Analysis of the Association between Copy Number Variation and Ventricular Fibrillation in ST-Elevation Acute Myocardial Infarction.

Sudden cardiac death due to ventricular fibrillation (VF) during ST-elevation acute myocardial infarction (STEAMI) significantly contributes to cardiovascular-related deaths. Although VF has been linked to genetic factors, variations in copy number variation (CNV), a significant source of genetic variation, have remained largely unexplored in this context. To address this knowledge gap, this study performed whole exome sequencing analysis on a cohort of 39 patients with STEAMI who experienced VF, aiming to elucidate the role of CNVs in this pathology. The analysis revealed CNVs in the form of duplications in the PARP2 and TTC5 genes as well as CNVs in the form of deletions in the MUC15 and PPP6R1 genes, which could potentially serve as risk indicators for VF during STEAMI. The analysis also underscores notable CNVs with an average gene copy number equal to or greater than four in DEFB134, FCGR2C, GREM1, PARM1, SCG5, and UNC79 genes. These findings provide further insight into the role of CNVs in VF in the context of STEAMI.

Preliminary Investigation on Efficacy and Safety of Substance P-Coated Stent for Promoting Re-Endothelialization: A Porcine Coronary Artery Restenosis Model.

BACKGROUND: Current polymer-based drug-eluting stents (DESs) have fundamental issues about inflammation and delayed re-endothelializaton of the vessel wall. Substance-P (SP), which plays an important role in inflammation and endothelial cells, has not yet been applied to coronary stents. Therefore, this study compares poly lactic-co-glycolic acid (PLGA)-based everolimus-eluting stents (PLGA-EESs) versus 2-methacryloyloxyethyl phosphorylcholine (MPC)-based SP-eluting stents (MPC-SPs) in in-vitro and in-vivo models. METHODS: The morphology of the stent surface and peptide/drug release kinetics from stents were evaluated. The in-vitro proliferative effect of SP released from MPC-SP is evaluated using human umbilical vein endothelial cell. Finally, the safety and efficacy of the stent are evaluated after inserting it into a pig's coronary artery. RESULTS: Similar to PLGA-EES, MPC-SP had a uniform surface morphology with very thin coating layer thickness (2.074 µm). MPC-SP showed sustained drug release of SP for over 2 weeks. Endothelial cell proliferation was significantly increased in groups treated with SP (n = 3) compared with the control (n = 3) and those with everolimus (n = 3) (SP: 118.9 ± 7.61% vs. everolimus: 64.3 ± 12.37% vs. the control: 100 ± 6.64%, p < 0.05). In the animal study, the percent stenosis was higher in MPC-SP group (n = 7) compared to PLGA-EES group (n = 7) (MPC-SP: 28.6 ± 10.7% vs. PLGA-EES: 16.7 ± 6.3%, p < 0.05). MPC-SP group showed, however, lower inflammation (MPC-SP: 0.3 ± 0.26 vs. PLGA-EES: 1.2 ± 0.48, p < 0.05) and fibrin deposition (MPC-SP: 1.0 ± 0.73 vs. PLGA-EES: 1.5 ± 0.59, p < 0.05) around the stent strut. MPC-SP showed more increased expression of cluster of differentiation 31, suggesting enhanced re-endothelialization. CONCLUSION: Compared to PLGA-EES, MPC-SP demonstrated more decreased inflammation of the vascular wall and enhanced re-endothelialization and stent coverage. Hence, MPC-SP has the potential therapeutic benefits for the treatment of coronary artery disease by solving limitations of currently available DESs.

Rare Variants in Genes of the Cholesterol Pathway Are Present in 60% of Patients with Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a pandemic in which conventional risk factors are inadequate to detect who is at risk early in the asymptomatic stage. Although gene variants in genes related to cholesterol, which may increase the risk of AMI, have been identified, no studies have systematically screened the genes involved in this pathway. In this study, we included 105 patients diagnosed with AMI with an elevation of the ST segment (STEMI) and treated with primary percutaneous coronary intervention (PPCI). Using next-generation sequencing, we examined the presence of rare variants in 40 genes proposed to be involved in lipid metabolism and we found that 60% of AMI patients had a rare variant in the genes involved in the cholesterol pathway. Our data show the importance of considering the wide scope of the cholesterol pathway in order to assess the genetic risk related to AMI.

Systemic Treatment of Immune-Mediated Keratoconjunctivitis Sicca with Allogeneic Stem Cells Improves the Schirmer Tear Test Score in a Canine Spontaneous Model of Disease.

Keratoconjunctivitis sicca (KCS) is characterized by ocular discomfort, conjunctival hyperaemia, and corneal scarring, causing reduced aqueous tear production that can be measured using the standard Schirmer tear test (STT). Canine adipose tissue-derived MSCs (cATMSCs) have been proposed as treatment due to their anti-inflammatory effect, by releasing cytokines and immunomodulatory soluble factors. PURPOSE: The aim of this study was to evaluate the effect of the systemic administration of cATMSCs on tear production in dogs with immune-mediated KCS, compared to classical Cyclosporine A (CsA) treatment. METHODS: Twenty-eight client-owned dogs with spontaneous KCS were allocated in the experimental group (n = 14, treated with systemic cATMSCs or control group (n = 14, treated with CsA). SST values increased significantly at days 15 (p = 0.002), 45 (p = 0.042) and 180 (p = 0.005) with no observed side-effects in the experimental group. Eyes with an initial STT value of 11-14 mm/min maintained significant improvement at day 180, needing only artificial tears as treatment. Eyes with an initial STT value <11 mm/min needed cyclosporin treatment at day 45, so follow-up was stopped. Control animals treated with CsA did not improve their STT at day 180. RESULTS AND CONCLUSIONS: Systemic allogeneic cATMSCs application appeared to be a feasible and effective therapy with positive outcome in dogs with initial STT between 11-14 mm/min, with a significant improvement in tear production. The STT increment was maintained for at least 180 days, without needing additional medication, thus suggesting it could constitute an alternative therapy to classical immunosuppressive treatments.

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation.

BACKGROUND: Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. METHODS: This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2` → 0RS3). Relative expression (2-∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. RESULTS: A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-∆Cq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. CONCLUSIONS: miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

AGT haplotype in ITGA4 gene is related to antibody-mediated rejection in heart transplant patients.

INTRODUCTION: One of the main problems involved in heart transplantation (HT) is antibody-mediated rejection (AMR). Many aspects of AMR are still unresolved, including its etiology, diagnosis and treatment. In this project, we hypothesize that variants in genes involved in B-cell biology in HT patients can yield diagnostic and prognostic information about AMR. METHODS: Genetic variants in 61 genes related to B-cell biology were analyzed by next generation sequencing in 46 HT patients, 23 with and 23 without AMR. RESULTS: We identified 3 single nucleotide polymorphisms in ITGA4 gene (c.1845G>A, c.2633A>G, and c.2883C>T) that conformed the haplotype AGT-ITGA4. This haplotype is associated with the development of AMR. Moreover, AMR patients with the haplotype AGT-ITGA4 present lower levels of integrin α-4 in serum samples compared to the reference GAC haplotype in control patients. CONCLUSION: We can conclude that polymorphisms in genes related to the biology of B-cells could have an important role in the development of AMR. In fact, the AGT haplotype in ITGA4 gene could potentially increase the risk of AMR.

Allogeneic adipose-derived mesenchymal stem cell therapy in dogs with refractory atopic dermatitis: clinical efficacy and safety.

Canine atopic dermatitis (AD) is a common skin disease with a 10-15 per cent prevalence. Current treatments vary in their efficacy and safety. The immunomodulatory properties of mesenchymal stem cells (MSCs) make them a promising alternative treatment. The aim of this study was to evaluate the therapeutic efficacy and safety of allogeneic canine adipose MSCs (cAd-MSCs) in dogs with refractory AD. Twenty-six dogs, suffering from AD for at least 12 months, not responding to conventional therapy, received an intravenous dose of 1.5×106 cAd-MSCs/kg bodyweight. Clinical signs, haematological and biochemistry profiles, and AD severity were assessed in a six-month follow-up using a validated scoring system (Canine Atopic Dermatitis Extent and Severity Index, version 4 (CADESI-04)). The degree of pruritus was quantified using a validated visual analogue scale, and also owner's global assessment of treatment efficacy. Twenty-two animals completed the study. Pruritus and CADESI-04 scores decreased significantly after one week or month of treatment, respectively, and remained stable for six months. Owner's global assessment score was 2.15±1.15 for all the animals in the study. In conclusion, systemic administration of allogeneic cAd-MSCs appeared to be a simple therapy with positive outcome in the remission of clinical signs for AD refractory to conventional medications, for at least six months and with no adverse events.

Allogeneic Adipose-Derived Mesenchymal Stem Cells (Horse Allo 20) for the Treatment of Osteoarthritis-Associated Lameness in Horses: Characterization, Safety, and Efficacy of Intra-Articular Treatment.

Osteoarthritis commonly causes lameness in the horse and has a great impact in performance animals. Due to the limitations of current medical therapies, allogenic mesenchymal stem cells (MSCs) may become an alternative method to control inflammation, reduce tissue damage and pain, and therefore improve lameness. We present the results of a regulatory clinical trial testing adipose-derived MSCs (Horse Allo 20) in veterinary (Agencia Española del Medicamento y Productos Sanitarios, Spanish Medicines Agency, Reference number 325/ECV) involving a total number of 80 participants and with 90 days of follow-up period. The manufacturing process of Horse Allo 20 was robust with no influence of the adipose tissue donor (gender, age, or breed), sample origin (intraperitoneal or subcutaneous), or storage conditions (fresh vs. frozen product presentations) on the quality, safety, and efficacy of the drug product. An in vivo safety study showed that local and systemic tolerance was safe even after repeated intra-articular administration (three injections). An in vivo efficacy study demonstrated the efficacy of the treatment after one or two injections by a reduction in lameness (P < 0.05) for an extended period of time (90 days), decreasing the need for prolonged local and/or systemic anti-inflammatory therapies and their well-known deleterious effects and toxicities.

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation.

BACKGROUND: Heart transplantation (HT) is a well-established lifesaving treatment for endstage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donor-recipient pairs.Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next-generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology,interleukin-4 receptor subunitα (p.Ile75Val-IL4Rα), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case inadenosine deaminase(ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR. CONCLUSIONS: Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR.

Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection.

BACKGROUND: Heart transplantation (HT) is a life-saving treatment for patients with end-stage heart failure. One of the main problems after HT is the humoral response termed antibody-mediated rejection (AMR). Complement activation plays a key role in AMR contributing to graft damage. The aim of this study was to analyze genetic variants in genes related to the complement pathways that could be associated with the development of AMR. METHODS: Analysis of 51 genes related to the complement pathway was performed by next-generation sequencing in 46 HT recipients, 23 with and 23 without AMR. Statistical analysis was performed with SNPstats and R. RESULTS: We identified 2 single nucleotide polymorphisms, 1 in the mannose-binding lectin 2 gene (p.Gly54Asp-MBL2) and 1 in the complement factor properdin gene (p.Asn428(p=)-CFP), that showed significant association with the absence and development of AMR, respectively. Moreover, the presence of the rare allele in p.Gly54Asp-MBL2 control patients correlated with an immunodeficiency of mannose-binding lectin (6.24 ng/ml vs 207.50 ng/ml, p < 0.01), whereas the presence of the rare allele p.Asn428(p=)-CFP in patients with AMR correlated with higher levels of properdin protein (14.65 µg/ml vs 10.77 µg/ml, p < 0.05). CONCLUSIONS: AMR is a complex phenotype affected by many recipient factors. Variants in p.Gly54Asp-MBL2 and p.Asn428(p=)-CFP genes, encoding mannose-binding lectin 2 and properdin, may influence the risk of AMR.

Macrophagic enhancement in optical coherence tomography imaging by means of superparamagnetic iron oxide nanoparticles.

BACKGROUND: The ability of optical coherence tomography (OCT) to visualise macrophages in vivo in coronary arteries is still controversial. We hypothesise that imaging of macrophages in OCT could be enhanced by means of superparamagnetic nanoparticles. METHODS: We compared the optical backscattering and attenuation of cell pellets containing RAW 264.7 macrophages with those of macrophagic cell pellets labelled with very small superparamagnetic oxydised nanoparticles (VSOP) by means of light intensity analysis in OCT. The labelled macrophages were incubated with VSOP at a concentration of 1 mM Fe, corresponding to intracellular iron concentrations of 8.8 pg/cell. To study the effect of intracellular accumulation on the backscattering, VSOP dilutions without cells were also compared. OCT pullbacks of the PCR tubes containing the cell pellets were obtained and light intensity analysis was performed on raw OCT images in polar view, after normalisation by the backscattering of the PCR tube. The backscattering was estimated by the peak normalised intensity, whilst the attenuation was estimated by the number of pixels between the peak and the normalised intensity 1 (peak-to-one). RESULTS: VSOP-loaded macrophages have higher backscattering than the corresponding unlabelled macrophages (peak normalised intensity 6.30 vs. 3.15) with also slightly higher attenuation (peak-toone 61 vs. 66 pixels). The backscattering of the nanoparticles in suspension was negligible in the light intensity analysis. CONCLUSIONS: VSOP increase significantly the optical backscattering of macrophages in the nearinfrared region, with minimal increase in signal attenuation. This finding enables the enhancement of macrophages in conventional OCT imaging with an easily implementable methodology.

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report.

BACKGROUND: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8-10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4). METHODS: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied. RESULTS: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients. CONCLUSIONS: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.

Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. METHODS AND RESULTS: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. CONCLUSIONS: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.

Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3.

BACKGROUND: Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype-phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. METHODS: 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. RESULTS: 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. CONCLUSIONS: The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile.

Severe cardiac conduction disturbances and pacemaker implantation in patients with hypertrophic cardiomyopathy.

The aims of this study were to determine the prevalence of severe cardiac conduction disturbances in a cohort of 451 patients with hypertrophic cardiomyopathy and to describe the characteristics of, and outcomes in, those who required a permanent pacemaker. A pacemaker was implanted in 48 patients (11%): 20 had sinus node dysfunction and 28 had an atrioventricular conduction disturbance. Primary bradyarrhythmia (which was not related to iatrogenic atrioventricular block or therapeutic ablation of the atrioventricular node) was the reason for permanent pacemaker implantation in 36 patients (8%). In 18% of cases, at least one other family member had a permanent pacemaker. In this patient series, a high prevalence of severe cardiac conduction disturbance leading to permanent pacemaker implantation was observed. Severe cardiac conduction disturbance in hypertrophic cardiomyopathy may also have a familial component.

Trastornos graves de la conducción cardiaca e implante de marcapasos en pacientes con miocardiopatía hipertrófica / Severe cardiac conduction disturbances and pacemaker implantation in patients with hypertrophic cardiomyopathy

El objetivo de este estudio es analizar la prevalencia de trastornos graves de la conducción cardiaca en una cohorte de 451 pacientes con miocardiopatía hipertrófica, describiendo las características y la evolución de aquellos que requirieron marcapasos. En 48 pacientes (11%) se implantó un marcapasos: 20 casos por disfunción del nodo sinusal y 28 casos por trastorno de la conducción auriculoventricular. Las bradiarritmias primarias (las no relacionadas con bloqueo auriculoventricular iatrogénico o ablación terapéutica del nodo auriculoventricular) fueron causa de implante en 36 pacientes (8%). En un 18% se detectó un marcapasos en al menos otro miembro de la familia. En nuestra serie, encontramos una elevada prevalencia de trastornos graves de la conducción cardiaca que determinaron el implante de marcapasos. Los trastornos severos de la conducción en la miocardiopatía hipertrófica tienen también una presentación familiar (AU)

The aims of this study were to determine the prevalence of severe cardiac conduction disturbances in a cohort of 451 patients with hypertrophic cardiomyopathy and to describe the characteristics of, and outcomes in, those who required a permanent pacemaker. A pacemaker was implanted in 48 patients (11%): 20 had sinus node dysfunction and 28 had an atrioventricular conduction disturbance. Primary bradyarrhythmia (which was not related to iatrogenic atrioventricular block or therapeutic ablation of the atrioventricular node) was the reason for permanent pacemaker implantation in 36 patients (8%). In 18% of cases, at least one other family member had a permanent pacemaker. In this patient series, a high prevalence of severe cardiac conduction disturbance leading to permanent pacemaker implantation was observed. Severe cardiac conduction disturbance in hypertrophic cardiomyopathy may also have a familial component (AU)

The R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular non-compaction in humans.

BACKGROUND: The R820W mutation in the MYBPC3 gene has been associated with the development of hypertrophic cardiomyopathy (HCM) in rag-doll cats, but had not been described in humans. AIMS: To describe the phenotype associated with the R820W mutation identified in a human family. METHODS: The R820W was identified by direct sequencing of the MYBPC3 gene in a 47 year old woman with HCM and left ventricular non-compaction (LVNC). Clinical and genetic studies of the R820W mutation were performed in her family. RESULTS: The index patient was homozygous for the mutation and had no additional mutations in the main sarcomeric genes (MYH7, TNNT2, TNNI3, and TPM1). She had HCM with LVNC and normal systolic function. One brother had died suddenly at age 43 years. Another brother diagnosed of LVNC with severe systolic dysfunction and a cardiac arrest was also homozygous for the mutation. One heterozygous 31 year old sister, and three heterozygous sons of the index (ages 14, 20 and 23 years old) were clinically unaffected. The father of the index was apparently healthy and her mother had atrial fibrillation and an electrocardiographic diagnosis of left ventricular hypertrophy at age 86 years. CONCLUSION: The R820W mutation in the MYBPC3 gene, previously associated with HCM in rag-doll cats, causes both HCM and LVNC in homozygous human carriers, with mild or null clinical expression in heterozygous carriers.

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy.

BACKGROUND: MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients. METHODS: Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families. RESULTS: 16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9]. CONCLUSIONS: Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.