👤 Arrigo F G Cicero

Although recommended for cardiovascular (CV) risk stratification in adults, the role of lipoprotein(a) [Lp(a)] in hypertension is not fully established. To evaluate Lp(a) levels in adult outpatients with essential arterial hypertension. A retrospective, observational study was conducted in outpatients of both sexes, aged ≥ 18 years, with treated or untreated essential hypertension, who were consecutively evaluated at the Hypertension Unit, Excellence Hypertension Center, Sant'Andrea Hospital, Rome, Italy. Participants underwent office and out-of-office blood pressure (BP) measurements, as well as assessment of hypertension-mediated organ damage (HMOD). BP measurements were performed, and hypertension phenotypes were classified according to 2023 European hypertension guidelines. Lp(a) levels were measured, and the study population was stratified according to a Lp(a) cut-off value of ≥50 mg/dl. Due to the non-uniform distribution, absolute Lp(a) values were logarithmically transformed. A total of 230 patients with available Lp(a) values were included (42.6% women, mean age 66.3 ± 11.5 years, BMI 27.1 ± 4.5 kg/m2, office BP 137.1 ± 18.1/83.7 ± 11.0 mmHg, 24-hour BP 129.8 ± 14.5/79.6 ± 9.8 mmHg, Lp(a) 51.4 ± 65.3 mg/dL), among whom 32.2% had Lp(a) ≥50 mg/dl. There were significantly higher proportions of men (74.3% vs. 49.4%; P < 0.001), dyslipidaemia (97.3% vs. 75.0%; P < 0.001) and comorbidities (55.4% vs. 30.8%; P < 0.001) in patients with high Lp(a) than in those with normal Lp(a), who also received more frequently lipid lowering therapies (P < 0.001) and aspirin (P = 0.003). However, lower office systolic BP values (133.5±18.8 vs. 138.8±17.6 mmHg: P = 0.036) were observed in patients with Lp(a) ≥50 mg/dL than in those with < 50 mg/dl. Also, no significant differences for Lp(a) levels were observed among various hypertension phenotypes, as defined by office (P = 0.156) or out-of-office BP values (P = 0.065). No significant correlations were found between Lp(a) and office or out-of-office BP levels, both in treated and untreated hypertensive outpatients. In our population, Lp(a) levels were not associated with either office or out-of-office BP values, irrespective of antihypertensive treatment status. The role of Lp(a) in hypertension warrants further investigation. Show less

Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment. Show less

An 8.5-month-old female British Shorthair (case 1) and a 2-month-old female domestic shorthair (case 2) were referred for dyspnoea and lethargy. Echocardiography was compatible with unrestrictive patent ductus arteriosus (PDA) with continuous left-to-right shunting and concomitant iso-systemic pulmonary hypertension (PH) (case 1) and restrictive PDA with mild PH (case 2). Radiography showed cardiomegaly, increased pulmonary vascular markings and diffuse interstitial-alveolar pattern consistent with congestive heart failure (CHF) in both cats. After testing for pulmonary vascular reactivity (case 1) and treatment for acute CHF (case 2), surgical ligation of the PDA was attempted. In case 1, PDA ligation led to severe hypotension and asystole, prompting loosening of the ligature because of suspected intolerance to PDA closure. Cardiac massage was initiated and successfully restored the sinus rhythm. The procedure was aborted after partial PDA attenuation. Postoperative echocardiography raised suspicion of pulmonary artery ligation and supra-systemic right ventricle. No surgical revision was performed as the cat remained clinically stable; however, she died 10 days after surgery. In case 2, severe bradycardia developed 20 mins after duct ligation, followed by cardiorespiratory arrest unresponsive to resuscitation. Anatomopathological examination revealed main pulmonary artery and PDA ligation (case 1), and complete left pulmonary artery (LPA) ligation (case 2). Inadvertent ligation of the pulmonary artery has been reported in human medicine, and to the best of our knowledge, this is the first report in cats. Prompt recognition and correction of such errors are critical for a favourable immediate perioperative outcome and improved long-term prognosis. Show less

Direct measurement of apolipoprotein B (ApoB) is not always standardized and is relatively expensive, making it unavailable in several low-income settings. To address this issue, several formulas have been developed to estimate ApoB levels. Therefore, our study aims to compare the reliability of 23 formulas for estimating ApoB levels in a large cohort of South-European individuals. We retrospectively assessed 4.577 clinical records in which ApoB measurements were obtained using the same standardized method. Overall concordance was defined as the proportion of cases where the directly measured ApoB level fell within the same category as the estimated ApoB level, based on ApoB quartiles (<80 mg/dL, 80-94 mg/dL, 95-114 mg/dL, and ≥115 mg/dL). In addition, overall concordance was assessed for different lipoprotein(a) (Lp(a)) and non-high density lipoprotein cholesterol (non-HDL-C) sub-levels. Ordinary least squares linear regression analyses were performed to compare estimated and measured ApoB values. Residual error plots were generated to visualize the difference between each estimation method and the actual ApoB measurements, stratified by Lp(a) and non-HDL-C levels. Plasma ApoB levels were best predicted by a non-HDL-C based formula and a formula using Friedewald's low-density lipoprotein cholesterol (LDL-C), regardless of ApoB plasma levels. Non-HDL-C levels did not significantly affect the concordance between measured and estimated ApoB across the different formulas, except at low non-HDL-C levels. Similarly, Lp(a) levels did not significantly impact concordance. However, the highest concordance level was 41 %. Some simple formulas based on low-cost and widely available parameters can estimate ApoB levels independently of ApoB, non-HDL-C, and Lp(a) plasma levels. This approach may be particularly useful for estimating ApoB levels in low-resource settings. 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

To revise the clinical evidence supporting the use of volanesorsen as new lipid-lowering drug and to assess the efficacy and safety of volanesorsen (ISIS 304801) through a systematic review of the literature and a meta-analysis of the available phase 2 and phase 3 clinical studies. The meta-analysis of three clinical studies comprising 11 arms (N = l 156 subjects, with 95 in the active-treated arm and 61 in the control one) shows that volanesorsen significantly affects plasma levels of triglycerides (TG) [MD = - 67.90%, 95%CI = - 85.32, - 50.48, P < 0.001], high-density lipoprotein cholesterol (HDL-C) [MD = 40.06%, 95%CI: 32.79, 47.34, P < 0.001], very-low-density lipoprotein cholesterol (VLDL-C) [MD = - 72.90%, 95%CI = - 82.73, - 63.07, P < 0.001], apolipoprotein B (Apo B) [MD = 8%, 95%CI = 2.17, 13.84, P = 0.007], Apo B-48 [MD = - 64.63, 95%CI = - 105.37, - 23.88, P = 0.002], ApoCIII [MD = - 74.83%, 95%CI = - 85.93, - 63.73, P < 0.001], and VLDL ApoCIII [MD = - 83.69%, 95%CI = - 94.08, - 73.29, P < 0.001], without significant impact on LDL-C [MD = 47.01%, 95%CI = - 1.31, 95.33, P = 0.057] levels. Treatment with volanesorsen was associated with an higher risk of injection site reaction (OR = 32.89, 95%CI = 7.97,135,74, P < 0.001) and with an increased risk of upper respiratory tract infections (OR = 10.58, 95%CI = 1.23, 90.93, P < 0.05) when compared to placebo. Volanesorsen has a relevant impact on plasma TG and related parameters without affecting LDL cholesterolemia and is associated with an acceptable safety profile. Show less

Hypercholesterolemia is the main modifiable risk factor for atherosclerosis progression and cardiovascular disease (CVD) development. Its pharmacological management is usually based on the prescription of statins, that in some cases are not however fully effective to reach the desired Low-Density-Lipoproteins cholesterol (LDL-C) target, or are not tolerated by patients due to side effects. Areas covered: This manuscript summarizes the basic properties of the emerging new classes of lipid-lowering drugs such as ezetimibe, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, and Microsomal Triglyceride Transfer Protein (MTP) inhibitors, also citing new drugs in development. Our aim is to describe the main pharmacodynamic and pharmacokinetic characteristics, the available efficacy, tolerability and safety data obtained in randomized clinical trials where these drugs were tested. Expert opinion: Non-statin lipid-lowering drugs can be considered an excellent strategy to reduce the residual CV risk, also represented by non-target LDL-C values and high lipoprotein(a) serum levels. In particular, the approved PCSK9 inhibitors (Evolocumab and Alirocumab) have been very effective in optimizing plasma LDL-C values and reducing CV event risk. Show less