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Aims: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). Methods and Results: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = −0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = −0.46, p = 0.006; FRS: score r = −0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). Conclusions: We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk.

Myocardial perfusion imaging with SPECT/CT or with PET/CT is a mainstay in clinical practice for the diagnostic assessment of downstream, flow-limiting effects of epicardial lesions during hyperemic flows and for risk stratification of patients with known or suspected coronary artery disease (CAD). In patients with multivessel CAD, the relative distribution of radiotracer uptake in the left ventricular myocardium during stress and rest accurately identifies flow-limiting epicardial lesions or the most advanced, so called culprit, lesion. Often, less severe obstructive CAD lesions may go undetected or underdiagnosed. The concurrent ability of PET/CT with radiotracer kinetic modeling to determine myocardial blood flow (MBF) in absolute terms (mL/g/min) at rest and during vasomotor stress allows the computation of regional myocardial flow reserve (MFR) as an adjunct to the visual interpretation of myocardial perfusion studies. Adding the noninvasive evaluation and quantification of MBF and MFR by PET imaging to the visual analysis of myocardial perfusion may (1) identify subclinical CAD, (2) better characterize the extent and severity of CAD burden, and (3) assess "balanced" decreases of MBF in all 3 major coronary artery vascular territories. Recent investigations have demonstrated that PET-determined reductions in hyperemic MBF or MFR in patients with subclinical or clinically manifest CAD are predictive of increased relative risk of future cardiovascular events and clinical outcome. Quantifying MFR with PET enables the identification and characterization of coronary vasodilator dysfunction as functional precursor of the CAD process, which offers the unique opportunity to monitor its response to lifestyle or risk factor modification by preventive medical care. Whether an improvement or even normalization of hyperemic MBF or the MFR in subclinical or in clinically manifest CAD confers an improved long-term cardiovascular outcome remains untested. Nonetheless, given the recent growth in the clinical utilization of myocardial perfusion PET, image-guided and personalized preventive care of vascular health may become a reality in the near future.

ObjectivesThe purpose of this study was to evaluate the diagnostic value of a positron emission tomography (PET)/computed tomography (CT)–determined longitudinal decrease in myocardial blood flow (MBF) gradient during hyperemia and myocardial flow reserve (MFR) for the identification of epicardial stenosis ≥50%.BackgroundAlthough PET-determined reductions in MFR are increasingly applied to identify epicardial lesions in coronary artery disease (CAD), it may be seen as a suboptimal approach due to the nonspecific origin of decreases in MFR.MethodsIn 24 patients with suspected or known CAD, MBF was measured with 13N-ammonia and PET/CT in ml/g/min at rest, during dipyridamole stimulation, and the corresponding MFR was calculated. MBF was also determined in the mid and mid-distal myocardium of the left ventricle (LV). A decrease in MBF from mid to mid-distal LV myocardium was defined as longitudinal MBF gradient. MBF parameters were determined in the myocardial region with stress-induced perfusion defect and with stenosis ≥50% (territory 1), without defect but with stenosis ≥50% (territory 2), or without stenosis ≥50% (territory 3).ResultsIn territories 1 and 2 with focal stenosis ≥50%, the severity of epicardial artery stenosis correlated with the Δlongitudinal MBF gradient (stress-rest) (r = 0.52; p < 0.0001), while this association was less pronounced for corresponding MFR (r = −0.40; p < 0.003). On a vessel-based analysis, the sensitivity and specificity of the Δlongitudinal MBF gradient in the identification of epicardial lesions was higher than those for MFR (88% vs. 71%, p ≤ 0.044; and 81% vs. 63%, p = 0.134, respectively). Combining both parameters resulted in an optimal sensitivity of 100% and intermediate specificity of 75%. The diagnostic accuracy was highest for the combined analysis than for the Δlongitudinal MBF gradient or MFR alone (94% vs. 86%, p ≤ 0.003; and 94% vs. 70%, p ≤ 0.0002).ConclusionsThe combined evaluation of a Δlongitudinal MBF gradient and MFR may evolve as a new promising analytic approach to further optimize the identification of CAD lesions.

We present the case of a 74 year old woman suffering from severe mitral valve incompetence and rapid atrial fibrillation. After an appropriate vitamin K antagonist (VKA) therapy, the patient underwent mitral valve replacement by bioprosthesis. Then, the patient was re-hospitalized for jaundice. Suspecting hepatotoxicity, VKA was discontinued and fondaparinux was started. During this treatment, the patient developed a symptomatic atrial thrombus. After exclusion of a hepatic disease, VKA was re-established with hemodynamic and liver enzymes normalization and atrial thrombus resolution. Caution has to be used when considering fondaparinux as an alternative strategy to VKA in patients with multiple thrombotic risk factors.

SummaryPharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.

Background: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. Methods: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. Results: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score

Background Among endocannabinoid (EC)-related mediators, Oleoyl-ethanolamide (OEA) and Palmitoyl-ethanolamide (PEA), two endogenous PPARα agonists with lipolytic and anti-inflammatory action, respectively, are being actively investigated. Here, we assessed the potential association between plasma levels of PEA and OEA and coronary function in a cohort including normal, overweight, obese, and morbidly obese (MOB) individuals. Methods Myocardial perfusion and endothelium-related myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13 N-ammonia positron emission tomography/computed tomography. OEA and PEA were extracted from human plasma by liquid-liquid extraction, separated by liquid chromatography and quantified by mass spectrometry. Serum levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1) were measured by colorimetric enzyme-linked immunosorbent assay. Results Circulating levels of PEA and VCAM-1 were increased in MOB as compared to normal weight subjects. Circulating levels of OEA and PEA were associated with body mass index, but not with adhesion molecules. Increases of PEA levels were associated with and predictive of worsened coronary function in MOB and the overall cohort studied. Conclusion Plasma levels of PEA are increased in MOB patients and associated with coronary dysfunction as a functional precursor of CAD process. Larger trials are needed to confirm PEA as a potential circulating biomarker of coronary dysfunction in both MOB patients and the general population.

SummarySeveral studies have been carried out on vulnerable plaque as the main culprit for ischaemic cardiac events. Historically, the most important diagnostic technique for studying coronary atherosclerotic disease was to determine the residual luminal diameter by angiographic measurement of the stenosis. However, it has become clear that vulnerable plaque rupture as well as thrombosis, rather than stenosis, triggers most acute ischaemic events and that the quantification of risk based merely on severity of the arterial stenosis is not sufficient. In the last decades, substantial progresses have been made on optimisation of techniques detecting the arterial wall morphology, plaque composition and inflammation. To date, the use of a single technique is not recommended to precisely identify the progression of the atherosclerotic process in human beings. In contrast, the integration of data that can be derived from multiple methods might improve our knowledge about plaque destabilisation. The aim of this narrative review is to update evidence on the accuracy of the currently available non-invasive and invasive imaging techniques in identifying components and morphologic characteristics associated with coronary plaque vulnerability.

Objectives This study sought to investigate abnormalities in coronary circulatory function in 2 different disease entities of obese (OB) and morbidly obese (MOB) individuals and to evaluate whether these would differ in severity with different profiles of endocannabinoids, leptin, and C-reactive protein (CRP) plasma levels. Background There is increasing evidence that altered plasma levels of endocannabinoids, leptin, and CRP may affect coronary circulatory function in OB and MOB. Methods Myocardial blood flow (MBF) responses to cold pressor test from rest and during pharmacologically induced hyperemia were measured with N-13 ammonia positron emission tomography/computed tomography. Study participants (n = 111) were divided into 4 groups based on their body mass index (BMI) (kg/m2): 1) control group (BMI: 20 to 24.9, n = 30); 2) overweight group (BMI: 25 to 29.9, n = 31), 3) OB group (BMI: 30 to 39.9, n = 25); and 4) MOB group (BMI ≥40, n = 25). Results The cold pressor test–induced change in endothelium-related MBF response (ΔMBF) progressively declined in overweight and OB groups when compared with the control group [median: 0.19 (interquartile range [IQR] 0.08, 0.27) and 0.11 (0.03, 0.17) vs. 0.27 (0.23, 0.38) ml/g/min; p ≤ 0.01, respectively], whereas it did not differ significantly between OB and MOB groups [median: 0.11 (IQR: 0.03, 0.17) and 0.09 (–0.01, 0.19) ml/g/min; p = 0.93]. Compared with control subjects, hyperemic MBF subjects comparably declined in the overweight, OB, and MOB groups [median: 2.40 (IQR 1.92, 2.63) vs. 1.94 (1.65, 2.30), 2.05 (1.67, 2.38), and 2.14 (1.78, 2.76) ml/g/min; p ≤ 0.05, respectively]. In OB individuals, ΔMBF was inversely correlated with increase in endocannabinoid anandamide (r = –0.45, p = 0.044), but not with leptin (r = –0.02, p = 0.946) or with CRP (r = –0.33, p = 0.168). Conversely, there was a significant and positive correlation among ΔMBF and elevated leptin (r = 0.43, p = 0.031) and CRP (r = 0.55, p = 0.006), respectively, in MOB individuals that was not observed for endocannabinoid anandamide (r = 0.07, p = 0.740). Conclusions Contrasting associations of altered coronary endothelial function with increases in endocannabinoid anandamide, leptin, and CRP plasma levels identify and characterize OB and MOB as different disease entities affecting coronary circulatory function.

BACKGROUND To define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight overweight and obese individuals with normal global left ventricular function. METHODS AND RESULTS Myocardial blood flow at rest and during pharmacologic vasodilation was measured with (13)N ammonia PET/CT in mL/g/minute in normal weight control (CON n = 12) overweight (OW n = 10) and obese individuals (OB n = 10). In addition resting myocardial function was evaluated as circumferential strain (?c ) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98 ± 0.96 vs 2.70 ± 0.66 P = .290) whereas it declined significantly in OB (1.98 ± 1.04 P = .030). Further global ?c () was comparable between CON OW and OB ( 0.24 ± 0.03 0.23 ± 0.02 and 0.23 ± 0.04) but it was lowest in OB when normalized to the rate pressure product (N?c: 0.31 ± 0.06 0.32 ± 0.05 and 0.26 ± 0.08). When MFR of the three major coronary territories was correlated with corresponding ?c a positive association was observed in CON (r = 0.36 P = .030) in OW (r = 0.54 P = .002) and also in OB when relating N?c to coronary vascular resistance during pharmacologic vasodilation (r = 0.46 P = .010). CONCLUSIONS Higher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non obese individuals while this is also observed for reduced MFR in obesity.

SummaryThe “blood vulnerability”, resulting from the complex balance between serum molecules and inflammatory cell atherosclerotic activities, is a major determinant in the evaluation of the “global patient cardiovascular vulnerability”. In the present study, we focused on the role of the soluble receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL, a potential marker of coronary calcification and vulnerability) in the release of neutrophilic proteases. Then, the association between these mediators and the degree of coronary calcification (assessed by coronary calcium score [CCS]) was investigated in 20 subjects (aged ≥65 years) asymptomatic for cardiovascular disease. Results showed that RANKL dose-dependently induced matrix metalloprotease (MMP)-8 and MMP-9 release from human primary neutrophils cultured in Teflon dishes (suspension condition, mimicking cells circulating in the blood stream). Conversely, when adherent to polystyrene, neutrophils became unresponsive to RANKL. RANKL did not influence the release of other neutrophilic products in suspension and adherence cultures as well as neutrophil migration. RANKL-induced release of MMPs was dependent on the activation of defined intracellular signalling pathways (PI3K/Akt and ERK1/2). In asymptomatic subjects, serum levels of RANKL, MMP-8 and MMP-9 positively correlated with CCS, reflecting a potential relationship between circulating RANKL and coronary calcification. In conclusion, RANKL increased the release of neutrophilic products potentially related to the “blood” vulnerability via defined intracellular pathways. Serum levels of RANKL might represent a potential biomarker of coronary calcification and related cardiovascular risk.

SummaryThe definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral infarction. This “tissular” definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post-ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangio-genesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke.

Aims Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Methods and results Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13 N -ammonia PET/CT. Study participants ( n = 77) were divided into three groups based on their body mass index (BMI, kg/m2): control group 20≤ BMI

Atherosclerotic plaque calcification represents a common pathophysiologic process in the advanced phases of the disease. Both inflammatory and vascular cells (such as osteoblast-like cells, osteoclast-like cells, dendritic cells, macrophages, smooth muscle cells, and endothelial cells) are active players in the balance between intraplaque bone deposition and resorption. Inflammatory processes underlying plaque calcification are regulated by soluble mediators that also contribute to plaque destabilization and increased vulnerability. Among different mediators, the receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL)/osteoprogerin (OPG) system is a major determinant in inflammatory cell differentiation toward osteoclast-like cells. Thus, this system might be a promising parameter to be investigated as a marker of calcification-related cardiovascular risk and a therapeutic target. Despite some promising results, several limitations have been shown in the potential clinical use of serum RANKL/OPG to better assess the cardiovascular risk. At present, the potential relationship between RANKL/OPG and the content of calcium within the intima of the coronary arteries (CAC score, assessed by computed tomography) needs to be explored in large clinical studies. On the other hand, the antiatherosclerotic relevance of treatments antagonizing RANKL is still under investigation. Despite that clinical evidence is needed, this therapeutic approach might be of particular benefit in selective populations (such as rheumatoid arthritis patients) with an increased cardiovascular risk.

Eur J Clin Invest 2010; 40 (7): 645–654 Abstract Background Coronary artery disease (CAD) represents the most relevant cause of death and morbidity in the adult population of developed and developing countries. During the last decades, a strong research effort has been performed to identify more selective markers and better assess the cardiovascular risk in both primary and secondary prevention. Materials and methods This review updates current knowledge regarding the pathophysiological relevance as possible markers of coronary calcification of the receptor activator of nuclear factor-kappa ligand (RANKL)/osteoprotegerin (OPG) system. Furthermore, the potential clinical use of both RANKL/OPG and coronary calcium score (CAC) to assess cardiovascular vulnerability has been discussed. Results Emerging evidence indicates that atherosclerotic plaque calcification is positively correlated with vulnerability. Several inflammatory mediators have been shown to modulate arterial calcification, thus increasing the risk of plaque rupture. Among these factors, RANKL/OPG axis might be of particular interest as a promising biomarker of plaque vulnerability in subjects with diffuse coronary calcification. Conclusion Together with clinical parameters of coronary calcification (such as CAC), circulating RANKL/OPG levels could contribute to better assess and predict cardiac events.

Summary Purpose: To evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECGpulsing CT angiography (CTA) in the evaluation of myocardial perfusion, myocardial blood flow (MBF) and coronary morphology for the identification of subclinical CAD. Patients, material, methods: Following rest-stress 13N-ammonia PET/CT perfusion imaging and MBF quantification, ECG-pulsing CTA at a pulse window of 70% of the R-R cycle was performed in ten healthy controls and in sixteen individuals with cardiovascular risk factors. Individual radiation dose exposure for ECG-pulsing CTA was estimated from the dose-length product. Results: PET demonstrated normal perfusion in all study individuals, while hyperemic MBFs during dipyridamole stimulation and the myocardial flow reserve (MFR) in cardiovascular risk individuals were significantly lower than in healthy controls (1.34 ± 0.26 vs. 2.28 ± 0.47 ml/g/min and 1.48 ± 0.39 vs. 3.24 ± 0.81, both p . 0.0001). Further, ECG-pulsing CTA identified mild calcified and non-calcified coronary plaque burden in 7 (43%) individuals of the cardiovascular risk group. Rest-stress 13N-ammonia PET/CT perfusion study yielded a mean effective radiation dose of 3.07 ± 0.06 mSv (2.07 ± 0.06 mSv from the rest-stress 13N-ammonia injections and 1.0 mSv from the 2 CT transmission scans), while ECG-pulsing CTA was associated with 5.57 ± 2.00 mSv. The mean effective radiation dose of the combined 13N-ammonia PET/CT and ECG-pulsing CTA exams in the evaluation of myocardial perfusion and coronary morphology was 8.0 ± 1.5 mSv. Conclusion: 13N-ammonia PET/CT and ECG-pulsing CTA affords cardiac hybrid imaging studies in the evaluation of subclinical CAD with a relatively low mean effective radiation exposure of 8.0 ± 1.5mSv.

In spite of the huge amount of research recently performed in this area, the pathogenesis of human hypertension remains elusive. Thus, hypertension has to be defined as "essential" for the majority of patients with high blood pressure. Given the lack of animal models useful to investigate essential hypertension, we analyze and discuss both clinical and basic research studies indicating that essential hypertension should be considered as a potential multifactorial inflammatory disease. The pathophysiology of essential hypertension might result from interactions between genetic and environmental factors. Morphological abnormalities in the renal parenchyma and arteries have also been shown to determine hypertension. Inflammatory processes might induce renal vasoconstriction, ischemia and injury that can sustain systemic hypertension. Arterial and tubulointerstitial infiltration of inflammatory cells in response to renal damage might further increase renal and vascular alterations through the production of oxidants and other soluble inflammatory mediators. The present review gives an update regarding the latest research on the possible direct role of inflammation in the pathophysiology of essential hypertension.

Selective pharmacological treatments targeting reperfusion injury produced modest protective effects and might be associated with immunosuppression. In order to identify novel and better-tolerated approaches, we focused on the neutralization of receptor activator of nuclear factor kappa-B ligand [RANKL], a cytokine recently shown to activate inflammatory cells (i.e. neutrophils) orchestrating post-infarction injury and repair. Myocardial ischemia (60min) and reperfusion injury was surgically induced in C57Bl/6 mice. In hearts and serum, RANKL was early upregulated during reperfusion. A "one-shot" injection with neutralizing anti-RANKL IgG during ischemia ameliorated myocardial infarct size and function, but not adverse remodeling (determined by Magnetic Resonance Imaging [MRI]) as compared to Vehicle or control IgG. These beneficial effects were accompanied in vivo by reduction in cardiac neutrophil infiltration, reactive oxygen species (ROS) and MMP-9 release. Anti-RANKL IgG treatment suppressed sudden peak of neutrophil granule products in mouse serum early after reperfusion onset. In vitro, RANK mRNA expression was detected in isolated mouse neutrophils. Co-incubation with neutralizing anti-RANKL IgG abrogated RANKL-induced mouse neutrophil degranulation and migration, suggesting a critical role of RANKL in neutrophil-mediated injury. Conversely, anti-RANKL IgG did not affect salvage pathways in cardiac cells (i.e. ERK p42/p44, Akt and STAT-3) or macrophage cardiac infiltration. Finally, treatment with anti-RANKL IgG showed no effect on B and T lymphocyte polarization (in serum, spleen and infarcted myocardium) and circulating chemokines as compared with Vehicle or control IgG. In conclusion, acute treatment with anti-RANKL IgG improved cardiac infarct size and function by potentially impacting on neutrophil-mediated injury and repair.

SummaryParadoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation ofthe “endocannabinoid” system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.

Background: The aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments.Patients and methods: We used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis.Results: Of the 1380 patients enrolled, 27.9% had HF (age 80 ± 7, BMI 27 ± 6 kg/m2) and 17.4% CKD (age 81 ± 7, BMI 26.8 ± 6 kg/m2). Both groups were significantly older (P

Background The clinical history of heart failure (HF) is usually characterized by frequent hospitalizations for decompensation. Therefore, several markers of subclinical hemodynamic congestion are under investigation for predicting early rehospitalization. In this field, the potential of ultrasound inferior vena cava (IVC) assessment has been recently investigated in HF but not yet assessed in the different aetiological categories. Material and methods Forty-eight patients admitted for decompensated HF (n = 25 with ischaemic heart disease [IHD] and n = 23 non-IHD) underwent biochemical examination (including NT-proBNP), echocardiography and IVC assessment by hand-carried ultrasound (HCU). During 60-day follow-up after discharge, the re-hospitalization rate for HF was recorded to investigate the predictive power of NT-proBNP and IVC assessment among the two study groups. Results IHD and non-IHD patients with HF were similar except for gender distribution. During follow-up, 16·7% of patients were rehospitalized for decompensated HF, with higher prevalence in IHD group (28% vs. 4·3% P = 0·031). IVC assessment at discharge significantly predicted re-admission in the overall population and in IHD group, whereas NT-proBNP failed to predict rehospitalization in IHD group. In adjusted hazard ratio, only IVC min and the changes of IVC from admission significantly predicted re-admission. ROC analysis confirmed the change in IVC min as the best predictor of rehospitalization in patients with IHD. Conclusion This pilot study showed a higher early re-admission rate in patients with HF due to IHD. In addition, the change in IVC min diameter from admission to discharge was the best predictor of re-admission in patients with IHD.

Increases in intra-abdominal visceral adipose tissue have been widely appreciated as a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, whereas this is not the case for peripheral or subcutaneous obesity. While the underlying mechanisms that contribute to these differences in adipose tissue activity remain uncertain, increases in visceral fat commonly induce metabolic dysregulation, in part because of increased venous effluent of fatty acids and/or adipokines/cytokines to the liver. Increased body weight, paralleled by an increase in plasma markers of the insulin-resistance syndrome and chronic inflammation, is independently associated with coronary circulatory dysfunction. Recent data suggest that plasma proteins originating from the adipose tissue, such as endocannabinoids (EC), leptin, and adiponectin (termed adipocytes) play a central role in the regulation and control of coronary circulatory function in obesity. Positron emission tomography (PET) in concert with tracer kinetic modeling is a well established technique for quantifying regional myocardial blood flow at rest and in response to various forms of vasomotor stress. Myocardial flow reserve assessed by PET provides a noninvasive surrogate of coronary circulatory function. PET also enables the monitoring and characterization of coronary circulatory function in response to gastric bypass-induced weight loss in initially morbidly obese individuals, to medication and/or behavioral interventions related to weight, diet, and physical activity. Whether the observed improvement in coronary circulatory dysfunction via weight loss may translate to diminution in cardiovascular events awaits clinical confirmation.

Conventional scintigraphic myocardial perfusion imaging with SPECT/CT or with PET/CT has evolved as an important clinical tool for the diagnostic assessment of flow-limiting epicardial lesions and risk stratification of patients with suspected CAD. By determining the relative distribution of radiotracer-uptake in the left-ventricular (LV) myocardium during stress, the presence of flow-limiting CAD lesions can be identified. While this approach successfully identifies epicardial coronary artery lesions, the presence of subclinical and non-obstructive CAD may go undetected. In this direction, the concurrent ability of PET/CT to assess absolute myocardial blood flow (MBF) in ml/g/min, rather that relative regional distribution of radiotracer-uptake, and myocardial flow reserve (MFR), expands the scope of conventional myocardial perfusion imaging from the identification of more advanced and flow-limiting epicardial lesions to (1) subclinical CAD, (2) an improved characterization of the extent and severity of CAD burden, and (3) the discovery of "balanced" reduction in myocardial blood flow as a consequence of 3 vessel CAD. Concurrent to the PET data, the CT component of the hybrid PET/CT allows the assessment of coronary artery calcification as an indirect surrogate for CAD burden, without contrast, or with contrast angiography to directly denote coronary stenosis and/or plaque morphology with CT. Hybrid PET/CT system, therefore, has the potential to not only identify and characterize flow-limiting epicardial lesions but also subclinical stages of functional and/or structural stages of CAD. Whether the application of PET/CT for an optimal assessment of coronary pathology, its downstream effects on myocardial perfusion, and coronary circulatory function will in effect lead to changes in clinical decision-making process, investiture in preventive health care, and improved long-term outcome, awaits scientific verification.

Aims To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. Methods and results Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with 13N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m2 at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m2 ( P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (−0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT ( r = −0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs ( r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function ( r = 0.22, P = 0.400, and r = −0.31, P = 0.250). Conclusions Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.

Metabolic syndrome has been widely associated with an increased risk for acute cardiovascular events. Emerging evidence supports metabolic syndrome as a condition favoring an adverse cardiac remodeling which might evolve towards heart dysfunction and failure. This pathological remodeling has been described to result from the cardiac adaptive response to clinical mechanical conditions (such as hypertension dyslipidemia and hyperglycemia) soluble inflammatory molecules (such as cytokines and chemokines) as well as hormones (such as insulin) characterizing the pathophysiology of metabolic syndrome. Moreover these cardiac processes (resulting in cardiac hypertrophy and fibrosis) are also associated with the modulation of intracellular signalling pathways within cardiomyocytes. Amongst the different intracellular kinases mitogen activated protein kinases (MAPKs) were shown to be involved in heart damage in metabolic syndrome. However their role remains controversial. In this paper we will discuss and update evidence on MAPK mediated mechanisms underlying cardiac adverse remodeling associated with metabolic syndrome. © 2013 Mohamed Asrih et al.

Hybrid PET/MRI imaging techniques are become more readily available, and its role in viability assessment appears promising.

We aimed at determining whether anti-apolipoprotein (apo) A-1 IgG levels are independent predictors of coronary artery calcification (CAC) and coronary endothelial dysfunction in obese and nonobese subjects without cardiovascular disease. 48 nonobese and 43 obese subjects were included. CAC score was measured by thorax scanner and defined by an Agatston score > 0. Coronary endothelial dysfunction was determined by measuring myocardial blood flow responses to cold pressor test (CPT) on PET/CT. Serum anti-apoA-1 IgG levels were measured by ELISA. Prevalence of coronary calcification was similar between the two study groups, but the prevalence of coronary endothelial dysfunction was higher in obese subjects. Anti-apoA-1 IgG levels and positivity rate were higher in obese than in nonobese individuals. CAC score was higher in anti-apoA-1 IgG positive subjects. ROC analyses indicated that anti-apoA-1 IgG levels were significant predictors of CAC > 0, but not of coronary endothelial dysfunction with a negative predictive value of 94%. Anti-apoA-1 IgG positivity was associated with a 17-fold independent increased risk of CAC > 0. In conclusion, those preliminary results indicate that anti-apoA-1 IgG autoantibodies are raised in obese subjects and independently predict the presence of coronary calcification in this population but not the presence of coronary endothelial dysfunction.

Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients ( n = 11) or healthy controls ( n = 8). Serum and plasma was collected before acipimox administration ( time 0) as well as 2–5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophil and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time 0 and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum-induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNK1/2 phosphorylation. Although mRNA expression of acipimox receptor (GPR109) was shown in human neutrophils, 5–500 μM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin.

Nicotinic acid (at a daily dose of grams) has been shown to induce potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional anti-atherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) are drugs active in the blockade of cholesterol synthesis and thus lowering cholesterol serum levels. Since their discovery, experimental evidence showed that statins strongly reduced atherogenesis and the risk of acute ischemic complications, such as acute myocardial infarction and stroke. More recently, direct anti-atherosclerotic effects of statins (independently of lipid profile improvement) have been also shown, suggesting new potential applications for these drugs in both primary and secondary prevention of acute cardiovascular events. Despite some controversies exist, the use of statins has been shown to improve both incidence and survival in acute ischemic stroke. The molecular mechanisms underlying statin-mediated clinical benefits were recently identified in the reduction of carotid plaque vulnerability and the increase of neuroprotection. In the present review, we will update evidence on the promising results with statins to improve ischemic stroke outcomes.

Obstructive sleep apnea syndrome (OSAS) is an often underestimated sleep disorder that has been associated with cardiovascular disease. OSAS is characterized by cycles of apnea and/or hypopnea during sleep caused by the collapse of the upper airways. Intermittent hypoxia deriving from the cycles of apnea/arousals (to retrieve the ventilation) plays a pivotal role in the pathogenesis of the disease. Obesity is the most frequent predisposing condition of OSAS. Recent evidence suggests that OSAS could be considered as a pro-atherosclerotic disease, independently of visceral fat amount. Oxidative stress, cardiovascular inflammation, endothelial dysfunction, and metabolic abnormalities in OSAS could accelerate atherogenesis. The present review is focused on the possible pathophysiological mediators which could favor atherosclerosis in OSAS.

1. Chlorhexidine digluconate has been used as a topical antiseptic in the treatment of acne vulgaris and periodontitis. The acute phase of these diseases involves neutrophilic infiltration. Neutrophil activation and recruitment to inflammatory sites are crucial in both protection against bacterial infection and the induction of hystotoxic damage. Activated neutrophils release several enzymes, including elastase and myeloperoxidase (MPO), which contribute to tissue injury via direct toxic actions, the generation of oxidants and inactivation of protective factors, such as alpha1-antitrypsin (alpha1-AT). In the present study, we investigated whether chlorhexidine can modulate neutrophil-mediated histotoxicity. 2. Human primary neutrophils were isolated from healthy donors. Inactivation of alpha1-AT by neutrophils or hypochlorous acid (HOCl) was evaluated by spectrophotometry and sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis of its capacity to complex with porcine pancreatic elastase (PPE). Neutrophil generation of HOCl, superoxide anion and MPO release were assessed spectrophometrically. 3. Chlorhexidine (0, 0.5, 1, 5 and 10 micromol/L) dose-dependently prevented HOCl-induced inactivation of alpha1-AT and reduced HOCl recovery from phorbol myristate acetate (PMA)-treated human neutrophils, but did not inhibit superoxide anion and MPO release. Chlorhexidine directly inhibited HOCl recovery from neutrophils and HOCl-induced inactivation of alpha1-AT in a cell-free assay. Accordingly, chlorhexidine reversed HOCl-mediated inhibition of alpha1-AT capacity to complex with PPE. 4. These data suggest that chlorhexidine prevents neutrophil-induced alpha1-AT inactivation via a direct inhibitory action on HOCl. Although highly speculative, the present study indicates that chlorhexidine may protect inflamed tissues not only through its antimicrobial properties, but also via a direct anti-inflammatory effect on neutrophil toxic products.

BACKGROUND: Treatments with ezetimibe/simvastatin (combined or alone) have been indicated as very promising approaches to strongly reduce cholesterol levels in hyperlipidemic patients. OBJECTIVE: We will discuss the efficacy and safety of ezetimibe/simvastatin and their potential to reduce atheroprogression. The molecular mechanisms underlying the possible benefits in atherosclerosis and its complications will also be described. RESULTS/CONCLUSIONS: Combined therapy with ezetimibe/simvastatin has been shown to improve lipid profile inducing a very rapid reduction of low-density lipoprotein cholesterol levels in clinical trials. In the near future, potential clinical benefits could be observed in the IMPROVE-IT or SHARP trials. Although clinical studies are needed to further confirm safety of ezetimibe/simvastatin therapy, the greater efficacy in lipid-lowering was not associated with the increase of adverse events. Also the possible association between ezetimibe and cancer, which was observed in the SEAS trial, was not confirmed by further studies and meta-analyses. At present, ezetimibe should be considered an effective lipid-lowering agent that can be used in conjunction with simvastatin at the beginning of therapy, or included in the treatment of patients who do not achieve their low-density lipoprotein cholesterol goal with statins alone.

The modulation of CD40L activity might represent a promising therapeutic target to reduce monocyte inflammatory functions in chronic diseases, such as rheumatoid arthritis. In the present study, we investigated the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on CD40L-induced monocyte survival. Monocytes were isolated from buffy coats by using Ficoll-Percoll gradients. Monocyte apoptosis was evaluated by fluorescence microscopy on cytopreps stained with acridine orange or using flow cytometry analysis of Annexin-V and Propidium Iodide staining. Akt and NF-κB activation was assessed using western blot. Caspase 3 activity was determined spectrophotometrically. Among different NSAIDs, only oxaprozin dose-dependently increased apoptosis of CD40L-treated monocytes. Oxaprozin pro-apoptotic activity was associated with the inhibition of CD40L-triggered Akt and NF-κB phosphorylation and the activation of caspase 3. In conclusion, our data suggest that oxaprozin-induced apoptosis in CD40L-treated human monocytes is associated with previously unknown cyclooxygenase (COX)-independent pathways. These intracellular proteins might be promising pharmacological targets to increase apoptosis in CD40L-treated monocytes.

1. Neutrophils release several histotoxic molecules that cause tissue injury. Neutrophil apoptosis is a crucial process that governs the persistence of inflammatory disorders and tissue damage. Thus, in the present study, we investigated whether the anti-inflammatory drug sulphasalazine (SSZ) affects neutrophil apoptosis in the presence of insoluble immune complex (IC). 2. Neutrophils were obtained from healthy donors. Neutrophils were resuspended in incubation medium and incubated for 2-12 h with or without 10, 30 or 100 micromol/L SSZ and 25 microg/mL IC. In some experiments, cells were co-incubated with 20 micromol/L Z-IETD-fmk (a caspase 8 inhibitor) or 20 micromol/L Z-LEHD-fmk (a caspase 9 inhibitor). Apoptosis was evaluated morphologically on cytological preparations stained with May-Grünwald-Giemsa as well as by flow cytometry analysis of annexin V and propidium iodide staining. Caspase 3 activity was determined spectrophotometrically. 3. At 100 micromol/L, SSZ significantly accelerated IC-induced neutrophil apoptosis. Treatment of neutrophils with 20 micromol/L of the caspase 8 or 9 inhibitors Z-IETD-fmk or Z-LEHD-fmk, respectively, demonstrated that the SSZ-induced pro-apoptotic effect was mediated by a caspase 8- but not caspase 9-dependent pathway. The caspase 3 activity assay showed that treatment with 100 micromol/L SSZ increased caspase 3 activation. 4. In conclusion, the results of the present study indicate that it is possible that the molecular mechanism underlying SSZ protection against neutrophil-mediated tissue injury inflammatory disorders, such as rheumatoid arthritis and inflammatory bowel diseases, involves a caspase 8-dependent pathway.

In their paper published in this issue of Heart , Pazhenkottil et al 1 demonstrate for the first time that left ventricular (LV) dyssynchrony, as determined by phase analysis of gated myocardial perfusion SPECT (GMPS), is a strong predictor of major adverse cardiac events independent of other known predictors such as regional myocardial perfusion defects or decreased LV ejection fraction (LVEF) ( see page 33 ). The current investigation agrees with previous investigations in patients with heart failure and LV dyssynchrony2–5 but extends it now to an unselected patient population with suspected or known coronary artery disease. Similar observations were also reported more recently by Aljaroudi et al 6 in 144 patients with end-stage renal disease. In their specific study population with end-stage renal disease, the proof of LV dyssynchrony by phase analysis with GMPS was associated with increased all-cause mortality during a mean follow-up of 41±28 months. The reasons for LV dyssynchrony in these two populations studied1 6 remain uncertain but could be related to volume overload of the left ventricle, pulmonary hypertension with right ventricular dilatation associated with septal wall flattening, leading to abnormal contraction, left bundle branch block, LV hypertrophy, myocardial interstitial fibrosis in the process of LV remodelling and other, but not yet determined, factors. Independent of …

Objectif Nous avons evalue une possible association entre les concentrations plasmatiques d’endocannabinoids (ECs) comme l’andamide (AEA) et le 2-arachidonoylglycerol (2-AG), et la fonction de la circulation coronarienne en tant que precurseur fonctionnel de la maladie coronarienne manifeste chez des sujets obeses. Patients et methodes La reponse du flux sanguin myocardique (FSM) a la stimulation avec la glace (cold pressor test ; (CPT)) et pendant vasodilatation pharmacologique avec dipyridamole ont ete mesurees avec 13N-ammonia tomographie par emission des positrons (TEP) en ml/g/min. La population d’etude (n = 77) a ete divisee en trois groups selon l’index de mass corporelle (IMC, kg/m2): group de control 20 ≤ IMC Resultats Les concentrations plasmatiques de AEA et 2-AG augmentaient seulement chez les obeses par rapport aux controles, respectivement (0.70 ± 0.20 vs. 0.56 ± 0.10 ng/ml, p Conclusion Des concentrations plasmatiques elevees d’EC comme l’AEA et le 2-AG sont associees independamment avec une dysfonction de la microcirculation coronarienne chez les sujets obeses.

Positron emission tomography (PET) myocardial perfusion imaging in concert with tracer-kinetic modeling affords the assessment of regional myocardial blood flow (MBF) of the left ventricle in absolute terms (milliliters per gram per minute). Assessment of MBF both at rest and during various forms of vasomotor stress provides insight into early and subclinical abnormalities in coronary arterial vascular function and/or structure, noninvasively. The noninvasive evaluation and quantification of MBF and myocardial flow reserve (MFR) extend the scope of conventional myocardial perfusion imaging from detection of end-stage, advanced, and flow-limiting, epicardial coronary artery disease (CAD) to early stages of atherosclerosis or microvascular dysfunction. Recent studies have shown that impaired hyperemic MBF or MFR with PET, with or without accompanying CAD, is predictive of increased relative risk of death or progression of heart failure. Quantitative approaches that measure MBF with PET identify multivessel CAD and offer the opportunity to monitor responses to lifestyle and/or risk factor modification and to therapeutic interventions. Whether improvement or normalization of hyperemic MBF and/or the MFR will translate to improvement in long-term cardiovascular outcome remains clinically untested. In the meantime, absolute measures of MBF with PET can be used as a surrogate marker for coronary vascular health, and to monitor therapeutic interventions. Although the assessment of myocardial perfusion with PET has become an indispensable tool in cardiac research, it remains underutilized in clinical practice. Individualized, image-guided cardiovascular therapy may likely change this paradigm in the near future.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver damage and alteration of hepatic enzymes. NAFLD is strongly associated with metabolic syndrome and obesity. It is characterized by fat accumulation in the liver that may progress throughout hepatic steatosis and inflammation (non-alcoholic steatohepatitis [NASH]) toward cirrhosis and liver failure. In the last decade several studies suggested that NAFLD is an independent cardiovascular risk factor that increases cardiovascular mortality. At present, several studies investigating possible therapeutic approaches are ongoing. The present review is focused on the current and promising treatments of NAFLD.