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Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.Die arrhythmogene Kardiomyopathie (AC) ist eine seltene Herzmuskelerkrankung mit genetischem Hintergrund und autosomal-dominantem Erbgang. Die AC ist charakterisiert durch ventrikuläre Arrhythmien (VA), Herzinsuffizienz (HF) und ein erhöhtes Risiko des plötzlichen Herztods (SCD). Schwangerschaften bei jungen Patientinnen mit AC stellen eine besondere Herausforderung mit hoher Bedeutung für die Lebens- und Familienplanung betroffener Frauen dar. Neben genetischen Mechanismen mit ihrem Einfluss auf die komplexe Pathophysiologie der AC belegen experimentelle und klinische Daten den pathogenetischen Zusammenhang von Ausdauerbelastung und Leistungssport mit dem frühzeitigen Auftreten und der raschen Progression von Symptomen und Komplikationen der AC. Schwangerschaft und Leistungssport teilen einige physiologische Anpassungsvorgänge. Bei AC führen beide zu ventrikulärer Volumenbelastung und myokardialen Dehnungsreizen. Daher wurde postuliert, dass bei AC Schwangerschaften mit einem erhöhten Risiko von HF, VA, und SCD sowie schwangerschaftsspezifischen Komplikationen einhergehen. Diese Hypothese konnte jedoch bislang nicht belegt werden. Bei der Mehrzahl der Frauen mit AC werden Schwangerschaften gut toleriert und verlaufen unauffällig. Schwangerschaftsbedingte Symptome (VA, Synkope, HF), und peripartale Komplikationen treten bei AC nicht häufiger auf, die Mortalität ist nicht erhöht. Auch die Anzahl vollendeter Schwangerschaften korreliert nicht mit einem früheren Auftreten oder beschleunigten Verlauf pathologischer Veränderungen oder einem erhöhten Risiko von VA oder HF während der Schwangerschaft oder im postpartalen Verlauf. Zusammenfassend bestehen somit bei Frauen mit AC keine medizinischen Argumente, von einer Schwangerschaft abzuraten. Voraussetzungen sind eine stabile Ausgangssituation von Rhythmus und Hämodynamik sowie eine multidisziplinäre Mitbetreuung und klinische Verlaufskontrolle während und nach der Schwangerschaft. Zudem sollte jeder Patientin mit AC, ihrem Partner sowie der Familie vor einer Schwangerschaft eine genetische Beratung angeboten werden.

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

ObjectivesN-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.MethodsWe prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.ResultsOf 357 patients enrolled, the median age was 52 (IQR: 36–65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p–4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1–2 vs 3–4 (HR=0.35, 95% CI 0.16 to 0.77, pConclusionsMR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients.

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Summary Aim: To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2 15O-PET). Results: Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml-1*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml-1*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml-1*min*ml; p = ns) showed sex-related differences. Conclusion: Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

□ Die arrhythmogene rechtsventrikulare Kardiomyopathie (ARVC) ist charakterisiert durch regional betonte Degeneration und Atrophie des rechtsventrikularen Myokards mit nachfolgendem Ersatz durch Fett- und Bindewebe. Die Erkrankung manifestiert sich im Jugend- oder jungen Erwachsenenalter, Manner sind haufiger betroffen. Leitsymptome der ARVC sind ventrikulare Tachyarrhythmien mit linksschenkelblockartiger Konfiguration. Auch plotzliche Herztodesfalle konnen die primare Manifestation der ARVC darstellen.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. Methods During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). Results Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. Conclusions The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of β-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.

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 (p0.0001) and Cx45 (p0.0001) 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.

A 73-year-old patient with permanent atrial fibrillation presented for left atrial appendage (LAA) occlusion. Transesophageal echocardiography demonstrated a thrombus in the distal LAA. This image series illustrates a "no touch" technique that was used to ensure successful implantation of an Amplatzer Amulet LAA occlusion device without the use of an embolization protection system.

To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET).Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences.Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

We appreciated the interest of Barison and colleagues in our International Consensus Statement on the treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).1 Our document provided a comprehensive overview and recommendations for risk stratification and therapy of patients fulfilling the diagnostic criteria for ARVC/D. These criteria had been addressed by a previous International Task Force consensus document dedicated to diagnosis of ARVC/D.2 According to the revised criteria proposed by the International Task Force in 2010, the diagnosis of ARVC/D is based on the presence of major and minor criteria encompassing electrocardiographic, arrhythmic, morphological, histopathologic, and genetic factors. Diagnosis of definite ARVC/D is fulfilled in the presence of 2 major criteria or 1 major plus 2 minor or 4 minor criteria from different groups; the ARVC/D diagnosis is possible or borderline in the presence of insufficient criteria. In their Letter to the Editor, Barison and colleagues emphasized the valuable role of cardiac magnetic resonance (CMR) for diagnosis of ARVC/D, which relies on its ability to combine evaluation of ventricular size, function, and regional wall motion with characterization by late-gadolinium enhancement (LGE) of fibro-fatty myocardial scar, which is the hallmark lesion of ARVC/D. We totally agree that CMR is becoming the gold standard tool for detection of structural and functional ventricular abnormalities in ARVC/D. In the 2010 International Task Force consensus document, CMR was appropriately included among the diagnostic imaging techniques, and specific CMR reference values for normal (and abnormal) ventricular size, systolic function, and regional dyssynergy were provided. Tissue characterization by LGE was not included among these diagnostic criteria because of the potential risk of misdiagnosis of ARVC/D related to the difficulty of assessing LGE at the level of the thin right ventricular wall and possible confusion with normal epicardial fat tissue. More recently, the frequent involvement by the disease of the left ventricular wall in the form of epicardial-mediomural LGE has been recognized. As pointed out by the authors, LV LGE may enhance sensitivity for early/minor or predominant left variants of the ARVC/D; however, its diagnostic accuracy remains to be established. The prognostic role of CMR and, in particular, of postcontrast sequences for tissue characterization in patients with a diagnosis of definitive ARVC/D remains elusive. In our consensus statement on the treatment of ARVC/D, we performed a systematic review of outcome studies on ARVC/D available in the literature to identify predictor variables that were associated with an increased risk of major arrhythmic events (ie, sudden cardiac death, appropriate defibrillator interventions, or defibrillator therapy on fast ventricular tachycardia/ventricular fibrillation), nonsudden cardiac death, or heart transplantation in at least 1 published multivariable analysis. Although the predicting value of CMR for worse arrhythmic outcome was shown in the general population of patients showing premature ventricular beats with a left bundle branch morphology4 and in patients with suspected diagnosis of ARVC/D,5 no specific features of CMR, either alone or in combination, have been reported yet as independent predictors of life-threatening arrhythmic events in patients with a definite diagnosis of ARVC/D. This lack of evidence underscores the importance of undertaking future studies on this field.

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 V 1 , V 2 , and V 3 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.

Aims Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC and RVOT using a body surface mapping (BSM). Methods and results A 120-channel BSM with quantitative signal analysis of the T-wave integral was performed in 10 patients with ARVC. Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects (controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right lower anterior region of the torso when compared with RVOT ( P < 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of −0.3 mV ms, sensitivity and specificity were 83% [area under curve (AUC) 0.85 ± 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced in ARVC patients with a plakophlin-2 mutation ( P < 0.001). Conclusion Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from RVOT patients and controls and may serve as an additional diagnostic tool.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a nonischaemic cardiomyopathy and leading cause of sudden death in the young. It has been shown that microvascular dysfunction reflected by an impaired myocardial blood flow (MBF) response to stress is present in patients with other forms of nonischaemic cardiomyopathy, e.g. dilated cardiomyopathy, and that the reduced MBF may be related to a poor prognosis. Therefore, we quantified MBF, coronary flow reserve and coronary vascular resistance in patients with nonfailing ARVC using H 2 15 O and PET. In ten male patients with ARVC (mean age 49 ± 14 years), MBF was quantified at rest and during adenosine-induced hyperaemia using H 2 15 O PET. Results were compared with those obtained in 20 age-matched healthy male control subjects (mean age 46 ± 14 years). Resting MBF was not significantly different between patients with ARVC and controls (MBFrest 1.19 ± 0.29 vs. 1.12 ± 0.20 ml/min/ml). However, hyperaemic MBF was significantly lower in patients with ARVC than in controls (2.60 ± 0.96 vs. 3.68 ± 0.84 ml/min/ml; p = 0.005). Consequently, patients with ARVC had a significantly lower coronary flow reserve than control subjects (2.41 ± 1.34 vs. 3.39 ± 0.93; p = 0.030). In addition, hyperaemic coronary vascular resistance was increased in patients with ARVC (36.79 ± 12.91 vs. 26.31 ± 6.49 mmHg × ml-1 × min × ml; p = 0.007), but was found to be unchanged at rest. In this small well-characterized cohort of patients with nonfailing ARVC, we found a significantly reduced hyperaemic MBF and increased coronary vascular resistance. Further studies are necessary to corroborate this potential new functional aspect of the pathophysiological mechanisms underlying ARVC.

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 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.

Background: In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS. Methods and Results: Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 ± 15 years) and five controls (three male; age 43 ± 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5′monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (Gi1,2α), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, Gi1,2α, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations. Conclusions: The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of β-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis. (PACE 2011; 34:1147–1153)

Aims Dilated cardiomyopathy (DCM) is familial in ∼30% of cases, and mutations have been identified in several genes. However, in a majority of familial cases, the responsible genes are still to be discovered. The ANKRD1 gene is over-expressed in heart failure in human and animal models. The encoded protein CARP interacts with partners such as myopalladin or titin, previously shown to be involved in DCM. We hypothesized that mutations in ANKRD1 could be responsible for DCM. Methods and results We sequenced the coding region of ANKRD1 from 231 independent DCM cases. We identified five missense mutations (three sporadic and two familial) absent from 400 controls and affecting highly conserved residues. Expression of the mutant CARP proteins after transfection in rat neonate cardiomyocytes indicated that most of them led to both significantly less repressor activity measured in a reporter gene assay and greater phenylephrin-induced hypertrophy, suggesting altered function of CARP mutant proteins. Conclusion On the basis of genetic and functional analysis of CARP mutations, we have identified ANKRD1 as a new gene associated with DCM, accounting for ∼2% of cases.

Background— Brugada syndrome (BrS) is characterized by the presence of coved ST-segment elevations in the right precordial leads (so-called type I ECG) and additional clinical features. Caused by cardiac ion channel gene mutations, BrS may be associated with ventricular and atrial conduction disturbances as well as ventricular fibrillation. Recent studies have discussed whether BrS is merely a primary electric disorder or whether inflammatory or other histopathologic abnormalities in the right ventricle (RV) underlie the ECG phenotype. Methods and Results— We retrospectively analyzed BrS biopsy samples from 21 unrelated patients for histopathologic abnormalities (hypertrophy, fibrosis, inflammation, fatty tissue) together with the patients’ clinical, genetic, and imaging data. Eleven patients (52%) had normal RV imaging (by angiography, echocardiography, or cardiac MRI). Results of myocardial biopsies were normal in 3 patients (14%) and revealed mostly moderate abnormalities in the others. Four patients (19%) had predominant fatty tissue in the RV myocardium. Using immunohistochemistry and conventional tissue staining, we could not detect inflammatory tissue changes, an observation compatible with the clinical absence of signs for myocarditis. Conclusions— Imaging and histopathologic evaluation may detect moderate but uncharacteristic cardiac abnormalities in patients with BrS. None of the patients had arrhythmogenic RV cardiomyopathy or overt myocarditis. Only in a small subset did predominant histopathologic abnormalities in the biopsy samples of the RV outflow tract occur that could provide a link to the ECG phenotype. A variety of mechanisms, including genetic and structural RV alterations, may underlie the Brugada ECG phenotype.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterized by ARVC and abnormalities of hair and skin. Here, we report, for the first time, a dominant mutation in the gene encoding plakoglobin in a German family with ARVC but no cutaneous abnormalities. The mutation (S39_K40insS) is predicted to insert an extra serine residue at position 39 in the N-terminus of plakoglobin. Analysis of a biopsy sample of the right ventricle from the proband showed markedly decreased localization of plakoglobin, desmoplakin, and connexin43 at intercalated discs in cardiac myocytes. A yeast-two-hybrid screen revealed that the mutant protein established novel interactions with histidine-rich calcium-binding protein and TGF beta induced apoptosis protein 2. Immunoblotting and confocal microscopy in human embryonic kidney 293 (HEK293) cell lines transfected to stably express either wild-type or mutant plakoglobin protein showed that the mutant protein was apparently ubiquitylated and was preferentially located in the cytoplasm, suggesting that the S39_K40insS mutation may increase plakoglobin turnover via proteasomal degradation. HEK293 cells expressing mutant plakoglobin also showed higher rates of proliferation and lower rates of apoptosis than did cells expressing the wild-type protein. Electron microscopy showed smaller and fewer desmosomes in cells expressing mutant plakoglobin. Taken together, these observations suggest that the S39_K40insS mutation affects the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms mediated by Wnt-signaling pathways. These results implicate novel molecular mechanisms in the pathogenesis of ARVC.

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%, p0.001). 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' ratio13.5, outcome was markedly worse compared with patients with an E/E' ratio/=13.5 (event-free survival rate, 64% vs 31%, p0.001). In conclusion, in patients with CHF and severe secondary MR, a higher mitral E/E' ratio is associated with increased morbidity and an adverse outcome. TDI appears to be a useful adjunct in the diagnostic workup and risk stratification of such patients.

In combined PET/CT studies, x-ray attenuation information from the CT scan is generally used for PET attenuation correction. Iodine-containing contrast agents may induce artifacts in the CT-generated attenuation map and lead to an erroneous radioactivity distribution on the corrected PET images. This study evaluated 2 methods of thresholding the CT data to correct these contrast agent–related artifacts. Methods: PET emission and attenuation data (acquired with and without a contrast agent) were simulated using a cardiac torso software phantom and were obtained from patients. Seven patients with known coronary artery disease underwent 2 electrocardiography-gated CT scans of the heart, the first without a contrast agent and the second with intravenous injection of an iodine-containing contrast agent. A 20-min PET scan (single bed position) covering the same axial range as the CT scans was then obtained 1 h after intravenous injection of 18F-FDG. For both the simulated data and the patient data, the unenhanced and contrast-enhanced attenuation datasets were used for attenuation correction of the PET data. Additionally, 2 threshold methods (one requiring user interaction) aimed at compensating for the effect of the contrast agent were applied to the contrast-enhanced attenuation data before PET attenuation correction. All PET images were compared by quantitative analysis. Results: Regional radioactivity values in the heart were overestimated when the contrast-enhanced data were used for attenuation correction. For patients, the mean decrease in the left ventricular wall was 23%. Use of either of the proposed compensation methods reduced the quantification error to less than 5%. The required time for postprocessing was minimal for the user-independent method. Conclusion: The use of contrast-enhanced CT images for attenuation correction in cardiac PET/CT significantly impairs PET quantification of tracer uptake. The proposed CT correction methods markedly reduced these artifacts; additionally, the user-independent method was time-efficient.

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 m 2 ], 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.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inheritable heart muscle disease that predominantly affects the right ventricle (RV) and predisposes to ventricular arrhythmias and sudden cardiac death (SCD).1–17 In the last three decades, there have been a significant number of studies defining the pathogenesis, genetic aspects, and clinical manifestations of the disease (See ‘Etiology, pathogenesis, diagnosis and natural history’ in the online-only Data Supplement). In 1994 and 2010, an International Task Force (ITF) document proposed guidelines for the standardized diagnosis of ARVC/D based on electrocardiographic (ECG), arrhythmic, morphological, histopathologic, and clinico-genetic factors.18,19 The growing knowledge regarding arrhythmic outcome, risk factors, and life-saving therapeutic interventions, make it particularly timely to critically address and place into perspective the issues relevant to the clinical management of ARVC/D patients. The present ITF consensus statement is a comprehensive overview of currently used risk stratification algorithms and approaches to therapy, either pharmacological or nonpharmacological, which often poses a clinical challenge to cardiovascular specialists and other practitioners, particularly those infrequently engaged in the management of ARVC/D. This document should be regarded as a guide to clinical practice where rigorous evidence is still lacking, because of the relatively low disease prevalence and the absence of controlled studies. Recommendations are based on available data derived from nonrandomized and observational studies and consensus within the conference panellists. When development of prognostic-therapeutic algorithms was controversial, management decisions were recommended to be individualized. Recommendation and level of evidence of specific management options were classified according to predefined scales, as outlined in Tables 1 and 2 (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). Because randomized studies are not available, most consensus recommendations on treatment of ARVC/D are based on data derived from follow-up registries and/or experts opinions (ie, level of evidence B or C). View this table: Table 1. Classes of Recommendations View this table: Table 2. Levels of Evidence All members of …

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A--G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.

Aims We report three young patients presenting with life-threatening ventricular tachycardia (VT) or ventricular fibrillation (VF) and/or survived sudden cardiac arrest, who were admitted to our institution for further diagnostic evaluation. Methods and results In all patients, idiopathic left ventricular (LV) aneurysms were identified after a detailed non-invasive and invasive evaluation. Sustained VT/VF was inducible during programmed ventricular stimulation in two of the three patients. Left ventricular aneurysms were depicted and characterized by various imaging modalities (echocardiography, magnetic resonance imaging, LV angiography). To elucidate the pathogenesis further, both myocardial viability and regional sympathetic innervation were assessed by radionuclide imaging techniques. Defects of innervation and metabolism were documented in the area of the aneurysm but distal to the aneurysm there were no signs of downstream denervation. Conclusion Life-threatening arrhythmias may be the first manifestation of an idiopathic LV aneurysm, which can be reliably diagnosed with modern imaging techniques. Radionuclide imaging may yield additional information as to the involvement of the autonomic nervous system potentially associated with arrhythmogenesis. Management strategies in patients with an idiopathic LV aneurysm range from antiarrhythmic drug treatment, implantation of an automatic cardioverter–defibrillator to surgical aneurysmectomy.

Background It was the aim of this study to compare the prognostic impact of echocardiography and brain natriuretic peptide and its N-terminal fragment (NT-proBNP) in patients with chronic heart failure (CHF). Methods In all, 73 patients with CHF underwent conventional 2-dimensional/Doppler echocardiography and Doppler tissue analysis of systolic, early and late diastolic mitral annular velocities. The mitral filling pattern was classified as restrictive or nonrestrictive. NT-proBNP measurements were carried out on a bench-top analyzer. A cardiac event (rehospitalization caused by worsening CHF, cardiac death, urgent cardiac transplantation) was defined as combined study end point. Results During follow-up of 226 ± 169 days, 27 patients had an event (rehospitalization because of CHF, n=18; cardiac death, n=7; urgent transplantation, n=2). On multivariate Cox regression analysis, a restrictive filling pattern, NT-proBNP, the ratio of peak early diastolic mitral flow to mitral annular E′ velocity were independent prognostic predictors. A risk stratification model based on the 3 strongest independent predictors separated groups into those with good, intermediate, and poor outcome (event-free survival of 78%, 46%, and 0%, respectively). Conclusions In patients with CHF, Doppler echocardiography, Doppler tissue imaging, and NT-proBNP provide independent and incremental prognostic information. A combined use of echocardiography and NT-proBNP may help to improve risk stratification in this patient population.

Idiopathic ventricular fibrillation (IVF) is defined as VF in the absence of any identifiable structural or functional cardiac disease. The underlying pathophysiological mechanisms are unknown. This study was performed to investigate the potential impact of sympathetic dysfunction, assessed by 123I-meta-iodo-benzylguanidine scintigraphy (123I-MIBG SPECT), on the long-term prognosis of patients with IVF. 123I-MIBG SPECT was performed in 20 patients (mean age 37±13 years) with IVF. Mean follow-up of patients after study entry was 7.2±1.5 years (range 4.9–10.5 years). Ten patients (five men, five women; mean age 43±12 years; p=NS versus study group) with medullary carcinoma of the thyroid gland served as an age-matched control group. Abnormal 123I-MIBG uptake was observed in 13 patients (65%). During follow-up, 18 episodes of VF/fast polymorphic ventricular tachycardias occurred in four IVF patients with abnormal 123I-MIBG uptake whereas only two episodes of monomorphic ventricular tachycardia (and no VF) occurred in a single IVF patient with normal 123I-MIBG uptake. Impairment of sympathetic innervation may indicate a higher risk of future recurrent episodes of life-threatening ventricular tachyarrhythmias in patients with IVF. Studies in larger cohorts are required to validate the significance of 123I-MIBG SPECT during the long-term follow-up of these patients.

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 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.

Background/Aim: Patients with ventricular ectopy from the right ventricular (RV) outflow tract (RVOT) are often referred for RV angiography to exclude disorders such as arrhythmogenic RV cardiomyopathy/dysplasia (ARVC/D). This is usually based on a qualitative assessment of the wall motion. We present a method to quantify the wall motion and to apply this method to compare patients with RVOT ectopy to normal subjects. Methods: RV angiograms were analyzed from 19 normal subjects and 11 subjects with RVOT ventricular arrhythmias (RVOT arrhythmia subjects) who had no other clinical or other evidence for ARVC/D. By a newly developed computer-based method, RV contours were first traced from multiple frames spanning the entire cardiac cycle. The fractional change in area between contours was then calculated as a serial function of time and location to determine both total contour area change and timing of contour movement. Contour area strain, defined as the differential change in area between nearby regions, was also computed. Results: The contour area change was greatest in the tricuspid valve region and least in the RVOT and midanterior regions. The onset of contraction was earliest in the RVOT region and latest in the apical, inferior, inferoapical, and subtricuspid valve regions. The contour strain was largest in superior tricuspid valve and inferior wall and near zero within the lateral tricuspid valve region. There were significant pairwise differences in contraction area, timing, and strain in the various regions. There were no significant differences between normal subjects and RVOT arrhythmia subjects. Conclusions: The RV wall motion is nonuniform in contour area change, strain, and timing of motion. Patients with RVOT ventricular ectopy demonstrate wall motion parameters similar to those of normal subjects. This technique should be applicable in analyzing RV wall motion in patients suspected of having ARVC/D.

Background— Life-threatening ventricular tachyarrhythmias can occur in young patients without structural heart disease (idiopathic forms). In many patients, these are typically triggered by an increased sympathetic tone, eg, by physical or mental stress. In contrast, in Brugada syndrome, ventricular tachyarrhythmias more often occur during rest or sleep when the vagal tone is predominant. Furthermore, adrenergic agonists can reduce the level of ST-segment elevation, whereas it is increased by parasympathetic agonists or adrenergic antagonists. The aim of this study was to investigate presynaptic and postsynaptic myocardial sympathetic function in patients with Brugada syndrome. Methods and Results— Nine patients with Brugada syndrome (6 male, 3 female; age, 41±13 years) were enrolled in this study. The cardiac autonomic nervous system was assessed noninvasively, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analogue 11 C-Hydroxyephedrine ( 11 C-HED) and the nonselective β-blocker 11 C-CGP 12177 ( 11 C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11 C-HED, was globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects (92.9±16.2 mL/g versus 69.1±14.2 mL/g; P 11 C-CGP, was similar in patients and control subjects (10.4±6.7 pmol/g versus 10.2±2.9 pmol/g; P =NS). Conclusions— The present study on autonomic innervation in Brugada syndrome describes an enhanced presynaptic norepinephrine recycling with preserved β-adrenoceptor density, further supporting the hypothesis of an autonomic dysfunction in Brugada syndrome. This is a further step toward the understanding of the pathophysiology of the disease with potential future impact on therapeutic strategies.

A multidisciplinary collaborative European study has been designed with the aim to investigate the clinical, pathological and genetic features of arrhythmogenic right ventricular cardiomyopathy (ARVC), which is a progressive, genetically determined disorder of the right ventricular myocardium and a major risk of sudden death particularly in the young.1–3 The disease is reported familial up to 50% with autosomal dominant inheritance while an autosomal recessive form (Naxos disease) associated with cutaneous abnormalities also exists. Nine genetic loci and mutations in three genes have been discovered so far.4–7 Treatment and prevention of ventricular tachyarrhythmias and sudden death include antiarrhythmic drug therapy, catheter ablation and the implantable cardioverter-defibrillator.2,8–11 However, a systematic evaluation of treatment options is not yet available. The need to set up an International Registry for ARVC has been perceived since years and many attempts have been accomplished after the publication of the diagnostic criteria.12–14 The European venture was not costless and a financial support was searched for. The occasion was given by the 5th Framework Programme of the European Community in the field of research and technological development called “Quality of Life and Management of Living Resources”, Action lines 1999/c 64/14 1.1.1.–7.2 “Evaluation of therapies through multinational large scale study/trials” 7.3 “Optimised use of databases, registries, reagents and sample banks”.15 A successful application was submitted by G. Thiene, on behalf of a multinational consortium. The project involves seven European countries: | Italy | Institute of Pathological Anatomy (G. Thiene), Department of Clinical and Experimental Medicine, Cardiology (A. Nava) and Department of Biology, Genetics (G.A. Danieli), University of Padua | || | Germany | Department of Cardiology and Angiology, University Hospital of Munster (T. Wichter) | | France | Institute de Cardiologie, Group Hospitalier Pitie-Salpetriere, Paris (G. Fontaine) | | United Kingdom | The Heart Hospital, University College of London (W. J. McKenna) | | Greece | Yannis Protonotarios Medical Center, Naxos (N. Protonotarios) | | Poland | Department of Pathology, Children's Memorial Health Institute (E. Czarnowska), Department of Noninvasive Cardiology and Congenital Heart Defects, Institute of Cardiology (E.K. Wlodarska) | | Cyprus | Department of Cardiology, Nicosia General Hospital (L. Antoniades) | The project consists …

To determine left ventricular (LV) volumetric and functional parameters from retrospectively electrocardiographically gated multi-detector row computed tomography (CT) by using semiautomated analysis software and to correlate results with those of magnetic resonance (MR) imaging.In 30 patients (mean age, 59.2 years +/- 7.1 [SD]) known to have or suspected of having coronary artery disease, four-channel multi-detector row CT was performed with standard technique, and diastolic and systolic image reconstructions were generated. With commercially available analysis software capable of semiautomated contour detection, end diastolic and end systolic LV volumes were determined from short-axis secondary CT reformations. Steady-state free-precession cine MR images were acquired in short-axis orientation within 48 hours and analyzed by using dedicated software. Bland-Altman analysis was performed to calculate limits of agreement and systematic errors between CT and MR imaging.Mean end diastolic (138.8 mL +/- 31.9) and end systolic (53.9 mL +/- 21.2) LV volumes as determined with CT correlated well with MR imaging measurements (142.0 mL +/- 32.5 [r = 0.93] and 54.9 mL +/- 22.8 [r = 0.94], respectively [P.001]). LV ejection fraction (61.6% +/- 10.6 for CT vs 62.3% +/- 10.1 for MR imaging; r = 0.89) and stroke volume (84.6 mL +/- 20.9 for CT vs 86.9 mL +/- 21.5 for MR imaging; r = 0.88) also showed good correlation (P.001). Bland-Altman analysis showed acceptable limits of agreement (+/-9.8% for ejection fraction) without systematic errors.In selected patients, semiautomated analysis software enables LV volumetric and functional analysis based on multi-detector row CT data sets, the results of which correlate well with MR imaging findings.

Aims It has recently been proposed that anaemia is an independent risk factor for development of cardiovascular disease in the general population. The impact of anaemia on long-term survival of patients with manifest coronary heart disease (CHD) has not been assessed so far. In this study, we examined the influence of haemoglobin concentrations on the outcome after percutaneous coronary interventions (PCI). Methods and results In a retrospective cohort study, we analysed in-hospital and long-term mortality in all male patients admitted to our institution for elective PCI from 1998 to 1999. In 689 cases, complete follow-up information could be obtained (98.4%). Depending on their baseline haemoglobin, patients were divided in quintiles. In all subgroups, angiographic success after PCI (90–94%) was comparably high and in-hospital mortality was low (0–0.7%). During follow-up (median 697 days), patients in the lowest haemoglobin quintile (≤12.9 g/dl) were significantly more likely to suffer from all-cause death (22.2%) than those of the other quintiles (3.7–12.1%; estimated mortality rates from Kaplan–Meier models, P

In general, the failing human heart is characterized by a selective reduction in beta(1)-adrenoceptors (beta(1)-ARs) without change in beta(2)-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 beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-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 beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-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 beta(1)-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 beta(1)-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.

In athletes, ventricular arrhythmias and sudden cardiac death are rare and unpredictable events. Often, an underlying heart disease is present, but pre-existing clinical signs or symptoms may not be recognized. Primary electrical disorders (such as the long QT syndrome) are rarely present in athletes but, so far, are a considerable reason for disqualification from sport activity. These disorders are mostly inherited, and patients should be referred to a cardiologist with special experience. Through the efforts of molecular genetics and cellular electrophysiology, an increasing understanding of the underlying mechanisms of arrhythmogenesis is being gathered. During the past decade, evidence has grown that establishing accurate genetic diagnoses and dissection of molecular disease mechanisms can have an impact on prognosis, and help direct therapy in a range of cardiovascular diseases. Further achievements in the areas of clinical and molecular research, improvement of medical education, and expansion of genotyping facilities will facilitate the correct and immediate identification of affected patients.

Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. Present Knowledge: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified (“channelopathy”), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. Future Perspectives: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. Conclusion: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias.

Aim: This study investigated the value of epicardial mapping immediately before CABG in the differentiation of hibernating from scarred myocardium in correlation to the noninvasive gold standard 18F-FDG PET. Methods and Results: In 35 patients with CAD, myocardial perfusion (99mTc-Tetrofosmin-SPECT), viability (18F-FDG-PET), and function (LVangiography) were assessed before CABG. 102 bipolar epicardial electrograms per patient (n = 3570 electrograms) were recorded simultaneously with a ventricular jacket array. Based on the scintigraphic and LV angiographic data at the site of each electrode with good myocardial contact (n = 1963), segments (n = 492, 14.1 ± 5.6 per patient; mean ± SD) were classified into three groups: hibernating (n = 139), scarred (n = 104), and control (n = 249). Regional mean bipolar voltage values were calculated for Receiver Operating Characteristic (ROC) analysis. Mean bipolar voltage was significantly lower in scarred when compared to hibernating myocardium. ROC curve analysis (area under the curve of O.92 ± 0.47, mean ± SE) for mean bipolar voltage to discriminate between hibernating and scarred myocardium revealed a sensitivity of 94% with a specificity of 83% at a cut-off value of 8.75 mV. Conclusion: Hibernating myocardium can be differentiated correctly from scarred myocardium by direct epicardial mapping. In the future, hibernating myocardium may be detectable by body surface mapping techniques using inverse solutions. A.N.E. 2002;7(4):349–356

Josep und Pedro Brugada beschrieben 1992 eine Gruppe von acht, ansonsten herzgesunden Patienten mit ventrikularen Tachyarrhythmien und einem atypischen Rechtsschenkelblock sowie ST-Hebungen in den rechtsprakordialen EKG-Ableitungen. Zur Kennzeichnung von Patienten mit Synkopen und/oder (uberlebtem) plotzlichen Herztod und diesen EKG-Veranderungen hat sich in der Literatur der Begriff „Brugada-Syndrom” durchgesetzt. Das Brugada-Syndrom wird heutzutage als eine Ionenkanalerkrankung verstanden, die zumindest bei einem Teil der Patienten autosomal dominant vererbt wird. Die Zahl der weltweit identifizierten Patienten mit ahnlicher Klinik und EKG-Veranderungen, die haufig lediglich transient auftreten, wachst kontinuierlich. Die einzige erwiesene Masnahme zur Verhinderung eines plotzlichen Herztods bei diesen Patienten ist der implantierbare Kardioverter/Defibrillator. Da die charakteristischen EKG-Veranderungen vielfach auch bei asymptomatischen Patienten beobachtet werden, stellt sich die Frage, wer von diesen Patienten einen ICD benotigt und welche diagnostischen Masnahmen bei der Risikostratifizierung helfen. Die folgende Ubersicht, fasst die aktuellen Erkenntnisse zur Genese, Klinik, Risikostratifizierung sowie Therapie und Prognose bei Patienten mit Brugada-Syndrom zusammen.