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

National Heart Centre Singapore200 enrolled

Overview

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 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

200

Conditions

CAD Patients

Interventions

Eligibility

Sex: ALLMin age: 21 YearsHealthy volunteers:

Medical Language ↔ Plain English

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. \- 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

Outcomes

Primary Outcomes

"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

Time frame: 2 years