Kinetic Study of Lp(a) and PCSK9 in Humans

NCT ID: NCT04247048

Last Updated: 2022-02-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-31
• Study Completion Date: 2021-12-23

Brief Summary

The aim is to study the relationship between lipoprotein(a) [Lp(a)] and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) in humans with a kinetic study of lipoproteins in patients with dramatic increase of Lp(a) and controls.

Detailed Description

Elevated plasma levels of lipoprotein(a) [Lp(a)] are independently associated with an increased risk of cardiovascular diseases (CVD). Recently an unexpected and significant 15 to 30 % reduction of Lp(a) was reported with PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors. The relation between Lp(a) and PCSK9 are unclear and debated.

Kinetic studies of lipoprotein are an important tool to decipher the complexity of apolipoprotein metabolism in human. The comparison of apoprotein(a) and PCSK9 kinetic parameters of patients with extreme lipid disorder link to PCSK9 and apo(a) will allow to better understand the impact of PCSK9 on apo(a). From one previous in vitro study, the hypothesize is that PCSK9 increases the production rate and the assembly of Lp(a).

The objectives are to explore the relationship between the plasma concentration of PCSK9 and apo(a) production rate as well as the impact on the catabolic rate. Patients with extreme Lp(a) levels and healthy controls will be explored by performing a continuous infusion of deuterated leucine for 14 hours. LC/MS-MS will be used to analyze the samples and kinetic data of apo(a) and PCSK9 will be generated from a compartmental model. Tracer enrichment analysis could be complicated for proteins with low plasma concentrations as PCSK9. This issue will be solved with SPE and/or immune affinity concentration techniques. Non-parametrical test and multivariate analysis will be use to describe the relationship between these two variables.

This study will provide new knowledge on Lp(a) and PCSK9 metabolism and their interactions in humans.

Conditions

Cholesterol; Metabolic Disorder; Lipoproteinemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Control group

Patients with no major LDL cholesterol abnormalities (patients eligible for LDL-apheresis, eg LDL-C\> 200 mg / dL for secondary prevention and 300 mg / LDL-C) dl in primary prevention)) and a level of Lp (a) \<50 mg / dl

Group Type: EXPERIMENTAL

infusion of tracer [5,5,5-2H3] -L-leucine

Intervention Type: OTHER

A bolus of 6ml of \[5,5,5-2H3\] -L-leucine tracers will be performed followed by an infusion of 90 ml of \[5,5,5-2H3\] -L-leucine infused over 14 hours. This tracer participates in protein synthesis and especially in the synthesis of all apolipoproteins and PCSK9. Blood samples will be taken at T0, T2min, T5min, T10 minutes, T30 minutes and then every hour until 14 hours (a total of 240 ml of blood will be collected) to measure the stable tracer enrichment in the proteins of interest.

High-dose group

Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C\> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)\> 80 mg / dl

Group Type: EXPERIMENTAL

infusion of tracer [5,5,5-2H3] -L-leucine

Intervention Type: OTHER

A bolus of 6ml of \[5,5,5-2H3\] -L-leucine tracers will be performed followed by an infusion of 90 ml of \[5,5,5-2H3\] -L-leucine infused over 14 hours. This tracer participates in protein synthesis and especially in the synthesis of all apolipoproteins and PCSK9. Blood samples will be taken at T0, T2min, T5min, T10 minutes, T30 minutes and then every hour until 14 hours (a total of 240 ml of blood will be collected) to measure the stable tracer enrichment in the proteins of interest.

Interventions

infusion of tracer [5,5,5-2H3] -L-leucine

A bolus of 6ml of \[5,5,5-2H3\] -L-leucine tracers will be performed followed by an infusion of 90 ml of \[5,5,5-2H3\] -L-leucine infused over 14 hours. This tracer participates in protein synthesis and especially in the synthesis of all apolipoproteins and PCSK9. Blood samples will be taken at T0, T2min, T5min, T10 minutes, T30 minutes and then every hour until 14 hours (a total of 240 ml of blood will be collected) to measure the stable tracer enrichment in the proteins of interest.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• age: 18 to 75 years
• For subjects in the "Control" group: Patients with no major LDL-cholesterol deficiency (patients eligible for LDL-apheresis, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a) <50 mg / dl or
• For subjects in the "high-dose" group: Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)> 80 mg / dl Whenever possible, groups will be balanced for age, sex, familial forms of hypercholesterolemia and their major groups of mutations.

Exclusion Criteria

• Patients treated with PCSK9 antibodies.
• Patients with acute illness and considered incompatible by the investigator
• Uncontrolled diabetes (HbA1c> 8.5%)
• Severe hepatic insufficiency
• Creatinine clearance <30 ml / min
• Patients not covered by a social security scheme or beneficiary of such a scheme
• Patients unable to understand and / or sign consent
• Pregnant or lactating women
• Minors
• Majors under guardianship or trusteeship or safeguard of justice

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre de Recherche en Nutrition Humaine Ouest (CRNH)

UNKNOWN

Sponsor Role: collaborator

Nantes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Nantes University Hospital

Nantes, , France

Countries

France

Other Identifiers

RC18_0281

Identifier Type: -

Identifier Source: org_study_id