A nonsense mutation in the optic atrophy 3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein cattle

Cardiomyopathies are severe degenerative disorders of the myocardium that lead to heart failure. During the last three decades bovine dilated cardiomyopathy (BDCMP) was observed worldwide in cattle of Holstein-Friesian origin. In the Swiss cattle population BDCMP affects Fleckvieh and Red Holstein breeds. The heart of affected animals is enlarged due to dilation of both ventricles. Clinical signs are caused by systolic dysfunction and affected individuals die as a result of severe heart insufficiency. BDCMP follows an autosomal recessive pattern of inheritance and the disease-causing locus was mapped to bovine chromosome 18 (BTA18). In the present study we describe the successful identification of the causative mutation in the OPA3 gene located on BTA18 that was previously reported to cause 3-methylglutaconic aciduria type III in Iraqi-Jewish patients. We demonstrated conclusive genetic and functional evidence that the nonsense mutation c.343C>T in the bovine OPA3 gene causes the late-onset dilated cardiomyopathy in Red Holstein cattle.

A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers

Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

Kidney infarction in Friedreich's ataxia with dilated cardiomyopathy

A 37-year-old man with advanced Friedreich's ataxia was referred to our emergency department with acute exacerbated abdominal pain of unclear aetiology. Laboratory tests showed slightly increased inflammatory parameters, elevated troponin and B-type natriuretic peptide, as well as minimal proteinuria. Transthoracic echocardiography revealed a pre-existing dilated cardiomyopathy. Abdominal sonography showed no pathological alterations. Owing to persistent pain under analgesia, a contrast-enhanced CT-abdomen was performed, which revealed a non-homogeneous perfusion deficit of the right kidney, although neither abdominal vascular alteration, cardiac thrombus, deep vein thrombosis nor a patent foramen ovale could be detected. Taking all clinical and radiological results into consideration, the current incident was diagnosed as a thromboembolic kidney infarction. As a consequence, lifelong oral anticoagulation was initiated.

The locus for bovine dilated cardiomyopathy maps to chromosome 18

Bovine dilated cardiomyopathy (BDCMP) is a severe and terminal disease of the heart muscle observed in Holstein-Friesian cattle over the last 30 years. There is strong evidence for an autosomal recessive mode of inheritance for BDCMP. The objective of this study was to genetically map BDCMP, with the ultimate goal of identifying the causative mutation. A whole-genome scan using 199 microsatellite markers and one SNP revealed an assignment of BDCMP to BTA18. Fine-mapping on BTA18 refined the candidate region to the MSBDCMP06-BMS2785 interval. The interval containing the BDCMP locus was confirmed by multipoint linkage analysis using the software loki. The interval is about 6.7 Mb on the bovine genome sequence (Btau 3.1). The corresponding region of HSA19 is very gene-rich and contains roughly 200 genes. Although telomeric of the marker interval, TNNI3 is a possible positional and a functional candidate for BDCMP given its involvement in a human form of dilated cardiomyopathy. Sequence analysis of TNNI3 in cattle revealed no mutation in the coding sequence, but there was a G-to-A transition in intron 6 (AJ842179:c.378+315G>A). The analysis of this SNP using the study's BDCMP pedigree did not conclusively exclude TNNI3 as a candidate gene for BDCMP. Considering the high density of genes on the homologous region of HSA19, further refinement of the interval on BTA18 containing the BDCMP locus is needed.

The bovine dilated cardiomyopathy locus maps to a 1.0-Mb interval on chromosome 18

Cardiomyopathies are myocardial diseases that lead to cardiac dysfunction, heart failure, arrhythmia, and sudden death. In human medicine, cardiomyopathies frequently warrant heart transplantation in children and adults. Bovine dilated cardiomyopathy (BDCMP) is a heart muscle disorder that has been observed during the last 30 years in cattle of Holstein-Friesian origin. In Switzerland BDCMP affects Swiss Fleckvieh and Red Holstein breeds. BDCMP is characterized by a cardiac enlargement with ventricular remodeling and chamber dilatation. The common symptoms in affected animals are subacute subcutaneous edema, congestion of the jugular veins, and tachycardia with gallop rhythm. A cardiomegaly with dilatation and hypertrophy of all heart chambers, myocardial degeneration, and fibrosis are typical postmortem findings. It was shown that all BDCMP cases reported worldwide traced back to a red factor-carrying Holstein-Friesian bull, ABC Reflection Sovereign. An autosomal recessive mode of inheritance was proposed for BDCMP. Recently, the disease locus was mapped to a 6.7-Mb interval MSBDCMP06-BMS2785 on bovine Chr 18 (BTA18). In the present study the BDCMP locus was fine mapped by using a combined strategy of homozygosity mapping and association study. A BAC contig of 2.9 Mb encompassing the crucial interval was constructed to establish the correct marker order on BTA18. We show that the disease locus is located in a gene-rich interval of 1.0 Mb and is flanked by the microsatellite markers DIK3006 and MSBDCMP51.

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. RESULTS Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. CONCLUSION Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.

Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology

The cardiac voltage-gated Na(+) channel Na(v)1.5 generates the cardiac Na(+) current (INa). Mutations in SCN5A, the gene encoding Na(v)1.5, have been linked to many cardiac phenotypes, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. The mutations in SCN5A define a sub-group of Na(v)1.5/SCN5A-related phenotypes among cardiac genetic channelopathies. Several research groups have proposed that Na(v)1.5 may be part of multi-protein complexes composed of Na(v)1.5-interacting proteins which regulate channel expression and function. The genes encoding these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Na(v)1.5 may be classified as (1) anchoring/adaptor proteins, (2) enzymes interacting with and modifying the channel, and (3) proteins modulating the biophysical properties of Na(v)1.5 upon binding. The aim of this article is to review these Na(v)1.5 partner proteins and to discuss how they may regulate the channel's biology and function. These recent investigations have revealed that the expression level, cellular localization, and activity of Na(v)1.5 are finely regulated by complex molecular and cellular mechanisms that we are only beginning to understand.

Cardiac Sodium Channel Nav1.5 Mechanosensitivity is Inhibited by Ranolazine

The cardiac action potential (AP) is initiated by the depolarizing inward sodium current (I(Na)). The pore-forming subunit of the cardiac sodium channel, Na(v)1.5, is the main ion channel that conducts I(Na) in cardiac cells. Despite the large number of studies investigating Na(v)1.5, year after year, we are still learning new aspects regarding its roles in normal cardiac function and in diseased states. The clinical relevance of this channel cannot be understated. The cardiac I(Na) is the target of the class 1 anti-arrhythmic drugs(1), which are nowadays less frequently prescribed because of their well-documented pro-arrhythmic properties(2). In addition, since the first description in 1995 by Keating's group(3) of mutations in patients suffering from congenital long QT syndrome (LQTS) type 3, several hundred genetic variants in SCN5A, the gene coding for Na(v)1.5, have been reported and investigated(4). Interestingly, many of these genetic variants have been found in patients with diverse cardiac manifestations(5) such as congenital LQTS type 3, Brugada syndrome, conduction disorders, and more recently, atrial fibrillation and dilated cardiomyopathy. This impressive list underlines the importance of Na(v)1.5 in cardiac pathologies and raises the question about possible unknown roles and regulatory mechanisms of this channel in cardiac cells. Recent studies have provided experimental evidence that the function of Na(v)1.5, among many other described regulatory mechanisms(6), is also modulated by the mechanical stretch of the membrane in which it is embedded(7), thus suggesting that Na(v)1.5, like other ion channels, is "mechanosensitive". What does this mean? (SELECT FULL TEXT TO CONTINUE).

Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model

The cardiac sodium current (INa) is responsible for the rapid depolarization of cardiac cells, thus allowing for their contraction. It is also involved in regulating the duration of the cardiac action potential (AP) and propagation of the impulse throughout the myocardium. Cardiac INa is generated by the voltage-gated Na(+) channel, NaV1.5, a 2016-residue protein which forms the pore of the channel. Over the past years, hundreds of mutations in SCN5A, the human gene coding for NaV1.5, have been linked to many cardiac electrical disorders, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. Similar to many membrane proteins, NaV1.5 has been found to be regulated by several interacting proteins. In some cases, these different proteins, which reside in distinct membrane compartments (i.e. lateral membrane vs. intercalated disks), have been shown to interact with the same regulatory domain of NaV1.5, thus suggesting that several pools of NaV1.5 channels may co-exist in cardiac cells. The aim of this review article is to summarize the recent works that demonstrate its interaction with regulatory proteins and illustrate the model that the sodium channel NaV1.5 resides in distinct and different pools in cardiac cells. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Lifespan and disease predispositions in the Irish Wolfhound: a review

Several disease predispositions of Irish Wolfhounds are mentioned in the veterinary literature, but these lists vary greatly between different publications. This article reviews findings on lifespan as well as disease predispositions that have been reported in the literature. Hereditary mechanisms found so far are discussed, including their implications for breeding healthier dogs, the ethical necessity of which is stressed under the aspect of animal welfare. An open health registry, combined with the estimation of breeding values, seems to be the most promising approach. Furthermore, routine male castration is discouraged as being associated with an increased osteosarcoma risk. Mean lifespan estimates in Irish Wolfhounds vary between 4.95 and 8.75 years, but bias due to right censored data is common. The diseases reported to occur most frequently are dilated cardiomyopathy, osteogenic sarcoma, gastric dilation and volvulus and diseases of the osteochondrosis spectrum. Furthermore, intrahepatic portosystemic shunt plays an important role. Several other diseases have been reported in the literature, including rhinitis, epilepsy, progressive retinal atrophy, von Willebrand's Disease, and juvenile fibrocartilaginous embolism.

His-Purkinje system re-entry in patients with clustering ventricular tachycardia episodes

AIMS: Multiple arrhythmia re-inductions were recently shown in His-Purkinje system (HPS) ventricular tachycardia (VT). We hypothesized that HPS VT was a frequent mechanism of repetitive or incessant VT and assessed diagnostic criteria to select patients likely to have HPS VT. METHODS AND RESULTS: Consecutive patients with clustering VT episodes (>3 sustained monomorphic VT within 2 weeks) were included in the analysis. HPS VT was considered plausible in patients with (i) impaired left ventricular function associated with dilated cardiomyopathy or valvular heart disease; or (ii) ECG during VT similar to sinus rhythm QRS or to bundle-branch block QRS. HPS VT was plausible in 12 of 48 patients and HPS VT was demonstrated in 6 of 12 patients (50%, or 13% of the whole study group). Median VT cycle length was 318 ms (250-550). Catheter ablation was successful in all six patients. CONCLUSION: His-Purkinje system VT is found in a significant number of patients with repetitive or incessant VT episodes, and in a large proportion of patients with predefined clinical or electrocardiographic characteristics. Since it is easily amenable to catheter ablation, our data support the screening of all patients with repetitive VT in this regard and an invasive approach in a selected group of patients.

Ventricular tachycardia arising from the aortomitral continuity in structural heart disease: characteristics and therapeutic considerations for an anatomically challenging area of origin

BACKGROUND: The aortomitral continuity (AMC) has been described as a site of origin for ventricular tachycardias (VT) in structurally normal hearts. There is a paucity of data on the contribution of this region to VTs in patients with structural heart disease. METHODS AND RESULTS: Data from 550 consecutive patients undergoing catheter ablation for VT associated with structural heart disease were reviewed. Twenty-one (3.8%) had a VT involving the peri-AMC region (age, 62.7+/-11 years; median left ventricular ejection fraction, 43.6+/-17%). Structural heart disease was ischemic in 7 (33%), dilated cardiomyopathy in 10 (47.6%), and valvular cardiomyopathy in 4 (19%) patients, respectively. After 1.9+/-0.8 catheter ablation procedures (including 3 transcoronary ethanol ablations) the peri-AMC VT was not inducible in 19 patients. The remaining 2 patients underwent cryosurgical ablation. Our first catheter ablation procedure was less often successful (66.7%) for peri-AMC VTs compared with that for 246 VTs originating from the LV free wall (81.4%, P=0.03). During a mean follow-up of 1.9+/-2.1 years, 12 (57.1%) patients remained free of VT, peri-AMC VT recurred in 7 patients, and 1 patient had recurrent VT from a remote location. Three patients died. Analysis of 50 normal coronary angiograms demonstrated an early septal branch supplying the peri-AMC area in 58% of cases that is a potential target for ethanol ablation. CONCLUSIONS: VTs involving the peri-AMC region occur in patients with structural heart disease and appear to be more difficult to ablate compared with VTs originating from the free LV wall. This region provides unique challenges for radiofrequency ablation, but cryosurgery and transcoronary alcohol ablation appear feasible in some cases.

Two cases of trisomy 16 mosaicism ascertained postnatally

Postnatally ascertained trisomy 16 mosaicism is a rare diagnosis, with only three reported cases to date with no defined clinical phenotype. Trisomy 16 mosaicism diagnosed prenatally is common and associated with variable pregnancy outcomes ranging from stillbirth with multiple congenital abnormalities to an apparently normal newborn, making the genetic counseling very challenging. It is not clear whether uniparental disomy (UPD) 16 contributes to the phenotype, although it has been suggested that maternal UPD 16 affects the rate of intra-uterine growth retardation (IUGR) and congenital anomalies. We report on two further cases of trisomy 16 mosaicism confined to fibroblasts diagnosed postnatally. Patient 1 presented at birth with severe hypospadias, unilateral postaxial polydactyly, and different hair color with midline demarcation. His growth and development were normal at 11 months of age. Patient 2 was born with IUGR, significant craniofacial and body asymmetry, asymmetric skin hyperpigmentation, unilateral hearing loss, scoliosis, VSD, unexplained dilated cardiomyopathy, feeding difficulties, failure to thrive, and recurrent respiratory tract infections. She died at 7 months of age from respiratory failure. These two further cases of postnatally diagnosed trisomy 16 mosaicism highlight the variability of clinical features and outcome in this diagnosis. While Patient 2 presented with typical features of chromosomal mosaicism, Patient 1 had mild and transient features with essentially normal outcome, suggesting that trisomy 16 mosaicism may be under-diagnosed.

Endocardial Ablation to Eliminate Epicardial Arrhythmia Substrate in Scar-Related Ventricular Tachycardia

OBJECTIVES We evaluated the feasibility and safety of epicardial substrate elimination using endocardial radiofrequency (RF) delivery in patients with scar-related ventricular tachycardia (VT). BACKGROUND Epicardial RF delivery is limited by fat or associated with bleeding, extra-cardiac damages, coronary vessels and phrenic nerve injury. Alternative ablation approaches may be desirable. METHODS Forty-six patients (18 ischemic cardiomyopathy [ICM], 13 non-ischemic dilated cardiomyopathy [NICM], 15 arrhythmogenic right ventricular cardiomyopathy [ARVC]) with sustained VT underwent combined endo- and epicardial mapping. All patients received endocardial ablation targeting local abnormal ventricular activities in the endocardium (Endo-LAVA) and epicardium (Epi-LAVA), followed by epicardial ablation if needed. RESULTS From a total of 173 endocardial ablations targeting Epi-LAVA at the facing site, 48 (28%) applications (ICM: 20/71 [28%], NICM: 3/39 [8%], ARVC: 25/63 [40%]) successfully eliminated the Epi-LAVA. Presence of Endo-LAVA, most delayed and low bipolar amplitude of Epi-LAVA, low unipolar amplitude in the facing endocardium, and Epi-LAVA within a wall thinning area at CT scan were associated with successful ablation. Endocardial ablation could abolish all Epi-LAVA in 4 ICM and 2 ARVC patients, whereas all patients with NICM required epicardial ablation. Endocardial ablation was able to eliminate Epi-LAVA at least partially in 15 (83%) ICM, 2 (13%) NICM, and 11 (73%) ARVC patients, contributing to a potential reduction in epicardial RF applications. Pericardial bleeding occurred in 4 patients with epicardial ablation. CONCLUSIONS Elimination of Epi-LAVA using endocardial RF delivery is feasible and may be used first to reduce the risk of epicardial ablation.