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Background Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). Objectives The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). Methods Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. Results Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell’s C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell’s C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. Conclusions Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Background Complication rates of paravalvular aortic regurgitation (PVR) and permanent pacemaker insertion remain high in patients undergoing trans-catheter aortic valve insertion for severe aortic stenosis. The spatial distribution of calcium between individual aortic valve leaflets, and its potential role in these complications is gaining interest. We aimed to assess the accuracy of individual aortic valve leaflet calcium quantification, and to determine its effect on the frequency of these complications. Methods This was a retrospective study of 251 patients who underwent trans-catheter aortic valve insertion using the Evolut RTM valve. The off-line Terarecon software platform was used for Agatston scoring the short axis views. Results There was a correlation between the sum of the individual leaflet and the total aortic valve calcium score. There was a univariate association between an increase [per 100 Agatston unit (AU)] in both right coronary leaflet (RCL) and left coronary leaflet (LCL) calcium with the risk of PVR. There was an association between an increase in LCL calcium score (per 100 AU) and need for post-implantation balloon aortic valvuloplasty (BAV). There was no association between individual leaflet calcification on the risk of permanent pacemaker insertion. Conclusions This study supports the idea that a quantifiable and reproducible method of individual valve leaflet calcification score may serve as an independent risk factor for paravalvular regurgitation, beyond visual assessment of asymmetry. However, the same may not be true of spatial calcium distribution and permanent pacemaker implantation (PPI).

Left ventricular hypertrophy (LVH) is an independent risk factor for clinical events (CE), and regression of LVH is associated with reduction of cardiovascular risk. However, whether a continuous relationship between reduction of LVH and risk of CE exists has not been investigated.Randomized clinical trials evaluating LVH at baseline and reporting quantitative LVH changes and CE, stroke or new onset heart failure) were included. Meta-regression analysis was performed to test the relationship between changes in LVH and incidence of the composite outcome (all-cause death, MI, stroke or new onset heart failure) and between changes of LVH and occurrence of each component of the composite outcome. Analysis of potential confounder variables was also performed.Fourteen trials including 12,809 participants and reporting 2259 events were included. Follow-up ranged from 0.50 to 5 years, with mean 1.97 ± 1.50 years. Mean age was 62 ± 5 years and 52% of patients were women. The composite outcome was significantly reduced by active treatments (OR: 0.851, IC: 0.780 to 0.929, p0.001), as well stroke (OR: 0.756, IC: 0.638 to 0.895, p0.001) whereas MI and new onset heart failure were not significantly reduced by treatments. LVH changes did not predict the reduction of CE. No significant influence on the association of baseline patients and studies characteristics was found.A significant continuous relationship between LVH changes and CE could not be demonstrated in hypertensive patients, independently on the technique or drug used. Ad hoc designed studies should further explore the relationship between LVH modification and outcomes in hypertensive patients.

SummaryVentricular arrhythmias are frequent in patients with systemic sclerosis and may result in sudden cardiac death. We report the case of a patient with systemic sclerosis and recent syncopes in whom induction of unstable sustained ventricular tachycardia of 2 different morphologies accompanied by syncopal event was demonstrated at the electrophysiological study. He was then implanted a 3rd generation implantable cardioverter defibrillator and remained thereafter asymptomatic. We suggest that aggressive testing is warranted in systemic sclerosis patients with suspected malignant arrhythmias to identify candidates for defibrillator implantation and prevent sudden deaths.

Objectives The goal of this study was to explore the association between changes in B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) plasma levels and risk of hospital admission for heart failure (HF) worsening in patients with chronic HF. Background The relationship between BNP and NT-proBNP plasma levels and risk of cardiovascular events in patients with chronic HF has been previously demonstrated. However, it is unclear whether changes in BNP and NT-proBNP levels predict morbidity in patients with chronic HF. Methods The MEDLINE, Cochrane, ISI Web of Science, and SCOPUS databases were searched for papers about HF treatment up to August 2013. Randomized trials enrolling patients with systolic HF, assessing BNP and/or NT-proBNP at baseline and at end of follow-up, and reporting hospital stay for HF were included in the analysis. Meta-regression analysis was performed to test the relationship between BNP and NT-proBNP changes and the clinical endpoint. Sensitivity analysis was performed to assess the influence of baseline variables on results. Egger's linear regression was used to assess publication bias. Results Nineteen trials enrolling 12,891 participants were included. The median follow-up was 9.5 months (interquartile range: 6 to 18 months), and 22% of patients were women. Active treatments significantly reduced the risk of hospital stay for HF worsening. In meta-regression analysis, changes in BNP and NT-proBNP were significantly associated with risk of hospital stay for HF worsening. Results were confirmed by using sensitivity analysis. No publication bias was detected. Conclusions In patients with HF, reduction of BNP or NT-proBNP levels was associated with reduced risk of hospital stay for HF worsening.

Molecular imaging is an innovative and promising approach in cardiology for functional characterization of atherosclerosis. Nuclear, ultrasound and magnetic resonance imaging have been used for assessment of atherosclerosis of large and small arteries in several clinical and experimental studies. Positron Emission Tomography with fluorodeoxyglucose can measure metabolic activity and vulnerability of atherosclerotic plaques, identifying individuals at risk of future cardiovascular events. Magnetic resonance imaging can quantify carotid artery inflammation using iron oxide nanoparticles as contrast agent. In addition, macrophage accumulation of iron particles in atherosclerotic plaques may allow monitoring of inflammation during drug therapy, whereas contrast-enhanced ultrasound imaging may detect plaque neovascularization. Currently, technical factors, including cardiac and diaphragmatic motion and small size of coronary vessels, limit routine application of these techniques for coronary imaging. Purpose of this review is to describe state of the art and potential areas of clinical applications of molecular imaging of atherosclerosis.

Takotsubo cardiomyopathy (TTC) is a unique acute syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant coronary artery disease, occurring mostly in postmenopausal women after emotional and/or physical stress. Given the nonspecific symptoms and signs, a high clinical index of suspicion is necessary to detect the disease in different clinical settings and scenarios. Noninvasive multimodality imaging may be useful to distinguish this cardiomyopathy from other acute cardiac and thoracic diseases. Coronary angiography remains, however, mandatory to differentiate TTC from acute coronary syndromes. This article reviews the clinical features and management of TTC and some new insights.

Objectives The objectives of this study were to verify whether improvement in 6-min walk distance (6MWD) is associated with clinical outcome in pulmonary arterial hypertension (PAH). Background 6MWD is used as an endpoint to assess the benefit of therapies in PAH. However, whether changes in 6MWD correlate with clinical outcome is unknown. Methods Randomized trials assessing 6MWD in patients with PAH and reporting clinical endpoints were included in a meta-analysis. The meta-analysis was performed to assess the influence of treatment on outcomes. Meta-regression analysis was performed to test the relationship between 6MWD changes and outcomes. Results Twenty-two trials enrolling 3,112 participants were included. Active treatments led to significant reduction of all-cause death (odds ratio [OR]: 0.429; 95% confidence interval [CI]: 0.277 to 0.664; p Conclusions In patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes.

Background: We attempted to test the hypothesis that the direct renin inhibitor aliskiren can improve diastolic dysfunction, glucose, and insulin metabolism (GIM) in overweight and obese hypertensive patients. Methods and results: Seventy-eight hypertensive patients were divided into two groups: 38 treated with aliskiren for six months, and 40 treated without aliskiren but with only traditional anti-hypertensive therapy, as controls. Doppler mitral flow velocity patterns were assessed before and after aliskiren during a six-month period. GIM (three-hour intravenous glucose tolerance test) was measured after four to six weeks of washout and six months of treatment. The mitral E/A ratio increased from 0.65 ± 0.11 to 0.75 ± 0.19. None of the indexes changed in the control group. In the control group, GIM parameters, fasting glucose levels (5.3 ± 0.9 to 6.0 ± 1.5 mmol/l; p = 0.003), fasting insulin levels (121 ± 121 to 189 ± 228 pmol/l; p = 0.03), and most other relevant metabolic measures (p < 0.05 for all) significantly worsened. Aliskiren did not affect GIM. In the control group LVM/height was not affected (119 ± 12 to 120 ± 17 g/m; p = 0.8), whereas aliskiren significantly reduced LVM/height (120 ± 13 to 111 ± 19 g/m; p = 0.04). Conclusions: Optimal target BP was achieved in the group as a whole and in both obese patient groups, while benefits to cardiac structure were of a smaller magnitude. In high-risk, overweight/obese patients with hypertension, traditional therapy provides significantly greater BP- versus aliskiren-lowering throughout the 24-hour dosing interval. Therefore in obese, hypertensive individuals, adequate and similar blood pressure control was achieved with aliskiren; however, the aliskiren group and not the control group was associated with a more favorable GIM profile and led to a significant regression of LVM; overall aliskiren-based treatment offers sustained control of PRA. © 2014 The Author(s).

Takotsubo Cardiomyopathy: Overview Eduardo Bossone, Gianluigi Savarese, Francesco Ferrara, Rodolfo Citro, Susanna Mosca, Francesca Musella, Giuseppe Limongelli, Roberto Manfredini, Antonio Cittadini, and Pasquale Perrone Filardi Takotsubo cardiomyopathy (TTC) is a unique acute syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant coronary artery disease, occurring mostly in postmenopausal women after emotional and/or physical stress. Given the nonspecific symptoms and signs, a high clinical index of suspicion is necessary to detect the disease in different clinical settings and scenarios. Noninvasive multimodality imaging may be useful to distinguish this cardiomyopathy from other acute cardiac and thoracic diseases. Coronary angiography remains, however, mandatory to differentiate TTC from acute coronary syndromes. This article reviews the clinical features and management of TTC and some new insights.

Objectives The purpose of this paper was to assess whether statins reduce all-cause mortality and cardiovascular (CV) events in elderly people without established CV disease. Background Because of population aging, prevention of CV disease in the elderly is relevant. In elderly patients with previous CV events, the use of statins is recommended by guidelines, whereas the benefits of these drugs in elderly subjects without previous CV events are still debated. Methods Randomized trials comparing statins versus placebo and reporting all-cause and CV mortality, myocardial infarction (MI), stroke, and new cancer onset in elderly subjects (age ≥65 years) without established CV disease were included. Results Eight trials enrolling 24,674 subjects (42.7% females; mean age 73.0 ± 2.9 years; mean follow up 3.5 ± 1.5 years) were included in analyses. Statins, compared with placebo, significantly reduced the risk of MI by 39.4% (relative risk [RR]: 0.606 [95% confidence interval (CI): 0.434 to 0.847]; p = 0.003) and the risk of stroke by 23.8% (RR: 0.762 [95% CI: 0.626 to 0.926]; p = 0.006). In contrast, the risk of all-cause death (RR: 0.941 [95% CI: 0.856 to 1.035]; p = 0.210) and of CV death (RR: 0.907 [95% CI: 0.686 to 1.199]; p = 0.493) were not significantly reduced. New cancer onset did not differ between statin- and placebo-treated subjects (RR: 0.989 [95% CI: 0.851 to 1.151]; p = 0.890). Conclusions In elderly subjects at high CV risk without established CV disease, statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term.

Objectives Lower limbs arterial disease (LLAD) portends high risk of cardiovascular events. Yet, the prevalence of significant occult coronary artery (CAD) and cerebrovascular (CVD) disease in patients without CAD and CVD has not been widely investigated. The purpose of this study was to evaluate the prevalence and severity of CAD and CVD in patients with LLAD of the lower extremities. Methods From January 2008 through December 2011 we studied 200 consecutive patients admitted for symptomatic LLAD, with normal global and regional systolic function, no symptoms of angina or dyspnea. During hospital admission all patients underwent carotid Doppler study and invasive angiography. Results Significant CAD was observed in 110 of 200 (55%) patients. Fifty-eight (53%) patients with significant CAD showed either left main ( n = 7), 3 vessels ( n = 35) or proximal left anterior descending ( n = 16) CAD, corresponding to 29% of total cohort. CVD was detected in 86(43%) patients (69% with concomitant CAD), including 30(35%) with severe and 15(17%) with significant disease. In thirty-two (37%) patients with CVD either left main ( n = 4), 3 vessels ( n = 18) or proximal left anterior descending ( n = 10) CAD was observed. The percent of patients with left main, 3 vessel or proximal left anterior descending stenosis among those with CVD was significantly higher (37%; p = 0.03) compared to those without CVD. Conclusions Severe asymptomatic CAD and CVD are quite prevalent in LLAD, and 29% of patients fulfill indications for coronary revascularization. Cost-effective strategies to detect occult CAD or CVD in LLAD patients need to be investigated in large multicenter studies.

Coronary artery disease (CAD) is the major cause of morbidity and mortality worldwide. More than 50% of CAD deaths occur in previously asymptomatic individuals at intermediate cardiovascular risk, highlighting the need of more accurate individual risk assessment to decrease cardiovascular events. Cardiac computed tomography (CCT) has emerged as a valuable technique for risk stratification in asymptomatic subjects and in symptomatic patients without known CAD. The absence of coronary artery calcium (CAC) identifies asymptomatic subjects at very low cardiac risk and is reasonable in intermediate risk individuals, in whom CAC measurement reclassifies a substantial number of subjects to different risk categories. In symptomatic patients with suspected CAD, detection of non-obstructive or obstructive CAD by CCT angiography is associated with increased all-cause mortality, and provides incremental risk stratification to CAC. Further studies are needed to assess the impact of CCT on clinical outcomes and its cost-effectiveness in different clinical settings.

Heart failure is characterized by several abnormalities of sympathetic cardiac activity that can be assessed by 123I metaiodobenzylguanidine single photon emission computed tomography (MIBG SPECT). This technique may be useful in the clinical management of heart failure patients. Abnormal MIBG uptake has been demonstrated to be a predictor of death and arrhythmic events in heart failure patients with a prognostic power incremental to that of conventional risk markers; it may also be useful to identify patients at low risk of arrhythmias despite current guideline indications for an implantable cardioverter-defibrillator (ICD) or patients at high risk for arrhythmias not fulfilling ICD indications. This review will focus on the clinical applications of MIBG SPECT in chronic heart failure, on the basis of the most recent evidence.

aortic flow, pulsed Doppler of LV outflow tract and brachial blood pressure were recorded; mean aortic gradient, SVi and aortic valve area by continuous equation were obtained both at rest and during Valsalva maneuver. SVi percent changes (Delta SVi %) were calculated in each patient. Differences between baseline and Valsalva maneuver were tested by paired t-test, whereas differences in patients with and without dyspnea were determined by t-test for unpaired data.

Background The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality. Methods MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality. Results Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p=0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p=0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p=0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:−0.0047 to 0.0103; p=0.486) and CV mortality (RC:0.0028; CI:−0.0047 to 0.0103; p=0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected. Conclusions Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice.

The goal of this study was to explore the association between changes in B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma levels and risk of hospital admission for heart failure (HF) worsening in patients with chronic HF.The relationship between BNP and NT-proBNP plasma levels and risk of cardiovascular events in patients with chronic HF has been previously demonstrated. However, it is unclear whether changes in BNP and NT-proBNP levels predict morbidity in patients with chronic HF.The MEDLINE, Cochrane, ISI Web of Science, and SCOPUS databases were searched for papers about HF treatment up to August 2013. Randomized trials enrolling patients with systolic HF, assessing BNP and/or NT-proBNP at baseline and at end of follow-up, and reporting hospital stay for HF were included in the analysis. Meta-regression analysis was performed to test the relationship between BNP and NT-proBNP changes and the clinical endpoint. Sensitivity analysis was performed to assess the influence of baseline variables on results. Egger's linear regression was used to assess publication bias.Nineteen trials enrolling 12,891 participants were included. The median follow-up was 9.5 months (interquartile range: 6 to 18 months), and 22% of patients were women. Active treatments significantly reduced the risk of hospital stay for HF worsening. In meta-regression analysis, changes in BNP and NT-proBNP were significantly associated with risk of hospital stay for HF worsening. Results were confirmed by using sensitivity analysis. No publication bias was detected.In patients with HF, reduction of BNP or NT-proBNP levels was associated with reduced risk of hospital stay for HF worsening.

The purpose of this paper was to assess whether statins reduce all-cause mortality and cardiovascular (CV) events in elderly people without established CV disease.Because of population aging, prevention of CV disease in the elderly is relevant. In elderly patients with previous CV events, the use of statins is recommended by guidelines, whereas the benefits of these drugs in elderly subjects without previous CV events are still debated.Randomized trials comparing statins versus placebo and reporting all-cause and CV mortality, myocardial infarction (MI), stroke, and new cancer onset in elderly subjects (age ≥ 65 years) without established CV disease were included.Eight trials enrolling 24,674 subjects (42.7% females; mean age 73.0 ± 2.9 years; mean follow up 3.5 ± 1.5 years) were included in analyses. Statins, compared with placebo, significantly reduced the risk of MI by 39.4% (relative risk [RR]: 0.606 [95% confidence interval (CI): 0.434 to 0.847]; p = 0.003) and the risk of stroke by 23.8% (RR: 0.762 [95% CI: 0.626 to 0.926]; p = 0.006). In contrast, the risk of all-cause death (RR: 0.941 [95% CI: 0.856 to 1.035]; p = 0.210) and of CV death (RR: 0.907 [95% CI: 0.686 to 1.199]; p = 0.493) were not significantly reduced. New cancer onset did not differ between statin- and placebo-treated subjects (RR: 0.989 [95% CI: 0.851 to 1.151]; p = 0.890).In elderly subjects at high CV risk without established CV disease, statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term.

Takotsubo cardiomyopathy (TTC) is a unique acute syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant coronary artery disease, occurring mostly in postmenopausal women after emotional and/or physical stress. Given the nonspecific symptoms and signs, a high clinical index of suspicion is necessary to detect the disease in different clinical settings and scenarios. Noninvasive multimodality imaging may be useful to distinguish this cardiomyopathy from other acute cardiac and thoracic diseases. Coronary angiography remains, however, mandatory to differentiate TTC from acute coronary syndromes. This article reviews the clinical features and management of TTC and some new insights.

Background Ranolazine (R), as add-on therapy in symptomatic patients with chronic stable coronary artery disease (CAD), has been tested in randomized clinical studies. Aim of the study was to assess in a meta-analysis the effects of R on angina, nitroglycerin consumption, functional capacity, electrocardiographic signs of ischemia and hemodynamic parameters in patients with chronic CAD. Methods Randomized trials assessing the effects of R compared to control on exercise duration, time to onset of angina, time to 1mm ST-segment depression, weekly nitroglycerin consumption and weekly angina frequency were included in the analysis. The effects of R compared to control on heart rate and blood pressure were also analyzed. Results Six trials enrolling 9223 patients were included in the analysis. At trough and peak levels, R compared to control significantly improved exercise duration, time to onset of angina and time to 1mm ST-segment depression. Additionally, R compared to control significantly reduced weekly angina frequency and weekly nitroglycerin consumption. Finally, R compared to control did not significantly reduce supine systolic and diastolic blood pressure as well as heart rate, standing heart rate and diastolic blood pressure, whereas it modestly reduced standing systolic blood pressure. At sensitivity analysis, results were not influenced by concomitant background therapy. Conclusions In symptomatic patients with chronic CAD, R, added to conventional therapy, effectively reduces angina frequency and sublingual nitroglycerin consumption while prolonging exercise duration as well as time to onset of ischemia and to onset of angina with no substantial effects on blood pressure and heart rate.

The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4±10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3-0.7; p

Atorvastatin (A) and rosuvastatin (R) are highly effective and widely used statins. However, conflicting results have been reported regarding their renal effects. The aim of the present study was to compare the effects of A and R on glomerular filtration rate (GFR) and new onset proteinuria in patients at high cardiovascular risk.Randomized trials about A or R treatments reporting clinical end-points were included in the meta-analysis. Influence of both treatments on GFR and new onset proteinuria was assessed.23 trials enrolling 29,147 participants were included. A significant reduction in GFR was detected in placebo-treated compared to statin-treated patients (standard mean difference [SMD]: 0.056, 95% confidence interval [CI]:0.028 to 0.083, p0.01). In particular, a significant reduction in GFR was detected in placebo as compared to either R-treated (SMD: 0.052, CI: 0.022 to 0.081, p=0.001) or A-treated patients (SMD: 0.084, CI: 0.008 to 0.161, p=0.031). No significant difference in GFR was detected in 5 head-to-head studies comparing A to R (SMD: 0.043, CI: -0.041 to 0.126, p=0.319). In 9 studies comparing A to R, R treatment significantly increased the risk of proteinuria when compared to A (odds ratio [OR]: 0.656, CI: 0.440 to 0.977, p=0.038, heterogeneity p=0.026), but this effect was no longer significant when studies using highest therapeutic doses of R (40 mg/daily) were excluded from analysis, abolishing significant heterogeneity (OR: 1.505, CI: 0.827 to 2.739, p=0.181).A and R show similar reno-protective effects in patients at high cardiovascular risk, with comparable rates of new onset proteinuria when commonly used doses are considered.

6-minute walk test (6MWT) is usually used as end-point in clinical trials to assess the benefit of therapies in patients with pulmonary arterial hypertension (PAH). The purpose of this study was to verify whether improvement in 6MWT is associated with reduced incidence of clinical outcomes in PAH.

Carotid Intima Media Thickness (IMT) has been widely used to predict cardiovascular events in primary and secondary prevention studies. Yet, the power of IMT to reclassify risk level on top of conventional risk assessment based on classical risk factors remains unsettled. In fact, recent data indicate that the prognostic power of IMT is lower than that provided by the identification of carotid plaques. The role of IMT as surrogate endpoint to assess the efficacy of cardiovascular protective therapies is also still debated. In fact, no studies have ever been designed and powered to show a relationship between changes in carotid IMT during follow-up and cardiovascular events. Recently, two metaanalysis of trials using IMT as surrogate endpoint failed to demonstrate an association between IMT regression and cardiovascular events. The reasons for the lack of predictive role for changes in IMT are uncertain. It has been shown that IMT is not a pure atherosclerotic index, being substantially affected by age and hemodynamic factors including blood pressure and vessel wall shear stress. In addition, the status of carotid vessels does not strictly reflect that of coronary arteries. Finally, intra and inter-observer variability of measurements may further limit the association between IMT changes in individual patients and cardiovascular risk. Thus, IMT represents a valuable risk marker in population studies but its role for tailoring cardiovascular therapy in clinical practice remains currently uncertain.

Aims Amino-terminal portion of pro-B-type natriuretic peptide (NT-pro-BNP) is a valuable diagnostic and prognostic marker in congestive heart failure (CHF). In CHF patients, elevation of natriuretic peptide levels correlate with decreased left ventricular (LV) ejection fraction (EF) and increased left atrial (LA) volumes, but a correlation with LA function that is a determinant of haemodynamic and clinical status in CHF with independent prognostic value has never been investigated. Aim of this study was to evaluate the relationship between cardiac neurohormonal activation and LA function in patients with CHF due to dilated cardiomyopathy. Methods and results One hundred and one patients (86% males; mean age, 64 ± 11 years) with dilated ischaemic or non-ischaemic cardiomyopathy, LV EF ≤45% (mean LV EF, 33 ± 8%), and New York Heart Association class II-IV underwent transthoracic echocardiography to evaluate LA fractional active and total emptying from M- and B-Mode images, and, on the same day, venous blood sample collection to dose NT-pro-BNP. By univariate analyses, NT-pro-BNP significantly correlated to age, LA dimensions, LA function indexes, EF, and functional class. At multivariate analysis, LV EF and M- or B-Mode indexes of LA function were the only independent predictors of NT-pro-BNP values. A NT-pro-BNP cut-off of 1480 pg/mL identified LA dysfunction with 89% specificity and 54% sensitivity. Conclusion In CHF patients with severely impaired systolic function, NT-pro-BNP levels reflect LA and LV dysfunction. These data should prompt studies to investigate the relationship between changes of LA function and NT-pro-BNP levels and their clinical value as prognostic and therapeutic targets in CHF.

Cardiac sympathetic activity can be assessed by (123)I-labelled meta-iodobenzylguanidine (MIBG) scintigraphy. Abnormalities of sympathetic cardiac activity have been shown in patients with heart failure, resulting in reduced MIBG uptake. Abnormal MIBG uptake predicts cardiac death, arrhythmias and all-cause mortality in patients with heart failure with a prognostic power incremental to that of conventional risk markers, and may identify patients at low risk of arrhythmias despite current guideline indications for implantable cardioverter defibrillator or patients at high risk for arrhythmias not fulfilling implantable cardioverter defibrillator indications. Prospective outcome studies are needed to assess whether MIBG imaging will have an impact on the mortality and morbidity of patients with heart failure.

Sleep apnea, defined as a pathologic pause in breathing during sleep10 s, promotes the progression of chronic heart failure and may be a predictor of poor prognosis. It causes, in fact, several mechanical, hemodynamic, chemical and inflammatory changes that negatively compromise cardiovascular homeostasis of heart failure patients. Sleep apnea is recognized as sleep apnea syndrome when specific symptoms, such as sleepiness and headache during the daytime and snoring, are present and is diagnosed with an overnight test called polysomnography. There are two different forms of sleep apnea, central and obstructive. Breathing is interrupted by the loss of respiratory drive and the lack of respiratory effort in the central form, which affects about 40-60% of heart failure patients. In obstructive sleep apnea, breathing stops when throat muscles relax, despite respiratory effort. This form affects about 3% of the general population, while it is present in at least 30% of heart failure patients. The diagnosis of sleep disorders in heart failure becomes very important to help patients adopting lifestyle changes and starting specific therapies to improve quality of life and retard the progression of chronic heart failure.

Background: Since ageing of the population is steadily raising, prevention of Cardiovascular (CV) disease in the elderly is relevant. In elderly patients with previous CV events, use of statins is recommended by guidelines, whereas the employ of these drugs in elderly subjects without previous CV events is still debated. The aim of the present study was to verify whether statins reduce all-cause mortality and CV events in elderly people without previous established CV disease. Methods: MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched for articles about statin treatment in patients without CV disease until December 2012. Study inclusion criteria were: randomized allocation to statin or placebo; age at randomization >65 years or report of outcomes in the subgroup of patients with age >65 years; report of at least 1 clinical event among all-cause death, CV death, Myocardial Infarction (MI), coronary revascularization, stroke and new cancer onset; report of outcomes separately for patients without established CV disease. Meta-analysis was performed to assess the influence of treatments on outcomes. Meta-regression analysis was performed to test the influence of potential effect modifiers on our results. Publication bias was assessed by a modified Macaskill's test. Results: Seven randomized trials comparing statins versus placebo in 23,258 subjects without CV disease were included in a meta-analysis. Statins compared to placebo reduced the risk of MI by 39.5% (relative risk [RR]: 0.605 [95% confidence interval (CI): 0.459 to 0.797]; p=0.000), coronary revascularization by 50.3% (RR: 0.497 [95% CI: 0.326 to 0.758]; p=0.001) and stroke by 24.6% (RR: 0.754 [95% CI: 0.588 to 0.966]; p=0.026), whereas the risk of all-cause death (RR: 0.938 [95% CI: 0.851 to 1.034]; p=0.196, CV death (RR: 0.911 [95% CI: 0.681 to 1.219]; p=0.530) and new cancer onset (RR: 0.934 [95% CI: 0.776 to 1.126]; p=0.476) was not influenced by treatment. Conclusions: In elderly subjects at high CV risk without established CV disease statins substantially reduce the incidence CV morbidities, but do not significantly prolong survival.

Background: The association between Urinary Albumin Excretion (UAE) and Cardiovascular (CV) risk has been well established. However, it has been not demonstrated whether regression of UAE is associated with reduced CV risk. The aim of the current study was to evaluate the relationship between changes of UAE induced by pharmacologic therapies and CV events. Methods: The MEDLINE, Cochrane, ISI Web of Science and SCOPUS database were searched for articles about UAE until October 2012. Randomized trials assessing UAE at baseline and at the end of follow-up, enrolling more than 200 hypertensive and/or diabetic patients and reporting clinical end-points (all-cause death, Myocardial Infarction (MI), stroke and CV death) were included in the study. Meta-regression analysis was performed to test the relationship between UAE changes and clinical end-points. The influence of baseline patients' characteristics, follow-up, study publication year, Detsky quality score, changes in blood pressure from baseline to the end of follow-up, degree of albuminuria, glomerular filtration rate, comorbidities and concomitant pharmacological treatments were also explored. Egger's method was used to assess publication bias. Results: 32 trials enrolling 80,812 participants were included. In meta-regression analysis, a relationship between UAE changes from baseline to end of follow-up and risk MI (change in Tau2 (t)=2.74; p Tau (p)=0.011), stroke (t=2.35; p=0.030) and CV events (including MI, stroke and CV death) (t=3.74; p=0.001) was found. Results were confirmed by sensitivity analysis. No heterogeneity among studies or publication bias were detected. Conclusions: In diabetic and/or hypertensive patients, a decrease in UAE is associated with reduced risk of MI, stroke and the composite of MI/stroke/CV death. These findings may have implications for monitoring CV risk in clinical practice.

Right heart catheterization remains the gold standard in diagnosis and evaluation of pulmonary arterial hypertension (PAH). The aim of this study was to verify whether changes in hemodynamics reflect the incidence of clinical events in PAH patients. MEDLINE, Cochrane, ISI Web of Science and SCOPUS

The relationship between B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma levels and risk of cardiovascular events in patients with chronic heart failure (HF) has been previously demonstrated. However, it is unclear whether changes of BNP and NT

The relationship between brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma levels and risk of cardiovascular events in patients with heart failure (HF) has been demonstrated in previous studies. However, it is unclear whether changes of BNP and NT

Several studies have reported the association between renal dysfunction and the risk of cardiovascular (CV) events and mortality. However, it has been not demonstrated whether regression of UAE is associated with reduced CV risk. The aim of the current study was to evaluate the relationship between

ObjectivesThe objectives of this study were to verify whether improvement in 6-min walk distance (6MWD) is associated with clinical outcome in pulmonary arterial hypertension (PAH).Background6MWD is used as an endpoint to assess the benefit of therapies in PAH. However, whether changes in 6MWD correlate with clinical outcome is unknown.MethodsRandomized trials assessing 6MWD in patients with PAH and reporting clinical endpoints were included in a meta-analysis. The meta-analysis was performed to assess the influence of treatment on outcomes. Meta-regression analysis was performed to test the relationship between 6MWD changes and outcomes.ResultsTwenty-two trials enrolling 3,112 participants were included. Active treatments led to significant reduction of all-cause death (odds ratio [OR]: 0.429; 95% confidence interval [CI]: 0.277 to 0.664; p < 0.01), hospitalization for PAH, and/or lung or heart-lung transplantation (OR: 0.442; 95% CI: 0.309 to 0.632; p < 0.01), initiation of PAH rescue therapy (OR: 0.555; 95% CI: 0.347 to 0.889; p = 0.01), and composite outcome (OR: 0.400; 95% CI: 0.313 to 0.510; p < 0.01). No relationship between 6MWD changes and outcomes was detected.ConclusionsIn patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes.