HCM Patients Research Articles

High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort

BackgroundHypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine.MethodologyIn this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population.ResultsHRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations.ConclusionsHRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations.

Appropriate implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: What happens on Sunday afternoons in May?

This editorial refers to ‘The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy’ by C. O'Mahony et al ., on page 724 Hypertrophic cardiomyopathy (HCM) is a clinically and genetically heterogeneous disease. Sudden cardiac death (SCD) is the most devastating complication of HCM. The substrate for potentially life-threatening ventricular arrhythmias (VA) in HCM is complex. The hypertrophy causes dispersion of repolarization and refractoriness, which increases the vulnerability to triggered arrhythmia. Myocardial disarray, the histological hallmark of the disease leads to a disruption of cell-to-cell alignment and together with the expansion of the interstitial compartment and replacement fibrosis creates unidirectional conduction block that predispose to re-entry arrhythmia. Sarcomeric protein gene mutations influence calcium homeostasis, and abnormalities in ion fluxes during repolarization can cause after-depolarization and triggered activity. This unpredictable, complex arrhythmogenic substrate is further influenced by maladaptive autonomic responses, myocardial ischaemia, left ventricular outflow tract obstruction, and currently unknown factors.1 Although these characteristics are to some extent present in most HCM patients, risk of SCD in the general HCM population is low.2 The risk of sudden death increases in the presence of the following clinical risk factors: positive family history of SCD, unexplained syncope, abnormal blood pressure response to exercise, left ventricular wall thickness ≥30 mm, …

Predictors of atrial emptying function in patients with hypertrophic cardiomyopathy: insights from cardiovascular magnetic resonance

Background Atrial function is an integral part of cardiac function that is often neglected. Previous studies have shown that the left atrium (LA) is dilated and its contractile capacity is reduced in HCM patients. Whether this is related to pathophysiological aspects of HCM such as the degree of left ventricular (LV) hypertrophy, myocardial fibrosis or diastolic dysfunction remains to be established. Methods 56 patients with HCM (44M/12F, mean age 55±14 years) and 50 normal controls (35M/15F, mean age 52 ±11 years) underwent CMR (Siemens Avanto 1.5T). HCM patients with reduced ejection fraction (EF<55%), known coronary artery disease, atrial fibrillation, hypertension, and moderate or severe valve disease were excluded. The imaging protocol included standard long and short-axis SSFP cines and late gadolinium enhancement (LGE) imaging. In addition to standard LV measurements (volumes, ejection fraction, mass), atrial volumes (max, min volume indexed for BSA) were measured using biplane-length-area method in 2 orthogonal planes (HLA and VLA SSFP retro-gated cine sequences). Diastolic function parameters (peak flow rate, time-topeak-flow, deceleration time) were assessed using manual tracing of endocardial border across all temporal phases of the short axis stack and corrected for end-diastolic volume and RR interval respectively. Ventricular fibrosis was calculated using a full-width at half-maximum algorithm and expressed as LV mass percentage. Results Maximum LA volume was increased (63.3±16.6 vs 50.8 ±14.5 ml/m2; p<0.001) and LA ejection fraction (LAEF) was significantly reduced (54.1±11.2% vs 63.9±4.8%; p<0.001) in HCM patients compared to normal controls, respectively (Figure). HCM patients had increased ejection fraction (76±6 vs 71±5%, p<0.001) and mass index (88±24 vs 57±12 g/m2, p<0.001) compared to normals. The average amount of fibrosis in HCM patients was 11 ±7%. Univariate and multivariate analysis for LAEF in HCM patients are summarised in table 1. Age, LV mass index, LV wall thickness, and myocardial fibrosis showed significant bivariate correlations with LAEF. To analyse the relation between LAEF and ventricular parameters we performed linear regression analysis. This showed that LAEF is predicted independently by 4 variables in a backward selection model (R2=0.415): age, LV mass index, extent of myocardial fibrosis, and the LV time to peak flow. Conclusions

Cardiomyopathies: Classification, Clinical Characterization, and Functional Phenotypes

Cardiomyopathies: Classification, Clinical Characterization, and Functional Phenotypes

All That Glitters is not Gold: Apical Hypertrophic Cardiomyopathy Mimicking Acute Coronary Syndrome

Hypertrophic cardiomyopathy is characterized by the idiopathic hypertrophy of the left ventricle (and occasionally right ventricle). HCM is an autosomal dominant disease, with variable penetration. In Asian population, apical hypertrophic cardiomyopathy is relatively common (25%). However, this is relatively rare in Caucasian population (0.2%). Patients with HCM, often presents with typical exertional chest pain and shortness of breath. Apical HCM patients tend to have milder symptoms. However, the clinical presentation and electrocardiographic features of Apical HCM often mimic acute coronary syndrome and high index of suspicion is warranted in differentiating this condition. Patients with apical HCM have relatively better prognosis when compare to the other varieties. Here, we are presenting a patient who presented with typical exertional chest pain whose electrocardiographic changes are concerning for acute ischemic changes.

Myosin binding protein C: implications for signal-transduction

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

Abstract 16924: Multimodality Imaging Reveals Decreased Creatine-Kinase Flux and Systolic Strain in Patients with Hypertrophic Cardiomyopathy and Preserved LVEF

Background/Objectives: We investigated in vivo cardiac creatine kinase (CK) ATP supply and function in a family with HCM who carry an extensively characterized point mutation (R403Q) in the cardiac β-myosin heavy chain gene. Methods: Quantitative phosphorus ( 31 P) saturation transfer MRS was used to noninvasively measure cardiac CK energy transfer-the forward CK flux and the CK rate constant, k f -and CK metabolite concentrations (phosphocreatine, [PCr], and [ATP]) in patients with HCM (n=10), and in age-matched healthy controls (n=15). Systolic strain, LV ejection fraction (EF), diastolic function and cardiac morphology were assessed by echocardiography in HCM patients (n=11) and a second group of healthy controls (n=10). Results: LV mass was higher in HCM patients than controls (307.21 ± 12.37 vs 167.63 ± 42.53; p=0.0037). [PCr] was significantly decreased by 22% in HCM patients (7.36 ± 2.29µmol/g wet weight) as compared to controls (9.41 ± 1.2µmol/g; p=0.005), but PCr/ATP ratio was not significantly altered (1.54 ± 0.4 in HCM vs. 1.69 ± 0.29, p=0.26). The pseudo-first-order rate-constant for the CK reaction, k f was reduced by 26% (0.266 ± 0.14 vs. 0.36 ± 0.08, p&lt;0.04) and the forward CK flux was reduced by 43% (1.94 ± 1.27 vs 3.39 ± 0.96, p&lt;0.003) in HCM patients when compared to controls. Diastolic function (E/A) was impaired (0.90 ± 0.31 in HCM vs 1.48 ± 0.27 controls; p=0.0003) and peak systolic strain (longitudinal; εL) was significantly decreased in HCM patients (-13.40 ± 5.32 vs -18.93 ± 2.46; p=0.0076). Peak longitudinal strain and diastolic function (E/A) correlated with NYHA class (R²=0.50; p =0.0007); E/A &lt;1 correlated with NYHA class progression over 5 years of follow up (R 2 =0.6, p=0.024). Conclusions: PCr, k for and CK flux are significantly reduced in patients compared to age-matched healthy control subjects, indicating impaired CK ATP energy supply even at rest, consistent with prior work on a HCM (R403Q) mouse model. However, only systolic strain and diastolic function were correlated with NYHA class and progression respectively, suggesting that while bioenergetic alterations are associated with the underlying mutation, other downstream molecular effects contribute to the severity of dysfunction and clinical status of these patients.

Abstract 17364: Abnormal Repolarizations in Electrocardiogram Correlate with Abnormal Diastolic Mechanics in Patients with Hypertrophic Cardiomyopathy

Introduction: HCM is often characterized by marked repolarization abnormalities. However the significance of repolarization changes in these patients has not been investigated. Aim: We investigated the prevalence and significance of ECG repolarization patterns on sensitive measures of systolic and diastolic function in a cohort of 110 patients (mean age 52± 17 yrs, male 65%, Caucasian 73%) with HCM. Method: We performed echocardiography and ECG evaluation in 110 HCM patients. ECG repolarization parameters including strain pattern, early repolarization pattern, ST elevation, ST depression and T wave inversion were measured. Conventional and longitudinal tissue Doppler- derived tissue velocity and strain were analyzed off-line. Result: The mean left ventricular mass index was 141± 48 g/m, 2 LVEF was 69± 10% and left ventricular outflow tract gradient was 27±29 mmHg. ECG analysis revealed mean QTc of 451± 34 ms; 45/110 had strain pattern, 17/110 had early repolarization pattern and 14/110 had deeply inverted T waves. Patients with strain pattern on ECG, demonstrated decreased early diastolic velocity (lateral: -3.7± 2.2 vs. -4.6± 2.3 cm/s, p= 0.044, anterior: -2.6± 1.5 vs. -3.4± 1.4 cm/s, p= 0.04 and inferior:-2.7± 1.4 vs. -3.9± 1.6 cm/s, p= 0.005 regions), and late diastolic velocity (lateral:-1.2+- 0.76 vs -2.3+- 1.6, p= 0.001, anterior: -1.6+- 0.7, -2.7+- 1.3, p= 0.0006 and inferior: -2.7+- 1.8 vs -4.1 +- 1.7, p= 0.0003) in the corresponding regional myocardium, when compared to HCM patients without strain pattern. Patients who exhibited deeply inverted T waves on ECG exhibited decrease in late diastolic strain rate in the corresponding regional myocardium (lateral: 0.44± 0.32 vs. 0.84±0.48 s -1 , p= 0.001 and anterior: 0.56±0.19 vs. 1.0± 0.56 s -1 , p= 0.005), when compared to HCM patients without this finding. In contrast, early diastolic strain rate was increased in the corresponding regional myocardium (lateral: 1.75± 0.6 vs. 1.1± 0.62 s -1 , p= 0.015 and anterior: 1.17± 0.3 vs. 0.87± 0.5 s -1 , p= 0.01) in patients with evidence of early repolarization on ECG, when compared to patients without this feature. Conclusion: Strain pattern and deeply inverted T waves are markers for abnormal diastolic mechanics in patients with hypertrophic cardiomyopathy.

Epicardial Ablation for Ventricular Tachycardia

Background— The purpose of this study was to describe the epicardial percutaneous ablation experience of 6 European high-volume ventricular tachycardia (VT) ablation centers. Methods and Results— Data from 218 patients with coronary artery disease (CAD, n=85 [39.0%]), idiopathic dilated of patients with idiopathic VT cardiomyopathy (IDCM, n=67 [30.7%]), arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARCD/C, n=13 [6%]), hypertrophic cardiomyopathy (HCM, n=5 [2.3%]), and absence of structural heart disease (n=48 [22%]) undergoing epicardial subxyphoid access for VT ablation were collected. The epicardial approach was attempted as first-line treatment in 78 patients (35.8%). Acute prevention of VT inducibility was obtained in 156 patients (71.6%). There were no procedure-related deaths. Cardiac tamponade occurred in 8 patients, and abdominal hemorrhage in 1 patient. Six patients died of electrical storm recurrence within 48 hours from the procedure. After a mean follow-up of 17.3±18.2 months, 60 patients (31.4%) presented with VT recurrence (39.3% of IDCM patients; 34.7% of CAD patients; 30.8% of ARVD/C patients; 25% of HCM patients; 17.1% of patients with idiopathic VT). Twenty patients (10.4%) died during follow-up (12 of heart failure, 2 of cardiac arrest, and 6 of extracardiac causes). Conclusions— In experienced centers, epicardial ablation of VT has an acceptable risk and favorable outcome. In selected patients, it is reasonable to consider as a first-line ablation approach.

The Mitral Valve in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) has evoked both fascination and controversy since its first modern description >50 years ago.1 Originally described as “functional aortic subvalvar stenosis” by Brock, the majority of articles about HCM in the ensuing first decade emanated from observations made in the operating room or in the cardiac catheterization laboratory.1 The actual cause of left ventricular outflow tract (LVOT) obstruction in patients with this condition had not yet been clarified. Ironically, the mechanisms of LVOT obstruction in HCM were only elucidated several years after surgery was first performed in these patients. In fact, an early report by Morrow described the septal myotomy procedure as surgical treatment for HCM and proposed that the myotomy interfered with the sphincter-like muscular contraction ring in the LVOT.1 Article see p 40 Noninvasive cardiovascular imaging studies have greatly advanced our knowledge about HCM.2 Hypertrophic cardiomyopathy is now felt to have tremendous genetic,3 clinical, morphological, and hemodynamic heterogeneity.1 Nevertheless, the presence of LVOT obstruction in patients with HCM has continued to inspire interest. The often contentious debates surrounding LVOT obstruction have centered on its very existence, its causes, its clinical impact and prognosis, and its optimal management.1 These issues have inextricably included the mitral valve, which has long been felt to play a pivotal role in the pathophysiology of LVOT obstruction in patients with HCM. In the present issue of Circulation , Maron et al use cardiovascular magnetic resonance (CMR) imaging to characterize mitral valve leaflets in patients with HCM.4 This study assessed the lengths of the anterior mitral leaflet (AML) and posterior mitral leaflet in 172 consecutive patients with HCM. Their findings were compared with 172 normal control subjects matched for age, sex, and body surface area. In addition, the study included a small cohort of …

MYOCARDIAL DYSFUNCTION AND METABOLIC DERANGEMENT IN TYPE 2 DIABETES: RELATIONSHIP WITH PROCOLLAGEN BIOMARKERS OF MYOCARDIAL FIBROSIS

culated, and two novel indices of ventricular compliance; LV circumferential (CRI) and longitudinal (LRI) relaxation indices. Results: LV EF was significantly lower in ICM (32± 2 vs 65± 2, p< 0.001) and hyperdynamic in HCM (72± 2 vs 65± 2, p= 0.03) when compared to VOL. SV was similar in all groups. ICM LV EDV was 1.8× greater than VOL (p< 0.001) and 2.2× greater than HCM (p< 0.001). CRI was impaired in ICM patients (19% lower than VOL, p< 0.001) and preserved in HCM. LRI was significantly lower in ICM (72% lower, p< 0.001) and HCM patients (50% lower, p< 0.001) when compared to VOL. Atrial EF was significantly lower in both ICM (22.6± 10.2) andHCM (28.8± 10.5) than VOL (49.1± 9.1, p< 0.001). Conclusions: This work demonstrates cMRI is capable of producing measures of diastolic function, which are at least comparable with current techniques in echocardiography. Using novel LR and CR indices, we have shown that impairment of diastolic function is primarily due to abnormal relaxation of LV longitudinal fibers and that this maybe compensated for byhyperdynamic circumferential fibers in order to maintain SV. doi:10.1016/j.hlc.2011.05.452

Pathological CMR findings and their clinical value in patients with high grade ventricular arrythmias without previously known cardiac conditions

Recent studies have demonstrated the ability of CMR to identify the anatomic correlate of high grade ventricular arrhythmia (VA) in HCM and CHD patients. However, little is known about the value of CMR in patients with VAs, without previously known cardiac conditions.

The HCM-Associated Cardiac Troponin T Mutation K273N in a Human Heart Sample Studied by in Vitro Motility Assay

We isolated troponin from left ventricular muscle of a patient with a homozygous K273N mutation in troponin T and compared it with troponin from donor heart muscle using the quantitative in vitro motility assay. Motility of thin filaments reconstituted with skeletal muscle actin, human tropomyosin and mutant native troponin was indistinguishable from thin filaments containing donor heart troponin (Sliding speed at 4µM Ca2+, K273N/donor = 0.98±0.09, n=9; Ca2+- sensitivity, EC50 fraction filaments motile K273N/donor = 0.94±0.28, n=9).This pattern of results was also observed with troponin from human HCM muscle caused by mutations in myosin and MyBP-C and in this case it was ascribed to a secondary modification of troponin not related to the mutation. To test for this possibility with our K273N mutant sample, we exchanged recombinant K273N TnT into troponin from a donor heart. In the non-HCM context the K273N mutation caused a substantial increase in Ca2+-sensitivity (EC50 fraction filaments motile K273N/donor = 0.54±0.17, n=5, p=0.004). We also exchanged recombinant K273N TnT into troponin from a patient with HCM due to a mutation in MyBP-C.We conclude that the K273N TnT mutation increases thin filament Ca2+-sensitivity, in common with other HCM-causing mutations, but in the heart muscle of patients with HCM this effect is largely masked by secondary changes in troponin function due to post-translational modifications. We are investigating whether troponin I phosphorylation is uncoupled from decreased Ca2+-sensitivity in this sample, since this dysfunction was observed in troponin from HCM patients with MYH7 and MYBPC3 mutations.Supported by Seventh Framework Program of the European Union “BIG-HEART,” grant agreement 241577.

Effect of Hypertrophic Cardiomyopathy Mutations on Protein-Protein Interactions in the Thin Filament

Familial hypertrophic cardiomyopathy (FHC) refers to a heterogeneous group of cardiac diseases linked to over 630 mutations in sarcomeric proteins. Analysis of the phenotype of the associated disease, the disease outcome, and the functional consequences of FHC mutations all indicate a complex process of pathogenesis that cannot be predicted solely by the localization of the mutation. However, mutations linked to HCM patients tend to increase the calcium sensitivity of contraction in skinned fiber and myosin ATPase experiments.

Surgery for Non-Ischemic Ventricular Tachycardia

Objective: Radiofrequency catheter ablation of non-ischemic VT frequently fails because of a possible non-transmural ablation due to an epicardial or intramural activation focus or hypertrophic myocardium. Methods: Surgeries for non-ischemic VT were performed in 17 patients from 2002 to 2011. The underlying heart diseases were cardiomyopathy in 11 patients, an idiopathic LV aneurysm in 2, an LV lipoma in 2, idiopathic VT in 1, and ARVC in 1. The indication for the surgery was medically refractory or incessant VT in all, including in 10 patients with VT storms. Ten patients had an ICD or CRTD implanted preoperatively and 10 had undergone a failed endocardial and/or epicardial RFCA. In the patients with HCM, the thickness of the LV at the origin of the VT was 14.3±1.9 mm. All the patients underwent a map-guided procedure for VT. Results: There were no operative or late deaths. The intraoperative electro-anatomical mapping demonstrated epicardial or intramural origin or reentry in the HCM patients. There was one early recurrence of clinical VT and an additional endocardial RFCA was performed. Three patients were inducible of non-clinical VT or VF, and an ICD was implanted. There were no recurrences of VT or ICD shocks in any patients during a follow-up period of 42±33 months. Conclusions: The surgery provides an excellent suppression of VT in the patients with non-ischemic VT.

Late Gadolinium Enhancement and Signal Average Electrocardiogram for Predicting Ventricular Tachyarrhythmia

Late gadolinium enhancement (LGE) during cardiac magnetic resonance (CMR) is associated with the prevalence of ventricular tachycardia/ventricular fibrillation (VT/VF). Signal average electrocardiogram (SAECG) is also relevant to VT/VF. The purpose of this study was to investigate the clinical significance of LGE and SAECG for patients with organic heart disease. We studied 150 patients with organic heart disease who performed CMR from 2006 to 2011. We examined them about LGE and SAECG for incidence of VT/VF. Their mean age was 62.9 years old, their mean left ventricular ejection fraction was 45.3%, and mean brain natriuretic peptide was 440 pg/ml. Their underlying heart disease were ischemic heart disease (IHD, 46 patients), dilated cardiomyopathy (38 patients), hypertrophic cardiomyopathy (HCM, 38 patients), and others. Ninety-four patients showed LGE in CMR, and 26 patients experienced VT/VF during follow-up of 13.4±9.4 months. In IHD patients, incidence of VT/VF was higher in patients with positive SAECG than patients with negative SAECG (37% vs 9%, p<0.05). In HCM patients, VT/VF occurred more frequently in patients with LGE than patients without LGE (24% vs 0%, p<0.05). In IHD, SAECG is more valuable in predicting tachyarrhythmia event. On the other hand, in HCM, LGE offers more useful information.

Myocardial Dysfunction and Metabolic Derangement in Type 2 Diabetes: Relationship with Procollagen Biomarkers of Myocardial Fibrosis

culated, and two novel indices of ventricular compliance; LV circumferential (CRI) and longitudinal (LRI) relaxation indices. Results: LV EF was significantly lower in ICM (32± 2 vs 65± 2, p< 0.001) and hyperdynamic in HCM (72± 2 vs 65± 2, p= 0.03) when compared to VOL. SV was similar in all groups. ICM LV EDV was 1.8× greater than VOL (p< 0.001) and 2.2× greater than HCM (p< 0.001). CRI was impaired in ICM patients (19% lower than VOL, p< 0.001) and preserved in HCM. LRI was significantly lower in ICM (72% lower, p< 0.001) and HCM patients (50% lower, p< 0.001) when compared to VOL. Atrial EF was significantly lower in both ICM (22.6± 10.2) andHCM (28.8± 10.5) than VOL (49.1± 9.1, p< 0.001). Conclusions: This work demonstrates cMRI is capable of producing measures of diastolic function, which are at least comparable with current techniques in echocardiography. Using novel LR and CR indices, we have shown that impairment of diastolic function is primarily due to abnormal relaxation of LV longitudinal fibers and that this maybe compensated for byhyperdynamic circumferential fibers in order to maintain SV. doi:10.1016/j.hlc.2011.05.452

The Usefulness of Electrophysiological Test (EPS) for Implantable Cardioverter Defibrillator (ICD) Therapy in Patients with Hypertrophic Cardiomyopathy (HCM)

Background: Patients with HCM are at substantial risk for sudden cardiac death (SCD). There are observational studies that show HCM patients with inducible arrhythmias are at increased risk for SCD, however, the usefulness of EPS, which predicts the necessity of preoperative management for ICD therapy, is not established. Method: In 76 patients with HCM implanted ICD between May 2000 and August 2010 followed for mean (±SD) of 38.3 +⁄− 3.2 months, consists of 50 patients implanted ICD for primary prevention and 26 patients for secondary prevention, 9 patients (18%) in primary prevention group and 10 patients (38%) in secondary prevention group have received appropriate ICD therapies. Arrythmogenic risk was assessed by occurrence of NSVT in Holter ECG and induced Sustained Ventricular tachycardia (SVT) and fibrillation (VF) in EPS. Results: In the primary prevention group, all patients has a history of NSVT on Holter ECG, of which max beats are significantly higher (17.22/8.357 P=0.0017) in therapy group. EPS shows there is no tendency to the occurance of SVT/VF in therapy group (P=0.17). In therapy group, SVT/VF had induced by double ventricular extrastimuli in only 2 patients (25%), triple entricular extrastimuli in 5 patients (62%). In non-therapy group, SVT/VF had induced by double ventricular extrastimuli in 37 patients (51%), triple ventricular extrastimuli in 14 patients (37%). Conclusion: In HCM patients, EPS suggest not to be the prior predictor for the indication of primary ICD implantation.

Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle

A unique feature of MyBP-C in cardiac muscle is that it has multiple phosphorylation sites. MyBP-C phosphorylation, predominantly by PKA, plays an essential role in modulating contractility as part of the cellular response to β-adrenergic stimulation. In vitro studies indicate MyBP-C can be phosphorylated at Serine 273, 282, 302 and 307 (mouse sequence) but little is known about the level of MyBP-C phosphorylation or the sites phosphorylated in heart muscle. Since current methodologies are limited in specificity and are not quantitative we have investigated the use of phosphate affinity SDS-PAGE together with a total anti MyBP-C antibody and a range of phosphorylation site-specific antibodies for the main sites (Ser-273, -282 and -302). With these newly developed methods we have been able to make a detailed quantitative analysis of MyBP-C phosphorylation in heart tissue in situ. We have found that MyBP-C is highly phosphorylated in non-failing human (donor) heart or mouse heart; tris and tetra-phosphorylated species predominate and less than 10% of MyBP-C is unphosphorylated (0, 9.3 ± 1%: 1P, 13.4 ± 2.7%: 2P, 10.5 ± 3.3%: 3P, 28.7 ± 3.7%: 4P, 36.4 ± 2.7%, n = 21). Total phosphorylation was 2.7 ± 0.07 molPi/mol MyBP-C. In contrast in failing heart and in myectomy samples from HCM patients the majority of MyBP-C was unphosphorylated. Total phosphorylation levels were 23% of normal in failing heart myofibrils (0, 60.1 ± 2.8%: 1P, 27.8 ± 2.8%: 2P, 4.8 ± 2.0%: 3P, 3.7 ± 1.2%: 4P, 2.8 ± 1.3%, n = 19) and 39% of normal in myectomy samples. The site-specific antibodies showed a distinctive distribution pattern of phosphorylation sites in the multiple phosphorylation level species. We found that phosphorylated Ser-273, Ser-282 and Ser-302 were all present in the 4P band of MyBP-C but none of them were significant in the 1P band, indicating that there must be at least one other site of MyBP-C phosphorylation in human heart. The pattern of phosphorylation at the three sites was not random, but indicated positive and negative interactions between the three sites. Phosphorylation at Ser-282 was not proportional to the number of sites available. The 2P band contained 302 but not 273; the 3P band contained 273 but not 302.

Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

BackgroundAngiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).MethodsWe genotyped five polymorphisms of the AGT, ACE, AT1R, 5-HT2A, and 5-HTT genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.ResultsWe found a significantly higher frequency of AT1R 1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The AT1R 1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.ConclusionsThe 1166 C AT1R allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the AGT, ACE, 5-HT2A and 5-HTT did not contribute to the risk of cardiac hypertrophy.