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Aims Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. Methods and results In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85–1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80–0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79–0.98), all-cause mortality (HR 0.89, 95% CI 0.81–0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76–0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86–0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82–1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83–1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. Conclusion Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Although in heart failure (HF) there is a strict correlation between heart and kidney, no data are available on the potential relationship in HF between renal dysfunction (RD) and the impaired sympathetic innervation. Aim of the present study was to assess the relationship between RD and cardiac sympathetic innervation in HF patients with reduced ejection fraction. Two hundred and sixty-three patients with mild-to-severe HF underwent iodine-123 meta-iodobenzylguanidine myocardial scintigraphy to assess sympathetic innervation, evaluating early and late heart-to-mediastinum (H/M) ratios and washout rate. In all patients, glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was assessed. A direct association was found between EPI-eGFR and late H/M (r = .215; P

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce cardiovascular (CV) events in diabetic patients, with a consistent effect on heart failure (HF) related outcomes. However, the effects on ischemic CV events appear less certain, in particular in patients with history of HF. The aim of this meta-analysis is to investigate CV benefits of SGLT2i and to assess the effects in patients with and without established atherosclerotic cardiovascular disease (ASCVD), with and without HF, and with estimated glomerular filtration rate (eGFR) < or ³60 ml/min.Methods: We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases. We performed a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials (CVOT) of SGLT2i in diabetic patients, assessing the effects of SGLT2i on 3-point major adverse cardiac events (MACE) (CV death, non fatal myocardial infarction (MI), non fatal stroke) and composite of HF hospitalization or CV death.Of 205 articles, 7 CVOTs were included in the meta-analysis. Results: Compared to placebo, SGLT2i significantly reduced by 10% the risk of 3-point MACE (HR 0.90; p=0.025) and the risk of CV death or HF hospitalization by 24% (Hazard Ratio (HR) 0.76; pConclusions: SGLT2i significantly reduce CV outcome in diabetic patients. SGLT2i remarkably and consistently reduce HF hospitalization, in patients with and without HF at baseline and independently on the presence of ASCVD.

Aims Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. Data synthesis MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804–0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757–0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830–1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759–1.023; p = 0.097), HF (RR: 0.967; CI: 0.803–1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807–1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625–1.199; p = 0.385). Conclusions Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.

The presence of comorbidities significantly influences long-term morbidity and mortality of symptomatic and asymptomatic heart failure (HF) patients. Metabolic syndrome and diabetic cardiomyopathy are two clinical conditions that share multiple pathophysiological mechanisms and that might be both responsible for cardiac dysfunction. However, it is argued whether metabolic syndrome (MS) independently increases HF risk or the association between MS and HF merely reflects the impact of individual risk factors included in its definition on HF development. Similarly, in the context of diabetic cardiomyopathy, many aspects are still challenging starting from the definition up to the therapeutic management. In this clinical review, we focused the attention on molecular pathways, myocyte alterations, and specific patterns of metabolic syndrome and diabetic cardiomyopathy in order to better define the potential diagnostic and therapeutic approaches of these two pathological conditions.

Exercise intolerance is a typical manifestation of patients affected by heart failure with reduced ejection fraction (HFrEF); however, the relationship among functional capacity, mortality, and exercise-induced heart rate response during exercise remains unclear in either sinus rhythm or atrial fibrillation subjects. Heart rate increase during incremental load exercise has a typical pattern in normal subjects, whereas it is commonly compromised in HFrEF patients, mainly due to the imbalance of the autonomic nervous system. In the present review, we aim to describe the behavior of heart rate during exercise in normal subjects and in HFrEF patients in sinus rhythm and atrial fibrillation, understanding and explaining the mechanism leading to a different exercise performance and functional limitation. Moreover, the role of chronotropic incompetence and the need of standardizing the cutoff criteria are also discussed in order to clarify the clinical importance, the prognostic relevance, and the potential therapeutic implications of this condition. Looking into the relative contribution and interaction of heart rate response during exercise might represent an important issue to guide individualized therapeutic interventions and prognostic assessment in HFrEF patients.

To asses the accuracy of stress myocardial perfusion scintigraphy (MPS) and stress echocardiography for the diagnosis of coronary artery disease (CAD) in patients with arterial hypertension. We searched for studies in which stress MPS or stress echocardiography were performed to detect CAD in hypertensive patients, with coronary angiography used as the reference test, published from January 1980 to December 2010. Studies performed in patients with known CAD, acute coronary syndrome and previous revascularization procedures were excluded. Of 1,263 studies, 13 met the inclusion criteria. Pooled summary estimates showed that stress MPS had a sensitivity of 0.90 [95% confidence interval (CI) 0.82-0.95] and a specificity of 0.63 (95% CI 0.53-0.72). For stress MPS, the area under the curve (AUC) at the summary receiver-operating characteristic (SROC) graph was 0.83 (95% CI 0.80-0.86). At meta-regression analysis, the presence of positive stress electrocardiography as inclusion criterion was the only significant effect modifier (p < 0.01). Pooled summary estimates showed that stress echocardiography had a sensitivity of 0.77 (95% CI 0.69-0.83) and a specificity of 0.89 (95% CI 0.83-0.93). For stress echocardiography, the AUC at SROC was 0.91 (95% CI 0.88-0.93). At the meta-regression analysis no significant effect modifier was detected. In conclusion, MPS has high sensitivity for detecting CAD in hypertensive patients, with specificity comparable to that reported in the general population, whereas stress echocardiography shows higher specificity but substantially reduced sensitivity compared to MPS.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), contributes to the progression of cardiac disease, and is associated with adverse prognosis. Previous evidence indicates that epicardial adipose tissue (EAT) is independently associated with sleep apnea in obese individuals. We explored the relationship between SDB and EAT in HF patients. METHODS AND RESULTS: EAT thickness was assessed by echocardiography in 66 patients with systolic HF undergoing nocturnal cardiorespiratory monitoring. A significantly higher EAT thickness was found in patients with SDB than in those without SDB (10.7 ± 2.8 mm vs. 8.3 ± 1.8 mm; p = 0.001). Among SDB patients, higher EAT thickness was found in both those with prevalent obstructive sleep apnea (OSA) and those with prevalent central sleep apnea (CSA). Of interest, EAT thickness was significantly higher in CSA than in OSA patients (11.9 ± 2.9 vs. 10.1 ± 2.5 p = 0.022). Circulating plasma norepinephrine levels were higher in CSA than in OSA patients (2.19 ± 1.25 vs. 1.22 ± 0.92 ng/ml, p = 0.019). According to the apnea-hypopnea index (AHI), patients were then stratified in three groups of SDB severity: Group 1, mild SDB; Group 2, moderate SDB; Group 3, severe SDB. EAT thickness progressively and significantly increased from Group 1 to Group 3 (ANOVA p < 0.001). At univariate analysis, only left ventricular ejection fraction and AHI significantly correlated with EAT (p = 0.019 and p < 0.0001, respectively). At multivariate analysis, AHI was the only independent predictor of EAT (β = 0.552, p < 0.001). CONCLUSIONS: Our results suggest an association between the presence and severity of sleep apneas and cardiac visceral adiposity in HF patients.

Background To assess endothelial function (EF) in type 2 diabetic patients with angiographically normal coronaries compared to diabetic patients with obstructive coronary artery disease (CAD) and to non-diabetic patients, with and without CAD. Methods One hundred eighty-three patients undergoing coronary angiography were divided in: group 1 with diabetes mellitus (DM) and CAD ( n =58); group 2 with DM without CAD ( n =58); group 3 with CAD without DM ( n =31) and group 4 without CAD and DM ( n =36). EF was assessed by reactive hyperemia index (RHI) using a fingertip peripheral arterial tonometry and compared to values obtained in 20 healthy volunteers. Results RHI was significantly lower in patients with DM compared to patients without DM (1.69±0.38 vs 1.84±0.44; p =0.019). RHI was comparable among groups 1, 2 and 3, each value being significantly lower compared to group 4 (2±0.44; p p p p =0.012; OR=2.76; p =0.001, respectively), whereas diabetic patients ( n =116) CAD and glycated haemoglobin (HbA1c) were independent significant predictors of ED (OR=3.05; p =0.009; OR=1.96; p =0.004, respectively). Diabetic patients with ED ( n =67) had higher levels of HbA1c than diabetic patients with normal endothelial function (7.35±0.97 vs 6.87±0.90; p =0.008) and RHI inversely correlated to HbA1c ( p =0.02; r =−0.210). Conclusions Diabetic patients with and without CAD show significantly impaired peripheral vascular function compared to non-diabetic patients without CAD. ED in diabetic patients without CAD is comparable to that of patients with CAD but without DM. HbA1c is a weak independent predictor of ED.

Aim The aim of this review was to summarize evidence on the role of Vitamin D deficiency in heart failure (HF), from pathophysiological mechanisms to clinical effects of Vitamin D supplementation. Data synthesis Chronic HF secondary to left ventricular (LV) systolic dysfunction is a growing health problem, still associated with poor clinical outcome. In recent years, experimental and epidemiological evidence focused on the role of Vitamin D in HF. Cross sectional studies demonstrated that prevalence of HF is increased in patients with Vitamin D deficiency or parathyroid hormone (PTH) plasma level increase, whereas longitudinal studies showed enhanced risk of developing new HF in patients with Vitamin D deficiency. In addition, in patients with established HF, low plasma levels of Vitamin D are associated with worsening clinical outcome. Yet, clinical studies did not definitively demonstrate a benefit of Vitamin D supplementation for preventing HF or ameliorating clinical outcome in patients with established HF. Conclusions Despite convincing experimental and epidemiological data, treatment with Vitamin D supplementation did not show clear evidence of benefit for preventing HF or influencing its clinical course. Ongoing clinical studies will hopefully shed lights on the effects of Vitamin D supplementation on clinical endpoints along the spectrum of HF.

Background Dipeptidyl Peptidase 4 Inhibitors (DPP4-I) and Sodium-Glucose Linked coTransporter-2 Inhibitors (SGLT2-I) improve glycemic control in patients with type 2 diabetes mellitus (DM). However, only few studies were designed to assess the efficacy and safety of these drugs on cardiovascular (CV) events and mortality. The purpose of the current study was to evaluate the effects of DPP4-Is and SGLT2-Is on CV events and mortality by meta-analysis. Methods Randomized trials enrolling more than 200 patients, comparing DPP-4-Is or SGLT2-Is versus placebo or active treatments in patients with DM, and reporting at least one event among all-cause and CV mortality, stroke, myocardial infarction (MI) and new onset of heart failure (HF), were included. Results 157 randomized trials (114 on DPP4-Is and 43 on SGLT2-Is) enrolling 140,470 patients (107,100 in DPP4-I and 33,370 in SGLT2-I studies) were included in the analysis. Compared to control, treatment with DPP4-Is did not affect all-cause (RR: 1.010; 95% CI: 0.935–1.091) and CV (RR: 0.975; CI: 0.887–1.073) mortality as well as risk of MI (RR: 0.915; CI: 0.835–1.002), stroke (RR: 0.933; CI: 0.820–1.062) and HF (RR: 1.083; CI: 0.973–1.205). Treatment with SGLT2-Is significantly reduced the risk of all-cause death by 28% (RR: 0.718; CI: 0.613–0.840), CV death by 33% (RR: 0.668; CI: 0.544–0.821), MI by 20% (RR: 0.803; CI: 0.668–0.965) and HF by 35% (RR: 0.652; CI: 0.517–0.823) without effect on stroke (RR: 1.158; CI: 0.912–1.469). Conclusions DPP4-Is show a safe CV profile as they do not affect mortality and CV events, including HF, in patients with type 2 DM. SGLT2-Is are associated with improved CV outcome and survival in DM patients.

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.

We assessed the impact of type 2 diabetes, in the presence of other major cardiovascular risk factors, on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease (CAD).In this prospective study, 23 patients with type 2 diabetes and 26 nondiabetic patients matched for age, sex and other cardiovascular risk factors underwent a cold pressure test (CPT) and dipyridamole transthoracic echocardiography to determine their coronary flow (CF) ratio. Within 2 weeks, all diabetic patients also underwent dipyridamole-rest myocardial perfusion single-photon emission (MPS) CT. None of the patients with or without diabetes had significant CAD on invasive coronary angiography.

Objective The aim of this study was to assess the effect of calcium channel blocker (CCB) treatment, compared with other drugs or placebo/top of therapy, on all-cause mortality, cardiovascular death, major cardiovascular events, heart failure, myocardial infarction and stroke. Methods We performed a meta-analysis of randomized controlled trials that compared a long-acting calcium channel blocker with another drug or placebo/top of therapy and that assessed all-cause mortality and cardiovascular events. Results We included 27 trials (175 634 patients). The risk of all-cause death was reduced by dihydropyridine CCBs [odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93–0.99; comparison P = 0.026; heterogeneity P = 0.87)] without influence of placebo trials. The risk of heart failure was increased by CCBs compared with active treatment (OR 1.17; 95% CI 1.11–1.24; comparison P = 0.0001; heterogeneity P = 0.0001), and it was decreased when compared with placebo (OR 0.72; 95% CI 0.59–0.87; comparison P = 0.001; heterogeneity P = 0.77), also in the subgroup of coronary artery disease patients (OR 0.76; 95% CI 0.61–0.95; comparison P = 0.01; heterogeneity P = 0.29). CCBs did not increase the risk of myocardial infarction (OR 1; 95% CI 0.95–1.04; comparison P = 0.83, heterogeneity P = 0.004), cardiovascular death (OR 0.97; 95% CI 0.93–1.02; comparison P = 0.24; heterogeneity P = 0.16), major cardiovascular events (OR 0.97; 95% CI 0.90–1.06; comparison P = 0.53; heterogeneity P = 0.0001). CCBs decreased the risk of fatal or nonfatal stroke (OR 0.86; 95% CI 0.82–0.90; comparison P = 0.0001, heterogeneity P = 0.12), also, when compared with angiotensin-converting enzyme inhibitors (OR 0.87; 95% CI 0.78–0.97; comparison P = 0.016; heterogeneity P = 0.48). Conclusion Our study demonstrates that CCBs reduce the risk of all-cause mortality compared with active therapy and prevent heart failure compared with placebo. Furthermore, with the inclusion of recent trials, we confirm that they reduce the risk of stroke, also in comparison to angiotensin-converting enzyme inhibitors and do not increase the risk of cardiovascular death, myocardial infarction and major cardiovascular events.

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.

Heart failure with reduced ejection fraction is a common and malignant condition, which recognizes a lot of causes and that carries a poor long-term prognosis. All patients with reduced left ventricular ejection fraction, both asymptomatic and symptomatic, should be evaluated with transthoracic echocardiography as a depth analysis of first level, due to its characteristics of accuracy, availability, safety and low costs. In fact, echocardiography is an essential tool to establish not only the diagnosis, but also the aetiology and the understanding pathophysiology of heart failure. Moreover, by the new more sensitive and more specific echocardiographic technologies, such as tissue Doppler imaging or strain rate or speckle tracking or three-dimensional echocardiography, it is possible to identify other recognized high-risk parameters associated with adverse outcome, which are useful to guide therapy and follow-up management of heart failure patients. Therefore, this review would underline the prognostic role of some echocardiographic parameters in the evaluation and management of patients with heart failure and reduced ejection fraction.

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.

Dear Sir, We fully agree with the comments in the letter regarding the statistical significance of the association between fasting glycaemia and coronary flow reserve reported in our article [1] in the whole group of diabetic and nondiabetic patients. Indeed, when the four outlier patients were excluded the association was no longer statistically significant. However, there are two main considerations that we would like to point out regarding the overall relevance of this association in our study. The first is methodological, and concerns the exclusion of outlier values when assessing a relationship, which in our opinion is always arbitrary and can be object of criticism. This is why we included these patients in the statistics. The second is more relevant and concerns the pathophysiological meaning of the association we reported. The r value was 0.34, which is very consistent with the value of 0.42 reported previously by Di Carli et al. [2]. Thus, the pathophysiological relevance is quite modest, as we acknowledged in the Discussion, where we state that the relationship was lost in the subgroup of diabetic patients, and that the weakness of the association indicates the presence of additional pathogenetic mechanisms that explain the abnormalities of microvascular function in these patients. Therefore, in agreement with the comments reported, we believe that the data presented in the article do not overemphasize the meaning of the relationship, despite its statistical significance.

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

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.

To assess endothelial function (EF) in type 2 diabetic patients with angiographically normal coronaries compared to diabetic patients with obstructive coronary artery disease (CAD) and to non-diabetic patients, with and without CAD.One hundred eighty-three patients undergoing coronary angiography were divided in: group 1 with diabetes mellitus (DM) and CAD (n = 58); group 2 with DM without CAD (n = 58); group 3 with CAD without DM (n = 31) and group 4 without CAD and DM (n = 36). EF was assessed by reactive hyperemia index (RHI) using a fingertip peripheral arterial tonometry and compared to values obtained in 20 healthy volunteers.RHI was significantly lower in patients with DM compared to patients without DM (1.69 ± 0.38 vs 1.84 ± 0.44; p = 0.019). RHI was comparable among groups 1, 2 and 3, each value being significantly lower compared to group 4 (2 ± 0.44; p0.001 vs group 1; p0.005 vs group 2; p0.002 vs group 3). At multivariate analysis DM and CAD were significant predictors of endothelial dysfunction (ED) (OR = 2.29; p = 0.012; OR = 2.76; p = 0.001, respectively), whereas diabetic patients (n = 116) CAD and glycated haemoglobin (HbA1c) were independent significant predictors of ED (OR = 3.05; p = 0.009; OR = 1.96; p = 0.004, respectively). Diabetic patients with ED (n = 67) had higher levels of HbA1c than diabetic patients with normal endothelial function (7.35 ± 0.97 vs 6.87 ± 0.90; p = 0.008) and RHI inversely correlated to HbA1c (p = 0.02; r = -0.210).Diabetic patients with and without CAD show significantly impaired peripheral vascular function compared to non-diabetic patients without CAD. ED in diabetic patients without CAD is comparable to that of patients with CAD but without DM. HbA1c is a weak independent predictor of ED.

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.

Functional characterization of atherosclerosis is a promising application of molecular imaging. Radionuclide-based techniques for molecular imaging in the large arteries (e.g. aorta and carotids), along with ultrasound and magnetic resonance imaging (MRI), have been studied both experimentally and in clinical studies. Technical factors including cardiac and respiratory motion, low spatial resolution and partial volume effects mean that noninvasive molecular imaging of atherosclerosis in the coronary arteries is not ready for prime time. Positron emission tomography imaging with fluorodeoxyglucose can measure vascular inflammation in the large arteries with high reproducibility, and signal change in response to anti-inflammatory therapy has been described. MRI has proven of value for quantifying carotid artery inflammation when iron oxide nanoparticles are used as a contrast agent. Macrophage accumulation of the iron particles allows regression of inflammation to be measured with drug therapy. Similarly, contrast-enhanced ultrasound imaging is also being evaluated for functional characterization of atherosclerotic plaques. For all of these techniques, however, large-scale clinical trials are mandatory to define the prognostic importance of the imaging signals in terms of risk of future vascular events.

The development and progression of cardiovascular disease can be regarded as a continuum (Fig. 1) [1]. Targeting different points within this continuum is therefore of major importance for reducing cardiovascular morbidity and mortality. Inhibition of the renin-angiotensin-aldosterone system (RAAS) has become a key target in this regard, given that angiotensin II (Ang II) has been implicated as a pathogenic factor at many steps in the development and progression of cardiovascular disease [2, 3].

Purpose: Endothelial dysfunction (ED) is a common feature of Chronic Kidney Disease (CKD) and Diabetes Mellitus (DM), and is thought to underlie the increased cardiovascular risk of both conditions. However, while the association between coronary artery ED and DM has been evidenced in previous studies, no data are available about the relationship between CKD and coronary ED. Methods: 63 consecutive patients (mean age 60±10; 40 males), 25 of whom affected by Type II DM (mean age 62±10; 13 males) and 38 non diabetic subjects (mean age 59±11; 27 males), underwent, on the same day, transthoracic echocardiographic coronary flow reserve (CFR) evaluation during cold pressure test (CPT), to assess endothelium dependent vasodilation, and dipyridamole (Dip) infusion (0.84 mg/kg i.v. in 6 min), to evaluate endothelium independent vasodilation. Glomerular Filtration Rate (GFR), as an index of renal function, was estimated by serum creatinine values using Cockroft-Gault formula. All patients had no significant stenosis at coronary angiography performed within one month from enrolment. Results: Mean GFR was 90.27±26.98 ml/min in the whole population, 86.2±27.9 ml/min in DM patients and 92.94±26.39 ml/min in non DM patients (p=ns). Mean Dip-CFR (2.42±0.72 vs 2.84±0.73; p=0.028), as well as CPT-CFR (1.47±0.28 vs 1.65±0.29; p=0.02) were significantly lower in DM compared to non DM patients. In diabetic group, GFR correlated with both Dip-CFR (r=0.41; p=0.042) and CPT-CFR (r=0.579; p=0.002); moreover, DM patients in stage II/III of CKD (GFR

Elderly subjects are expected to account for 30% of the European population by 2050. Currently, more than two-thirds of all cardiovascular deaths are registered in subjects >65 years of age. In the elderly, exercise electrocardiogram (ECG) testing (EET) may be more difficult both to perform and to interpret compared with the situation in younger subjects, but it is still recommended as the initial non-invasive method for evaluating coronary artery disease (CAD). Single-photon-emission computed tomography (SPECT) myocardial perfusion scintigraphy (MPS) has demonstrated the ability to successfully stratify risk of adverse cardiac events in elderly (>65 years of age) as well as in very elderly (>80 years of age) patients. The finding of a normal MPS study in an elderly patient has been repeatedly associated with a low level of risk (~1% annual event rate). Practical advantages over EET are the possibility of accurately identifying myocardial ischaemia in the large subgroup of elderly subjects with ECG abnormalities and of using pharmacological stress in subjects unable to exercise.

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

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.