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.

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.

Plasma nociceptin/orphanin FQ levels in response to the hyperventilation test in healthy subjects.

In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release. Fifty-six healthy subjects (26 females, mean age 63+/-2 and 30 males, mean age 63+/-3) underwent the hyperventilation test. A hierarchical cluster analysis based on BP response to hyperventilation identified three groups of subjects: group 1 (n=20) with a decrease in BP, norepinephrine (1311.1+/-45.5 fmol/ml versus 900.0+/-55.3 fmol/ml, P<0.01) and nociceptin/orphanin FQ (13.0+/-0.7 pg/ml versus 7.9+/-0.8 pg/ml, P<0.01), group 2 (n=18) without any change in BP and norepinephrine (1133.0+/-31.5 fmol/ml versus 1176.0+/-44.6 fmol/ml), with a decrease in nociceptin/orphanin FQ (12.5+/-3.2 pg/ml versus 7.4+/-0.6 pg/ml, P<0.01) and group 3 (n=18) with an increase in BP, norepinephrine (1216.7+/-50.9 fmol/ml versus 1666.7+/-44.9 fmol/ml, P<0.01) and nociceptin/orphanin FQ values (11.5+/-1.6 pg/ml versus 19.9+/-1.5 pg/ml, P<0.01). Norepinephrine changes in response to hyperventilation in groups 1 and 3 were directly (P<0.01) correlated with those of nociceptin/orphanin FQ. Our results showed that vigorous and prolonged hyperventilation changes plasma nociceptin/orphanin FQ levels due to the direct effects of hypocapnic alkalosis or to different sympatho-adrenergic system responses.

Plasma nociceptin/orphanin FQ levels rise after spontaneous episodes of angina, but not during induced myocardial ischemia.

The aim of our study was to evaluate the effects of repeated episodes of angina and induced myocardial ischemia on plasma nociceptin/orphanin FQ (N/OFQ) levels. Patients with unstable angina (23 with new onset severe angina or accelerated angina and 18 with subacute angina at rest) who had had repeated spontaneous episodes of chest pain in the last week before the study underwent myocardial perfusion single-photon emission computed tomography using adenosine infusion. Twenty subjects without clinical symptoms of angina matched for age, sex and cardiac risk factors served as a control group. N/OFQ levels were significantly (P<0.01) higher in the patients (15.2+/-2.1 pg/ml) than in the control group (8.5+/-2.6 pg/ml). Blood pressure and heart rate did not significantly differ. All patients showed transient adenosine infusion myocardial ischemia that did not induce chest pain or significantly modify plasma N/OFQ levels or hemodynamic parameters. Our findings show that unstable angina is associated with a significant increase in circulating N/OFQ levels unrelated to intervening transient myocardial ischemia or hemodynamic changes. This increase is probably related to the chest pain repeatedly occurring in the course of coronary artery disease, but absent during transient adenosine-induced myocardial ischemia.

Plasma brain natriuretic peptide at rest and after adenosine-induced myocardial ischemia in normotensive and essential hypertensive patients with suspected coronary artery disease.

This study investigated plasma brain natriuretic peptide (BNP) levels in normotensive and hypertensive patients with suspected coronary artery disease during radionuclide pharmacological stress testing. Twenty-seven normotensive patients (15 males, aged 63.0+/-4.5 years and 12 females, aged 63.0+/-4.1 years) and 38 essential hypertensive patients (25 males, aged 63.3+/-3.3 years and 13 females, aged 64.6+/-2.6 years) with chest pain and exercise stress testing inconclusive for coronary artery disease underwent myocardial perfusion single-photon emission computed tomography (SPECT) using adenosine infusion. SPECT identified patients without (16 normotensive and 22 hypertensive) and patients with (11 normotensive and 16 hypertensive) transient perfusion defects. Basal BNP levels in normotensive patients without transient myocardial ischemia (3.1+/-1.2 fmol/ml) were significantly (P<0.01) lower than those observed in normotensive patients with transient ischemia (8.2+/-1.2 fmol/ml), whereas BNP levels in hypertensive patients without transient ischemia (8.2+/-1.0 fmol/ml) did not significantly differ from those in hypertensive patients with transient ischemia (8.1+/-2.0 fmol/ml). No significant difference was found in BNP levels between males or females either in normotensive or hypertensive patients without or with ischemia. Adenosine infusion did not significantly change BNP levels in any subject group without or with myocardial perfusion defects. Our findings show that increases in BNP allow early detection of myocardial ischemia in normotensive patients, but not in hypertensive patients with suspected coronary artery disease. Adenosine-induced myocardial ischemia does not affect BNP production already activated by coronary artery disease in normotensive patients and by hemodynamic changes in hypertensive patients.

Endothelin-1 response to mental stress in early ischemic lesions of the extremities due to systemic sclerosis.

We studied circulating levels of endothelin-1, catecholamines and nitric oxide after a mental arithmetic test in 14 patients with early ischemic lesions of the extremities due to systemic sclerosis and slightly impaired peripheral vascular flow. The test induced an increase (P<0.01) in blood pressure, heart rate, endothelin-1 and catecholamine levels, whereas it did not change the low basal levels of nitric oxide. In healthy subjects (n=20) the test significantly (P<0.01) decreased endothelin-1 without affecting nitric oxide. The low basal levels of nitric oxide and the high plasma concentration of endothelin-1 after psychological stress cannot be explained by an impaired release from the limited ischemic lesions alone. This suggests a diffuse microvascular derangement that aggravates the course of peripheral microvascular ischemic lesions.

Changes in autonomic nervous system activity: spontaneous versus balloon-induced myocardial ischaemia.

AIMS: Cardio-cardiac reflexes may be evoked by both myocardial ischaemia and coronary occlusion itself. The aim of the study was to assess the intrapatient behaviour of autonomic nervous system balance during spontaneous and balloon-induced coronary ischaemia. METHODS AND RESULTS: We studied a group of patients admitted to the coronary care unit for acute coronary syndrome without ST-segment elevation who experienced spontaneous episodes of myocardial ischaemia during bed rest and ECG monitoring. The inclusion criterion was 80-90% lumen stenosis, amenable to angioplasty. Balloon coronary occlusion was performed at 4-6 atmospheres for 120 s. Autonomic nervous system activity was assessed by heart rate variability (HRV) analysis in frequency domain. We analysed 14 episodes of spontaneous ischaemia and 14 episodes of balloon coronary occlusion. During spontaneous ischaemia, HRV showed an increase in the low/high frequencies ratio (11.8 +/- 5.7), as compared to 5 min before and 5 min after (4.4 +/- 2.7 and 3.9 +/- 1.8, respectively) (p = 0.001). The opposite occurred during balloon coronary occlusion (0.8 +/- 0.4 vs. 3.9 +/- 2.0 and 5.1 +/- 2.1, respectively; p = 0.001). CONCLUSIONS: Balloon inflation and occlusion evokes baroreceptor vagal predominance in response to a stretch stimulus of the coronary artery. Conversely, spontaneous occlusion during unstable angina is accompanied by naturally occurring sympathetic activation. Sympathetic activation may have a role in the natural history of the disease.

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.

Opioid peptide response to spinal cord stimulation in chronic critical limb ischemia.

Twelve patients with chronic critical limb ischemia in whom a spinal cord stimulation (SCS) system had been implanted for at least one year had increased microvascular flow and achieved healing of trophic acral lesions. After switching off the system, the clinical improvement persisted for 10 days and the neurohormonal pattern showed high plasma values of beta-endorphin and Met-enkephalin, normal dynorphin B, endothelin-1 and catecholamines, and low nitric oxide. Met-enkephalin levels were further increased (P < 0.01) immediately after switching on the electrical stimulation again. The persistence of high plasma opioid levels after switching off the spinal cord stimulation explains the absence of subjective complaints and suggests an involvement of opioids in the regulation and improvement of the microcirculation.

Effect of pravastatin on myocardial perfusion after percutaneous transluminal coronary angioplasty.

We studied the effect of pravastatin on coronary perfusion after percutaneous transluminal coronary angioplasty. An exercise test performed within 2 weeks after percutaneous transluminal coronary angioplasty induced reversible perfusion defects in 66% of patients taking pravastatin and 64% of those taking placebo. At follow-up, the exercise test still induced reversible perfusion defects in 3% of patients taking pravastatin and 29% of those taking placebo.

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.

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.

Blood pressure response to hyperventilation test reflects daytime pressor profile.

Recent studies show that healthy subjects and patients with moderate hypertension have different pressor responses to hyperventilation, depending on their sympathoadrenergic reactivity. In the present study, we investigated whether a different response to the hyperventilation test is related to differences in the daily blood pressure profiles recorded with noninvasive ambulatory monitoring. Forty-five healthy subjects and 67 patients with essential hypertension of grades 1 and 2 (Joint National Committee VI and World Health Organization) were investigated. Healthy subjects and hypertensive patients responding to hyperventilation with an increase in systolic blood pressure had, during daytime ambulatory blood pressure assessment, peak systolic blood pressure values (146.0+/-5.0 mm Hg, 182.2+/-9.0 mm Hg, respectively) similar to the hyperventilation peak systolic blood pressure values (147.2+/-3.5 mm Hg, 183.0+/-4.7 mm Hg, respectively). Hypertensive patients responding to hyperventilation with a decrease in blood pressure showed clinic systolic blood pressure values (178.4+/-3.2 mm Hg) higher than daytime average ambulatory systolic blood pressure (155.2+/-7.1 mm Hg; P<0.01). Our results indicate that a hyperventilation test yields information on daily peak blood pressure values in healthy subjects and hypertensive patients when it induces a pressor increase and can identify hypertensive patients with the so-called "white coat effect" when it induces a pressor decrease.

beta-Endorphin modulation of pressor response to hyperventilation in hypertensive patients.

After hyperventilation, systolic and diastolic blood pressure (BP) significantly decreased in 14 hypertensive patients (group 1), did not change in 9 (group 2) and increased in 8 (group 3). Basal BP, norepinephrine and dynorphin B levels were higher in group 1 than in groups 2 and 3. The decrease in BP after hyperventilation was associated with a decrease in plasma norepinephrine, Met-enkephalin and dynorphin B and an increase in beta-endorphin. Naloxone abolished the hyperventilation-induced BP and norepinephrine decreases. Our findings indicate that hyperventilation may select hypertensive patients with different sympatho-adrenergic activity and that the increase in beta-endorphin reduces BP response to hyperventilation in patients with high sympatho-adrenergic tone.

Plasma atrial natriuretic factor levels, impaired myocardial contractility and pain intensity in uncomplicated acute myocardial infarction.

To investigate the relationship between plasma atrial natriuretic factor (ANF) levels, impaired myocardial contractility and pain intensity in acute myocardial infarction (AMI) we introduced a procedure estimating the pain component not influenced by the individual emotional reaction to stress, i.e., the original pain sensation. We deduced this pain component during AMI by correcting the personal report of AMI pain, quantified on a VAS, with the emotional reaction of each patient estimated by using a custom-built instrument which applies electrical stimuli of different intensities. Twenty-five patients with uncomplicated AMI were studied. According to plasma ANF levels and AMI pain values reported on the VAS, patients were categorized into 2 groups: pain and no-pain. Plasma ANF levels were significantly lower in pain (35.9 +/- 2.5 pg/ml) than in no-pain patients (70.8 +/- 3.3 pg/ml), whereas the ejection fraction (EF) was significantly higher in pain (49.6 +/- 1.7%) than in no-pain patients (29.3 +/- 1.9%). Within each group, a negative correlation was found between ANF and EF; the corresponding regression lines did not differ significantly in their slopes or intercepts, suggesting that AMI pain does not affect ANF release. The significant negative correlation between original pain sensation and EF found in pain patients indicates that this pain component may be useful to gauge the severity of impaired myocardial contractility during AMI. Moreover, the much higher plasma ANF levels observed in no-pain patients suggest that ANF may be involved in preventing AMI pain.