Fabio Marsico

Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis.

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.

Detection of significant coronary artery disease by noninvasive anatomical and functional imaging.

Background—The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. Methods and Results—A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ⩽0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88–0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69–0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65–0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). Conclusions—In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure From Bench to Bedside

G-protein–coupled receptors (GPCRs) are a superfamily of more than 1000 membrane proteins that respond to a wide spectrum of extracellular signals, modulating various physiopathological processes.1,2 Several GPCRs, such as adrenergic, angiotensin, endothelin, and adenosine receptors, are expressed in cardiovascular (CV) tissues to maintain CV homeostasis. Importantly, GPCR-mediated adrenergic deregulation has been shown to both cause and contribute to the onset and progression of major CV diseases ultimately leading to heart failure (HF). Thus, GPCRs have become salient targets of current pharmacotherapy in CV disorders, and in past decades, many efforts have been made to better clarify their role in the pathophysiology of cardiac disease, focusing not only on receptor functions but also on postreceptor components that mediate or regulate their responses. Among the latter, a relevant role has been attributed to G-protein–coupled receptor kinases (GRKs). In this review, we focus on GRK2, the most abundant and versatile GRK expressed on CV system, tracing the way from initial experimental evidence to more recent data suggesting a potential role for this kinase in the clinical management of HF.1,2 ### GPCR Signaling and GRK Functions: Pathophysiological Background On stimulation, GPCRs interact with heterotrimeric G proteins, which in turn dissociate into 2 functional monomers, namely Gα and Gβγ, both of which modulate different effector systems. Agonist binding to GPCR promotes the activation of complex regulatory mechanisms to protect the receptor from both acute and chronic stimulation, a process termed desensitization. As extensively described, GPCR desensitization involves 3 main events in chronological order: receptor phosphorylation and uncoupling from G proteins, internalization of membrane-bound receptors, and downregulation through reduced mRNA and protein synthesis or increased degradation of internalized receptors.1,2 The desensitization process is mediated by 3 families of proteins: second-messenger–dependent protein kinases, GRKs and arrestins. The defining feature of GRKs is that …

Multicentre multi-device hybrid imaging study of coronary artery disease: results from the EValuation of INtegrated Cardiac Imaging for the Detection and Characterization of Ischaemic Heart Disease (EVINCI) hybrid imaging population

AIMS Hybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor setting. METHODS AND RESULTS Fourteen centres enrolled 252 patients with stable angina and intermediate (20-90%) pre-test likelihood of coronary artery disease (CAD) who underwent myocardial perfusion scintigraphy (MPS), CT coronary angiography (CTCA), and quantitative coronary angiography (QCA) with fractional flow reserve (FFR). Hybrid MPS/CTCA images were obtained by 3D image fusion. Blinded core-lab analyses were performed for CTCA, MPS, QCA and hybrid datasets. Hemodynamically significant CAD was ruled-in non-invasively in the presence of a matched finding (myocardial perfusion defect co-localized with stenosed coronary artery) and ruled-out with normal findings (both CTCA and MPS normal). Overall prevalence of significant CAD on QCA (>70% stenosis or 30-70% with FFR≤0.80) was 37%. Of 1004 pathological myocardial segments on MPS, 246 (25%) were reclassified from their standard coronary distribution to another territory by hybrid imaging. In this respect, in 45/252 (18%) patients, hybrid imaging reassigned an entire perfusion defect to another coronary territory, changing the final diagnosis in 42% of the cases. Hybrid imaging allowed non-invasive CAD rule-out in 41%, and rule-in in 24% of patients, with a negative and positive predictive value of 88% and 87%, respectively. CONCLUSION In patients at intermediate risk of CAD, hybrid imaging allows non-invasive co-localization of myocardial perfusion defects and subtending coronary arteries, impacting clinical decision-making in almost one every five subjects.

Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: A digital reactive hyperemia study

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<0.001 vs group 1; p<0.005 vs group 2; p<0.002 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). 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.

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure

G-protein–coupled receptors (GPCRs) are a superfamily of more than 1000 membrane proteins that respond to a wide spectrum of extracellular signals, modulating various physiopathological processes.1,2 Several GPCRs, such as adrenergic, angiotensin, endothelin, and adenosine receptors, are expressed in cardiovascular (CV) tissues to maintain CV homeostasis. Importantly, GPCR-mediated adrenergic deregulation has been shown to both cause and contribute to the onset and progression of major CV diseases ultimately leading to heart failure (HF). Thus, GPCRs have become salient targets of current pharmacotherapy in CV disorders, and in past decades, many efforts have been made to better clarify their role in the pathophysiology of cardiac disease, focusing not only on receptor functions but also on postreceptor components that mediate or regulate their responses. Among the latter, a relevant role has been attributed to G-protein–coupled receptor kinases (GRKs). In this review, we focus on GRK2, the most abundant and versatile GRK expressed on CV system, tracing the way from initial experimental evidence to more recent data suggesting a potential role for this kinase in the clinical management of HF.1,2 ### GPCR Signaling and GRK Functions: Pathophysiological Background On stimulation, GPCRs interact with heterotrimeric G proteins, which in turn dissociate into 2 functional monomers, namely Gα and Gβγ, both of which modulate different effector systems. Agonist binding to GPCR promotes the activation of complex regulatory mechanisms to protect the receptor from both acute and chronic stimulation, a process termed desensitization. As extensively described, GPCR desensitization involves 3 main events in chronological order: receptor phosphorylation and uncoupling from G proteins, internalization of membrane-bound receptors, and downregulation through reduced mRNA and protein synthesis or increased degradation of internalized receptors.1,2 The desensitization process is mediated by 3 families of proteins: second-messenger–dependent protein kinases, GRKs and arrestins. The defining feature of GRKs is that …

Left ventricular hypertrophy reduction and clinical events. A meta-regression analysis of 14 studies in 12,809 hypertensive patients

BACKGROUND 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. METHODS 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. RESULTS 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, p<0.001), as well stroke (OR: 0.756, IC: 0.638 to 0.895, p<0.001) 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. CONCLUSIONS 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.

Molecular imaging of atherosclerosis in translational medicine

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.

Ischemic heart disease in systemic inflammatory diseases. An appraisal

Systemic inflammatory diseases are inflammatory syndromes that are associated with increased cardiovascular morbidity and mortality. The link between inflammatory and cardiovascular diseases can be attributed to coexistence of classical risk factors and of inflammatory mechanisms activated in systemic inflammatory diseases and involving the immune system. Yet, clinical implications of these findings are not entirely clear and deeper knowledge and awareness of cardiac involvement in inflammatory diseases are necessary. The aims of this review are to summarize cardiac involvement in systemic inflammatory diseases and to identify areas where evidence is currently lacking that deserve further investigation in the future.

NSAIDs and cardiovascular risk.

NSAIDs are the most largely used class of drugs in the world, due to their large use in many diseases, in particular for the systemic inflammatory diseases. Nevertheless, today NSAIDs are less used for some of these diseases, due to several side-effects correlated to these drugs. The antiinflammatory mechanism of NSAIDs consist in the inibhition of two forms of cyclooxygenase, namely COX-1 (its block contributes to an antiplatelet effect) and COX-2 (its block has a greater antiinflammatory, antipyretic and analgesic effect). The COX-2 inhibition might reduce the risk of gastrointestinal toxicity, but several studies have shown the cardiovascular side effects of this inhibition. Mechanisms of the cardiovascular side effects are controversial yet, so the aim of this document is to review side-effects profile of NSAIDs and, specifically, to investigate cardiovascular consequences of NSAIDs use in clinical practice.