Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia

Abstract

Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1.

Figure 1

Methionine rich protein diet increases Hcy levels. The hyper de-methylation of methionine by methyl transferase (MT) and SAHH activity during DNA/RNA methylation cause HHcy. The hypo re-methylation of Hcy to methionine by MTHFR/vitamin b₁₂/folate dependent pathways cause increase in Hcy levels. The heterozygous/homozygous in cystathione β synthase (CBS) activity, b₆, and transsulphuration deficiency exacerbate HHcy. The renal disease and volume retention increase plasma Hcy levels.

Figure 2

Oxidative stress and increase ROS in HHcy decrease constitutive NO in ternary MMP/NO/TIMP complex and generate RNS and nitrotyrosine. This process oxidizes the TIMP and liberates active MMP.

Figure 3

Panel A shows comparative heart rates for animals of different sizes. There was a correlation between the size and the heart rate of mice, rat, rabbit, human, and dog (Henegar et al., 2001; Cox et al., 2002; Hunt et al., 2002; Carroll & Tyagi, 2005; Moshal et al., 2005), cow, horse and elephant (Webb et al., 1998; Breukelman et al., 2006; Gehlen et al., 2006). Panels B, C and D show quantitative data. The data in panels B, C and D is from our previous reports (Tyagi et al., 1995; Sood et al., 2002). After chronic oral administration of Hcy (32 μmol/L) in drinking water for 12 weeks, the heart rate and blood pressure were measured by a PE-50 catheter in femoral artery of the rats (Sood et al., 2002).

Figure 4

Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1. In mitochondria Hcy decreases thioredoxin, peroxiredoxin and SOD and increases NADPH oxidase increasing ROS and RNS.