Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy.

The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts as well as an increase in diastolic Ca2+ level, slower Ca2+ transient decay and longer Ca2+ transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy.

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium.

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.

Treatment course and its predictors in patients with somatoform disorders: A routine outcome monitoring study in secondary psychiatric care.

AIM: Somatoform disorders are common and often chronic. It would be helpful to distinguish those patients who are likely to have a positive treatment course from those who are likely to follow a negative course. Such studies of different somatoform disorders are scarce, especially in secondary psychiatric care. This study examined the 6-month treatment course of psychological, physical symptoms, and functioning, and its predictors in a naturalistic sample of secondary psychiatric care outpatients with somatoform disorders. METHOD: The present study used routine outcome monitoring data of patients with somatoform disorders regarding their 6-month treatment course of psychological and physical symptoms as well as functioning. The following patient groups were included: total group of somatoform disorders (N = 435), and undifferentiated somatoform disorder (N = 242), pain disorder (N = 102), body dysmorphic disorder (N = 51), and hypochondriasis (N = 40). Measures were Mini-International Neuropsychiatric Interview plus, Brief Symptom Inventory, Montgomery-Ǻsberg Depression Rating Scale, Brief Anxiety Scale, Short Form Health Survey 36, and Physical Symptom Checklist (PSC). RESULTS: The study population generally showed high co-morbidity, especially with anxiety and mood disorders. The PSC total score, body dysmorphic disorder, and hypochondriasis were significant predictors for the treatment course of symptoms (Brief Symptom Inventory), whereas the PSC total score was the only significant predictor for the course of functioning (Short Form Health Survey 36). CONCLUSION: Secondary psychiatric care outpatients with somatoform disorders showed high co-morbidity with anxiety and mood disorders, and an unfavourable 6-month course of both symptoms and functioning. Clinical implications are discussed, such as additional treatment of co-morbidity in somatoform disorders.

Gold open access: the best of both worlds.

Gold open access provides free distribution of trustworthy scientific knowledge for everyone. As publication modus, it has to withstand the bad reputation of predatory journals and overcome the preconceptions of those who believe that open access is synonymous with poor quality articles and high costs. Gold open access has a bright future and will serve the scientific community, clinicians without academic affiliations and the general public.

Potential new mechanisms of pro-arrhythmia in arrhythmogenic cardiomyopathy: focus on calcium sensitive pathways.

Arrhythmogenic cardiomyopathy, or its most well-known subform arrhythmogenic right ventricular cardiomyopathy (ARVC), is a cardiac disease mainly characterised by a gradual replacement of the myocardial mass by fibrous and fatty tissue, leading to dilatation of the ventricular wall, arrhythmias and progression towards heart failure. ARVC is commonly regarded as a disease of the intercalated disk in which mutations in desmosomal proteins are an important causative factor. Interestingly, the Dutch founder mutation PLN R14Del has been identified to play an additional, and major, role in ARVC patients within the Netherlands. This is remarkable since the phospholamban (PLN) protein plays a leading role in regulation of the sarcoplasmic reticulum calcium load rather than in the establishment of intercellular integrity. In this review we outline the intracellular cardiac calcium dynamics and relate pathophysiological signalling, induced by disturbed calcium handling, with activation of calmodulin dependent kinase II (CaMKII) and calcineurin A (CnA). We postulate a thus far unrecognised role for Ca2+ sensitive signalling proteins in maladaptive remodelling of the macromolecular protein complex that forms the intercalated disk, during pro-arrhythmic remodelling of the heart.

The clinical effectiveness of concise cognitive behavioral therapy with or without pharmacotherapy for depressive and anxiety disorders; a pragmatic randomized controlled equivalence trial in clinical practice.

BACKGROUND: Depressive and anxiety disorders contribute to a high disease burden. This paper investigates whether concise formats of cognitive behavioral- and/or pharmacotherapy are equivalent with longer standard care in the treatment of depressive and/or anxiety disorders in secondary mental health care. METHODS: A pragmatic randomized controlled equivalence trial was conducted at five Dutch outpatient Mental Healthcare Centers (MHCs) of the Regional Mental Health Provider (RMHP) 'Rivierduinen'. Patients (aged 18-65 years) with a mild to moderate anxiety and/or depressive disorder, were randomly allocated to concise or standard care. Data were collected at baseline, 3, 6 and 12 months by Routine Outcome Monitoring (ROM). Primary outcomes were the Brief Symptom Inventory (BSI) and the Web Screening Questionnaire (WSQ). We used Generalized Estimating Equations (GEE) to assess outcomes. RESULTS: Between March 2010 and December 2012, 182 patients, were enrolled (n=89 standard care; n=93 concise care). Both intention-to-treat and per-protocol analyses demonstrated equivalence of concise care and standard care at all time points. Severity of illness reduced, and both treatments improved patient's general health status and subdomains of quality of life. Moreover, in concise care, the beneficial effects started earlier. DISCUSSION: Concise care has the potential to be a feasible and promising alternative to longer standard secondary mental health care in the treatment of outpatients with a mild to moderate depressive and/or anxiety disorder. For future research, we recommend adhering more strictly to the concise treatment protocols to further explore the beneficial effects of the concise treatment. The study is registered in the Netherlands Trial Register, number NTR2590. Clinicaltrials.gov identifier: NCT01643642.

Gender differences in outpatients with anxiety disorders: the Leiden Routine Outcome Monitoring Study.

BACKGROUND: Data from the general population show higher prevalence of different anxiety disorders in women as compared with men. We analysed gender differences in a naturalistic sample of outpatients with anxiety disorders in a mental healthcare setting. METHOD: Routine outcome monitoring data were collected from 1333 patients (age: 18-65; 63.3% women) fulfilling Diagnostic and Statistical Manual of Mental Disorders IV criteria of current anxiety disorder according to the Mini-International Neuropsychiatric Interview between 2004 through 2006. Data included Comprehensive Psychopathological Rating Scale, Brief Symptom Inventory (BSI), Short Form Health Survey (SF-36), Mood and Anxiety Symptom Questionnaire (MASQ). Chi-squared test and t-test were used to compare women with men for variables with parametric distributions, and Mann-Whitney test for non-parametric distribution. Adjustments for potential confounders (age, level of education, ethnicity and comorbidites) were made by logistic regression models (for discrete variables) or analysis of covariance. RESULTS: The female-to-male ratio (i.e., 844 women, 489 men) for any anxiety disorder was 1.73 : 1 (95% confidence interval [CI]: 1.63-1.83), with the strongest skewness for post-traumatic stress disorder (2.80 : 1) and the smallest one for social phobia (1.18 : 1). Compared with men, women reported more severe self-rating scores on the BSI (on average, the scores were 12.3% higher on 3 of 9 subscales: somatisation, interpersonal sensitivity and anxiety), SF-36 (self-reported generic health status was lower on 5 of 8 subscales: physical functioning, social functioning, physical problems, vitality and bodily pain) and MASQ (on average, the scores were 6.6% higher on 4 of 5 subscales: anxious arousal, general distress, general distress depression, general distress anxiety). On the contrary, no gender difference was found in the severity of anxiety symptoms measured by the Brief Anxiety Scale. Women were more likely to suffer from comorbid depression and bulimia nervosa, and less likely from substance abuse. CONCLUSIONS: In a treatment-seeking population the prevalence rate of anxiety disorders was 1.7 times higher in female compared with men. Female outpatients were more severely affected on self-rated but not on observer-rated scales.

[The generalisability of depression trials to clinical practice]. / Generaliseerbaarheid van depressietrials naar de dagelijkse praktijk.

BACKGROUND: Evidence-based therapies for major depression, as described in the clinical guidelines, are based on results from randomised controlled trials (RCTs). So far, it is not known to what extent results of RCTs on major depression can be generalised to 'real life' clinical practice. AIM: To compare treatment results for major depression from RCTs (efficacy) and results from daily practice (effectiveness); furthermore, to assess to what extent eligibility criteria and (un)intended selection by recruitment procedures influences treatment outcomes in daily practice. METHOD: In a 'real life' patient population (n=1653) suffering from major depression (established by the MINIplus) and assessed in routine outcome monitoring at baseline, we explored how many patients met the eligibility criteria for antidepressant and psychotherapy efficacy trials. Furthermore we explored to what extent RCT participants differed in socio-demographic and socio-economic status from 'daily practice' patients. 626 of the ROM patients had at least one follow-up assessment. In this follow-up group we compared the treatment outcome (assessed by the MADRS and BDI-II) to the results of 15 meta-analyses of RCTs. We also explored to what extent patient selection based on eligibility criteria and socio-demographic/socio-economic status influenced treatment outcome. RESULTS: Remission percentages (21-27% in ROM versus 34-58% in RCTs) and effect sizes (0.85 in ROM versus 1.71 in RCTs, within-group data) were lower in daily practice than in RCTs. ROM patients differed from RCT participants in many disease-specific and socio-economic features. These differences are due to patient selection in RCTs. However, the influence of patient selection based on eligibility criteria and socio-demographic differences in treatment outcome were very modest (explained variances 1-11%). CONCLUSION: Treatment success for major depression is lower in daily practice than in RCTs and 'real life' patients differ in many features from RCT participants. However, these differences cannot explain the difference between efficacy and effectiveness. The generalisability of the results of depression trials to daily practice might not be jeopardised by the use of eligibility criteria and recruitment procedures to the extent suggested in earlier research.

Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management.

Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.

New antiarrhythmic targets to control intracellular calcium handling.

Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

Are childhood and adult life adversities differentially associated with specific symptom dimensions of depression and anxiety? Testing the tripartite model.

BACKGROUND: Different types of adverse events may have general or specific effects on depression and anxiety symptomatology. We examined the effects of adversities on the dimensions of the tripartite model: general distress, anhedonic depression and anxious arousal. METHODS: Data were from 2615 individuals from the Netherlands Study for Depression and Anxiety (NESDA), with or without depressive or anxiety disorders. We analysed associations of childhood trauma, childhood life events (childhood trauma interview), and recent life events (List of Threatening Events Questionnaire, LTE-Q) with anhedonic depression, anxious arousal, and general distress (assessed by the adapted Mood and Anxiety Symptoms Questionnaire, MASQ-D30). RESULTS: We controlled for co-occurrence of adversities. Regarding childhood trauma, only emotional neglect was associated with all three symptom dimensions. Psychological and sexual abuse were associated with general distress and anxious arousal, whereas physical abuse was associated only with anxious arousal. Particularly strong associations were seen for emotional neglect with anhedonic depression and for sexual abuse with anxious arousal. Childhood life events showed no associations with symptom dimensions. The recent life events 'Serious problems with friend', 'Serious financial problems', and 'Becoming unemployed' were associated with all three dimensions. The recent life event 'death of parent/child/sibling' was associated with anxious arousal. Several associations remained significant when controlled for current diagnosis of depression or anxiety. LIMITATIONS: Our cross-sectional analyses do not allow for causal interpretation. CONCLUSIONS: Distinct childhood traumas had different effects on the symptom dimensions, whereas most recent adult life events were associated with all three symptom dimensions. Our observations help to understand the often reported associations of these adversities with depressive and anxiety symptomatology. In addition, symptom dimensions of the tripartite model were shown to capture effects of adverse events on top of those captured by diagnostic categories.

Influence of sociodemographic and socioeconomic features on treatment outcome in RCTs versus daily psychiatric practice.

PURPOSE: Sociodemographic and socioeconomic characteristics of participants in antidepressant and psychotherapy efficacy trials (AETs and PETs) for major depressive disorder (MDD) may limit the generalizability of the results. We compared trial participants with daily practice patients. We subsequently assessed the influence of socio-demographic and socioeconomic status on treatment outcome in daily practice. METHODS: Data on daily practice patients were derived through routine outcome monitoring (ROM). We included 626 patients with MDD according to the MINIplus. Distributions of age, gender, race, marital status and employment status were compared with participants in 63 selected AETs and PETs. Influence of these features on treatment outcome was explored through multivariate regression analysis. RESULTS: Trial participants were older, more often male (diff. 4 %, p = 0.05), white (diff. 4 %, p < 0.001) and not married (diff. 7 %, p = 0.003). Although significant, most differences were relatively small. However, the difference in employment status was striking: 34 % of the ROM patients were currently working versus 68 % of the trial participants (diff. 34 %, p < 0.001). Being employed contributed to a positive treatment outcome: OR 1.8 for response [50 % reduction of Montgomery Asberg Rating Scale for Depression (MADRS)], OR 1.9 for remission (MADRS ≤10). CONCLUSIONS: Employment status should be taken into account while interpreting results from randomized controlled trials and as predictor of treatment success in daily practice.

Monitoring cardiac fibrosis: a technical challenge.

The heart contains a collagen network that contributes to the contractility of the heart and provides cardiac strength. In cardiac diseases, an increase in collagen deposition is often observed. This fibrosis formation causes systolic and diastolic dysfunction, and plays a major role in the arrythmogenic substrate. Therefore, accurate detection of cardiac fibrosis and its progression is of clinical importance with regard to diagnostics and therapy for patients with cardiac disease. To evaluate cardiac collagen deposition, both invasive and non-invasive techniques are used. In this review the different techniques that are currently used in clinical and experimental setting are summarised, and the advantages and disadvantages of these techniques are discussed.

Low maternal middle cerebral artery Doppler resistance indices can predict future development of pre-eclampsia.

OBJECTIVE: To determine if decreased resistance (vasodilatation) in the maternal middle cerebral artery (MCA) in the second trimester can predict third-trimester development of pre-eclampsia. METHODS: Four-hundred and five low-risk gravidas had MCA transcranial Doppler (TCD) once in the second trimester. Maternal/neonatal outcomes were evaluated after delivery. Mean blood pressure, MCA velocities, resistance index (RI), pulsatility index (PI) and cerebral perfusion pressure (CPP) were compared between normotensive and pre-eclamptic cohorts. RESULTS: Seven subjects (1.7%) developed pre-eclampsia. An RI of < 0.54 and a PI of < 0.81 were clinically useful in predicting subsequent pre-eclampsia. Areas under the receiver-operating characteristics curves for RI and PI were 0.93 and 0.93, respectively, with optimal sensitivity and specificity of 86% and 93% for both variables. Positive and negative likelihood ratios were 11.8/0.15 (RI) and 12.3/0.15 (PI). CONCLUSION: TCD indices of low maternal MCA resistance in the second trimester are predictive of the subsequent development of pre-eclampsia in a low-risk, ethnically homogeneous population.

Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.

BACKGROUND AND PURPOSE: Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of I(Kr) blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). EXPERIMENTAL APPROACH: Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models. KEY RESULTS: At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. CONCLUSION AND IMPLICATIONS: Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.

The generalizability of antidepressant efficacy trials to routine psychiatric out-patient practice.

BACKGROUND: Generalizability of antidepressant efficacy trials (AETs) to daily practice is questioned because of their very stringent patient selection. This study aims to determine eligibility for AETs of out-patients suffering from major depression in a routine out-patient setting and investigates influence of eligibility on treatment outcome. METHOD: Data collection (n = 1653) was performed through routine outcome monitoring by independent trained research nurses. The Mini-International Neuropsychiatric Interview Plus and the Dimensional Assessment of Personality Pathology, short Dutch version were used for diagnostic assessment and personality pathology screening. The Montgomery-Asberg Depression Rating Scale (MADRS) was used for assessment of baseline severity and treatment outcome. Eligibility was assessed by stepwise application of commonly used exclusion criteria. Influence of eligibility on treatment outcome was investigated in a subsample of the 1653 patients who had at least one follow-up assessment (n = 626). Eligible and non-eligible patients were compared on proportion of response (50% reduction) and remission on MADRS (MADRS ≤ 10). RESULTS: Altogether, 17-25% of the patients were eligible for AETs. The most common reasons for exclusion would be 'not meeting minimum baseline severity' and 'presence of co-morbid Axis I disorder'. Eligible and non-eligible patients did not differ in treatment outcome. Only 'meeting the minimum baseline severity' is associated with remission. CONCLUSIONS: The majority of 'real life' out-patients are not eligible for AETs. However, the influence of eligibility on treatment outcome seems to be small. This suggests that stringent patient selection by eligibility criteria is not the major reason for lack of generalizability of AETs. Exclusion of less severely depressed patients from the analyses resulted in better treatment outcome. Milder depression is highly prevalent in daily practice and more research into treatment effectiveness in milder depression is warranted.

Poor replication of candidate genes for major depressive disorder using genome-wide association data.

Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload.

INTRODUCTION: Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure due to adverse electrical remodelling. To establish whether abnormal conduction is responsible for arrhythmogenic remodelling in progressed stages of heart failure, we have monitored functional, structural and electrical remodelling in a murine model of heart failure, induced by longstanding pressure overload. METHODS: Mice were subjected to transverse aortic constriction (TAC; n=18) or sham operated (n=19) and monitored biweekly by echocardiography and electrocardiography. At the 16-week endpoint, electrical mapping was performed to measure epicardial conduction velocity and susceptibility to arrhythmias. Finally, tissue sections were stained for Cx43 and fibrosis. RESULTS: In TAC mice, fractional shortening decreased gradually and was significantly lower compared with sham at 16 weeks. Left ventricular hypertrophy was significant after six weeks. TAC mice developed PQ prolongation after 12 weeks, QT prolongation after 16 weeks and QRS prolongation after two weeks. Right ventricular conduction velocity was slowed parallel to fibre orientation. In 8/18 TAC hearts, polymorphic ventricular tachyarrhythmias were provoked and none in sham hearts. TAC mice had more interstitial fibrosis than sham. Immunohistology showed that Cx43 levels were similar but highly heterogeneous in TAC mice. All parameters were comparable in TAC mice with and without arrhythmias, except for Cx43 heterogeneity, which was significantly higher in arrhythmogenic TAC mice. CONCLUSION.: Chronic pressure overload resulted in rapid structural and electrical remodelling. Arrhythmias were related to heterogeneous expression of Cx43. This may lead to functional block and unstable reentry, giving rise to polymorphic ventricular tachyarrhythmias. (Neth Heart J 2010;18:509-15.).