Desmond J. Sheridan

Functional Changes in Coronary Microcirculation After Valve Replacement in Patients With Aortic Stenosis

Background—Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT. Methods and Results—Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129±30 to 94±24 g/m2; P <0.0001), and there was a significant reduction in resting MBF and increase in CVR corrected for rate-pressure product after AVR, although these changes displayed marked heterogeneity. Regression of LVM was linearly related to change in resting total LV blood flow but not CVR. Increase in hyperemic MBF and CVR transmurally was directly related to the increase in AVA after AVR. A significant relationship existed between the change in hyperemic DPT (1.0±4.7 s/min [range, 6.8 to 9.6]) and change in transmural CVR (y=0.08x+0.18; r =0.44; P =0.04). Conclusions—Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.

Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates

OBJECTIVE To determine pulmonary capillary filtration in experimental chronic heart failure and to investigate some morphological and haemodynamic mechanisms that could account for reduced filtration in lungs adapted to chronic heart failure. METHODS We studied pulmonary capillary filtration, vascular resistances and morphology in lungs from guinea-pigs adapted to chronic heart failure. Heart failure was induced by banding of the ascending aorta (n=66) or sham control operation (n=78) in guinea-pigs which were studied at 150+/-8 days post-operation. RESULTS Reduced cardiac output, increased systemic vascular resistance and LV end diastolic pressure and increased LV and RV weight:body weight ratio (all P<0.05) indicated chronic heart failure at 5 months following aortic banding in guinea-pigs. Lung weight was increased (61%, P<0.05) in heart failure compared with controls, but lung water content was reduced (5.5%, P<0.05), a reversal of the pattern seen acutely. Studies in isolated perfused lungs demonstrated a reduced capillary filtration coefficient (0. 018+/-0.003 vs. 0.003+/-0.002 ml min(-1)mmHg(-1)g(-1), P<0.001), increased arterial (61%) and venous resistance (50%) in heart failure lungs, P<0.05. Wall thickness:lumen ratio was increased in small (<250 microm) pulmonary arterioles (0.15+/-0.02 vs. 0.08+/-0. 01) and venules (0.06+/-0.005 vs. 0.04+/-0.002) in heart failure, P<0.01. Alveolar septal volume fractions (35.2+/-5.1 vs. 23.1+/-2.7) and septal:air-space volume ratios (60.5+/-13.6 vs. 31.9+/-5.3) were also increased in heart failure, P<0.05. CONCLUSIONS Pulmonary adaptation to chronic heart failure is associated with vascular and alveolar remodelling that contributes to increased vascular resistance and reduced capillary filtration. These changes are likely to be important in mediating resistance to pulmonary oedema in chronic heart failure.

Reversing the decline of academic medicine in Europe

Medicine has never been a static profession. The ancient Greeks took medicine out of the realms of magic and gave it a scientifi c, ethical, and philosophical foundation, which continued into Roman times, lasting in all for about 500 years. With the death of Galen (199 AD) during the decline of the Roman Empire, the curtain came down on medical progress in Europe until the re-awakening of scientifi c thought almost 1300 years later. Arguably, it was the collapse of the schools of medicine and the consequent loss of community intelligence that was most important in this decline. During the past 200 years, the prestige of medicine and doctors has grown steadily, peaking in the latter part of the 20th century. Progress of clinical research during this time based on a two-way interaction between “bench and bedside” has been remarkable with developments in imaging techniques, molecular biology, genetics, and therapeutics. 1 However, over the past 20 years, medicine—academic medicine in particular—entered a period of uncertainty and decline which has begun at last to cause widespread alarm. 2–7

Arrhythmogenic and electrophysiological effects of alpha adrenoceptor stimulation during myocardial ischaemia and reperfusion

To examine possible arrhythmogenic effects of alpha adrenoceptor stimulation, we studied the effects of methoxamine 10(-6) M on arrhythmias and cellular electrophysiology during global myocardial ischaemia and reperfusion in isolated Langendorff perfused guinea-pig hearts. To avoid interference from release of endogenous catecholamines during ischaemia or reperfusion, experiments were performed using catecholamine depleted hearts (myocardial noradrenaline = 11% of control). Catecholamine depletion markedly reduced the incidence of VT and VF during ischaemia and reperfusion and perfusion with methoxamine significantly reversed this. This arrhythmogenic effect of methoxamine was only observed during ischaemia or reperfusion, was independent of beta adrenoceptor blockade and H2 receptor blockade but was abolished by alpha adrenoceptor blockade with phentolamine. Catecholamine depletion blunted the ischaemia induced fall in action potential amplitude and Vmax and prolonged action potential duration and refractory period. Perfusion with methoxamine either partially or completely reversed these effects. Thus, alpha adrenoceptor stimulation has little effect on normally perfused myocardium, but may induce VT or VF during ischaemia or reperfusion.

Soluble adhesion molecules in reperfusion during coronary bypass grafting

OBJECTIVE Adhesion of activated leukocytes to the endothelial cells as a result of myocardial ischaemia/reperfusion during open chest coronary artery surgery has been shown to be involved in the development of tissue damage. Activated leukocytes adhere to endothelium via adhesion molecules expressed by both cell types, resulting in the impairment of coronary capillary flow. Upon cell activation, adhesion proteins may be released in the soluble form to circulating blood. The purpose of our study was to verify whether myocardial ischaemia/reperfusion occurring during coronary artery bypass grafting results in release of the soluble adhesion molecules VCAM-1, ICAM-1, E-selectin and L-selectin into the circulation. METHODS Plasma levels of the soluble adhesion molecules were measured in vein, arterial and coronary sinus blood samples taken from 15 patients undergoing coronary artery bypass grafting (CABG). Blood samples for estimations were collected during the procedure: before aorta cross-clamping, at the beginning of reperfusion and 30 min after reperfusion. Soluble adhesion molecules levels were measured by standard ELISA assays. RESULTS Mean plasma levels of soluble VCAM-1 in arterial samples increased significantly at the beginning of reperfusion and 30 min after reperfusion. In contrast, soluble L-selectin plasma levels in arterial samples remained unchanged. In coronary sinus samples, levels of soluble ICAM-1 significantly increased 30 min after reperfusion. Moreover, in coronary sinus samples collected 30 min after reperfusion, soluble ICAM-1 levels were significantly higher than in arterial samples obtained at the same time. The mean concentration of soluble E-selectin in samples obtained from coronary sinus decreased significantly 30 min after reperfusion. Moreover, plasma levels of soluble E-selectin in coronary sinus samples obtained 30 min after reperfusion were significantly decreased compared with these observed in arterial samples collected at the same time. CONCLUSIONS The reperfusion of ischaemic myocardium during CABG results in a significant increase in plasma levels of the soluble endothelial adhesion molecules VCAM-1 and ICAM-1 and significant decrease in soluble E-selectin plasma levels. L-selectin plasma levels during CABG procedure remain unchanged. We propose that the increased plasma concentrations of soluble VCAM-1 and ICAM-1 are a result of endothelial cell activation during ischaemia/reperfusion following bypass surgery.

Nitric oxide and prostacyclin modulate the alterations in cardiac action potential duration mediated by platelets during ischaemia.

OBJECTIVE To investigate the effects of alterations of nitric oxide (NO) and prostacyclin (PGI2) availability on platelet-mediated electrophysiological effects during myocardial ischaemia. METHODS Transmembrane action potentials and electrograms were recorded from isolated, Langendorff-perfused guinea-pig hearts during normal perfusion, global myocardial ischaemia and reperfusion during infusion of washed human platelets. Experiments were performed in the presence of 100 microM NG-nitro-L-arginine methyl ester (L-NAME), 30 microM L-arginine, 10 microM haemoglobin, 100 microM sodium nitroprusside and 2.3 nM iloprost, or using hearts obtained from DL-lysine monoacetylsalicylate (Aspisol, 50 mg.kg-1 i.p.)-treated animals. RESULTS Perfusion with L-NAME and haemoglobin increased perfusion pressure by 33% (P = 0.0017) and 23% (P = 0.0026) while sodium nitroprusside and iloprost reduced it (17%, P = 0.0004, and 24%, P = 0.0006). In the absence of platelets, these compounds had no effect on arrhythmogenesis, but in the presence of platelets L-NAME reduced the onset time of ventricular tachycardia during ischaemia from 19.4 (s.e.m. 2.0) min to 12.9 (2.1) min, P = 0.04 and accentuated the ischaemia-induced reduction of action potential duration at 95% repolarization (APD95): 95(6) vs. 115(5) ms, P < 0.05 at 25 min. Sodium nitroprusside in the presence of platelets attenuated the ischaemia-induced reduction in APD95, while iloprost in the presence of platelets was antiarrhythmic (ventricular fibrillation 25 vs. 75%, P = 0.04) and attenuated the reduction in APD95 during ischaemia 115(4) vs. 94(4) ms, P < 0.05 at 20 min. Infusion of platelets into hearts obtained from DL-lysine-monoacetylsalicylate-treated guinea-pigs accentuated the ischaemia-induced reduction in APD95 (94(4) vs. 119(7) ms, P < 0.05 at 20 min) and this was reversed by sodium nitroprusside (117(7) ms, P < 0.05 at 20 min). L-NAME and haemoglobin had no effect on the aggregatory responses of the platelets to 5 microM ADP and 4 micrograms.ml-1 collagen, while sodium nitroprusside and iloprost ablated the responses to ADP and reduced the responses to collagen (maximum height of the aggregatory response reduced by 75 and 84%, respectively, both P = 0.03.) CONCLUSIONS Inhibition of NO and PGI2 synthesis exacerbates the reduction in cardiac action potential duration associated with platelet activation during ischaemia, while provision of exogenous NO and PGI2 attenuates the reduction in cardiac action potential duration. Provision of exogenous NO and PGI2 (as iloprost) was associated with inhibition of platelet reactivity.

Structural remodelling of lungs in chronic heart failure

Abstract.In order to determine whether morphological changes could account for a previously reported reduction in pulmonary capillary filtration in heart failure, we studied pulmonary morphology in lungs from a guineapig chronic heart failure model. Heart failure was induced by banding the ascending aorta with sham operated animals serving as controls; all animals were studied at 158 ± 6 days post-operation. Following banding, a reduction in aortic flow, increased peripheral vascular resistance and raised left ventricular end diastolic, left atrial and right ventricular pressures together with increased right ventricle to body weight ratio (all p < 0.05) are indicative of established pulmonary hypertension and heart failure. This was associated with an increase in pulmonary septal volume fraction (38.1 ± 3.1% vs 24.6 ± 2.3 %, p < 0.01) and reticulin fibre density. There was also evidence of siderophage infiltration and examination of pulmonary ultra structure revealed a significantly thicker alveolar-capillary barrier in heart failure (1278 ±76 vs 638 ± 32 nm, p < 0.001), thickening of both the alveolar (89%, p < 0.01) and capillary (69%, p < 0.05) basal laminae with pericyte and collagen infiltration of the alveolar-capillary barrier. We hypothesise that these pulmonary adaptations provide protection from oedema formation, but whilst initially protective, are also likely to confer major long-term disadvantages in chronic heart failure.

Assessment of left ventricular mass regression after aortic valve replacement – cardiovascular magnetic resonance versus M-mode echocardiography

OBJECTIVE In patients with aortic valve disease, the presence of left ventricular hypertrophy (LVH) carries a significant risk of adverse cardiovascular events. Regression of hypertrophy after aortic valve replacement (AVR) is associated with a reduction in risk. In general, M-mode echocardiography has been used for quantitative assessment of left ventricular mass (LVM) and regression, but this technique is believed to have limitations from which cardiovascular magnetic resonance (CMR) does not suffer. The objective of this study therefore was to determine whether quantitative assessment of LVM and regression after AVR using the two techniques was comparable. METHODS Thirty-nine patients with aortic valve disease were studied before and 1 year after AVR. Transthoracic M-mode echocardiography and four different formulae were used to calculate left ventricular mass index (LVMI), and then compared with CMR measurements. RESULTS Overall, correlation between the techniques for single measurement of LVMI was moderate (r-values from 0.64 to 0.69), with a tendency for overestimation by echocardiography; there was no agreement in degree of regression (r-values from 0.004 to 0.18). The Bland-Altman limits of agreement ranged from 85 to 131% for single measurement of LVMI, and 328-470% for regression. The change in LVMI with CMR was 43+/-28 g/m2, vs. 27 to 54+/-19 to 41 g/m2 using echocardiography. CONCLUSIONS M-mode echocardiography does not provide reliable quantification of regression of LVH in individuals, and for accurate measurement CMR is superior. The use of CMR in future studies may reduce costs since fewer subjects are needed to accurately detect significant changes in LVMI after AVR.

Conduction velocity and gap junction resistance in hypertrophied, hypoxic guinea-pig left ventricular myocardium

The passive and active electrical properties of left ventricular myocardium were measured, using conducted action potentials and current clamp of isolated myocytes. The objective was to quantify changes of intracellular resistivity, Ri, during hypertrophic growth and the simultaneous imposition of cellular hypoxia. Ri was estimated from the time course of the rising phase of a conducted action potential using a solution of the two‐dimensional cable equation. The thoracic aorta of guinea‐pigs was constricted to induce left ventricular hypertrophy (LVH) and myocardium used 50 and 150 days post‐operation. Conduction velocity increased in the earlier stage of LVH and declined in the later stage, compared with age‐matched controls. Hypoxia reduced conduction velocity in all experimental groups. Ri increased only in the later stage of hypertrophy (253 +/− 39 Omega cm to 544 +/− 130 Omega cm) and was additionally increased by hypoxia in all groups (e.g. control myocardium 252 +/− 39 Omega cm to 506 +/− 170 Omega cm). The magnitude of the increase of Ri in hypertrophied, hypoxic myocardium can create conditions required to generate re‐entrant arrhythmias.

The release of soluble adhesion molecules ICAM-1 and E-selectin after acute myocardial infarction and following coronary angioplasty

Endothelial cells express surface adhesion molecules for leukocytes in response to myocardial ischaemia. These molecules may be released into plasma by activated cells and be detectable in soluble form. Samples were collected from the peripheral vein of 14 consecutive patients with acute myocardial infarction (AMI) at the time of admission, 6 h, and 1 and 5 days post-admission. Additionally, samples were drawn from the coronary sinus ostium and peripheral artery of seven patients undergoing coronary angioplasty (PTCA) before and after the first balloon inflation. We measured the plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sELAM-1). In patients with AMI plasma levels of sICAM-1 exceeded those observed in age and sex-matched healthy subjects, (mean+/-SEM; 220.6+/-18 ng/ml) at all the time intervals assessed (358.9+/-24.5; 330.9+/-24.4; 379.4+/-39.7 and 366.8+/-47.5 ng/ml, respectively, p<0.01). sELAM-1 levels, however, were normal on admission, increased at 6 h to 52.7+/-3.8 ng/ml, p<0.05, and at day 1 (56.0+/-4.6 ng/ml) before decreasing to normal levels on the fifth day. After brief myocardial ischaemia occurring during PTCA, an increased level of sICAM-1 was observed following balloon deflation in the coronary sinus (329.2+/-20 ng/ml; p<0.05) as compared to the subjects undergoing coronary angiography, but not in the peripheral artery. sELAM-1 levels remained unchanged during angioplasty. Thus, soluble adhesion molecules expressed by activated endothelial cells are released into peripheral blood during both AMI and brief myocardial ischaemia and measurement of such molecules may prove useful for monitoring vascular endothelium activation following myocardial ischaemia/necrosis.