Abstract 432: Hypervolemic Hyponatremia Aggravates Myocardial Ischemia/Reperfusion Injury: Normalization with Tolvaptan
Tolvaptan (OPC-41061) is a selective vasopressin V2 antagonist. It generates increased, dose-dependent production of diluted urine without altering serum electrolyte balance, and without activation of renin-angiotensin system. Tolvaptan is effective in correcting hypervolemic hyponatremia, a condition often associated with congestive heart failure (CHF) and is being evaluated in patients with worsening CHF (EVEREST trial). Hyponatremia is a known risk factor for worsening prognosis in patients with CHF and acute myocardial infarction. However, the underlying mechanisms are not clear. Using a V2 agonist (DDAVP) induced hypervolemic hyponatremia model in rat, we compared myocardial infarction after a 20-minute regional myocardial ischemia and 3-hour reperfusion. We also investigated the expression of sodium/calcium exchanger-1 (NCX-1), which has been shown to be increased in CHF and resulting in increased cardiac injury. We hypothesized that lowered plasma Na+may induce upregulation of NCX-1 to compensate for the reduced driving force to remove diastolic intracellular Ca++via NCX-1. As expected DDAVP infusion for 14 days significantly decreased plasma sodium (from 145±2 in saline treated to 114±7 mmol/L, Mean±SD) and osmolarity (from 311±5 to 264±6 mOsm/L). Myocardial infarction was significantly increased in DDAVP infused rats: 49±9% infarction of the ischemic area compared with that of 21±7% in saline treated (p<.001). Oral administration of tolvaptan using an escalating regime from 0.25mg/kg to 10mg/kg once daily corrected the plasma sodium and osmolarity levels. The treatment with tolvaptan reversed the effect of DDAVP on myocardial infarction: myocardial infarct size was reduced to 22±8%. There is a strong negative correlation between infarct size and plasma sodium or osmolarity level: i.e., the lower the sodium or osmolarity level, the higher the infarct size. The R values are 0.88 and 0.83, respectively. NCX-1 expression level was slightly but not significantly increased by DDAVP. We conclude that hypervolemic hyponatremia is associated with increased myocardial injury. The underlying mechanisms require future investigation. By treating hypervolemic hyponatremia, tolvaptan may reduce myocardial injury in CHF patients.