Introduction:
Adenosine triphosphate-sensitive potassium (K
ATP
) channel opener diazoxide (DZX) and Antioxidant MitoSNO are both independently cardioprotective in animal models. The cardioprotective mechanism of diazoxide is unknown, and involves a non-sarcolemmal location, requires the inhibition of succinate dehydrogenase, and the K
ATP
channel subunit SUR1. Mitochondrial - targeted Antioxidant MitoSNO is a S-nitrosylating agent that stalls complex 1, reduces ROS production and succinate accumulation. In an isolated myocyte model of stress due to hyperkalemic cardioplegia (CPG), that the combination of DZX and MitoSNO negated the beneficial effects of each alone.
Hypothesis:
We hypothesized that the combination of DZX and MitoSNO would negate the beneficial effects of each alone in an isolated heart model of global ischemia.
Methods:
Isolated mouse hearts underwent assessment of end diastolic pressure (EDP) and left ventricular developed pressure (LVDP) utilizing an LV balloon in a Langendorff model before and after 90 min of global ischemia. Hearts received test solution (CPG (9°C) or CPG±DZX (100μM) at onset of ischemia +/- MitoSNO (1μM/L) at end of ischemia), followed by 30 min reperfusion. LVDP and EDP were compared between groups utilizing a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume.
Results:
Similar to previous results, DZX improved LVDP and reduced EDP after ischemia compared to CPG (Figure). Similarly, MitoSNO improved LVDP and reduced EDP compared to CPG (Figure). The addition of MitoSNO with DZX was associated with the loss of cardioprotection observed with MitoSNO or DZX alone.
Conclusions:
Similar to data in a myocyte model, both MitoSNO and DZX provide cardioprotection that is lost with the combination of both, suggesting mutually exclusive mechanisms of action and that DZX’s mechanism requires a functional complex 1, ROS production, or succinate accumulation.
Introduction:
Adenosine triphosphate - sensitive potassium (K
ATP
) channels provide endogenous myocardial protection by coupling cell membrane potential to metabolism, as they are inhibited by ATP and open during times of metabolic stress. Pharmacologic opening of K
ATP
channels mimics ischemic preconditioning, and diazoxide (DZX) preserves myocardial function following prolonged global ischemia.
Hypothesis:
We hypothesized that DZX would reduce myocardial stunning after left anterior descending coronary artery (LAD) occlusion followed by global ischemia, similar to a clinical situation of acute myocardial infarction followed by coronary revascularization.
Methods:
Twelve swine underwent LAD occlusion (30 min), followed by 120 min global ischemia protected with hyperkalemic cardioplegia (CPG) +/- DZX (N=6 each), followed by intermittent CPG (q 20 min), then 60 min reperfusion (RF). Cardiac output (CO), mean time to wean from cardiopulmonary bypass (CPB), left ventricular ejection fraction (LVEF), left ventricular developed pressure (LVDP), caspase - 3 (apoptosis), and infarct size were compared.
Results:
All 6 animals in the DZX group separated from CPB by 30 min RF whereas only 1 and 4 animals in the CPG group had separated at 15 and 30 min, respectively (Figure). DZX was associated with shorter average time to wean from CPB (17.5 vs 27.0 min, p=0.13) and higher CO at all time points during reperfusion (2.9 vs 1.5 L/min at 30 min RF, p=0.05), however, these were not significantly different. DZX was associated with higher LVEF after 30 minutes of reperfusion (42.5 vs 15.8%, p=0.009; Figure). There were no differences between groups in vasopressor use, infarct size, caspase - 3, or LVDP.
Conclusions:
DZX reduces myocardial stunning and facilitates separation from CPB following LAD occlusion and subsequent global ischemia in a porcine model. The addition of DZX to hyperkalemic cardioplegia has the potential to reduce myocardial stunning in the clinical setting.
Medionecrosis and medial degeneration are rare complications associated with intramural hematomas (IMHs). We present a case of a 69-year-old Asian female with an IMH with medionecrosis and medial degeneration of the aortic wall. The patient underwent successful surgical intervention, and pathological findings were significant for cystic medial degeneration of the aortic wall.
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