angiotensinogen and Long-QT-Syndrome

Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.. Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.. Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

Topics: Anemia; Angiotensin II; Angiotensinogen; Animals; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Diabetes Mellitus; Dyslipidemias; Gene Regulatory Networks; Genotype; Heterozygote; Hyperkalemia; Ischemia; Long QT Syndrome; Mice; Mice, Knockout; Potassium Channels, Voltage-Gated

Polymorphisms of renin-angiotensin system (RAS) genes in patients with end-stage renal disease (ESRD) on chronic hemodialysis may be associated with QTc interval prolongation, leading to fatal arrhythmias. The objective of this study was to determine (1) the prevalence of QTc prolongation in hemodialysis patients, and (2) the association of a prolonged QTc in these patients with RAS polymorphisms [angiotensin-converting enzyme-insertion/deletion (ACE-I/D), angiotensin type 1 receptor-A1166C (AT1R-A1166C), and angiotensinogen-M235T (AGT-M235T)].. Twelve-lead electrocardiograms (ECGs), serum electrolytes (sodium, potassium, and calcium), and ACE and angiotensin II levels were obtained 10 to 12 hours after a hemodialysis session in 43 patients with ESRD on chronic hemodialysis [mean age (+/-SD), 55 +/- 14 years]. Using polymerase chain reaction (PCR), the presence of polymorphisms of the ACE-I/D, AT1R-A1166C, and AGT-M235T genes was determined from the buccal cells. A maximum QT interval in patients with sinus rhythm and normal QRS duration was corrected for heart rate using Hodges' formula.. Fifty-eight percent of the patients had QTc interval prolongation (>440 msec). The ACE-DD genotype (P = 0.002) and the C allele of the AT1R-A1166C gene (P = 0.004), but not the AGT-M235T gene, contributed to QTc prolongation.. Polymorphisms of ACE and AT1R genes additively contribute to QTc prolongation found in a great majority of ESRD patients. Therefore, ESRD patients with both or one of these polymorphisms may be at a higher risk for sudden cardiac death.

Topics: Adult; Aged; Angiotensinogen; Death, Sudden, Cardiac; Female; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Long QT Syndrome; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prevalence; Receptor, Angiotensin, Type 1; Renal Dialysis; Renin-Angiotensin System; Risk Factors