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Objective— The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. Methods and Results— Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower ( P P Conclusions— Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.

Eotaxin (CCL11) is an eosinophil-specific chemoattractant which has been found to be highly expressed at sites of vascular pathology. In the present study, we aimed to evaluate the association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease (CAD). Three hundred and fifty six consecutive patients attending for elective coronary angiography were investigated. Compared with 111 patients without CAD, 245 with CAD showed higher eotaxin concentrations [median (interquartile range): 76.0 (56.3-103.0)pg/ml versus 116.0 (80.5-162.0)pg/ml, respectively; P0.001]. Importantly, a significant Spearman correlation was found between eotaxin levels and the extent score of coronary artery stenosis (r=0.449, P0.001). A stepwise increase in plasma levels of eotaxin was also found depending on the number of50% coronary stenosis: median value 76.0 pg/ml in CAD(-) subjects, 96.0 pg/ml in 1-vessel disease, 128.0 pg/ml in 2-vessel disease, and 129.0 pg/ml in 3-vessel disease (P0.001 for trend). After confounding variables were controlled for, multiple stepwise regression analysis demonstrated that plasma eotaxin was an independent predictor of angiographic extent of CAD (beta=0.426, P0.001). Our data suggest that increased eotaxin levels are associated with the presence of CAD and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis.

Background We have recently reported that homozygosity for the minor A-allele of RAGE (receptor for advanced glycation end products) −374T/A polymorphism may exert a protective effect toward the development of angiographic coronary artery disease (CAD). Here we focused on the putative involvement of this functional RAGE polymorphism on the severity of coronary atherosclerosis as assessed by angiography. Methods In a total of 234 consecutive Caucasian patients with angiographically proven CAD, the severity of coronary atherosclerosis was assessed by the number of diseased vessels (greater than 50% stenosis). Genotyping for the −374T/A variant was performed by means of PCR-RFLPs. Results The mean number of diseased vessels was significantly lower in patients with the AA genotype (1.47±0.68) than in those with the AT or TT genotype (1.88±0.82, p =0.029). After confounding variables were controlled for, the number of diseased vessels remained significantly different in the AA genotype carriers from that in the AT or TT carriers ( p =0.041, ANCOVA). Conclusions Our data suggest that the RAGE −374T/A polymorphism is one of the likely candidate determinants for the genetic variance of disease phenotype in coronary atherosclerosis.

High lipoprotein(a) [Lp(a)] levels and small-sized apolipoprotein(a) [apo(a)] phenotypes have been linked to acute coronary syndromes (ACS). We sought to determine whether Lp(a) concentrations and apo(a) phenotypes may be related to the clinical syndrome of presentation among ACS patients.Two hundred ten ACS patients and 105 controls were enrolled. One hundred thirteen patients presented with acute myocardial infarction (AMI) and 97 with unstable angina pectoris (UAP). Lp(a) concentrations were determined by ELISA and apo(a) isoforms were detected with a high-resolution immunoblotting method.Lp(a) levels and the percentage of subjects with at least one small-sized apo(a) isoform were significantly higher both in AMI patients and in UAP subjects as compared with controls. Among ACS patients, the percentage of subjects with at least one small apo(a) phenotype was significantly higher in patients who presented with AMI than in those with UAP (p0.001). Multivariate logistic regression analysis showed that the presence of at least one small-sized apo(a) isoform was associated with AMI as the patient's clinical syndrome of presentation (OR=2.51, 95% CI: 1.38-4.58, p0.01).Among ACS patients, apo(a) isoforms of low molecular weight were associated with AMI onset. High-resolution apo(a) phenotyping might be helpful to identify individuals at high risk for developing AMI.

Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic molecule formed by the covalent binding of the highly polymorphic apolipoprotein(a) [apo(a)] to apoprotein B-100 of LDL. High Lp(a) concentrations are a recognized genetic risk factor for coronary heart disease (CHD) and have been shown to be related with a familial clustering of ischemic cardiac events. Nevertheless, the association between apolipoprotein(a) isoforms and a positive familial history of CHD has received far less attention. In this report, we explored the distribution of apo(a) phenotypes in 127 CHD subjects with a family history of coronary events and in 92 CHD patients without such a history. Twenty-two apo(a) isoforms were detected by a high-resolution immunoblotting method. In univariate analysis, the percentage of subjects with at least one small sized apo(a) isoform was significantly higher in CHD patients with a positive family history than in those without (P

The disturbances in coronary vasomotor tone have been extensively analyzed, but the exact molecular mechanisms underlying abnormal coronary vasomotion remain to be elucidated. It has been suggested that impaired coronary vasoreactivity can be the expression of a defect in vascular smooth muscle cells. A mouse model of human variant (vasospastic) angina has been recently obtained by disruption of Kir6.1/Kcnj8, a gene coding for a small pore-forming inward rectifier potassium channel. A phenotype resembling variant angina was also reported in mice lacking Sur2, the partner protein of Kir6.1. To better define the role of the smooth muscular ATP-sensitive potassium channels in the pathogenesis of abnormal coronary vasomotion, a complete mutational analysis of Kir6.1/KCNJ8 gene was performed in a series of 18 Italian patients with impaired coronary vasomotility. Polymerase chain reaction and direct sequencing of PCR products were done. No mutations were detected in the sample analyzed, thus suggesting that Kir6.1/KCNJ8 aberrations are not a common cause of abnormal coronary vasomotion in Italians. To the best of our knowledge, this study represents the first mutational analysis of Kir6.1/ KCNJ8 gene in humans. Since major racial differences in the prevalence of abnormal coronary vasomotion have been described, further mutation screenings of Kir6.1/KCNJ8 gene are required to assess its role in the pathogenesis of impaired coronary vasomotility among various ethnic groups.

Patients with diabetes mellitus are at increased risk for CAD; silent ischemia is reported to be frequent in diabetic populations. The aim of the present study was to evaluate the prevalence of silent ischemia in diabetic and nondiabetic patients with assessed CAD.We recruited a total of 618 patients with CAD: 309 were consecutive diabetic patients and 309 were age- and gender-matched nondiabetic patients. Myocardial ischemia was evaluated both during daily life and during exercise testing. Angina pectoris during daily life was more frequent in diabetic than in nondiabetic patients (80% vs. 74%, P0.05). The anginal pain intensity either during daily life or acute myocardial infarction (MI), the prevalence of a previous MI, the extent of CAD and ergometric parameters were similar in diabetics and nondiabetics. Silent ischemia during exercise was documented in 179 (58%) diabetics and in 197 (64%) nondiabetics (nonsignificant, ns). Both diabetics and nondiabetics with silent exertional myocardial ischemia differed from symptomatic subjects in higher heart rate values (P0.01), systolic blood pressure (P0.01), rate-pressure product (P0.001), work load (P0.01) and maximum ST-segment depression at peak exercise (P0.05).The incidence of silent myocardial ischemia during exercise was similar in diabetic and nondiabetic CAD patients. Surprisingly, diabetics showed a higher prevalence of angina pectoris during daily activity than nondiabetics. A significant association between the presence of symptoms during daily life and exercise was observed in both groups. Our results may contribute to the planning of the clinical management of diabetic CAD patients and confirm the individual attitude to pain of CAD patients independent of the presence of diabetes.

Background Overweight is associated with an increased cardiovascular risk which is only partially explained by conventional risk factors. The objective of this study was to evaluate lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in relation to coronary heart disease (CHD) in overweight subjects. Methods A total of 275 overweight (BMI ≥ 27 kg/m2) subjects, of which 155 had experienced a CHD event, 337 normal weight subjects with prior CHD and 103 CHD-free normal weight subjects were enrolled in the study. Lp(a) levels were determined by an ELISA technique and apo(a) isoforms were detected by a high-resolution immunoblotting method. Results Lp(a) levels were similar in the three study groups. Overweight subjects with CHD had Lp(a) concentrations significantly higher than those without [median (interquartile range): 20 (5–50.3) versus 12.6 (2.6–38.6) mg/dl, P < 0.05]. Furthermore, overweight subjects with CHD showed a higher prevalence of low molecular weight apo(a) isoforms than those without (55.5% versus 40.8%, P < 0.05) and with respect to the control group (55.5% versus 39.8%, P < 0.05). Stepwise regression analysis showed that apo(a) phenotypes, but not Lp(a) levels, entered the model as significant independent predictors of CHD in overweight subjects. Conclusions Our data indicate that small-sized apo(a) isoforms are associated with CHD in overweight subjects. The characterization of apo(a) phenotypes might serve as a reliable biomarker to better assess the overall CHD risk of each subject with elevated BMI, leading to more intensive treatment of modifiable cardiovascular risk factors.

The relationship between lipoprotein(a) [Lp(a)] and restenosis after intracoronary stent implantation has never been analysed in diabetic patients. The aim of the present prospective study was to evaluate whether Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes are predictors of restenosis after elective stent implantation in Type 2 diabetic patients with de novo lesions of coronary arteries. We recruited 102 Type 2 diabetic patients with a new lesion successfully treated with elective placement of one or two Palmaz-Schatz stents. Follow-up angiography was scheduled at 6 months or earlier if clinically indicated. Seven patients were lost to the follow up. Among 95 patients enrolled, restenosis was present in 37 (38.9%) and absent in 58 (61.1%). The restenosis group showed Lp(a) levels higher than the nonrestenosis group (25.1+/-14.4 vs. 21.3+/-14.6 mg/dl), but the difference was not significant. The restenosis group had a percentage of subjects with at least one apo(a) isoform of low molecular weight (MW) significantly greater than the nonrestenosis group (75.7% vs. 55.1%; P.05). A multiple logistic regression analysis showed that presence of multivessel disease (risk relative [RR]: 5.83; 95% confidence interval [CI]: 1.21-28.15; P.05) was the only predictor of restenosis after stent placement in diabetic patients. Lp(a) and apo(a) polymorphisms did not enter the model as predictive variables. Our study shows that the presence of multivessel disease is a predictor of restenosis after intracoronary stent implantation in diabetic patients. On the contrary, Lp(a) and apo(a) polymorphisms do not appear to be reliable markers of restenosis in patients with Type 2 diabetes mellitus.

Background: The relationship between lipoprotein(a) and restenosis after intracoronary stent implantation has been analysed by two specific studies, but the role of apoliprotein(a) polymorphism was not considered. The aim of the present prospective study was to evaluate whether lipoprotein(a) levels and apolipoprotein(a) phenotypes are predictors of restenosis after elective stent implantation in patients with de novo lesions of coronary arteries. Methods: We recruited 182 patients with a new lesion successfully treated with elective placement of one or two Palmaz–Schatz stents. Follow-up angiography was scheduled at 6 months or earlier if clinically indicated. Nine patients were lost to the follow up. Among 173 patients enrolled, restenosis was present in 52 (30.0%) and absent in 121 (70.0%). Results: Lipoprotein(a) levels were higher in the restenosis than in the nonrestenosis group (29.5±17.2 versus 27.4±20.2 mg/dl), even if the difference did not attain statistical significance ( P =0.067). The restenosis group had a percentage of subjects with at least one apolipoprotein(a) isoform of low molecular weight significantly greater than the nonrestenosis group (82.7 versus 66.9%; P =0.035). A multiple logistic regression analysis showed that multiple stenting (RR: 4.01; CI 95%: 1.65–13.91; P =0.004), presence of diabetes (RR: 3.96; CI 95%: 1.67–9.37; P =0.002) and presence of multivessel disease (RR: 2.71; CI 95%: 1.19–6.16; P =0.017) were predictors of restenosis after stent placement. Lipoprotein(a) and apolipoprotein(a) polymorphism did not enter the model as predictive variables. Conclusions: Our study confirms that multiple stenting, diabetes and multivessel disease are powerful predictors of restenosis after intracoronary stent implantation. On the contrary, lipoprotein(a) and apolipoprotein(a) polymorphism do not appear to be reliable markers of restenosis in patients with stent implantation.

Background There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients. Methods 1,971 type 2 diabetic patients without clinical signs of cardiovascular diseases and with a negative history of CAD were consecutively evaluated. Among them, 179 patients showed electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction. These 179 patients were subjected to a non-invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients with a highly positive stress testing (n = 19) or a positive scintigraphy (n = 74), 75 showed an angiographically documented CAD (CAD group). Seventy-five patients without CAD (NO CAD group) were matched by age, sex and duration of diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour ambulatory ECG and a stress echocardiogram were negative for CAD. Results Lipoprotein(a) levels (22.0 ± 18.9 versus 16.0 ± 19.4 mg/dl; p < 0.05), homocysteine levels (13.6 ± 6.6 versus 11.4 ± 4.9 mmol/l; p < 0.05) and the percentage of subjects with at least one small apolipoprotein(a) isoform (70.7% versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65; 95%CI:3.05–24.55), microalbuminuria (OR:6.16; 95%CI:2.21–17.18), smoking (OR:2.53; 95%CI:1.05–6.08), HDL (OR:3.16; 95%CI:1.28–7.81), homocysteine (OR:2.25; 95%CI:1.14–4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01–6.79) were independent predictors of asymptomatic CAD. Conclusions The present investigation shows an independent association of Lipoprotein(a), homocysteine and apo(a) polymorphism with silent CAD. Other studies are needed to establish whether these parameters are suitable for CAD screening in diabetic patients.

In patients with uncomplicated diabetes, there is low probability of finding significant coronary artery disease (CAD) by noninvasive tests. Therefore, screening for its presence is not justified, and it is important to find reliable predictors of silent CAD to identify patients with uncomplicated diabetes for further screening. The relationship between lipoprotein(a) [Lp(a)], apolipoprotein(a) [apo(a)] polymorphism, and silent CAD has never been studied. We investigated the association of Lp(a) and apo(a) polymorphism with angiographically documented asymptomatic CAD in type 2 diabetic patients without evident complications.A total of 1,323 diabetic patients without any clinical and electrocardiographic evidence of CAD were evaluated. Of 121 patients with highly positive results of exercise electrocardiography (ECG) (n = 30) or positive results on exercise thallium scintigraphy (n = 91), 103 subjects showed angiographically documented CAD (CAD group). Of 1,106 patients with negative results on exercise ECG, 103 subjects without CAD (NO CAD group) were selected and matched by age, gender, and duration of diabetes to patients in the CAD group. In patients in the NO CAD group, results of exercise ECG, 48-h ambulatory ECG, and stress echocardiography were negative for CAD.The CAD group had higher Lp(a) levels (21.7 +/- 17.7 vs. 15.2 +/- 19.0 mg/dl; P = 0.0093) than the NO CAD group, and a percentage of subjects had at least one small apo(a) isoform (68.9 vs. 29.1%; P = 0.0000) higher than the NO CAD group. Logistic regression analysis showed that apo(a) phenotypes (odds ratio [OR] 8.13, 95% CI 3.65-21.23), microalbuminuria (5.38, 2.44-11.88), smoking (2.72, 1.31-5.64), and Lp(a) levels (2.41, 1.15-5.03) were predictors of asymptomatic CAD.Our investigation reports the first evidence of an independent association of Lp(a) and apo(a) polymorphism with asymptomatic CAD. This suggests that Lp(a) levels and apo(a) phenotypes could be used together with other risk factors as markers of asymptomatic CAD in patients with diabetes.

OBJECTIVES The aim of the study was to examine the inflammatory cytokines in patients with myocardial ischemia to evaluate whether silent ischemia patients exibit any particular cytokine pattern. BACKGROUND Silent myocardial ischemia is frequently observed in patients with coronary artery disease. Various endogenous mechanisms control a patient’s perceived intensity of pain. Among them, the inflammatory process and the related cytokine production are known to modulate the threshold for activating the primary afferent nociceptors. METHODS Seventy-eight patients with reproducible exercise-induced myocardial ischemia were studied: 34 symptomatic patients, with rest and/or stress angina; 44 asymptomatic patients, with no symptoms during daily life activities or during positive exercise stress test. Venous blood samples were taken from all patients to evaluate the expression of CD11b receptors both on neutrophils and monocytes. Frozen plasma samples (at −80°C) were used to quantify the anti-inflammatory (interleukin-4 and -10, transforming growth factor-β) and the proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1β and -6). RESULTS In asymptomatic patients lower CD11b receptor expression and higher concentration of anti-inflammatory cytokines were observed. Proinflammatory cytokine production was similar in the two groups. CONCLUSIONS The data suggest that an “anti-inflammatory pattern” of cytokine production correlates with silent ischemia and that the immune and inflammatory system activation may be crucial for angina symptoms.

Aims We investigated whether in Type 2 diabetic patients lipoprotein(a) (Lp(a)) levels and apolipoprotein(a) (apo(a)) polymorphism are associated with angiographically documented coronary artery disease (CAD). We also examined whether there are differences in the distributions of Lp(a) levels and apo(a) phenotypes between CAD patients with and without diabetes. Methods A hundred and seven diabetic patients with CAD, 274 diabetic patients without CAD, 201 non-diabetic patients with CAD, and 358 controls were enrolled. Results Diabetic patients with CAD showed Lp(a) levels (21.2 ± 17.7 vs. 15.1 ± 17.8 mg/dl; P = 0.0018) and a percentage of subjects with at least one apo(a) isoform of low molecular weight (MW) (67.2% vs. 27.7%; P = 0.0000) significantly greater than diabetic patients without CAD. Multivariate analysis showed that in diabetic patients Lp(a) levels and apo(a) phenotypes were significantly associated with CAD; odds ratios (ORs) of high Lp(a) levels for CAD were 2.17 (1.28–3.66), while ORs of the presence of at least one apo(a) isoform of low MW were 5.35 (3.30–8.60). Lp(a) levels (30.2 ± 23.7 vs. 21.2 ± 17.7 mg/dl; P = 0.0005) and the percentage of subjects with at least one apo(a) isoform of low MW (87.0% vs. 67.2%; P = 0.0001) were significantly higher in CAD patients without than in those with diabetes. Conclusions Our data suggest that Lp(a) levels and apo(a) phenotypes are independently associated with CAD in Type 2 diabetic patients; thus both these parameters may be helpful in selecting diabetic subjects at high genetic cardiovascular risk. However, Lp(a) levels and apo(a) polymorphism seem to be cardiovascular risk factors less important in diabetic than in non-diabetic subjects. Diabet. Med. 18, 589–594 (2001)

Near-Infrared Spectroscopy (NIRS) can be employed to monitor local changes in haemodynamics and oxygenation of human tissues. A preliminary study has been performed in order to evaluate the NIRS transmittance response to induced forearm ischaemia in patients with coronary artery disease (CAD). The population consists in 40 patients with cardiovascular risk factors and angiographically documented CAD, compared to a group of 13 normal subjects. By inflating and subsequently deflating a cuff placed around the patient arm, an ischaemia has been induced and released, and the patients have been observed until recovery of the basal conditions. A custom NIRS spectrometer (IRIS) has been used to collect the backscattered light intensities from the patient forearm throughout the ischaemic and the recovery phase. The time dependence of the near-infrared transmittance on the control group is consistent with the available literature. On the contrary, the magnitude and dynamics of the NIRS signal on the CAD patients show deviations from the documented normal behavior, which can be tentatively attributed to abnormal vessel stiffness. These preliminary results, while validating the performance of the IRIS spectrometer, are strongly conducive towards the applicability of the NIRS technique to ischaemia analysis and to endothelial dysfunction characterization in CAD patients with cardiovascular risk factors.

Objectives. The purpose of this study was to investigate lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] phenotypes in relation to age of onset of coronary heart disease (CHD).Background. Although Lp(a) levels have been extensively analyzed in relation to age of CHD, apo(a) phenotypes have not.Methods. Three hundred and thirty-five consecutive CHD patients were enrolled and grouped according to their age of CHD onset (

Abstract An association between a decreased responsiveness to varying painful stimuli and arterial hypertension both in animals and in humans has been documented. The relationship between essential hypertension and silent myocardial ischemia in coronary artery disease (CAD) populations is not well understood. The aims of this study in CAD patients with and without essential hypertension were (1) to determine dental pain threshold and reaction to tooth pulp stimulation and (2) to ascertain whether hypertensive CAD patients differ from normotensive ones in reactivity to pain. This study involved 182 patients who were affected by mild and moderate hypertension (G1) and 174 normotensive patients (G2). The inclusion criteria were reproducible exercise-induced myocardial ischemia, CAD documented at angiography, and dental formula suitable for pulp test. All patients underwent an ergometric stress test, coronary angiography, and pulp test. Our CAD hypertensive patients showed a lower prevalence of angina during daily life (64.8% in G1 versus 81.6% in G2, P P P

BACKGROUND Besides hypertension, several cardiovascular risk factors can play a role in the development of coronary heart disease (CHD) in hypertensive patients. Lipoprotein(a) [Lp(a)] is an important and independent cardiovascular risk factor, but its role in the development of CHD in hypertensives has not been studied. OBJECTIVE To investigate whether or not Lp(a) levels and isoforms of apolipoprotein(a) [apo(a)] are predictors of CHD in patients with essential hypertension. METHODS Lp(a) levels and apo(a) polymorphism were evaluated in 249 patients with essential hypertension, in 142 non-hypertensive patients with CHD and in 264 healthy controls. RESULTS Hypertensives with CHD (n = 61) had Lp(a) levels [19 (range 0.5-73.5) versus 7 mg/dl (range 0-83.5), P < 0.001] and a percentage of apo(a) isoforms of low (< 655 kDa) relative molecular mass (RMM, 59.2 versus 25.9%, P < 0.001) higher than did those without CHD (n = 188). Moreover, there were more subjects with at least one apo(a) isoform of low RMM in the subgroup of patients with CHD than there were in that of those without CHD (80.3 versus 30.8%, P< 0.001). Lp(a) levels and apo(a) polymorphism did not differ significantly between hypertensive and non-hypertensive patients with CHD. Stepwise regression analysis indicated that high Lp(a) levels (P= 0.002073) and particularly the presence of at least one apo(a) isoform of low RMM (P < 0.000001) are strong predictors of CHD in hypertensive patients. CONCLUSIONS Our data show that high Lp(a) levels and the presence of at least one apo(a) isoform of low RMM are strong and independent genetic risk factors for CHD in hypertensive patients. These findings suggest that Lp(a) and apo(a) isoforms should be assessed together with other cardiovascular risk factors to establish the overall CHD risk status of each hypertensive patient

FUNCTIONAL POLYMORPHISMSOF THE RECEPTOR FOR THE ADVANCED GLYCATION END PRODUCT (RAGE) PROMOTER GENE INFLUENCE SUSCEPTIBILITY TO INFLAMMATORY BOWEL DISEASE (IBD) R. Ciccocioppo∗ ,1, V. Imbesi 1, E. Betti 1 , A. Gallia 1 , V. Boccaccio1 , S. Bozzini 2 , C. Falcone2 , M. Guerci 1, A. Di Sabatino1 , G.R. Corazza1 11Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Universita degli Studi di Pavia, Pavia, Italy; 22Centro Interdipartimentale per la Ricerca in Medicina Molecolare e Sezione di Cardiologia, Istituto di Cura Citta di Pavia; Universita degli Studi di Pavia, Pavia, Italy

Respiratory sinus arrhythmia has been described in heart transplanted subjects. In order to investigate the mecha nisms involved in the generation of this condition in the transplanted heart and its evolution after surgery, graded exercise was performed (0–75 W in 25 W steps) on a cycle ergometer by 41 subjects (mean age 44 years) who had undergone heart transplantation 28 months (range 3–60) earlier and by six age matched-control subjects. R-R interval, respiratory signal, O2 consumption (VO2 and CO2 production (VCO were measured. Respiratory sinus arrhythmia was assessed by the autoregressive power spectrum of the R-R interval and respiration. All subjects reached the anaerobic threshold (heart transplants: 60% at 50 W, 40% at 75W Controls: 150 W). In control subjects, the respiratory sinus arrhythmia was higher than in heart transplanted subjects (5·80 ± 0·30 vs 1·45 ± 0·16 ln ms2) and it decreased significantly (4·66 ± 0·30 In ms2 P

To investigate the level of mucosal expression and the involvement of the receptor for the advanced glycation end products (RAGE) in delayed apoptosis and tumor necrosis factor (TNF)-α production in Crohn's disease (CD).Surgical and endoscopic specimens from both inflamed and non-inflamed areas of the ileum and/or colon were collected from 20 and 14 adult CD patients, respectively, and used for the assessment of RAGE expression by means of immunohistochemistry and western blotting analysis. Normal tissues from 21 control subjects were used for comparison. The same polyclonal anti-human RAGE antibody (R and D System) was used in all experimental conditions. RAGE staining was quantized by a score including both the amount of positive cells and intensity of immunoreactivity; cellular pattern was also described. The effects of RAGE blocking on apoptotic rate and TNF-α production were investigated on immune cells freshly isolated from CD mucosa and incubated both with and without the muramyl dipeptide used as antigenic stimulus. Statistical analysis was performed via the test for trend, with regression models to account for intra-patient correlations. A 2-sided P0.05 was considered significant.In inflamed areas, RAGE expression in both the epithelial and lamina propria compartments was higher than control tissues (P = 0.001 and 0.021, respectively), and a cluster of positive cells were usually found in proximity of ulcerative lesions. Similar results were obtained in the lamina propria compartment of non-inflamed areas (P = 0.025). The pattern of staining was membranous and granular cytosolic at the epithelial level, while in the lamina propria it was diffuse cytosolic. When evaluating the amount of protein expression by immunoblotting, a significant increase of both surface area and band intensity (P0.0001 for both) was observed in CD inflamed areas compared to control tissue, while in non-inflamed areas a significant increase was found only for band intensity (P0.005). Moreover, a significantly lower expression in non-inflamed areas in comparison with inflamed areas was found for both surface area and band intensity (P0.0006 for both). Finally, RAGE blocking largely affects both the apoptotic rate of mucosal cells (towards an increase in both non-inflamed and inflamed areas of P0.001 and0.0001, respectively) and TNF-α secretion (towards a decrease in both non-inflamed and inflamed areas of P0.05 and0.01, respectively), mainly in the presence of antigenic stimulation.RAGE is up-regulated in CD, especially in inflamed areas, and it appears to play a role in the mechanisms involved in chronic inflammation.

The first experiences of nonpharmacological treatment of ectopic atrial tachycardia (EAT), common atrial flutter (AFl), and atrial fibrillation (AF) were performed by surgical techniques. Many studies reported a very high success rate on the use of catheter ablation with radiofrequency current for the treatment of supraventricular arrhythmias; and recently, various preliminary reports are dedicated to the treatment of EAT, AFl, and AF with that source of energy. To our knowledge 108 cases of EAT treated by catheter ablation of the ectopic focus are reported in the literature with a success rate superior to 90%. On the basis of our personal experience regarding 11 cases (4 of right atrium EAT and 7 of left) we discuss here the essential role of unipolar leads derived from the mapping catheter to select the target for radiofrequency applications. Two hundred and one cases of AFl tested by catheter ablation were previously reported. The majority of them (> 80%) were successfully treated with radiofrequency. Some working groups performed the procedure as the basis of electrophysiological findings, while others preferred an anatomical approach applying radiofrequency energy at the isthmus lying between the coronary sinus ostium and the tricuspid ring, near the vena cava orifice. On the basis of these assumptions, we obtained 83% of final success in 12 cases of AFl treated by radiofrequency. Finally, we discuss the problem related to the modulation of atrioventricular (AV) nodal conduction during AF. In our laboratory, five cases with chronic AF and very fast ventricular response were treated with radiofrequency with a posterior septal approach. In all patients, we obtained very encouraging results with a constant decrease of ventricular rate (from 137 +/- 33 to 69 +/- 14 beats per minute). All cases treated by modulation of AV nodal conduction demonstrated an appropriate chronotropic response to the variations of the functional state that persists during the follow-up. More experience with longer follow-up and accurate pre- and postprocedure evaluations are needed to finalize the most appropriate technique of radiofrequency applications in these cases.

Silent myocardial ischemia can be defined as a condition of discrepancy between the supply of oxygen to the myocardium and the metabolic demand thereof to such an extent as to induce biochemical mechanical and electric alterations which are characteristic of myocardial ischemia but cause no pain. Such a situation can be transient (a silent transient ischemic attack) and end with the metabolic and functional recovery of the affected myocardial fibrous cells, or continue until it causes irreversible damage, finally leading to necrosis (silent myocardial infarction). A flow which is chronically reduced but nonetheless sufficient to keep the myocardium vital (hibernating myocardium) [1] is very often not associated with angina but with signs and symptoms of an alteration of the pump function: the term ‘silent chronic ischemia’, however, is questionable in view of the probable metabolic reset, which casts doubts on the definition of ischemia itself.

To assess the prevalence of abnormal coronary vasoconstriction in stable exertional angina and to evaluate whether the presence of increased coronary tone may have therapeutic implications, we studied 83 consecutive patients with typical exertional angina, positive response to exercise stress testing and documented coronary artery disease. Abnormal coronary vasoconstriction was induced by a hyperventilation test in 16 patients (group I) while the remaining 67 had a negative response (group II). No differences were observed between the 2 groups with regard to clinical, exercise and angiographic data. All group I patients and 16 patients in group II repeated hyperventilation and exercise tests after the administration of dihydropyridine-type calcium antagonists (7 patients nifedipine, 9 patients felodipine). After treatment 15 of 16 group I patients had a negative response to the hyperventilation test. The total exercise duration was significantly increased (278 +/- 183 vs 554 +/- 248 seconds; p less than 0.001) with higher values of rate pressure product at peak exercise (168 +/- 47 vs 235 +/- 67 mm Hg x beats/min/100; p less than 0.0025). In group II no significant differences were observed between pre- and posttreatment values for total exercise duration (244 +/- 210 vs 308 +/- 243 seconds) and rate pressure product at peak exercise (170 +/- 46 vs 188 +/- 56 mm Hg x beats/min/100). These data show that the hyperventilation test can be used to select a subset of patients with stable exertional angina and detectable abnormal coronary vasoconstriction who will improve their exercise tolerance with coronary vasodilator treatment.

There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients. 1,971 type 2 diabetic patients without clinical signs of cardiovascular diseases and with a negative history of CAD were consecutively evaluated. Among them, 179 patients showed electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction. These 179 patients were subjected to a non-invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients with a highly positive stress testing (n = 19) or a positive scintigraphy (n = 74), 75 showed an angiographically documented CAD (CAD group). Seventy-five patients without CAD (NO CAD group) were matched by age, sex and duration of diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour ambulatory ECG and a stress echocardiogram were negative for CAD. Lipoprotein(a) levels (22.0 ± 18.9 versus 16.0 ± 19.4 mg/dl; p < 0.05), homocysteine levels (13.6 ± 6.6 versus 11.4 ± 4.9 mmol/l; p < 0.05) and the percentage of subjects with at least one small apolipoprotein(a) isoform (70.7% versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65; 95%CI:3.05–24.55), microalbuminuria (OR:6.16; 95%CI:2.21–17.18), smoking (OR:2.53; 95%CI:1.05–6.08), HDL (OR:3.16; 95%CI:1.28–7.81), homocysteine (OR:2.25; 95%CI:1.14–4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01–6.79) were independent predictors of asymptomatic CAD. The present investigation shows an independent association of Lipoprotein(a), homocysteine and apo(a) polymorphism with silent CAD. Other studies are needed to establish whether these parameters are suitable for CAD screening in diabetic patients.

Eight patients with coronary artery disease performed a cold pressor test (CPT) and hand-grip isometric exercise (HG) before and 20 min following sublingual administration of nifedipine. CPT performed before nifedipine did not change coronary blood flow determined by the thennodilution technique, but increased coronary resistance (control 0.95 ± 18 mm Hg/ml/min; CPT 1.17 ± 0.30, P < 001). Nifedipine prevented the increase of coronary resistance induced by CPT (control after nifedipine 0.74 ± 018 mm Hg/ml/min; CPT after nifedipine 0.76 ± 0.19, NS) and the absolute value of coronary resistance was significantly lower when CPT was repeated after nifedipine. In contrast, during HG, coronary blood flow increased while coronary resistance did not change (control 0.94 ± 0.10 mm Hg/ml/min; HG 0.99 ± 0.23, NS). When HG was repeated after nifedipine, coronary blood flow was greater and coronary resistance lower than during the test performed before nifedipine. The drug's ability to block inappropriate coronary vasoconstriction induced by cutaneous cold stimuli and to increase coronary blood flow during isometric exercise further substantiates its usefulness in the treatment of patients with coronary artery disease.

Out of 3,900 patients who performed an exercise test at our clinic, 3 patients demonstrated a walk-through phenomenon (WTP), defined as the occurrence of mild angina during the first stages of exercise with disappearance of chest pain at higher workloads despite a greater pressure-rate product. 2 patients had variant angina, one with normal coronary arteries and the other with single vessel disease, while the third patient had stable exertional angina and a severe coronary artery disease with occlusion of two major vessels retrogradely filled by collateral channels. Repeat exercise tests failed to reproduce constantly the WTP in the 2 patients with variant angina, while in the third patient the phenomenon was repeatedly induced by exercise testing. Thus the WTP, although rarely found during exercise testing, can be observed in two subsets of patients. In variant angina the WTP is not reproducible and is probably due to coronary spasm, spontaneously subsiding during exercise. In patients with exertional angina and severe coronary artery disease, the WTP can be repeatedly observed during exercise and is likely to be secondary to a delayed vasodilation of collateral vessels. The clinical characteristics of the patients and the response to repeat exercise tests may be useful in identifying the different pathogenetic mechanisms.

In order to determine individual variability of ischaemic threshold on different days, 18 patients with exertional ischaemia at low workload were studied. All patients performed two exercise tests during different days in the morning and three on the same day at 9 am, 2 pm and 5 pm. The test performed in the morning on different days resulted in a significant difference in the mean values of rate pressure product at the ischaemic threshold as a consequence of individual variability observed in 10 patients. In 8 of these patients the differences were greater than 4000 mmHg beats min-1. Two patients showed respectively, 1 and 5 negative exercise tests despite the greater values of rate pressure product reached. Only 3 patients showed circadian variation of the ischaemic threshold; in these 3 patients variations of rate pressure product at the ischaemic threshold were also observed between different days. These data indicate that in patients with exertional ischaemia at low workload the rate pressure product at the ischaemic threshold shows considerable variability between tests performed on different days.

Two patients complained of chest pain while at rest and during physical activities. However there seemed to be no direct relation between exertional angina and an increasing level of work performed, indicating that these patients had a variable threshold of angina during exercise. In one patient spontaneous chest pain was associated with transient S-T segment changes in precordial leads, and during coronary arteriography the administration of ergonovine induced spasm of the left anterior descending coronary artery. The other patient showed S-T segment elevation in inferior leads during an ergonovine-induced anginal attack and coronary arteriography revealed a spontaneous spasm of the right coronary artery. In both patients repeated exercise tests yielded different results, because the chest pain and S-T segment depression occurred at different work loads with large differences in heart rate-systolic blood pressure product. It is concluded that a variable threshold of angina during exercise is a clinical manifestation in some patients with vasospastic angina and is probably due to the difference in coronary arterial tone at the onset of exercise.

Exercise-induced silent myocardial ischemia is a frequent feature in patients with coronary artery disease. The purpose of this study was to compare the clinical and angiographic characteristics of 269 patients who complained of chest pain during an exercise test (group I) with those of 204 who developed exercise-induced silent myocardial ischemia (group II). Group I patients more frequently had anginal symptoms of class III and IV of the Canadian Cardiovascular Society than did group II patients, who had milder symptoms (p less than 0.001). The only angiographic difference observed between the two groups was a slightly but significantly higher left ventricular end-diastolic pressure in group II patients (p less than 0.05), who also showed a longer exercise duration (p less than 0.01) with a higher heart rate-systolic pressure product (p less than 0.01) and more pronounced ST segment depression at peak exercise (p less than 0.001). Moreover, ventricular ectopic beats during exercise were more frequently observed in group II patients (p less than 0.05). Coronary bypass surgery was performed in 45% of patients of group I and in 24% of patients of group II (p less than 0.05). Survival curves of medically treated patients did not show any statistically significant difference between the two groups. Thus, although patients with a defective anginal warning system may have more pronounced signs of myocardial ischemia and a greater incidence of ventricular arrhythmias during exercise, their long-term prognosis is not different from that of patients who are stopped by angina from the activity that is inducing myocardial ischemia.

Thirty-five of 70 patients with vasospastic angina at rest complained of chest pain during exercise or during usual daily activity. In 22, the angina threshold was described as variable during exercise: that is, the amount of exertion that induced angina was not always the same. In 12 patients with variable threshold exertional angina, 3 exercise tests performed in the morning on different days yielded different results, because chest pain and ischemic electrocardiographic changes occurred at different work loads with a wide range in heart rate-systolic pressure product. Two patients, in whom great cardiac vein flow was measured during exercise before and after taking nifedipine, tolerated heavier work loads after receiving the drug, with a more marked increase in flow during exercise. It is concluded that variable threshold exertional angina can be objectively demonstrated by repeat exercise tests in patients with vasospastic angina. Variability of the angina threshold may be due to a functional mechanism that causes myocardial ischemia in addition to the increased myocardial metabolic requirements provoked by exercise. Because in such patients fluctuations in coronary arterial tone play an important role in determining the response to exercise, calcium antagonistic drugs, which lower coronary tone and prevent the occurrence of coronary spasm, are effective in increasing exercise capacity.

Regional myocardial blood flow during exercise was determined using the thermodilution technique in 2 patients suffering from both spontaneous and exertional chest pain. In both cases we observed that effort-related anginal attacks were due to coronary spasm with sudden reduction of regional left ventricular blood flow. In 1 patient the exercise-induced ST-segment elevation in the anterior leads was accompanied by a reduction of flow in the great cardiac vein. In the second patient the exercise-induced ST-segment depression in the lateral leads was accompanied by a reduction of coronary flow in the area supplied by the circumflex artery. In 1 patient, nifedipine was effective in prolonging exercise tolerance by preventing the occurrence of coronary spasm and by increasing blood supply to the ischemic region during exercise.

One hundred eight consecutive patients with proved coronary artery disease and reproducible exercise-induced myocardial ischemia were studied. During repeated exercise testing, 52 patients (Group I) had myocardial ischemia in the absence of pain (silent ischemia) whereas 56 patients (Group II) experienced anginal symptoms in the presence of electrocardiographic signs of ischemia. A puipal test was carried out in all patients using an electrical dental stimulator commonly used in dentistry. Electrical current was delivered in increasing intensity from 10 to 500 mA, and the dental pain threshold and the reaction of the patients to maximal stimulation were determined.During the puipal test, 71.2% of the patients in Group I did not experience pain, even at maximal stimulation (threshold 0), 11.5% were sensitive at threshold I (10 to 200 mA) and 17.3% felt pain at threshold II (210 to 500 mA). In Group 11, 69.7% of the patients complained of dental pain at the low intensity test current (threshold I), 10.7% at threshold II and 19.6% at threshold 0. In Group I, 71.2% of patients did not have discomfort (reaction −), even at maximal stimulation, 21.1% had a mild reaction (reaction +) and 7.7% had an intense painful reaction (reaction ++). In Group II, 80.4% of patients were sensitive to the pulpar test (67.9% reported intense painful sensation at maximal stimulation, 12.5% had a mild reaction); 19.6% of patients had no reaction.The two groups of patients were similar with respect to age, sex and angiographic features. Patients in Group I (silent ischemia) achieved a significantly longer duration of exercise (p < 0.01) in the presence of more pronounced ST segment depression (p < 0.001) and had a higher rate-pressure product at peak exercise (p < 0.01).The significant difference in dental pain threshold (p < 0.0005) and reaction (p < 0.0005) in patients with and those without anginal symptoms during exercise testing suggests that a generalized, nonsegmental hyposensitivity to pain may partly explain the lack of symptoms in patients with silent myocardial ischemia.

Objectives. This study in patients with coronary artery disease (CAD) sought to 1) determine the dental pain threshold and reaction to tooth pulp stimulation; 2) correlate the clinical, ergometric and angiographic features of patients with and without pain during percutaneous transluminal coronary angioplasty (PTCA) to pulpal test response; 3) verify whether reactivity to dental pulp stimulation could help to identify patients particularly prone to perceiving angina during myocardial ischemia. Background. Silent myocardial ischemia is frequently observed in patients with CAD. Higher pain thresholds have been documented in asymptomatic subjects, suggesting a generalized hyposensitivity to pain. Methods. Eighty-six consecutive male patients with reproducible exercise-induced myocardial ischemia and CAD documented by angiography underwent PTCA. A pulpal test was performed in all patients by means of an electrical tooth pulp stimulator. Results. Seventy-one patients (82.6%) with and 15 (17.4%) without angina during daily life were studied. During the pulpal test, 57 patients (66.2%) reported dental pain, whereas 29 (33.7%) were asymptomatic, even at maximal stimulation of 500 mA. The study cohort was classified into two groups according to the presence (58 patients [group 1]) or absence (28 patients [group 2]) of angina during myocardial ischemia induced by PTCA. Ergometric variables, extent of CAD, presence of ST segment elevation during PTCA, number of inflations, inflation time and maximal inflation pressure were similar in the two patient groups. Dental pain was provoked by pulpal test in 81% of patients with and 36% of patients without symptoms during PTCA (p = 0.0004). The absence of dental pain even at maximal tooth pulp stimulation (500 mA) was observed in 11 (18.9%) patients in group 1 and 18 (64.2%) in group 2. Patients who were asymptomatic during PTCA had a higher mean dental pain threshold, lower mean threshold reaction and lower mean maximal reaction than those who were symptomatic during both PTCA and the pulpal test. Conclusions. A correlation between the prevalence of symptoms during pulpal test, daily life, exercise-induced myocardial ischemia and PTCA was found. A higher dental pain threshold and lower reactivity characterized those subjects who were prone to silent ischemia both during daily life and during PTCA. Ergometric variables, extent of CAD and techniques used during PTCA were unrelated to the tendency to perceive pain during myocardial ischemia. Response to the pulpal test and the presence of symptoms during daily life were highly related to the presence of angina during PTCA.

To verify whether beta-endorphin plasma levels influence the presence of anginal symptoms, 74 consecutive male patients were studied. All patients had previously documented coronary artery disease and reproducible exercise-induced myocardial ischemia. Thirty-five patients (Group I) had a history of angina and reported anginal symptoms during exercise stress testing; 39 patients (Group II) were asymptomatic and had documented silent myocardial ischemia during exercise. Baseline beta-endorphin plasma levels were measured in blood samples taken before exercise stress testing and analyzed by beta-endorphin-I125-RIA Kit-NEN (a radioimmunoassay method). The mean baseline beta-endorphin plasma level was 22.5 +/- 19 pg/ml in patients with anginal symptoms compared with 43.7 +/- 28 pg/ml in asymptomatic patients (p less than 0.001). Baseline blood pressure and heart rate-systolic pressure (rate-pressure) product at baseline and at ischemia threshold (1 mm ST segment depression) were similar in the two groups. Group II patients had a longer exercise duration (p less than 0.01), more pronounced ST segment depression (p less than 0.001) and a higher peak rate-pressure product (p less than 0.01). The extent of coronary artery disease, ejection fraction and left ventricular end-diastolic pressure were similar in the two groups. These data suggest that higher baseline beta-endorphin plasma levels may play a role in the decreased sensitivity to pain in patients with silent myocardial ischemia. In addition, different beta-endorphin levels can be associated with a different sensitivity to pain.

To investigate the mechanism by which nifedipine improves exercise tolerance in patients with coronary artery disease, we studied 14 patients with stable exertional angina and left anterior descending artery disease by measuring great cardiac vein flow (GCVF) and calculating anterior regional coronary resistance (ARCR) during exercise before and after sublingual administration of 20 mg of nifedipine. After nifedipine seven patients (group I) had no increase in exercise capacity and showed a similar magnitude of ST segment depression at peak exercise, while another seven patients (group II) had prolonged exercise duration (p less than .001) with less ST segment depression at peak exercise (p less than .01). Such effects were achieved despite a significant increase in double product, an indirect index of myocardial oxygen consumption. In group I patients no significant change was induced by nifedipine in GCVF or in ARCR either at rest or at peak exercise. In contrast, in group II patients nifedipine significantly increased GCVF at rest (p less than .05) and at peak exercise (p less than .001). Moreover, resting ARCR was decreased (p less than .01) and remained significantly lower at peak exercise (p less than .01) compared with the prenifedipine values. These data show that nifedipine may increase GCVF and decrease ARCR at rest and at peak exercise in patients with left anterior descending artery disease. Such increase in myocardial oxygen supply seems the most likely mechanism by which nifedipine may improve exercise capacity in patients with stable exertional angina.

Three patients complained of spontaneous and exertional chest pain, both associated with S-T segment depression in anterior electrocardiographic leads. In each, coronary spasm was demonstrated on coronary arteriography during a spontaneous attack of pain. Coronary arteriograms taken during exercise-induced angina did not show evidence of spastic obstruction; this suggests that exercise-induced chest pain and S-T segment depression were secondary to the increase in oxygen requirements rather than to a sudden decrease in coronary blood flow. Thus, two pathogenetic mechanisms coexisting in the same patient may cause chest pain associated with subendocardial ischemia.

Four patients with variant angina pectoris exhibited reproducible exercise-induced chest pain and ST-segment elevation. Coronary arterial spasm was documented with arteriography during exercise-induced ST-segment elevation (three patients) or after intravenous administration of ergonovine maleate (one patient). Our observations show that in patients with variant angina exercise can trigger coronary arterial spasm, thus inducing anginal pain and ST-segment elevation.

To investigate the significance of hyperventilation-induced ST segment depression, 329 consecutive patients with angina and documented coronary artery disease who underwent hyperventilation and exercise tests during pharmacologic washout were studied. The hyperventilation test induced ST segment depression in 79 patients. In 36 of these 79 patients; the electrocardiographic changes occurred early during overbreathing (Group I), whereas in 26 they occurred late during recovery (Group II). Seventeen patients developed ST segment depression both during overbreathing and during recovery (Group III).Group I patients had a higher frequency of history of angina during exercise, multivessel disease and lower tolerance to exercise as compared with patients in Group II. In Group I, the rate-pressure product at the time to onset of ST depression during overbreathing was similar to that during exercise (152 ± 24 versus 148 ± 42; p = NS), whereas in Group II the rate-pressure product at the time to onset of ST depression during recovery was comparable with that under control conditions (104 ± 30 versus 98 ± 27; p = NS) and far less than that required to produce ischemia during exercise (104 ± 30 versus 201 ± 56; p < 0.001). In nine Group III patients, the acute administration of propranolol prevented the early hyperventilation-induced ST segment depression, whereas nifedipine abolished the delayed hyperventilation-induced ST segment depression.These findings suggest that early hyperventilation-induced ST segment depression is due to increased oxygen demand in patients with poor coronary reserve and may be prevented by beta-adrenergic blockers, which are useful for lowering oxygen consumption. Delayed hyperventilation-induced ST segment depression, occurring in patients with a high incidence of angina at rest and longer exercise duration, is probably related to a primary reduction in coronary blood flow and may be prevented by calcium antagonists that abolish abnormal coronary vasoconstriction.

A mental arithmetic stress test was performed by 122 consecutive patients undergoing diagnostic coronary arteriography. Twenty-two patients showed significant ST segment abnormalities during the test (group 1). Of these patients, 20 performed a bicycle exercise test, which was positive in all of them. Seventy patients had a negative mental stress but a positive exercise test (group 2), whereas in 30 patients both tests were negative (group 3). There were no patients with a positive mental stress test and a negative exercise test. Mental stress induced a significant increase in heart rate and systolic blood pressure in the three groups of patients. Group 1 patients, however, achieved higher values of double product during mental stress and had a shorter exercise duration than group 2 and group 3 patients. The extent of coronary artery disease (CAD) was similar in groups 1 and 2, while group 3 patients had a significantly lower prevalence of two or more vessel disease. To investigate the pathogenetic mechanism of mental stress-induced myocardial ischemia, great cardiac vein flow was measured by means of the thermodilution technique in four patients with isolated left anterior descending artery disease, who showed ST segment depression in anterior leads in response to mental stress. In three patients without vasospastic angina the calculated coronary resistance decreased during mental stress, as a result of a normal vasodilatory response to the increased myocardial oxygen consumption induced by the test. By contrast, in one patient with variant angina, coronary resistance increased suggesting coronary vasoconstriction. Our findings demonstrate that mental arithmetic stress testing may induce significant ST segment abnormalities in patients with CAD.(ABSTRACT TRUNCATED AT 250 WORDS)