Patient-specific hiPSC-derived cardiomyocytes indicate allelic and contractile imbalance as pathogenic factor in early-stage Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is often caused by heterozygous mutations in β-myosin heavy chain (MYH7, β-MyHC). In addition to hyper- or hypocontractile effects of HCM-mutations, heterogeneity in contractile function (contractile imbalance) among individual cardiomyocytes was observed in end-stage HCM-myocardium. Contractile imbalance might be induced by burst-like transcription, leading to unequal fractions of mutant versus wildtype mRNA and protein in individual cardiomyocytes (allelic imbalance).

AQUA Mutant Protein Quantification of Endomyocardial Biopsy-Sized Samples From a Patient With Hypertrophic Cardiomyopathy.

In genetic diseases like hypertrophic cardiomyopathy, reliable quantification of the expression level of mutant protein can play an important role in disease research, diagnosis, treatment and prognosis. For heterozygous β-myosin heavy chain (β-MyHC) mutations it has been shown that disease severity is related to the fraction of mutant protein in the myocardium. Yet, heart tissue from patients with genetically characterized diseases is scarce.

Generation of two iPSC clones (MHHi021-A and MHHi021-B) from a patient with hypertrophic cardiomyopathy with p.Arg723Gly mutation in the MYH7 gene.

Hypertrophic cardiomyopathy (HCM) is the most common form of genetic heart disease and is characterized by abnormal thickening of the left ventricular wall and interventricular septum. Here we describe the generation of two induced pluripotent stem cell (iPSC) clones from a HCM patient, heterozygous for the p.Arg723Gly (c.

Burst-Like Transcription of Mutant and Wildtype -Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) has been related to many different mutations in more than 20 different, mostly sarcomeric proteins. While development of the HCM-phenotype is thought to be triggered by the different mutations, a common mechanism remains elusive. Studying missense-mutations in the ventricular beta-myosin heavy chain (β-MyHC, ) we hypothesized that significant contractile heterogeneity exists among individual cardiomyocytes of HCM-patients that results from cell-to-cell variation in relative expression of mutated vs.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1.

Optimized pacing mode for hypertrophic cardiomyopathy: Impact of ECG fusion during pacing.

Background: Electrocardiographic (ECG) fusion with intrinsic QRS could reduce the benefit of atrial synchronous biventricular pacing (AS-BiVP) in patients with hypertrophic obstructive cardiomyopathy (HOCM).

Objectives: The purpose of this study was to assess the benefit of AS-BiVP and the influence of ECG fusion for reduction of left ventricular outflow tract gradient (LVOTG) in these patients.

Methods: Twenty-one symptomatic HOCM patients with severe LVOTG were included.

Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes.

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers.

A common variant of the ABO gene protects against hypertension in a Spanish population.

The objective of this study was to establish whether genetic polymorphisms that could be related to angiotensin-converting enzyme (ACE) levels are associated with hypertension. A total of 10 haplotype-tagging single-nucleotide polymorphisms in ACE, the ACE I/D polymorphism, and 2 polymorphisms in the ABO (rs495828 and rs8176746) were investigated for association with hypertension in 269 hypertensive patients and 254 healthy controls. All analyses were adjusted for age and body mass index, and corrected for multiple testing.

Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes.

Background And Objective: Dry cough is the most common reason for stopping angiotensin-converting enzyme inhibitors (ACEi) therapy. The role of ACE in the metabolism of bradykinin has been proposed as a pathogenic mechanism. This study included a complete analysis of the variability of the genes involved in bradykinin metabolism (ACE and XPNPEP2) and bradykinin receptors (BDKRB2).

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level.

Biventricular pacing in hypertrophic obstructive cardiomyopathy: a pilot study.

Background: Right ventricular apex pacing for gradient reduction in hypertrophic obstructive cardiomyopathy (HOCM) with severe left ventricular (LV) obstruction has yielded conflicting results.

Objective: The purpose of this study was to assess the feasibility and effectiveness of biventricular pacing in HOCM.

Methods: Transvenous biventricular pacing was attempted in 12 severely symptomatic HOCM patients.

The left and right ventricle of a patient with a R723G mutation of the beta-myosin heavy chain and severe hypertrophic cardiomyopathy show no differences in the expression of myosin mRNA.

Background: In familial hypertrophic cardiomyopathy (FHC), asymmetric left ventricular (LV) hypertrophy has been considered to be the predominant phenotypic expression, whereas right ventricular (RV) involvement is still ambiguous. In most cases, the right ventricle remains unaffected until secondary pulmonary hypertension develops. Several FHC-causing mutations of genes encoding sarcomere-related proteins have been identified which are transmitted in an autosomal-dominant manner.

Toward an implantable wireless cardiac monitoring platform integrated with an FDA-approved cardiovascular stent.

Continuous monitoring of blood pressure from a minimally invasive device in the pulmonary artery can serve as a diagnostic and early warning system for cardiac health. The foremost challenge in such a device is the wireless transfer of data and power from within the blood vessel to an external device while maintaining unrestricted flow through the artery. We present a miniaturized system, which is attached to the outer surface of a regular or drug-eluting FDA-approved stent.

Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance.

The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W).

Quantification of mutant versus wild-type myosin in human muscle biopsies using nano-LC/ESI-MS.

A liquid chromatography/electrospray ionization mass spectrometry (nano-LC/ESI-MS) approach is described by which abundance of proteins (e.g., of beta-myosin heavy chain; MW 223 kDa) carrying a point mutation can be determined in tissue samples where the mutant protein is coexpressed with its wild-type forms.

[Clinical and echocardiographic follow-up of patients with hypertrophic obstructive cardiomyopathy treated by percutaneous septal ablation].

Introduction And Objectives: Alcohol septal ablation is a therapeutic option for patients with hypertrophic obstructive cardiomyopathy who remain symptomatic despite medical treatment. Our aim was to monitor clinical and echocardiographic progression in patients with hypertrophic obstructive cardiomyopathy treated by septal ablation at our center.

Methods: Thirty-five septal ablations were performed in 34 patients (79% male) who had symptomatic hypertrophic obstructive cardiomyopathy despite optimum medical treatment.

Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells.

Disease-causing mutations in cardiac myosin heavy chain (beta-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa(50)) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations.

Utility of ambulatory 24-hour esophageal pH and motility monitoring in noncardiac chest pain: report of 90 patients and review of the literature.

It is unclear whether prolonged motility monitoring improves the diagnostic yield of standard esophageal tests in patients with noncardiac chest pain. Our aim was to assess the diagnostic value of ambulatory 24-hr pH and pressure monitoring in patients with noncardiac chest pain. Stationary manometry, edrophonium testing, and ambulatory pH and motility studies were performed in 90 consecutive patients with recurrent chest pain and normal coronary angiograms.

[Late T-lymphocyte and monocyte activation in coronary restenosis. Evidence for a persistent inflammatory/immune mechanism?].

Aims: This study was made to determine if restenosis after percutaneous coronary angioplasty is associated with acute or chronic inflammatory/immunologic activity, and explored possible relationships with latent infection.

Patients And Method: Forty-six consecutive patients underwent elective PTCA and 6 months of angiographic follow-up. Peripheral venous blood samples were obtained at baseline, 24-48 h, and 4-6 months post-intervention.

Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene.

Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation.

Lack of association between ACE gene polymorphism and left ventricular hypertrophy in essential hypertension.

The possible association between the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene and left ventricular hypertrophy (LVH) was investigated in a group of essential hypertensive patients. Seventy-one essential hypertensive patients (35 men and 36 women), aged 51 +/- 1 years, were genotyped by PCR for the I/D polymorphism of the ACE gene. Cardiac morphology and function were assessed by means of M-mode echocardiography.

Myocardial uptake of antimyosin antibody in idiopathic dilated cardiomyopathy and its relation to functional and morphological parameters.

Monoclonal 111In antimyosin (AMS) uptake indicates the presence of ongoing myocyte damage. In idiopathic dilated cardiomyopathy (IDC), there is diffuse myocyte damage. We have attempted to find a correlation between AMS uptake and functional myocardial parameters.

[The predictive value of ventricular function during exercise after a myocardial infarct].

To assess the prognostic value of exercise left ventricular function, and if this test improves the prognostic value of clinical data and exercise test, 146 patients (mean age 56 +/- 9 years) underwent rest and exercise radionuclide angiography, 10 days after myocardial infarction. During follow-up (mean 16 +/- 5 months), 32 patients had new coronary events: 5 died, 9 had a new myocardial infarction and the remaining 18 developed unstable angina (Class III-IV of the CCS classification). Patients with new coronary events had more frequently severe left ventricular failure (Killip III-IV) (15% vs 3%; p less than 0.