Circulation.2015;131:1054-60

BACKGROUND

Patients with chest pain and normal findings on coronary arteriography may represent as many as 10% to 30% of those undergoing coronary arteriography because of clinical suspicion of angina.

proportion may be substantially higher in women

in the initial WISE (Women’s Ischemic Syndrome Evaluation) study, approximately two thirds of women with chest pain and other findings suggestive of SIHD had no critical coronary stenosis detected with angiography

Della Rocca DG, Pepine CJ: Some thoughts on the continuing dilemma of angina pectoris. Eur Heart J (in press). ePub only, 2012

Johnson BD, Shaw LJ, Buchthal SD, et al: Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: Results from the National Institutes of Health–National Heart, Lung, and Blood Institute–Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109:2993, 2004.

?Coronary microcirculationCoronary microvascular

dysfunction

Angina with normal coronary arteries, a continuous dilemma

* Cardiac syndrome X : 1973* Microvascular angina : 1985

Can we open the “black

box” ?Finding the missing piece to the puzzle

42 years

(1973-2015)

• Coronary Microcirculation• Classification of CMVD• Pathophysiologic mechanisms• Clinical presentation• Assessment • Management

Coronary microvascular

dysfunction(CMVD) Much

discussed but little

understood

What we can see is only 5% of the total coronary tree.

Coronary blood flow is driven by the pressure difference between the aorta and the capillary bed and modulated further by various physical and neural factors, which affect the microcirculation. Moreover, the different compartments of the microcirculation are influenced by one main physiological mechanism to control their vascular tone with cardiac metabolism as the final determining factor.

MICROVASCULAR DYSFUNCTION• Pepine CJ, er al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluate for suspected

ischemia: results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010;55:2825–2832

• Lerman A, Holmes DR, Herrmann J, Gersh BJ. Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur Heart J. 2007;28:788–797

EPICARDIAL ENDOTHELIAL DYSFUNCTION

• Halcox JP et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653–658

FOCAL EPICARDIAL CORONARY SPASM

• Halcox JP et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653–658

OCCULT DIFFUSE EPICARDIAL CORONARY DISEASE

• De Bruyne B, et al. Abnormal epicardial coronary resistance In patients with diffuse atherosclerosis but “normal” coronary angiography. Circulation. 2001;104:2401–6

MYOCARDIAL BRIDGING

• Kramer JR, Kitazume H, Proudfit WL, Sones FM Jr. Clinical significance of isolated coronary bridges: benign and frequent condition involving the left anterior descending artery. Am Heart J. 1982;103:283–288

The prevalence of these causes in the same population is not defined.

The percentage of patients without any of these abnormalities and presumably noncardiac symptoms is also unknown

Why important????

AIM

To Investigate The Potential Underlying Causes Of Angina In Symptomatic Patients With Nonobstructive CAD With A Comprehensive CombinationOf Invasive Investigations

What for???

• Unnecessary overtreatment/ anxiety/ stress/ health expenditure

• Treatment deprivation when they really need/ increasing risk of progression

METHODS

All adult patients With a clinical suspicion of coronary ischemia based on the presence of angina with or without an abnormal stress test

Typical angina - 3 characteristics: substernal chest discomfort, provoked by exertion or emotional stress, was relieved by rest or nitroglycerin. Atypical angina was defined as meeting 2 of the above characteristics

Exclusion criteria acute coronary syndrome, prior heart transplantation, prior PCI or CABG, renal insufficiency (creatinine>1.5 mg/dL), abnormal ejection fraction (<55%), or presence of another likely explanation of angina such as pulmonary hypertension, HCM, or valvular heart disease.

fasting lipids, serum glucose, insulin, and glycosylatedhemoglobin. Homeostasis model assessment index was calculated toevaluate for insulin resistance

A baseline coronary angiogram was performed via the femoral artery to rule out obstructive CAD (>50% diameter stenosis) in the right and left coronary arteriesIn patients with nonobstructive CAD, a comprehensiveinvasive evaluation was conducted

ENDOTHELIAL DYSFUNCTION - intracoronary acetylcholine, CORONARY MICROVASCULAR DYSFUNCTION - index of microcirculatory resistance (IMR) and coronary flow reserve (CFR),OCCULT DIFFUSE EPICARDIAL CORONARY DISEASE - FFR, MYOCARDIAL BRIDGING - IVUS.

Coronary Endothelial Function Testing

• Intravenous heparin (50–70 U/kg) was administered, and a 6F guiding catheter without side holes was used to engage the left main coronary artery.

• To test endothelial function, 50 μg acetylcholine was slowly injected directly into the left coronary artery over 2 to 3 minutes. Unless there was significant bradycardia or severe vasoconstriction, 100 μg acetylcholine was subsequently administered. After each injection, coronary angiography was performed.

• Quantitative coronary angiography (QCA) was performed offline, and endothelial dysfunction was diagnosed if the epicardial coronary artery diameter decreased by >20% compared with baseline.

• Finally, a 200-μg bolus of intracoronary nitroglycerin was administered, and a coronary angiogram was obtained to document endothelium-independent vasodilation of the epicardial artery.

Quantitative Coronary Angiography

• Researchers at the Stanford QCA Core Laboratory who were blinded to the clinical, physiological, and IVUS results performed QCA on the left anterior descending artery (LAD) using the computer-assisted method QAngio XA7.3 (Medis)

• They determined the lumen diameter at baseline, after intracoronary acetylcholine injection, and after intracoronary nitroglycerin administration.

• QCA was performed on the first 50 mm of length from the LAD ostium

Coronary Physiology Measurements

• Within 10 minutes after endothelial function testing, CFR, IMR, and FFR were measured.

• A pressure-temperature sensor guidewire (Certus Pressure Wire, St. Jude Medical, St. Paul, MN) was used for physiology measurements.

• With the sensor positioned at the tip of the catheter, the pressure measurement from the wire was equalized with that of the guiding catheter.

• The sensor was then positioned in the distal third of the LAD. • Three injections of 3 mL of room-temperature saline were

made down the coronary artery, and the transit time was measured after each and averaged to calculate the resting mean transit time.

• An intravenous infusion of adenosine (140 μg/kg/min) was then administered via a large peripheral or central vein to induce steady-state maximal hyperemia, and 3 more injections of 3 mL of room temperature saline were made.

• The transit time was measured after each and averaged to calculate the hyperemic mean transit time.

• Simultaneous measurements of mean aortic pressure (by guiding catheter) and mean distal coronary pressure (by pressure wire) were also made during maximal hyperemia.

• IMR was calculated as the distal coronary pressure at maximal hyperemia divided by the inverse of the hyperemic mean transit time.

• CFR was calculated as resting mean transit time divided by hyperemic mean transit time.

• FFR was calculated by the ratio of mean distal coronary pressure to mean aortic pressure at maximal hyperemia.

• Microvascular dysfunction was defined as an IMR ≥25. An abnormal FFR was defined as ≤0.80.

Intravascular Ultrasound

• IVUS was performed with a 40-MHz mechanical transducer ultrasound catheter (Atlantis SR Pro2, Boston Scientific Corp, Natick, MA) advanced down the LAD so that the IVUS transducer was positioned as close as possible to the pressure transducer mounted on the pressure wire.

• An automated pullback at 0.5 mm/s was performed, and the IVUS images were stored onto DVD for offline analysis.

Intravascular Ultrasound

• The presence of a myocardial bridge was defined by either the identification of an echolucent half-moon sign or evidence of systolic compression (≥10% systolic compression during the cardiac cycle).

• Maximum percent systolic compression was calculated by echo- Plaque software (Indec Systems, Inc) and was defined as the change in vessel area during the cardiac cycle divided by vessel area during diastole.

RESULTS

Epicardial Endothelial dysfunction

Paradoxical vasoconstriction after intracoronary acetylcholine injection

low fractional flow reserve (FFR) with occult diffuse epicardial disease

Microvascular dysfunction

There was no significant angiographic stenosis in the LAD, but the index of microcirculatory resistance was high

Myocardial bridging

An IVUS image of myocardial bridging during diastole and systole. An echolucent area surrounding the coronary artery is seen during the entire cardiac cycle

Results of invasive assessment for coronary circulation

Total 139 patients

Prevalence of occult coronary abnormalities on invasive assessment

LIMITATIONS

• Small single center study• Complex and expensive• No case of focal epicardial spasm• Invasive assessment only in LAD• Symptom occurrence and ECG changes not

recorded during Ach administration

Take home messages

More than 75% patients with angina in the absence of obstructive CAD have occult coronary abnormalities which may be

causing their symptoms

• These occult abnormalities mainly include:

Endothelial dysfunctionMicrovascular dysfunctionMyocardial bridgingFocal epicardial spasmLow FFR

Take home messagesA comprehensive invasive assessment of

these problems at the time of CART provides important diagnostic info that may

affect treatment and outcomes

Large RCTs are warranted to check their cost effectiveness and benefits in changing

disease outcome

ThankYou