Fiorella Fontana

Endothelial Function Predicts Future Development of Coronary Artery Disease A Study of Women With Chest Pain and Normal Coronary Angiograms

Background—The prognosis for women with chest pain and angiographically normal coronary arteries is believed to be totally benign. Previous studies, however, did not account for the delay of a decade or so in the development of coronary artery disease that women may experience. Methods and Results—This study assessed long-term follow-up of 42 women with de novo angina, evidence of reversible myocardial perfusion defects on SPECT, and normal coronary angiograms. At recruitment, all women underwent endothelial function testing (intracoronary acetylcholine) during catheterization. Patients were followed up for >10 years. Angiography was repeated at the end of the follow-up in 37 patients. At recruitment, 22 patients developed diffuse vasoconstriction during acetylcholine in the absence of identifiable focal coronary spasm (acetylcholine-positive group). The remaining 20 patients showed vasodilation (acetylcholine-negative group). At the end of follow-up, in the acetylcholine-positive group, 1 patient developed cardiac death, 13 still complained of chest pain, and 8 had remission of symptoms. In the acetylcholine-negative group, all patients showed complete resolution of chest pain beginning 6 to 36 months after baseline assessment. Angiography showed development of coronary artery disease in the 13 symptomatic patients in the acetylcholine-positive group. Conclusions—In women with angiographically normal-appearing coronary arteries, persistence of chest pain over the years often relates to development of coronary artery disease. Endothelial dysfunction in a setting of normal coronary arteries is a sign of future development of atherosclerosis.

Angiotensin-Converting Enzyme Inhibitors and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Cardiac Syndrome X. Role of Superoxide Dismutase Activity

Background—Morbidity of patients with Syndrome X (SX; chest pain and normal coronary angiograms) is high and is associated with continuing episodes of chest pain and hospitalization. Impairment of microvascular endothelial function caused by increased oxidative stress has been suggested to be a mechanism of the disease. Superoxide dismutase (SOD) is the major antioxidant enzyme system of the vascular wall. This study sought to establish whether combination treatment with ACE inhibitors and statins reduces oxidative stress and improves quality of life of patients with cardiac SX. Methods and Results—Forty-five patients with SX were randomly assigned to receive either a combination of ramipril (10 mg/d) and atorvastatin (40 mg/d) or placebo for 6 months. We determined the activity of extracellular SOD and its relation to flow-dependent endothelium-mediated dilation (FMD) and quality of life (exercise capacity and score with Seattle Angina Questionnaire [SAQ]) before and after treatment. After 6 months, patients with SX who received atorvastatin and ramipril had significantly reduced (P =0.001) SOD levels (188.1±29.6 U/mL). No significant changes were seen on placebo (262.9±48.8 U/mL). Reduction of SOD after therapy was negatively correlated with FMD (r =0.38; P =0.01) and positively with total cholesterol (r =−0.56; P <0.001). At follow-up, patients taking atorvastatin and ramipril improved their quality of life both in terms of exercise duration (by 23.46%) and SAQ (by 64.1%). Conclusions—Six months of therapy with atorvastatin and ramipril improves endothelial function and quality of life of patients with SX. Reduced SOD activity may reflect low superoxide anion production. Benefits of these drugs may be related to reduction of oxidative stress.

Meta-Analysis of Selective Serotonin Reuptake Inhibitors in Patients With Depression and Coronary Heart Disease

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.

Effects of selective serotonin reuptake inhibitor therapy on endothelial function and inflammatory markers in patients with coronary heart disease.

We investigated the effect of sertraline on inflammation and endothelial function in patients with coronary heart disease (CHD) and symptoms of depression. One hundred patients with CHD and depression were randomized in a double‐blind fashion to receive sertraline or a placebo. We measured symptoms of depression (Beck Depression Inventory (BDI) score), levels of inflammatory markers (C‐reactive protein (CRP) and interleukin‐6 (IL‐6)), and flow‐dependent endothelium‐mediated dilation (FMD) before and after 20 weeks of treatment. Sertraline treatment significantly reduced the BDI score as compared with both baseline and placebo. Levels of CRP and IL‐6 also decreased after 20 weeks of sertraline treatment, whereas they did not significantly change in the placebo group. There was a significant improvement in FMD in patients on sertraline treatment, whereas there was no change in FMD in the placebo group. Sertraline improves endothelial function and reduces inflammatory markers in patients with CHD and symptoms of depression.

Autonomic nervous system, inflammation and preclinical carotid atherosclerosis in depressed subjects with coronary risk factors.

OBJECTIVES We investigated the relationship between intima-media thickening (IMT) as an expression of preclinical atherosclerosis and coronary risk factors, including the autonomic nervous system and inflammation markers, in depressed subjects free from coronary artery disease. METHODS We studied 391 asymptomatic subjects with a cluster of risk factors, and we evaluated depression using the Beck Depression Inventory. IMT of the common carotid artery was determined by B-mode ultrasound imaging. Traditional risk factors for atherosclerosis were recorded. Markers of inflammation (C-reactive protein, CRP; interleukin 6, IL-6) and heart rate variability (time domain) were determined. RESULTS A total of 90 (23.0%) subjects showed a depressive symptomatology. The average IMT was increased in depressed subjects (0.87+/-0.35 mm) at risk for CHD but free from disease as compared to controls (0.77+/-0.19 mm; p<0.001). Heart rate variability was reduced in depressed subjects. Levels of SDNN (103+/-14 ms) and SDANN (93+/-20 ms) were decreased in depressed subjects as compared to non-depressed subjects (SDNN 113+/-22 ms and SDANN 108+/-35 ms; p<0.001). Subjects with depression had higher CRP (1.14+/-0.65 mg/dl) and IL-6 (2.00+/-0.40 pg/ml) than subjects without depression (CRP: 0.79+/-0.34 mg/dl; IL-6: 1.6+/-0.6 pg/ml; p<0.001, respectively). In multivariate analysis, depression was positively correlated with CRP and IL-6 and IMT, and inversely associated with levels of SDANN. CONCLUSIONS IMT is higher in depressed subjects, indicating that atherosclerosis is accelerated in this sub-group of patients. This is mainly due to patho-physiological mechanisms which connect depression and coronary artery disease, such as inflammation and imbalance of the autonomic nervous system.

Parasympathetic failure and risk of subsequent coronary events in unstable angina and non-ST-segment elevation myocardial infarction

AIM Previous animal studies suggested that vagal tone contributes to tonic dilatation of coronary arteries. We hypothesized that low parasympathetic activity might be among the causes of coronary instability in the setting of acute coronary syndrome without ST-segment elevation. METHODS AND RESULTS We studied 172 consecutive patients. Vagal and sympathetic activities were assessed by time domain measures of heart rate variability. PNN50 <3% was used as a marker of low parasympathetic activity. At 6-month follow-up 32 patients developed coronary events. Coronary events were lower during hospitalization (n=9) than during follow-up (n=23). Extremely low values of parasympathetic activity (pNN50 <3%) were strongly related to subsequent events (P<0.001). PNN50 <3% was found in 56% of patients having adverse events versus 5% of patients who had good outcome. Among patients who had pNN50 <3%, 18 patients (72%) had subsequent coronary events vs seven patients (28%) who had a good outcome. CONCLUSIONS These data show that in acute coronary syndrome without ST-segment elevation, a significant number of patients developing subsequent coronary events have a loss of vagal tone. Simple electrocardiographic variables, as pNN50 <3%, may be of great clinical value in identifying patients at high risk of subsequent coronary events even after apparent clinical stabilization.

Opioid Peptide Modulation of Circulatory and Endocrine Response to Mental Stress in Humans

Healthy subjects were classified according to their percent increase in systolic blood pressure (SBP) after mental arithmetic test (MAT) as low (delta SBP 9.3-15.1%, n = 15) and high (delta SBP 35.1-45.4%, n = 15) responders. During MAT, low responders showed significantly (p < 0.01) increased plasma levels of beta-endorphin, cortisol, catecholamines, and atrial natriuretic factor (ANF) and decreased levels of endothelin-1, whereas high responders showed increased (p < 0.01) levels of Metenkephalin, dynorphin B, and catecholamines. Pretreatment with naloxone hydrochloride enhanced (p < 0.01) SBP, heart rate, noradrenaline, cortisol, and endothelin-1 levels, and reduced (p < 0.01) ANF in low responders in response to MAT, whereas it decreased (p < 0.01) hemodynamic parameters, noradrenaline, and endothelin-1 in high responders. The individual differences in hemodynamic and endocrine responses to MAT may depend on a different activation of the endogenous opioid system.

ENDOGENOUS OPIOID SYSTEM AND ATRIAL NATRIURETIC FACTOR IN NORMOTENSIVE OFFSPRING OF HYPERTENSIVE PARENTS AT REST AND DURING EXERCISE TEST

Objective: To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity. Design: We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system. Methods: We assessed plasma β-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 μg/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction. Results: At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring. Conclusions: Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Pressor Effects of Endogenous Opioid System During Acute Episodes of Blood Pressure Increases in Hypertensive Patients

To investigate the involvement of endogenous opioids in acute increases in blood pressure and their functional relationship with atrial natriuretic factor and endothelin-1, we assessed plasma levels of beta-endorphin, met-enkephalin, dynorphin B, catecholamines, atrial natriuretic factor, and endothelin-1 before and after administration of the opioid antagonist naloxone hydrochloride (8 mg i.v.) in 28 hypertensive patients with a stress-induced acute increase in blood pressure. Ten patients with established mild or moderate essential hypertension and 10 normotensive subjects served as control groups. Opioids, atrial natriuretic factor, and endothelin-I were radioimmunoassayed after chromatographic preextraction; catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Patients with an acute increase in blood pressure (systolic, 203.2 +/- 2.2 mm Hg; diastolic, 108.4 +/- 1.3) had plasma opioid, catecholamine, and atrial natriuretic factor levels significantly (P < .01) higher than hypertensive control patients (systolic pressure, 176.4 +/- 1.0 mm Hg; diastolic, 100.0 +/- 1.4), who had a hormonal pattern similar to that of normotensive subjects (systolic pressure, 123.2 +/- 1.5 mm Hg; diastolic, 75.0 +/- 2.0). Endothelin-1 did not differ in any group. In patients with an acute increase in blood pressure, naloxone significantly (P < .01) reduced blood pressure, heart rate, opioids, catecholamines, and atrial natriuretic factor 10 minutes after administration. Naloxone effects on blood pressure, heart rate, opioids, and catecholamines wore off within 20 minutes. In control groups, naloxone failed to modify any of the considered parameters. Our findings suggest that pressor effects of opioid peptides mediated by the autonomic nervous system during stress-induced acute episodes of blood pressure increase in hypertensive patients.

Endogenous Opioid Peptides and Mental Stress in Congestive Heart Failure Patients

Two groups of patients with acute congestive heart failure (CHF), New York Heart Association class III, presenting elevated plasma values of beta-endorphin, norepinephrine, atrial natriuretic factor (ANF) and endothelin-1, underwent the Mental Arithmetic Test (MAT) during placebo (n = 10) and naloxone hydrochloride (n = 10) infusion. The MAT during placebo significantly (p < 0.01) increased blood pressure, heart rate, plasma levels of Met-enkephalin, dynorphin B, beta-endorphin, norepinephrine, ANF and endothelin-1. The increases in norepinephrine, ANF and hemodynamics after the MAT during naloxone infusion were higher (p < 0.01) than those during placebo; thus, the transient upregulation of the endogenous opioid system during stress in CHF patients attenuates the hemodynamic response by reducing norepinephrine release.