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.

Neoadjuvant immunotherapy in primary and metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second most common solid organ cancer. Traditional treatment is with surgery and chemotherapy. Immunotherapy has recently emerged as a neoadjuvant therapy that could change treatment strategy in both primary resectable and metastatic CRC. METHODS: A literature review of PubMed with a focus on studies exploring upfront immunotherapy in operable CRC, either for primary resectable stage I-III cancers or for (potentially) operable liver metastasis. RESULTS: Immune checkpoint blockade by the programmed cell death 1 (PD-1) receptor inhibitors nivolumab and pembrolizumab and the cytotoxic T cell-associated protein 4 (CTLA-4) inhibitor ipilimumab has shown good results in both early-stage and advanced CRC. The effects of immune checkpoint inhibitors have so far been demonstrated in small phase I/II studies and predominantly in treatment-refractory stage IV disease with defect Mismatch repair (dMMR). However, recent data from phase I/II (NICHE-1) studies suggest an upfront role for immunotherapy in operable stage I-III disease. By blocking crucial immune checkpoints, cytotoxic T cells are activated and release cytotoxic signals that initiate cancer cell destruction. The very high complete response rate in dMMR operable CRC with neoadjuvant immunotherapy with nivolumab and ipilimumab, and even partial pathological response in some patients with proficient MMR (pMMR) CRC, calls for further attention to patient selection for neoadjuvant treatment, beyond MMR status alone. CONCLUSION: Early data on the effect of immunotherapy in CRC provide new strategic thinking of treatment options in CRC for both early-stage and advanced disease, with prospects for new trials.

Immunotherapy has proven to be highly effective as first-line treatment of metastatic colorectal cancer (CRC). Further, immune checkpoint blockade by the programmed cell death 1 (PD-1) receptor inhibitors nivolumab and pembrolizumab and the cytotoxic T cell-associated protein 4 (CTLA-4) inhibitor ipilimumab has provided very good results in both early-stage and advanced CRC. The high response rate in dMMR in operable colon cancers by preoperative use of double nivolumab and ipilimumab therapy warrants further investigation into its impact on long-term overall survival. Hence, immunotherapy has emerged as a neoadjuvant approach, possibly changing treatment strategy for both primary resectable and metastatic CRC. Larger phase III trials are needed to evaluate overall effects on survival.

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.

Neutrophilic Asthma Is Associated With Smoking, High Numbers of IRF5+, and Low Numbers of IL10+ Macrophages.

Asthma is a heterogenous disease with different inflammatory subgroups that differ in disease severity. This disease variation is hampering treatment and development of new treatment strategies. Macrophages may contribute to asthma phenotypes by their ability to activate in different ways, i.e., T helper cell 1 (Th1)-associated, Th2-associated, or anti-inflammatory activation. It is currently unknown if these different types of activation correspond with specific inflammatory subgroups of asthma. We hypothesized that eosinophilic asthma would be characterized by having Th2-associated macrophages, whereas neutrophilic asthma would have Th1-associated macrophages and both having few anti-inflammatory macrophages. We quantified macrophage subsets in bronchial biopsies of asthma patients using interferon regulatory factor 5 (IRF5)/CD68 for Th1-associated macrophages, CD206/CD68 for Th2-associated macrophages and interleukin 10 (IL10)/CD68 for anti-inflammatory macrophages. Macrophage subset percentages were investigated in subgroups of asthma as defined by unsupervised clustering using neutrophil/eosinophil counts in sputum and tissue and forced expiratory volume in 1 s (FEV1). Asthma patients clustered into four subgroups: mixed-eosinophilic/neutrophilic, paucigranulocytic, neutrophilic with normal FEV1, and neutrophilic with low FEV1, the latter group consisting mainly of smokers. No differences were found for CD206+ macrophages within asthma subgroups. In contrast, IRF5+ macrophages were significantly higher and IL10+ macrophages lower in neutrophilic asthmatics with low FEV1 as compared to those with neutrophilic asthma and normal FEV1 or mixed-eosinophilic asthma. This study shows that neutrophilic asthma with low FEV1 is associated with high numbers of IRF5+, and low numbers of IL10+ macrophages, which may be the result of combined effects of smoking and having asthma.

The different faces of the macrophage in asthma.

PURPOSE OF REVIEW: Asthma is a chronic inflammatory disease in which changes in macrophage polarization have been shown to contribute to the pathogenesis. The present review discusses the contribution of changes in macrophage function to asthma related to polarization changes and elaborates on possible therapeutic strategies targeting macrophage function and polarization. RECENT FINDINGS: Macrophage function alterations were shown to contribute to asthma pathology in several ways. One is by impaired phagocytosis and efferocytosis. Another is by changing inflammation, by altered (anti)inflammatory cytokine production and induction of the inflammasome. Finally, macrophages can contribute to remodeling in asthma, although little evidence is present in humans yet.Novel therapeutic strategies targeting macrophages include dampening inflammation by changing polarization or by inhibiting the NLRP3 inflammasome, and by targeting efferocytosis. However, many of these studies were performed in animal models leaving their translation to the clinic for future research. SUMMARY: The present review emphasizes the contribution of altered macrophage function to asthma, gives insight in possible new therapeutic strategies targeting macrophages, and indicates which knowledge gaps remain open.

Oxidative stress and macrophages: driving forces behind exacerbations of asthma and chronic obstructive pulmonary disease?

Oxidative stress is a common feature of obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Lung macrophages are key innate immune cells that can generate oxidants and are known to display aberrant polarization patterns and defective phagocytic responses in these diseases. Whether these characteristics are linked in one way or another and whether they contribute to the onset and severity of exacerbations in asthma and COPD remain poorly understood. Insight into oxidative stress, macrophages, and their interactions may be important in fully understanding acute worsening of lung disease. This review therefore highlights the current state of the art regarding the role of oxidative stress and macrophages in exacerbations of asthma and COPD. It shows that oxidative stress can attenuate macrophage function, which may result in impaired responses toward exacerbating triggers and may contribute to exaggerated inflammation in the airways.

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.

A Potent Tartrate Resistant Acid Phosphatase Inhibitor to Study the Function of TRAP in Alveolar Macrophages.

The enzyme tartrate resistant acid phosphatase (TRAP, two isoforms 5a and 5b) is highly expressed in alveolar macrophages, but its function there is unclear and potent selective inhibitors of TRAP are required to assess functional aspects of the protein. We found higher TRAP activity/expression in lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma compared to controls and more TRAP activity in lungs of mice with experimental COPD or asthma. Stimuli related to asthma and/or COPD were tested for their capacity to induce TRAP. Receptor activator of NF-κb ligand (RANKL) and Xanthine/Xanthine Oxidase induced TRAP mRNA expression in mouse macrophages, but only RANKL also induced TRAP activity in mouse lung slices. Several Au(III) coordination compounds were tested for their ability to inhibit TRAP activity and [Au(4,4'-dimethoxy-2,2'-bipyridine)Cl2][PF6] (AubipyOMe) was found to be the most potent inhibitor of TRAP5a and 5b activity reported to date (IC50 1.3 and 1.8 µM respectively). AubipyOMe also inhibited TRAP activity in murine macrophage and human lung tissue extracts. In a functional assay with physiological TRAP substrate osteopontin, AubipyOMe inhibited mouse macrophage migration over osteopontin-coated membranes. In conclusion, higher TRAP expression/activity are associated with COPD and asthma and TRAP is involved in regulating macrophage migration.

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.

Emergency general surgery in the geriatric patient.

BACKGROUND: Emergency general surgery in the elderly is a particular challenge to the surgeon in charge of their care. The aim was to review contemporary aspects of managing elderly patients needing emergency general surgery and possible alterations to their pathways of care. METHODS: This was a narrative review based on a PubMed/MEDLINE literature search up until 15 September 2015 for publications relevant to emergency general surgery in the geriatric patient. RESULTS: The number of patients presenting as an emergency with a general surgical condition increases with age. Up to one-quarter of all emergency admissions to hospital may be for general surgical conditions. Elderly patients are a particular challenge owing to added co-morbidity, use of drugs and risk of poor outcome. Frailty is an important potential risk factor, but difficult to monitor or manage in the emergency setting. Risk scores are not available universally. Outcomes are usually severalfold worse than after elective surgery, in terms of both higher morbidity and increased mortality. A care bundle including early diagnosis, resuscitation and organ system monitoring may benefit the elderly in particular. Communication with the patient and relatives throughout the care pathway is essential, as indications for surgery, level of care and likely outcomes may evolve. Ethical issues should also be addressed at every step on the pathway of care. CONCLUSION: Emergency general surgery in the geriatric patient needs a tailored approach to improve outcomes and avoid futile care. Although some high-quality studies exist in related fields, the overall evidence base informing perioperative acute care for the elderly remains limited.

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.

Liking the good guys: amplifying local adaptation via the evolution of condition-dependent mate choice.

Local adaptation can be strengthened through a diversity of mechanisms that reduce gene flow between contrasting environments. Recent work revealed that mate choice could enhance local adaptation when females preferentially mate with locally adapted males and that such female preferences readily evolve, but the opposing effects of recombination, migration and costs of female preferences remain relatively unexplored. To investigate these effects, we develop a two-patch model with two genes, one influencing an ecological trait and one influencing female preferences, where both male signals and female preferences are allowed to depend on the match between an individual's ecological trait and the local environment (condition). Because trait variation is limited when migration is rare and the benefits of preferential mating are short-lived when migration is frequent, we find that female preferences for males in high condition spread most rapidly with intermediate levels of migration. Surprisingly, we find that preferences for locally adapted males spread fastest with higher recombination rates, which contrasts with earlier studies. This is because a stronger preference allele for locally adapted males can only get uncoupled from maladapted ecological alleles following migration through recombination. The effects of migration and recombination depend strongly on the condition of the males being chosen by females, but only weakly on the condition of the females doing the choosing, except when it comes to the costs of preference. Although costs always impede the spread of female preferences for locally adapted males, the impact is substantially lessened if costs are borne primarily by females in poor condition. The abundance of empirical examples of condition-dependent mate choice combined with our theoretical results suggests that the evolution of mate choice could commonly facilitate local adaptation in nature.

Long-Term Follow-Up and Survivorship After Completing Systematic Surveillance in Stage I-III Colorectal Cancer: Who Is Still at Risk?

PURPOSE: In patients with a high life expectancy at the time of surgery for colorectal cancer (CRC), the long-term outcome may be influenced by factors other than their cancer. We aimed to investigate the long-term outcome and cause of death beyond a 5-year surveillance programme. METHODS: We evaluated the overall survival (OS) and cancer-specific survival (CSS) of a population-based cohort of stage I-III CRC patients <75 years old who completed a systematic surveillance programme. RESULTS: In total, 161 patients <75 years old, 111 (69 %) of whom were node negative (pN0), were included. The median follow-up time was 12.1 years. The OS was 54 % at 15 years and differed significantly between the pN0 and pN+ patients (65 vs. 30 %; P < 0.001); CSS (72 %) also differed between the pN0 and pN+ patients (85 vs. 44 %; P < 0.001). For the 5-year survivors (n = 119), 14 (12 %) died of CRC during additional long-term follow-up (7 each for pN0 and pN+), and 6 patients (5 %; all pN0) died of other cancers. Patients aged <65 years exhibited better long-term survival (81 %), but most of the deaths were due to CRC (10/12 deaths). Only two of the 14 cancer-related deaths involved microsatellite instable (MSI) CRC. Females exhibited better OS and CSS beyond 5 years of surveillance. CONCLUSIONS: The long-term survival beyond 5-year survivorship for stage I-III CRC is very good. Nonetheless, cancer-related deaths are encountered in one-third of patients and occur most frequently in patients who are <65 years old at disease onset-pointing to a still persistent risk several years after surgery.

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.