Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm

Summary

Myocardial lactate production (coronary arterial-venous difference in serum lactate level) during coronary spasm provocation testing is considered as a highly sensitive marker that reflects acetylcholine-induced myocardial ischemia due to microvascular spasm. This article presents the procedures to assess myocardial lactate production for the diagnosis of coronary microvascular spasm.

Abstract

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina attack. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Myocardial lactate production, which could be defined as a negative myocardial lactate extraction ratio (ratio of the coronary arterial-venous difference in lactate concentration to arterial concentration), is considered indicative of objective evidence to support the emerging myocardial ischemia. Thus, monitoring of the myocardial lactate production and the emergence of chest pain and ischemic electrocardiographic changes during acetylcholine (ACh) provocation testing is of significant value for detecting the entity of MVS. Practically, 1 min after incremental doses of ACh (20, 50, and 100 μg) are administered into the left coronary artery (LCA), paired samples of 1 mL of blood are collected from the LCA ostium and coronary sinus for measurement of lactate concentration by a calibrated automatic lactate analyzer. Then, the development of MVS could be confirmed by negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial coronary spasm or before its occurrence throughout ACh provocation testing. In conclusion, assessment of myocardial lactate production is essential and valuable for the diagnosis of MVS.

Introduction

Recent studies demonstrated that ischemia with non-obstructive coronary arteries (INOCA) is caused mainly by functional coronary vasomotion disorders, including epicardial and microvascular spasms¹. The diagnosis of coronary vasoconstrictor dysfunction at the epicardial and/or microvascular levels often requires intracoronary provocation testing with a pharmacological vasoactive agent such as acetylcholine (ACh) during coronary angiography². Many patients with INOCA have no epicardial spasm on coronary arteriography despite the development of angina attack and ischemic electrocardiographic (ECG) changes in response to intracoronary ACh³. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Additionally, MVS also seems to be involved in angina in a quarter of patients with vasospastic angina (VSA) due to epicardial coronary spasm⁴.

Since no technique is available for visualizing coronary microvessels in humans in vivo, MVS is defined as ischemic ECG changes associated with the reproduction of usual chest pain in the absence of epicardial spasm (90%) intracoronary provocation testing⁵. Usually, upon the development of ischemia, myocardial lactate consumption decreases, and a shift to lactate production occurs as myocardial ischemia increases in severity^6,7. Thus, an additional myocardial lactate production measurement is considered to be useful in confirming ACh-induced microvascular myocardial ischemia during provocation testing^3,4,8. Here, the current protocol presents coronary sinus (CS) lactate measurements for the diagnosis of MVS.

Protocol

The measurement of myocardial lactate production during ACh provocation testing to evaluate coronary vasoreactivity was conducted following the ethical principles in the Declaration of Helsinki, and the protocol was approved by the Ethics Committees of Tohoku University (No.2016-1-643). All the patients provided written informed consent before the procedure. In this article, ACh provocation testing was performed following the guidelines of the Japanese Circulation Society⁹.

1. Preparation for the procedure

1. Ensure that the measurement of myocardial lactate production is performed in patients undergoing ACh provocation testing to diagnose VSA and/or microvascular angina (MVA) due to vasospasm.
2. Ensure that the patients discontinue all vasoactive agents for accuracy of those diagnoses, including calcium channel blockers, long-acting nitrates, and nicorandil, at least 48 h before catheterization study⁹.
3. Do shave hair at puncture sites, including both inguinal regions and wrists.

2. Insertion of catheters before ACh provocation testing

1. Use local anesthesia at puncture sites with subcutaneous 1% lidocaine to insert intravenous and radial artery sheaths.
   NOTE: The anesthesia effect is confirmed by the loss of pain sensation at the anesthetized area by pricking with a needle.
2. Place two 5 Fr venous sheaths through the right or left femoral vein with ultrasound guidance.
   NOTE: One venous sheath is used to insert a temporary pacing electrode in the right ventricle in case of severe bradycardia after intracoronary ACh. The other one is for a CS catheter to obtain blood samples to measure lactate levels in the CS.
3. Place a 5 or 6 Fr arterial sheath through the radial or femoral artery.
4. Administer intravenous heparin (50 to 70 U/kg) to achieve therapeutic anticoagulation (activated clotting time ~250 s) before coronary instrumentation.
5. Canulate a 5 Fr or 6 Fr Judkins-left catheter into LCA through the radial or femoral artery.
   NOTE: The usual catheter manipulations are performed with the Judkins left catheter.
6. Advance a CS catheter, for often a hydrophilic coating Amplatz-left catheter is used, from a venous sheath placed at the right femoral vein to the right atrium.
7. Confirm the configuration of CS and the location of its orifice in the right atrium in advance by detecting the CS image in the venous phase of LCA angiography (Figure 1A).
8. Canulate an Amplatz-left catheter into CS by turning the catheter counterclockwise at the right atrium with the left anterior oblique (LAO) view.
9. Verify whether the catheter is cannulated into CS and its position in CS is adequate by contrast injection from the end of the catheter (Figure 1B).
   NOTE: The venous phase of the LCA angiography confirms whether the catheter is cannulated into CS.
10. Take a pair of blood samples from the CS and the ostium of LCA simultaneously to examine myocardial lactate metabolism at baseline. Then, measure lactate levels in those samples using blood gas analysis equipped with automatic lactate measurement function.

3. Measurement of myocardial lactate production during ACh provocation testing

1. Perform the baseline left coronary angiography in an appropriate projection that ensures the best separation of the branches of each coronary artery, and serial angiographies after intracoronary injection of ACh should be performed in the same projection.
   NOTE: Since the great coronary sinus drains blood from perfusion regions of the LCA but not from the right coronary artery, evaluation of myocardial lactate production is possible only for the LCA during ACh provocation testing^8,10.
2. Administer ACh into the coronary artery in a cumulative manner (ACh 20, 50, and 100 µg in 10 mL of solution) over 20 s with careful monitoring of blood pressure and 12-lead electrocardiography (ECG). Perform coronary angiography when chest pain or any ECG ST-segment change occurs, or routinely after completing each ACh injection^9,11.
3. Collect paired samples of 1 mL of blood from the LCA ostium and the CS to measure lactate concentrations at 1 min after each dose of ACh is given to LCA and determine lactate concentrations with a calibrated automatic lactate analyzer.
4. Calculate the lactate extraction ratio (LER) by dividing the coronary arteriovenous difference in the lactate concentration by the arterial lactate concentration as follows^4,8,10:
   LER = (arterial lactate concentration [mmol/L] - coronary venous lactate concentration [mmol/L])/arterial lactate concentration (mmol/L).
   ​NOTE: Myocardial lactate production defined by negative LER is objective evidence to support the emerging myocardial ischemia^4,8,10. Therefore, the occurrence of MVS as myocardial lactate production (negative LFR) becomes recognizable without or before the occurrence of angiographically apparent epicardial coronary spasm during ACh provocation testing³.
5. Administer 5 mg of isosorbide dinitrate into the LCA if epicardial coronary spasms were induced. Promptly, perform coronary angiography while the coronary artery is maximally dilated.
   1. Simultaneously, collect blood samples of 1 mL of blood from the LCA ostium and the CS to measure lactate concentrations after the relief of ACh-induced spasm.

Results

A 56-year-old woman with no coronary risk factors suffered from transient chest discomfort at rest. She underwent ACh provocation testing and measurement of myocardial lactate production for diagnosis of MVS. As shown in Figure 2, chest pain, ischemic ECG changes, and negative LER were noted immediately following 100 µg of ACh administration into the LCA. Still, no relevant epicardial coronary spasm was observed on angiography. Thus, she was diagnosed as having MVS. Intriguingly, she ha...

Discussion

Detection of enhanced coronary vasoconstriction is possible by an additional pharmacological provocation testing with ACh or ergometrine during coronary angiography. Even now, there is no technique to directly visualize the coronary microvasculature for evaluation of its function in vivo, the occurrence of coronary spasm at microvascular level could be solely deduced by the reproduction of usual symptoms together with ischemic ECG changes despite the absence of epicardial coronary spasm during ACh provocation te...

Materials

Name	Company	Catalog Number	Comments
ABL8000 FLEX blood gas analyzer	RADIOMETER, Copenhagen, Denmark	k041874	The automatic lactate analyzer
OUTLOOK	Terumo Corp, Tokyo, Japan	RQ-5JL4000	The Judkins-left catheter for coronary angiography
Ovisot for injection	Daiichi sankyo company, limited, Tokyo, Japan	871232	Injectable product of acetylcholine chloride for acetylcholine provocation testing
Supersheath	MEDIKIT CO., LTD., Tokyou, Japan	CS50P11TSM	The sheath for insertion of a catheter
Technowood SoftNAV Catheter	Technowood Corp, Tokyo, Japan	H710-FL445SH	The Amplatz-left catheter for blood sampling from coronary sinus