Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration

Summary

This protocol presents the acetylcholine rechallenge after nitroglycerine as an add-on procedure to spasm provocation testing. The purpose of this technique is to unmask co-existing microvascular spasm in patients with epicardial spasm and to assess the protective efficacy of nitroglycerine on a per-patient level to guide medical therapy.

Abstract

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using acetylcholine (ACh) spasm provocation testing. CAS can further be divided into different subtypes (e.g., focal, diffuse epicardial, or microvascular spasm), each with different pathophysiological mechanisms that may require tailored drug treatment. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. In order to assess on a per-patient level whether nitroglycerine (NTG) can prevent inducible spasm, the vasospastic ACh dose can be readministered after NTG administration as part of the spasm provocation test. The preventive effect of NTG is assessed by evaluating improvements in the severity of induced symptoms, ischemic ECG changes, and by reassessing the site and mode of spasm on angiography. This technique can therefore be used to assess the nitrate responsiveness on a per-patient level and unmask co-existing microvascular spasm in patients with epicardial spasm that is prevented with NTG. The NTG rechallenge, therefore, allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders.

Introduction

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina and non-obstructive coronary artery disease (ANOCA) by means of spasm provocation testing with acetylcholine(ACh)^1,2,3,4.The recent CorMicA trial demonstrated that identification and concurrent tailored treatment of CAS persistently improve the patient's quality of life and reduce the burden of angina⁵. Usually, once CAS is diagnosed, it is regarded as one distinct disease and treated with anti-vasospastic medication, such as calcium antagonists and nitrates¹. Although, CAS can be divided into different subtypes with different pathophysiological mechanisms that may require tailored drug treatment⁶. CAS can occur on an epicardial level, either focally or diffusely, throughout the epicardial coronary arteries or on a microvascular level. The former is defined as vasospastic angina (VSA) and the latter as microvascular angina (MVA) due to microvascular spasm according to the COronary VAsomotor DISorders study group (COVADIS)^3,4. Moreover, combinations of endotypes of CAS may co-exist that can further complicate tailored treatment. This is especially important as the occurrence of microvascular spasm may be masked during spasm provocation when a simultaneous epicardial spasm occurs.

As a consequence, treatment of these patients in clinical practice can be cumbersome and initiates a period of trial and error based treatment with various anti-vasospastic or anti-anginal medications. Nitrates, in particular, are often initiated as first-line treatment in short-acting form as rescue medication for acute anginal attacks or in the long-acting form as maintenance therapy. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. Especially in the case of microvascular or diffuse distal epicardial spasm, the effect of NTG is controversial^7,8. Furthermore, the therapeutic efficacy of chronic NTG treatment has to be weighed against potential side effects, such as severe headaches and a worsened exercise capacity^9,10,11.

Recently Seitz et al. demonstrated the clinical usefulness of the ACh rechallenge technique after NTG administration as an add-on procedure to the spasm provocation test¹². This is performed after a positive spasm provocation test by readministering the vasospastic dose of ACh in a similar fashion as the vasospastic dose itself 3 min after NTG administration. To this end, the COVADIS criteria are revisited in order to evaluate the preventive effect of NTG, e.g., improvement in symptoms, ischemic ECG changes, and reassessment of the site and mode of spasm by angiography^3,4. Moreover, prevention of epicardial spasm during rechallenge can unmask the co-existence of microvascular spasm.

The purpose of the rechallenge after NTG, therefore, is two-fold: (1) to assess the preventive effect of NTG on the re-occurrence of spasm on a per patients level in order to improve clinical outcomes and tailor treatment immediately after diagnosis that is made during spasm provocation and (2) to assess the co-existence of microvascular spasm in patients with epicardial coronary artery spasm^10,13.

A previous publication by Ong et al. extensively covered the spasm provocation test¹⁴. In our institute, we use a variation of this protocol where the ACh dosages are administered in 60 s instead of 20 s. The purpose of this paper is to describe the NTG rechallenge as an add-on procedure to the ACh spasm provocation test. This technique can be performed with each type of protocol, as demonstrated by Seitz et al. since the results of the NTG rechallenge did not differ among the participating centers that used different protocols.

Protocol

Intracoronary ACh testing has been approved by the local ethics committee of the Academic Medical Centre, and the protocol follows the guidelines of Amsterdam UMC for human research. 1. Preparation of the ACh stock solution Mix the 20 mg of ACh with the 2 mL of solvent provided with the package (Table of Materials). Add 1 mL of the ACh solution to 499 mL of 0.9% NaCl to create the stock solution, corresponding to a 20 µg/mL dose.</li…

Representative Results

Interpretation of the ACh-test and rechallenge are based on criteria defined by the COVADIS study group4. A positive diagnosis for CAS is defined as (i) reproduction of the previously reported symptoms such as chest pain, shortness of breath, or other symptoms and (ii) the induction of ischemic ECG changes (ST-segment elevation or depression, or U-waves) in reaction to ACh. (Figure 2). It is therefore important to register a 12-lead-ECG continuously throughout the tes…

Discussion

The usefulness of the ACh after NTG rechallenge has shown to be two-fold: (1) to unmask the co-existence of microvascular spasm in patients with epicardial spasm and (2) to assess the preventive efficacy of NTG on a per-patient level in order to guide medical therapy¹². Regardless of the result of the spasm provocation test, intracoronary NTG is always routinely administered into the target vessel after the test or when severe symptoms, ischemic ECG changes, or epicardial spasm occur. Adding …

Materials

Cannula (various manufacturers)	BBraun	4206096
ComboMap system	Volcano-Philips	Model No. 6800 (Powers Up)
ComboWire XT Guide Wire	Volcano-Philips	9515	Doppler guidewire
Diagnostic catheter	Boston scientific	34356-661	H749343566610/ MODEL-6F MACH 1 JL3.5
Diagnostic catheter	Boston scientific	34356-686	H749343566860/MODEL – 6F MACH 1 JR4
FINECROSS MG Coronary Micro-Guide Catheter	Terumo	NC-F863A
Intracoronary NTG	hameln pharma gmbh	RVG 119982
Lidocaine HCL	Fresenius Kabi	RVG 51673
Miochol-E Acetylcholine chloride	Bausch & Lomb	NDC 240208-539-20
Sheath Radialis	Teleflex	AA15611S
Syringe- 10 mL	BBraun	4606108V
Visipaque	GE Healthcare	RVG 17665	Iodixanol injectable contrast medium