to safety concerns, EMB are often obtained from the RV septum, which is usually spared from characteristic alterations. At our institution, EMB in ARVC patients were sampled target-directed from predilection areas and areas with abnormal contraction. Methods: Under fluoroscopic guidance, 3,777 EMB samples from 6 different RV sites were obtained in 482 patients who were evaluated for unclear cardiomyopathy (n = 280; 58%), assumed myocarditis (n = 59; 12%), or unexplained ventricular tachyarrhythmias (n = 143; 30%). Complication rates were compared with those from exclusively septal EMB procedures (n = 2,321) in 271 patients after heart transplantation (HTx). Results: Overall, no procedure-related deaths or sustained ventricular tachyarrhythmias occurred. A pericardial effusion was reported in 6 of 161 patients with the final diagnosis of ARVC (3.7%) needing no further intervention in all but 1 patient (0.6%) who required pericardiocentesis. Among the non-ARVC patients (n = 321), the incidence of a minor pericardial effusion (3.9%) and cardiac tamponade (2.2%) was comparable to that in ARVC (p = NS) but was higher when compared with HTx (p < 0.001). A transient complete atrioventricular block occurred in 1 of 321 non-ARVC (0.3%) and 2 of 271 HTx patients (0.1%). Conclusions: Multisite target-directed EMB sampling in ARVC is a safe procedure when performed by experienced interventionalists. The procedure-related complication rates were low and comparable to those in other cardiomyopathies. [Copyright &y& Elsevier]

Background: Prior reports on patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) focused on individuals with advanced forms of the disease. Data on the diagnostic performance of various testing modalities in newly identified individuals suspected of having ARVC/D are limited. Objective: The purpose of the Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia was to study the clinical characteristics and diagnostic evaluation of a large group of patients newly identified with ARVC/D. Methods: A total of 108 newly diagnosed patients with suspected ARVC/D were prospectively enrolled in the United States and Canada. The patients underwent noninvasive and invasive tests using standardized protocols that initially were interpreted by the enrolling center and adjudicated by blind analysis in six core laboratories. Patients were followed for a mean of 27 ± 16 months (range 0.2–63 months). Results: The clinical profile of these newly diagnosed patients differs from the profile of reported patients with more advanced disease. There was considerable difference in the initial and final classification of the presence of ARVC/D after the diagnostic tests were evaluated by the core laboratories. Final clinical diagnosis was 73 affected, 28 borderline, and 7 unaffected. Individual tests agreed with the final diagnosis in 50% to 70% of the 73 patients with a final classification of affected. Conclusion: The clinical profile of 108 newly diagnosed probands with suspected ARVC/D indicates that a combination of diagnostic tests is needed to evaluate the presence of right ventricular structural, functional, and electrical abnormalities. Echocardiography, right ventricular angiography, signal-averaged ECG, and Holter monitoring provide optimal clinical evaluation of patients suspected of ARVC/D. [Copyright &y& Elsevier]

Abstract: Background: The prognostic value of tissue Doppler imaging (TDI) in patients with chronic congestive heart failure (CHF) has not been compared against conventional measures of systolic, diastolic and overall left ventricular LV performance. The aim of this study was to assess the prognostic value of TDI-derived parameters in patients with CHF. Methods: One hundred thirty-two subjects with chronic CHF [due to ischemic (n=82) or dilated (n=50) cardiomyopathy, 101 males, mean age 57±11 years] underwent conventional two-dimensional/Doppler echocardiography and assessment of the Tei-index (isovolumic contraction time and isovolumic relaxation time divided by ejection time). Systolic, early and late diastolic mitral annular velocities (S′, E′ and A′) were derived from pulsed TDI. A cardiac event (cardiac death, urgent cardiac transplantation or hospitalization due to decompensated CHF) was defined as the combined study endpoint. Results: The patients were followed for a mean of 224±123 days. Thirty-one patients suffered an event (cardiac death, n=5; urgent cardiac transplantation, n=2; hospitalization due to CHF, n=24). In patients with event, ejection fraction was lower (25±10 vs. 32±9%), mitral deceleration time was shorter (138±58 vs. 193±72 ms), and the peak mitral E/E′-ratio (16.1±6.6 vs. 10.6±5.0) was significantly elevated as compared to patients free of events (p&#60;0.001 for all comparisons). In those patients, the Tei-index was elevated (1.09±0.39 vs. 0.86±0.26, p&#60;0.01), and a restrictive mitral filling pattern was more frequent (51.6 vs. 17.5%, p&#60;0.001). Stepwise multivariate analysis identified the mitral E/E′-ratio (p&#60;0.001) and the Tei-index (p=0.019) as the only independent predictors of a combined event. E/E′-ratio was the best predictor of hospitalization due to CHF also. In patients with mitral E/E′-ratio>12.5 or Tei-index>0.90, outcome was poor. Conclusions: In subjects with chronic CHF, the mitral E/E′-ratio is a stronger predictor of future cardiac events than conventional parameters of systolic, diastolic or overall LV performance. The E/E′-ratio may be a useful addition in the routine follow-up of such patients. [Copyright &y& Elsevier]

B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall tension. We studied the relation of NT-proBNP to Heart Failure Survival Score (HFSS) and New York Heart Association (NYHA) class in patients with chronic heart failure (CHF). We also studied the impact for recipient selection for cardiac transplant and assessed it as a predictive and prognostic marker of CHF.A total of 550 patients with dilative cardiomyopathy (n = 323), and coronary artery disease (n = 227) were prospectively examined. All patients underwent spiroergometry, echocardiography, right heart catheterization, and electrocardiogram. Routine blood levels and NT-proBNP were measured. The clinical selection for cardiac transplant candidates was adjudicated by 2 independent cardiologists who were blinded to the results of NT-proBNP assays. Clinical outcome and predictive power of NT-proBNP were analyzed.NT-proBNP levels in patients clinically considered for cardiac transplantation were significantly higher (2293 ng/ml vs 493 ng/ml; p < 0.001). The receiver operating characteristic (ROC) analysis regarding transplant candidacy showed an area under the ROC curve (AUC) of 0.84 ± 0.01 for HFSS, 0.86 ± 0.001 for NYHA, and 0.96 ± 0.01 for NT-proBNP. Patients with increasing NT-proBNP levels or remaining elevated levels despite adequate heart insufficiency treatment were maintained with left ventricular assist device implantation (n = 10) or urgent heart transplantation (n = 2). Patients with NT-proBNP levels above 5000 pg/ml had a mortality rate of 28.4% per year. Twenty-eight patients died during the observation period; all these patients were within NYHA Classes 3 and 4 (NT-proBNP 5423 ± 423 ng/ml).NT-proBNP discriminates patients at high likelihood of being a candidate for transplantation and provides prognostic informations in patients with CHF. NT-proBNP levels above 5000 pg/ml at admission were associated with death, and these levels markedly discriminated candidates for left ventricular assist devices or urgent transplantation. [Copyright &y& Elsevier]

Objectives: We used a murine model of arrhythmogenic right ventricular cardiomyopathy (ARVC) to test whether reducing ventricular load prevents or slows development of this cardiomyopathy. Background: At present, no therapy exists to slow progression of ARVC. Genetically conferred dysfunction of the mechanical cell–cell connections, often associated with reduced expression of plakoglobin, is thought to cause ARVC. Methods: Littermate pairs of heterozygous plakoglobin-deficient mice (plako+/–) and wild-type (WT) littermates underwent 7 weeks of endurance training (daily swimming). Mice were randomized to blinded load-reducing therapy (furosemide and nitrates) or placebo. Results: Therapy prevented training-induced right ventricular (RV) enlargement in plako+/– mice (RV volume: untreated plako+/– 136 ± 5 μl; treated plako+/– 78 ± 5 μl; WT 81 ± 5 μl; p < 0.01 for untreated vs. WT and untreated vs. treated; mean ± SEM). In isolated, Langendorff-perfused hearts, ventricular tachycardias (VTs) were more often induced in untreated plako+/– hearts (15 of 25), than in treated plako+/– hearts (5 of 19) or in WT hearts (6 of 21, both p < 0.05). Epicardial mapping of the RV identified macro–re-entry as the mechanism of ventricular tachycardia. The RV longitudinal conduction velocity was reduced in untreated but not in treated plako+/– mice (p < 0.01 for untreated vs. WT and untreated vs. treated). Myocardial concentration of phosphorylated connexin43 was lower in plako+/– hearts with VTs compared with hearts without VTs and was reduced in untreated plako+/– compared with WT (both p < 0.05). Plako+/– hearts showed reduced myocardial plakoglobin concentration, whereas β-catenin and N-cadherin concentration was not changed. Conclusions: Load-reducing therapy prevents training-induced development of ARVC in plako+/– mice. [Copyright &y& Elsevier]

In patients with chronic heart failure (CHF) and severe secondary mitral regurgitation (MR), the diagnostic usefulness and prognostic impact of tissue Doppler imaging (TDI) is unknown. This prospective study enrolled 370 patients with stable CHF. Severe secondary MR, defined as effective regurgitant orifice area >/=0.20 cm(2), was present in 92 patients (25%). Echo measurements comprised left ventricular volumes, ejection fraction, mitral E/A ratio, deceleration time, and TDI-derived mitral annular velocities (e.g., S', E', A', E/E'). During a follow-up of 790 +/- 450 days, all-cause mortality and rehospitalization data were analyzed. Patients with or without MR did not differ with respect to age or ejection fraction, but patients with MR were in a poorer New York Heart Association functional class and had a higher mitral E/E' ratio. During follow-up, 70 patients (18%) died and 134 patients (36%) were rehospitalized for worsening heart failure. Mortality rate was significantly higher in patients with versus without severe MR (33% vs 14%, p <0.001). In the MR group, the mitral E/E' ratio independently predicted all-cause mortality and was also significantly associated with rehospitalization for worsening heart failure. In patients with MR with an E/E' ratio >13.5, outcome was markedly worse compared with patients with an E/E' ratio

Abstract: Background: In patients with chronic heart failure (CHF), chronic kidney disease (CKD) is associated with increased morbidity and mortality, but contributing mechanisms are not well defined. This study tested the impact of CKD on intracardiac conduction, diastolic function and prognosis in patients with underlying CHF. Methods: We prospectively enrolled 269 patients with stable CHF, of whom 135 had CKD (estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2). Echo measurements comprised left ventricular dimensions/volumes, ejection fraction, mitral E/A-ratio, deceleration time and tissue Doppler mitral annular velocities (S′, E′, A′). PQ and QRS intervals were derived from the 12-lead ECG. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. Results: Patients with CKD had longer PQ and QRS intervals, and were in a poorer NYHA functional class as compared to patients without CKD. In patients with CKD, the mitral annular E′ velocity was lower, the mitral E/E′-ratio was higher and a restrictive mitral filling pattern was more frequent. By linear regression analysis, PQ and QRS intervals and the mitral E/E′-ratio were inversely related to the eGFR. During a follow-up of 507±375 days, 39 patients suffered a cardiac event. In CKD patients, outcome was markedly poorer as compared to those without CKD (event-free survival rate 51% vs. 87% in those without KD, p =0.001) Conclusions: In patients with CHF, CKD is associated with impaired intracardiac conduction and progressive diastolic dysfunction. Both mechanisms may contribute to increased morbidity and mortality of such patients. [Copyright &y& Elsevier]

Background: Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)–free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus. Methods: During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months. Results: After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 ± 0.6 vs 1.5 ± 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 ± 21.6 vs 61.8 ± 23.4 ml/[min · 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3). Conclusion: Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients. [Copyright &y& Elsevier]

Background: In patients with chronic heart failure (CHF), N-terminal pro–brain natriuretic peptide (NT-proBNP) provides relevant prognostic information, but its usefulness in the presence of kidney disease has been questioned. Methods: We prospectively enrolled 142 patients with stable CHF and a wide spectrum of renal function (estimated glomerular filtration rates [eGFRs] ranging from 17.1 to 100.3 ml/min/1.73 m2). Chronic kidney disease, defined as eGFR <60 ml/min/1.73 m2, was present in 63 patients (44%). NT-proBNP measurements were carried out on a bench-top analyzer (Elecsys 2010). Cardiac death or urgent cardiac transplantation were considered as a combined study end-point. Results: During a follow-up of 383 ± 237 days, 19 patients underwent a cardiac event (cardiac death, n = 17; urgent cardiac transplantation, n = 2). By multivariate Cox analysis, including clinical and laboratory variables, NT-proBNP and serum hemoglobin were independent prognostic predictors. In patients with NT-proBNP >1,129 pg/ml, outcome was significantly worse compared to patients with NT-proBNP <1,129 pg/ml (event-free survival rate 67% vs 94% in those with NT-proBNP <1,129 pg/ml, p = 0.001). By linear regression analysis, NT-proBNP levels were related to New York Heart Association (NYHA) functional class (R = 0.41, p < 0.001), and inversely related to eGFR (R = −0.29, p = 0.001) and to left ventricular ejection fraction (R = −0.43, p < 0.001). Conclusions: In CHF patients with and without kidney disease, NT-proBNP provides independent prognostic information. In such patients, NT-proBNP levels are not only reflective of a reduced clearance (i.e., a lower eGFR) but also of the severity of the underlying structural heart disease. [Copyright &y& Elsevier]

In patients with chronic heart failure and reduced systolic function, an implantable cardioverter-defibrillator (ICD) improves the prognosis, but morbidity and mortality remain high. We attempted to identify the prognostic impact of Doppler echocardiography and QRS duration in such patients. We prospectively enrolled 84 patients with chronic heart failure, an ICD, and impaired systolic function (mean ejection fraction 29 ± 10%). Echocardiographic measurements included left ventricular dimensions/volumes, ejection fraction, mitral E/A ratio, deceleration time, and tissue Doppler analysis of mitral annular velocities (S′, E′, A′). A cardiac event (death from pump failure or appropriate ICD therapy, i.e., antitachycardia pacing/shock due to sustained ventricular tachycardia or ventricular fibrillation) was defined as the study end point. During a follow-up of 373 ± 254 days, 22 patients (26%) had an event (death from pump failure, n = 7; patients who received an appropriate ICD therapy, n = 16). In patients with an event, the QRS duration was longer (169 ± 41 vs 146 ± 37 ms, p = 0.023), the mitral E/E′ ratio was higher (16.0 ± 6.5 vs 12.8 ± 5.9, p = 0.044), and a restrictive filling pattern was more frequent (44% vs 9%, p = 0.017). Stepwise multivariate Cox regression analysis identified a restrictive filling pattern as the only independent predictor of an event (hazard ratio 3.65, 95% confidence interval 1.54 to 8.64, p = 0.003). For patients with a restrictive filling pattern, the outcome was markedly poorer than that for patients with a nonrestrictive pattern (event-free survival rate 38% vs 72%, p = 0.005). In conclusion, in patients with chronic heart failure, an ICD, and systolic dysfunction, a restrictive filling pattern is an independent predictor of adverse cardiac events. [Copyright &y& Elsevier]

Objectives: This prospective study tested whether Doppler echocardiographic variables add incremental value to QRS duration in determining the prognosis of patients with chronic heart failure (CHF) and systolic dysfunction. Background: Diastolic dysfunction frequently is observed in patients with CHF, but its prognostic impact relative to that of QRS duration is unknown. Methods: A total of 193 patients with CHF and an ejection fraction <45% were enrolled prospectively. Echo measurements included left ventricular dimensions/volumes, ejection fraction, mitral early/late diastolic velocity ratio, deceleration time, and tissue Doppler mitral annular velocities. The mitral filling pattern was classified as either restrictive (RFP) or nonrestrictive. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. Results: During a follow-up of 385 ± 270 days, 24 patients suffered an event (cardiac death, n = 21; urgent transplantation, n = 3). The RFP, QRS duration, left ventricular systolic diameter, and mitral annular early diastolic velocity were independent predictors of an event. In patients with QRS duration >144 ms, the outcome was markedly poorer in the presence of RFPs as compared with their absence. Similarly, despite a QRS duration ≤144 ms, the outcome was worse in the presence of a RFP. A risk-stratification model based on the three strongest independent predictors separated groups into those with good prognosis and those with high, intermediate, and low event-free survival rates. Conclusions: In subjects with CHF and systolic dysfunction, transmitral flow patterns add incremental value to QRS duration in determining the prognosis. [Copyright &y& Elsevier]

The diagnostic usefulness of the mitral E/E′ ratio (derived from tissue Doppler imaging) as an estimate of left ventricular filling pressures was studied in 28 patients with diastolic heart failure (defined by heart failure signs and symptoms but with preserved ejection fraction) and in 46 patients with systolic heart failure (heart failure signs and symptoms and reduced ejection fraction). E/E′ was reflective of filling pressures in subjects with diastolic and systolic heart failure and may be of special use in ruling out elevated filling pressures in subjects with suspected diastolic heart failure. [Copyright &y& Elsevier]

Mitral annular velocities derived from tissue Doppler (S′, E′, A′) and left ventricular (LV) end-diastolic pressures were obtained in 11 patients with significant primary mitral regurgitation (MR), 26 patients with significant MR secondary to ischemic or dilated cardiomyopathy, and in 29 asymptomatic controls. The mitral E/E′ ratio was related significantly to LV end-diastolic pressure in patients with secondary, but not in patients with primary MR. In patients with secondary MR, a mitral E/E′ ratio >15 predicted an elevated LV end-diastolic pressure with a sensitivity of 80% and a specificity of 100%. Thus, the mitral E/E′ ratio is a reliable estimate of filling pressures only in subjects with significant secondary, but not with significant, primary MR. [Copyright &y& Elsevier]

In general, the failing human heart is characterized by a selective reduction in β1-adrenoceptors (β1-ARs) without change in β2-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing β-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac β1-ARs. The aim of this study was to develop potential high affinity β1-selective AR radioligands for the non-invasive in vivo imaging of the β1-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N′-[2-[3-aryloxy-2-hydroxy-propylamino]-ethyl]-urea derivatives and chain-elongated analogues, related to the established β1-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [125I]iodocyanopindolol ([125I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher β1-AR affinities (up to 76-fold) and β1-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity β1-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r–t). Future steps will include radiolabelling and pharmacokinetic evaluation of the β1-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias. [Copyright &y& Elsevier]

Objectives: To assess the potential of the donor heart to respond to interleukin-6 (IL6), the present study investigated the expression of IL6 receptor components in the myocardium of donor hearts before transplantation.Background: Donor heart dysfunction early after transplantation has been associated with the cytokine storm after donor brain death. Proinflammatory cytokines are thought to play a central role in this process. Interleukin-6 is of specific interest because it has been associated with cardiac allograft dysfunction and is related to an impaired prognosis. Its action requires expression of the specific IL6 receptor (IL6R), and the common signal transducer of the IL6 family glycoprotein 130 (gp130) in the donor heart.Methods: The activation of IL6, IL6R and gp130 messenger ribonucleic acid (mRNA) and protein was studied via reverse transcription-polymerase chain reaction (RT-PCR) and immunohistology in donor hearts (n = 6) and compared with patients undergoing evaluation of ventricular arrhythmias (control, n = 9) or with advanced heart failure (n = 20).Results: Messenger RNA of IL6, IL6R and gp130 was strongly expressed in all chambers of donor hearts, whereas right ventricles of control patients did not show any expression (donor vs. control: p < 0.005). Right ventricles of failing hearts showed IL6, IL6R and gp130 mRNA levels comparable with those found in donor hearts. Immunohistochemistry paralleled the RT-PCR data on the protein level. While IL6 was mainly expressed by myocytes, both receptor components were preferentially found mainly on interstitial cells.Conclusions: The expression of the IL6 receptor components in the donor heart before transplantation establishes the condition sine qua non for the response of the donor heart to circulating IL6. This mechanism may explain the close association of elevated IL6 serum levels to acute cardiac allograft dysfunction in the early perioperative period. [ABSTRACT FROM AUTHOR]