Grazia Maria Costa

Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function.

AIMS We investigated the relationship between autonomic nervous system balance, systemic immune activation, endothelial dysfunction, and depression in patients free of coronary heart disease (CHD) with increased CHD risk. METHODS AND RESULTS Depression status (Beck Depression Inventory, BDI), selected CHD risk factors, inflammation markers, measures of heart rate variability (HRV), and indices of endothelial function (flow-mediated dilation, FMD) were evaluated in 415 subjects free of CHD, diabetes mellitus, and other life-threatening conditions, with at least two CHD risk factors among the following: older age, male gender, current smoking, hypertension, and dislipidaemia. Overall, 51.7% of the participants were males, aged 57.6 +/- 8.8 years on average (minimum 30, maximum 70). Almost half were hypertensive, 43.9% were dyslipidemic, 30.4% current smokers, and 23.1% showed a depressive symptomatology (BDI > or = 10). Logistic regression showed that, as compared with non-depressed individuals and after adjustment for age, gender, and hypertension, depressive subjects were significantly more likely to be smokers, to have higher total cholesterol, higher C-reactive protein, and Interleukin-6. In addition, depressed subjects were more likely to have altered HRV and their FMD was severely impaired (adjusted odds ratio of 1% increase = 0.72; 95% CI: 0.61-0.86). CONCLUSION Our data indicate an independent association between depression and impaired HRV, systemic inflammatory, and endothelial function. These mechanisms play a role not only in the complication of advanced forms of disease, but also promote and/or accelerate the early disease and connect depression and CHD.

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.

Preventing Left Ventricular Hypertrophy by ACE Inhibition in Hypertensive Patients With Type 2 Diabetes: A prespecified analysis of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT)

OBJECTIVE—In patients with type 2 diabetes, left ventricular hypertrophy (LVH) predicts cardiovascular events, and the prevention of LVH is cardioprotective. We sought to compare the effect of ACE versus non-ACE inhibitor therapy on incident electrocardiographic (ECG) evidence of LVH (ECG-LVH). RESEARCH DESIGN AND METHODS—This prespecified study compared the incidence of ECG-LVH by Sokolow-Lyon and Cornell voltage criteria in 816 hypertensive type 2 diabetic patients of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), who had no ECG-LVH at baseline and were randomly assigned to at least 3 years of blinded ACE inhibition with trandolapril (2 mg/day) or to non-ACE inhibitor therapy. Treatment was titrated to systolic/diastolic blood pressure <130/80 mmHg. ECG readings were centralized and blinded to treatment. RESULTS—Baseline characteristics of the two groups were similar. Over a median (interquartile range) follow-up of 36 (24–48) months, 13 of the 423 patients (3.1%) receiving trandolapril compared with 31 of the 376 patients (8.2%) receiving non-ACE inhibitor therapy developed ECG-LVH (hazard ratio [HR] 0.34 [95% CI 0.18–0.65], P = 0.0012 unadjusted, and 0.35 [0.18–0.68], P = 0.0018 adjusted for predefined baseline covariates). The HR was significant even after adjustment for follow-up blood pressure and blood pressure reduction versus baseline. Compared with baseline, both Sokolow-Lyon and Cornell voltages significantly decreased with trandolapril but did not change with non-ACE inhibitor therapy. CONCLUSIONS—ACE inhibition has a specific protective effect against the development of ECG-LVH that is additional to its blood pressure–lowering effect. Because ECG-LVH is a strong cardiovascular risk factor in people with hypertension and diabetes, early ACE inhibition may be cardioprotective in this population.

PREVENTING LEFT VENTRICULAR HYPERTROPHY BY ACE INHIBITION IN HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES: A PRESPECIFIED ANALYSIS OF THE BENEDICT TRIAL

OBJECTIVE—In patients with type 2 diabetes, left ventricular hypertrophy (LVH) predicts cardiovascular events, and the prevention of LVH is cardioprotective. We sought to compare the effect of ACE versus non-ACE inhibitor therapy on incident electrocardiographic (ECG) evidence of LVH (ECG-LVH). RESEARCH DESIGN AND METHODS—This prespecified study compared the incidence of ECG-LVH by Sokolow-Lyon and Cornell voltage criteria in 816 hypertensive type 2 diabetic patients of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), who had no ECG-LVH at baseline and were randomly assigned to at least 3 years of blinded ACE inhibition with trandolapril (2 mg/day) or to non-ACE inhibitor therapy. Treatment was titrated to systolic/diastolic blood pressure <130/80 mmHg. ECG readings were centralized and blinded to treatment. RESULTS—Baseline characteristics of the two groups were similar. Over a median (interquartile range) follow-up of 36 (24–48) months, 13 of the 423 patients (3.1%) receiving trandolapril compared with 31 of the 376 patients (8.2%) receiving non-ACE inhibitor therapy developed ECG-LVH (hazard ratio [HR] 0.34 [95% CI 0.18–0.65], P = 0.0012 unadjusted, and 0.35 [0.18–0.68], P = 0.0018 adjusted for predefined baseline covariates). The HR was significant even after adjustment for follow-up blood pressure and blood pressure reduction versus baseline. Compared with baseline, both Sokolow-Lyon and Cornell voltages significantly decreased with trandolapril but did not change with non-ACE inhibitor therapy. CONCLUSIONS—ACE inhibition has a specific protective effect against the development of ECG-LVH that is additional to its blood pressure–lowering effect. Because ECG-LVH is a strong cardiovascular risk factor in people with hypertension and diabetes, early ACE inhibition may be cardioprotective in this population.

Depression symptoms and the progression of carotid intima-media thickness: a 5-year follow-up study.

OBJECTIVE Only a few studies have investigated the changes in carotid intima-media thickness (IMT) over time, and uncertainties remain on the underlying mechanisms linking depression and subclinical atherosclerosis. We carried out a prospective cohort study to evaluate whether depression is associated with changes in carotid IMT in subjects with cardiac risk factors but free from coronary heart disease (CHD), and to what extent the atherogenicity of depression can be explained by inflammatory markers and autonomic nervous system dysfunction. METHODS During baseline and follow-up visits: all participants were asked to provide blood samples and compile a structured questionnaire; trained physicians assessed depression symptoms using Beck Depression Inventory (BDI); altered cardiac autonomic tone was measured using time-domain components of heart rate variability in 24 h Holter recordings; measurements of carotid IMT were carried out using B-mode ultrasound image acquisition. Logistic and linear regression analyses were used to adjust for potential confounders and explore potential mediators. RESULTS A total of 381 subjects completed the 5-year follow-up. The mean carotid IMT significantly increased in all subjects but the amount of increase was significantly larger among subjects with depression symptoms: mean IMT increased by 0.16±0.14 mm; 0.31±0.28 mm and 0.61±0.54 mm among the subjects with no, mild and moderate/severe depression, respectively (all p<0.01). The association between moderate/severe depression and IMT increase remained highly significant even after controlling for all the variables considered, however when both IL-6 and CRP were included in multivariate models the regression coefficient decreased by 42.3%. Some of the inflammation markers and autonomic nervous system dysfunction were also independently correlated with carotid IMT increase. CONCLUSION Depression symptoms are independently associated with an accelerated progression of carotid IMT in subjects with CHD risk factors, and inflammation may substantially modulate the association between depression and carotid IMT progression.

Nonobstructive Versus Obstructive Coronary Artery Disease in Acute Coronary Syndrome: A Meta‐Analysis

Background Differences in prognosis and baseline clinical presentation have been documented among patient with acute coronary syndrome and coronary artery disease with obstructive (ObCAD) or nonobstructive arteries (NObCAD), but the rates of events largely varied across single studies. We carried out a meta‐analysis to compare the clinical presentation and prognosis of NObCAD versus ObCAD acute coronary syndrome patients, as well as of the subjects with zero versus mild occlusion. Methods and Results Searches were made in MedLine, EMBASE, Cochrane databases, and proceedings of international meetings up to June 30, 2015. We compared the risk of events of NObCAD versus ObCAD patients using random‐effect meta‐analyses. We also performed meta‐analyses to estimate the yearly or monthly outcome rates in each single group. In NObCAD and ObCAD patients, respectively, the combined yearly rates were as follows: 2.4% versus 10.1% (all‐cause mortality); 1.2% versus 6.0% (myocardial infarction), 4.0% versus 12.8% (all‐cause mortality plus myocardial infarction), 1.4% versus 5.9% (cardiac death), and 9.2% versus 16.8% (major cardiovascular events). In the studies directly comparing NObCAD versus ObCAD, all of the above outcomes were significantly less frequent in NObCAD subjects (with risk ratios ranging from 0.33 to 0.66). No differences in any outcome rate were observed between mild occlusion (1–49% stenosis) and zero occlusion patients. Conclusions NObCAD in patients with acute coronary syndrome has a significantly lower cardiovascular risk at baseline and a subsequent lower likelihood of death or main cardiovascular events. However, these subjects are still at high risk for cardiovascular mortality and morbidity, suggesting potential undertreatment and calling for specific management.

Impact of atrial fibrillation termination mode during catheter ablation procedure on maintenance of sinus rhythm

BACKGROUND Catheter ablation is a common and effective procedure for addressing atrial fibrillation (AF) refractory to antiarrhythmic drugs. AF can be terminated in 3 modes: (1) directly into sinus rhythm (SR); (2) evolving into regular atrial tachycardia (AT) and subsequently into SR; and (3) after direct current (DC) cardioversion if AF persists. Scarce data are available on the relationship between clinical outcomes and termination mode after 1 catheter ablation. OBJECTIVE The purpose of this study was to evaluate for the first time the association between 1-year ablation efficacy and termination mode after repeated catheter ablations in patients presenting with persistent or long-standing persistent AF. METHODS This prospective study involved 400 consecutive patients (age 62.7 ± 7.2 years) who underwent catheter ablation for drug-refractory persistent AF (4.6 ± 2.4 months) using a stepwise ablation approach. RESULTS AF was terminated by radiofrequency application directly into SR in 135 patients; passing through AT into SR in 195 patients; and through DC cardioversion in 70 patients. After 1-year follow-up with repeated Holter monitoring, the percentages of SR maintenance were 72.6%, 80.0%, and 28.6%, respectively (P < .001). Compared with the subjects who were converted directly into SR, the adjusted hazard ratios (HRs) of SR maintenance were significantly lower for those who required DC cardioversion (HR = 0.54; P < .001) and higher for those converted through AT (HR = 1.69; P = .027). The latter association was even stronger in the 104 subjects who required a second procedure (HR = 6.25; P = .001). CONCLUSION Termination of AF through AT during catheter ablation was more effective than both DC shock and direct SR in maintaining stable SR 1 year after both the first and the second procedures.

Stepwise ablation approach versus pulmonary vein isolation in patients with paroxysmal atrial fibrillation: Randomized controlled trial

BACKGROUND Pulmonary vein isolation (PVI) is a central procedure for the treatment of paroxysmal atrial fibrillation (PAF). However, in patients with PAF and structural atrial disease, PVI may fail and cause progressive atrial remodeling, often leading to persistent/permanent atrial fibrillation. OBJECTIVE We performed a prospective, single-blind, 2-center randomized controlled trial to compare the efficacy of PVI alone with that of PVI plus stepwise ablation in achieving sinus rhythm and nonatrial arrhythmia inducibility in patients with PAF refractory to antiarrhythmic therapy. METHODS Patients were randomized to perform a first catheter ablation procedure either through PVI alone or through PVI plus substrate modification in stepwise ablation. Data were recorded at 3, 6, and 12 months after both ablation procedures. Patients who experienced atrial fibrillation/atrial tachycardia (AF/AT) recurrence were encouraged to undergo repeat ablation using the technique of the first ablation procedure. RESULTS A total of 150 patients were enrolled (mean age 62.8 ± 8.7 years; 92 (61.3%) men; 104 (69.3%) hypertensive; AF mean duration 10.7 months), with 75 patients in each group. After 12 months of the first procedure, patients who were converted to sinus rhythm using stepwise ablation showed a significantly lower rate of AF/AT recurrence (26.7%) than did those who were treated using PVI alone (46.7%; P < .001). Similar results were observed in the 52 patients who underwent a second catheter ablation procedure. After adjusting for several potential confounders, the hazard ratio of 12-month AF/AT recurrence after the first ablation procedure was 0.53 (95% confidence interval 0.30-0.91) for those treated using stepwise ablation. CONCLUSION In addition to PVI, stepwise ablation achieving sinus rhythm and nonatrial arrhythmia inducibility has relevantly improved the clinical outcome of the PAF control strategy.

Depression, inflammation and therapy: Which way is right?

We would like to congratulate Hamer M. and colleagues for their interesting article which was recently published in this journal in which tricyclic anti-depressant (TCA) therapy was associated with higher levels of systematic inflammation as compared to patients who were not treated with anti-depressant therapy (Hamer et al., 2011). The authors declared that this association might be a potential mechanism through which anti-depressant medication increased cardiovascular risk (Hamer et al., 2011). However, some issues should be addressed. First, this study is a cross-sectional study which compares the effects of anti-depressant drug therapy on C-reactive protein. We know that a randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on biological measurements or cardiovascular events. In fact, in this article, the evaluation of mental illness and inflammation markers were performed in the same period, and this association might be due to mental illness and not to anti-depressant use. Recent evidence has suggested that depression increased inflammation markers (Pizzi et al., 2010, 2008). The interrelationship between inflammation and depression is well documented and is one of the several patho-physiological mechanisms which might have contributed to an adverse prognosis earlier in depressed patients (Pizzi et al., 2010). When the authors performed the regression analysis, they considered those patients who were treated with any anti-depressant drugs as a reference group. In their reference study, population, about 65% of the patients had no symptoms of psychological distress according to the General Health Questionnaire. This might signify that patients had no mental distress and, consequently, inflammation markers were low whereas 67% of patients who were treated with anti-depressant drugs had symptoms of psychological distress (1). We do not know the exact cause of the elevation of C-reactive protein in the blood patients. Psychological distress or anti-depressant drugs may be involved in inflammatory activation. However, recent reports in the literature support the association of depression and inflammatory activity. Second, in their study, Hamer et al. demonstrated that TCA medication is associated with higher levels of C-reactive protein; this association did not exist in patients with depression who were treated with serotonin reuptake inhibitor (SSRi) (Hamer et al., 2011). A number of other scenarios are possible to explain this association. For example, both depression and TCA might cause inflammatory elevation through separate pathways. Alternatively, only depression might increase C-reactive protein without TCA having a casual role