Long-term endothelial dysfunction after coronary artery stenting.

OBJECTIVES: We assessed the endothelial-dependent vasomotor function in nonrestenotic coronary arteries more than six months following stent implantation, balloon angioplasty (BA), and directional atherectomy (DCA). BACKGROUND: Catheter-based coronary interventions are associated with extensive arterial injury. Endothelial function has been shown to remain chronically abnormal after vascular injury. The long-term effects of different percutaneous coronary interventions on endothelial function are not known. METHODS: Thirty-nine patients treated at least six months earlier with a coronary intervention for isolated proximal left anterior descending (LAD) stenosis, with no evidence of restenosis, were studied. Twelve patients had been stented, 15 had been treated with BA, and 12 had undergone DCA. Changes in diameter of the intervened LAD, and the unintervened circumflex coronary artery (Cx), in response to intracoronary acetylcholine infusions were assessed by quantitative angiography. RESULTS: The groups had similar angiographic characteristics and risk factors for endothelial dysfunction. The LAD constricted significantly more (p = 0.02) in previously stented patients (-21.8+/-4.3%), as compared to patients previously treated with BA (-9.5+/-2.8%) or with DCA (-9.1+/-3.6%). In contrast, acetylcholine infusion resulted in mild constriction in the Cx, which was similar in the three groups (p = 0.47). By multiple regression analysis, previous implant of a stent was the only significant predictor of LAD constriction (p = 0.008). CONCLUSIONS: More severe endothelial dysfunction was observed long term after stenting as compared to BA or DCA. These findings may have implications with respect to the progression of atherosclerosis in coronary arteries subjected to percutaneous interventions.

Cardiac sympathetic activity in response to acute myocardial ischemia.

Although experimental evidence has demonstrated that brief periods of myocardial ischemia are not associated with norepinephrine overflow from the heart, cardiac sympathetic responses to myocardial ischemia in humans remain unclear. Eleven patients undergoing angioplasty of the left anterior descending coronary artery had cardiac norepinephrine spillover measured immediately before inflation, during the final minute of a 5-min balloon inflation, and 1 min after deflation. Angioplasty caused significant S-T segment elevation and a reduction in the transcardiac lactate extraction ratio. Cardiac norepinephrine spillover was reduced from a mean value of 58 +/- 14 pmol/min at control to 41 +/- 15 pmol/min during balloon inflation and 38 +/- 14 pmol/min after deflation (P < 0.05 vs. control for both inflation and deflation values). In contrast, during balloon inflation, there were significant increases in arterial norepinephrine and epinephrine concentrations. Therefore, a brief period of myocardial ischemia caused by angioplasty of the left anterior descending coronary artery does not result in cardiac sympathetic activation, despite evidence of generalized sympathoadrenal activation.

Antithrombotic and thrombolytic therapy in patients undergoing coronary artery interventions: a review.

The controlled arterial injury that occurs with balloon angioplasty and other coronary interventions is characterized by evanescent endothelial denudation and vascular disruption. As a consequence, platelet activation occurs at the treated site, and there is a risk of thrombotic occlusion. This risk is heightened by several factors including unstable clinical presentation, lesion complexity, deep injury, and dissection. Aspirin has been shown to unquestionably reduce, although not eliminate, acute complications and is now part of the routine periprocedural regimen. Heparinization with more intense anticoagulation than is conventionally used is also standard treatment and is initiated before vessel instrumentation. Adjunctive thrombolysis is rarely necessary unless refractory thrombus precedes or complicates the procedure. However, thrombolysis may have a role in the treatment of saphenous vein graft obstructive lesions in which guide wire- or catheter-induced distal thromboembolization may cause infarction in spite of successful graft recanalization. In contrast to their success in the periprocedural phase of coronary interventions, anticoagulants and a wide variety of platelet active agents have been ineffective in reducing the 30% to 40% incidence of restenosis. Only 7E3, which targets the final common pathway of platelet aggregation by irreversibly blocking the IIb/IIIa receptor, has been shown to decrease the 6-month clinical event rate after balloon angioplasty, possibly by a surface pacification mechanism. This suggests that newer more potent antiplatelet and anticoagulant agents may also find a role in the long-term management of these patients.

Cardiopulmonary resuscitation: effect of training junior house officers on outcome of cardiac arrest.

The cardiopulmonary skills of one intake of junior house officers (JHOs) were assessed and all then underwent a six hour training course. In the following six months we studied the outcomes of 83 cardiopulmonary resuscitation attempts and compared them with results obtained in our hospital two years earlier as part of a multicentre survey when no formal training was undertaken. The JHOs performed poorly in all assessments before training. The initial and long-term survival rates in the present study were no better than in the earlier. There were 12 long-term survivors, 11 required defibrillation. Decreasing the time taken to defibrillation and training other members of the arrest team in addition may lead to improved survival. The training of junior house officers alone is not an effective strategy for improving survival from cardiac arrest.

Angiotensin II augments the stroke volume response to isoprenaline in man.

Many studies in experimental animal models suggest that there is an interaction between angiotensin II and the sympathetic nervous system. We have now sought evidence for such an interaction using angiotensin II and beta-adrenoceptor stimulation with isoprenaline. Ten normal volunteers were infused with placebo/placebo, placebo/angiotensin II, placebo/isoprenaline and angiotensin II/isoprenaline in a randomized single-blind fashion. Isoprenaline alone caused a non-significant 11-20% rise in stroke volume. Angiotensin II alone caused no significant change in stroke volume. However, the combination of angiotensin II/isoprenaline caused a significant increase in stroke volume of 31-55% (p less than 0.01), and this increase was significantly greater than with isoprenaline alone (P less than 0.02, by repeated-measures analysis of variance). This occurred with no difference in heart rate change. Isoprenaline significantly reduced total peripheral resistance and this reduction was not affected by concomitant infusion of angiotensin II. This study provides evidence that a physiological dose of angiotensin II can synergistically augment the stroke volume effect of beta-agonism in man. There are several possible mechanisms, but a regional redistribution of venous blood which causes increased cardiac filling seems likely.

Angiotensin II augments sympathetically mediated arteriolar constriction in man.

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and post-synaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man. 2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5-150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography. 3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure. 4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P less than 0.01). Blood flow was reduced by 21 +/- 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 +/- 7% in the infused arm, but only by 21 +/- 4% in the control arm (P less than 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline. 5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of angiotensin II on haemodynamic and plasma noradrenaline responses to tyramine infusion in man.

Six normal volunteers were studied on four separate occasions. On each occasion they received two concomitant infusions which were either placebo/placebo, placebo/tyramine, angiotensin II/placebo or angiotensin II/tyramine. Angiotensin II infusion was given at a constant rate of 2ng/kg/min whereas the tyramine infusion consisted of 10 min increments at 1.25, 2.5, 3.75, 5, 7.5 and 10 micrograms.kg-1.min-1. Tyramine infusion caused a dose dependent increase in systolic blood pressure with increases in diastolic blood pressure and plasma noradrenaline only at the highest doses. These changes were not affected by concomitant angiotensin infusion. We have therefore found no evidence to support the enhancement of haemodynamic or plasma noradrenaline responses to tyramine infusion by low dose infusion of angiotensin II in man.

Mechanisms of the antinatriuretic action of physiological doses of angiotensin II in man.

1. Angiotensin II (ANG II; 1 ng min-1 kg-1) or 5% (w/v) D-glucose (placebo) was infused in six normal male volunteers, pretreated with 500 mg of lithium carbonate, who were undergoing maximal water diuresis. 2. This dose of ANG II caused a circulating increment within the physiological range (27 +/- 4 to 48 +/- 9 pmol/l). 3. Compared with placebo, ANG II caused a significant fall in urinary sodium excretion (113 +/- 13 to 82 +/- 10 mumol/min). This antinatriuretic effect occurred without a fall in creatinine clearance (107 +/- 3 versus 113 +/- 3 ml/min). 4. ANG II caused a significant fall in fractional lithium clearance (28 +/- 2 to 23 +/- 2%). This may indicate a proximal tubular effect of ANG II. 5. ANG II also reduced fractional distal delivery [(sodium clearance plus free water clearance) divided by creatinine clearance], another measure of proximal tubular outflow. A parallel change in these two separate markers of proximal function supports an action of ANG II at this nephron segment. 6. Furthermore, the antinatriuretic effect of ANG II was unlikely to be due to stimulation of aldosterone secretion because (a) the fall in sodium excretion was temporally dissociated from the rise in aldosterone secretion, (b) potassium excretion also tended to fall during ANG II infusion and (c) aldosterone has a distal nephron effect, while, in this study, proximal nephron fractional reabsorption of sodium increased and distal nephron fractional reabsorption of sodium was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of angiotensin II and noradrenaline alone and in combination on renal sodium excretion in man.

1. The renin-angiotensin-aldosterone-system is important for the maintenance of sodium balance in man. Recent animal evidence suggests the angiotensin II can modulate the effect of the renal sympathetic nervous system on renal function. We have investigated the possible interaction of physiological doses of angiotensin II and noradrenaline on sodium excretion in man. 2. Seven normal volunteers were studied on four occasions during maximum water diuresis sustained by oral hydration. Samples were obtained during a baseline and four subsequent 20 min periods (A-E). Placebo or noradrenaline was infused over periods B-E, and angiotensin II infused over period C. 3. There was no change in systemic blood pressure, heart rate or creatinine clearance caused by infusion of either angiotensin II, noradrenaline or both in combination. 4. Noradrenaline alone caused a significant fall in absolute and fractional sodium excretion. Angiotensin II when infused with placebo caused a 37% fall in absolute sodium excretion and a 32% fall when infused with noradrenaline (no significant difference between the 2 days). Similar changes were seen for urinary flow and fractional sodium excretion. 5. We have therefore found no evidence to support a postsynaptic interaction of low doses of angiotensin II and noradrenaline on renal sodium excretion in man.

The basic and advanced cardiopulmonary resuscitation skills of trained hospital nursing staff.

The cardiopulmonary resuscitation skills of 105 trained hospital nurses were tested. Both basic and, for the first time in the UK, advanced skills were examined; basic skills were assessed by practical evaluation with a standard manikin and advanced knowledge by multiple choice questionnaire. No nurse adequately performed all four practical skills tested. Knowledge of the ventilatory aspects of resuscitation, defibrillation and advanced technique and drug management were also found to be poor. The findings add further support to adequate training of nurses in resuscitation skills. We describe a solution to overcome the heavy demands of such teaching and suggest that the same model be applied to the training of medical staff in resuscitation skills.

Evidence for a proximal and distal nephron action of atrial natriuretic factor in man.

The intrarenal mechanism of action of atrial natriuretic (ANF) remains uncertain. Animal work suggests that part of the natriuretic effect of ANF may be due to inhibition of proximal and distal nephron sodium reabsorption and we now present evidence for similar effects of ANF in man. Six sodium replete normal male volunteers were studied during maximal water diuresis. Lithium clearance was used to assess segmental nephron function. ANF infusion caused a significant increase in fractional lithium clearance (FELi) compared to placebo infusion. A similar change in fractional distal delivery, a conventional marker of proximal tubular outflow, also occurred during ANF infusion independently corroborating the increase in FELi. These findings suggest that ANF inhibits whole-kidney fractional proximal tubular sodium reabsorption in man. Evidence is also presented to show that ANF depresses distal nephron fractional sodium reabsorption as evaluated both by the lithium method and by estimation of solute-free water clearance.

Noradrenaline attenuates the natriuretic effect of atrial natriuretic factor in man.

1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.

Sympathetically mediated vasoconstriction is augmented by angiotensin II in man.

In order to determine whether angiotensin II may influence sympathetically mediated arteriolar constriction in man, we have examined the effect of angiotensin II, infused directly into the left brachial artery of normal subjects, on the reduction in forearm blood flow produced by a lower-body negative pressure (LBNP) of 15 mmHg. Angiotensin II (320 fmol/min) caused no reduction in blood flow when given alone but significantly augmented the reduction in blood flow in response to LBNP. The same dose of angiotensin II did not affect a similar reduction in forearm blood flow produced by infused noradrenaline (12.5-50 ng/min). We conclude that angiotensin II augments sympathetically mediated constriction of resistance vessels in man at concentrations with no direct effect on vessel tone. The lack of an effect of angiotensin II on constriction in response to infused noradrenaline suggests the involvement of a presynaptic mechanism.

Regulation of regional vascular tone: the role of angiotensin conversion in human forearm resistance vessels.

Inhibition of the action of endothelially-located angiotensin converting enzyme (ACE) in blood vessels of the human forearm was studied using enalaprilat, the active metabolite of the prodrug enalapril. In a dose of 5 micrograms/min enalaprilat inhibits arteriolar vasoconstriction in response to angiotensin I (Ang I) and enhances vasodilation in response to bradykinin. At this dose enalaprilat had no effect on resting forearm blood flow, or on the reduction in forearm blood flow in response to application of lower body negative pressure, in subjects with normal sodium intake. Following sodium depletion, however, enalaprilat produced an increase in resting forearm blood flow compared with the response in the same subjects under normal-sodium conditions. It appears that local ACE within forearm resistance vessels of healthy volunteers is unlikely to play an important role in regulation of local vascular tone in the sodium-replete state. However, in sodium-depleted subjects, and perhaps also in other circumstances where circulating concentrations of Ang I are elevated, local ACE may significantly affect vascular tone.

The effect of atrial natriuretic factor on urinary albumin and beta 2-microglobulin excretion in man.

The effect of a 20-min infusion of atrial natriuretic factor (ANF) 99-126, 0.4 microgram/kg per min, on both urinary albumin and beta 2-microglobulin excretion was examined in nine normal male subjects during stable water diuresis. ANF caused a rise in urinary albumin in excretion (from 4.19 +/- 0.66 to 13.49 +/- 3.07 ng/min, P less than 0.01) without any significant change in either creatinine clearance of beta 2-microglobulin excretion. These findings suggest that ANF may enhance glomerular permeability to albumin in man.

Physiological increases in circulating noradrenaline are antinatriuretic in man.

Low-dose (0.025 micrograms/kg per min) noradrenaline infusion, resulting in a physiological plasma increment (280 pg/ml), was antinatriuretic in normal salt-replete male subjects. The reduction in sodium excretion (-20%, P less than 0.01) occurred without any change in the glomerular filtration rate but was associated with a significant (P less than 0.02) decline in lithium clearance. These results suggest that changes in circulating noradrenaline, within the physiological range, can decrease sodium excretion in man by enhancing proximal tubular sodium reabsorption. These findings extend previous investigations in man which used pharmacological doses of noradrenaline and are in agreement with animal evidence for a renal tubular antinatriuretic effect of the sympathetic nervous system.

The interaction between noradrenaline and angiotensin II in man: evidence for a postsynaptic and against a presynaptic interaction.

Recent evidence from animal studies suggests an interaction between the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS). We sought evidence for a similar interaction in man, to determine whether this interaction is presynaptic, whereby angiotensin II (ANG II) facilitates noradrenaline (NA) release, or postsynaptic, whereby ANG II facilitates the effect of NA. In our first study, a subpressor dose of ANG II was infused and NA release stimulated by physiological tests. The haemodynamic responses and plasma NA responses to SNS stimulation were not augmented by ANG II. In the second study normal volunteers were infused with either saline, ANG II, or a combination of ANG II and NA. Analysis of variance showed that ANG II interacts synergistically with NA to increase systolic blood pressure (SBP). Plasma NA and ANG II levels were not altered by the coincidental presence of NA or ANG II. These results suggest that there is a pharmacodynamic interaction between NA and ANG II which acts synergistically at a postsynaptic site to maintain SBP.