Paul J. Pearson

Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries.

Experiments were designed and performed to determine whether endothelial function remained chronically impaired after coronary artery reperfusion. Canine left anterior descending coronary arteries were exposed to ischemia (60 minutes) followed by reperfusion (12 weeks). Rings (3-4 mm wide) of the reperfused artery and of normal left circumflex (control) coronary artery segments were suspended in organ chambers containing physiological saline solution (37 degrees C, gassed with 95% O2-5% CO2) for isometric force measurement. Endothelium-independent contractions to KCl or prostaglandin F2 alpha and endothelium-independent relaxations to nitric oxide or isoproterenol were comparable in control and chronically reperfused arteries. However, chronically reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to aggregating platelets. In addition, the reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to the platelet-derived compounds adenosine diphosphate, serotonin, and thrombin. However, the endothelium-dependent relaxations to acetylcholine were comparable between control and reperfused arteries. Thus, after 12 weeks of reperfusion, previously occluded coronary arteries exhibited a selective impairment of endothelium-dependent relaxation evoked by aggregating platelets. In vivo, this phenomenon could favor platelet adhesion, aggregation, and platelet-induced contraction of coronary smooth muscle and thus facilitate ischemic events such as vasospasm and coronary thrombosis.

Hypomagnesemia Inhibits Nitric Oxide Release From Coronary Endothelium: Protective Role of Magnesium Infusion After Cardiac Operations

BACKGROUND Postoperative hypomagnesemia is common in patients who have undergone cardiac operations and is associated with clinically significant morbidity resulting from atrial and ventricular dysrhythmias. Magnesium supplementation may increase the cardiac index in the early postoperative period. METHODS The action of the magnesium cation on coronary vascular reactivity was studied. Segments of canine epicardial coronary artery were suspended in organ chambers to measure isometric force (95% O2/5% CO2, 37 degrees C). RESULTS In coronary segments constricted with prostaglandin F2alpha (2 x 10[-6] mol/L), acetylcholine and adenosine diphosphate (10[-9] to 10[-4] mol/L) induced vasodilation in arteries with endothelium (n=10, each group; p < 0.05). Acetylcholine-mediated vasodilation was blocked by NG-monomethyl-L-arginine (10[-4] mol/L) and NG-nitro-L-arginine (10[-4] mol/L), two inhibitors of nitric oxide synthesis from L-arginine (n=10, p < 0.05). The removal of magnesium from the organ chamber solution impaired vasodilation in response to acetylcholine and adenosine diphosphate. However, normal endothelium-dependent vasodilation could be restored by return of magnesium to the bathing solution. Vascular relaxation in response to bradykinin (10[-9] to 10[-6] mol/L), which was found to induce endothelium-dependent vasodilation independent of nitric oxide production, was unaffected by magnesium removal (n=10). CONCLUSIONS Hypomagnesemia selectively impaired the release of nitric oxide from the coronary endothelium. Because nitric oxide is a potent endogenous nitro-vasodilator and inhibitor of platelet aggregation and adhesion, hypomagnesemia could promote vasoconstriction and coronary thrombosis in the early postoperative period.

Bioassay of EDRF From Internal Mammary Arteries: Implications for Early and Late Bypass Graft Patency

To study the basal, luminal release of endothelium-derived relaxing factor, 35-mm segments of canine internal mammary artery (IMA) were cannulated and perfused at 5 mL/min in vitro with physiological salt solution. Vasoactive properties of the effluent were bioassayed on coronary artery smooth muscle. Effluent from IMAs produced significant vasodilation of the bioassay ring compared with effluent from a prosthetic conduit (n = 24; p < 0.05). The vasodilation by the effluent could be eliminated by mechanically removing the intima of the IMA, or by treating the IMA segments with NG-monomethyl-L-arginine or NG-nitro-L-arginine, two competitive inhibitors of nitric oxide synthesis from L-arginine; vasodilation was not influenced by treatment with indomethacin. In 83% of the superfusion experiments, effluent from the left IMA induced greater relaxation of the bioassay ring than did effluent from the right IMA. In addition, the average vasodilation induced by left IMA effluent was 28% +/- 2.3% versus 17.4% +/- 3.1% for the right (n = 24; p < 0.05). However, in organ chamber experiments, right and left IMAs exhibited comparable endothelium-dependent vasodilation to acetylcholine (n = 6). Because endothelium-derived relaxing factor induces vasodilation and also inhibits platelet adhesion, platelet aggregation, and atherogenesis, luminal release of endothelium-derived relaxing factor by the IMA could contribute to superior results when the artery is used in bypass grafting.

Protamine releases endothelium-derived relaxing factor from systemic arteries. A possible mechanism of hypotension during heparin neutralization.

BackgroundWhen used to reverse the anticoagulant effect of heparin, protamine sulfate often causes vasodilation that can lead to systemic hypotension. Protamine is rich in the basic amino acid arginine, which is the precursor of endothelial cell synthesis of nitric oxide, and nitric oxide is the active component of endothelium-derived relaxing factor (EDRF). Methods and ResultsTo determine whether the hypotensive effect of protamine could be due to stimulated release of EDRF, we studied rings (4–5 mm) of canine coronary, femoral, and renal artery suspended in organ chambers containing physiological salt solution (37°C and 95% O2–5% CO2). Arterial rings with and without endothelium were contracted with prostaglandin F2α (2×10−6 M) and exposed to increasing concentrations of protamine (final organ bath concentration, 40–400 μg/ml). In arterial segments without endothelium, protamine caused only a modest decrease in tension. However, protamine induced concentration-dependent relaxation in all arterial segments with endothelium, which was significantly greater than in segments without endothelium (p<0.05). The endothelium-dependent relaxation induced by protamine was inhibited by NG monomethyl-L-arginine (L-NMMA) (10−5 M), but L-NMMA had no effect on rings without endothelium. The action of L-NMMA could be reversed by L-arginine (10−4 M) but not D-arginine (10−4 M). ConclusionsThis study demonstrates that protamine stimulates the release of EDRF from arterial endothelium, and that endothelium-dependent vasodilation may be an important cause of systemic hypotension during protamine infusion.

Left Atrial Appendage Occlusion: Lessons Learned From Surgical and Transcatheter Experiences

Since the 1950s, the pathophysiologic role of the left atrial appendage (LAA) has been known in thromboembolic disease. A variety of surgical techniques have been described to close the LAA, with various degrees of efficacy. Today, transcatheter devices for LAA occlusion may offer a less invasive solution. This review looks at the surgical experience with LAA occlusion, with a focus on the techniques of closure, the prospects for stroke reduction, and the percutaneous trials completed so far, to formulate some meaningful conclusions about the status of LAA closure today.

Oxygen radical-mediated vascular injury selectively inhibits receptor-dependent release of nitric oxide from canine coronary arteries.

Reperfusion after global cardiac ischemia may injure coronary artery endothelium and lead to vasospasm and thrombosis. Oxygen-derived radicals have been implicated as mediators of this process, but the precise mechanism of injury is unknown. We hypothesized that oxygen-derived radicals impair coronary endothelial production of nitric oxide, a potent endogenous vasodilator and inhibitor of platelet adhesion. To test this theory, we developed an in vitro model of reperfusion injury in which segments of epicardial canine coronary artery were suspended in organ chambers (physiologic salt solution, 37 degrees C, 95% oxygen and 5% carbon dioxide) and exposed to oxygen-derived radicals (generated by adding xanthine [10(-4) mol/L] and xanthine oxidase [100 mU/ml] to the bathing solution for 70 minutes). After exposure to oxygen-derived radicals, epicardial coronary artery smooth muscle exhibited normal contraction to potassium ions (20 mmol/L) and prostaglandin F2 (4 x 10(-6) mol/L); also, the rings relaxed normally on exposure to isoproterenol and sodium nitroprusside (10(-9) to 10(-4) mol/L) (n = 6). In contrast, endothelium-dependent vasodilatation to receptor-dependent agonists acetylcholine and adenosine diphosphate (10(-9) to 10(-4) mol/L) was impaired as compared with the reaction of control vessels not exposed to oxygen-derived radicals (n = 18, P < 0.001, and n = 10, P < 0.002, respectively). Importantly, receptor-independent, endothelium-dependent relaxation to the calcium ionophore A23187 was normal (n = 6). Further, endothelium-dependent vasodilatation to receptor-dependent agonist bradykinin (non-nitric oxide pathway) was normal after exposure to oxygen-derived radicals. This is the first study to demonstrate that oxygen-derived radicals selectively impair receptor-dependent nitric oxide production by the coronary endothelium. Diminished nitric oxide production is a likely mechanism of vasospasm and thrombosis after reperfusion of the ischemic heart.

Production of endothelium-derived contracting factor is enhanced after coronary reperfusion

To determine whether coronary reperfusion enhances the production of endothelium-derived contracting factor, we investigated dogs subjected to global cardiac ischemia (45 minutes) followed by reperfusion (60 minutes). Segments of reperfused and control coronary arteries were suspended in organ chambers to measure isometric force. Perfusate hypoxia caused endothelium-dependent contraction in the control and reperfused arteries. However, reperfused arteries exhibited hypoxic contraction that was significantly greater than control segments. The hypoxic contractions in both the control and reperfused arteries could be inhibited by NG-monomethyl-L-arginine (L-NMMA), the blocker of endothelial cell synthesis of nitric oxide from L-arginine. The action of L-NMMA could be reversed by L-arginine but not D-arginine. Thus, after reperfusion, augmented production of endothelium-derived contracting factor occurs by an L-arginine-dependent pathway. We hypothesize that nitric oxide produced by L-arginine metabolism combines with superoxide anion to produce the peroxynitrite anion (ONOO-), which is metabolized to endothelium-derived contracting factor or induces its synthesis. Augmented production of endothelium-derived contracting factor would favor vasospasm after reperfusion.

Impaired endothelium-dependent relaxation after coronary reperfusion injury : evidence for G-protein dysfunction

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.

Inoperable Plasma Cell Granuloma of the Heart: Spontaneous Decrease in Size During an 11-Month Period

Plasma cell granuloma occurs in children, typically as an intrapulmonary mass. Surgical excision is the treatment of choice and is usually curative. We report an atypical and unresectable plasma cell granuloma that occurred asymptomatically in the heart of a child and spontaneously decreased in size by 40% during an 11-month period. Thus, plasma cell granuloma should be considered in the differential diagnosis of any child who has a cardiac mass. Observation should be considered a treatment option because this case demonstrated that the cardiac mass can spontaneously recede without therapy.

Isolated Mitral Valve Surgery Risk in 77,836 Patients From The Society of Thoracic Surgeons Database

BACKGROUND Understanding the operative outcomes of mitral valve (MV) surgery across the spectrum of predicted risk of mortality (PROM) is necessary to determine the best use of novel percutaneous approaches. METHODS The Society of Thoracic Surgeons Adult Cardiac Surgery Database was utilized to study isolated MV operations during two time periods: era 1 (2002 to 2006, n = 37,743) and era 2 (2007 to 2010, n = 40,093). In each era, four PROM groups were defined: low risk (PROM 0% to <4%); intermediate risk (PROM 4% to <8%); high risk (PROM 8% to <12%); and extreme risk (PROM ≥ 12%). In each risk group, mortality rates and observed to expected mortality ratios were compared across eras. RESULTS A total of 63,645 cases (82%) were classified as low risk, 8,032 (10%) as intermediate risk, 2,765 (4%) as high risk, and 3,394 (4%) as extreme risk. Sixty-seven percent of MV repairs (n = 30,488) and 18% of MV replacements (n = 5,749) had a PROM less than 1%. PROM less than 4% was seen for 93% of MV repairs (n = 42,196) and 66% of replacements (n = 21,449). Across the two eras, the MV repair rate increased from 54.8% to 61.8% (p = 0.0017); and a significant reduction in operative mortality was observed in high risk and extreme risk cohorts (p < 0.05). CONCLUSIONS The frequency with which MV repair for isolated MV disease is performed has increased over time and is associated with very low early mortality. A significant reduction in mortality among patients at highest risk has occurred, and must be considered as patients are evaluated for percutaneous therapies.