Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway.

AIMS: Anti-platelet agents, such as dipyridamole, have several clinical benefits for peripheral artery disease with the speculation of angiogenic potential that could preserve ischaemic tissue viability, yet the effect of dipyridamole on ischaemic arteriogenesis or angiogenesis is unknown. Here we test the hypothesis that dipyridamole therapy augments arteriolar vessel development and function during chronic ischaemia. METHODS AND RESULTS: Mice were treated with 200 mg/kg dipyridamole twice daily to achieve therapeutic plasma levels (0.8-1.2 microg/mL). Chronic hindlimb ischaemia was induced by permanent femoral artery ligation followed by measurement of tissue perfusion using laser Doppler blood flow along with quantification of vascular density, cell proliferation, and activation of nitric oxide (NO) metabolism. Dipyridamole treatment quickly restored ischaemic hindlimb blood flow, increased vascular density and cell proliferation, and enhanced collateral artery perfusion compared with control treatments. The beneficial effects of dipyridamole on blood flow and vascular density were dependent on NO production as dipyridamole did not augment ischaemic tissue reperfusion, vascular density, or endothelial cell proliferation in endothelial NO synthase (eNOS)-deficient mice. Blood and tissue nitrite levels were significantly higher in dipyridamole-treated mice compared with controls and eNOS(-/-) mice, verifying increased NO production that was regulated in a PKA-dependent manner. CONCLUSION: Dipyridamole augments nitrite/NO production, leading to enhanced arteriogenesis activity and blood perfusion in ischaemic limbs. Together, these data suggest that dipyridamole can augment ischaemic vessel function and restore blood flow, which may be beneficial in peripheral artery disease.

Clinical profile and predictors of complications in peripartum cardiomyopathy.

BACKGROUND: Clinical profile and predictors of major adverse events (MAE) associated with peripartum cardiomyopathy (PPCM) have not been characterized. METHODS AND RESULTS: A retrospective review and analysis of clinical data of 182 patients with PPCM. Forty-six patients had >or=1 MAE, including death (13), heart transplantation (11), temporary circulatory support (4), cardiopulmonary arrest (6), fulminant pulmonary edema (17), thromboembolic complications (4), and defibrillator or pacemaker implantation (10). Diagnosis of PPCM was delayed >or=1 week in 48% of patients with MAE that preceded the diagnosis in 50% of these patients. Seven (32%) of the surviving patients who had MAE and did not undergo heart transplantation had residual brain damage. Significant predictors of MAE were: left ventricular ejection fraction

Poor outcome of indigent patients with peripartum cardiomyopathy in the United States.

OBJECTIVE: Peripartum cardiomyopathy (PPCM) patients from Haiti and South Africa have poor survival and poor left ventricular (LV) function recovery compared with patients from the United States. There are no reported studies of PPCM among the African American population in the United States. We evaluated the prognosis of PPCM in a mostly African American population. STUDY DESIGN: We analyzed the clinical and echocardiographic data of 44 (39 African American) patients with PPCM over an 11 year period (1992-2003). RESULTS: Thirty-nine patients were indigent and 5 had health insurance. During a mean follow-up of 24.0 (range, 0.1-264) months, 7 (15.9%) patients died and LV function returned to normal in 14 (35%). CONCLUSION: LV function recovery and survival rates of PPCM patients observed in our study are similar to those reported from Haiti and South Africa and different from what is generally accepted in the United States.

Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis.

Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 mug/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.