NIHR Barts and The London CVBRUCentre for Advanced Cardiovascular Imaging
NIHR Barts and The LondonCardiovascular Biomedical Research Unit
William HarveyResearch Institute
Investigation of the mechanisms and effects of intracoronary nitrite infusion
during acute myocardial infarction (AMI)
Dr Daniel Jones
PhD Supervisors
Prof A Mathur Prof A Ahluwalia
The Problem
• Coronary heart disease is the commonest cause of death, in the UK
• Opening the occluded artery with primary percutaenous coronary intervention (PPCI) remains the most effective treatment of AMI.
• However, substantial mortality and morbidity persist:-– 5-6% have a subsequent cardiovascular event by 30 days – 15-20% developing heart failure
• One of the main determinants of prognosis is infarct size
• Several strategies have reduced Infarct size in pre-clinical models, but have not translated clinically
The Solution
Nitrite (NONitrite (NO22--))
Blood vesselBlood vessel lumenlumen
NO
White cellWhite cellleukocyte leukocyte
EndotheliumEndothelium
Vascular smooth muscle
vasodilatation
The endothelium and NO
.
..
. ..
...
.. ....
....
Clotting cellClotting cellPlateletPlatelet
X
Ahluwalia et al. PNAS, 101, 1386-1391.
L-Arginine NO.NOS
NO2-
NO3-
O2
Nitric oxide synthesis in hypoxia
HypoxiaAcidosis
Zweier et al, 1995, Nature Medicine;1:804-809
An alternative source of endogenous NO in ischaemia
Webb et al, 2004, PNAS;101:13683-13688.
Planned Fellowship
• Mechanistic In-Vitro studies– Cell culture/Flow cytometry– Effect of Nitrite on cell growth during hypoxia and reperfusion injury – Human coronary artery endothelial cells and cardiomyocytes
• Clinical Trial: NITRITE-AMI– Translating inorganic nitrite ameliorates the damaging effects of I/R injury– A double-blind, randomized, single-centre, placebo-controlled trial– London Chest Hospital Heart Attack Centre:- Prof Mathur (Regenerate AMI)– 80 patients– 1.8micromol Sodium Nitrite in 10mls 0.9% saline
NITRITE-AMI
• Primary endpoint: Infarct size assessed by creatine kinase (AUC) during 1st 48 hours
• Secondary endpoints: • Clinical
– Advanced imaging using CMR– Acute safety and tolerability of intra-coronary nitrite in STEMI – Assessment of MACE endpoints at 6 and 12 months (death, HF, MI, stroke,
need for repeat revascularisation
• Mechanistic– Measuring markers of inflammation – Measuring markers of platelet activity– Measuring NO pathway
William HarveyResearch Institute
NITRITE-AMI
Flow Cytometry (FACS)