Search

Background There is limited literature available on the impact of myocardial ischemia but no obstructive coronary arteries (INOCA) on patients' lives. Purpose We sought to determine how INOCA impacts the physical, social, and mental health of persons with this diagnosis. Methods A survey was made available to all members of the patient support group from INOCA International over a 3-month time period. Fitness was estimated using the Duke Activity Status Index (DASI), assessing levels of activities performed prior to the onset of INOCA symptoms, and after the diagnosis of INOCA. The formula to estimate fitness in metabolic equivalents (METs) = 0.43 × DASI + 9.6 / 3.5 Results A total of 297 patients with INOCA responded to the survey; 91.2% were women. The most common diagnosis was coronary microvascular dysfunction (64.3%) and coronary artery spasm (50.5%) (Table 1). 34.4% reported living with symptoms for ≥3 years before their diagnosis of INOCA was made. 77.8% who had been told their symptoms were not cardiac. The symptoms the respondents experienced were numerous, but 92.9% reported symptoms of chest pain, pressure, or discomfort. Fitness levels prior to the onset of INOCA symptoms were significantly higher compared to after diagnosed with INOCA (8.6±1.8 METs vs 5.6±1.8 METs; P Conclusions Living with INOCA has significant impact on physical, mental and social health. Significant physical fitness declines are seen in those living with INOCA and are lower in those experiencing any adverse impact of living with INOCA. Additionally, the impact of INOCA on the ability to work has important economic consequences to both the patient and society. Increased recognition of the impact of INOCA on these aspects of health need to be recognized and further work is needed to better diagnosis and treat the symptoms of INOCA to improve the quality of life, cardiovascular outcomes, and overall health of this frequently encountered cardiovascular disorder. Funding Acknowledgement Type of funding sources: None.

Background Previous studies using experimental models and clinical retrospective samples have pointed to a potential role of glycosylated apolipoprotein J (ApoJ-Glyc) as a marker for the early detection of myocardial ischaemia. Ischaemia induces intracellular accumulation of non-glycosylated ApoJ that mirrors the reduction in ApoJ-Glyc serum levels in patients presenting with ST-segment elevation myocardial infarction (STEMI). Purpose The EDICA (Early Detection of Myocardial Ischaemia in Suspected Acute Coronary Syndromes by Apo J-Glyc as a Novel Pathologically based Ischaemia Biomarker) clinical trial assessed the performance of ApoJ-Glyc as a biomarker for the early detection of myocardial ischaemia in patients attending the A&E department with chest pain suggestive of acute coronary syndrome. Here, we report the observed changes in ApoJ-Glyc concentration in STEMI patients at baseline and after primary percutaneous coronary intervention (PPCI). Methods The EDICA trial, a multi-centre (10 sites), international, in vitro diagnostic study, assessed 404 patients attending the A&E department with suspected ACS. Of these, 291 patients had a final diagnosis of “non-ischaemic” event and 113 of “ischaemic” event. The main inclusion criterion was chest pain of suspected cardiac origin. Blood samples were obtained for the simultaneous assessment of high sensitivity-troponin and ApoJ-Glyc on admission (time 0) and at 1h and 3h thereafter. Two different glycosylated variants of ApoJ (ApoJ-GlycA2 and ApoJ-GlycA6) were analyzed with a novel ELISA in serum samples. Of the “ischaemic” patients, 33 had STEMI, of whom 85% underwent PPCI. Results As expected, in the presence of myocardial ischaemia, time 0 ApoJ-GlycA2 and ApoJ-GlycA6 serum levels decreased by 34% and 48%, respectively in STEMI patients, compared with non-ischaemic patients, i.e. ApoJ-GlycA2 in STEMI: 66 [52–95] μg/ml vs. non-ischaemic: 100 [72–131] μg/ml; P=0.0002; ApoJ-GlycA6 STEMI: 38 [34–67] vs. non-ischaemic: 73 [56–95] μg/ml; P Conclusions ApoJ-Glyc concentrations are reduced in STEMI patients on admission and increase rapidly after improved perfusion with PPCI, pointing to a potential role of this biomarker in the early detection of reversible ischaemia and the mapping of reversible changes. The mechanisms whereby ApoJ-Glyc levels rapidly and markedly increase after PPCI are speculative at present and deserve further investigation, together with the potential prognostic value of ApoJ-Glyc in this setting. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Commission 2020-EIC-SMEInstrument Phase 2; Spanish Ministry of Science, Innovation and Universities

Syndrome X (SX) is usually diagnosed in the presence of angina and normal coronary arteriograms. It is an heterogeneous syndrome which encompasses different pathogenic mechanisms. Whether myocardial ischaemia is responsible for the condition remains controversial. The term "microvascular angina" has been used to define the syndrome of chest pain and normal coronary arteries with heightened sensitivity of the coronary microcirculation to vasoconstrictor stimuli. It has been suggested that the abnormal vasodilator response of the coronary circulation in patients with SX is due to impaired endothelial function. Plasma levels of endothelin in patients with chest pain and normal coronary arteries were found to be significantly raised compared to normal controls. Endothelial dysfunction in SX is likely to be multifactorial and many cardiac risk factors, such as hypertension, hypercholesterolemia, oestrogen deficiency and smoking, can contribute to its development. As the majority of SX patients are women and most are post-menopausal, oestrogen deficiency has been proposed as a pathogenic factor. A large proportion of patients satisfying the stated criteria for SX have one or more coronary risk factors. Additional factors, such as abnormal pain perception, may contribute to the evolution of chest pain in patients with normal coronaries and endothelial dysfunction. Combined alteration of pain perception and microvascular dysfunction are likely to explain a proportion of all cases of SX. The treatment of this syndrome represents a major challenge for the cardiologist. Beta-blockers and calcium channel blockers are effective in controlling chest pain in SX patients. A very important therapeutic intervention in microvascular angina is the control of risk factors that can lead to endothelial dysfunction. Different approaches, including spinal cord stimulation and psychological treatment, have been proposed especially for those patients in whom a cardiac origin of pain is unlikely.

OBJECTIVE—To determine the efficacy and safety of the potassium channel blocker tedisamil versus placebo in the treatment of patients with stable angina. DESIGN—Prospective, double blind, placebo controlled study. 203 patients first completed a seven day placebo run in. They were then randomised to receive 50 mg, 100 mg or 150 mg tedisamil twice daily, or placebo. Treadmill exercise testing was carried out at baseline and after 14 days of double blind treatment. MAIN OUTCOME MEASURES—Primary efficacy parameters were an increase in total exercise duration and a reduction of the sum of ST segment depression using six ECG leads at maximum workload at trough (12 hours after last medication). Secondary aims included increase in exercise time to onset of 0.1 mV ST segment depression, increase in exercise time to onset of any anginal pain, and reduction in ST segment depression in any of the six specified leads at maximum workload. These were all at trough. The same parameters were also assessed at peak concentrations (two hours after administration). Overall attacks of angina and the use of short acting nitrates were assessed from patient diaries. RESULTS—Tedisamil led to a dose dependent prolongation of exercise duration (significant at all concentrations), an effect that was greater at peak than at trough. Treatment also led to a significant dose dependent reduction in the sum of ST segment depression at both trough and peak concentrations. Tedisamil also decreased (in a dose dependent way) the frequency of anginal attacks and the consumption of short acting nitrates, an improvement that became significant for all doses in the second treatment week. Adverse events with tedisamil were few. There was a pronounced rise in the incidence of diarrhoea with the 150 mg twice daily regimen. Bradycardic effects and increases in QT interval were dose dependent, but were no more evident at exercise than at rest. CONCLUSIONS—Tedisamil, at doses of 50-100 mg twice daily, was found to be an effective antianginal and anti-ischaemic agent. At doses above 100 mg twice daily its main side effect, diarrhoea, becomes pronounced; therefore the 50—100 mg twice daily regimen appears to be appropriate. Keywords: stable angina; potassium channel blocker; tedisamil

1.Many studies have shown that hyperhomocysteinaemia is a risk factor for atherosclerotic vascular disease. A mutation (C-677T) in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) enzyme has been shown to produce a thermolabile form of the enzyme. Homozygosity for this mutation has been correlated with an elevated plasma homocysteine concentration. The present study aimed to determine whether this mutation was a risk factor for coronary artery disease (CAD). This was achieved by comparing the frequency of the C-677T mutation in patients with angiographically proven CAD against angiographically normal patients in two separate U.K. samples. The analysis was repeated with CAD patients split into those with ⩾ 99% stenosis of arteries and those without, to establish whether the C-677T mutation could be correlated with severity of CAD. 2.Two patient groups were selected from London and Sheffield. The London group comprised 174 cases and 148 controls. The Sheffield group comprised 93 cases and 85 controls. The DNA samples of the patients were genotyped by polymerase chain reaction and restriction enzyme digestion. 3.For London the homozygous C-677T frequencies were: 0.07 (controls), 0.09 (CAD without ⩾ 99% stenosis) and 0.10 (CAD with ⩾ 99% stenosis). For Sheffield the homozygous C-677T frequencies were: 0.08 (controls), 0.10 (CAD without ⩾ 99% stenosis) and 0.11 (CAD with ⩾ 99% stenosis). No association was found between the C-677T mutation and CAD in our sample geographical groups. Statistical comparison by genotype distribution for 0 ;VD (no vessel disease, i.e. 0% diameter reduction in all epicardial arteries) versus CAD without ⩾ 99% stenosis: London, P = 0.19; Sheffield, P = 0.53; 0 ;VD versus CAD with ⩾ 99% stenosis: London, P = 0.23; Sheffield, P = 0.55.

To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG).MEDLINE and EMBASE were searched from 1966 until 30 November 2008.We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model.We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario).Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.

BACKGROUND It has been suggested that recurring coronary artery spasm may lead to the development of fixed atherosclerotic coronary obstructions. METHODS AND RESULTS We studied 10 patients with typical Prinzmetal's variant angina in whom the disease remained active for years and in whom occlusive coronary spasm occurred reproducibly at the same arterial site during repeat coronary arteriography (25 +/- 12 months after initial angiography). At initial evaluation, four patients had significant (greater than or equal to 50% fixed coronary diameter reduction) one-vessel coronary artery disease, and six had nonsignificant disease. Spasm developed at stenotic sites (20-65% diameter reduction) in nine patients and at an angiographically normal site in one patient. Progression of coronary disease was assessed in 62 segments: 10 spastic (of which nine were stenotic) and 52 nonspastic (eight stenotic and 44 angiographically normal), using computerized arteriography. Mean diameters (millimeters) of spastic segments, nonspastic stenoses, and angiographically normal nonspastic segments were not significantly different at first and second arteriograms (1.52 +/- 0.14 versus 1.43 +/- 0.21, 1.32 +/- 0.17 versus 1.12 +/- 0.23, and 2.40 +/- 0.12 versus 2.42 +/- 0.12, respectively). Stenosis progression (from 65% diameter reduction to total occlusion) occurred in one patient at a spastic site and in two at nonspastic sites (from 34% to 65% and from 84% to 100%). Complicated stenoses suggestive of plaque fissuring were not observed during the study. CONCLUSIONS In patients with chronic Prinzmetal's variant angina without myocardial infarction, stenosis progression was not frequently observed at spastic sites despite the recurrence of focal coronary spasm over relatively long periods of time.

Background Risk stratification of patients with unstable angina or non-ST-segment elevation myocardial infarction (UA/NSTEMI) is problematic given the heterogeneous presentation of the condition. This study was undertaken to compare, in UA/NSTEMI patients, the prognostic value of two clinical risk scores (RS) (i.e. Thrombolysis in Myocardial Infarction (TIMI) and physician's risk assessment (PRA)) and to assess whether serum biomarkers can increase the prognostic accuracy of these RS. Methods We prospectively assessed 610 consecutive UA/NSTEMI patients, 217 (36%) UA and 393 (64%) NSTEMI. In all patients RS, high sensitivity C-reactive protein, CD40 ligand, IL6, IL10, IL18, E-selectin, P-selectin, white blood cell count, neopterin, myeloperoxidase, fibrinogen and NT proBNP were assessed at study entry. The primary study endpoint was death and non-fatal MI at 30 and 360days of follow-up. Results At 1year, 54 patients (8.9%) had reached the primary study endpoint (26 suffered a cardiac death (4.3%) and 34 (5.6%) a non-fatal MI). For both RS, the study endpoint occurred more commonly in patients at a "higher risk" compared to those classified as being at a "lower risk". Moreover, TIMI and PRA RS had similar discriminatory accuracy. TIMI RS, however, was a better predictor of events than PRA at both 30- and 360-day follow-up. The inflammatory biomarkers assessed in the study did not improve significantly the predictive value of RS. Conclusions Our study suggests both that TIMI RS is a better marker of risk than PRA RS and inflammatory biomarkers do not increase the predictive value of these clinical risk scores.

Purpose: Accelerated coronary disease is a leading cause of morbidity and mortality in patients (pts) suffering from immune-mediated inflammatory diseases (IMID), such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We tested the hypothesis that inflammation, in the absence of conventional cardiovascular risk factors, could result in coronary microvascular dysfunction (CMD) which is known to precede atherosclerosis in large vessels in pts with cardiovascular risk factors. Methods: Myocardial blood flow (MBF, ml/min/g) was measured using positron emission tomography at rest and during i.v. adenosine (140 μg/Kg/min) in 8 SLE and 10 RA pts aged 47 ± 8 years without conventional cardiovascular risk factors and in 18 age and gender matched controls. In pts multislice (64 slices) CT coronary angiography was performed to exclude coronary stenoses. Results: Mean disease duration was 18 ± 11 and 14 ± 6 years in RA and SLE respectively. There was no difference in resting MBF between pts and controls (1.27 ± 0.25 vs 1.11 ± 0.23; p=0.06). However, adenosine MBF was diffusely reduced in pts compared with controls (2.72 ± 0.84 vs 4.20 ± 0.75; p ). Coronary flow reserve (CFR; adenosine/resting MBF) was significantly reduced in pts (2.24 ± 0.74) compared with controls (4.00 ± 0.83; p Conclusions: Patients with IMID and without conventional cardiovascular risk factors have evidence of CMD which can result in reductions of CFR severe enough to cause myocardial ischemia.

The endothelium plays a crucial role in the maintenance of vascular homeostasis; endothelial cells produce a series of molecules that determine vascular tone and modulate the interactions between the arterial wall components and the circulating blood. Endothelial dysfunction (ED) thus results in significantly impaired physiological responses that often lead to atheroma formation. Recent studies suggest that endothelial dysfunction as assessed invasively during coronary angiography is a prognostic marker. Recently, a non-invasive ultrasound technique has been developed which may allow screening of ED in both patients and healthy subjects. This article reviews current knowledge regarding non-invasive assessment of endothelial dysfunction and proposes potential uses of a promising ultrasound technique.

It is established that the progression of coronary artery disease is neither linear nor predictable. The unpredictable and often episodic nature of coronary disease progression can be explained by rapid increase of stenosis severity due to thrombosis, which occurs as a complication of the atherogenic process. Rapid coronary stenosis progression is most often responsible for the acute clinical manifestations of coronary artery disease, i.e. sudden cardiac death, acute myocardial infarction and unstable coronary syndromes. Recently, it has been shown that stenosis progression, whether clinically "silent" or associated with acute coronary events, is a strong predictor of cardiovascular risk. Atheromatous plaques associated with rapid coronary artery disease progression have well defined anatomo-pathological characteristics and are usually termed "vulnerable" or "unstable", terms which indicate both their propensity to acute disruption and increased thrombogenicity that may lead to the development of acute coronary events. Plaques have been regarded, in the past, as being inert and staying almost unchanged for years. However, they are very active entities. The fibrous cap is in a balance between smooth muscle cells producing collagen and the macrophages degrading collagen. The thickness of the cap depends on the relative activity of those two components and there is, therefore, a danger of the fibrous cap rupturing. Although only a relatively small proportion of all coronary artery lesions in patients with angina pectoris undergo complications that lead to fibrous cap disruption and acute coronary events, these stenoses are responsible for the majority of cases of serious coronary events. Thus the identification of vulnerable plaques that may lead to increased risk of coronary events will most certainly help in the rational management of patients with coronary artery disease. Angiographic studies have indicated that "complex" lesion morphology is associated with increased risk of myocardial infarction and "ulcerated" plaques identify vulnerable lesions. We therefore reasoned that the identification of angiographically complex coronary stenoses could provide a valuable marker of cardiovascular risk in relation to rapid disease progression. Our group sought to investigate the role of angiographically complex lesions as a marker of rapid disease progression in different clinical settings. We took advantage of the fact that patients with stable angina pectoris requiring routine myocardial revascularisation in our institution are put on waiting lists. We observed that complex lesions progressed more than smooth stenoses of similar severity both in patients presenting with stable angina and in patients presenting with unstable angina. Why complex plaques should be particularly vulnerable to rapid stenosis progression is speculative. In this paper we discuss the possible mechanisms that may explain an association between complex stenosis and acute coronary events.

The rapidly changing patterns of coronary heart disease (CHD) prevalence and presentation fail to be explained by conventional cardiovascular risk factors alone. An infectious basis to atherosclerosis may, at least in part, be contributing to the variable rates of prevalence of CHD in different parts of the world. The evidence for such an association appears to be strongest for Chlamydia pneumoniae. Results of recent anti-chlamydia antibiotic intervention pilot studies have renewed interest in the role of C. pneumoniae, and corroborated the evidence from sero-epidemiological, pathological and animal-model studies. The results of larger, on-going, purpose-designed intervention studies should help to increase our understanding of the role of infection in atherogenesis and potentially lead to a novel and effective treatment strategy for patients with CHD--broad spectrum antibiotics.

Evidence is accumulating to suggest that Chlamydia pneumoniae may have a role in the development and/or progression of atherosclerotic-related disorders, in particular coronary heart disease (CHD). The evidence for C. pneumoniae as a potential causative agent is largely based on the findings of (1) seroepidemiological studies, (2) examination of atheromatous plaque specimens, (3) in vitro experiments and animal models and, recently, (4) preliminary anti-chlamydial antibiotic intervention studies. This chapter aims at focusing on the potential, and intriguing, role of antimicrobial therapy in the secondary prevention of CHD. The findings of the preliminary pilot studies are reviewed, as are the aims and controversies surrounding large-scale, prospective intervention trials, now in progress.

In 1908 Sir William Osier first proposed a causative role of infection in the pathogenesis of atherosclerosis [1]. The view that infectious processes may contribute to cardiovascular diseases did not gain wide support, as autopsy and epidemiological studies shifted the attention towards other mechanisms, some of which have now become established risk factors. In recent years, however, it has become apparent that recognised risk factors for coronary heart disease (CHD) do not fully explain the diversity of this disease, or why risk factor modifications have not reduced its incidence as much as has been predicted. Recent observations have prompted research into other potential and hitherto unrecognised influences in the causation of atherogenesis. Amongst these, chronic infection by Gram-negative bacteria and herpesviridae have been shown to have a major role. Current evidence indicates that chronic Chlamydia pneumoniae infection may play a causal role in atherogenesis.

Raised plasma endothelin concentrations have previously been reported in patients with cardiac syndrome X, but it is not known whether these levels vary between clinically distinct subgroups in this heterogeneous condition.We compared plasma immunoreactive endothelin levels in 54 patients with angina pectoris and normal coronary angiograms and 21 healthy control subjects. The patient group was divided into 4 clinically distinct subgroups: 7 with left bundle branch block (group A); 7 with previous myocardial infarction (group B); 24 with positive exercise electrocardiography (group C); and 16 with negative exercise electrocardiography (group D). The plasma endothelin concentration was significantly higher in patients compared with control subjects (3.7 [2.9 to 4.3] vs 2.96 [2.4 to 3.4] pg/mL, respectively, median [interquartile range]; P=0.002). Endothelin concentrations were most significantly elevated in group A and group B (4.5 [3.6 to 5.2] pg/mL; P=0.005 and 4.1 [3.9 to 4.5] pg/mL; P=0.001, respectively). Plasma endothelin concentrations were also significantly elevated in group C (3.7 [2.8 to 4.1] pg/mL; P=0.02) but not in group D (3.0 [2.5 to 3.8] pg/mL; P=0.3).Plasma endothelin concentration is elevated in patients with angina pectoris and angiographically normal coronary arteries, particularly those with left bundle branch block or previous myocardial infarction.

We sought to assess the relation between plasma lipoprotein(a) [Lp(a)] levels, clinical variables and angiographic coronary artery disease (CAD) in patients with chronic stable angina.The relation between plasma Lp(a) levels and the severity and extent of angiographic CAD has not been studied in well characterized patients with stable angina pectoris.We investigated clinical variables, lipid variables and angiographic scores in 129 consecutive white patients (43 women) undergoing coronary angiography for chronic stable angina.Plasma Lp(a) levels were significantly higher in patients with than in those without significant angiographic stenoses (or =70%) (372 mg/liter [interquartile range 87 to 884] vs. 105 mg/liter [interquartile range 56 to 366], respectively, p=0.002). This difference remained significant when patients with mild or severe angiographic disease were compared with those with completely normal coronary arteries (312 mg/liter [interquartile range 64 to 864] vs. 116 mg/liter [interquartile range 63 to 366], respectively, p=0.02). However, subset analysis indicated that this difference achieved statistical significance only in women. Multiple logistic regression analysis indicated that Lp(a) concentration was independently predictive of significant angiographic stenoses (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 2.0 to 42.1, p=0.006) and remained true even after exclusion of patients receiving lipid-lowering treatment (n=27) (OR 10.4, 95% CI 1.1 to 102.9, p=0.05). Lp(a) also had independent predictive value in a similar analysis using mild or severe angiographic disease as the outcome variable (OR 11.8, 95% CI 1.5 to 90.8, p=0.02).Our results indicate that elevated plasma Lp(a) is an independent risk factor for angiographic CAD in chronic stable angina and may have particular significance in women.

The role played by angiotensin in the development of coronary heart disease is a subject of increasing interest. This interest is due to the results of several trials suggesting that treatment with angiotensin I-converting enzyme inhibitors decrease the incidence of clinical manifestations of coronary heart disease. The relationship between angiotensin and coronary heart disease is being analyzed both from basic and clinical approaches. As a result of such investigations, a polymorphism in the angiotensin converting enzyme gene has been described and the role of this polymorphism as a possible risk factor for coronary heart disease has been reported. In this paper the current knowledge about the angiotensin-converting enzyme gene is reviewed and its relationship with coronary heart disease is discussed.

Whether myocardial ischaemia is the mechanism underlying chest pain in patients with angina and normal coronary arteriograms is controversial. We sought to detect the presence of transient myocardial ischaemia using continuous monitoring of coronary sinus blood pH during atrial pacing.We studied 14 patients (eight women, six men, mean age 51 +/- 3 years) with typical exertional angina and normal coronary arteriograms and nine patients with coronary artery disease (two men, seven women, mean age 61 +/- 7 years). Of the 14 patients with normal coronary arteries, eight had a reduced coronary blood flow reserve (2.5-fold increase), 11 had an ischaemic-appearing response to exercise testing, six had reversible perfusion detects on exercise thallium scans and one had resting left bundle branch block. All patients underwent continuous pH monitoring of coronary sinus blood at rest and during incremental atrial pacing (up to 160 bpm). Coronary sinus oxygen saturation and myocardial lactate extraction ratio were also evaluated at rest and at peak pacing. Eleven patients with angina and normal coronary arteries and eight with coronary artery disease had angina during pacing. Both patients with angina and normal coronary arteries (n = 13) and patients with coronary artery disease (n = 9) showed a fall in coronary sinus pH (-0.02 +/- 0.02 vs -0.11 +/- 0.03 pH units, respectively, P0.01). Coronary sinus oxygen saturation expressed as a percentage dropped by 19 +/- 6% in patients with coronary artery disease and by 6 +/- 2% in patients with angina and normal coronary arteriograms (P0.05). Myocardial lactate extraction ratio decreased from 33 +/- 6% to -1.4 +/- 4% in patients with coronary artery disease and from 23 +/- 8% to 20 +/- 8% in those with angina and normal coronary arteriograms. Three patients with angina and normal coronary arteries had a drop in coronary sinus pH0.02 pH units (-0.043 +/- 0.006 pH units) and in coronary sinus oxygen saturation8% (16 +/- 3%) consistent with myocardial ischaemia.Despite severe chest pain and reduced coronary flow reserve after pacing, most patients with angina and normal coronary arteriograms do not show metabolic evidence of myocardial ischaemia.

A point mutation in the factor V gene (FV Q506) renders factor V resistant to inactivation by activated protein C. The frequency of this mutation is known to be significantly increased in patients with thrombophilia. There are conflicting reports on the significance of the polymorphism in patients with ischaemic heart disease. We determined the frequency of FV Q506 in a control Caucasian population, and compared it with 192 Caucasian patients admitted to coronary care and assessed as having myocardial infarction (MI) or unstable angina plus previous MI. There was no significant difference between the two groups. A cohort of 105 asymptomatic Afro-Caribbeans showed a much reduced frequency of the polymorphism.

Cyclosporine has been reported to induce endothelial dysfunction, arterial vasculitis, and accelerated atherosclerosis in experimental models. The purpose of the present study was to evaluate whether low-dose cyclosporine treatment started 1 year after heart transplantation reduces graft coronary artery narrowing compared with conventional cyclosporine doses.One year after heart transplantation, 30 patients were randomly assigned to receive low-dose cyclosporine A (whole-blood polyclonal cyclosporine target trough levels 200 to 400 micrograms/L; group A; n = 15) or usual cyclosporine dosage (target levels 400 to 600 micrograms/L; group B; n = 15). Proximal and distal diameters of the left anterior descending, circumflex, and right coronary arteries were measured by quantitative coronary angiography at baseline (1 year after transplantation) and at 2 and 3 years after transplantation.One major cardiac event occurred in group A (retransplantation) and two in group B (sudden deaths). Moderate to severe allograft rejection (International Society for Heart and Lung Transplantation score 3A or higher) occurred in seven patients in group A and five in group B during the study period. Mean biopsy sample rejection score during the same period was increased in group A compared with that in group B (1.44 +/- 0.63 versus 1.05 +/- 0.59; p0.05). New angiographic evidence of vascular disease was observed in four patients of group A and in one patient of group B. Proximal coronary artery diameter was slightly, although not significantly, reduced in both groups at follow-up angiography. Distal segments showed a significant diameter reduction, which was greater in group A than in group B (-9.7% +/- 1.1% and -5.2% +/- 1.3%, respectively; p0.05).Cyclosporine dose reduction started 1 year after heart transplantation is ineffective in reducing coronary luminal narrowing and may be associated with an increased prevalence of cardiac allograft vasculopathy, especially in the distal coronary tree. Low-dose cyclosporine treatment may slightly enhance the risk of allograft rejection. Further investigations are needed to evaluate the effects of cyclosporine dose reduction started at an earlier time after heart transplantation.

The existence of myocardial damage during percutaneous transluminal coronary angioplasty (PTCA) is controversial. Mild elevations in creatine kinase (CK) activity and its isoenzyme MB (CKMB) in patients who underwent PTCA have been reported. However, other authors failed to confirm these elevations. The low sensitivity of total CK and CKMB activity for the detection of myocardial damage in different settings other than myocardial infarction might account for the controversial findings. Measurement of CKMB isoforms has been shown to have a higher sensitivity than the assessment of CK or CKMB activity for early diagnosis of myocardial infarction. Its sensitivity for the diagnosis of myocardial damage in settings other than infarction is not well described.The aim of our study was two-fold: 1) to assess the incidence of myocardial damage after PTCA and 2) to compare the sensitivity of total CK and CKMB activity and measurement of CKMB isoforms for the detection of myocardial damage.14 patients (11 men and 3 women) with chronic stable angina underwent PTCA. Two electrocardiographic leads were monitored from the beginning of the procedure until 30 minutes after the PTCA. ST segment shifts of at least 1 mm, lasting for more than 1 minute, were considered indicative of myocardial ischemia. The duration of ischemic episodes was measured from the onset of the ST shift until its return to baseline. Total ischemic time, in minutes, was the sum of the duration of every ischemic episode. Blood samples were drawn before PTCA and serially during the first 24 hours post PTCA. CK (normal200 U/l) and CKMB (normal14 U/l) activities were measured. The CKMB isoforms were separated by electrophoresis, measured by densitometric scanning and their ratio calculated (CKMB2/CKMB1 normal1.5).Vessels which underwent PTCA were: the left anterior descending artery (LDA) in 5 patients, the circumflex coronary artery (Cx) in 3 patients, right coronary artery (RCA) in 3 patients, LDA and Cx in 1 patient and Cx and RCA in 2 cases. Eleven patients underwent balloon dilatation, 1 underwent atherectomy (Rotablator) and two patients had treatment with both Rotablator and balloon angioplasty. Ischemic ST segment shifts were found in ten patients and the median of total ischemic time was 13.5 minutes (interquartile range: 2-15 minutes). Total CK and CKMB activities were within the normal range in every patient whereas in 7 patients (50%) the peak ratio CKMB2/CKMB1 was above the normal range. There were no differences in age, sex, number of vessels or lesions treated or in the time of balloon inflation between patients with and without abnormal CKMB2/CKMB1 peak. However, the ischemic time was significantly higher in patients with CKMB2/CKMB11.5 (median 15 vs 0 minutes; p = 0.023).Myocardial damage during PTCA is not an uncommon finding. The CKMB isoforms are more sensitive markers of myocardial damage during PTCA than total CK or CKMB activities.

Our aim was to study the clinical characteristics and evolution of symptoms and left ventricular function in a clinically homogeneous group of patients with syndrome X (angina pectoris, positive exercise test results and normal coronary arteriograms).The syndrome of angina with normal coronary arteriograms is heterogeneous and encompasses different pathogenetic entities. These characteristics may contribute to the existing controversy concerning the cause of syndrome X.We studied 99 patients with syndrome X (78 women, 21 men; mean age +/- SD 48.5 +/- 8 years). All underwent clinical characterization, ambulatory electrocardiographic (ECG) monitoring and echocardiographic assessment of left ventricular function during a follow-up period of 7 +/- 4 years.The syndrome was more common in women than in men. Of the women, 61.5% were postmenopausal before the onset of chest pain. All 99 patients had exertional angina, and 41 also had rest angina. The average duration of episodes of chest pain was10 min in 53% of patients. Sublingual nitrate was effective for relief of pain in 42% of patients. Transient ST segment depression was observed during ambulatory ECG monitoring in 64 patients and myocardial perfusion abnormalities in 22. During the first stage of the exercise test, 32 patients had an increase20 mm Hg in systolic blood pressure and showed an earlier onset of ST depression and shorter exercise time than did patients whose blood pressure increasedor = 20%. During follow-up, no deaths or myocardial infarctions occurred, ventricular function was unchanged (shortening fraction 35.4 +/- 4% vs. 35.6 +/- 3%; heart failure developed in only one patient), systemic hypertension occurred in eight patients and conduction disturbances in four. Symptoms lessened in 11 patients, were variable or unchanged in 64 and worsened in 24.Syndrome X, as defined in this study, occurs predominantly in postmenopausal women. Patients usually have chest pain typical for angina, but conventional antianginal treatment is not often successful. Myocardial perfusion abnormalities occur in a small proportion of patients. Long-term survival is not adversely affected, and deterioration of cardiac function rarely occurs.

Endothelin (ET)-1 is an endothelium-derived constrictor peptide that is believed to play a pathophysiologic role in coronary artery disease. Receptors for this peptide have been identified on human coronary tissue by in vitro autoradiography. A number of available compounds are selective for ETA or ETB receptors. Here we have used radiolabeled PD 151242 and BQ 3020 to identify ETA and ETB binding sites on sections of human coronary vasculature. ETA receptors are associated with smooth muscle of the coronary artery. Smooth muscle ETB receptor binding is weak at proximal portions of this vessel but increases toward distal regions. ETB receptors are exclusively associated with myocardial capillaries. Our results indicate that, apart from ETA-induced vasoconstriction, stimulation of ETB receptors at distal regions of the coronary vasculature and myocardial microvessels may play an important role in the pathophysiology of coronary syndromes.

The binding characteristics and localization of bosentan, an orally active endothelin-1 (ET-1) antagonist, were studied on sections of human coronary artery by in vitro autoradiography. Competition studies were performed to determine the ability of bosentan to prevent [125I]ET-1 binding to the coronary vasculature. The effects of bosentan on ET-1-induced contraction of the coronary artery were also studied in vitro. [3H]Bosentan bound to the tunica media of the human coronary artery. Unlabeled bosentan prevented [125I]ET-1 binding to this vessel in a concentration-dependent manner, and functional studies indicated that bosentan antagonizes ET-1--induced constriction. These data show that bosentan is able to reduce ET-1 binding to the human coronary artery and ET-1 constrictor effects in vitro. Bosentan is an orally active ET-1 antagonist, and these results suggest that this compound might be used to block the effects of locally released ET-1 in pathologic conditions, such as atherosclerosis, angina, and myocardial ischemia.

We investigated the use of creatine kinase (CK) MB isoforms as a marker of myocardial cell injury in a preliminary study of 16 patients with chronic stable angina after successful percutaneous transluminal coronary angioplasty (PTCA) and 25 patients after coronary artery bypass grafting (CABG). Three control groups were studied: apparently healthy volunteers (n = 31), patients undergoing thoracotomy (n = 10), and patients undergoing routine coronary angiography (n = 9). Patients in the PTCA group showed an association between ischemic ST segment changes lasting3 min and a transient increase in the MB2/MB1 ratio; however, all had total CK-MB activity within normal limits. Routine coronary angiography subjects had no significant change in MB2/MB1. In the CABG patients, MB2/MB1 peaked within 1 h after the cross-clamp release and returned to baseline by 24 h postoperatively. The median time to peak MM3/MM1 and total CK-MB activity was 2 and 8 h after reperfusion, respectively, returning to baseline values by 2 and 5 days, respectively. After thoracotomy, MB2/MB1 was increased only in elderly patients (n = 5) with risk factors for ischemic heart disease; total CK-MB activity was increased in only three of these. Apparently, CK-MB isoforms can detect myocardial damage in clinical settings with less overt damage than myocardial infarction.

Clinicians have long suspected that hypertrophied hearts have an inadequate coronary circulation. This clinical suspicion resulted from the observation that a large proportion of patients with left ventricular hypertrophy who have normal coronary arteriograms complain of angina and have ischaemia-like ST segment depression during effort. Hypertension is a known risk factor for the development of coronary artery disease and therefore the presence of angina in a patient with systemic hypertension is usually attributed to obstructive atherosclerotic coronary artery disease. However, angina may occur in hypertensive patients in the absence of coronary stenosis. A limitation of coronary flow reserve is responsible for signs and symptoms of myocardial ischaemia in many of these patients. This article will focus on the role of the coronary microcirculation in the genesis of ischaemia in patients with systemic hypertension who have no obstructive coronary artery disease. It will also briefly discuss other mechanisms potentially responsible for the angina syndrome in patients who have left ventricular hypertrophy but angiographically normal coronary arteries.

BACKGROUND Previous experimental studies have shown that the effect of serotonin on a coronary stenosis depends on whether that stenosis is compliant or fixed. However, the relation between coronary stenosis morphology and the response to serotonin in patients with angina is not known. METHODS AND RESULTS Using computerized quantitative coronary angiography, we studied the effects of intracoronary infusion of serotonin on 38 coronary stenoses of different morphologies (concentric, eccentric, complicated) in 11 patients with stable angina and 4 with variant angina. In response to the maximum infused concentration of serotonin, 100% of complicated stenoses and 50% of concentric stenoses constricted by > or = 20% (P < .05). The magnitude of constriction was greater at eccentric stenoses (32.08 +/- 4.1%) than concentric stenoses (15.68 +/- 2.8%, P < .05) and greater in complicated stenoses (57.69 +/- 7.6%, P < .05) than eccentric stenoses. At complicated stenoses, the constriction was greater (0.85 +/- 0.16 mm, P < .05) than at the adjacent reference segments (0.42 +/- 0.12 mm). It was similar to the reference segment for both concentric and eccentric stenoses. The constriction at the stenosis was greater for irregular (complicated) lesions than for smooth (concentric and eccentric) lesions in both patients with stable (51.8 +/- 7.3% versus 22.5 +/- 4.1%, P < .001) and those with variant (77 +/- 17% versus 28.2 +/- 8.1%, P < .05) angina. There was a weak correlation (r = .39) of magnitude of constriction with stenosis length but not with baseline stenosis severity (minimum diameter). CONCLUSIONS In these patients, the magnitude of the vasoconstrictor response to serotonin at the site of an atheromatous coronary plaque depends on the morphological characteristics of the plaque and is more closely related to irregular contour than stenosis severity or length. This relation suggests that variations in receptor type or density or in the smooth muscle cell response to stimulation may determine the response to locally released serotonin in patients with coronary disease.

Patterns of constriction and dilatation of angiographically normal coronary artery segments and coronary stenoses, in response to vasoactive stimuli, remain speculative.We compared the vasomotor response of angiographically normal and stenotic coronary segments and assessed the effects of stenosis location and morphology on coronary stenosis vasomotion in 52 patients with chronic stable angina (40 men and 12 women) who underwent intracoronary ergonovine or isosorbide dinitrate administration or both. Changes in coronary diameter in response to nitrate and ergonovine were assessed by computed arteriography. The "predicted" change in stenosis diameter was calculated according to the "geometric theory" (based on the vasomotor response of angiographically normal segments adjacent to the lesion and on stenosis severity). Coronary diameter was assessed at baseline and after nitrate administration in 58 stenoses (34 concentric and 24 eccentric), of which 40 were located proximally and 18 distally, and also after ergonovine administration (23 stenoses: 14 proximal and 9 distal, 14 concentric and 9 eccentric).Significant (or = 10% lumen diameter change) vasoconstriction was observed after ergonovine administration in 14 of the 23 stenoses (61%), and significant vasodilation was noted after nitrate administration in 29 of 58 stenoses (50%). A larger proportion of distal (89%) and eccentric (89%) compared with proximal (43%) and concentric (43%) stenoses showed a greater than 10% vasoconstriction after ergonovine administration (P0.05). Vasodilatation after nitrate administration was also observed in a larger proportion of distal (78%) and eccentric (67%) than in proximal (38%) and concentric (38%) stenoses (P0.05). On average, the "observed" changes in coronary diameter in response to nitrate and ergonovine administration were of significantly less magnitude than those "predicted" by the geometric theory in both proximal and distal stenoses and in concentric and eccentric stenoses. In only 17% of stenoses were observed and predicted vasoconstriction similar.Our results suggest that in patients with chronic stable angina, calculations based on the "geometric theory" cannot predict the actual vasomotor response of a stenosis. Factors other than severity, such as baseline coronary tone, stenosis location, and stenosis morphology, appear to modulate stenosis vasomotion in vivo.

Twenty-three patients with sustained, recurrent, symptomatic ventricular tachycardia were treated with oral amiodarone. Initial doses were 600-2000 mg/day and maintenance doses were 200-1200 mg/day. Amiodarone was highly effective in 20 patients (87%), seven of whom had a follow-up of 30 months or longer, including two who were followed for 5 years. Three patients died within the first 45 days, three died suddenly after a follow-up of 33.5 months, and four had a nonarrhythmic death after a follow-up of 25 months. Fifteen patients (65%) had no recurrence during a follow-up of 21.5 months, while five (22%) had isolated recurrences during a follow-up of 32.2 months. The average maintenance dose was 713 mg/day in the 15 patients who did not have recurrences and 375 mg/day in the five patients who had recurrences (p less than 0.001). Both short- and long-term tolerance were excellent and there was not a single case in which treatment had to be discontinued. The main disadvantage of amiodarone was that it took an average of 9.5 days to reach anti-arrhythmic efficacy. The main advantages were prolonged duration of action (recurrences occurred only 15-60 days after the drug was discontinued or the dose lowered, virtual absence of contraindications, doses as high as 2000 mg/day were safe and patient compliance was excellent.

Coronary spasm is an accepted cause of transient myocardial ischemia in patients with variant angina; more recently it has been suggested that dynamic stenoses could also play an important role in the pathophysiology of exertional angina. To test this hypothesis we submitted 31 patients with histories typical of exertional angina to ergonovine testing and compared the electrocardiographic and clinical responses to those observed in seven patients with variant angina. All underwent bicycle ergometric exercise testing and coronary angiographic examination. For all tests, ST segment shifts of 0.1 mV or greater were considered to be diagnostic of myocardial ischemia. In patients with exertional angina, exercise testing produced diagnostic ST segment depression in 21 (68%). Ergonovine testing produced diagnostic ST segment depression in nine (29%). All nine had positive exercise test results and two- or three-vessel disease, yet the test was negative in seven other patients with positive exercise test results and similar angiographic findings. Conversely, in the seven patients with variant angina, results of exercise testing were positive in five (ST segment depression in two, ST elevation in three), while ergonovine produced ST segment elevation in all seven. Coronary angiographic examination showed normal arteries in two, one-vessel disease in four, and three-vessel disease in one. Results of all ergonovine tests were positive at values of rate pressure product much lower than those observed during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate whether ergonovine acts directly on coronary arteries or via remote neurohumoral reflexes, we administered small titrated increments of intracoronary ergonovine up to a maximum cumulative dose of 50 micrograms to 15 patients. In six patients with variant angina (group 1), ischemic electrocardiographic ST changes, angina, and localized coronary spasm (local coronary diameter reduction of 87.8 +/- 18.9% [mean +/- SD]) followed after 6 to 50 micrograms (mean 20.7) cumulative intracoronary ergonovine. In nine patients with atypical chest pain, normal baseline coronary arteriograms, and no evidence of variant angina (group 2), there was no ischemic ST segment change or localized coronary spasm after 6 to 50 micrograms (mean 31.6) intracoronary ergonovine. Coronary diameter of proximal vessels of patients in group 2 was reduced by 16.2 +/- 6.5% and did not differ from the response of nonspastic vessels of comparable size of group 1 (20.5 +/- 13.8%; p = .7). There was no significant difference in the median effective dose values in the dose-response curves of the spastic and nonspastic segments between groups 1 and 2. Ergonovine causes coronary spasm by a direct local effect, which seems to be caused by localized arterial hyperreactivity rather than supersensitivity. Intracoronary delivery may be safer than intravenous administration because negligible drug recirculation may prevent perpetuation of spasm and selective coronary administration can avoid branches with critical stenoses.