Name: acetylcholine re-challenge after intracoronary nitroglycerine administration
Uploaded: 2022-04-04T13:00:00.000+00:00
Duration: 7 min 59 s
Description: Watch this Scientific Journal Video about Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration at JoVE.com

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
<ol>
	<li>Mix the 20 mg of ACh with the 2 mL of solvent provided with the package (Table of Materials).</li>
	<li>Add 1 mL of the ACh solution to 499 mL of 0.9% NaCl to create the stock solution, corresponding to a 20 &#181;g/mL dose.</li>
	<li>Fill a sterile dish with 50 mL of the stock solution, which will be used to prepare the syringes under sterile conditions.</li>
</ol>
2. Preparation of the syringes containing ACh for intracoronary injection
<ol>
	<li>Prepare five 10 mL syringes under sterile conditions for the intracoronary injection according to the Supplementary Material. 
	&#8203;NOTE: It is advised to prepare each syringe sequentially after administration and not all at once to avoid confusion when administering the syringes</li>
</ol>
3. Diagnostic coronary angiography
<ol>
	<li>Anesthetize the puncture site of the right radial artery (usually 2 mL of lidocaine) or the area of the puncture site of the right femoral artery (usually 15 mL of lidocaine) when the femoral artery is the preferred route of catheterization. 
	NOTE: By puncturing the skin with the needle, the successfulness of the local anesthesia can be assessed.</li>
	<li>Puncture the artery with a cannula using the Seldinger wire technique, then insert a wire through the cannula. After removing the cannula, insert a sheath (6F) over the wire. Perform coronary angiography under sterile conditions.</li>
	<li>Advance the wire into the ascending aorta through the sheath and subsequently position the diagnostic catheter (6Fr) above the aortic valve. Withdraw the wire and attach the contrast syringe to the catheter. 
	NOTE: The contrast agent used is iodixanol Injectable Contrast Medium.</li>
	<li>Position the tip of the diagnostic catheter for the left coronary artery in the left main coronary artery. Confirm the position of the catheter by injecting 2 mL of the contrast agent.</li>
	<li>Exclude the presence of obstructive coronary artery disease by perming coronary angiography. Inject ~5-10 mL of the contrast agent to visualize the coronary arteries in different views. 
	&#8203;NOTE: Most often, the following projections provide the best overview: LAO 40&#176; and RAO 35&#176; for the right coronary artery and LAO 45&#176;/CRAN 25&#176;, RAO 30&#176;/CRAN 30&#176; and RAO 20&#176;/ CAUD 30&#176; for the left coronary artery.</li>
</ol>
4. Preparations for Doppler flow assessment
NOTE: Here, ComboWire was used as the Doppler guidewire with the ComboMap system (Table of Materials)
<ol>
	<li>Connect the Doppler guidewire to the system and zero the pressure on the console and the aortic pressure on the hemodynamic system.</li>
	<li>Advance the Doppler guidewire through the guiding catheter into the ostium of the coronary artery with the pressure sensor of the Doppler guidewire placed just distally of the tip of the guiding catheter. Press normalization (Norm) on the system to equalize the two pressures.</li>
	<li>After normalization, reintroduce the wire via the microcatheter into the proximal or mid LAD and acquire a stable flow signal. 
	NOTE: The Doppler guidewire can alternatively be introduced more distally into the LAD or in the CX when acquiring an adequate signal in the proximal LAD is not feasible, such as in the case of tortuous anatomy or when another position is otherwise required, for instance, proximal from a myocardial bridge.</li>
	<li>Document the position of the wire using fluoroscopy.</li>
	<li>Start ACh testing as described in section 5 after exclusion of any relevant epicardial stenosis (&#8805;50%) by visual assessment.</li>
</ol>
5. Intracoronary administration of ACh
<ol>
	<li>Administer the first syringe containing 2 &#181;g of acetylcholine as described in the Supplementary Material into the LCA through the guiding. Inject this in 60 s with continuous monitoring of the ECG, average peak velocity (APV), and the patient&#39;s symptoms (e.g., angina and/or dyspnea).
	<ol>
		<li>Flush the ACh that remains in the guiding into the left coronary artery at a similar injection speed to the injection itself with contrast using the contrast syringe.</li>
		<li>Perform coronary angiography of the left coronary artery by injecting 10 mL of the contrast agent into the catheter in the same projection as done for the baseline coronary angiography. Bookmark and print a 12-lead ECG after every dose of ACh or when symptoms and/or ECG changes occur.</li>
		<li>If diagnostic criteria are not met, continue with the administration of the second syringe containing 20 &#181;g of acetylcholine as described in the Supplementary Material using the same technique as described in steps 5.1.1-5.1.3. Pause for 3 min between every dose.</li>
		<li>If diagnostic criteria are not met after the second dose, continue with the administration of the third syringe containing 100 &#181;g of acetylcholine as described in the Supplementary Material using the same technique as described in steps 5.1.1-5.1.3. Pause for 3 min between every dose. 
		NOTE: At dose 3 most patients will report some symptoms, ischemic ECG changes can occur, and some epicardial diameter reduction may occur. In some cases, the speed of the manual injection will have to be slowed down. For instance, at doses 3 and 4, bradycardia may occur, and the speed of the injection will have to be slowed down. An extended injection over 1-3 min may also be feasible.</li>
		<li>If diagnostic criteria are not met after the third dose, continue with the administration of the fourth syringe containing 100 &#181;g of acetylcholine as described in the Supplementary Material using the same technique as described in steps 5.1.1-5.1.3. Pause for 3 min between every dose. 
		NOTE: At dose 4 most patients will report some symptoms, ischemic ECG changes can occur, and some epicardial diameter reduction may occur. In some cases, the speed of the manual injection will have to be slowed down. For instance, at doses 3 and 4, bradycardia may occur, and the speed of the injection will have to be slowed down. An extended injection over 1-3 min may also be feasible.</li>
	</ol>
	</li>
	<li>When diagnostic criteria according to COVADIS are not met after step 5.1.6 in the LCA, continue with RCA as the target vessel. Inject 80 &#181;g of ACH (10 mL, syringe #RCA) in 60 s into the right coronary artery while continuously monitoring the ECG and the patient&#39;s symptoms. 
	NOTE: Clinical practice on testing of the RCA can vary among centers as routine testing of the RCA is advocated according to the JCS guidelines as multi-vessel epicardial coronary vasospasm is associated with worse prognosis2,15. In contrast, vasospasm provocation protocols from European and United states centers do not routinely test the RCA16. Acetylcholine can induce bradycardia and can be resolved by decreasing the speed of the injection to prevent prolonged bradycardia and/or asystole.
	<ol>
		<li>Flush the remaining ACh in the guiding into the left coronary artery at a similar injection speed to the injection itself with contrast using the contrast syringe. Perform coronary angiography of the RCA (perform angiography in the same projection as the baseline angiography).</li>
		<li>Inject 200 &#181;g of intracoronary NTG into each target vessel after the test, or when severe symptoms (e.g., angina and/or dyspnoea)), ischemic ECG changes or epicardial spasm occurs. Continuously monitor the APV and patient&#39;s symptoms to monitor the effect of NTG.</li>
		<li>Perform coronary angiography of the target vessel after 1 min or when the APV has returned to baseline, and no symptoms are present to document reversion of spasm</li>
	</ol>
	</li>
</ol>
6. Rechallenge
<ol>
	<li>In the case of a positive diagnosis, wait for 3 min after NTG administration until the patient is free of symptoms, ECG changes have resolved, and APV values have returned to baseline before starting the rechallenge.</li>
	<li>Inject 10 mL of the syringe containing the acetylcholine dose that previously induced vasospasm as described in the Supplementary Material into guiding. Inject this in 60 s with continuous monitoring of the ECG, APV and the patient&#39;s symptoms (e.g., angina and/or dyspnea).</li>
	<li>Flush the remaining ACh in the guiding into the left coronary artery at a similar injection speed to the injection itself with contrast using the contrast syringe. Image the target vessel in the same projection as done in the baseline angiography after injection of the 10 mL.</li>
	<li>Perform coronary angiography of the left coronary artery by injecting 10 mL of contrast into the catheter in the same projection as done for the baseline coronary angiography. Bookmark and print a 12-lead ECG after every dose of ACh or when symptoms and/or ECG changes occur.</li>
	<li>Inject 200 &#181;g of intracoronary NTG into each target vessel after the test or when severe symptoms (i.e., angina and/or dyspnea), ischemic ECG shifts, or epicardial spasm occurs.</li>
	<li>Perform coronary angiography of the target vessel after 1 min or when the APV has returned to baseline, and no symptoms are present to document reversion of spasm</li>
</ol>

<ol>
	<li>Knuuti, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=2019+ESC+Guidelines+for+the+diagnosis+and+management+of+chronic+coronary+syndromes.">2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.</a> European Heart Journal. 41 (3), 407-477 (2020).</li><li>JCS Joint Working Group. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Guidelines+for+diagnosis+and+treatment+of+patients+with+vasospastic+angina+(Coronary+Spastic+Angina)+(JCS+2013).">Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013).</a> Circulation Journal: Official Journal of the Japanese Circulation Society. 78 (11), 2779-2801 (2014).</li><li>Ong, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=International+standardization+of+diagnostic+criteria+for+microvascular+angina.">International standardization of diagnostic criteria for microvascular angina.</a> International Journal of Cardiology. 250, 16-20 (2018).</li><li>Beltrame, J. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=International+standardization+of+diagnostic+criteria+for+vasospastic+angina.">International standardization of diagnostic criteria for vasospastic angina.</a> European Heart Journal. 38 (33), 2565-2568 (2017).</li><li>Ford, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=1-Year+Outcomes+of+angina+management+guided+by+invasive+coronary+function+testing+(CorMicA).">1-Year Outcomes of angina management guided by invasive coronary function testing (CorMicA).</a> JACC: Cardiovascular Interventions. 13 (1), 33-45 (2020).</li><li>Bairey Merz, C. N., Pepine, C. J., Walsh, M. N., Fleg, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ischemia+and+no+obstructive+coronary+artery+disease+(INOCA):+Developing+evidence-based+therapies+and+research+agenda+for+the+next+decade.">Ischemia and no obstructive coronary artery disease (INOCA): Developing evidence-based therapies and research agenda for the next decade.</a> Circulation. 135 (11), 1075-1092 (2017).</li><li>Sun, H., Fukumoto, Y., Ito, A., Shimokawa, H., Sunagawa, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+microvascular+dysfunction+in+patients+with+microvascular+angina:+analysis+by+TIMI+frame+count.">Coronary microvascular dysfunction in patients with microvascular angina: analysis by TIMI frame count.</a> Journal of Cardiovascular Pharmacology. 46 (5), 622-626 (2005).</li><li>Kiyooka, T., Kobayashi, Y., Ikari, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+case+of+vasospastic+angina+in+which+the+ergonovine+provocation+test+with+intracoronary+isosorbide+dinitrate+and+nicorandil+was+effective+in+the+diagnosis+of+microvascular+spasm.">A case of vasospastic angina in which the ergonovine provocation test with intracoronary isosorbide dinitrate and nicorandil was effective in the diagnosis of microvascular spasm.</a> Cardiovascular Intervention and Therapeutics. 29 (4), 344-349 (2014).</li><li>Takahashi, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prognostic+impact+of+chronic+nitrate+therapy+in+patients+with+vasospastic+angina:+multicentre+registry+study+of+the+Japanese+coronary+spasm+association.">Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.</a> European Heart Journal. 36 (4), 228-237 (2015).</li><li>Ferrari, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Expert+consensus+document:+A+'diamond'+approach+to+personalized+treatment+of+angina.">Expert consensus document: A 'diamond' approach to personalized treatment of angina.</a> Nature Reviews Cardiology. 15 (2), 120-132 (2018).</li><li>Redfield, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isosorbide+mononitrate+in+heart+failure+with+preserved+ejection+fraction.">Isosorbide mononitrate in heart failure with preserved ejection fraction.</a> The New England Journal of Medicine. 373 (24), 2314-2324 (2015).</li><li>Seitz, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acetylcholine+rechallenge:+A+first+step+towards+tailored+treatment+in+patients+with+coronary+artery+spasm.">Acetylcholine rechallenge: A first step towards tailored treatment in patients with coronary artery spasm.</a> Journal of the American College of Cardiology: Cardiovascular Interventions. 15 (1), 65-75 (2022).</li><li>Crea, F., Lanza, G. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+microvascular+angina:+The+need+for+precision+medicine.">Treatment of microvascular angina: The need for precision medicine.</a> European Heart Journal. 37 (19), 1514-1516 (2016).</li><li>Ong, P., Athanasiadis, A., Sechtem, U. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intracoronary+acetylcholine+provocation+testing+for+assessment+of+coronary+vasomotor+disorders.">Intracoronary acetylcholine provocation testing for assessment of coronary vasomotor disorders.</a> Journal of Visualized Experiments: JoVE. (114), e54295 (2016).</li><li>Han, S. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Impact+of+multi-vessel+vasospastic+angina+on+cardiovascular+outcome.">Impact of multi-vessel vasospastic angina on cardiovascular outcome.</a> Atherosclerosis. 281, 107-113 (2019).</li><li>Feenstra, R. G. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Principles+and+pitfalls+in+coronary+vasomotor+function+testing.">Principles and pitfalls in coronary vasomotor function testing.</a> EuroIntervention: Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. , (2021).</li><li>Seitz, A., Beck, S., Pereyra, V. M., Bekeredjian, R., Sechtem, U., Ong, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Testing+acetylcholine+followed+by+adenosine+for+invasive+diagnosis+of+coronary+vasomotor+disorders.">Testing acetylcholine followed by adenosine for invasive diagnosis of coronary vasomotor disorders.</a> Journal of Visualized Experiments: JoVE. (168), e62134 (2021).</li></ol>

The authors have nothing to disclose.

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&#160;occur. Adding the ACh rechallenge after spasm provocation will only minimally extend the overall length of the total procedure. ACh rechallenge technique can be performed with each type of protocol as demonstrated by Seitz et al. as sub-analysis revealed that the results of the preventive effect of NTG during rechallenge did not differ among centers that used different protocols12.
An ACh rechallenge after NTG can provide valuable information regarding the preventive effect of NTG on a per-patient level to guide medical treatment in the outpatient clinic. For instance, when NTG prevents the occurrence of vasospasm during rechallenge and improvement in symptoms, nitrate-based medications are more likely to have a substantial clinical benefit to the patient. Whereas when NTG does not or only minimally prevent the re-occurrence of spasm, this will most likely also translate into a decreased clinical effectivity of nitrate-based therapies, and other vasospastic medication should be considered. Most patients with epicardial spasm&#160;are good NTG responders, whereas, in a large proportion of patients with microvascular spasm, the effect of NTG is limited in preventing spasm12.
Intracoronary NTG of 200 &#181;g can be safely administered in most patients; however, should the blood pressure be low, a dose of 100 &#181;g can be considered keeping in mind that a lower dose could influence the response. In some patients, additional NTG administration and time are needed to revert spasm&#160;and start the rechallenge. Be aware of a possible drop in blood pressure when administering additional dosages of NTG. Once the patient is free of symptoms, the ACh rechallenge can commence. Taking into account the short half-life of ACh, we advise waiting 3 min before readministering the vasospastic dose of ACh to allow any spasm to resolve. In addition, a return of APV to baseline levels may also be a sign that vasospasm has revolved.
When performing an Ach rechallenge, we suggest using a Doppler flow wire during the procedure because this allows to better assess all vascular domains. As discussed in another contribution, collection testing with adenosine using Doppler flow velocity measurements is advocated to further assess impaired vasodilation in ANOCA17. Furthermore, the endothelial function can be measured during ACh administration with a Doppler flow wire. The use of a Doppler flow wire also provides valuable information during spasm provocation. Most importantly, it provides a safety feature as flow alterations most often occur prior to ECG changes (Figure 5), improving operator awareness and patient safety. It is important to note that when using a microcatheter to stabilize the flow or combowire in spasm provocation, only 6 Fr catheters should be used to allow for rapid backflow and NTG administration.
In the future, the ACh rechallenge technique could be applied to vasoactive medication other than NTG that can also be administered intracoronary with immediate effect. The advantage of this is that the rechallenge can be performed in one setting, whereas with medication without immediate effect this would require two procedures.&#160;The main limitation of this technique is that it is not performed blindly or in a cross-over manner with saline.
Nevertheless, rechallenging the coronary circulation with the vasospastic dose of ACh allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders on a per-patient level.

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&#39;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 controversial7,8.&#160;Furthermore, the therapeutic efficacy of chronic NTG treatment has to be weighed against potential side effects, such as severe headaches and a worsened exercise capacity9,10,11.
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 angiography3,4. Moreover, prevention of epicardial spasm&#160;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 spasm10,13.
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.

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

acetylcholine re-challenge after intracoronary nitroglycerine administration

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.

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 test and monitor for ischemic changes during ACh administration or when symptoms are reported. Finally, the distinction between epicardial and microvascular spasm&#160;is made by comparing coronary diameter reduction in reaction to the spasm provocating dose and NTG (Figure 2 and Figure 4). When epicardial vasoconstriction of &#62;90% is evident on angiography, epicardial spasm can be diagnosed, and when this is &#60;90% occurs, this is considered to be a microvascular spasm. Furthermore, the epicardial spasm may occur within the confines of one isolated coronary segment (focal spasm) or in &#8805;2 adjacent coronary segments (diffuse spasm)4.
When performing an ACh rechallenge, it can be useful to obtain a VAS score at the initial spasm provocation and rechallenge to quantify the improvement in symptoms. Improvement in provoked ischemic ECG changes, changes in APV, and severity of vasoconstriction on angiography can help as an objective measure of the preventive effect of NTG (Figure 2, Figure&#160;3, and Figure&#160;4).
Continuous assessment of Doppler flow provides valuable information during spasm provocation. Most importantly, it provides a safety feature as flow alterations most often occur prior to ECG changes (Figure 5). This improves operator awareness and patient safety.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/62406/62406fig01.jpg" /> 
Figure 1: Flow chart protocol. The ACh rechallenge can be applied to any protocol version and can therefore be performed according to local protocol. After NTG administration, the spasm provocative dose can be readministered to perform the rechallenge. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/62406fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/62406/62406fig02.jpg" /> 
Figure 2: Coronary angiographical evaluation of the NTG rechallenge. The coronary angiography performed during rest shows that no significant lumen reduction is present in the LAD depicted by the arrow (Rest). At the fourth dose (ACh) &#60;90%, epicardial lumen reduction occurs together with ECG changes and recognizable symptoms and therefore meets the diagnostic criteria for epicardial vasospasm. The last image depicts the preventive effect of NTG when the coronary artery is rechallenged after intracoronary administration of NTG. Now some vasoconstriction occurs although no &#62;90% lumen reduction and the severity of anginal complaints are reduced. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/62406fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/62406/62406fig03.jpg" /> 
Figure 3: Example of APV changes during spasm provocation. At the fourth dose, epicardial vasoconstriction causes very high APV values, whereas the preventive effect of NTG causes lower APV values because the epicardial coronary artery does not constrict. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/62406fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/62406/62406fig04.jpg" /> 
Figure 4: Example of a non-responder. In this example, the patient experiences recognizable anginal symptoms and ischemic ECG changes at the fourth acetylcholine dose without epicardial vasospasm consistent with the diagnosis of microvascular spasm according to COVADIS (left). After nitroglycerine administration, when symptoms have disappeared and ECG changes have normalized, the rechallenge with the same ACh dose commenced. Besides some epicardial vasodilation, the patient experienced symptoms and ischemic ECG changes of comparable severity compared to the spasm provocative dose. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/62406fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/62406/62406fig05.jpg" /> 
Figure 5: Example of APV changes during ACh infusion where a change in APV precedes symptoms or ECG changes and can be heard as a change in pitch of the acoustic signal. This example is from a 3 min infusion with acetylcholine. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/62406fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Supplementary Material: Instruction for preparing the syringes for ACh spasm provocation. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/62406/Supplementary Material.zip" target="_blank">Please click here to download this File.</a>

Watch this Scientific Journal Video about Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration at JoVE.com

Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration

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&#160;in patients with epicardial spasm&#160;and to assess the protective efficacy of nitroglycerine on a per-patient level to guide medical therapy.

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) ...

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1.2K Views.  Amsterdam UMC. 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.

Video: Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration

Manual Muscle Testing:  A Method of Measuring Extremity Muscle Strength Applied to Critically Ill Patients 

Survivors of acute respiratory distress syndrome (ARDS) and other causes of critical illness often have generalized weakness, reduced exercise tolerance, and persistent nerve and muscle impairments after hospital discharge.1-6 Using an explicit protocol with a structured approach to training and quality assurance of research staff, manual muscle testing (MMT) is a highly reliable method for assessing strength, using a standardized clinical examination, for patients following ARDS, and can be completed with mechanically ventilated patients who can tolerate sitting upright in bed and are able to follow two-step commands. 7, 8 
This video demonstrates a protocol for MMT, which has been taught to &ge;43 research staff who have performed &gt;800 assessments on &gt;280 ARDS survivors. Modifications for the bedridden patient are included. Each muscle is tested with specific techniques for positioning, stabilization, resistance, and palpation for each score of the 6-point ordinal Medical Research Council scale.7,9-11 Three upper and three lower extremity muscles are graded in this protocol: shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion. These muscles were chosen based on the standard approach for evaluating patients for ICU-acquired weakness used in prior publications. 1,2.

Manual Muscle Testing:  A Method of Measuring Extremity Muscle Strength Applied to Critically Ill Patients

Survivors of acute respiratory distress syndrome (ARDS) and critical illness frequently develop long-lasting muscle weakness. Manual muscle testing (MMT) is a standardized clinical examination commonly used to measure strength of peripheral skeletal muscle groups. This video demonstrates MMT using the 6-point Medical Research Council scale.

Survivors of acute respiratory distress syndrome (ARDS) and other causes of critical illness often have generalized weakness, reduced exercise tolerance, ...

A Research Method For Detecting Transient Myocardial Ischemia In Patients With Suspected Acute Coronary Syndrome Using Continuous ST-segment Analysis

Each year, an estimated 785,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS). The pathophysiology of ACS involves rupture of an atherosclerotic plaque; hence, treatment is aimed at plaque stabilization in order to prevent cellular death. However, there is considerable debate among clinicians, about which treatment pathway is best: early invasive using percutaneous coronary intervention (PCI/stent) when indicated or a conservative approach (i.e., medication only with PCI/stent if recurrent symptoms occur).
There are three types of ACS: ST elevation myocardial infarction (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA). Among the three types, NSTEMI/UA is nearly four times as common as STEMI. Treatment decisions for NSTEMI/UA are based largely on symptoms and resting or exercise electrocardiograms (ECG). However, because of the dynamic and unpredictable nature of the atherosclerotic plaque, these methods often under detect myocardial ischemia because symptoms are unreliable, and/or continuous ECG monitoring was not utilized.
Continuous 12-lead ECG monitoring, which is both inexpensive and non-invasive, can identify transient episodes of myocardial ischemia, a precursor to MI, even when asymptomatic. However, continuous 12-lead ECG monitoring is not usual hospital practice; rather, only two leads are typically monitored. Information obtained with 12-lead ECG monitoring might provide useful information for deciding the best ACS treatment.
Purpose. Therefore, using 12-lead ECG monitoring, the COMPARE Study (electroCardiographic evaluatiOn of ischeMia comParing invAsive to phaRmacological trEatment) was designed to assess the frequency and clinical consequences of transient myocardial ischemia, in patients with NSTEMI/UA treated with either early invasive PCI/stent or those managed conservatively (medications or PCI/stent following recurrent symptoms). The purpose of this manuscript is to describe the methodology used in the COMPARE Study.
Method. Permission to proceed with this study was obtained from the Institutional Review Board of the hospital and the university. Research nurses identify hospitalized patients from the emergency department and telemetry unit with suspected ACS. Once consented, a 12-lead ECG Holter monitor is applied, and remains in place during the patient's entire hospital stay. Patients are also maintained on the routine bedside ECG monitoring system per hospital protocol. Off-line ECG analysis is done using sophisticated software and careful human oversight.

Continuous 12-lead electrocardiographic (ECG) monitoring can identify transient myocardial ischemia, even when asymptomatic, among patients with suspected acute coronary syndrome (ACS). In this article we describe our method for initiating patient monitoring using a Holter device, downloading the ECG data for off-line analysis, and how to utilize the ECG software to identify transient ischemia.

Each year, an estimated 785,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS). The pathophysiology of ACS involves rupture ...

Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the catheterization laboratory which was introduced more than 30 years ago. Due to the short half-life of acetylcholine it can only be applied directly into the coronary arteries. Several studies have demonstrated the safety and clinical usefulness of this test. However, acetylcholine testing is only rarely applied in the U.S. or Europe. Nevertheless, it has been shown that 62% of Caucasian patients with stable angina and unobstructed coronary arteries on coronary angiography suffer from coronary vasomotor disorders that can be diagnosed with acetylcholine testing. In recent years it has been appreciated that the ACH-test not only assesses the presence of epicardial spasm but that it can also be useful for the detection of coronary microvascular spam. In such cases no epicardial spasm is seen after injection of acetylcholine but ischemic ECG shifts are present together with a reproduction of the patient's symptoms during the test. This article describes the experience with the ACH-test and its implementation in daily clinical routine.

Intracoronary acetylcholine testing has been established for the assessment of epicardial coronary spasm more than 30 years ago. Recently, the focus has shifted towards the microcirculation and it has been shown that microvascular spasm can be detected using ACH-testing. This article describes the ACH-test and its implementation in daily routine.

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the ...

Improvement of a Closed Chest Porcine Myocardial Infarction Model by Standardization of Tissue and Blood Sampling Procedures

Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved drug to prevent or reduce myocardial I/R injury. The study and understanding of the pathophysiological mechanisms of myocardial I/R injury is essential to develop successful treatments. Large animal experiments are an important step in translational methods. The porcine model of acute myocardial infarction has been established and described by ourselves and others. We aimed to further improve the value of the model by focusing in detail on the sampling techniques for use in future experiments. Furthermore, we emphasize small but important steps that can affect the quality of the final results. To mimic the clinical situation of myocardial I/R injury, a percutaneous coronary intervention (PCI) catheter was inserted into the left anterior descending coronary artery (LAD) of an anesthetized pig. &#176;&#176;&#176;This model mimics acute myocardial infarction and PCI treatment in humans with the possibility of accurately determining the area at risk as well as the necrotic- and viable ischemic tissue. Here the model was used to investigate the effect of a bicyclic peptide inhibitor of FXIIa. The model can also be modified to allow longer reperfusion times to study later effects of myocardial infarction.

Here we demonstrate a protocol to standardize sampling procedures of an established porcine model of acute myocardial infarction in order to increase its translational value in the understanding of the pathophysiology of myocardial ischemia/reperfusion injury and to test novel drug candidates.

Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved ...

Evaluation of Coronary Flow Reserve After Myocardial Ischemia Reperfusion in Rats

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via recanalization of the coronary artery is the most effective strategy for reducing the size of ischemic myocardium. The coronary microvasculature cannot be visualized and imaged&#160;in vivo, but there are several invasive and noninvasive techniques that can be used to assess parameters which depend directly on coronary microvascular function. The endothelial function after ischemia reperfusion can be assessed also at the level of the coronary circulation via the coronary flow reserve (CFR).&#160;In this study, peak velocity of left anterior descending (LAD) coronary arteries was measured in rats in vivo via Transthoracic Doppler Echocardiography during resting and stress challenge (induced by Dobutamine). A normal heart can increase its coronary blood flow up to four times above the resting values during stress induction. Following ischemia reperfusion, we found a significantly diminished CFR, which can be used as a marker of coronary microvascular dysfunction. CFR has opened a window on the importance of microvascular dysfunction and has been shown to predict cardiovascular risk independent of whether the severe obstructive disease is present.

Coronary flow reserve (CFR), is defined as the ratio of maximal coronary blood flow to the resting coronary blood flow. We present a protocol for evaluating CFR in rats via ultrasound, which offers the opportunity to predict cardiovascular risk factors in the absence of obstructive coronary disease.

Coronary artery disease is the leading cause of death worldwide. After an acute myocardial infarction, early and successful myocardial intervention via ...

Postconditioning with Lactate-enriched Blood for Cardioprotection in ST-segment Elevation Myocardial Infarction

The beneficial effects of reperfusion therapy for ST-segment elevation myocardial infarction (STEMI) is attenuated by reperfusion injury. No approach has been proven successful in preventing this injury in the clinical setting to date. Meanwhile, a novel approach for cardioprotection in patients with STEMI, i.e., postconditioning with lactate-enriched blood (PCLeB), has recently been reported. PCLeB is a modification of the original protocol of postconditioning, aimed at increasing the delay in the recovery from tissue acidosis produced during ischemia. This was sought to achieve controlled reperfusion with tissue oxygenation and minimal lactate washout. In this modified postconditioning protocol, the duration of each brief reperfusion is gradually increased in a stepwise manner from 10 to 60 s. Each brief ischemic period lasts for 60 s. At the end of each brief reperfusion, injection of lactated Ringer&#39;s solution (20&#8211;30 mL) is performed directly into the culprit coronary artery immediately before the balloon inflation and the balloon is quickly inflated at the lesion site, so that the lactate is trapped inside the ischemic myocardium during each brief repetitive ischemic period. After seven cycles of balloon inflation and deflation, full reperfusion is performed. Stenting is performed thereafter, and the percutaneous coronary intervention is completed. Excellent in-hospital and 6 month outcomes in a limited number of patients with STEMI treated using PCLeB have already been reported. This method article provides a detailed description of each step of the PCLeB procedures.

Herein, we present a protocol for postconditioning with lactate-enriched blood, which is a novel approach for cardioprotection. This protocol comprises&#160;intermittent reperfusion and timely coronary injections of lactated Ringer&#39;s solution. This can be applied to ST-segment elevation myocardial infarction patients who undergo primary percutaneous coronary intervention.

The beneficial effects of reperfusion therapy for ST-segment elevation myocardial infarction (STEMI) is attenuated by reperfusion injury. No approach has ...

Testing Acetylcholine Followed by Adenosine for Invasive Diagnosis of Coronary Vasomotor Disorders

More than 50% of patients with signs and symptoms of myocardial ischemia undergoing coronary angiography have unobstructed coronary arteries. Coronary vasomotor disorders (impaired vasodilatation and/or enhanced vasoconstriction/spasm) represent important functional causes for such a clinical presentation. Although impaired vasodilatation may be assessed with non-invasive techniques such as positron emission tomography or cardiac magnetic resonance imaging, there is currently no reliable non-invasive technique for the diagnosis of coronary spasm available. Thus, invasive diagnostic procedures (IDP) have been developed for the diagnosis of coronary vasomotor disorders including spasm testing as well as assessment of coronary vasodilatation. The identification of the underlying type of disorder (so called endotype) allows the initiation of targeted pharmacological treatments. Despite the fact that such an approach is recommended by the current European Society of Cardiology guidelines for the management of chronic coronary syndromes based on the CorMicA study, comparability of results as well as multicenter trials are currently hampered by major differences in institutional protocols for coronary functional testing. This article describes a comprehensive IDP protocol including intracoronary acetylcholine provocation testing for diagnosis of epicardial/microvascular spasm, followed by Doppler wire-based assessment of coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) in search of coronary vasodilatory impairment.

Coronary vasomotion disorders represent frequent functional causes of angina in patients with unobstructed coronaries. The underlying mechanism of angina (endotype) in these patients can be determined by a comprehensive invasive diagnostic procedure based on acetylcholine provocation testing followed by Doppler-derived assessment of the coronary flow reserve and microvascular resistance.

More than 50% of patients with signs and symptoms of myocardial ischemia undergoing coronary angiography have unobstructed coronary arteries. Coronary ...

Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function

Approximately 40% of patients undergoing invasive coronary angiography for investigation of angina are found to have no obstructive coronary artery disease (ANOCA). Abnormal coronary function underlies coronary vasomotion syndromes including coronary endothelial dysfunction, microvascular angina, vasospastic angina, post-PCI angina and myocardial infarction with no obstructive coronary arteries (MINOCA). Each of these endotypes are distinct subgroups, characterized by specific disease mechanisms. Diagnostic criteria and linked therapy for these conditions are now established by expert consensus and clinical guidelines.
Coronary function tests are performed as an adjunctive interventional diagnostic procedure (IDP) in appropriately selected patients during coronary angiography. This aids differentiation of patients according to endotype. The IDP includes two distinct components: a diagnostic guidewire test and a pharmacological coronary reactivity test. The tests last approximately 5 minutes for the former and 10-15 minutes for the latter. Patient safety and staff education are key.
The diagnostic guidewire test measures parameters of coronary flow limitation (fractional flow reserve [FFR], coronary flow reserve [CFR], microvascular resistance [index of microvascular resistance (IMR)], basal resistance index, and vasodilator function [CFR, resistive reserve ratio (RRR)]).
The pharmacological coronary reactivity test measures the vasodilator potential and propensity to vasospasm of both the main coronary arteries and the micro-vessels. It involves intra-coronary infusion of acetylcholine and glyceryl trinitrate (GTN). Acetylcholine is not licensed for parenteral use and is therefore prescribed on a named-patient basis. Vasodilatation is the normal, expected response to infusion of physiological concentrations of acetylcholine. Vascular spasm represents an abnormal response, which supports the diagnosis of vasospastic angina.
The purpose of this practical guide is to provide information on the preparation and administration of the IDP in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success. The IDP supports stratified medicine for a personalized approach to health and wellbeing.

The purpose of this practical guide is to provide information on the preparation and administration of an interventional diagnostic procedure in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success.

Approximately 40% of patients undergoing invasive coronary angiography for investigation of angina are found to have no obstructive coronary artery ...

Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm

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 &#956;g) 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.

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.

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina ...

Investigating Novel Mechanisms of Microvascular Dysfunction in Humans

Intradermal Microdialysis: An Approach to Investigating Novel Mechanisms of Microvascular Dysfunction in Humans

The cutaneous vasculature is an accessible tissue that can be used to assess microvascular function in humans. Intradermal microdialysis is a minimally invasive technique used to investigate mechanisms of vascular smooth muscle and endothelial function in the cutaneous circulation. This technique allows for the pharmacological dissection of the pathophysiology of microvascular endothelial dysfunction as indexed by decreased nitric oxide-mediated vasodilation, an indicator of cardiovascular disease development risk. In this technique, a microdialysis probe is placed in the dermal layer of the skin, and a local heating unit with a laser Doppler flowmetry probe is placed over the probe to measure the red blood cell flux. The local skin temperature is clamped or stimulated with direct heat application, and pharmacological agents are perfused through the probe to stimulate or inhibit intracellular signaling pathways in order to induce vasodilation or vasoconstriction or to interrogate mechanisms of interest (co-factors, antioxidants, etc.). The cutaneous vascular conductance is quantified, and mechanisms of endothelial dysfunction in disease states can be delineated.

Author Spotlight: A Pharmacodissection Approach to Uncover Mechanisms in Cardiovascular Disease Risk Populations 

Intradermal microdialysis is a minimally invasive technique used to investigate microvascular function in health and disease. Both dose-response and local heating protocols can be utilized for this technique to explore mechanisms of vasodilation and vasoconstriction in the cutaneous circulation.

The cutaneous vasculature is an accessible tissue that can be used to assess microvascular function in humans. Intradermal microdialysis is a minimally ...