Breathing Maneuvers as a Vasoactive Stimulus for Detecting Inducible Myocardial Ischemia – An Experimental Cardiovascular Magnetic Resonance Study

RESEARCH ARTICLE Breathing Maneuvers as a Vasoactive Stimulus for Detecting Inducible Myocardial Ischemia – An Experimental Cardiovascular Magnetic Resonance Study Kady Fischer1,2,3, Dominik P Guensch1,2,3, Nancy Shie1, Julie Lebel1,4, Matthias G Friedrich1,5,6,7,8* a11111 OPEN ACCESS Citation: Fischer K, Guensch DP, Shie N, Lebel J, Friedrich MG (2016) Breathing Maneuvers as a Vasoactive Stimulus for Detecting Inducible Myocardial Ischemia – An Experimental Cardiovascular Magnetic Resonance Study. PLoS ONE 11(10): e0164524. doi:10.1371/journal. pone.0164524 Editor: Wolfgang Rudolf Bauer, Universitatsklinikum Wurzburg, GERMANY Received: May 19, 2016 Accepted: September 27, 2016 1 Philippa & Marvin Carsley CMR Centre at the Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada, 2 University Hospital Bern, Department Anaesthesiology and Pain Therapy, Inselspital, University of Bern, Bern, Switzerland, 3 University Hospital Bern, Institute for Diagnostic, Interventional and Paediatric Radiology, Inselspital, University of Bern, Bern, Switzerland, 4 Research Institute of the McGill University Health Centre, Montreal, QC, Canada, 5 Department of Radiology, Université de Montréal, Montreal, QC, Canada, 6 Departments of Medicine and Diagnostic Radiology, McGill University, Montreal, QC, Canada, 7 Department of Cardiology, Heidelberg University Hospital, Heidelberg, Germany, 8 Departments of Cardiac Sciences and Radiology, University of Calgary, Calgary, Canada * Abstract Background Breathing maneuvers can elicit a similar vascular response as vasodilatory agents like adenosine; yet, their potential diagnostic utility in the presence of coronary artery stenosis is unknown. The objective of the study is to investigate if breathing maneuvers can noninvasively detect inducible ischemia in an experimental animal model when the myocardium is imaged with oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR). Published: October 14, 2016 Copyright: © 2016 Fischer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper or will be uploaded with the Supporting Information files. Funding: Funding was provided by the Montreal Heart Institute Foundation, the Canadian Foundation for Innovation (https://www.innovation. ca) and the Fonds de Recherche du Québec (http:// www.frq.gouv.qc.ca/en). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Methods and Findings In 11 anesthetised swine with experimentally induced significant stenosis (fractional flow reserve <0.75) of the left anterior descending coronary artery (LAD) and 9 control animals, OS-CMR at 3T was performed during two different breathing maneuvers, a long breath-hold; and a combined maneuver of 60s of hyperventilation followed by a long breath-hold. The resulting change of myocardial oxygenation was compared to the invasive measurements of coronary blood flow, blood gases, and oxygen extraction. In control animals, all breathing maneuvers could significantly alter coronary blood flow as hyperventilation decreased coronary blood flow by 34±23%. A long breath-hold alone led to an increase of 97±88%, while the increase was 346±327% (p<0.001), when the long breath-hold was performed after hyperventilation. In stenosis animals, the coronary blood flow response was attenuated after both hyperventilation and the following breath-hold. This was matched by the observed oxygenation response as breath-holds following hyperventilation consistently yielded a significant difference in the signal of the MRI images between the perfusion territory of the stenosis LAD PLOS ONE | DOI:10.1371/journal.pone.0164524 October 14, 2016 1 / 15 Breathing Maneuvers for Coronary Vascular Function Competing Interests: Matthias G. Friedrich, Dominik Guensch and Kady Fischer hold a pending U.S. patent regarding the use of breathing maneuvers for diagnostics purpose (“Inducing and measuring myocardial oxygenation changes as a marker for heart disease”, Serial No. PCT/CA2013/ 050608). Matthias G. Friedrich is also a board member, advisor and shareholder of Circle Cardiovascular Imaging Inc., the manufacturer of the software used for CMR image evaluation. There are no other conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. and remote myocardium. There was no difference between the coronary territories during the other breathing maneuvers or in the control group at any point. Conclusion In an experimental animal model, the response to a combined breathing maneuver of hyperventilation with subsequent breath-holding is blunted in myocardium subject to significant coronary artery stenosis. This maneuver may allow for detecting severe coronary artery stenosis and have a significant clinical potential as a non-pharmacological method for diagnostic testing in patients with suspected coronary artery disease. Introduction The numbers for prescribed cardiac diagnostic tests and interventions are rapidly growing[1]. Notably, imaging for inducible myocardial ischemia or coronary artery stenosis has become one of the most critical cost factors in today’s health care systems[2]. While imaging techniques such as stress echocardiography and nuclear cardiology are useful for identifying ischemia-producing coronary artery stenosis, they require pharmacological or physical stress protocols. Nuclear techniques are also limited by radioactivity of tracers. Cardiovascular magnetic resonance imaging (CMR) can identify significant coronary artery stenosis without radiation, commonly using either dobutamine stress or first-pass perfusion protocols[3,4]. Yet again, the infusion of pharmacological stress agents or contrast media is required, increasing effort, cost and procedure-related risk. Oxygenation-sensitive CMR (OS-CMR) imaging allows for monitoring changes of myocardial oxygenation, based on the so-called blood oxygen level-dependent (BOLD) effect: A reduction of tissue oxygenation leads to a relative increase of deoxyhemoglobin, which in turn causes a signal intensity (SI) drop in CMR images sensitive to this effect[5]. In the presence of coronary artery stenosis, this effect can be augmented further by post-stenotic capillary recruitment [6]. In addition to the lack of radiation and contrast agents, OS-CMR differs from perfusion imaging techniques in that it directly reflects the oxygenation status of the tissue instead of using surrogate markers such as blood supply. Alterations of blood gases by breathing maneuvers or inhalation of gas mixtures were identified as an alternative to pharmacologic vasodilation in functional MRI studies of the brain and m (...truncated)