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Author Affiliations: 
Correspondence to: 

David P Ripley, Department of Cardiology, Northumbria Specialist Care Emergency Hospital, Northumbria Healthcare NHS Foundation Trust, Northumbria Way, Northumberland NE23 6NZ, UK  Email:

Journal Issue: 
Volume 49: Issue 3: 2019
Cite paper as: 
J R Coll Physicians Edinb 2019; 49: 182–4



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Coronary heart disease (CHD) is a leading global health problem resulting in 7.2 million annual worldwide deaths.1 A variety of investigations and diagnostic pathways may be used to diagnose CHD and determine the need for revascularisation. In the UK alone 260,000 invasive coronary catheterisation procedures per annum are performed, with 38% of these undergoing revascularisation with percutaneous coronary intervention (PCI).2 It is well recognised that the concordance between the visual assessment of the severity of the coronary stenosis observed at coronary angiography and demonstrable ischaemia is poor.3 Current guidelines, therefore, recommend that ischaemia should be demonstrated in those with stable angina before PCI is performed.4,5

Myocardial fractional flow reserve (FFR) is a lesion-specific index of the functional significance of an epicardial coronary stenosis. It is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow. Maximal flow (hyperaemia) is typically induced by intravenous infusion of adenosine, or with an intracoronary bolus of adenosine. The ratio of the pressure distal to (i.e. guidewire pressure) and proximal to (i.e. the aortic pressure) stenotic lesions at maximal flow is the FFR. An FFR value of 1.0 is considered normal, whereas a ratio of ≤0.80 is an evidence-based physiological threshold that correlates with the presence of inducible ischaemia.6,7

In addition, intravenous adenosine may also be administered for the assessment of the microvascular coronary circulation.8 Under normal physiological conditions, myocardial perfusion is autoregulated by arterioles within the myocardium and prearterioles in the epicardium. Owing to their small calibre (≤300 µm in diameter) the microcirculation is not directly visualised during invasive coronary angiography. These small blood vessels, however, contribute the majority of coronary resistance. Pathological changes, including perivascular fibrosis, occur in those with hypertension,9 coronary artery disease10 and after cardiac transplantation. Following the induction of maximal hyperaemia with adenosine the index of microcirculatory resistance can be quantified using pressure and temperature sensitive coronary guidewires.11 Since resistance is a property of microvascular tone, this provides a direct assessment of microvascular function and is independent of coronary stenosis severity. This is helpful in the assessment of microvascular angina and there is increasing evidence of the prognostic value of microcirculatory resistance following revascularisation for ST-elevation myocardial infarction.12

Noninvasive cardiovascular imaging

Evidence from large populations of patients undergoing invasive angiography have demonstrated that only around 40% will undergo revascularisation.2,13 Thus, over the last decade there has been a rapid expansion in the use of noninvasive cardiovascular imaging with the development of new technologies, such as CT coronary angiography and cardiovascular magnetic resonance (CMR). Noninvasive imaging has become the first-line investigation in national and international guidelines for the investigation of stable coronary artery disease.5,14 Vasodilating agents, such as adenosine, can be used to induce stress in CMR, myocardial perfusion scintigraphy (MPS) and stress echocardiography. MPS with vasodilator stress has for decades been used as an investigation and risk-stratification tool in those presenting with stable angina.15 Furthermore, there is recent clear demonstrable evidence that using noninvasive imaging in those with stable CHD can safely reduce the inappropriate use of invasive coronary angiography (which may result in potential cost savings and risk reduction).16 Stress perfusion CMR with adenosine stress has recently been demonstrated to result in fewer revascularisations with no difference in major adverse cardiovascular events.17


Adenosine exerts its biological effect on four receptor subtypes (A1, A2A, A2B and A3AR).18 Adenosine has a very short half-life (<10 s) and, therefore, is administered intravenously or via the intracoronary route. Potential complications of adenosine not only include the risk of acute bronchospasm but also other serious arrhythmias, including ventricular fibrillation in those with an accessory conduction pathway. In this issue of JRCPE Morrow et al.19 demonstrate the very rare incidence of bronchospasm following the administration of adenosine. There is overwhelming evidence for its beneficial use in the functional assessment of CHD (either invasively in the catheterisation laboratory or with noninvasive cardiovascular imaging) or of the microvascular physiology. These data, therefore, add support to the argument for the safety of adenosine and the continued use for the functional assessment of cardiovascular conditions. It ought to be recognised that adenosine is not the only agent to be used for the assessment of functional coronary disease. Other options include regadenoson, dipyridamole, dobutamine, electrical stress and physiological (treadmill or bicycle) exercise.

The future

As an alternative to FFR, instantaneous wave free ratio provides a similar validated method for assessing epicardial coronary disease without the need for administration of adenosine. In addition, CT-FFR has recently been approved by the US Food and Drug Administration. The technology combines anatomical and functional assessment demonstrating coronary physiology simulation using proprietary software. This is able to assess the functional significance of an epicardial stenosis without inducing stress. CT-FFR has been demonstrated to modify treatment recommendation, and reduce rates of invasive coronary angiography and revascularisation without any expense of major adverse cardiovascular events.20

Whilst adenosine plays a fundamental role in the current invasive and noninvasive assessment of stable coronary disease and has an excellent safety profile, administration may be uncomfortable for patients and in rare cases have serious side effects. The changing landscape of available technology may allow us to move towards different techniques to evaluate coronary stenosis.


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Financial and Competing Interests: 
DPR reports personal fees from A Menarini, Bayer and Takeda, these are outside of the submitted work