NIHR Barts and The London CVBRU Centre for Advanced Cardiovascular Imaging NIHR Barts and The London Cardiovascular Biomedical Research Unit William Harvey.

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)