A bioenergetics assessment of aortic regurgitation: A new tool to assess severity?

Aortic regurgitation is frequently classified as mild, moderate or severe based on echocardiography. Patients with mild aortic regurgitation are usually managed medically. Decisions with regard to moderate aortic regurgitation can be difficult. We hypothesise that mild aortic regurgitation as assessed volumetrically can in fact be moderate to severe when analysed from a bioenergetics point of view. The conservation of energy predicts that any regurgitant volume will require the heart to provide more work energy to support the circulation. Aortic regurgitation involves the left ventricle imparting potential energy, via blood pressure, and kinetic energy, via increased ejected volume and velocity respectively. This implies that regurgitant volume, ejection velocity, diastolic and systolic blood pressure, heart rate, and regurgitant orifice area are all important factors. We present limited data to demonstrate our hypothesis. A bioenergetic analysis of aortic regurgitation, reveals that correlation between regurgitant volume and effective regurgitant orifice can be poor in certain physiological circumstances. In addition we identify the importance of systolic and diastolic blood pressure, and heart rate control in patients with aortic regurgitation. The concept that mild aortic regurgitation can be ignored is from an engineering point fundamentally flawed in some cases.

Mechanism of failure of the Cabrol procedure: A computational fluid dynamic analysis.

Sudden failure of the Cabrol graft is common and frequently fatal. We utilised the technique of computational fluid dynamic (CFD) analysis to evaluate the mechanism of failure and potentially improve on the design of the Cabrol procedure. CFD analysis of the classic Cabrol procedure and a number of its variants was performed. Results from this analysis was utilised to generate further improved geometric options for the Cabrol procedure. These were also subjected to CFD analysis. All current Cabrol and variations of the Cabrol procedure are predicated by CFD analysis to be prone to graft thrombosis, secondary to stasis around the right coronary artery button. The right coronary artery flow characteristics were found to be the dominant reason for Cabrol graft failure. A simple modification of the Cabrol geometry is predicated to virtually eliminate any areas of blood stasis, and graft failure. Modification of the Cabrol graft geometry, due to CFD analysis may help reduce the incidence of graft thrombosis. A C shaped Cabrol graft with the right coronary button anastomosed to its side along its course from the aorta to the left coronary button is predicted to have the least thrombotic tendency. Clinical correlation is needed.

A bioenergetic assessment of mitral regurgitation: a new tool to assess severity?

Mitral regurgitation is frequently classified as mild, moderate or severe based on echocardiography. Patients with mild mitral regurgitation are usually managed medically. We hypothesise that mild mitral regurgitation as assessed volumetrically can in fact be severe when analysed from a bioenergetics point of view. The conservation of energy predicts that any regurgitant volume will require the heart to provide more work energy to support the circulation. Mitral regurgitation involves the left ventricle imparting potential energy, via blood pressure, and kinetic energy, via regurgitant velocity, to the regurgitant blood volume. This implies that regurgitant volume, regurgitant velocity, systolic blood pressure, heart rate, regurgitant orifice area and cardiac output are all important factors. We present limited data to demonstrate our hypothesis. A bioenergetic analysis of mitral regurgitation, may identify patients whose mitral regurgitation, assessed via echocardiography as mild, is actually clinically significant. In addition we identify the importance of blood pressure and heart rate control in patients with mitral regurgitation. The concept that a bit of mitral regurgitation in patients with poor left ventricles is a good thing, as it helps offload the left ventricle is from an engineering point fundamentally flawed.

Mechanism of development of aortic transection: a possible new angle.

Aortic transection injury is a frequently fatal injury secondary to sudden deceleration. To date magnitude of deceleration is the only factor known to influence the development of an aortic transection injury. We hypothesise that different 3D geometries of the aortic arch in healthy young adult patients as a possible predisposing factor for transection injuries when undergoing sudden deceleration. We extend this to hypothesise that the direction of deceleration may be important as well. In addition we hypothesise that the stage in the cardiac cycle, which determines central aortic blood pressure, when the deceleration occurs as an important factor. We utilise known engineering principles such as Newton's second Law of motion, moment of inertia, law of Laplace, and the theory of superposition to explain our hypothesis. We present limited data to demonstrate the wide variation in aortic arch 3D geometry to explain the possible an individual's variable susceptibility to transection injuries via the principle of moment of inertia. Engineering principles suggest that 3D aortic arch geometry, direction of deceleration and stage in the cardiac cycle, in addition to the magnitude of deceleration are potentially important factors in predisposing certain individuals in a given situation to aortic transaction injuries.

Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention.

OBJECTIVE: To study the effect of unfractionated heparin (UFH) versus low molecular weight heparin (LMWH) in combination with glycoprotein (Gp) IIb/IIIa blockers on platelet activation and aggregation. METHODS: Washed platelets were stimulated with thrombin in the presence or absence of UFH (monoparin), LMWH (enoxaparin), and a Gp IIb/IIIa blocker (abciximab, eptifibatide, or tirofiban). RESULTS: Although Gp IIb/IIIa antagonists blocked the final common pathway of thrombin induced platelet aggregation, UFH and LMWH were better at blocking upstream platelet activation. UFH was significantly more effective than LMWH at inhibiting P selectin expression (p = 0.001) and platelet derived growth factor release from thrombin activated platelets (p = 0.012). CONCLUSIONS: UFH and LMWH exert complementary effects to Gp IIb/IIIa blockers by inhibiting afferent pathways of platelet activation. Coadministration of heparin with Gp IIb/IIIa blockers provides improved protection against persistent platelet activation, thereby improving outcome after percutaneous coronary intervention. Judging from these data, UFH may be more effective in this regard than LMWH, at least in vitro. The use of LMWH in preference to UFH during percutaneous coronary intervention, although initially attractive, may inadequately protect against platelet activation despite the presence of Gp IIb/IIIa blockers.

Preventing of chylothorax after oesophagectomy by routine pre-operative administration of oral cream.

The anatomy of the thoracic duct varies considerably. This can make it difficult to locate during oesophageal surgery, especially in the fasted patient. We describe the technique of administering cream orally before primary oesophageal surgery, to aid in the identification of the thoracic duct. The duct along with other lymphatic channels can then be ligated as appropriate, helping to reduce the incidence of post-operative chylothorax.

Aprotinin: is it prothrombotic?

Controversy continues as to whether aprotinin (Trasylol) is prothrombotic. The recent discovery of the thrombin receptor family, known as the protease-activated receptor family (PAR) has been essential in aiding our understanding of the mechanism of action of aprotinin. Our results show that aprotinin has no effect on platelet aggregation induced by adrenaline, adenosine diphosphate, phorbol-12-myristate-13-acetate, collagen or PAR 1 agonist peptide. However, aprotinin inhibits thrombin-induced platelet activation as assessed by macroaggregation, microaggregation and platelet membrane calcium flux. Aprotinin inhibits proteolytic activation of platelets, but platelets can still be activated by non-proteolytic mechanisms.

Concomitant thymectomy and cardiac operation in a patient with pure red cell aplasia.

Pure red cell aplasia is a rare condition resulting in severe anemia. Medical therapy is indicated, unless a thymoma is present. In patients with concurrent cardiac pathology requiring operation, simultaneous operation should be contemplated to avoid risky resternotomy. We describe an exceptionally rare case of a patient with pure red cell aplasia secondary to a thymoma who underwent concomitant thymectomy and coronary artery grafting with a successful surgical outcome.

Effect of aprotinin (trasylol) on the inflammatory and thrombotic complications of conventional cardiopulmonary bypass surgery.

Before the discovery of its hemostatic properties, aprotinin was thought of as a potential anti-inflammatory agent. Its clinical introduction in 1987 to prevent blood loss during cardiac surgery [Royston 1987, van Oeveren 1987] led to its anti-inflammatory benefits being largely overlooked in favor of a vigorous debate centering on whether aprotinin may be pro-thrombotic when given to patients. In this article, we summarize evidence for the anti-inflammatory activity of aprotinin and discuss our recent contributions in this area. We also summarize the state of the thrombosis debate and discuss our recent evidence from purified platelets which shows that aprotinin is simultaneously hemostatic yet anti-thrombotic.

The antithrombotic and antiinflammatory mechanisms of action of aprotinin.

Aprotinin (Trasylol) is generally regarded to be an effective hemostatic agent that prevents blood loss and preserves platelet function during cardiac surgery procedures requiring cardiopulmonary bypass (CBP). However, its clinical use has been limited by the concern that such a potent hemostatic agent might be prothrombotic, particularly in relation to coronary vein graft occlusion. In this review we present a mechanism of action that challenges such a viewpoint and explains how aprotinin can be simultaneously hemostatic and antithrombotic. Aprotinin achieves these two apparently disparate properties by selectively blocking the proteolytically activated thrombin receptor on platelets, the protease-activated receptor 1 (PAR1), while leaving other mechanisms of platelet aggregation unaffected. We also review recent research leading to the discovery of novel antiinflammatory targets for aprotinin. A better understanding of its mechanisms of action has led to the conclusion that aprotinin is a remarkable drug with the capacity to correct many of the imbalances that develop in the coagulation system and the inflammatory system after CPB. Nonetheless, it has been clinically underused for fear of causing thrombotic complications, a fear that in light of recent evidence may be unfounded.

The antithrombotic effect of aprotinin: actions mediated via the proteaseactivated receptor 1.

BACKGROUND: Despite aprotinin being in widespread clinical use to prevent bleeding during cardiac surgery, there remains concern that such a powerful hemostatic agent may also be prothrombotic, particularly in relation to coronary vein graft occlusion. The major thrombin receptor on platelets, protease-activated receptor 1 (PAR1) requires proteolytic cleavage to transmit activating signals. Here we have investigated the effect of aprotinin on thrombin-induced PAR1 activation of platelets. METHODS AND RESULTS: Proteolysis-dependent and -independent responses of washed platelets were studied in vitro. Platelet aggregation induced by trypsin was dependent on PAR1 (inhibited by the PAR1-specific antagonist peptide, FLLRN) and was completely blocked by aprotinin at doses more than 100 KIU/mL. Aggregation in response to thrombin, 1 nmol/L, was predominantly mediated through PAR1 and was inhibited 42.6% to 86.6% (P <.05-.001) by pharmacologic doses of aprotinin (50-160 KIU/mL). Aprotinin did not inhibit the nonproteolytic agonists collagen, epinephrine, adenosine diphosphate, or phorbol 12-myristate 13-acetate. Furthermore, blockade of the thrombin response by aprotinin did not prevent subsequent platelet aggregation through collagen or epinephrine. Experiments with intraplatelet Ca(2+) fluxes, which provided an earlier measure of platelet activation, placed the effect of aprotinin proximal to the PAR1 activation event. Since aprotinin did not inhibit platelet responses to the nonproteolytic PAR1 agonist peptide, SFLLRN, this implied that aprotinin acted by preventing PAR1 receptor cleavage by thrombin. CONCLUSIONS: Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the PAR1 receptor. These findings argue against aprotinin being prothrombotic and suggest instead that aprotinin may have significant antithrombotic effects.