Wim Stooker

Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium

Changes in myosin heavy chain (MHC) isoform expression and protein composition occur during cardiac disease and it has been suggested that even a minor shift in MHC composition may exert a considerable effect on myocardial energetics and performance. Here an overview is provided of the cellular basis of the energy utilisation in cardiac tissue and novel data are presented concerning the economy of myocardial contraction in diseased atrial and ventricular human myocardium. ATP utilisation and force development were measured at various Ca2+ concentrations during isometric contraction in chemically skinned atrial trabeculae from patients in sinus rhythm (SR) or with chronic atrial fibrillation (AF) and in ventricular muscle strips from non-failing donor or end-stage failing hearts. Contractile protein composition was analysed by one-dimensional gel electrophoresis. Atrial fibrillation was accompanied by a significant shift from the fast α-MHC isoform to the slow β-MHC isoform, whereas both donor and failing ventricular tissue contained almost exclusively the β-MHC isoform. Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure.

The impact of heparin-coated cardiopulmonary bypass circuits on pulmonary function and the release of inflammatory mediators

Reduction of the inflammatory reaction with the use of heparin coating has been found during and after cardiopulmonary bypass (CPB). The question remains whether this reduced reaction also decreases the magnitude of CPB-induced pulmonary dysfunction. We therefore evaluated the effects of a heparin-coated circuit versus a similar uncoated circuit on pulmonary indices as well as on inflammatory markers of complement activation (C3b/c), elastase-&agr;1-antitrypsin complex, and secretory phospholipase A2 (sPLA2) during and after CPB. Fifty-one patients were randomly assigned into two groups undergoing coronary artery bypass grafting with either a heparin-coated (Group 1) or an uncoated (Group 2) circuit. During CPB, a continuous positive airway pressure of 5 cm H2O and a fraction of inspired oxygen (FIO2) of 0.21 were maintained. Differences in favor of the coated circuit were found in pulmonary shunt fraction (P < 0.05), pulmonary vascular resistance index (P < 0.05), and PaO2/FIO2 ratio (P < 0.05) after CPB and in the intensive care unit. During and after CPB, the coated group demonstrated lower levels of sPLA2. After CPB, C3b/c and the elastase-&agr;1-antitrypsin complex were significantly less in the coated group (P < 0.001). The coated circuit was associated with a reduced inflammatory response, decreased pulmonary vascular resistance index and pulmonary shunt fraction, and increased PaO2/FIO2 ratio, suggesting that the coated circuit may have beneficial effects on pulmonary function. The correlation with sPLA2, leukocyte activation, and postoperative leukocyte count suggests reduced activation of pulmonary capillary endothelial cells.

Pressure-diameter relationship in the human greater saphenous vein

BACKGROUND Compliance of artificial and autologous vascular grafts is related to future patency. We investigated whether differences in compliance exist between saphenous vein grafts derived from the upper or lower leg, which might indicate upper or lower leg saphenous vein preference in coronary artery bypass surgery. Furthermore, the effect of perivenous application of fibrin glue on mechanical vein wall properties was studied to evaluate its possible use as perivenous graft support. METHODS Vein segments (N = 10) from upper or lower leg saphenous vein grafts were collected for histopathologic examination and smooth muscle cell/extracellular matrix (SMC/ECM) ratio was calculated. This ratio is suggested to be related with vascular elastic compliance. In a second group vein graft segments (N = 6) from upper and lower leg were placed in an in vitro model generating stepwise increasing static pressure up to 150 cm H(2)O. Outer diameter was measured continuously with a video micrometer system. Distensibility was calculated from the pressure-diameter curves. A third group of vein graft segments (N = 7) was pressurized after fibrin glue application to prevent overdistension, and studied in the same setup. RESULTS Vein segments from the lower leg demonstrated a consistent higher relative response compared with the upper leg saphenous vein graft (0.9176 +/- 0.03993 vs 0.5245 +/- 0.02512). Both reach a plateau in the high-pressure range (> 100 cm H(2)O). A significant difference in in vitro distensibility between upper and lower leg saphenous vein was only found at a pressure of 50 cm H(2)O (p < 0.05). With fibrin glue, support overdistension is prevented as revealed by the maximum relative response between fibrin glue supported upper and lower leg saphenous vein segments (0.4080 +/- 0.02464 vs 0.582 +/- 0.051), and no plateau is reached in the pressure range up to 150 cm H(2)O. CONCLUSIONS No upper or lower leg saphenous vein preference could be deduced from the differences in pressure-diameter response due to loss of distensibility (and thus of compliance) in the high-pressure range. Fibrin glue effectively prevents overdistension and preserves some distensibility in the high-pressure range in both the upper and lower leg saphenous vein. This might provide a basis for clinical application of perivenous support.

Atrial Fibrillation Coincides with the Advanced Glycation End Product Nε-(Carboxymethyl)Lysine in the Atrium

Presence of advanced glycation end products (AGEs) in the heart induces a proinflammatory phenotype. However, the presence of AGEs within atrial tissue of atrial fibrillation (AF) patients is unknown and was analyzed here. Left atrial appendage tissue from 33 AF patients and 9 controls was analyzed for the presence of the major AGEs N(ε)-(carboxymethyl)lysine (CML), VCAM-1, neutrophilic granulocytes, lymphocytes, and macrophages in both the fat tissue and myocardium separately. The total amount of fibrosis was also analyzed. Presence of CML was significantly higher in blood vessels of the left atrial appendage in AF patients as compared to controls, independent of diabetes mellitus. In AF patients, VCAM-1 expression in blood vessels and the numbers of infiltrated neutrophilic granulocytes, lymphocytes, and macrophages significantly increased compared to controls, and were highest in the fat tissue; there was no significant difference in fibrosis compared to controls. Interestingly, total amount of CML and fibrosis in AF and control patients correlated positively. Finally, there was no difference between AF patients based on AF type or surgical indication in the presence of CML, VCAM-1 expression, inflammatory cells, and fibrosis. Our results indicate that in AF the intramyocardial blood vessels of the left atrial appendage have an increased CML presence and proinflammatory status coinciding with a local increase in the number of inflammatory cells.

C1-esterase inhibitor protects against early vein graft remodeling under arterial blood pressure.

OBJECTIVES Arterial pressure induced vein graft injury can result in endothelial loss, accelerated atherosclerosis and vein graft failure. Inflammation, including complement activation, is assumed to play a pivotal role herein. Here, we analyzed the effects of C1-esterase inhibitor (C1inh) on early vein graft remodeling. METHODS Human saphenous vein graft segments (n=8) were perfused in vitro with autologous blood either supplemented or not with purified human C1inh at arterial pressure for 6h. The vein segments and perfusion blood were analyzed for cell damage and complement activation. In addition, the effect of purified C1inh on vein graft remodeling was analyzed in vivo in atherosclerotic C57Bl6/ApoE3 Leiden mice, wherein donor caval veins were interpositioned in the common carotid artery. RESULTS Application of C1inh in the in vitro perfusion model resulted in significantly higher blood levels and significantly more depositions of C1inh in the vein wall. This coincided with a significant reduction in endothelial loss and deposition of C3d and C4d in the vein wall, especially in the circular layer, compared to vein segments perfused without supplemented C1inh. Administration of purified C1inh significantly inhibited vein graft intimal thickening in vivo in atherosclerotic C57Bl6/ApoE3 Leiden mice, wherein donor caval veins were interpositioned in the common carotid artery. CONCLUSION C1inh significantly protects against early vein graft remodeling, including loss of endothelium and intimal thickening. These data suggest that it may be worth considering its use in patients undergoing coronary artery bypass grafting.

Mast cells are increased in the media of coronary lesions in patients with myocardial infarction and may favor atherosclerotic plaque instability

OBJECTIVES Mast cells (MCs) may play an important role in plaque destabilization and atherosclerotic coronary complications. Here, we have studied the presence of MCs in the intima and media of unstable and stable coronary lesions at different time points after myocardial infarction (MI). METHODS Coronary arteries were obtained at autopsy from patients with acute MI (up to 5 days old; n=27) and with chronic MI (5-14 days old; n=18), as well as sections from controls without cardiac disease (n=10). Herein, tryptase-positive MCs were quantified in the intima and media of both unstable and stable atherosclerotic plaques in infarct-related and non-infarct-related coronary arteries. RESULTS In the media of both acute and chronic MI patients, the number of MCs was significantly higher than in controls. This was also found when evaluating unstable and stable plaques separately. In patients with chronic MI, the number of MCs in unstable lesions was significantly higher than in stable lesions. This coincided with a significant increase in the relative number of unstable plaques in patients with chronic MI compared with control and acute MI. No differences in MC density were found between infarct-related and non-infarct-related coronary arteries in patients with MI. CONCLUSION The presence of MCs in the media of both stable and unstable atherosclerotic coronary lesions after MI suggests that MCs may be involved in the onset of MI and, on the other hand, that MI triggers intra-plaque infiltration of MCs especially in unstable plaques, possibly increasing the risk of re-infarction.

The impact of heparin coated circuits upon metabolism in vital organs: effect upon cerebral and renal function during and after cardiopulmonary bypass.

During cardiopulmonary bypass (CPB), the brain and the kidneys may be damaged because of microemboli, ischemia, and inflammation. The latter has been reduced by the use of heparin coated circuits. We questioned whether heparin coated circuits could also reduce cerebral and renal damage and whether inflammatory markers correlate with damage to the brain and the kidneys. Fifty-one patients scheduled for coronary artery bypass grafting were perfused with either a heparin coated or an uncoated circuit. To compare the effect of a heparin coated circuit with an uncoated circuit upon cerebral and renal function in relation to inflammation, we assessed markers of cerebral (S100&bgr;) and renal (N-acetyl-&bgr;-D-glucosaminidase [NAG], creatinine, and urea) function, inflammation, and oxygen metabolism. S100&bgr; levels and NAG levels increased during CPB in both groups as compared with baseline levels (p < 0.01), without differences between the groups. After 15 minutes on CPB, C4b/c levels were significantly higher in the coated group compared with the uncoated group (p < 0.02). C4b/c correlated with S100&bgr; (p < 0.01). Total body oxygen delivery (DO2) and consumption (VO2) decreased significantly in both groups during CPB (p < 0.01), but recovery was better in the coated group. After protamine infusion, total body oxygen delivery and consumption correlated negatively with S100&bgr; levels (both p < 0.05) and with NAG levels (both p < 0.01). This study suggests that, if adequate tissue perfusion is not maintained, the use of a heparin coated circuit gives no additional benefit beyond that of the uncoated circuit. The inverse relationship of both cerebral and renal markers with DO2 and VO2 suggests that increased levels of S100&bgr; and NAG during CPB may primarily be caused by an oxygen deficit and secondary to the inflammatory response.