Clinical trial NCT03980548: Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right
Official title: Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right - MITOFFA
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: CAD Patients
Lead sponsor: National Heart Centre Singapore
Sponsor class: OTHER
First posted: 2019-06-10
Enrollment: 200
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: OTHER
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

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease.
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: Hector A. Cabrera-Fuentes
Study officials:
References: