Papers by Alberico Catapano
Journal of the American College of Cardiology, 2011
Objective: Carotid intima media thickness (CIMT) is a marker of subclinical organ damage, and pre... more Objective: Carotid intima media thickness (CIMT) is a marker of subclinical organ damage, and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change with subsequent CVD events is uncertain, and its use as a surrogate endpoint in clinical trials is controversial. Our aim was to determine the relation of CIMT change with incident CVD events in people with diabetes. Research Design and Methods: In a comprehensive meta-analysis of individual participant data, we collated data from 3902 adults (age range 33-92) with type 2 diabetes from 21 population-based cohort studies. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery (CCA) IMT, or in CCA-CIMT progression, for each cohort, and combined the estimates with random effects meta-analysis. Results: Average annual mean CCA-IMT progression in people with diabetes ranged between-0.09 and 0.04mm/year across cohorts. The HR of CVD events was 1.22 (95% confidence interval 1.12-1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and a large set of cardiometabolic risk factors. The corresponding HR per SD difference in annual mean CCA-IMT progression was 0.99 (0.91-1.08). Conclusions: Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support of the use of CIMT progression as a surrogate endpoint in clinical trials in people with diabetes.
Circulation, Sep 1, 2020
Background: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disea... more Background: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid lowering in younger adults as a function of expected 30-year benefit. Methods: Data from 3148 National Health and Nutrition Examination Survey (2009–2016) participants, age 30 to 59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analyzed. We estimated the absolute and relative impact of lipid lowering as a function of age, age at initiation, and non–high-density lipoprotein cholesterol (HDL-C) level on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorter-term effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B). Results: In both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater with older age and higher non–HDL-C level. Immediate initiation of lipid lowering (ie, treatment for 30 years) in 40- to 49-year-old patients with non–HDL-C ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction [ARR], 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6% (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved ARR as a function of delay in treatment was also higher with older age and higher non–HDL-C level. Conclusions: Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid lowering in individuals in their 40s and 50s with non–HDL-C ≥160 mg/dL. For many, the question of when to start lipid lowering might be more relevant than whether to start lipid lowering.
Pharmacology & Therapeutics, Aug 1, 2023
Nutrition Metabolism and Cardiovascular Diseases, Jul 1, 2023
Research Square (Research Square), Jun 9, 2023
Background and aim: Unhealthy dietary habits and highly caloric foods induce metabolic alteration... more Background and aim: Unhealthy dietary habits and highly caloric foods induce metabolic alterations and promote the development of in ammatory consequences of obesity and insulin resistance, which are epidemic conditions leading to diabetes and cardiovascular diseases. Describing an in ammatory effect of diet is di cult to pursue, owing to the lack of quali-quantitative dietary assessment standardization. The Dietary In ammatory Index (DII) has been proposed as an estimator of the pro-or anti-in ammatory effect of nutritional components. Higher DII values, which indicate an increased intake of nutrients with proin ammatory effects, relates to an increased risk of metabolic and cardiovascular diseases in epidemiological studies. Whether higher DII values re ect biologically relevant variations of in ammatory proteins in plasma, has been poorly described today. Methods: In this cross-sectional study, seven-days dietary records from 663 subjects in primary prevention for cardiovascular diseases were analyzed to derive the intake of nutrients, foods and to calculate DII. To associate DII with the Normalized Protein eXpression (NPX), an index of abundance, of a targeted panel of 368 in ammatory biomarkers (Olink™) measured in the plasma, we divided the population by the median value of DII (1.60 (0.83-2.30)). Results: subjects with estimated DII over the median value reported a higher intake of saturated fats but lower intakes of poly-unsaturated fats, including omega-3 and omega-6 fats, versus subjects with estimated dietary DII below the median value (N = 331). The NPX of 61 proteins was increased in the plasma of subjects with DII > median vs subjects with DII < median. By contrast, in the latter group, we underscored only 3 proteins with increased NPX. Only 23, out of these 64 proteins, accurately identi ed subjects with DII > median (Area Under the Curve = 0.601 (0.519-0.668), p = 0.035). Conclusion: This large-scale proteomic study supports that higher DII re ects changes in the plasmatic abundance of in ammatory proteins. Larger studies are warranted to validate.
Nutrients, May 13, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Atherosclerosis, Jun 1, 2023
Clinical Chemistry, Dec 1, 1986
We produced and characterized several monoclonal antibodies directed toward human plasma apolipop... more We produced and characterized several monoclonal antibodies directed toward human plasma apolipoprotein A-I. Two of them, A-I-12 and A-I-57, individually precipitated purified or native high-density lipoprotein in agarose gel by double immunodiffusion. Because radial immunodiffusion performed with a single monoclonal antibody gave faint and diffuse rings of precipitation, we developed and optimized working conditions for using these two monoclonal antibodies combined to determine apolipoprotein A-I in human plasma. This combination gave easy-to-measure, clear, sharp rings, and linear and parallel standard curves for HDL3 (the primary standard) and a reference serum (the secondary standard). Moreover, no pretreatment of samples with dissociating agents or detergents is necessary. The assay was complete after overnight incubation, as compared with two to three days when polyclonal antisera were used. Apolipoprotein A-I concentrations as measured in 128 normolipidemic subjects and in 72 patients with various lipid disorders by the radial immunodiffusion technique with monoclonal antibodies (x) compared well (r = 0.882; y = 1.029x-0.036) with those measured by radial immunodiffusion with polyclonal antisera (y).
Trends in Pharmacological Sciences, Apr 1, 2013
Wiener Klinische Wochenschrift, Jun 8, 2023
Simulation of bempedoic acid and ezetimibe in the lipid-lowering treatment pathway in Austria usi... more Simulation of bempedoic acid and ezetimibe in the lipid-lowering treatment pathway in Austria using the.. .
Atherosclerosis, Aug 1, 2018
Aim: High-density lipoproteins (HDLs) transport endogenous miRNAs and deliver them to recipient c... more Aim: High-density lipoproteins (HDLs) transport endogenous miRNAs and deliver them to recipient cells with functional targeting capabilities. The impact of high-cholesterol levels on HDL-miRNA signature remains unknown. We investigated the effect of hypercholesterolemia on HDL-miRNA profile and miRNA delivery to endothelial cells. Methods: HDLs were isolated from pigs fed 10days a normocholesterolemic (NC; N¼10; total cholesterol:38.5[25.8-41.0]mg/dL) or a hypercholesterolemic (HyC; N¼10; total cholesterol: 245.5[166.2-291.2]mg/dL) diet. We performed a differential HDL-miRNA expression profiling (n¼149 miRNAs) between NC-and HyC-HDLs. Culture studies in porcine aortic endothelial cells were conducted to determine whether the identified differentially expressed miRNAs were delivered to endothelial recipient cells through a SRB-1 dependent mechanism. After qPCR and data analyses, networks, targets and miRNA interactions were analyzed by bioinformatics. Results: Five microRNAs were differentially transported between NC-and HyC-HDL particles (p<0.05). Particularly, HyC-HDL carried high levels of miR-126-5p, miR-126-3p and miR-30b-5p (2.7x, 1.7x and 1.3x respectively) while levels of miR-103a-3p and miR-let-7g-5p were found to be reduced (-1.6x,-1.4x, respectively) vs. NC-HDL. Only miR126-3p/-5p was found to be enhanced in endothelial cells upon HDL treatment. Interestingly, miR-126-3p/-5p levels were 3x higher in those endothelial cells incubated with HyC-HDL as compared to NC-HDL (p<0.05), an effect that persisted despite HDL removal and was dependent on SRB-1 transport. IPA revealed that miR126 regulated 101 transcripts involved in lipid metabolism, insulin sensitivity, apoptosis, inflammation and immunity, clot formation and angiogenesis. Conclusions: Hypercholesterolemia changes HDL-miRNA profile and enhances SRB-1-dependent HDL-miR126 delivery to endothelial cells likely modulating key genes involved vascular health.
Pharmacological Research, Oct 1, 2014
The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the re... more The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the results of observational studies and clinical trials provide compelling evidence that skeletal muscle toxicity is a frequent, dose-dependent, adverse event associated with all statins. It has been suggested that reduced availability of metabolites produced by the mevalonate pathway rather than intracellular cholesterol lowering per se might be the primary trigger of toxicity, however other alternative explanations have gained credibility in recent years. Aim of this review is: (i) to describe the molecular mechanisms associated to statin induced myopathy including defects in isoprenoids synthesis followed by altered prenylation of small GTPase, such as Ras and Rab proteins; (ii) to present the emerging aspects on pharmacogenetics, including CYP3A4, OATP1B1 and glycine amidinotransferase (GATM) polymorphisms impacting either statin bioavailability or creatine synthesis; (iii) to summarize the available epidemiological evidences; and (iii) to discuss the concepts that would be of interest to the clinicians for the daily management of patients with statin induced myopathy. The interplay between drug-environment and drug-drug interaction in the context of different genetic settings contribute to statins and skeletal muscles toxicity. Until specific assays/algorithms able to combine genetic scores with drug-drug-environment interaction to identify patients at risk of myopathies will become available, clinicians should continue to monitor carefully patients on polytherapy which include statins and be ready to reconsider dose, statin or switching to alternative treatments. The beneficial effects of adding agents to provide the muscle with the metabolites, such as CoQ10, affected by statin treatment will also be addressed.
Impairment of cholesterol homeostasis is one of the multiple etiopathological mechanisms at the o... more Impairment of cholesterol homeostasis is one of the multiple etiopathological mechanisms at the origin of both cardiovascular and neurodegenerative diseases. The PCSK9 protein, known for its role in the degradation of hepatic LDLR and plasma cholesterol regulation, is expressed also in the CNS, where it exacerbates β-amyloid neurotoxicity and reduces neuronal cholesterol uptake, suggesting an involvement in AD. This study proposes an in vitro screening of molecules (MR) with inhibitory activity on PCSK9, selecting the best compounds to test their activity on cerebral cell models and their in vivo tolerability. Methods: 30 newly synthesized compounds were tested at increasing concentrations on human hepatoma cells (HepG2) to evaluate their cytotoxicity and efficacy in inhibiting PCSK9. MR-3 was tested on human neuroblastoma cells (SH-SY5Y) overexpressing PCSK9 to assess neurotoxicity and cholesterol uptake. Cytotoxicity was determined through MTT assay; PCSK9 secretion was quantified with an ELISA kit; and radioisotopic techniques measured cholesterol uptake. Three compounds were selected to be tested in vivo on C57BL/6 mice at a dose of 40 mg/Kg for 7 days to evaluate: tolerability with SHIRPA test; plasma lipid profile by ELISA assay; biodistribution in plasma and brain through LC-MS/MS. Results: Among the tested compounds, MR-3, MR-532, MR-533 demonstrated no sign of cytotoxicity and the greatest efficacy on HepG2 cells (IC 50 =1.7μM; 5.7μM; 6.1μM). Neuronal cholesterol uptake was restored after treatment with MR-3 at 10μM (p<0,05). MR-3, MR-532, and MR-533 exhibited good in vivo tolerability; MR-3 and MR-532 were detected in plasma and brain tissue. Conclusions: Preliminary in vitro screening allowed the identification of MR-3, MR-532, MR-533 as promising PCSK9 inhibitors. The outcome of MR-3 on neuronal cholesterol uptake may suggest a neuroprotective effect to be further investigated. In vivo treatment with selected inhibitors shown absence of toxicity, however, it is necessary to bring proof of efficacy.
Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 ... more Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT. Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS. Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P&lt;0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P&lt;0.0001). No difference was observed following HDAC3 silencing in mature adipocytes. We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation. Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype. [FONDAZIONE CARIPLO 2015-0641]
Background: Inherited predisposition to atherosclerosis leads to higher risk for developing coron... more Background: Inherited predisposition to atherosclerosis leads to higher risk for developing coronary heart disease (CHD). There are mainly two ways to conceptualize inherited risk of CHD: family history and polygenic predisposition. We aimed at assessing the impact of family history of CHD and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE). Methods: Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated by a polygenic risk score including 350 variants). Results: A total of 445,744 UK-Biobank participants were included in the study (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75), suggesting an additive contribution to the characterization of the lifetime risk. Conclusions: We described the addictive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. In order to identify subjects at higher risk of having an early event, it is essential to retrieve information about both these hereditary components.
The causal role of low-density lipoprotein cholesterol LDL-C in atherosclerotic-related cardiovas... more The causal role of low-density lipoprotein cholesterol LDL-C in atherosclerotic-related cardiovascular disease (ASCVD) has been undoubtedly established over the last decades, and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular (CV) events. A large number of observations has definitely proven that the protective effect is independent of the drug used to lower LDL-C, with a continuous linear reduction of CV risk with further LDL-C reductions. Although high-intensity statin therapy may significantly reduce CV event incidence, frequently statins are insufficient to achieve the large reductions recommended by current guidelines for high and very high risk patients. Several non-statin drugs, having mechanisms of action complementary to that of statins, are now available, and include ezetimibe, monoclonal antibodies targeting PCSK9, and, more recently, inclisiran, bempedoic acid, and evinacumab. Combining these drugs based on the recommendations by current and future guidelines should be considered for optimal risk reduction, although several gaps in clinical practice remain to be filled.
Giornale italiano di cardiologia, Oct 1, 2004
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Papers by Alberico Catapano