Inheritable Cardiac Disease Research Articles

Zebrafish as a Model System for Brugada Syndrome.

Brugada syndrome (BrS) is an inheritable cardiac arrhythmogenic disease, associated with an increased risk of sudden cardiac death. It is most common in males around the age of 40 and the prevalence is higher in Asia than in Europe and the United States. The pathophysiology underlying BrS is not completely understood, but several hypotheses have been proposed. So far, the best effective treatment is the implantation of an implantable cardioverter-defibrillator (ICD), but device-related complications are not uncommon. Therefore, there is an urgent need to improve diagnosis and risk stratification and to find new treatment options. To this end, research should further elucidate the genetic basis and pathophysiological mechanisms of BrS. Several experimental models are being used to gain insight into these aspects. The zebrafish (Danio rerio) is a widely used animal model for the study of cardiac arrhythmias, as its cardiac electrophysiology shows interesting similarities to humans. However, zebrafish have only been used in a limited number of studies on BrS, and the potential role of zebrafish in studying the mechanisms of BrS has not been reviewed. Therefore, the present review aims to evaluate zebrafish as an animal model for BrS. We conclude that zebrafish can be considered as a valuable experimental model for BrS research, not only for gene editing technologies, but also for screening potential BrS drugs.

Abstract 15864: Genetic Findings of Cardiac Sarcoidosis in a Case of Apical Variant Hypertrophic Cardiomyopathy With Recurrent Ventricular Tachyarrhythmias

Background: Genetic sequencing is changing the way physicians practice medicine. Hypertrophic cardiomyopathy (HCM) is one of the most common inheritable cardiac diseases. Sarcoidosis is a multisystem disease involving granulomatous infiltration of the lungs, heart, and other organs thought to be caused by a dysregulated immune system, influenced by genetic factors. Here, we present a case where an individual initially diagnosed with HCM was experiencing frequent episodes of ventricular tachycardia (VT). Further workup, including advanced imaging along with whole genome screening (WGS), revealed an unlikely diagnosis of concurrent cardiac sarcoidosis (CS). Clinical History: A 62-year-old man had ventricular fibrillation with workup notable for an ECG with deeply inverted T-waves, normal coronary angiography, and an echocardiogram and MRI showing apical HCM. An ICD was placed. Six years later, he had VT requiring a shock and was started on sotalol. He has now developed recurrent exercise-induced VT. While VT is seen HCM, the increasing frequency prompted further evaluation. A CT coronary angiogram showed normal coronaries and mediastinal lymphadenopathy. Lymph node biopsy revealed noncaseating granulomas and a PET/CT revealed hypermetabolic basal myocardium meeting HRS criteria for CS. Given minimal apical FDG uptake and a low likelihood that he had CS for 9 years without significant fibrosis, he likely has both HCM and CS. Using WGS, four genetic variants previously described in CS and HCM were identified confirming this diagnosis, HLA-DRB1, HLA-DQA1, ALPK3, and TTN. Discussion: HLA-DRB1 and HLA-DQA1 are both major histocompatibility complexes associated with CS. ALPK3 encodes alpha kinase 3 while TTN encodes titin. Truncating variants of ALPK3 are associated with HCM while pathogenic TTN variants have been described to cause HCM, DCM, and ARVC. This case reflects the potential of WGS in aiding clinicians in confirming an unlikely diagnosis.

Generation of an iPSC line (ZZUNEUi016-A) derived from a hypertrophic cardiomyopathy patient with the heterozygote mutation in MYH7 gene.

HCM is one of the most common inheritable cardiac disease. In our study, we established a human-induced pluripotent stem cells (hiPSCs) line (ZZUNEUi016-A) from a hypertrophic cardiomyopathy patient with the pathogenic heterozygote mutation in MYH7 gene. ZZUNEUi016-A expressed pluripotency markers with normal karyotype and showed the ability to differentiate into all three germ layers in vitro.

Membrane Young's Modulus as a Function of Plakophilin-2 Expression: Implications to Arrhythmogenic Right Ventricular Cardiomyopathy

Mutations inPKP2 gene encoding the desmosomal protein Plakophilin-2 (PKP2), can lead to an inheritable cardiac disease called Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Various studies investigated the molecular and electrical properties of PKP2-deficient cardiomyocytes (CMs). However, data on the mechanical properties of PKP2-deficient CMs, and the disease association are missing. We studied the relation between PKP2 expression, membrane transverse Young's modulus (tYM), and their correlation with tubulin and intercalated disc protein (IDP) levels.

Abstract 13664: Membrane Stiffness as a Function of Plakophilin-2 Expression: Implications to Arrhythmogenic Right Ventricular Cardiomyopathy

Mutations in PKP2 , the gene coding for the desmosomal protein Plakophilin-2 (PKP2), can lead to an inheritable cardiac disease called Arrhythmogenic Right Ventricle Cardiomyopathy (ARVC). Various studies investigated the molecular and electrical properties of cardiomyocytes (CMs) with PKP2 deficiency. However, systematic studies on the mechanical properties of PKP2-deficient CMs, and their relation to the cardiomyopathic phenotype, are lacking. We studied the relation between PKP2 expression, membrane transverse Young’s modulus (tYM; a surrogate measure of membrane stiffness), and their correlation with tubulin expression and with substrate stiffness. Left and right ventricular (LV, RV) CMs were isolated from murine hearts control (ctrl), or with a cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (PKP2cKO). Three time points were studied: 14, 15 and 21 days post-tamoxifen injection (dpi). The phenotypes at these time points correspond to three disease stages: concealed, arrhythmogenic and cardiomyopathy of RV predominance, respectively. tYM was evaluated by mechanoSICM. Tubulin was visualized by confocal microscopy. tYM in LV myocytes from control hearts showed a tendency toward higher values when compared to RV myocytes (LV 2.9±0.2 kPa vs RV 2.6±0.2 kPa, n=53-59). At 14 dpi, LV and RV PKP2cKO CMs were softer than ctrl (LV 2.1±0.1 kPa, RV 2.1±0.1 kPa vs ctrl, n=30-59). The trend reversed a day later and by 21 dpi there was a clear increase in tYM, particularly in PKP2cKO RV myocytes (LV 4.5±0.3 kPa, RV 4.8±0.6 kPa vs ctrl, n=44-59). Z-groove index, a parameter of membrane organization, decreased in PKP2cKO CMs. Increased tYM at 21 dpi corresponded to upregulation of α-tubulin and particularly, acetylated tubulin, which was reduced at 14dpi but went up in 21dpi. We also observed an inverse correlation between membrane tYM, and substrate stiffness. We conclude that loss of PKP2 expression affects, in a disease stage-specific manner, CM mechanical properties and the MT network organization. Whether these effects are correlative or one is consequence of the other, remains to be determined. We speculate that changes in membrane mechanics at the single cell level are a component of mechanical dysfunction in hearts affected with ARVC.

Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1WTversus Kir2.1Δ314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiac disease and is characterised by unexplained ventricular myocardial hypertrophy. HCM is highly heterogeneous and is primarily caused by the mutation of genes encoding sarcomere proteins. As a result of its genetic basis, we investigated the underlying cause of HCM in a Chinese family by whole-exome sequencing. Whole-exome sequencing was performed for seven clinically diagnosed HCM family members and the resulting single nucleotide variants associated with cardiac hypertrophy or heart development were analysed by a polymerase chain reaction and Sanger sequencing. A non-frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member. Moreover, three single nucleotide variants associated with heart development and morphogenesis were identified in the proband but were absent in the other affected subjects. This is the first HCM family case of FHOD3 (p.S527del) variation in Asia. Additionally, RNF207 (p.Q268P), CCM2 (p. E233K) and SGCZ (p.Q134X) may be related to the clinical heterogeneity of the family. The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies.

P5026Diagnostic yield in victims of sudden cardiac death and their relatives

Abstract Background International guidelines recommend screening of relatives in families with sudden cardiac death (SCD) if the cause of death is suspected to be an inheritable cardiac disease. The inheritable cardiac diagnosis may either have been known before the death, established at the autopsy or identified through screening of relatives. Purpose To provide an estimate of the diagnostic yield of inherited cardiac disease in SCD victims. Methods In an observational study, we included all families consecutively referred to our tertiary unit for inheritable cardiac diseases in the period from 2005 to 2018 due to SCD. Families with SCD victims under 1 year of age were excluded. In total, 697 relatives from 305 families were included and all relatives underwent a standard screening protocol, which included clinical and genetic work-up. Premortem medical records and postmortem findings on the SCD victim were ascertained whenever possible. Results A definite inheritable cardiac disease was identified in 113 out of 305 SCD families prior to family screening. The diagnosis was established through autopsy findings (n=89), genetic analysis (n=3) or was established prior to death (n=21). In the remaining 192 families with no or a borderline diagnosis only, screening of the relatives yielded a diagnosis in additional 28 families (15%). On a family-basis, a total of 141 out of 305 families (46%) were diagnosed. Seventy-seven (11%) out of the 697 screened relatives received either a phenotype-positive and/or genotype-positive inheritable diagnosis and 70 (10%) relatives received a borderline diagnosis. The most common diagnoses in the relatives were ARVC (n=17) followed by DCM (n=10) (see figure). Conclusion Almost half of SCD families were diagnosed with an inheritable cardiac disease of which one fifth of the families were diagnosed as a result of family screening. In 11% of the screened relatives a probable inheritable diagnosis was identified.

P2821Diagnostic yield and outcomes of systematic work-up of aborted sudden cardiac death victims and their relatives

Abstract Introduction Cardiac arrest can be the first manifestation of most inherited cardiac diseases. This motivates the international guidelines recommending screening of relatives of cardiac arrest survivors (aSCD) if an inherited cardiac disorder might have caused the cardiac arrest. Purpose To assess the presence of inheritable cardiac diseases in cardiac arrest survivors and their relatives. Methods In this retrospective study we consecutively included cardiac arrest survivors (probands) and their relatives referred to our tertiary referral center from 2005 to 2018. All probands and relatives underwent a systematic screening protocol. Data were retrieved from medical files. Only probands with non-ischemic heart disease were included. Results We included 155 probands (41±16 years old, 94 (61%) male) and 284 relatives (36±19 years old, 144 (51%) male). We identified an inheritable cardiac disease in 70 (45%) probands, most frequently cardiomyopathies (41, 26%) followed by channelopathies (27, 17%) (figure). A borderline diagnosis was found in 32 (21%) probands. In the relatives, an inheritable diagnosis was identified in 38 (13%) individuals, most frequently channelopathies (23, 8%), and a borderline diagnosis was identified in 33 (12%) individuals. Conclusion Clinical assessment of aSCD cases on a non-ischemic basis identified an inheritable cardiac disease as the most likely etiology in almost half of the probands and in 13% of the relatives.

Demographic model for inheritable cardiac disease

The cardiac muscle proteins, generating and regulating energy transduction during a heartbeat, assemble in the sarcomere into a cyclical machine repetitively translating actin relative to myosin filaments. Myosin is the motor transducing ATP free energy into actin movement against resisting force. Cardiac myosin binding protein C (mybpc3) regulates shortening velocity probably by transient N-terminus binding to actin while its C-terminus strongly binds the myosin filament. Inheritable heart disease associated mutants frequently modify these proteins involving them in disease mechanisms. Nonsynonymous single nucleotide polymorphisms (SNPs) cause single residue substitutions with independent characteristics (sequence location, residue substitution, human demographic, and allele frequency) hypothesized to decide dependent phenotype and pathogenicity characteristics in a feed-forward neural network model. Trial models train and validate on a dynamic worldwide SNP database for cardiac muscle proteins then predict phenotype and pathogenicity for any single residue substitution in myosin, mybpc3, or actin. A separate Bayesian model formulates conditional probabilities for phenotype or pathogenicity given independent SNP characteristics. Neural/Bayes forecasting tests SNP pathogenicity vs (in)dependent SNP characteristics to assess individualized disease risk and in particular to elucidate gender and human subpopulation bias in disease. Evident subpopulation bias in myosin SNP pathogenicities imply myosin normally engages multiple sarcomere proteins functionally. Consistent with this observation, mybpc3 forms a third actomyosin interaction competing with myosin essential light chain N-terminus suggesting a novel strain-dependent mechanism adapting myosin force-velocity to load dynamics. The working models, and the integral myosin/mybpc3 motor concept, portends the wider considerations involved in understanding heart disease as a systemic maladaptation.

Neural/Bayes network predictor for inheritable cardiac disease pathogenicity and phenotype

The cardiac muscle sarcomere contains multiple proteins contributing to contraction energy transduction and its regulation during a heartbeat. Inheritable heart disease mutants affect most of them but none more frequently than the ventricular myosin motor and cardiac myosin binding protein c (mybpc3). These co-localizing proteins have mybpc3 playing a regulatory role to the energy transducing motor. Residue substitution and functional domain assignment of each mutation in the protein sequence decides, under the direction of a sensible disease model, phenotype and pathogenicity. The unknown model mechanism is decided here using a method combing neural and Bayes networks. Missense single nucleotide polymorphisms (SNPs) are clues for the disease mechanism summarized in an extensive database collecting mutant sequence location and residue substitution as independent variables that imply the dependent disease phenotype and pathogenicity characteristics in 4 dimensional data points (4ddps). The SNP database contains entries with the majority having one or both dependent data entries unfulfilled. A neural network relating causes (mutant residue location and substitution) and effects (phenotype and pathogenicity) is trained, validated, and optimized using fulfilled 4ddps. It then predicts unfulfilled 4ddps providing the implicit disease model. A discrete Bayes network interprets fulfilled and predicted 4ddps with conditional probabilities for phenotype and pathogenicity given mutation location and residue substitution thus relating the neural network implicit model to explicit features of the motor and mybpc3 sequence and structural domains. Neural/Bayes network forecasting automates disease mechanism modeling by leveraging the world wide human missense SNP database that is in place and expanding.

Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability.

In cardiomyocytes, NaV1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. The objective of this study was to test whether NaV1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1Δ314-315 or Kir2.1R44A/R46A with wild-type (WT) NaV1.5WT in heterologous cells reduced inward sodium current compared with NaV1.5WT alone or coexpressed with Kir2.1WT. In cell surface biotinylation experiments, expression of Kir2.1Δ314-315 reduced NaV1.5 channel surface expression. Glycosylation analysis suggested that NaV1.5WT and Kir2.1WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of NaV1.5WT, and vice versa, whereas coexpression with Kir2.1Δ314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1Δ314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with NaV1.5WT and Kir2.1WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1WT, NaV1.5WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that NaV1.5WT channels interact with AP1 through the NaV1.5Y1810 residue, suggesting that, like for Kir2.1WT, AP1 can mark NaV1.5 channels for incorporation into clathrin-coated vesicles at the trans-Golgi. Silencing the AP1 ϒ-adaptin subunit in human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. The NaV1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of NaV1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.

Is The Subcutaneous Fat Tissue Embolization Effective and Safe As A Septal Reduction Technique In A Patient With Hypertrophic Obstructive Cardiomyopathy?

Hypertrophic obstructive cardiomyopathy is an inheritable cardiac disease that typically manifests with an increased left ventricular outflow tract gradient. In most cases, basal septal hypertrophy and systolic anterior motion of the anterior mitral valve leaflet are the key components of the left ventricular outflow tract obstruction. The goal of septal reduction therapy, a widely accepted treatment modality, is to remove this obstruction. Although myectomy is a wellestablished and effective surgical technique for septal reduction therapy, transcoronary alcohol septal ablation is an alternative therapy for patients who decline to have surgery or who are not suited to a surgical intervention. A new septal reduction method has also been described in the literature. This case report describes the successful treatment of hypertrophic obstructive cardiomyopathy in a 57-year-old female using the new septal reduction technique.

Retrospective Genetic Analysis of 200 Cases of Sudden Infant Death Syndrome and Its Relationship with Long QT Syndrome in Korea

BackgroundThere has been a campaign by the National Education on Sleeping Habits and Living Environment, to reduce the incidence of sudden infant death syndrome (SIDS). However, more than 100 infants die suddenly and unexplainably before the age of 1 year in Korea. Long QT syndrome (LQTS), an inheritable cardiac disease, has been reported to likely be associated with up to 14% of SIDS cases. However, genetic studies of the association between SIDS and LQTS have not yet been conducted in Korea.MethodsWe conducted genetic analysis using genomic DNA extracted from paraffin-embedded tissue blocks from 200 SIDS cases autopsied between 2005 and 2013. We analyzed the following genetic mutations associated with LQTS, KCNQ1, SCN5A, KCNE1, KCNE2, KCNJ2, and CAV3.ResultsOf the 200 SIDS cases, 58% involved male infants (116 male and 84 female infants, respectively), the mean age was 140 days (median, 107 days; range, 24–270 days), and they were all of Asian-Korean ethnicity. SIDS IA category criteria comprised 45 cases (22.5%) while the rest were SIDS IB. Fifteen infants (7.5%) had R1193Q in SCN5A, of doubtful pathogenicity, and no pathogenic LQTS variants were observed.ConclusionThis genetic investigation of LQTS in SIDS showed a low diagnostic yield. These findings suggest that LQTS molecular autopsy could be cautiously conducted in selected cases with family involvement to improve the available genetic counseling information. Meanwhile, a national SIDS registry should be established to document and evaluate the genetic risk of SIDS in Korea.

Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. We aimed to explore the incidence and severity of ventricular arrhythmias in patients with CPVT before the initiation of β-blocker treatment, when treated with β1-selective β-blockers, and when treated with nadolol. In this study, 34 patients with CPVT were included (mean age 34 ± 19 years; 15 (44%) women; 30 (88%) ryanodine receptor 2 variant positive). We performed 3 bicycle exercise stress tests in each patient: (1) before the initiation of β-blocker treatment, (2) after >6 weeks of treatment with β1-selective β-blockers and (3) after >6 weeks of treatment with nadolol. We recorded resting and maximum heart rates and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. Resting heart rate was similar during treatment with nadolol and β1-selective β-blockers (54 ± 10 beats/min vs 56 ± 14 beats/min; P = .50), while maximum heart rate was lower during treatment with nadolol compared with β1-selective β-blockers (122 ± 21 beats/min vs 139 ± 24 beats/min; P = .001). Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with during treatment with β1-selective β-blockers (arrhythmic score 1.6 ± 0.9 vs 2.5 ± 0.8; P < .001) and before the initiation of β-blocker treatment (arrhythmic score 1.6 ± 0.9 vs 2.7 ± 0.9; P = .001); however, no differences were observed during treatment with β1-selective β-blockers compared with before the initiation of β-blocker treatment (arrhythmic score 2.5 ± 0.8 vs 2.7 ± 0.9; P = .46). The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with β1-selective β-blockers. β1-Selective β-blockers did not change the occurrence or severity of arrhythmias compared with no medication.

Family-based associations in measures of psychological distress and quality of life in a cardiac screening clinic for inheritable cardiac diseases: a cross-sectional study

BackgroundFamily-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic.MethodsProspective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data.ResultsThere was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p<0.0001), although there were overall no difference between the prevalence of a significant HADS score between the younger and older age groups (18.0% vs 20.0%, p=0.73). Significant positive associates of a higher HADS score were having lower educational attainment, being single or separated, and being closely related to the family proband. Between-family variance in anxiety and depression scores was greater than within-family variance.ConclusionsHigh levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.

Learning from failure: congestive heart failure in the postgenomic age

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.

Learning from failure: congestive heart failure in the postgenomic age

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.

Regulation of calcium release by interdomain interaction within ryanodine receptors.

In excitation-contraction (E-C) coupling, various types of activation signals, which are received presumably at the bulky cytoplasmic domain of the ryanodine receptor (RyR), are translated (or transduced) into the opening of the Ca2+ release channel located in the trans-membrane domain of the RyR. In order to elucidate the detailed mechanism of the signal transduction process, it is essential (i) to identify various sub-domains of the RyR that are involved in the Ca2+ channel regulation, (ii) to characterize the events occurring in these sub-domains during the activation process, and (iii) to characterize the modes of active interactions among these sub-domains. Recent developments in the E-C coupling research have provided us with new insight into each of these aspects, as outlined in this review. Of many putative regulatory sub-domains of the RyR, two domains (designated as N-terminal domain and central domain) are particularly interesting, because disease-linked mutations that have occurred in these domains (malignant hyperthermia and central core disease in skeletal muscle, and inheritable cardiac disease) induce abnormal modes of Ca2+ channel regulation. Pieces of evidence accumulated to this date suggest the following hypothesis. The N-terminal and central domains form, at least partly, the interacting domain pair, and unzipping and zipping actions of such domain-pair are involved in the opening and closing actions of the Ca2+ channel, respectively. We also propose that there are local conformational changes in the signal reception domains (e.g. the II-III loop-binding core), and such conformational changes are coupled with the aforementioned actions of the interacting domain pair. It seems that by virtue of such a coordination of the events occurring in various regions of the RyR, the Ca2+ channel can recognize the activation signal received at the cytoplasmic region of the RyR.

Regulation of calcium release by interdomain interaction within ryanodine receptors

In excitation-contraction (E-C) coupling, various types of activation signals, which are received presumably at the bulky cytoplasmic domain of the ryanodine receptor (RyR), are translated (or transduced) into the opening of the Ca2+ release channel located in the trans-membrane domain of the RyR. In order to elucidate the detailed mechanism of the signal transduction process, it is essential (i) to identify various sub-domains of the RyR that are involved in the Ca2+ channel regulation, (ii) to characterize the events occurring in these sub-domains during the activation process, and (iii) to characterize the modes of active interactions among these sub-domains. Recent developments in the E-C coupling research have provided us with new insight into each of these aspects, as outlined in this review. Of many putative regulatory sub-domains of the RyR, two domains (designated as N-terminal domain and central domain) are particularly interesting, because disease-linked mutations that have occurred in these domains (malignant hyperthermia and central core disease in skeletal muscle, and inheritable cardiac disease) induce abnormal modes of Ca2+ channel regulation. Pieces of evidence accumulated to this date suggest the following hypothesis. The N-terminal and central domains form, at least partly, the interacting domain pair, and unzipping and zipping actions of such domain-pair are involved in the opening and closing actions of the Ca2+ channel, respectively. We also propose that there are local conformational changes in the signal reception domains (e.g. the II-III loop-binding core), and such conformational changes are coupled with the aforementioned actions of the interacting domain pair. It seems that by virtue of such a coordination of the events occurring in various regions of the RyR, the Ca2+ channel can recognize the activation signal received at the cytoplasmic region of the RyR.