Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right (MITOFFA)

Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right - MITOFFA

Our preliminary data suggests that pharmacological inhibition of the mitochondrial fission protein, Drp1, reduced atherosclerotic plaque volume and attenuated macrophage accumulation within the plaque in an ApoE-/- mouse model of wire-induced carotid arterial injury. Furthermore, we hypothesize that modulation of mitochondrial morphology and metabolism with Drp1 inhibition prevents atherosclerosis by reducing monocyte activation and migration. In this research proposal, our overall objective will be to investigate the role of Drp1 in human monocytes and macrophages as novel therapeutic targets for preventing atherosclerosis.

Study Overview

• Status: Unknown
• Conditions: CAD Patients
• Intervention / Treatment: Procedure: CABG

Detailed Description

Study 1 (tissue sample study): To investigate the changes in mitochondrial function and pro-inflammatory markers in human arterial atherosclerotic plaques.

Hypothesis: Macrophages from femoral artery atherosclerotic plaques in patients with peripheral artery disease will display upregulation of mitochondrial fission proteins and features of pro-inflammatory activation.

Study 2 (white blood cell study): To investigate the changes in mitochondrial function and pro-inflammatory markers in white blood cells from patients with stable and unstable coronary artery didease (CAD).

Hypothesis: Monocytes from patients with unstable CAD will display upregulation of Drp1 and features of pro-inflammatory activation, mitochondrial fission, impaired mitochondrial respiratory function, and perturbed metabolism, when compared to monocytes from patients with stable CAD.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169609
    • Recruiting
    • Hector A. Cabrera-Fuentes
    • Contact: Tan Mui Teng; Phone Number: 67042297; Email: tan.mui.teng@nhcs.com.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Study 1 (tissue sample study):

• 25 adult patients undergoing coronary artery bypass graft (CABG) surgery: Control tissue will be collected from the left internal mammary artery (LIMA) or radial artery (RA) Atherosclerotic tissue will be collected from aortic root
• 25 adult patients undergoing surgical femoral or carotid endarterectomy Endarterectomy atherosclerotic tissue will be collected

Study 2 (white blood cell study):

• 50 healthy adult volunteers Control blood sample will be collected
• 50 adult patients with stable CAD Stable CAD blood sample will be collected
• 50 adult patients with unstable CAD Unstable CAD blood sample will be collected

Description

Inclusion Criteria:

Study 1 (tissue sample study):

CABG patients

1. Patients aged ≥21 years old
2. Undergoing elective CABG with aortic valve surgery

PAD patients:

1. Patients aged ≥21 years old
2. Undergoing either elective surgical femoral or carotid endarterectomy

Study 2 (white blood cell study):

1) Healthy volunteers aged ≥21 years old 2) Patients with stable CAD 3) Patients admitted with ACS treated by PCI in prior 24 hours.

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Exclusion Criteria:

1. General exclusion criteria will be a known history of leucopenia, thrombocytopenia, or severe hepatic or renal dysfunction, as well as evidence for inflammatory or malignant disease.
2. History of haematological disorders
3. Cardiac arrest, Cardiogenic shock, Poor pre-morbid status, Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy volunteers	Procedure: CABG; Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI; Other Names: PCI
CABG patients	Procedure: CABG; Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI; Other Names: PCI
PAD patients	Procedure: CABG; Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI; Other Names: PCI
Patients with CAD	Procedure: CABG; Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI; Other Names: PCI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
"mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease.	Primary outcome analysis for aim 1: The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis. Primary outcome analysis for aim 1: The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis. The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients	2 years

Collaborators and Investigators

• Sponsor: National Heart Centre Singapore

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2018
• Primary Completion (Anticipated): March 31, 2020
• Study Completion (Anticipated): March 31, 2020

Study Registration Dates

• First Submitted: June 6, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (Actual): June 10, 2019

Study Record Updates

• Last Update Posted (Actual): June 10, 2019
• Last Update Submitted That Met QC Criteria: June 6, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: 2018/2497; SHF/FG651P/2017 (Other Grant/Funding Number: SingHealth Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No