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Primary percutaneous coronary intervention (PPCI) is superior to thrombolysis in STEMI (ST segment elevation myocardial infarction) patients. Data on late stent thrombosis (ST) have raised concerns regarding the use of drug-eluting stents during PPCI. We report the first 3-year clinical evaluation of the zotarolimus-eluting stent (ZES) in patients undergoing PPCI for STEMI, a single-center, prospective cohort study of consecutive patients admitted with STEMI. All underwent PPCI within 12 hours of symptoms; each received one or more ZES in one or more target lesions. All patients received aspirin 300 mg, clopidogrel 600 mg, abciximab, and unfractionated heparin. A total of 102 STEMI patients (76 male, mean 62 years) received 162 ZES (mean 1.6 stents/patient). Median call-to-balloon time was 123 (102-152) minutes. Thirty-day combined major adverse cardiovascular event (MACE) rate was 3.9% (n = 4). Subacute ST occurred in 2 patients (1.96%). Combined MACE rates at 12 months and 3 years were 7.8% (n = 8) and 13.7% (n = 14). Late ST occurred in 1 patient (1%) with no occurrence of very late ST. This is the first 3-year report of the use of the ZES in an unselected, consecutive PPCI population. Overall 3-year incidence of MACE and target lesion revascularization (5.9%) was low, and was comparable to that seen with sirolimus- and paclitaxel-eluting stents in randomized controlled trials. At 3 years there was no occurrence of very late ST. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI)., Methods: Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1-54 PPCI per year; intermediate volume: 55-109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors., Results: During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality., Conclusions: Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume-outcome relationship in PPCI at a threshold higher than current recommendations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Female sex and South Asian race have been associated with poor clinical outcomes following primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) but remain understudied in large real-world series. We therefore investigated the association of sex and race with clinical outcomes following PPCI., Methods: We conducted a prospective study of all patients undergoing PPCI for STEMI between January 2009 and December 2011 at a large UK cardiac centre. Clinical characteristics and outcomes were compared according to sex and race using Chi-square test, independent samples Student's t-test and Mann-Whitney U-test. Primary and secondary outcomes were 12-month major adverse cardiovascular events (MACEs) - defined as all-cause mortality, myocardial infarction and unplanned revascularization, analysed using Cox proportional hazard models adjusting for cardiovascular risk factors., Results: Three thousand and forty-nine patients were included. Women ( n=826) were older than men ( n=2223) (median age 69 vs. 60 years, p <0.01). Mortality (hazard ratio 1.48 (1.15-1.90)) and MACE (hazard ratio 1.40 (1.14-1.72)) were higher in women in univariable analysis. However, there were no significant sex-differences in mortality or MACE after age-stratification alone. Multivariable analysis also showed no significant differences in outcomes between sexes. South Asians ( n=297) were younger but had a higher prevalence of most risk factors than White patients ( n=2570). Mortality and MACE did not differ significantly between South Asian and White patients in univariable or multivariable analysis., Conclusion: MACE and mortality was not greater in women, or in South Asian patients following PPCI after adjustment for cardiovascular risk factors including age, which was most strongly associated with both outcomes.

Background: recent studies report an age-dependent decline in mortality after acute myocardial infarction (AMI)., Objective: to investigate age-dependent improvements in survival after hospitalisation with AMI., Design: population-based cohort study using data from the Myocardial Ischaemia National Audit Project., Subjects: a total of 583,466 patients with AMI admitted to 247 hospitals between 1 January 2003 and 31 December 2010., Methods: six-month relative survival (RS) was calculated from the ratio of observed to expected survival using an age-, sex- and biennial year-matched population from the Office for National Statistics. Risk-adjusted mortality rates (RMAR) were estimated using shared frailty regression. Data were stratified by age group, AMI phenotype [(ST-elevation myocardial infarction, (STEMI) and non-STEMI, (NSTEMI)] and period of admission to hospital., Results: for STEMI, there was an increase in RS for patients aged 65-80 years (84.8 versus 89.2%) and those over 80 years (68.0 versus 71.8%), but not for patients aged 18 to <65 years (96.4 versus 96.9%). For NSTEMI patients aged 18 to <65 years RS was higher, but stable (95.5 versus 96.8%) and improved for patients aged 65-80 years (83.2 versus 88.5%) and patients aged >80 years (68.3% versus 75.5%). Likewise, RMAR improved for patients aged ≥65 years, were stable and higher for patients <65 years., Conclusions: there were significant improvements in survival after hospitalisation with AMI in the older but not younger patients. The scope for further reductions in mortality is likely to be much greater for older than younger patients with AMI., (© The Author 2013. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Acute coronary syndromes presenting with ST elevation are usually treated with emergency reperfusion/revascularisation therapy. In contrast current evidence and national guidelines recommend risk stratification for non ST segment elevation myocardial infarction (NSTEMI) with the decision on revascularisation dependent on perceived clinical risk. Risk stratification for STEMI has no recommendation. Statistical risk scoring techniques in NSTEMI have been demonstrated to improve outcomes however their uptake has been poor perhaps due to questions over their discrimination and concern for application to individuals who may not have been adequately represented in clinical trials. STEMI is perceived to carry sufficient risk to warrant emergency coronary intervention [by primary percutaneous coronary intervention (PPCI)] even if this results in a delay to reperfusion with immediate thrombolysis. Immediate thrombolysis may be as effective in patients presenting early, or at low risk, but physicians are poor at assessing clinical and procedural risks and currently are not required to consider this. Inadequate data on risk stratification in STEMI inhibits the option of immediate fibrinolysis, which may be cost-effective. Currently the mode of reperfusion for STEMI defaults to emergency angiography and percutaneous coronary intervention ignoring alternative strategies. This review article examines the current risk scores and evidence base for risk stratification for STEMI patients. The requirements for an ideal STEMI risk score are discussed.

The UK had previously established a comprehensive strategy for in-hospital nurse-led thrombolysis for patients with ST-elevation myocardial infarction, with a growing use of pre-hospital thrombolysis by paramedical staff in the ambulance services. The National Infarct Angioplasty Project was sponsored by the government and examined the introduction of primary percutaneous coronary angioplasty (PPCI) in a variety of urban, rural and mixed communities. The project found that PPCI could be delivered within acceptable timelines, would be cost-effective, and could be delivered to the majority of the population. A project was therefore undertaken in England to transform services. There has been a rapid change and by 2012/13 over 95% of eligible patients received PPCI. Survival of patients with STEMI has improved over time and length of stay in hospital halved. However, nearly a quarter of STEMI patients do not receive reperfusion therapy (often because of late presentation) and additional work is needed to minimise delays to treatment. There are unexplained differences between regions in numbers of PPCI procedures per million population, and there is also variance between centres in the proportion of patients who are in shock or on a ventilator. Additional research is needed to ensure a consistent approach for these sick patients, who might have the most to gain from early treatment. The national audit programmes have been instrumental in measuring the changes in strategies, monitoring performance and highlighting the associated improvements in outcomes. A new risk model is being developed to allow a more comprehensive comparison of outcomes in different hospitals.

In 2004 in the United Kingdom (UK), the infrastructural and organisational changes required for implementation of primary PCI for treatment of STEMI were unclear, and the cost-effectiveness and sustainability of a changed reperfusion strategy had not been tested. In addition, any proposed change was to be made against the background of a previously successful in-hospital thrombolysis strategy, with plans for greater use of pre-hospital administration. A prospective study (the "National Infarct Angioplasty Project - NIAP") was set up to collect information on all patients presenting with STEMI in selected regions in the UK over a one year period (April 2005 - March 2006). The key findings from the NIAP project included that PPCI could be delivered within acceptable treatment times in a variety of geographical settings and that the shortest treatment times were achieved with direct admission to a PPCI-capable cardiac catheter laboratory. The transformation from a dominant lytic strategy to one of PPCI across the UK was achieved both swiftly and consistently with the help of 28 cardiac networks. By the second quarter of 2011, 94% of those STEMI patients in England who received reperfusion treatment were being treated by PPCI compared with 46% during the third quarter of 2008.

Although clinical trials have demonstrated that primary percutaneous coronary intervention (PPCI) provides better outcomes than thrombolysis for STEMI, it cannot be assumed that similar results can be obtained in day-to-day practice. To determine whether standards are being met, continuous audit of PPCI programmes is necessary, with appropriate feedback to participating centres and operators. Both the MINAP and BCIS national audit projects allow central electronic collection of data on consecutive patients presenting to every hospital involved in the acute management of these patients. Regular programmed feedback is provided to centres performing primary PCI that attempts to take account of statistical variation and differences in case mix between units by making use of funnel plots, statistical process control graphs and risk adjustment models. This reporting of "process" and "outcome" data, both confidentially and within the public domain, has been used to drive up clinical performance and has been associated with steady improvements and reduced inequalities of care.

Background: We investigated the association between diabetes mellitus (DM) and all-cause mortality in a large cohort of consecutive patients treated with primary percutaneous coronary intervention (PPCI) in the contemporary era., Methods: We conducted a retrospective analysis of a single-centre registry of patients undergoing PPCI for ST-segment elevation myocardial infarction (STEMI) at a large regional PCI centre between 2005 and 2009. All-cause mortality in relation to patient and procedural characteristics was compared between patients with and without DM., Results: Of 2586 patients undergoing PPCI, 310 (12%) had DM. Patients with DM had a higher prevalence of multi-vessel coronary disease (p<0.001) and prior myocardial infarction (p<0.001). Patients with DM were less commonly admitted directly to the interventional centre (p=0.002). Symptom-to-balloon (p<0.001) and door-to-balloon time (p=0.002) were longer in patients with DM. Final infarct-related-artery TIMI-flow grade was lower in patients with DM (p=0.031). All-cause mortality at 30 days (p=0.0025) and 1 year (p<0.0001) was higher in patients with DM. DM was independently associated with increased mortality after multivariate adjustment for potential confounders., Conclusions: Mortality remains substantially higher in patients with DM following reperfusion for STEMI in comparison with those without diabetes, despite contemporary management with PPCI. Greater co-morbidity, delayed presentation, longer times-to-reperfusion, and less optimal reperfusion may contribute to adverse outcomes.

Aims: To quantify the determinants of primary percutaneous coronary intervention (PCI) performance in England and Wales between 2004 and 2007., Methods and Results: All 8653 primary PCI cases admitted to acute hospitals in England and Wales as recorded in the Myocardial Ischaemia National Audit Project (MINAP) 2004-2007. We studied the impact of the volume of primary PCI cases (hospital volume) on door-to-balloon (DTB) times and the proportion of patients treated with primary PCI (hospital proportion) on 30-day mortality and employed regression analysis to identify reasons for DTB time variations with a multilevel component to express hospital variation. The proportion of patients receiving primary PCI increased from 5% in 2004 to 20% in 2007. Median DTB times reduced from 84 min in 2004 to 61 min in 2007. Median DTB times decreased as the number of primary PCI procedures increased. The 30-day all-cause mortality rate for hospitals performing primary PCI on >25% of ST-elevation myocardial infarction patients [5.0%; 95% confidence interval (CI): 3.9-6.1%] was almost double that of hospitals performing primary PCI on more than 75% (2.7%; 95% CI: 2.0-3.5%). Time-of-day, year of admission, sex, and diabetes significantly influenced DTB times. Hospital variation was evident by a hospital-level DTB time standard deviation of 12 min., Conclusions: There was a large variation in DTB times between the best and worst performing hospitals. Although patient-related factors impacted upon DTB times, the volume and proportion of patients undergoing primary PCI were significantly associated with delay and early mortality-hospitals with the highest proportion of primary PCI had the lowest mortality.

Background: It remains unclear whether the superiority of primary percutaneous coronary intervention (PPCI) over thrombolysis for the treatment of ST elevation myocardial infarction (STEMI) extends to the very elderly. Furthermore, the deliverability and efficacy of PPCI in over the 80s has not been investigated in a real-world setting. The aim of this study was to compare outcome from STEMI in patients aged > or =80 before and after the introduction of routine 24/7 PPCI., Methods: Retrospective observational analysis of all patients aged > or =80 presenting with STEMI to 2 neighboring hospitals in the 3-year period after the introduction of a 24/7 PPCI service and in the preceding 2 years when reperfusion therapy was by thrombolysis., Results: Two hundred fifty-six STEMI patients aged > or =80 were included. After the introduction of PPCI, 84% (136/161) received reperfusion therapy, 73% PPCI, and 12% thrombolysis, compared to 77% ([73/95] 1% PPCI, 76% thrombolysis) previously. Mortality after inception of PPCI was reduced at 12 months (29% vs 41%, P = .04) and 3 years (43% vs 58%, P = .02). Improved outcome was attributable to treatment by PPCI, which was associated with numerically lower 12-month (26% vs 37%, P = .07) and significantly reduced 3-year (42% vs 55%, P = .05) mortality compared to thrombolysis., Conclusions: Primary PCI can be effectively delivered to very elderly patients presenting with ST elevation MI in a real-world setting and leads to a substantial reduction in mortality compared to patients treated by thrombolysis., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Primary percutaneous coronary intervention (PCI) is the preferred treatment for ST-segment elevation myocardial infarction (STEMI) provided it can be delivered within 90 minutes of hospital admission. In clinical practice this target is difficult to achieve. We aimed to determine the effect of direct ambulance admission to the cardiac catheterization laboratory on door-to-balloon and call-to-balloon times in primary PCI., Methods: We performed a prospective evaluation of a new system of paramedic electrocardiogram diagnosis of STEMI and subsequent direct ambulance admission to the cardiac catheterization laboratory for primary PCI. Door-to-balloon and call-to-balloon times were recorded for all patients. Direct admissions were compared with admissions via the emergency room of the interventional center and of 2 referring hospitals. All times are quoted as medians., Results: Five hundred and seventy-seven patients (70% male, age 63 +/- 13 years) underwent primary PCI between April 2005 and May 2007. After February 2006, 172 (44%) of 387 patients were admitted directly from the ambulance to the catheterization laboratory. Directly admitted patients had significantly reduced door-to-balloon (58 vs 105 minutes, P < .001) and call-to-balloon times (105 vs 143 minutes, P < .001). The 90-minute target for door-to-balloon time was achieved in 94% of direct admissions compared to 29% of patients referred from the emergency room., Conclusions: Direct admission of patients with suspected STEMI from the ambulance service to the catheterization laboratory significantly reduces time to treatment in primary PCI and allows the 90-minute door-to-balloon time target to be reliably achieved.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

1. The serotonergic type-2 (5HT2) antagonist ketanserin was given in a dose of 40 mg twice daily for 3 days to eight healthy subjects in a double-blind placebo controlled randomized crossover study. 2. The QTc interval was prolonged slightly but significantly (P less than 0.01) by a mean of 29 +/- 7 milliseconds after ketanserin compared to placebo. 3. Ketanserin reduced both mean arterial pressure and heart rate (P less than 0.05), by 5.7 +/- 1.8 mmHg and 3.5 +/- 1.5 beats minute-1 respectively, when compared to placebo. 4. There was a tendency (not statistically significant) for cardiac vagal outflow to be reduced after ketanserin (assessed by the heart rate responses to standing, deep breathing and the Valsalva manoeuvre). 5. In healthy man, ketanserin causes prolongation of the QTc interval and a reduction in heart rate. These changes do not appear to be due to enhanced cardiac parasympathetic activity.

Once-daily atenolol and celiprolol were compared in a placebo-controlled crossover study of 16 patients with stable angina pectoris. Atenolol and celiprolol equally and significantly reduced frequency of angina and electrocardiographic evidence of cardiac ischemia. Celiprolol, however, produced less suppression of the double product at 1 mm of ST-segment depression than atenolol, suggesting that actions other than reduction of heart rate may contribute to its antianginal efficacy.

In patients with hypertension, a pattern of left ventricular hypertrophy on the electrocardiogram is associated with a risk of sudden death in excess of the risk attributable to hypertension alone. We therefore investigated the frequency of complex ventricular arrhythmias by means of 48-hour ambulatory electrocardiographic monitoring in 100 treated hypertensive patients, of whom 50 had electrocardiographic evidence of left ventricular hypertrophy and 50 did not, and in 50 normotensive controls. The groups were matched for age, sex, and smoking habits, and the two hypertensive groups were matched for blood-pressure levels before and after antihypertensive therapy. Nonsustained ventricular tachycardia, defined as greater than or equal to 3 complexes at a rate greater than or equal to 120 beats per minute, occurred in 14 (28 percent) of the 50 patients with an electrocardiographic pattern of left ventricular hypertrophy, in 4 (8 percent) of the 50 patients without hypertrophy (P less than 0.05), and in 1 (2 percent) of the control subjects. Eight of the 50 patients (16 percent) with hypertrophy had episodes of nonsustained ventricular tachycardia longer than 5 complexes, whereas no patients without hypertrophy and no controls had such episodes. The group with nonsustained ventricular tachycardia was characterized by a high left ventricular mass on echocardiography and a high prevalence of ST-T abnormalities on electrocardiography. Ventricular tachycardia was not closely related to blood-pressure levels, nor was it associated with diuretic therapy or hypokalemia. The clinical importance of these arrhythmias is uncertain. Nevertheless, our data suggest that complex ventricular arrhythmias occur commonly in hypertensive patients with left ventricular hypertrophy and may contribute to the higher incidence of sudden death in these patients.

Celiprolol (400 mg) and atenolol (100 mg) were given once a day to 16 patients with stable angina pectoris in a double blind placebo controlled crossover study. Celiprolol produced less suppression of heart rate both at rest and during exercise than atenolol. Both drugs were equally effective in reducing the frequency of angina and in delaying the onset of ischaemia during exercise. Radionuclide ventriculography showed that atenolol but not celiprolol lowered cardiac output at rest and during exercise. Thus the ancillary properties of celiprolol, including partial beta 2 agonist activity and direct vasodilating activity, have detectable effects on cardiac function that may be beneficial in patients with angina.

A screening programme for cardiovascular risk factors in men aged 50-59 was undertaken in North Uist, and the results compared with an age- and sex-matched control group from Dundee screened as part of the Scottish Heart Health Study. Blood pressure levels were higher in the Islanders than in controls (148 +/- 20/89 +/- 10 mmHg vs 134 +/- 19/84 +/- 11 mmHg (P less than 0.001). Analysis of standard twelve-lead electrocardiograms revealed a greater prevalence of left ventricular hypertrophy in the Islanders (51% vs 16%, P less than 0.005), suggesting that the recorded BP differences were real and not artefacts of measurement. The explanation for the higher BP on North Uist is less clear. Environmental factors that might influence BP including body mass index, the amount of exercise taken, alcohol consumption, dietary salt and potassium intake were similar in North Uist and Dundee. By contrast, an analysis of family names in the two centres indicated a greater degree of common ancestry in North Uist (28 surnames/84 islanders v 98 surnames/110 controls, P less than 0.001). These results suggest that known environmental causes of hypertension are not responsible for higher BP amongst men of North Uist, and this with the data on family names raises the possibility that genetic factors are more important.

1. The sensitivity and specificity of four sets of electrocardiographic criteria for detection of left ventricular hypertrophy were evaluated in an echocardiographic study of 100 hypertensive patients. 2. All criteria gave reasonable specificity (87-94%) but poor sensitivity (39-52%). 3. When non-obese and obese patients were studied separately, criteria based on chest lead voltages were more sensitive than limb lead criteria for detection of left ventricular hypertrophy in non-obese subjects; however, the reverse was true in obese hypertensive patients, where criteria based on limb lead voltages were more sensitive than chest lead voltage criteria. 4. These data suggest that stratification of subjects by body build might improve the diagnostic performance of the electrocardiogram for detection of left ventricular hypertrophy.

Celiprolol, 400 mg once daily, and atenolol, 100 mg once daily, were compared in a double-blind placebo-controlled crossover study of 16 patients with stable angina. Both drugs reduced angina frequency and delayed the onset of ischaemia during exercise, although only celiprolol prolonged exercise time. Celiprolol produced less suppression of heart rate than atenolol during exercise, and atenolol, but not celiprolol, lowered resting and exercise cardiac output. Thus, the ancillary properties of celiprolol, including partial beta 2-adrenoceptor agonist activity and direct vasodilating activity, have detectable effects on cardiac function that may be beneficial in patients with angina.

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.