Primary percutaneous coronary intervention for acute ST elevation myocardial infarction--first year's experience of a tertiary referral centre in the UK.

This study evaluated the first year's experience of a large interventional centre in the UK after a primary percutaneous coronary intervention (PCI) programme that runs 24 hours a day and seven days a week was started. Workload, patient outcome, length of stay, and effect on the remainder of the interventional service were analysed. The primary PCI service for a mainly urban population of 800,000 was started in April 2005. All relevant characteristics, details of procedures, outcome, and other data on quality of care were collected and entered prospectively onto a computerised database. Data were analysed with SPSS (version 13.0). Over a 12-month period, 305 patients were diagnosed with ST elevation myocardial infarction (STEMI), of whom 259 (85%) were accepted for primary PCI. Median door-to-balloon time was 98 minutes, which decreased from 106 minutes in the first six months to 93 minutes in the second six months (p < 0.005). In-hospital mortality was 4.5% and 30-day mortality was 4.9%. Median length of stay was three days, which was reduced from the six days previously reported after thrombolysis. Waiting times for other acute and elective PCI procedures did not increase after initiation of the primary PCI programme. Primary PCI can be delivered successfully in a setting in the UK with low mortality and reduced length of stay and without a negative impact on other interventional services.

Haemodynamic performance of a 16-mm Carbomedics aortic prosthesis.

A 55-year-old lady underwent repeat aortic valve replacement using a 16-mm Carbomedics prosthesis. She made an uneventful postoperative recovery and now leads an unrestricted life. Doppler echocardiography reveals a 21-mm Hg gradient across the valve at rest. This did not increase with an infusion of 30 mcg/kg per min of dobutamine, which resulted in an increase in the cardiac output from 1.96 to 5.46 l/min.

Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation.

OBJECTIVE: To evaluate the role of haemostatic and haemodynamic variables in left atrial thrombosis in non-rheumatic atrial fibrillation. DESIGN: Case-control study. SUBJECTS: One hundred and nine patients with non-rheumatic atrial fibrillation. INTERVENTIONS: Peak blood velocity measured at three sites in the left atrium. Venous blood sampled for coagulant proteins and markers of haemostatic activation. MAIN OUTCOME MEASURES: Presence of left atrial thrombus and spontaneous echo contrast at transoesophageal echocardiography. RESULTS: Left atrial thrombus was identified in 19 patients (18%), 16 of whom had spontaneous echo contrast. Patients with thrombus had reduced peak left atrial appendage velocity compared with those without (0.17 v 0.26 m/s; P < 0.001), but no significant reductions in peak mid-left atrial or mitral valve outflow velocity. Patients with thrombus had increased plasma markers of platelet activation-beta thromboglobulin (56.8 v 30.4 IU/ml; P < 0.001) and platelet factor 4 (6.1 v 3.5 IU/ml; P < 0.01)-and of thrombogenesis: thrombin-antithrombin complexes (5.59 v 3.06 micrograms/ml; P < 0.001) and D-dimers (479 v 298 ng/ml; P < 0.01). von Willebrand factor was also increased (1.81 v 1.52 IU/ml; P < 0.05). A multiple logistic regression model identified left atrial appendage velocity (P = 0.001), beta thromboglobulin (P = 0.002), and von Willebrand factor (P = 0.04) as the independent associates of left atrial thrombosis, ahead of the presence of spontaneous echo contrast. CONCLUSIONS: Haemostatic and haemodynamic abnormalities are associated with left atrial thrombus in non-rheumatic atrial fibrillation, and may help stratify thromboembolic risk.

Twenty-four-hour beta-blockade in stable angina pectoris: a study of atenolol and betaxolol.

We examined the importance of a long plasma half-life (t1/2) on the antianginal effects of beta-blockade by comparing equivalent doses of once-daily atenolol 100 mg (t1/2 6-8 h) and betaxolol 20 mg (t1/2 20-22 h) in a double-blind placebo-controlled cross-over study of 20 patients with stable angina pectoris. At 20 h postdose, heart rate (HR) was lower with betaxolol than with atenolol whereas blood pressure (BP) was equally reduced by both drugs. Twenty-four-hour ambulatory HR recording demonstrated that this difference existed for the last 6 h of the dosage cycle. During treadmill exercise, HR remained lower with betaxolol than with atenolol and exercise time was significantly prolonged only by betaxolol. With placebo, radionuclide ventriculography demonstrated that left ventricular ejection fraction (LVEF) decreased during exercise. Betaxolol, but not atenolol, significantly attenuated the exercise-induced decrease in EF. Thus, the long plasma t1/2 of betaxolol is associated with a reduction in exercise-induced ischemia when tested toward the end of the 24-h dosage cycle. Plasma t1/2 therefore is of clinical relevance to the antianginal, but not antihypertensive, actions of beta-blockers.

Terodiline causes polymorphic ventricular tachycardia due to reduced heart rate and prolongation of QT interval.

Recent reports have suggested an association between terodiline hydrochloride and cardiac arrhythmias. We report 4 patients presenting over a six month period who developed polymorphic ventricular tachycardia (polymorphic VT) while receiving treatment with this agent. In each case there was prolongation of QT interval on electrocardiogram (ECG). Two patients had hypokalaemia associated with diuretic therapy. In the 3 cases in which follow-up ECG was available, QT interval returned to normal after discontinuation of terodiline. In order to define the effects of terodiline on corrected QT interval (QTc) and heart rate in the elderly, a prospective study was performed in 8 elderly in-patients treated with terodiline for urinary incontinence. After 7 days treatment with terodiline 12.5 mg twice daily, there was a significant increase in QT by a mean of 29 ms, QTc by 15 ms and a decrease in resting heart rate by a mean of 6.7 beats.min-1. Terodiline increases QTc and reduces resting heart rate in elderly patients. Both these effects may be associated with polymorphic VT, a potentially life threatening arrhythmia. This drug should be avoided in patients with other known risk factors for polymorphic VT, particularly hypokalaemia and cardiac disease.

Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis.

BACKGROUND: Healthy arteries exhibit endothelium-dependent dilation in response to both local acetylcholine and increased blood flow. In humans, clinically overt coronary artery disease is characterized by loss of dilation to both acetylcholine and blood flow. The temporal relation, however, between functional abnormalities of the endothelium and the development of atherosclerosis has not been established. METHODS AND RESULTS: We examined endothelial vasodilator function in vivo at an early stage of the development of atherosclerosis. Two groups of seven Macaca fascicularis monkeys were studied; one group was fed a high cholesterol diet (0.73-1.0 mg cholesterol per calorie) for 11 months. Cholesterol feeding was associated with increased plasma cholesterol levels and with intimal thickening of the iliac arteries but with no reduction in luminal diameter. Endothelium-dependent vasomotor responses of the iliac arteries were then examined in vivo by quantitative contrast angiography. Acetylcholine produced significant dilation in the controls but paradoxical constriction in the group with early atherosclerosis (+9.0 +/- 3.2% versus -5.3 +/- 5.4%, p less than 0.05). In response to a twofold increase in blood flow achieved by administering adenosine distal to the arterial segment under examination, the controls again dilated, whereas the atherosclerotic group failed to dilate (+ 11.6 +/- 2.1% versus + 0.5 +/- 2.4%, p less than 0.05). Both groups, however, were able to dilate, and dilated equally, to the nonendothelium-dependent agent nitroglycerin (+ 13.7 +/- 4.8% versus + 19.1 +/- 4.3%, NS). CONCLUSIONS: Endothelium-dependent vasodilation in response to both acetylcholine and increased blood flow may be lost early in the course of developing atherosclerosis before the appearance of stenosing and occlusive disease.

Hypercholesterolemia enhances macrophage recruitment and dysfunction of regenerated endothelium after balloon injury of the rabbit iliac artery.

BACKGROUND: We studied the effects on and possible interaction of balloon denudation and hypercholesterolemia on large arteries in the rabbit with special regard to structure and vascular reactivity. METHODS AND RESULTS: New Zealand White rabbits fed a 1% cholesterol diet or a standard diet for 14 weeks underwent balloon denudation of the left iliac artery 4 weeks before death. Both the balloon-injured and the control iliac arteries were harvested for in vitro studies of vascular reactivity, for immunohistochemical staining with monoclonal antibodies directed at smooth muscle cells and macrophages, and for scanning electron microscopy. Balloon injury caused intimal smooth muscle proliferation with little macrophage infiltration and was followed by recovery of endothelium-dependent vasodilator function within 4 weeks. Hypercholesterolemia caused macrophage-rich lesions confined to the intima with moderate impairment of endothelial vasodilator function. Balloon injury in the setting of hypercholesterolemia caused intimal smooth muscle cell proliferation and intense macrophage infiltration throughout the arterial wall and severe impairment of endothelial vasodilator function. Scanning electron microscopy confirmed regrowth of the endothelium in all balloon-injured vessels. In the balloon-injured arteries of hypercholesterolemic animals, the regenerated endothelium exhibited areas of atypical morphology not seen after balloon injury or hypercholesterolemia alone. CONCLUSIONS: The present study shows that balloon injury, hypercholesterolemia, and their combination cause distinct lesions and functional disturbances. An arterial balloon injury in the setting of hypercholesterolemia produces a diffuse inflammatory response that is accompanied by a sustained impairment of endothelial function and a marked proliferative response.

Double-blind randomised placebo-controlled dose-efficacy study of sustained release verapamil in chronic stable angina.

The efficacy and tolerability of sustained release verapamil (Securon SR) was investigated in twenty-four patients with chronic stable angina. Patients entered four randomised, double-blind treatment periods, each lasting one week of verapamil-SR 240 mg once daily, 360 mg once daily, 240 mg twice daily, and matching placebo. Four patients were withdrawn, but in one instance this was attributable to side effects from verapamil. Among the remaining twenty patients, mean frequency of angina fell from 4.25 episodes during the last five days of placebo to 2.35, 2.6 and 1.3 episodes during respective active treatments (all P less than 0.001). Compared with placebo the median percentage increase in time to 1 mV ST depression during treadmill exercise (12 hours post dose) was significant only with the regimen of verapamil-SR 240 mg given twice daily at +11% (P = 0.04). Total duration of exercise was also significantly longer and maximum ST depression significantly less only with the twice daily treatment (704 + 186 sec vs 648 + 203 sec; P = 0.03, and 1.75 + 0.73 mm vs 2.15 +/- 0.62 mm; P = 0.02). Side effects, predominantly constipation, breathlessness, and swollen ankles, occurred most frequently with verapamil-SR 360 mg. Thus, sustained release verapamil is well tolerated and effective in the treatment of angina. A regimen of 240 mg given twice daily emerges as superior to once daily treatments for 24-hour prophylaxis of angina.

Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease.

BACKGROUND: Previous studies have shown that little if any increase in heart rate occurs 1 minute before the onset of ischemia in ambulant patients with coronary artery disease. This study tested the hypothesis that there are characteristic relations between heart rate and ischemia in ambulant patients with coronary artery disease. METHODS AND RESULTS: Twenty-one patients with proven coronary disease demonstrated 212 episodes of ischemia during 504 hours of continuous monitoring of the electrocardiogram. An important increase in heart rate (from 74 +/- 11 to 90 +/- 14 beats/min, p less than 0.001) occurred between 5 and 30 minutes (not 1 minute) before the onset of ischemia. A significantly higher heart rate at onset of ischemia was seen during Bruce protocol exercise testing than during daily life (117 +/- 12 versus 95 +/- 15 beats/min, p less than 0.01). However, when a less-strenuous, but more prolonged, exercise protocol was used in a subgroup of patients (n = 12), ischemia occurred at a heart rate that was significantly lower than during the Bruce protocol (88 +/- 14 versus 103 +/- 15 beats/min, p less than 0.05) and was not significantly different from the threshold heart rate at onset of ischemia during daily life (88 +/- 14 versus 84 +/- 12 beats/min, p = NS). As part of two placebo-controlled trials, treatment with both propranolol and nitroglycerin altered the distribution of ischemic events by heart rate but in opposite directions. Although propranolol largely eliminated events occurring at high (greater than 100 beats/min) and moderate (80-100 beats/min) heart rates, the number of events at low (less than 80 beats/min) heart rates was increased. In contrast, nitroglycerin reduced episodes at low and moderate heart rates only. CONCLUSIONS: Important increases in heart rate occur before the onset of ischemia during daily life, but this increase occurs much earlier than has been reported. Duration of heart rate increase appears to influence the heart rate threshold for ischemia, and this may contribute to the occurrence of ischemia at lower heart rates during daily life than during standard exercise testing. Last, different classes of drugs appear to have characteristic effects on ischemia occurring at different heart rates that may be useful in planning therapy.

Submaximal, but not maximal, exercise testing detects differences in the effects of beta-blockers during treadmill exercise: a study of celiprolol and atenolol. II.

Celiprolol is a new-generation beta-blocker with ancillary properties that include partial beta 2-agonism and direct vasodilating activity. The effects of atenolol and celiprolol on maximal exercise capacity and on both respiratory variables and subjective indices of breathlessness and fatigue during submaximal exercise were compared in a placebo-controlled crossover study of 12 trained volunteers. Both atenolol and celiprolol equally and significantly reduced exercise capacity and maximal oxygen consumption. During constant submaximal exercise at 70% maximal oxygen uptake, however, differences emerged between the two beta-blockers. Atenolol was associated with a significantly higher minute ventilation than placebo. In contrast, values for minute ventilation and respiratory exchange ratio with celiprolol were similar to values with placebo. During the early stages of exercise, treatment with atenolol was also associated with higher scores for the subjective indices of breathlessness and fatigue. Thus submaximal exercise, which may be physiologically more relevant to the everyday activities of patients, may demonstrate potentially useful differences between drugs that are not seen during maximal exercise testing.

Determinants of ventricular arrhythmias in cardiac hypertrophy.

Ventricular arrhythmias occur with increased frequency in both experimental and human cardiac hypertrophy. Although the process of hypertrophy itself may be arrhythmogenic, other factors may contribute to the high prevalence of arrhythmias in hypertensive patients with left ventricular hypertrophy (LVH). Disease of the large epicardial coronary arteries or of the small intramyocardial vessels (coronary microangiopathy) may lead to myocardial ischemia and thus predispose to arrhythmia. Myocardial fibrosis, a common sequelae of cardiac hypertrophy, has also been shown to be associated with ventricular arrhythmias in experimental models. Other possible determinants of ventricular arrhythmias in this group of patients include metabolic abnormalities; studies relating to the importance of hypokalemia in particular have yielded conflicting results. Thus a number of factors may combine to explain the high prevalence of ventricular arrhythmias in hypertensive patients with LVH.

Ventricular arrhythmias in hypertensive left ventricular hypertrophy. Relationship to coronary artery disease, left ventricular dysfunction, and myocardial fibrosis.

Ventricular arrhythmias occur with increased frequency in hypertensive patients with left ventricular hypertrophy (LVH). The relationships, however, between ventricular arrhythmias and coexistent coronary artery disease, left ventricular dysfunction and left ventricular fibrosis have not been examined in hypertensive LVH. We carried out coronary arteriography on fifteen hypertensive patients with LVH and nonsustained ventricular tachycardia (greater than or equal to 3 consecutive ventricular complexes) of whom nine (60%) were free of significant (greater than 50% stenosis) coronary disease. To identify other possible correlates of left ventricular arrhythmias, 28 patients with LVH, comprising 17 with ventricular tachycardia and 11 without ventricular arrhythmias, underwent quantitative assessment of left ventricular function (angiographic ejection fraction), left ventricular mass (echocardiography), and left ventricular fibrosis (endomyocardial biopsy). Ejection fraction was not significantly different between the two groups (53 +/- 8% v 62 +/- 2%, P = NS). However, left ventricular mass was significantly greater (442 +/- 28 g v 339 +/- 34 g, P less than .05) and percentage fibrosis significantly higher (19 +/- 4% v 3 +/- 1%, P less than .001) in those patients with ventricular tachycardia. Thus ventricular arrhythmias in hypertensive patients with LVH cannot be entirely attributed to coexistent coronary disease, nor to left ventricular dysfunction, but are related to the degree of cardiac hypertrophy and subendocardial fibrosis.

Early evidence of endothelial vasodilator dysfunction at coronary branch points.

Intracoronary acetylcholine produces endothelium-dependent dilation of normal coronary arteries and paradoxical constriction of atherosclerotic vessels. Regional differences in endothelium-dependent vasomotion, however, have not been studied in relation to the nonuniform development of atherosclerosis. We compared the vasomotor response to increasing doses of acetylcholine of angiographically smooth coronary artery segments prone to atherosclerosis (coronary branch points) with segments remote from branch points (straight segments). In patients with entirely smooth coronary arteries and a dilator response to acetylcholine (group 1, n = 7), branch points and straight segments demonstrated equal and significant dose-dependent dilation to acetylcholine (14.7 +/- 8.9% and 12.3 +/- 12.7%, respectively; p identical to NS). In patients with early atherosclerosis as manifest by luminal coronary irregularities, the lowest dose of acetylcholine (10(-8) M) produced constriction at branch points and slight dilation at straight segments (-6.3 +/- 7.4% vs. +2.2 +/- 7.3%, p less than 0.05). At higher doses of acetylcholine, both branch point and straight segments constricted, but constriction remained more pronounced at branch points. Both branch point and straight segments, however, retained the ability to dilate to the non-endothelium-dependent agent, nitroglycerin. In a third group of patients with angiographically entirely smooth coronary arteries but without dilation to acetylcholine, constriction to acetylcholine again occurred first at branch points. Thus, coronary branch points demonstrate increased sensitivity to acetylcholine-induced constriction in patients with angiographic evidence of early coronary atherosclerosis and in middle-aged patients with smooth coronary arteries. These segments, however, retain the ability to dilate to nitroglycerin. Whether this early evidence of defective endothelium-dependent vasodilation predicts the later development of occlusive atherosclerosis is not yet known.

Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery.

This study investigated the vasodilator function of endothelium that regenerated after balloon angioplasty and the relation of this function to the extent of vascular injury and to subsequent intimal proliferation. Balloon angioplasty was performed in the left iliac artery of 47 New Zealand White rabbits. Vascular responses were examined in vitro 2 and 4 weeks after a "severe" injury (3.0-mm balloon) or a "moderate" injury (2.5-mm balloon). Both degrees of balloon injury caused complete endothelial denudation. Endothelial regrowth 2 weeks after either injury was confirmed histologically. Although the regenerated cells had irregular sizes and polygonal shapes and lacked the typical alignment in the direction of blood flow, immunocytochemical staining for factor VIII-related antigen identified these cells as endothelium. To study the vasodilator function of regenerated endothelium, rings of balloon-injured and control (contralateral) iliac arteries were suspended in organ chambers for recording of isometric force. Endothelium-dependent relaxation of balloon-injured vessels to acetylcholine and to the calcium ionophore A23187 were reduced at 2 and at 4 weeks after severe injury. After moderate injury, endothelium-dependent relaxations to these agents were reduced at 2 weeks but had normalized by 4 weeks. Endothelium-independent relaxation to sodium nitroprusside, however, was preserved in all study groups. Morphometric analysis revealed an inverse correlation between the degree of intimal thickening and maximal relaxation to acetylcholine (r = 0.45, p less than 0.01). Thus, there is a persistent attenuation of receptor- and nonreceptor-mediated endothelium-dependent relaxations after arterial injury. The regenerated cells have an altered morphological appearance, but staining for factor VIII-related antigen confirms their endothelial origin. The degree and duration of endothelial dysfunction depends on the severity of the initial injury and is related to the extent of intimal thickness.

A review of rhythm disorders in cardiac hypertrophy.

Ventricular arrhythmias frequently occur in both experimental and human left ventricular hypertrophy. The mechanism of arrhythmia is not clear but appears to be related to the process of hypertrophy and the accompanying fibrosis rather than to coexistent coronary artery disease or diuretic-induced hypokalemia. Although neither the independent prognostic value of ventricular arrhythmias nor the benefit of antiarrhythmic therapy has been demonstrated in prospective studies involving hypertensive patients, it is possible that appropriate antiarrhythmic therapy may reduce mortality in selected patients with severe hypertrophy.

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.

Left ventricular hypertrophy as a factor in arrhythmias and sudden death.

Hypertensive patients with left ventricular hypertrophy (LVH) are predisposed to sudden cardiac death. Several studies have demonstrated that complex ventricular arrhythmias, including episodes of nonsustained ventricular tachycardia, occur commonly during ambulatory electrocardiographic monitoring of hypertensive patients with LVH. The prognostic significance of such arrhythmias is not known. In other forms of cardiac hypertrophy, however, such as hypertrophic cardiomyopathy, complex ventricular arrhythmias detected during ambulatory monitoring are predictive of subsequent sudden death and there is some evidence that appropriate antiarrhythmic drug therapy may reduce mortality.