Clinical trial NCT06626659: Lipoprotein (a) and Vascular Regenerative Cell Content
Official title: Lipoprotein (a) and Vascular Regenerative Cell Content
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cardiovascular Diseases
Atherosclerosis Cardiovascular Disease
Ischemic Heart Disease
Dyslipidemia
Keywords: Lipoprotein (a)
Progenitor cells
Cardiovascular disease
Lead sponsor: Canadian Medical and Surgical Knowledge Translation Research Group
Sponsor class: OTHER
First posted: 2024-10-04
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants will be identified from primary care and cardiology outpatient clinics in the Greater Toronto Area using paper-based and electronic medical records.

Brief summary: Lp(a)-VRCE is an observational, cross sectional study looking at vessel reparative stem cell content in people with and without elevated lipoprotein (a) \[Lp(a)\]. Specifically, the type and number of these cells in peripheral blood samples will be measured in participants with Lp(a) ≥100 nmol/L and compared to participants with Lp(a) \< 100 nmol/L. Determining the presence or absence of specific cells with blood vessel repair capacity in participants with high Lp(a) will further our knowledge of potential mechanisms through which Lp(a) influences cardiovascular health.

Detailed description: Lipoprotein (a) \[Lp(a)\] is an independent, genetically determined, causal risk factor for the development of atherosclerotic cardiovascular disease. It is estimated that 20-30% of the global population have elevated Lp(a) and recent multinational guideline endorsements strongly advise the routine measuring of Lp(a), at least once in a person's life. Current Lp(a) risk level thresholds are described as \<75 nmol/L for low risk and \>125 nmol/L for high risk individuals. Despite ongoing clinical trials, there exists no approved therapeutic medication to specifically lower Lp(a).

Vascular regenerative cell exhaustion (VRCE) is described as the depletion of circulating pro-vascular reparative cells responsible for angiogenesis, vasculogenesis and arteriogenesis. Evidence in recent years has implicated VRCE as a novel mechanistic factor contributing to the aberrant cardiometabolic state present in type 2 diabetes, obesity, and in people of South Asian descent. It has been demonstrated that the VRCE phenotype can be reversed by treatment with sodium glucose co-transporter 2 inhibitors or bariatric surgery.

Lp(a)-VRCE is a cross-sectional, observational, two arm study enrolling 20 patients with elevated Lp(a) (≥100 nmol/L) and 20 patients with non-elevated Lp(a) (\<100 nmol/L). From peripheral blood, mononuclear cells are isolated and enumerated via a multi-parametric flow cytometry assay utilizing aldehyde dehydrogenase activity and side scatter properties. The hypothesis is that people with elevated Lp(a) have comparatively different progenitor cell phenotypes to people with normal Lp(a) levels.

Eligibility criteria: Inclusion Criteria:

1. Adults ≥18 years of age and ≤80 years of age who meet either of the following criteria:

   1. Elevated Lp(a) (defined as greater than or equal to 100 nmol/L)
   2. Non-elevated Lp(a) (defined as less than 100 nmol/L)
2. Willing and able to provide written informed consent and comply with study procedures.

Exclusion Criteria:

1. Unable or unwilling to provide written informed consent or provide a peripheral blood sample.
2. Any life-threatening disease expected to result in death within two years of consent.
3. Any malignancy not considered cured (except basal cell carcinoma of the skin). An individual is considered cured if there has been no evidence of cancer recurrence for the five years prior to screening.
4. Uncontrolled hypertension.
5. New York Heart Association Class IV heart failure.
6. Active liver disease or liver dysfunction.
7. Active kidney disease or kidney dysfunction.
8. History of hemorrhagic stroke or other major bleeding disorder.
9. White blood cell count ≥15 x 10\^9/L.
10. Women who are pregnant or nursing.
11. Previously received ribonucleic acid therapy specifically targeting Lp(a).
12. Active infectious disease requiring systemic antibiotic or anti-viral agents.
13. Known acquired immunodeficiency syndrome, such as human immunodeficiency virus.
14. On oral steroid therapy (e.g., prednisone or other corticosteroids) or other immunosuppressive agents (e.g., methotrexate).
15. Treated autoimmune disorders.
16. Participating in another study/trial that is likely to affect the primary outcome.

Primary outcomes:
measure: Difference in the frequency or absolute number of circulating ALDHhiSSClo primitive myeloid progenitor cells between individuals with elevated Lp(a) and individuals with non-elevated Lp(a)
timeFrame: Baseline
Secondary outcomes:
measure: Difference in the frequency/absolute count of ALDHhiSSCmid monocytes between individuals with elevated Lp(a) and individuals with non-elevated Lp(a)
timeFrame: Baseline
Other outcomes:
measure: Difference in the amount of intracellular reactive oxygen species (ROS) production in ALDHhi progenitor cell subsets
timeFrame: Baseline
measure: Difference in the levels of inflammatory and oxidative stress biomarkers
timeFrame: Baseline
Locations:
city: North York
country: Canada
facility: North York Diagnostic and Cardiac Centre
state: Ontario
city: Scarborough
country: Canada
facility: Diagnostic Assessment Centre
state: Ontario
Study officials:
affiliation: University of Toronto
name: Subodh Verma, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Western University, Canada
name: David A Hess, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, Lloyd-Jones DM, Marcovina SM, Yeang C, Koschinsky ML; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Peripheral Vascular Disease. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022 Jan;42(1):e48-e60. doi: 10.1161/ATV.0000000000000147. Epub 2021 Oct 14.
citation: Terenzi DC, Al-Omran M, Quan A, Teoh H, Verma S, Hess DA. Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into the Prevention of Ischemic Complications in Diabetes. JACC Basic Transl Sci. 2018 Nov 5;4(1):98-112. doi: 10.1016/j.jacbts.2018.10.005. eCollection 2019 Feb.
citation: Bakbak E, Verma S, Krishnaraj A, Quan A, Wang CH, Pan Y, Puar P, Mason T, Verma R, Terenzi DC, Rotstein OD, Yan AT, Connelly KA, Teoh H, Mazer CD, Hess DA. Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling. Am J Physiol Heart Circ Physiol. 2023 Nov 1;325(5):H1210-H1222. doi: 10.1152/ajpheart.00141.2023. Epub 2023 Sep 29.
citation: Park B, Krishnaraj A, Teoh H, Bakbak E, Dennis F, Quan A, Hess DA, Verma S. GLP-1RA therapy increases circulating vascular regenerative cell content in people living with type 2 diabetes. Am J Physiol Heart Circ Physiol. 2024 Aug 1;327(2):H370-H376. doi: 10.1152/ajpheart.00257.2024. Epub 2024 Jun 14.
citation: Krishnaraj A, Bakbak E, Teoh H, Pan Y, Firoz IN, Pandey AK, Terenzi DC, Verma R, Bari B, Bakbak AI, Kunjummar SP, Yanagawa B, Connelly KA, Mazer CD, Rotstein OD, Quan A, Bhatt DL, McGuire DK, Hess DA, Verma S. Vascular Regenerative Cell Deficiencies in South Asian Adults. J Am Coll Cardiol. 2024 Feb 20;83(7):755-769. doi: 10.1016/j.jacc.2023.12.012.
citation: Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, Dweck MR, Koschinsky M, Lambert G, Mach F, McNeal CJ, Moriarty PM, Natarajan P, Nordestgaard BG, Parhofer KG, Virani SS, von Eckardstein A, Watts GF, Stock JK, Ray KK, Tokgozoglu LS, Catapano AL. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022 Oct 14;43(39):3925-3946. doi: 10.1093/eurheartj/ehac361.