Familial Hypercholesterolemia Subjects Research Articles

"Eve is not Adam" - differences in efficacy, safety and clinical outcomes with lipoprotein apheresis between sexes.

In Familial Hypercholesterolemia (FH), female atherosclerotic cardiovascular disease occurs 20 years earlier than in women without FH. The aim of this study is to describe the differences in lipoprotein apheresis (LA), a last therapeutic option, in terms of efficacy, safety and clinical outcomes between the two sexes. Sex related differences were analysed in 31 subjects in on LA treatment with FH and not achieving LDL-cholesterol and/or Lp(a) target values on maximum lipid-lowering therapies. Moreover, sex related differences in time to major cardiovascular event (MACE) was investigated in 68 subjects, with at least one year of follow-up. Among the 31 patients currently undergoing LA treatment who did not achieve LDL-cholesterol and/or Lp(a) target values, no differences in comorbidity were recorded despite a worse pre-LA treatment lipid profile (LDL-C 77 ± 60 mg/dl in males vs. 128 ± 105 mg/dl in females; p 0.025) and a longer mean inter-apheresis interval (17 ± 4 days in males vs. 19 ± 5 days in females; p 0.012) reported in females compared to males. Additionally, in comparison with men, it was found that the time between the first cardiovascular event and the beginning of LA, as well as the age at the beginning of LA, were significantly higher in females than in males (p 0.027 and 0.007, respectively). Sex differences in FH subjects not only affect the diagnosis and treatment but also influence varied responses to the treatment itself.

Plasma legumain in familial hypercholesterolemia: associations with statin use and cardiovascular risk markers

Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p < 0.001). Children and young adults with FH (p = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.

Plasma proteomics identify fibroblast growth factor 5 as a biomarker for genetically proven Familial Hypercholesterolemia

Abstract Background Subjects affected by genetically proven heterozygous Familial Hypercholesterolemia (FH) present lifelong exposure to high Low Density Lipoprotein Cholesterol ("LDL-C burden") causing premature ACVD. Nevertheless, the diagnosis of FH is still far from being optimal due to shortcomings of the clinical algorithms in detecting this form of severe ACVD since early decades of life (1) and because a significant proportion of FH present comparable LDL-C levels to that of subjects who are hypercholesterolemic but are not diagnosed as FH ("non-FH") (2). Purpose We previously demonstrated that targeted proteomics identify subjects at high Atherosclerotic Cardiovascular Diseases (ACVD) risk in the general populations beyond the known risk factors (3). Hence, we now tested whether targeted proteomics may differentiate FH subjects from the general population and from "non-FH". Methods We compared the plasma relative abundance of 264 proteins (Proximity Extension Assay; Olink) in 133 genetically proven FH with that of 586 normocholesterolemic subjects ("controls") and that of 55 non-FH (LDL-C between 190-220 mg/dL, not on statins). We trained and validated a Machine Learning (ML) boosting prediction model (4) in these cohorts to identify the protein markers representative of FH (Random Forest classifiers). Results Fibroblast Growth Factor 5 (FGF-5) resulted as the most powerful plasma protein in differentiating FH subjects from the controls, with an excellent performance (Area Under the Curve (AUC)=0.995 (0.985-1.000); sensitivity=100%; specificity=99.54%; P&amp;lt;0.0001). FGF-5 also emerged as the top protein in differentiating the FH subjects from non-FH (AUC= 1.000 (0.914-1.000; sensitivity=100%, specificity=100% and P&amp;lt;0.001). Finally, when the two groups were matched for LDL-C, FGF-5 still differentiated the FH from the non-FH subjects, (AUC=1.000 (0.914-1.000), sensitivity=100%, specificity=100%, p&amp;lt;0.001). Conclusions FGF-5 allows a clear-cut identification of FH versus controls and, of even more importance, from non-FH with the same LDL-C. The LDL-C burden might be responsible for our findings.

Increased Lipoprotein (a) and familial hypercholesterolemia: a dangerous combination.Data from a 12-year follow-up study

Abstract Background Lipoprotein (a)[Lp(a)] is a molecule characterized by very increased atherogenicity. Mounting evidence support the causal link between high Lp(a) concentration and atherosclerotic cardiovascular (CV) disease in the general population. Purpose The role of Lp (a) in specific categories of patients at high CV risk, such as patients with familial hypercholesterolaemia (FH), is also of special importance. The aim of our study was to investigate the prognostic role of Lp (a) regarding major adverse CV outcomes in subjects with heterozygous FH. Methods 155 patients from the outpatient lipid clinic of our hospital (56 males,mean age 41.2±14.2 years, 26% smokers, 16% with diabetes mellitus), without history of CV disease, who fulfilled the FH criteria participated in the study. Participants were evaluated for a mean follow-up period of 12.4±7.1 years with at least one annual visit. Venous blood samples were obtained at baseline in all patients for the determination of plasma glucose, lipid profile and levels of Lp(a). All subjects were on lipid-lowering medication during the follow-up period. The endpoint of our study was the composite of major CV events (coronary artery disease events and stroke). Results The incidence of the composite endpoint of major CV events during the follow-up period was 9% (n=14). In the total population, the mean baseline Lp (a) levels were 34.9±33.7 mg/dl, while 42% had increased Lp (a) levels ≥30mg/dl. The group of FH patients with new-onset CV disease had higher levels of Lp(a) at baseline compared to those without new-onset CV disease (48.1±37.3 vs 33.6±33.1 mg/dl, p=0.01). Also, those with new-onset CV disease had higher percentage of increased Lp(a) levels (≥30mg/dl) at baseline compared to those without development of CV disease (71% vs 39%, p=0.02).Multiple Cox regression analysis revealed that during the follow-up period independent predictors of major adverse CV events were:increased baseline Lp(a) levels(≥30mg/dl)(HR 5.61, 95% CI 1.51-10.92, p=0.01), male sex (HR 8.11, 95% CI 2.02-12.48, p&amp;lt;0.01), baseline low-density cholesterol levels (HR 1.01, 95% CI 1.00-1.02, p=0.04) and the presence of hypertension at baseline (HR 3.59, 95% CI 1.03-12.49, p=0.04), after adjustment for confounding factors. Conclusions In patients with FH, increased baseline Lp(a) is an independent predictor of adverse CV events, after a 12-year follow-up period. FH patients with Lp (a)levels ≥30mg/dl have an almost 5-fold greater CV risk compared to those with lower Lp (a) levels. It seems that Lp (a) reclassifies the already increased CV risk of FH subjects into an even higher level.

Abstract 13186: Factors Associated With Dysglycemia and Type 2 Diabetes Mellitus Onset in Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by high blood LDL-C and cardiovascular disease (CVD). Type 2 diabetes mellitus (T2DM) is an independent cause of CVD and there is evidence that FH is associated with a lower frequency of its development. On the other hand, lipid lowering therapy (LLT) may increase T2DM risk. Goals: Evaluate the risk of dysglycemia and T2DM development in a cohort of molecularly proven FH individuals. Methods: This is a prospective analysis of a population enrolled on a genetic cascade screening program evaluated from March 2011 to January 2022. FH diagnosis was confirmed by molecular testing of variants in LDLR, APOB and PCSK9. Dysglycemia and T2DM diagnoses were done according to the ADA Criteria or use of any antidiabetic drugs. Results: 790 FH patients were included (age 45.5±15.0 years, 56.8% female, baseline LDL-C 198±74 mg/dL), 96.6% had LDLR variants. The prevalence of T2DM was 13.3% and 67.4% were taking LLT at baseline . There were 206 (26%) new cases of T2DM or dysglycemia after a median 51-month follow-up . In multivariate Cox regression analysis age (HR:1.026, CI95%: 1.014-1.038, p=0.000) , body mass index (HR: 1.062, CI95%: 1.035-1.090, p=0.000) and current smoking (HR: 2.005, HR: 1.337-3.008, p=0.001) were independently associated with T2DM and dysglycemia, while metformin use was associated with a lower risk (HR: 0.147, CI95%: 0.076-0.284, p=0.000). History of previous CVD, use of lipid lowering therapy at baseline, high intensity LLT , or type of molecular defect were not associated with higher T2DM/dysglycemia risk. Conclusions: In this cohort of molecularly proven FH subjects, T2DM affected more than 1 in 10 people at baseline. Previous CVD and classical risk factors but neither molecular defects nor lipid lowering therapy were associated with T2DM/dysglycemia onset.

Familial Hypercholesterolaemia in Children and Adolescents: Current and Future Perspectives.

Familial hypercholesterolemia (FH) is a genetic disease, the underlying cause of which is represented by mutations capable of influencing the metabolism of low-density lipoproteins (LDL). The distinguishing characteristic of FH has increased LDL cholesterol blood levels since birth, triggering early development of atherosclerosis-related diseases. Diagnosis of FH is frequently either missed or made with a considerable delay. Prompt identification of the disease is pivotal in implementing early prevention measures. Safe and effective drugs have been approved for use in children and adolescents, with statins, with or without ezetimibe, representing first-line therapy. At times, however, these medications may not be sufficient to achieve the therapeutic target, particularly in homozygous FH patients. Lipoprotein apheresis, which has proved safe and efficient, is strongly suggested in such cases. New drugs still at the investigational stage may represent a promising and personalised therapy. Lowering cholesterol levels in childhood hampers the formation of arterial atherosclerotic plaques, thus reducing cardiovascular events later in life. Accordingly, early detection, diagnosis, and therapy in FH subjects are priority aims.

Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease

Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease

Impact of high neutrophil-to-lymphocyte ratio on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia subjects with atherosclerotic cardiovascular disease

Impact of high neutrophil-to-lymphocyte ratio on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia subjects with atherosclerotic cardiovascular disease

Cholesterol efflux capacity is increased in subjects with familial hypercholesterolemia in a retrospective case–control study

Familial Hypercholesterolemia (FH) is characterized by an increase in Low-Density Lipoprotein Cholesterol (LDL-C) and by premature Cardiovascular Disease (CVD). However, it remains to be fully elucidated if FH impairs cholesterol efflux capacity (CEC), and whether CEC is related to lipoprotein subfraction distribution. This study aimed at comparing FH patients and age, sex and BMI matched controls in terms of LDL and HDL subfraction distribution as well as CEC. Forty FH patients and 80 controls, matched for age, sex and BMI, were enrolled in this case–control study. LDL and HDL subfractions were analyzed using the Quantimetrix Lipoprint System. CEC was evaluated as aq-CEC and ABCA1-CEC. FH subjects showed a significantly higher concentration of all LDL subfractions, and a shift from large to small HDL subfraction pattern relative to controls. FH subjects with previous CVD event had smaller LDL lipoproteins than controls and FH subjects without previous CVD event. Both aq-CEC and ABCA1-CEC were increased in FH patients with respect to controls. To conclude, FH subjects had a metabolic profile characterized not only by higher LDL-C but also by shift from large to small HDL subfraction phenotype. However, FH subjects showed an increase CEC than controls.

No effect of omega-3 polyunsaturated fatty acid supplementation on inflammatory markers in familial hypercholesterolemia: a randomized crossover trial

Individuals with familial hypercholesterolemia (FH) have increased cardiovascular risk despite lipid-lowering therapy, and additional therapy is warranted. Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplements have demonstrated an effect on cardiovascular endpoints in some clinical trials. Platelet-modifying and anti-inflammatory properties are among the proposed beneficial effects of n-3 PUFA. We investigated the effect of a high-dose n-3 PUFA supplement on platelet function and inflammatory markers in FH subjects. We performed a randomized, double-blind trial with a crossover design. Inclusion criteria were genetically verified heterozygous FH, stable disease, statin treatment >12 months, and age 18-75 years. Trial participants were allocated to two treatment periods in random order. The treatment periods (three months each) were separated by a three-month washout period. N-3 PUFA (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid) and placebo (olive oil) were administered in four capsules daily. Endpoints were platelet function and inflammatory markers, assessed by platelet function analyzer, soluble markers P-selectin, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), 27 cytokines, and hematological parameters. Thirty-four heterozygous FH individuals completed the trial. No treatment effect (p = 0.93) from n-3 PUFA on the platelet function analyzer was found (2 s, 95% CI [-13, 6]). In our FH population, n-3 PUFA did not influence the levels of P-selectin (-2.0, 95% CI [-5.0, 2.0], p = 0.41), VCAM (0, 95% CI [-14.2, 14.2], p > 0.99), ICAM (-27.0, 95% CI [-70.1, 16.5]; p = 0.21), cytokine levels, or hematological parameters. In statin-treated FH individuals, high dose n-3 PUFA supplement did not affect platelet function and inflammatory markers. Trial registration number: EUDRACTNR 2012-000505-68; ClinicalTrials.gov NCT01813006 Highlights Trial studying the effect of omega-3 fatty acids supplements in familial hypercholesterolemia. High-dose omega-3 fatty acids supplements had no impact on platelet function. Cytokine levels were unchanged after three months of omega-3 fatty acid supplementation. No effect of omega-3 fatty acids on C-reactive protein was observed.

Effectiveness of clinical scores in predicting coronary artery disease in familial hypercholesterolemia: a coronary computed tomography angiography study

PurposeOne of the major challenges in the management of familial hypercholesterolemia (FH) is the stratification of cardiovascular risk in asymptomatic subjects. Our purpose is to investigate the performance of clinical scoring systems, Montreal-FH-score (MFHS), SAFEHEART risk (SAFEHEART-RE) and FH risk score (FHRS) equations and Dutch Lipid Clinic Network (DLCN) diagnostic score, in predicting extent and severity of CAD at coronary computed tomography angiography (CCTA) in asymptomatic FH.Material and methodsOne-hundred and thirty-nine asymptomatic FH subjects were prospectively enrolled to perform CCTA. MFHS, FHRS, SAFEHEART-RE and DLCN were assessed for each patient. Atherosclerotic burden scores at CCTA (Agatston score [AS], segment stenosis score [SSS]) and CAD-RADS score were calculated and compared to clinical indices.ResultsNon-obstructive CAD was found in 109 patients, while 30 patients had a CAD-RADS ≥ 3. Classifying the two groups according to AS, values varied significantly for MFHS (p < 0.001), FHRS (p < 0.001) and SAFEHEART-RE (p = 0.047), while according to SSS only MFHS and FHRS showed significant differences (p < 0.001). MFHS, FHRS and SAFEHEART-RE, but not DLCN, showed significant differences between the two CAD-RADS groups (p < .001).MFHS proved to have the best discriminatory power (AUC = 0.819; 0.703–0.937, p < 0.001) at ROC analysis, followed by FHRS (AUC = 0.795; 0.715–0.875, p < .0001) and SAFEHEART-RE (AUC = .725; .61–.843, p < .001).ConclusionsGreater values of MFHS, FHRS and SAFEHEART-RE are associated to higher risk of obstructive CAD and might help to select asymptomatic patients that should be referred to CCTA for secondary prevention.

Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing

Familial hypercholesterolaemia (FH) is caused by mutations in lipid metabolism genes, predominantly in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin-type 9 (PCSK9) and LDL receptor adaptor protein 1 (LDLRAP1). The prevalence of genetically confirmed FH and the detection rate of pathogenic variants (PV) amongst clinically diagnosed patients is not well established. Targeted next-generation sequencing of LDLR, APOB, PCSK9 and LDLRAP1 was performed on 372 clinically diagnosed Malaysian FH subjects. Out of 361 variants identified, 40 of them were PV (18 = LDLR, 15 = APOB, 5 = PCSK9 and 2 = LDLRAP1). The majority of the PV were LDLR and APOB, where the frequency of both PV were almost similar. About 39% of clinically diagnosed FH have PV in PCSK9 alone and two novel variants of PCSK9 were identified in this study, which have not been described in Malaysia and globally. The prevalence of genetically confirmed potential FH in the community was 1:427, with a detection rate of PV at 0.2% (12/5130). About one-fourth of clinically diagnosed FH in the Malaysian community can be genetically confirmed. The detection rate of genetic confirmation is similar between potential and possible FH groups, suggesting a need for genetic confirmation in index cases from both groups. Clinical and genetic confirmation of FH index cases in the community may enhance the early detection of affected family members through family cascade screening.

Clinical and genetic characterization of FH children and adolescents enrolled in the Italian Lipigen paediatric group

Background and Aims : In the last decade, the implementation of familial hypercholesterolemia (FH) pathology registries allowed to investigate specific sub-groups as FH subjects <18 years. Here, we report recent advances from the Italian LIPIGEN Paediatric Group, with a focus on the genotype-phenotype relation.

Postprandial apolipoprotein(a) metabolism in familial hypercholesterolaemia: Therapeutic effect of omega-3 fatty acid supplementation

Background and Aims : Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle containing apolipoprotein(a) [apo(a)] that increases risk of atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia (FH). Postprandial redistribution of apo(a) protein from Lp(a) to triglyceride-rich lipoproteins (TRL) may also increase the atherogenecity of TRL particles. Omega-3 fatty acid (ω-3FA) supplementation improves postprandial TRL metabolism in FH subjects. However, its effect on postprandial apo(a) metabolism has not yet to be investigated.

Effect of PCSK9 inhibitors on cardio-ankle vascular index in familial hypercholesterolemia subjects

Background and Aims : Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of LDL-C that promotes a development of early atherosclerosis. Our aim was to evaluate the effect of PCSK9-i on atherosclerosis damage analyzed by cardio-ankle vascular index (CAVI) in a cohort of FH subjects.

Inhibition of PCSK9 affects serum lipoprotein functions in patients with familial hypercholesterolemia

Background and Aims : PCSK9, beyond regulating plasma cholesterol levels, exerts several pleiotropic effects modulating lipid metabolism in extrahepatic cells, including macrophages. Macrophage cholesterol homeostasis strictly depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (cholesterol efflux capacity, CEC) and the serum capacity to promote cell cholesterol accumulation (cholesterol loading capacity, CLC). The aim of the present study was to evaluate potential changes in HDL-CEC and serum CLC after six-month of treatment with PCSK9 inhibitors in Familial Hypercholesterolemia (FH) subjects.

Novel pathogenic variants of the LDLR gene identified in putative FH subjects

Background and Aims : Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism causing elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. FH is typically caused by deleterious variants of LDLR, APOB or PCSK9 genes and its prevalence is of about 1:300 in the general population. Aim of this study was the genetic characterization of suspected FH patients.

Effect of N-3 Polyunsaturated Fatty Acids on Lipid Composition in Familial Hypercholesterolemia: A Randomized Crossover Trial.

Individuals with familial hypercholesterolemia (FH) have an increased risk of cardiovascular disease. Treatment is mainly low-density lipoprotein cholesterol (LDL-C) reduction. How omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements affect lipoproteins in FH subjects is unknown. We hypothesized that a high-dose n-3 PUFA supplement would reduce atherogenic lipoproteins and influence the high-density lipoprotein cholesterol (HDL-C) function. We performed a randomized, double-blinded crossover study with 34 genetically verified FH individuals (18–75 years, clinically stable, statin treatment > 12 months). Treatment was 4 g n-3 PUFAs (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid daily) or four capsules of olive oil for three months in a crossover design with a washout period of three months. The defined outcomes were changes in triglycerides, lipoproteins, lipoprotein subfractions, apolipoproteins, and HDL-C function. After treatment with n-3 PUFAs, total cholesterol, LDL-C, and triglycerides were reduced compared to placebo (p ≤ 0.01 for all). Total HDL-C levels were unchanged, but the subfraction of large HDL-C was higher (p ≤ 0.0001) after n-3 PUFAs than after placebo, and intermediate HDL-C and small HDL-C were reduced after n-3 PUFAs compared to placebo (p = 0.02 and p ≤ 0.001, respectively). No changes were found in apolipoproteins and HDL-C function. N-3 PUFAs supplements reduced atherogenic lipoproteins in FH subjects, leaving HDL-C function unaffected.

Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (−41.6%, p < 0.0001 and −56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (−6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.

Effects of Lipid Lowering Therapy Optimization by PCSK9 Inhibitors on Circulating CD34+ Cells and Pulse Wave Velocity in Familial Hypercholesterolemia Subjects without Atherosclerotic Cardiovascular Disease: Real-World Data from Two Lipid Units.

Background: Circulating CD34+ progenitor cells (CD34+CPCs) are characterized by pronounced tissue regeneration activity. Dyslipidemic subjects seemed to have reduced CD34+CPCs, and statin therapy appeared to restore their levels. We aimed to evaluate the effects of PCSK9 inhibitors (PCSK9-i) on CD34+CPCs and pulse wave velocity (PWV) in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. Methods: We determined CD34+ cell count and its change after PCSK9-i in 30 selected HeFH subjects and 30 healthy controls. Lipid profile and PWV were evaluated at baseline (T0), 6 months after intensive lipid lowering strategy (statin plus ezetimibe, T1), and after 6 months of optimized therapy with PCSK9-i (T2); CD34+ cell count was reported at T1 and T2. Results: At T1, the median value of CD34+ cells was not significantly different between HeFH subjects and controls, and the same result was obtained at T2. PWV was significantly reduced at T1 (ΔPWV − 14.8%, p < 0.001 vs. T0) and T2 (ΔPWV − 10.96%, p < 0.001 vs. T1). Dividing HeFH subjects into two groups of high- and low-CD34+ cell count, CD34+CPCs appeared to be polarized with a significant difference between the two groups (1.2 (0.46) vs. 4.74 (1.92), p < 0.001), also with respect to controls (both p < 0.001). This polarization was no longer observed at T2, and neither with respect to controls. ΔCD34+ was +67.4% in the low-CD34+ group and −39.24% in the high-CD34+ group (p < 0.001). Lastly, we found a significant correlation between ΔCD34+ cell number and ΔPWV in HeFH subjects (rho = −0.365, p < 0.05), particularly in the low-CD34+ group (rho = −0.681, p < 0.001). Conclusion: PCSK9-i exhibited favorable effects on CD34 + CPCs as was on PWV values in a cohort of FH subjects. Our preliminary findings suggest a possible positive role of this novel lipid-lowering strategy on vascular homeostasis.