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

6. juni 2019 opdateret af: National Heart Centre Singapore

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.

Studieoversigt

Status

Ukendt

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

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.

Undersøgelsestype

Observationel

Tilmelding (Forventet)

200

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

21 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ja

Køn, der er berettiget til at studere

Alle

Prøveudtagningsmetode

Sandsynlighedsprøve

Studiebefolkning

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

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

Kohorter og interventioner

Gruppe / kohorte
Intervention / Behandling
Sunde frivillige
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Andre navne:
  • PCI
CABG patients
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Andre navne:
  • PCI
PAD patients
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Andre navne:
  • PCI
Patients with CAD
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Andre navne:
  • PCI

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
"mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease.
Tidsramme: 2 years

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

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

10. oktober 2018

Primær færdiggørelse (Forventet)

31. marts 2020

Studieafslutning (Forventet)

31. marts 2020

Datoer for studieregistrering

Først indsendt

6. juni 2019

Først indsendt, der opfyldte QC-kriterier

6. juni 2019

Først opslået (Faktiske)

10. juni 2019

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

10. juni 2019

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

6. juni 2019

Sidst verificeret

1. august 2018

Mere information

Begreber relateret til denne undersøgelse

Andre undersøgelses-id-numre

  • 2018/2497
  • SHF/FG651P/2017 (Andet bevillings-/finansieringsnummer: SingHealth Foundation)

Plan for individuelle deltagerdata (IPD)

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UBESLUTET

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