👤 Roberta Fazio

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2-3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin-melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive ( Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future. Show less

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases circulating LDL levels and cardiovascular disease (CVD) risk; its levels may be related to the dysregulation of glycemic control and may be affected by estrogens. The aim of this study was to assess factors related to PCSK9 levels, and to evaluate the correlation between PCSK9 levels and CV parameters in post-menopausal diabetic women in primary prevention. Generalized linear models (GLM) were adopted to evaluate predictors of PCSK9 levels as well as factors related to CV outcomes, such as pulse wave velocity (PWV), pulse pressure (PP), and augmentation index (AI). A total of 135 post-menopausal diabetic women, with a median (Q1-Q3) serum PCSK9 levels of 370.3 (344.0-409.4) ng/ml were enrolled. Apolipoprotein B values resulted an independent predictor of PCSK9 levels ( ApoB and LDL may influence PCSK9 levels and PCSK9 directly influence PWV in post-menopausal diabetic women in primary prevention. Therefore, the relationship between PCSK9 and primary prevention cannot be excluded, thus highlighting its role as biomarker of CV risk. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less

MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers. Show less

Apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]) are predictors of cardiovascular disease (CVD) risk; therefore, current recommendations for CVD risk assessment and management advocate that patients receive testing for ApoB and Lp(a) in addition to the standard lipid panel. However, US guidelines around ApoB and Lp(a) testing have evolved over time and vary slightly by expert committee. The objective of this analysis was to estimate the number of insured individuals in the USA who received any component of a lipid test, or ApoB and/or Lp(a) testing, during 2019. We conducted a cross-sectional analysis to estimate the prevalence of any component of a lipid test, ApoB, and/or Lp(a) in the USA using four different claim data sources (including Medicaid, Medicare, and commercially insured enrollees). Prevalence estimates were age-, sex-, payor-, and region-standardized to the 2019 US Annual Social and Economic Supplement of the Current Population Survey. We also described the clinical profile of patients who received lipid testing between 2019 and 2021 (cohort analysis) in Optum claims database. Enrollees were grouped into four non-mutually exclusive cohorts based on their completion of any component of the lipid panel, ApoB, Lp(a), or ApoB and Lp(a). In the prevalence cohort, over a third (38 %) of insured adults in the USA underwent testing for any component of a lipid panel in 2019. This proportion was higher for individuals aged ≥65 years compared to younger adults (62% vs 31 %). The proportion of ApoB and Lp(a) testing represented only <1 % of testing for any component of a lipid panel. In the cohort analysis, we found that lipid testing increased with age and comorbidities. These data should be considered by guideline-issuing agencies and organizations to develop education campaigns encouraging more frequent use of tests beyond the standard lipid panel. Show less

Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC). Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRAS Show less

Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction. Investigate the relationship between long-term functional recovery and HDL proteome and function. Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP [adipocyte plasma membrane-associated protein], GPLD1 [phosphate inositol-glycan specific phospholipase D], APOE [apolipoprotein E], IHH [Indian hedgehog protein], ITIH4 [inter-alpha-trypsin inhibitor chain H4], SAA2 [serum amyloid A2], APOA4 [apolipoprotein A-IV], CLU [clusterin], ANTRX2 [anthrax toxin receptor 2], PON1 [serum paraoxonase/arylesterase], SERPINA1 [alpha-1-antitrypsin], and APOF [apolipoprotein F]) were significantly (adjusted Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation. Show less

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM. Show less

We describe a case of a 36-year-old woman with severe hypertriglyceridemia likely caused by double heterozygosity of a known pathogenic APOA5 nonsense variant (p.Q275X) and a novel CREB3L3 nonsense variant (p.C296X) on a background of very strong polygenic susceptibility. Her clinical course worsened with development of eruptive xanthomata after oral administration of 2 mg estradiol twice daily for 2 weeks as part of a medical protocol for intrauterine embryo transfer following in vitro fertilization. Her triglyceride levels decreased to baseline and xanthomata resolved without treatment after discontinuation of hormonal therapy, which also resulted in termination of pregnancy. Before undergoing a second embryo transfer using her natural cycle and no exogenous hormones, the patient started combination therapy with eicosapentaenoic acid ethyl ester and gemfibrozil, leading to an ∼80% decrease in triglyceride levels. She continued treatment throughout pregnancy, which progressed to term with the delivery of healthy twins. Show less

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects. Show less

We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis. Show less

Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function. Show less

Multiple osteochondromas (MO), also known as hereditary multiple exostoses (HME), is one of the most common hereditary musculoskeletal diseases in Caucasians (1/50,000) with wide clinical variability and genetic heterogeneity. Two genes have thus far been identified as causing the disease, namely EXT1 and EXT2. Various methods to detect mutations in the EXT genes have been used. Here a cohort of 100 MO patients belonging to unrelated Italian families have been analyzed by single-strand conformation polymorphism (SSCP) analysis or by denaturing high performance liquid chromatography (DHPLC). However, neither of these techniques can detect deletions or duplications of entire exons. Families that were negative at SSCP/DHPLC analysis underwent two-color multiple ligation-dependent probe amplification (MLPA) analysis. By these complementary techniques mutation detection was significantly improved and 26 novel mutations have been revealed as well as 18 previously described mutations to give a total of 44 different mutations. Thus we can conclude that combining MLPA with DHPLC in point-mutations negative MO families, the detection of mutations in EXT genes can significantly improve the identification of both point-mutations and mid-size rearrangements. More important, we were able to characterize all those patients who were negative at the first PCR-based method screening. Show less

Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes. Show less