Comorbidity in lipoprotein apheresis: Their role in the era of new lipid-lowering therapies.

BACKGROUND: Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention. METHODS: Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA. RESULTS: Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia. DISCUSSION: Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues.

Alirocumab in lipoprotein apheresis: A synergy for patients with high-Lp(a).

Until today lipoprotein apheresis (LA) is considered the most effective treatment for patients with high-Lp(a) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are often combined with LA to dampen the rebound in lipoprotein concentrations. The aim of the present work is to evaluate the effect of dose-adjustment strategy for alirocumab in a small cohort of high-Lp(a) subjects with ischemic heart disease and in chronic LA treatment. Chronic LA effect on Lp(a) levels is a significant reduction in pre-LA Lp(a) concentrations compared to native Lp(a) value (118 [116-119] mg/dl vs 150 [137-155] mg/dl; p < 0.001). Furthermore, the administration of Arilocumab 75 mg after 7 days from LA shows a significant pre-LA reduction in the Lp(a) concentrations respect to those obtained with administration immediately after the LA treatment. In high-Lp(a) patients treated with chronic LA the deferred addition of alirocumab, resulted in lower LDL-cholesterol and Lp(a) values.

Is treating severe He FH so easy? A combined treatment between lipoprotein apheresis and PCSK9 inhibitors.

Despite advance in pharmacotherapy of lipid disorders, many heterozygous Familial Hypercholesterolemia patients do not achieve a desirable lipid target to significantly reduce the risk of atherosclerotic cardiovascular disease. The aim of the present work is to evaluate the interaction between Lipoprotein apheresis (LA) and PCSK9i in a small FH cohort in which the guidelines therapeutic target is not achieved. During one year, together with a complete adherence to PCSK9i therapy, we recorded a 3 to 5 LA sessions less per year in each patient. This therapeutic approach suggests: i) the possibility of increasing the number of patients treated with LA, ii) the improvement of their quality of life, and iii) the costs reduction for the single patient-treatment.

Reduced incidence of cardiovascular events in hyper-Lp(a) patients on lipoprotein apheresis. The G.I.L.A. (Gruppo Interdisciplinare Aferesi Lipoproteica) pilot study.

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.

Early senescence in heterozygous ABCA1 mutation skin fibroblasts: a gene dosage effect beyond HDL deficiency?

PURPOSE: Homozygous ABCA1 gene mutation causes Tangier disease (TD). The effects reported in heterozygous state regard plasma HDL, cell cholesterol efflux and coronary artery disease. We investigated whether in vitro replicative skin fibroblast senescence shown in TD proband (Hom), his father (Het), and in a healthy control might be induced in a "gene-dosage way". METHODS: Senescence was evaluated by staining test for ß-Galactosidase and telomere length (TL) on fibroblast DNA at different replicative stages. ABCG1 and LDLR (low density lipoprotein receptor) gene expression was also evaluated. RESULTS: Hom cells showed early senescent morphology and reduced growth at all passages in vitro. The cell positive percentage for ß-Galactosidase test was highly increased in Hom compared to Het cells at late replicative status (66.1% vs 41.3% respectively). TL was significantly shorter at high stage either in Hom (p<0.0001) or in Het (p<0.005). At early replication cycles ABCG1 gene expression was about 3-fold higher in Hom compared to Het cells (0.44 vs 0.14 arbitrary unit). CONCLUSIONS: ABCA1 gene mutation may have "gene-dosage way" effect on in vitro fibroblast senescence. Furthermore, increased ABCG1 and LDLR gene expression could highlight a role of ABCA1 on cytoskeleton regulation associated to cell cholesterol metabolism.

Widespread xanthomas regression by personalized lipid lowering therapy in heterozygous familial hypercholesterolemia.

"The lower, the better" is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas.

PCSK9 and leptin plasma levels in anorexia nervosa.

AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of low-density-lipoprotein cholesterol (LDL-C), a major risk factor for cardiovascular (CV) disease. Since the hormone leptin has been suggested as having a role in CV risk regulation, possibly by modulating LDL receptor expression through the PCSK9 pathway, nutritional status may represent a potential regulator. Thus, evaluation of PCSK9 levels in human eating disorders appears to be of interest. In this report, we evaluate the lipoprotein profile, PCSK9, and leptin levels in subjects affected by anorexia nervosa (AN) to improve our understanding of the metabolic alterations in this disease. METHODS AND RESULTS: We designed a case-control observational study, enrolling 20 anorexic adolescent females and 20 adolescent females without AN as the control group, age- and sex-matched. Subjects affected by AN showed lower BMI, total cholesterol, and LDL-C in comparison to the control group, with lipoprotein levels in the normal range. Furthermore, adolescent girls with AN show significantly higher PCSK9 (+24%, p < 0.005) and lower leptin levels (-43%, p < 0.01), compared to the control group. CONCLUSIONS: The findings of increased levels of PCSK9 and reduced leptin levels among AN subjects warrant further research in order to unravel the role of the liver and adipose tissue in the management of PCSK9/LDL metabolism in adolescents affected by AN.

Cognitive impairment and polidistrectual atherosclerotic disease in chylomicronemia syndrome: a case report.

A case of chylomicronemia syndrome is reported in a 72-year-old male with distinctive features of chronic pancreatic damage, severe hypertriglyceridemia, polidistrectual atherosclerosis and premature cognitive impairment. Although the patient had a positive history for recurrent episodes of pancreatitis the characteristic lesions of the hyperchylomicronemia syndrome, such as eruptive xanthomas and lipemia retinalis, were not present and splenomegaly could not be documented due to a previous post-traumatic splenectomy. Based on clinical phenotype, an apolipoprotein C-II deficiency was excluded by a fresh plasma infusion test, in which clarification of the patient plasma was not obtained. The absence of changes in the lipoprotein electrophoretic plasma after heparin infusion can be secondary to a lipoprotein lipase deficiency, a rare genetic disorder with an incidence of one per million. In relation to the resistance to diet and drugs, plasma exchange therapy was performed. After 3 years of this treatment there was no significant progression of atherosclerosis.

Major cardiovascular events increase in long-term proprotein convertase subtilisin/kexin type 9 inhibitors therapy: the Tuscany cost-effective study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a breakthrough in the treatment of hypercholesterolemia. The aim of this study was to perform a multicentre prospective analysis on the effects of PCSK9i since their distribution in Italy. METHODS: During the study period (July 2017 to February 2022) 246 patients (mean age 61 ±â€Š11 years, male 73%) who were evolocumab (142/246) or alirocumab (104/246) new users were enrolled in the CERTI (Costo Efficacia Regione Toscana Inibitori PCSK9) study. Lipid value, adverse events (AEs), major cardiovascular events (MACEs) and intima-media thickness were analysed. RESULTS: PCSK9i therapy allowed a significant improvement in patients' lipid profile [total cholesterol -35%, P < 0.001; triglycerides -9%, P < 0.05; low-density lipoprotein (LDL) cholesterol -51%, P < 0.001; Lp(a) levels -4%, P < 0.05], maintained during the follow-up. No significant variations in intima-media thickness were observed. In the subgroup of patients with more than 1 year of PCSK9i therapy (165/246 patients) we highlighted: a 66% reduction in MACEs compared with the year before recruitment; a progressive increase in MACEs during the follow-up (MACEs event/rate at first year 0.08 vs. MACEs event/rate at year 5: 0.47); a patients cluster with late MACEs older, with higher prevalence of hypertension, smoking habit and peripheral vascular disease. During the follow-up, we recorded AEs in 31% of patients, which mainly resulted in reduction/discontinuation of lipid-lowering therapy for 50 patients or in discontinuation/shift of PCSK9i (respectively 8 and 6 cases). CONCLUSION: Our data agree with the large evidence on the effectiveness/tolerability of PCSK9i therapy; however, although PCSK9i represents a good cholesterol-lowering therapeutic option, our study shows a progressive increase in MACEs during the late follow-up that deserve further research.

Acute Increase in Ocular Microcirculation Blood Flow Upon Cholesterol Removal. The Eyes Are the Window of the Heart.

BACKGROUND: Lipoprotein apheresis acutely increases coronary microvascular blood flow. However, measurement techniques are time-consuming, costly, and invasive. The ocular vasculature may be an appropriate surrogate and an easily accessible window to investigate the microcirculation. Recent advances in ocular imaging techniques enable quick, noninvasive quantification of ocular microcirculation blood flow. The insights from these techniques represent a significant opportunity to study the short-term changes in optic disk blood flow after lipoprotein apheresis for inherited hypercholesterolemia. METHODS: This study was performed at the Italian Reference Center for Inherited Dyslipidemias in Tuscany. The study sample was comprised of 22 patients with inherited hypercholesterolemia who were previously studied for coronary microcirculation. Laser speckle flowgraphy (LSFG) was used to measure optic disk blood flow before and after lipoprotein apheresis. The main outcomes measures were average tissue blood flow (referred to as mean tissue) and arteriolar/venular average blood flow (referred to as mean vessel). Eyes were divided into 2 groups based on pre-lipoprotein apheresis optic disk blood flow values. P < .05 was considered statistically significant. RESULTS: After each lipoprotein apheresis treatment resulting in the reduction of plasma lipids, there was a concurrent increase in all optic disk microcirculatory parameters. The increase was statistically significant in eyes with lower pre-apheresis optic disk blood flow values (mean tissue +7.0%, P < .005; mean vessel +7.2%, P < .05). CONCLUSIONS: A single lipoprotein apheresis session resulted in a statistically significant short-term increase in optic disk blood flow. These findings together with previous coronary microcirculation data suggest a similar ocular and coronary blood flow response to lipoprotein apheresis. Ocular microcirculation may represent a versatile biomarker for evaluating systemic microcirculatory health, including coronary microcirculation. Hence, it is plausible that plasma lipoprotein levels may influence optic disk blood flow.

Abnormal glucose and lipid control in non-ischemic left ventricular dysfunction.

BACKGROUND: Cardiovascular risk factors are classically associated with coronary atherosclerosis. We sought to investigate whether risk factors are also associated with left ventricular (LV) dilatation, contractile impairment and reduced myocardial blood flow (MBF) in patients with non-ischemic LV dysfunction. METHODS: We studied 81 patients (59 males, age 60 ± 9 years) with mild-to-severe LV dysfunction (mean ejection fraction 37%, range 19%-50%), no history of diabetes and normal coronary arteries. Absolute MBF was measured by positron emission tomography and (13)N-ammonia at rest and after dipyridamole (0.56 mg/kg I.V. over 4 min). RESULTS: Overt LV dysfunction (LV end-diastolic diameter >60 mm associated with LV ejection fraction <45%) was present in 42 patients (52%); severely depressed hyperemic MBF (<1.09 mL · min(-1) · g(-1)) was present in 41 patients (51%). Using multivariate logistic regression analysis, low high-density lipoprotein cholesterol (HDL-C, P < .036), newly diagnosed non-insulin-dependent diabetes or insulin-resistance (NIDD/IR, P < .019) and the use of diuretics (P = .001) were independently associated with overt LV dysfunction. Low HDL-C (P = .015) and NIDD/IR (P = .048) were also independently associated with severely depressed hyperemic MBF. CONCLUSIONS: Low HDL-C and NIDD/IR are associated with more severe LV impairment and reduced hyperemic MBF in non-ischemic LV dysfunction.

Myeloperoxidase modulation by LDL apheresis in familial hypercholesterolemia.

BACKGROUND: Myeloperoxidase (MPO) is a marker of plaque vulnerability and a mechanistic bridge between inflammation and cardiovascular disease, and thus is a suitable target for therapeutic strategy against cardiovascular disease. METHODS: Since hypercholesterolemia is associated with atherosclerosis and inflammation, we tested whether MPO serum levels were up-regulated in Familial Hypercholesterolemia (FH) and whether acute reduction of total cholesterol (TC) would also reduce MPO concentration. FH subjects undergoing LDL-apheresis (LDL-A) treatment are a paradigmatic clinical model where TC rapidly plunges from extremely high to extremely low levels after selective LDL removal, and then spontaneously rebounds to baseline conditions. This clinical setting allows multiple intra-patient observations at different plasma TC concentrations. We measured MPO levels in serum by ELISA tests, and in peripheral leukocytes by immunofluorescence, to learn whether they were affected by the changes in TC levels. Serum MPO was measured before and serially up to the 14th day following LDL-A. RESULTS: In both serum and peripheral leukocytes, MPO concentrations were i) higher than in sex- and age-matched healthy controls (p < 0.01); ii) decreased with TC reduction; iii) parallel with TC time course; iv) correlated with plasma TC. At regression analysis, plasma TC was the only variable considered that influenced MPO serum levels (ß 0.022 ± 0.010, p < 0.0001). CONCLUSIONS: In FH the MPO serum levels were modulated through changes in the TC concentrations carried out by LDL-A. Further study is needed to determine whether reduced MPO levels obtained by LDL-A could have any therapeutic impact.

Gender difference in lipoprotein(a) concentration as a predictor of coronary revascularization in patients with known coronary artery disease.

BACKGROUND AND AIMS: Whether there is a gender difference in the impact of elevated plasma Lp(a) levels on recurrent coronary events remains unclear. We, therefore, evaluated the association between Lp(a) levels and the occurrence of major adverse coronary events in a large series of coronary patients (32% women). METHODS: This single-center prospective cohort study investigated 3034 consecutive patients admitted to the Coronary Care Unit with a diagnosis of coronary ischemia. According to the inclusion criteria, 2374 patients completed the follow-up (mean of 2 years). The end-points were non-fatal myocardial infarction (MI), revascularization and coronary deaths. RESULTS: Elevated Lp(a) levels were significantly associated with rate of revascularization, but not with non-fatal MI and cardiac death. According to Lp(a) stratification (≤30 mg/dl, >30-50 mg/dl and ≥50 mg/dl), there was a significant rise of revascularization events in the whole sample of participants, with a trend in hazard ratio (HR) of 1.23 (95% CI 1.04-1.46) and a 6% rise for every 10 mg/dl increment in Lp(a) levels. This effect was mainly driven by women (HR 2.04, 95%CI 1.33-3.12) who showed a 14% incremental risk for every 10 mg/dl rise in Lp(a) levels. CONCLUSIONS: In patients with coronary artery disease, elevated plasma Lp(a) levels were found to be a potentially useful predictor of the need for coronary revascularizations, especially in women.

PCSK9 Inhibitors' New Users: Analysis of Prescription Patterns and Patients' Characteristics from an Italian Real-world Study.

BACKGROUND AND OBJECTIVE: Cardiovascular (CV) diseases represent a major cause of death and severe medical condition worldwide. Different therapeutic options are available to control low-density lipoprotein cholesterol (LDL-C) level in order to prevent CV events. In recent years, two new drugs were approved for patients who are unable to reduce circulating LDL-C with the current therapies: evolocumab and alirocumab (proprotein convertase subtilisin/kexin type nine [PCSK9] inhibitors). This study was aimed to characterise patients who started treatment with PCSK9 inhibitors in the Tuscany region of Italy during the first year of public healthcare service reimbursement and to describe the pattern of PCSK9 inhibitor use in the first 6 months of treatment. METHODS: Patients on PCSK9 inhibitor treatment in Tuscany (3.7 million inhabitants) from 07/2017 to 06/2018 were selected from regional healthcare administrative databases. Concomitant use of lipid-lowering therapies (LLTs), adherence and persistence during the 6 months preceding the first PCSK9 inhibitor dispensing, as well as comorbidities since 1996, were described. In the first 6 months of PCSK9 inhibitor treatment, adherence, persistence and concomitant LLTs were assessed. RESULTS: There were 269 (176 evolocumab, 93 alirocumab) new users of PCSK9 inhibitors. Patients (mean age of 59.1 years) were mainly male (71.0%) in secondary prevention (70.2%) and affected by familial hypercholesterolaemia (53.5%). Sixty-six patients (24.5%) had diabetes mellitus and 12 (4.5%) chronic renal failure. In the 6 months prior to the first PCSK9 inhibitor administration, 61.3% of patients received at least one prescription of ezetimibe or high-intensity statins and 45.7% were persistent to these drugs. During follow-up, 79.9% of patients were adherent to PCSK9 inhibitor and 73.3% were persistent. CONCLUSIONS: During the first year of availability, the rate of prescription of PCSK9 inhibitors appears below expectations. Patients were mainly in secondary prevention and had been slightly persistent to previous LLTs. During follow-up, the PCSK9 inhibitor monotherapy showed high levels of adherence and persistence. This real-world study sets the stage for future longer-term investigations useful to improve our knowledge on the appropriateness, drug access and public healthcare sustainability of PCSK9 inhibitors.