Turning Up the Flow: Cardiovascular 4D Flow MRI during Exercise

See also the article by Macdonald et al in this issue.

Michael Markl, PhD, is the vice chair for research in the department of radiology at Northwestern University Feinberg School of Medicine. He received his PhD in physics from the University of Freiburg, Germany (2000) and served as a postdoctoral fellow at the Lucas MRI/S Center at Stanford University (2001–2004). Dr Markl has been on faculty at Northwestern since 2011 during which time he has been the director of cardiovascular imaging research and led cardiovascular MR research in the Center for Translational Imaging. A central objective of Dr Markl’s research program is to develop multiparametric imaging techniques that can afford a better understanding of the underlying physiologic mechanisms of heart disease and stroke as well as the impact of therapy. He is an editorial board member of European Heart Journal Cardiovascular Imaging and JCMR, an associate editor of Radiology: Cardiothoracic Imaging, a fellow of the ISMRM and SCMR, a member of the Board of Trustees of SCMR, and the past president of the Society for Magnetic Resonance Angiography.

Jeesoo Lee, PhD, is a postdoctoral researcher in Dr Markl’s research group in the department of radiology at Northwestern University Feinberg School of Medicine. His research interests include in vivo and in vitro investigation of valvular hemodynamics using 4D flow MRI and echocardiography. Pathologies of interest are bicuspid aortic valve and mitral valve regurgitation.

Increased demand on the circulatory system due to exercise can unmask abnormalities in the cardiopulmonary system that are not apparent at rest. Cardiopulmonary exercise testing has served as a versatile tool capable of providing valuable diagnostic and prognostic information in patients with cardiovascular and pulmonary diseases (1). The use of imaging may enhance prognostic accuracy compared with conventional ventilatory gas exchange measures (eg, peak oxygen uptake [VO₂]) by providing important measures of cardiovascular responses to exercise. For example, the 10-year survival rate for patients with chronic heart failure was reported to be higher in patients with a greater increase in cardiac output from rest to the peak exercise (2).

Cardiac MRI is a useful imaging modality for the quantification of cardiovascular function and flow due to its noninvasiveness, robustness, and high reproducibility. For example, phase-contrast (PC) MRI has been extensively used for flow quantification in the aorta, pulmonary systems, and across heart valves. With the development of MRI-compatible exercise devices, a growing body of literature has emerged over the past decades that focuses on testing the feasibility of two-dimensional (2D) PC MRI for quantifying flow in great vessels either during or immediately following exercise (3–7). Major imaging challenges associated with exercise-induced respiratory motion, participant body movement, and deteriorated electrocardiographic gating signal have been addressed by implementing real-time acquisitions (3,4), peripheral pulse gating (5,6), or oximetry pulse gating (7). Previous studies have demonstrated that 2D PC MRI can be a useful tool to monitor and quantify changes in cardiac output of the left and right ventricle with exercise. In addition, 2D PC MRI has been utilized to investigate hemodynamics associated with exercise by quantifying reverse flow fraction in pulmonary arteries (5), systemic vascular resistance (4), arterial compliance (4), and pulse wave velocity (8) in the main pulmonary artery.

In the current issue of Radiology: Cardiothoracic Imaging, in a study with 11 healthy participants, Macdonald et al explored the feasibility of cardiopulmonary exercise testing in combination with free-breathing, time-resolved, three-directional velocity-encoded three-dimensional (3D) PC MRI (four-dimensional [4D] flow MRI) for the assessment of whole-heart 3D blood flow dynamics during rest and stress (9). According to the authors, this is the first study to test the feasibility of 4D flow MRI during exercise. They used a retrospectively gated, radially undersampled 4D flow MRI technique (PC vastly undersampled isotropic projection [10]) to quantify flow and kinetic energy in the heart and surrounding great vessels. The exercise protocol was carefully designed with participant-specific workload determined by the individual cardiovascular fitness level (70% of maximal VO₂) evaluated prior to the MRI scan. For an exercise device, they used a stepper with feedback workload control which helped participants to maintain exercise power output regardless of stepping frequency. Indeed, the authors evaluated heart rate variability during the scan and demonstrated no significant difference in variability at rest as well as during exercise. This is an important aspect of the study design because variation in physical exertion during the scan can be problematic for 4D flow MRI as it requires longer scan time (approximately 9 minutes in this study).

Despite noticeable exercise-induced reduction in signal-to-noise ratio (average 16%), the assessment for overall quality of reconstructed 4D flow MRI data was very promising, and the authors found no significant image quality deterioration compared with 4D flow MRI data at rest. In addition, results by Macdonald et al convincingly showed that flow measurements in the great vessels of the heart can be obtained during exercise with excellent repeatability (ICC > 0.9) and good internal consistency: Internal flow consistency (ie, conservation of mass in connected vessels) and reported flow differences were below 17% with exercise data. The results were comparable to that at rest of 12%.

As acknowledged by the authors, the study had limitations, and ventricular flow assessment during exercise remains challenging. While ventricular kinetic energy could be quantified during rest and exercise, these measurements had inadequate interobserver repeatability and will require further optimization, even for 4D flow MRI data acquired during rest. The primary source of uncertainty was likely introduced when identifying ventricular boundaries for hemodynamic quantification. In general, accurate delineation of a 2D or 3D region of interest is a key confounding factor for 4D flow–based flow quantification. Exercise includes blurring of vessel boundaries or ventricular and atrial boundaries, as evident from the MR images presented in the article by Macdonald et al, which can thus make flow quantification even more challenging. Future studies are thus warranted to systematically explore the impact of exercise on the reliable segmentation of cardiac and vascular structures and to develop improved methodology for the identification of cardiovascular boundaries during rest and exercise. Another limitation regarding the clinical use of 4D flow MRI was related to the long 4D flow scan time (approximately 9 minutes in this study), which limits the application to those who can maintain stable exercise during this time period. Future studies are needed to explore the performance of recently reported highly accelerated 4D flow for data acquisition with substantially reduced scan times during exercise.

Nonetheless, as the first attempt to test the feasibility of 4D flow MRI as a hemodynamic monitoring tool in cardiopulmonary exercise testing, the article contains promising results and may serve as a helpful guide for similar studies to follow. A combination of cardiopulmonary exercise testing with 4D flow MRI may enable new physiologic insights into the complex volumetric changes in in vivo 3D blood flow dynamics in healthy participants and patients with cardiovascular disease. This study is an important first step to demonstrate the feasibility of this approach. Future studies in larger cohorts of patients are needed to confirm these promising findings and further explore applications of 4D flow during rest and exercise to assess the impact of demographic factors (age, sex), as well as disease, on cardiovascular hemodynamics.