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Coronary Microvascular Disease: A Fellow’s Guide
Brett S Bernstein, BCIS Fellow Editor 2025-26
Setting the Scene
A 55 year old woman presents with angina. Her stress echo is positive for inducible ischaemia at the apex and she is referred for coronary angiography. Frequently these patients are found to have no obstructive epicardial disease. Understanding the physiology of the coronary microvasculature and how to test for its dysfunction are crucial to the further management of these patients.
Introduction
Whereas large epicardial coronary arteries only account for 5% of coronary resistance to blood flow, small calibre intramyocardial arterioles and capillaries, both of which are not visible on coronary angiography, account for a combined 75%1,2. The arterioles have high tone at baseline, but in the context of increased oxygen demand, can dilate significantly. As a result of the decreased coronary resistance caused by dilatation, blood flow can increase by about 5x in healthy patients during physical exercise or upon administration of pharmacological agents such as dobutamine.
Pathophysiology
Coronary Microvascular Disease (CMD) can be broadly categorised into functional and structural subtypes.
The functional subtype is characterised by increased baseline flow due to reduced microvascular resistance; enhanced nitric oxide synthase (NOS) activity causes relative vasodilatation at rest, hence there is less reserve for further vasodilatation when oxygen demand increases3,4. Smooth muscle cell dysfunction and autonomic dysregulation are also implicated in this subtype2.
Structural CMD is characterised by reduced hyperaemic coronary blood flow due to increased microvascular resistance during hyperaemia4. This is believed to be due to impairment of endothelial nitric oxide synthase (eNOS).
Other types of CMD include physical changes in the microvascular architecture (such as vascular remodelling, rarefaction, luminal obstruction from micro-emboli, perivascular fibrosis)2, and extrinsic compression of the vessels due to, for example, myocardial hypertrophy or raised end-diastolic pressures.
The relationship between CMD and heart failure with preserved ejection fraction (HFpEF) is the subject of active research, with proposed mechanistic links such as subendocardial ischaemia, impaired lusitropy and reduced left ventricular diastolic reserve, driven by eNOS uncoupling.
Derived Values
The most important value in microvascular assessment is Coronary Flow Reserve (CFR), defined as the ratio of coronary blood flow in maximal hyperaemia compared to baseline. This represents the greatest increase in flow that the circulation can provide in response to increased oxygen demand. There is relatively broad consensus that a normal CFR value should be >2.0-2.55,6, although, as CFR is not specific to the microcirculation, stenoses in large epicardial arteries can affect this figure.
The other key value in microvascular assessment is microvascular resistance (MR). There are a number of different indices representing MR, depending on the method of measurement utilised. If using thermodilution (bolus or continuous), the most common value derived will be IMR (Index of Microcirculatory Resistance; normal <25), whereas if using Doppler Ultrasound, values such as hMR (hyperaemic MR; normal >2-2.5), or mMR (minimal MR) will be obtained). Both thermodilution and Doppler techniques can also derive MRR (MR reserve).2
Although invasive microvascular testing is clearly stated as a class 1B recommendation from the European Society of Cardiology7,8, there is no specific guidance on which techniques (and measures of microvascular resistance) are preferred. Doppler and continuous thermodilution-derived CFR show superior agreement compared to bolus thermodilution-derived CFR8. Furthermore, Doppler-derived hMR has superior diagnostic accuracy compared to thermodilution-derived IMR8. However, since 10% of Doppler signals yield poor quality data9, the Doppler technique is largely confined to centres with significant experience only2.
A raised CFR alone is sufficient for a diagnosis of CMD; microvascular resistance provides additional information that may guide subtype and treatment.
Techniques
The LAD is the recommended artery for microvascular testing10 as the majority of experimental work on microvascular assessment has been performed in the LAD. However, operators may want to assess another artery due to concerns of spasm, or indeed simultaneous pressure wire testing of a moderate epicardial lesion, and this is acceptable.
Therapeutic anti-coagulation with heparin is advised before microvascular assessment, similar to its use in standard pressure wire assessment or with the use of coronary wires.
Regardless of the wire being used, once the guide catheter is in place, intracoronary nitrates should be administered and flushed with saline, the wire equalised at the catheter tip, and the wire advanced into the mid LAD.
Doppler Wire (Philips) or Combo Wire (Philips): After optimising the wire to achieve the best Doppler signal and envelope, the Average Peak Velocity (APV) can be calculated over a number of cardiac cycles. APV can also be similarly calculated at hyperaemia (see below), and the ratio of these two APVs gives CFR.
Pressure Wire X (Abbott): Most commonly, bolus thermodilution is used, whereby 3ml of room temperature saline is injected through the guide catheter, and a transit time between two thermistors on the wire can be calculated. Boluses are ideally repeated until 3 readings have <10% variability. This is repeated after hyperaemia is achieved, and as transit time is inversely related to flow, the ratio of transit time at rest to hyperaemia transit time gives CFR.
Continuous thermodilution using a dedicated microcatheter (Rayflow, Hexacath) uses the difference between the room temperature saline and a blood/saline mix produced proximal to the thermistors to calculate absolute flow. This may be more accurate and reproducible than bolus thermodilution derived flow rate.11 Repeat measurements are taken at hyperaemia and CFR derived as above.
Hyperaemia is most commonly obtained with an intravenous adenosine infusion at 140 µg/kg per minute. When a steady state is reached, with loss of the dicrotic notch (often after ~90 seconds), measurements should be taken while the adenosine is still running. If using the continuous infusion technique, it is possible to achieve hyperaemia through higher rates of saline infusion12 (20ml/min as opposed to 10ml/min). Mechanisms for the saline induced hyperaemia have not been entirely elucidated but proposed mechanisms include shear-induced eNOS-activated vasodilation13.
If clinically suspicious, coronary infusion of acetylcholine (ACh) can also be performed to assess for spasm in both epicardial arteries and the microvasculature. An ACh Flow reserve of <1.5 is indicative of a component of microvascular spasm2. A recent comprehensive review of patients who underwent ACh testing demonstrated a major complication rate (myocardial infarction, ventricular arrhythmia, cardiogenic shock) of 0.5%, and a minor complication rate (paroxysmal atrial fibrillation, hypotension, bradycardia requiring temporary pacing) of 3.3%14 – hence these patients require cautious monitoring during and after ACh administration.
The procedure is completed by a pullback of the wire to ensure there has been no significant drift (≤0.03) and a wire-out shot to demonstrate absence of coronary perforation.
Treatment
CorMicA demonstrated that patients randomly assigned to receive medical therapy guided by microvascular testing including ACh reactivity testing had less angina and better quality of life at one year5. CHAMP-CMD15 built on earlier work delineating distinct populations of functional and structural CMD3. Using a CFR cut-off of 2.5, Sinha et al. demonstrated that, compared to controls, both amlodipine and ranolazine improved exercise time in CMD patients, and that ranolazine (but not amlodipine) improved Seattle Angina Questionnaire summary score compared to controls.
ESC guidelines7 advise the provision of anti-anginal medical therapy based on microvascular testing, and specifically support the use of ACE-inhibitors in endothelial dysfunction. Calcium channel blockers and nitrates are advised in proven vasospastic angina.
Good secondary prevention is also a key cornerstone of CMD management, all the more so because of the significant overlap in risk factors between CMD and major cardiovascular disorders such as MI and stroke16.
Future Work
REMEDY-PILOT is an ongoing trial looking at the use of coronary sinus reducer (CSR) in refractory angina due to CMD, and COSIRA-II is more broadly looking at CSR use in refractory angina, but is aiming to recruit CMD patients.
Further elucidating the putative17 relationship between CMD and HFpEF will also be key to improving the understanding of both of these under-diagnosed18,19 conditions moving forwards.
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