Colomba Falcone

Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease in Nondiabetic Men

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<0.0001) in CAD cases [median (interquartile range): 966 (658–1372) pg/mL] than in control subjects [1335 (936–1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. 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.

Relationship Between Erectile Dysfunction and Silent Myocardial Ischemia in Apparently Uncomplicated Type 2 Diabetic Patients

Background—Erectile dysfunction (ED) is associated with coronary artery disease (CAD). In diabetic patients, CAD is often silent. Among diabetic patients with silent CAD, the prevalence of ED has never been evaluated. We investigated whether ED is associated with asymptomatic CAD in type 2 diabetic patients. Methods and Results—We evaluated the prevalence of ED in 133 uncomplicated diabetic men with angiographically verified silent CAD and in 127 diabetic men without myocardial ischemia at exercise ECG, 48-hour ambulatory ECG, and stress echocardiography. The groups were comparable for age and diabetes duration. Patients were screened for ED using the validated International Index of Erectile Function (IIEF-5) questionnaire. The prevalence of ED was significantly higher in patients with than in those without silent CAD (33.8% versus 4.7%; P =0.000). Multiple logistic regression analysis showed that ED, apolipoprotein(a) polymorphism, smoking, microalbuminuria, HDL, and LDL were significantly associated with silent CAD; among these risk factors, ED appeared to be the most efficient predictor of silent CAD (OR, 14.8; 95% CI, 3.8 to 56.9). Conclusions—Our study first shows a strong and independent association between ED and silent CAD in apparently uncomplicated type 2 diabetic patients. If our findings are confirmed, ED may become a potential marker to identify diabetic patients to screen for silent CAD. Moreover, the high prevalence of ED among diabetics with silent CAD suggests the need to perform an exercise ECG before starting a treatment for ED, especially in patients with additional cardiovascular risk factors.

Soluble Receptor for Advanced Glycation End Products: From Disease Marker to Potential Therapeutic Target

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimers disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimers disease.

Coronary arterial spasm as a cause of exercise-induced ST-segment elevation in patients with variant angina.

Four patients with variant angina pectoris exhibited reproducible exercise-induced chest pain ST-segment elevation. Coronary arterial spasm was documented with arteriography during exerciseinduced 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 ST-segment elevation.

Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension

Objectives Advanced glycation end-products (AGE) may cause vascular stiffening by forming crosslinks through the collagen molecule or by interaction with their cellular transductional receptor (RAGE). A secreted isoform of RAGE, termed soluble RAGE (sRAGE), may contribute to the removal/detoxification of AGE by acting as a decoy. Here we studied the plasma sRAGE levels in hypertensive and normotensive human subjects. We also investigated the relationship between blood pressure parameters and plasma sRAGE concentrations. Design A cross-sectional case–control study. Setting and participants The outpatient clinic of a university teaching hospital. Participants were 147 never-treated patients with essential hypertension (87 men and 60 women, aged 50 ± 10 years) and 177 normotensive controls (118 men and 59 women, aged 49 ± 10 years). Main outcome measures Plasma sRAGE levels determined by enzyme-linked immunosorbent assay, systolic blood pressure (SBP), diastolic blood pressure, pulse pressure (PP) and mean arterial pressure. Results The plasma concentration of sRAGE [median (interquartile range)] was 1206 (879–1658) pg/ml in hypertensive subjects and 1359 (999–2198) pg/ml in normotensive controls (P = 0.002). Simple correlation analysis revealed that log-transformed sRAGE levels were inversely correlated with SBP (r = −0.11; P < 0.001) and PP (r = −0.23; P < 0.001). Forward-selection multiple regression analysis revealed that log-transformed sRAGE levels were determined more strongly by PP (F = 3.127, P < 0.001). Conclusions Plasma sRAGE levels are decreased in patients with essential hypertension and are inversely related to PP. Our results raise the possibility that sRAGE may play a role in arterial stiffening and its complications.

Comparison of Dobutamine Stress Echocardiography, Dipyridamole Stress Echocardiography and Exercise Stress Testing for Diagnosis of Coronary Artery Disease

To compare the value of dobutamine and dipyridamole stress echocardiography with exercise stress testing for the diagnosis of coronary artery disease (CAD), 80 patients with chest pain of suspected myocardial ischemic origin (57 with CAD and 23 without significant CAD) underwent dobutamine stress echocardiography (5 to 40 micrograms/kg/min), dipyridamole echocardiography (0.84 mg/kg over 10 minutes) and bicycle exercise electrocardiography after discontinuation of antianginal treatment. Dobutamine echocardiography and exercise testing revealed a higher overall sensitivity than dipyridamole echocardiography (79 vs 60%, p < 0.005; 77 vs 60%, p < 0.05, respectively); this finding was due to a higher dobutamine and exercise sensitivity in 1-vessel CAD (62 vs 33%, p < 0.05 for both tests), whereas sensitivity of the 3 tests was similar in multivessel CAD. Dobutamine and dipyridamole showed a higher specificity than exercise (83 vs 43%, p < 0.01; 96 vs 43%, p < 0.005, respectively). Diagnostic accuracy of dobutamine echocardiography was higher than that of exercise (80 vs 67%, p < 0.05), whereas the difference with dipyridamole (80 vs 70%) was not significant. In the tests that yielded positive results, double product during exercise was significantly higher than that during dobutamine and dipyridamole echocardiography. No major complications occurred during the tests, but adverse effects were more frequent during dobutamine testing. Thus, dobutamine echocardiography may be superior to dipyridamole echocardiography and exercise electrocardiography for the diagnosis of CAD.

Clinical significance of exercise-induced silent myocardial ischemia in patients with coronary artery disease.

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.

Mental arithmetic stress testing in patients with coronary artery disease

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)

Rapid Heart Rate Increase at Onset of Exercise Predicts Adverse Cardiac Events in Patients With Coronary Artery Disease

Background—We previously demonstrated that reduced vagal activity and/or increased sympathetic activity identify post–myocardial infarction patients at high risk for cardiac mortality. Simple and inexpensive autonomic markers are necessary to perform autonomic screening in large populations. We tested our hypothesis that abnormally elevated heart rate (HR) responses at the onset of an exercise stress test, which imply rapid vagal withdrawal immediately preceding sympathetic activation, might predict adverse cardiac events in patients with documented coronary artery disease. Methods and Results—The HR increase during the first minute (&Dgr;HR1 minute) of a symptom-limited exercise stress test was quantified in 458 patients with documented coronary artery disease. During a 6-year (interquartile range 3.7 to 9.0 years) follow-up, 71 patients experienced adverse cardiac events (21 cardiac deaths, 56 nonfatal myocardial infarctions). In univariate analysis, &Dgr;HR1 minute ≥12 bpm (above the median value of its distribution) predicted both adverse outcome and cardiac death with a hazard ratio of 5.0 (95% CI 2.7 to 9.1; P<0.0001) and of 15.6 (95% CI 2.0 to 118.7; P<0.001), respectively. After adjustment for potential confounders, &Dgr;HR1 minute remained predictive for both combined end points and for cardiac death. Conclusions—A marked HR increase at the onset of a standard exercise stress test is a novel and easily available parameter that could be clinically useful as an independent predictor of adverse cardiac events, including death, among patients with documented coronary artery disease.

Dental pain threshold and angina pectoris in patients with coronary artery disease

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 pulpal 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 pulpal 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 II, 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.(ABSTRACT TRUNCATED AT 250 WORDS)