Can balneotherapy modify microRNA expression levels in osteoarthritis? A comparative study in patients with knee osteoarthritis.

The aim of this study was to evaluate the whole-blood levels of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e in patients with bilateral knee osteoarthritis (OA) after a cycle of mud-bath therapy (MBT). Thirty-two patients with knee OA defined by the ACR criteria were included. Twenty-one patients (MBT group) were daily treated with a combination of local mud-packs at 42 °C and baths in mineral water, at 37 °C for 15 min, for 12 applications over a period of 2 weeks, in addition to standard therapy; 11 patients (control group) continued their conventional treatment alone. Global pain score evaluated by visual analog scale (VAS), WOMAC subscores, and microRNA expression were evaluated at baseline and after 2 weeks. Peripheral whole blood was collected into PAXgene™ Blood RNA tubes, stored at - 80 °C, and total RNA was extracted. The expression of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e was determined by qRT-PCR. After MBT, we observed a statistically significant improvement of clinical parameters and a significant decrease of miR-155, miR-181a, miR-146a (p < 0.001), and miR-223 (p < 0.01) expression levels. No clinical and biochemical modifications were detected in the control group. No significant variations of miR-let-7e were shown in both groups after 2 weeks. In conclusion, MBT can modify the expression of miR-155, miR-181a, miR-146a, and miR-223, which are upregulated in OA. It could be due to the heat stress and the hydrostatic pressure, since some miRNAs were found to be temperature- and mechano-responsive. Further studies are needed to better explain the mechanism of action of MBT and the role of miRNAs in OA.

One-year follow-up of mud-bath therapy in patients with bilateral knee osteoarthritis: a randomized, single-blind controlled trial.

The objective of this prospective parallel randomized single-blind study was to assess that a cycle of mud-bath therapy (MBT) provides any benefits over usual treatment in patients with bilateral knee osteoarthritis (OA). Patients with symptomatic primary bilateral knee OA, according to ACR criteria, were included in the study and randomized to one of two groups: one group received a cycle of MBT at spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group continued their regular care routine alone. Clinical assessments were performed 7 days before enrollment (screening visit), at the time of enrollment (basal time), after 2 weeks, and after 3, 6, 9, and 12 months after the beginning of the study. All assessments were conducted by two researchers blinded to treatment allocation. The primary efficacy outcomes were the global pain score evaluated by Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscore for physical function (W-TPFS). Of the 235 patients screened, 103 met the inclusion criteria: 53 patients were included in the MBT group and 50 in the control group. In the group of patients treated with MBT, we observed a statistically significant (p < 0.001) reduction of VAS and W-TPFS score at the end of the treatment; this improvement was significant (p < 0.05) also at 3 months of follow-up. The control group did not show significant differences between baseline time and all other times. The differences between one group were significant for both primary parameters already from the 15th day and persisted up to the 9th month. This beneficial effect was confirmed by the significant reduction of symptomatic drug consumption. Tolerability of MBT seemed to be good, with light and transitory side effects. Our results confirm that a cycle of MBT added to usual treatment provides a beneficial effect on the painful symptoms and functional capacities in patients with knee OA that lasts over time. Mud-bath therapy can represent a useful backup to pharmacologic treatment of knee OA or a valid alternative for patients who do not tolerate pharmacological treatments.

MicroRNAs in autoimmune rheumatic diseases.

The etiology of autoimmune diseases remains largely unknown. In recent years, besides genetic factors, several studies proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically epigenetic regulatory mechanisms comprise DNA methylation, a variety of histone modifications, and microRNA (miRNA) activity, all of which act upon gene and protein expression levels. In particular it is well known that epigenetic mechanisms are important for controlling the pattern of gene expression during development, the cell cycle, and the response to biological or environmental changes. In the present review a description of the most frequent epigenetic deregulations, in particular the role of miRNAs, in rheumatic autoimmune disorders will be investigated.

Efficacy and safety of anti-TNF-alpha therapy combined with cyclosporine A in patients with rheumatoid arthritis and concomitant hepatitis C virus infection.

This study further expands our previous observation demonstrating the usefulness of combination therapy of anti-TNF-alpha and cyclosporine A in the treatment of rheumatoid arthritis and concurrent hepatitis C virus infection, as well its efficacy and safety in controlling HCV viremia and liver toxicity. Seven patients were included in the study; transaminase levels remained unchanged, HCV RNA serum levels decreased significantly and DAS 28 significantly improved after twelve month follow-up. No side effects were registered.

HCV infection: pathogenesis, clinical manifestations and therapy.

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.

[Viral genotype and HLA class II alleles influence on extra-hepatic manifestations of chronic HCV infection]. / Associazione tra genotipo virale, HLA e manifestazioni extra-epatiche dell'epatite C.

OBJECTIVE: To test whether an association between HCV genotype, HLA class II alleles distribution and extra-hepatic manifestations (EHM ) can be demonstrated in a group of Italian patients with chronic HCV infection . METHODS: Sixty patients affected by HCV infection with EHM were consecutively enrolled. 163 HCV patients without EHM were tested as controls for the prevalence of HCV genotypes, while we referred to literature as to the controls for HLA distribution. HCV-RNA was quantified by a RT-PCR. HLA class II alleles typing was performed using a standard microlymphocytotoxicity assay. We used chi-square or Fisher test (p<0.05 significant). Odds Ratio (OR) was performed by 2X2 contingency table. RESULTS: HCV 2c genotype was found in 63.46% of patients compared to 19.63% of controls (p<0.0001; OR=7.11). Furthermore, it correlated with carpal tunnel syndrome (p=0.03; OR=4.5) and autoimmune thyroiditis (p=0.02; OR=9.2). On the contrary, 1b genotype protected from EHM in toto (p=0.0004; OR=0.21) and particularly from carpal tunnel syndrome (p=0.0014; OR=0.07). Moreover, 3a genotype prevented HCV people from having cryoglobulinemia (p=0.05; OR=0.11). As to HLA, DR6 seemed to facilitate EHM in HCV patients (p=0.041; OR=1.61), while DQ2 (p=0.03; OR=0.5) and DQ3 (p=0.002; OR= 0.5) may play a protective role. In addition, HLA DR3 was associated with cryoglobulinemia (p=0.02; OR=9.5). CONCLUSIONS: According to our findings, 2c genotype can be considered as a major risk factor for developing HCVrelated EHM, while 1b genotype seems to prevent their onset; there are also evidences suggesting that HLA might play a role in chronic HCV infected patients.

Left ventricular volumes during exercise in normal subjects and patients with dilated cardiomyopathy assessed by first-pass radionuclide angiography.

During isotonic exercise, left ventricular (LV) suction and the Frank-Starling law of the heart may have important roles in the enhancement of early LV diastolic filling and in the increase of myocardial contractility, respectively. It remains controversial whether these mechanisms operate in normal subjects or patients with dilated cardiomyopathy. Ten healthy subjects and 10 patients with idiopathic dilated cardiomyopathy who underwent maximal upright bicycle exercise testing were studied. First-pass radionuclide angiography was performed at both rest and peak exercise using a multicrystal gamma camera. In normal subjects, LV end-systolic volume at peak exercise was smaller than during baseline (17 +/- 7 vs 30 +/- 15 ml/m2; p < 0.05), whereas rapid filling volume was greater (52 +/- 16 vs 38 +/- 8 ml/m2; p < 0.01). In patients with dilated cardiomyopathy, both end-systolic (108 +/- 34 to 123 +/- 53 ml/m2; p = NS) and rapid filling (24 +/- 6 to 28 +/- 9 ml/m2; p = NS) volumes did not change from rest to peak exercise. A significant correlation was found between the changes in end-systolic volume at peak exercise and in peak rapid filling rate in normal subjects (r = 0.6; p < 0.05), but not in patients with dilated cardiomyopathy (r = 0.3; p = NS). In normal subjects, end-diastolic volume at peak exercise was similar to that during baseline (78 +/- 14 and 85 +/- 15 ml/m2, respectively; p = NS), whereas in patients with dilated cardiomyopathy, it was greater (164 +/- 50 vs 146 +/- 33 ml/m2; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Peak exercise left ventricular performance in normal subjects and in athletes assessed by first-pass radionuclide angiography.

The role of Frank-Starling law of the heart in determining the increase in cardiac output during exercise in humans is still controversial (e.g., the mechanisms responsible for the enhancement of left ventricular [LV] filling during the shortened diastolic interval). Ten weight lifters, 12 swimmers and 12 sedentary subjects who underwent maximal upright bicycle exercise testing were studied. First-pass radionuclide angiography was performed both at rest and at peak exercise using a multicrystal gamma camera. Compared with resting values, heart rate and cardiac index at peak exercise increased by 101 +/- 16 beats/min (p less than 0.001) and 6.7 +/- 2.8 liters/min/m2 (p less than 0.001) in weight lifters, by 96 +/- 9 beats/min (p less than 0.001) and 9.5 +/- 2 liters/min/m2 (p less than 0.001) in swimmers, and by 103 +/- 9 beats/min (p less than 0.001) and 7.3 +/- 1.8 liters/min/m2 (p less than 0.001) in sedentary subjects. Stroke volume increased by 20.5 +/- 9.8 ml/m2 (p less than 0.001) in swimmers only. End-diastolic volume at peak exercise did not change in weight lifters and in swimmers; it decreased by 8.2 +/- 8.6 ml/m2 (p less than 0.01) in sedentary subjects. A significant correlation was found between the decrease in end-systolic volume and the increase in peak rapid filling rate at peak exercise in all 3 groups (r = 0.65, p less than 0.05 in weight lifters; r = 0.59, p less than 0.05 in swimmers; r = 0.67, p less than 0.05 in sedentary subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral haemorrhage in a patient with systemic lupus erythematosus and vasculitis treated with intravenous immunoglobulins for a long-time and in absence of other risk factors.

Central nervous system involvement has been reported in up to 60% of patients with systemic lupus erythematosus (SLE). Cerebral vasculitis in SLE is rare and its incidence in post-mortem studies has been documented from 7% to 15% of cases. Cerebral haemorrhage is described in 0.4-7% of cases and it is usually due to inherent or iatrogenic factors (e.g., arterial hypertension, thrombocytopenia or anticoagulation). We report a case of cerebral haemorrhage in a patient with SLE and histologically proven cerebral vasculitis, leading to the death of the patient within 12 months. In the patient presented herein, the cerebral haemorrhage was not correlated to possible known causes of these events, apart from the long-term use of intravenous immunoglobulins. The authors discuss the possible role of intravenous immunoglobulin therapy as pathogenetic factor for cerebral vasculitis in this patient.

[New evidences on spa therapy in fibromyalgia]. / Nuove acquisizioni sulla terapia termale nella fibromialgia.

Spa therapy is one of the most commonly used non-pharmacological approaches for many rheumatic diseases. In Fibromyalgia Syndrome (FS) it may be useful for the chronic widespread musculoskeletal pain. Because of the unknown aetiology and the not clear understood pathogenesis, there is no standard therapy regimen for FS. Also the mechanisms of action of spa therapy are not completely known, but most probably the benefits could be derived from mechanical, physical and chemical factors. Muscle tone and pain intensity can be positively influenced by mud packs and thermal baths. The review of international data from 2000 to 2007 confirms that spa therapy should be a valid tool in the multidisciplinary approach of the Primary FS.

[Improvement in the accuracy of diagnosis of ischemic heart disease with simultaneous radioisotope evaluation of regional myocardial function perfusion and an exercise test]. / Incremento di accuratezza nella diagnosi di cardiopatia ischemica mediante valutazione radioisotopica simultanea della funzione e della perfusione miocardica regionali ed unico test ergometrico.

The recently developed myocardial agent methoxy-isobutyl-isonitrile (MIBI), labelled to 99mTc, allows one to evaluate global and regional ventricular function as well as myocardial perfusion by means of a single exercise stress test, significantly increasing diagnostic accuracy for coronary artery disease. Between September 1988 and March 1989, 407 patients with either suspected or already ascertained coronary artery disease underwent simultaneous assessment of regional ventricular function with first pass radionuclide angiography, and of myocardial perfusion with single photon emission computerized tomography, by means of 2 injections of 99mTc-MIBI at rest and at peak of the same exercise test. Out of these patients, 56 (52 men and 4 women, whose mean age was 57 +/- 7 years) underwent coronary angiography within 6 months of radionuclide examination and were included in the study. There were 13 1-vessel, 26 2-vessel and 17 3-vessel disease patients. Thirty-six of them had had a previous (greater than 6 months old) myocardial infarction, on the anterior wall in 16 patients, on the inferior wall in 20. In all patients a computerized bicycle stress test was performed; interruption criteria were ST segment depression greater than or equal to 1 mm in 27 patients (48%), the achievement of a heart rate greater than 85% of maximal age-predicted heart rate in 12 patients (22%) and fatigue in 17 patients (30%). Scintigraphic results were compared to angiographic findings: global sensitivity and specificity of the simultaneous evaluation were 82% and 81%, respectively, vs 95% and 56% of functional results and 85% and 71% of perfusion results, respectively. Regional analysis was also performed, by dividing scintigraphic images into the territories supplied by the 3 main coronary vessels, i.e., left anterior descending artery (LAD), left circumflex artery (LCx) and posterior descending artery (PD). On LAD territory the simultaneous evaluation achieved a sensitivity of 88% and a specificity of 63%, vs 98% and 38% of functional analysis and 88% and 50% of perfusional analysis, respectively. On LCx territory sensitivity and specificity were respectively 71% and 96%, vs 91% and 64% of function, and 77% and 96% of perfusion alone. On PD territory sensitivity was 85%, vs 94% and 91%, respectively; specificity was 73%, vs 55% and 55%, respectively. Combined functional and perfusional analysis achieved a 68% sensitivity in identifying less than or equal to 75% coronary narrowings, and a 90% sensitivity for greater than 90% narrowings.(ABSTRACT TRUNCATED AT 400 WORDS)

[Exponential analysis of the relationship between ST segment depression and heart rate during exercise in patients with ischemic cardiopathy]. / Analisi esponenziale del rapporto fra sottolivellamento del tratto ST e frequenza cardiaca durante sforzo in pazienti con cardiopatia ischemica.

ST segment displacement sensitivity and specificity during exercise in the detection of myocardial ischemia are controversial, even when using mathematical approaches such as a linear regression analysis of ST/heart rate slope. In an attempt to see whether an exponential fit (ST = A-B*exp (-K*RR] of ST/heart rate relation during exercise could increase the diagnostic accuracy of exercise test in the detection of myocardial ischemia, we studied 165 patients (141 men and 24 women, mean age: 56 +/- 10 years) undergoing a simultaneous radionuclide assessment of regional ventricular function and myocardial perfusion at rest and at peak exercise in 4 hours by means of 2 injections of 99mTc-MIBI. Normal radionuclide findings were found in 4 subjects, whereas exercise-induced myocardial ischemia was detected in 90 patients with no evidence of previous myocardial infarction, and in 71 patients with previous myocardial infarction. ST segment depression was present at peak exercise in no normal subject, and in 52.2% and 60.4% of ischemic and infarcted patients, respectively, achieving a sensitivity of 55.9%, a specificity of 100% and a diagnostic accuracy of 57%. A, B and K coefficients of exponential analysis showed a wide variability among patients; however, the algebraic sign of K coefficient was negative in 50% of normal subjects versus 9.9% of patients (chi 2-test: p less than 0.02), thus achieving a sensitivity of 90.1%, a specificity of 50% and a diagnostic accuracy of 89.1% in the detection of exercise-induced myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Exponential fit of QT interval-heart rate relation during exercise used to diagnose stress-induced myocardial ischemia.

The aim of this study was to analyze the dynamic changes of QT interval--heart rate relation during exercise, fitting their reciprocal variations to an exponential formula (QT = A - B.exp(-k.RR], in order to see whether diagnostic contributions might so be derived. The authors studied 139 patients who underwent a simultaneous assessment of regional myocardial perfusion and ventricular function by means of two injections of 99mTc-methoxy-isobutyl-isonitrile at rest and at peak of a submaximal exercise test, using first pass radionuclide angiography with multielement gamma-camera and single photon emission computerized tomography, in order to detect and localize the presence of stress-induced myocardial ischemia. According to radionuclide results, patients were divided into three groups: group A, 7 individuals with no sign of stress-induced myocardial ischemia; group B, 79 patients with evidence of ischemia in 1 (16.5%), 2 (65.5%), or 3 (17.7%) main coronary territories; and group C, 53 patients with previous infarction and evidence of ischemia in other territories. Conventional analysis of the exercise test (greater than or equal to 0.1 mV ST depression) showed a pathological response in no individual of group A, in 34 patients of group B (43%), and in 27 patients of group C (50.9%); overall sensitivity was 46.2%, specificity 100%, and diagnostic accuracy 48.9%. Exponential coefficients A, B, and k showed wide overlap of values among the three groups, although a significant difference was present in mean k values between groups A and B (p less than 0.001), and group C (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Single-day combined evaluation of regional myocardial perfusion and function at rest and peak exercise with 99mTc-MIBI in patients with coronary artery disease.

99mTc-labeled methoxy-isobutyl-isonitrile (MIBI) allows a simultaneous radionuclide assessment of regional heart function and perfusion. In this study the effectiveness of functional and perfusional images obtained with 99mTc-MIBI in the detection of coronary stenoses was compared with that of their combination. We studied 197 patients who underwent coronary angiography and a single-day radionuclide protocol including first pass angiography (multicrystal gamma camera) and single photon emission computed tomography, by means of 2 injections of 99mTc-MIBI at rest and at peak exercise. Fifteen patients had < 50% stenoses, 50 had 1-vessel, 69 2-vessel and 63 3-vessel disease, for a total of 377 pathological major coronary vessels; 129 patients had previous myocardial infarction. Functional images, perfusional tomograms and their combination showed the same sensitivity (98%) and specificity (80%) in detecting coronary patients. Regional sensitivity and specificity of the combined analysis achieved 87% and 82%, respectively, vs. 94% (p < 0.005) and 60% (p < 0.001) of functional images, and 88% (p = N.S.) and 74% (p < 0.05) of perfusional tomograms. Thus, the combined analysis of regional functional and perfusional abnormalities increased significantly the specificity in the detection of coronary stenoses, in comparison with the separate evaluation of function and perfusion, achieving also a slightly higher diagnostic accuracy (85%, vs. 81% and 83%, respectively). The results confirm that a single-day protocol simultaneously assessing regional myocardial function and perfusion with 99mTc-MIBI represents a rapid and effective diagnostic method, that allows the physician to assess the presence and functional importance of coronary stenoses in less than 4 hours.

[Changes in R wave voltage during exercise: are they a sign of changes in ventricular volume or of myocardial ischemia?]. / Modificazioni di voltaggio dell'onda R sotto sforzo: indice di variazione dei volumi ventricolari o di ischemia miocardica?

In an attempt to assess the significance of R wave amplitude changes during exercise in patients with coronary artery disease, we retrospectively analysed radionuclide as well as exercise test results of 147 patients with either suspected or already ascertained coronary artery disease, 126 men and 21 women, whose mean age was 56.0 +/- 9.3 years, 56 of which with previous myocardial infarction (16 on the anterior, 33 on the inferior and 7 on the lateral wall), who underwent a simultaneous evaluation of regional ventricular function by means of first pass angiography with multielement gamma-camera and of myocardial perfusion by means of single photon emission computerized tomography. All patients received 2 iv injections of 99mTc-methoxy-isobutyl-isonitrile at rest and at peak of a computerized bicycle stress test, whose end-points were ST segment depression greater than or equal to 1 mm or the attainment of a heart rate greater than 85% of maximal age-predicted one. R wave amplitude was measured by means of a magnifying lens on an averaged ECG complex, selecting for each patient the precordial lead showing the largest R wave amplitude. Absolute values of left ventricular volumes were computed by means of a standardized method from first pass angiography data. Patients were divided in subgroups according to the presence and to the number of coronary territories with evidence of stress-induced myocardial ischemia at radionuclide study.(ABSTRACT TRUNCATED AT 250 WORDS)

ST/HR slope and improved exercise ECG detection of myocardial ischemia in patients with suspected coronary artery disease.

Predictive values of ST/HR slope and ST-segment displacement during symptom-limited exercise were determined in 85 patients who underwent coronary angiography for suspected coronary artery disease, using perfusional and functional radionuclide images with 99mTc-2-methoxy-isobutil-isonitrile as an index of stress-induced myocardial ischemia. ST/HR slope showed a better sensitivity than conventional stress-induced changes of ST-segment displacement (96% vs. 73%, respectively). In patients with clinical suspicion of coronary artery disease, the main result was the negative predictive value of ST/HR slope when compared with conventional ST-segment displacement (98% vs. 41%). ST/HR slope was unable to perfectly separate patients with different degrees of ischemia, however, subjects without scintigraphic signs of stress-induced ischemia and patients with ischemic impairment in three myocardial regions were correctly identified as distinct populations. In patients with a previous myocardial infarction, no difference was found between the two criteria and a wide overlap of ST/HR slope values was present. The authors conclude that ST/HR slope is useful to detect the rate of change in electric parameters during exercise and might therefore more adequately be used to separate normal from definitely abnormal responses to exercise.

[Variations in QT interval and ventricular volume during exercise-induced myocardial ischemia]. / Variazioni sotto sforzo dell'intervallo QT e dei volumi ventricolari indotte dall'ischemia miocardica.

Aim of this study was to evaluate the possible relationship among myocardial ischemia, left ventricular volume changes and QT interval changes during exercise in patients with coronary artery disease. QT interval, expressed as absolute value, corrected according to Bazett (QTc = aT/RR0.5) and Fridericia (QTf = QT/RR0.33) and calculated by adapting reciprocal changes in QT and heart rate during exercise to the exponential fit proposed by Sarma (QTs = A-B*exp (-K*RR], was compared to the scintigraphic finding of myocardial ischemia and to the changes in left ventricular volumes during exercise. We studied 151 patients (130 men and 21 women, mean age 56 +/- 11 years) with suspected or already ascertained coronary artery disease, who underwent a simultaneous evaluation of regional ventricular function and myocardial perfusion by means of first pass radionuclide angiography (multielement gamma-camera) and computerized tomography, with 2 injections of 99mTc-MIBI at rest and at peak of a computerized bicycle stress test. QT and RR intervals were measured on an averaged ECG complex through a magnifying lens, and the absolute values of left ventricular volumes were computed by radionuclide angiography. According to scintigraphic findings, patients were divided into normal subjects (n = 7) and ischemic patients with (n = 63) and without (n = 81) evidence of a previous myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)