Abstract 352: Lower Mortality With Direct Right Atrial Neuronal Nitric Oxide Synthase Gene Transfer In First Three Days Post Myocardial Infarction
Sudden cardiac death (SCD) post myocardial infarction (MI) is associated with increased sympathetic and decreased vagal activity. This may be related to oxidative stress disrupting the bioavailability of nitric oxide resulting in impaired autonomic neurotransmission. To investigate this 50 guinea pigs underwent coronary ligation surgery to induce myocardial infarction (13.7 ± 0.7% of free wall: Sirius Red). Control animals (n = 32) were sham operated. Death attributed to SCD was defined as death independent of any pre mortem morbidity or post mortem findings of cardiac rupture, respiratory or gastrointestinal pathology. Animals that died from another cause were removed from the study. At three days post MI 82% (n = 36/44) of guinea pigs survived compared to 94% (n = 29/31) in the sham operated group. In-vitro evoked right atrial [3H] acetyl choline (ACh) release was decreased in the MI group compared with the sham animals (MI 0.91 ± 0.12%, n=6 vs Sham 1.74 ± 0.12%, n = 6, p<0.01). MI reduced right atrial neuronal nitric oxide synthase (nNOS) activity (MI 18.1 ± 0.8fmol/mg/min, n = 9 vs Sham 26.0 ± 1.6fmol/mg/min, n = 9, p<0.01) and cyclic guanosine monophosphate (cGMP) levels (MI 3.2 ± 0.2pmol/mg, n = 10 vs Sham 5.2 ± 0.3pmol/mg, n = 10, p<0.01). In a separate group nNOS or enhanced green fluorescent protein (eGFP) adenovirus was injected directly into the right atria at the time of MI surgery. Infarct sizes in both groups were not significantly different (MI + nNOS 6.5 ± 0.8%, n = 11 vs MI + eGFP 9.3 ± 1.5%, n = 10, p>0.1%). All (n = 24/24) of the nNOS transduced guinea pigs survived from four hours to three days compared with 80% (n = 20/25) in the MI + eGFP group. The nNOS transduced group had increased right atrial [3H] ACh release (MI + nNOS 1.6 ± 0.1%, n = 6 vs MI + eGFP 1.2 ± 0.1%, n = 6, p<0.05). Furthermore, in these animals, right atrial nNOS activity was also enhanced (MI + nNOS 19.4 ± 0.3fmol/ mg/min, n = 11 vs MI+eGFP 16.6 ± 0.4fmol/mg/min, n = 11, p<0.01) along with cGMP level (MI+nNOS 6.6 ± 0.7pmol/mg, n = 13 vs MI + eGFP 3.2 ± 0.2pmol/mg, n = 15, p<0.01). In conclusion, acute MI disrupts NO neurobiology in the guinea pig and is associated with a sudden death phenotype. Following nNOS gene transfer there was a partial restoration of the NO-cGMP pathway paired with improved survival at three days post MI.