The role of lipid peroxidation and antioxidants in oxidative modification of LDL.

http://www.cardiologia-vigo.com/wp-content/uploads/2011/10/2011_HRS-EHRA_GeneticTesting.pdf

HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)

Cl− channels reside both in the plasma membrane and in intracellular organelles Their functions range from ion homeostasis to cell volume regulation, transepithelial transport, and regulation of e

https://www.leibniz-fmp.de/fileadmin/user_upload/Physiology_and_Pathology_of_Ion_Transport/documents/PhysRev2002.pdf

Molecular Structure and Physiological Function of Chloride Channels

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.

Writing recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1

The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts' opinions).

A Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Table 3), AND/OR when …

/pdf/hrs-ehra-expert-consensus-statement-on-the-state-of-genetic-4merwj3wnp.pdf

HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next...

Molecular Physiology of Cardiac Repolarization

Background— Experimental studies suggest that the interval between peak and end of T wave (Tpe) in transmural ECGs reflects transmural dispersion of repolarization (TDR), which is amplified by β-adrenergic stimulation in the LQT1 model. In 82 patients with genetically identified long-QT syndrome (LQTS) and 33 control subjects, we examined T-wave morphology and various parameters for repolarization in 12-lead ECGs including corrected QT (QTc; QT/R-R1/2) and corrected Tpe (Tpec; Tpe/R-R1/2) before and during exercise stress tests. Methods and Results— Under baseline conditions, LQT1 (n=51) showed 3 cardinal T-wave patterns (broad-based, normal-appearing, late-onset) and LQT2 (n=31) 3 patterns (broad-based, bifid with a small or large notch). The QTc and Tpec were 510±68 ms and 143±53 ms in LQT1 and 520±61 ms and 195±69 ms in LQT2, respectively, which were both significantly larger than those in control subjects (402±36 ms and 99±36 ms). Both QTc and Tpec were significantly prolonged during exercise in LQT1 ...

https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/144720/1/yigak02819.pdf

Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome

Background— Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K+ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na+ channel mutation in an individual who exhibited drug-induced LQTS. Methods and Results— An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na+ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na+ current with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS...

Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

Background Collateral growth is induced by chemical signals from the ischemic myocardium. We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids, and are increased by myocardial ischemia.

Methods and Results With the use of an enzyme-linked immunosorbent assay, we measured the concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in pericardial fluids of 12 patients with unstable angina (group 1) and of 8 patients with nonischemic heart diseases (group 2). The levels of protein in pericardial fluids were quite comparable between the two groups (34±2 versus 32±4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036±357 pg/mL, significantly ( P <.001) higher than the 289±72 pg/mL in group 2. The amount of bFGF per milligram of protein was also significantly ( P <.05) higher in group 1 than in group 2 (67±15 versus 12±4 pg/mg). The concentration of VEGF in pericardial fluids tended to be higher in group 1, but the difference was statistically insignificant (39±7 versus 22±6 pg/mL). The amount of VEGF per milligram of protein was 1.2±0.3 pg/mg in group 1, similar to the 0.8±0.4 pg/mg in group 2.

Conclusions This finding provides new evidence that bFGF plays an important role in mediating collateral growth in humans.

Elevated Basic Fibroblast Growth Factor in Pericardial Fluid of Patients With Unstable Angina

Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes.

Background— Mutations in the KCNJ2 gene, which codes cardiac and skeletal inward rectifying K+ channels (Kir2.1), produce Andersen’s syndrome, which is characterized by periodic paralysis, cardiac arrhythmia, and dysmorphic features. Methods and Results— In 3 Japanese family members with periodic paralysis, ventricular arrhythmias, and marked QT prolongation, polymerase chain reaction/single-strand conformation polymorphism/DNA sequencing identified a novel, heterozygous, missense mutation in KCNJ2, Thr192Ala (T192A), which was located in the putative cytoplasmic chain after the second transmembrane region M2. Using the Xenopus oocyte expression system, we found that the T192A mutant was nonfunctional in the homomeric condition. Coinjection with the wild-type gene reduced the current amplitude, showing a weak dominant-negative effect. Conclusions— T192, which is located in the phosphatidylinositol-4,5-bisphosphate binding site and also the region necessary for Kir2.1 multimerization, is a highly conserved...

Hideo Otani

Papers

Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome

Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation

Elevated Basic Fibroblast Growth Factor in Pericardial Fluid of Patients With Unstable Angina

Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes.

Novel KCNJ2 Mutation in Familial Periodic Paralysis With Ventricular Dysrhythmia