Coronary Reactivity Testing and Metabolic Syndrome

A 56-year old female patient with past medical history of obesity, hypertension, dyslipidemia, and family history of early coronary disease presented to preventive clinic. She reported intermittent nonexertional chest pain, substernal chest tightness, associated with exertion. She had a stress test in 2008 which was reportedly negative. She had a strong family history of premature coronary artery disease and was intolerant to statins.

A repeat stress test performed showed that she achieved 9.3 METS, and 101% of the target heart rate, but the test was terminated due to ventricular tachycardia, which resolved after 1 minute.

Subsequent coronary angiography showed mild non-obstructive coronary disease in the second diagonal, which was FFR negative (FFR = 0.86). (Video 1, Image 1) The patient experienced coronary artery spasm as well as radial artery spasm during the procedure.

Coronary Reactivity testing (Coronary Flow Reserve Testing), using the WISE protocol, showed

  1. Normal response to intracoronary adenosine (normal non endothelial microvascular function). (Normal response to adenosine defined as CFR ≥ 2.5) (Image 2)
  2. Abnormal response to intracoronary acetylcholine (abnormal endothelial dependent macro vascular function). (Normal endothelial dependent macrovascular function defined as coronary artery dilation >5%. Normal endothelial dependent microvascular function defined as an increase in coronary blood flow >50% at the highest dose of acetylcholine.) (Image 3)
  3. Abnormal response to intracoronary nitroglycerin (abnormal non endothelial dependent macrovascular function). (Normal function defined as an increase in diameter > 20%) (Image 4)

She was medically managed, and with advanced diagnostic labs, she was placed on a water soluble statin and calcium channel blocker, with good results and control of her symptoms.

Coronary Reactivity Testing and its Role in Diagnosis and Treatment of Angina

The syndrome previously known as cardiac syndrome X remains a challenging one, in which patients may have chest pain and evidence of angina on stress testing despite normal or non-obstructive disease on coronary angiography. The landmark study in the field, the NHLBI Women's Ischemia Syndrome Evaluation (WISE) study showed that microvascular and macrovascular dysfunction is more common than previously thought, affecting up to 50% of patients, and conferring an adverse prognosis.

The major epicardial vessels manifest with angina that is well correlated via fractional flow reserve. While the importance of the microvasculature is not readily apparent through coronary angiography, the small arteries and arterioles are actually the major sites of resistance in blood flow throughout the myocardium, contributing 80% of the total resistance.

The microvasculature has an active role to play, some of which can be measured through coronary reactivity testing. Intracoronary adenosine helps measure the non-endothelial dependent microvascular function, while acetylcholine helps measure endothelial dependent macro and microvascular function. Nitroglycerin helps measure non-endothelial dependent microvascular function. Combining the different studies in one coronary vasoreactivity study following the WISE protocol can help determine the level at which the dysfunction is seen in a particular patient.

Video 1: Angiography of patient's normal Left Coronary system.

Image 1: Left Anterior Descending artery with 0.014 inch Doppler pressure wire in situ.

Image 1
Coronary reactivity testing using adenosine, acetylcholine, nitroglycerin was performed.

Image 2: Adenosine testing was performed to calculate coronary flow reserve at maximal hyperemia. Our patient demonstrates CFR >2.5 with adenosine, indicating normal nonendothelial-dependent microvascular function.

Image 2

Image 3: Acetylcholine testing showed vasoconstriction proceeding from low dose to high dose Acetylcholine, indicating abnormal endothelial dependent macrovascular function (<5% increase in diameter). Coronary blood flow was measured using average peak velocities and diameter to measure blood flow. It was noted to increase >50%, indicating normal endothelial dependent microvascular function.

Image 3

Image 4: An abnormal nonendothelial dependent macrovascular response to Nitroglycerin 200 mcg was noted. (<20% increase in diameter)

Image 4


  1. Bairey Merz CN, Pepine CJ. Syndrome X and microvascular coronary dysfunction. Circulation 2011;124:1477-80.
  2. Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006;47:S21-9.
  3. Von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:722-5.
  4. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-906.
  5. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830-40.
  6. Kern MJ, Lerman A, Bech JW, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation 2006;114:1321-41.
  7. Crea F, Camici PG, Bairey Merz, CN. Coronary microvascular dysfunction: an update. Eur Heart J 2014;35:1101-11.

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