Quantitative CMR markers of impaired vascular reactivity associated with age and peripheral artery disease

Langham et al. Journal of Cardiovascular Magnetic Resonance 2013, 15:17 http://www.jcmr-online.com/content/15/1/17 RESEARCH Open Access Quantitative CMR markers of impaired vascular reactivity associated with age and peripheral artery disease Michael C Langham1, Erin K Englund1, Emile R Mohler III2, Cheng Li1, Zachary B Rodgers1, Thomas F Floyd3 and Felix W Wehrli1* Abstract Background: The aim of this study was to develop and evaluate an integrated CMR method incorporating dynamic oximetry, blood flow and pulse-wave velocimetry to assess vascular reactivity in patients with peripheral artery disease (PAD) and healthy controls. Methods and results: The study population consisted of young healthy subjects (YH, 30 ± 7 yrs, N = 19),PAD (71 ± 9 yrs, N = 38), and older healthy controls (OHC, 68 ± 9 yrs, N = 43). Peripheral vascular reactivity was evaluated with two methods, time-resolved quantification of blood flow velocity and oxygenation level in the femoral artery and vein, respectively, performed simultaneously both at rest and hyperemia. Aortic stiffness was assessed via pulsewave velocity. Oximetric data showed that compared to OHC, the time-course of the hemoglobin oxygen saturation in PAD patients had longer washout time (28.6 ± 1.2 vs 16.9 ± 1.1 s, p < 0.0001), reduced upslope (0.60 ± 0.1 vs 1.3 ± 0.08 HbO2/sec, p < 0.0001) and lower overshoot (8 ± 1.4 vs 14 ± 1.2 HbO2, p = 0.0064). PAD patients also had longer-lasting antegrade femoral artery flow during hyperemia (51 ± 2.1 vs 24 ± 1.8 s, p < 0.0001), and reduced peak-to-baseline flow rate (3.1 ± 0.5 vs 7.4 ± 0.4, p < 0.0001). Further, the pulsatility at rest was reduced (0.75 ± 0.32 vs 5.2 ± 0.3, p < 0.0001), and aortic PWV was elevated (10.2 ± 0.4 vs 8.1 ± 0.4 m/s, p = 0.0048). Conclusion: The proposed CMR protocol quantifies multiple aspects of vascular reactivity and represents an initial step toward development of a potential tool for evaluating interventions, extrapolating clinical outcomes and predicting functional endpoints based on quantitative parameters. Keywords: Peripheral arterial disease, Atherosclerosis, Microvascular function, Pulse-wave velocity, Blood oxygen saturation, Phase image, Magnetic resonance oximetry Background Peripheral artery disease (PAD) is most commonly due to atherosclerosis. Currently, it is estimated that approximately ten million people in the United States are affected by PAD and the number is expected to grow as the population ages [1]. In spite of its high prevalence the disease often goes unnoticed because the vast majority of PAD patients have no classic claudication symptoms, which typically occur at an advanced stage. The initial test for diagnosing patients with clinical * Correspondence: 1 Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA Full list of author information is available at the end of the article symptoms is measurement of the ankle-brachial index (ABI). A low ABI is a strong indicator of the presence of PAD but a normal ABI does not rule out risk due to the false negative rates [2], which can be understood based on the fact that the pressure decrease in the ankle can only be detected when lesions reduce the lumen’s diameter by ≥ 70%. Some of the manifestations of structural and functional alterations that associated with PAD involve increases in intimal-medial vessel wall thickness (IMT) [3], decreased vascular compliance [4], and impaired vascular reactivity [5]. Flow-mediated dilation (FMD) of the brachial artery following cuff-induced ischemia [6] is a widely used research technique for quantifying vascular reactivity. © 2013 Langham et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Langham et al. Journal of Cardiovascular Magnetic Resonance 2013, 15:17 http://www.jcmr-online.com/content/15/1/17 B-mode ultrasound measures intimal-medial thickness (IMT), typically performed in the common carotid artery, a procedure practiced clinically for cardiovascular disease (CVD) risk assessment [7,8]. Major limitations of ultrasound are poor reproducibility due to high inter- and intra-observer variability [9,10]. Further, the above US measures do not target vascular territories (brachial and carotid arteries) that are most commonly affected by PAD (lower peripheral arteries). Increased arterial stiffness is also associated with atherosclerosis [11-13] and may contribute to microvascular dysfunction [14]. Aortic stiffness can be estimated by quantifying PWV, typically by measuring the time delay of the systolic pressure wave at some downstream location, using pressure transducers [15,16] placed at the two locations, e.g. carotid and common femoral arteries. However, carotid-femoral PWV is merely a surrogate [17] for aortic arch PWV because by the time the pressure wave is detected at the carotid artery it has already propagated through the ascending aorta. Other non-invasive imaging techniques for quantifying reactive hyperemia in peripheral arteries include nearinfrared spectroscopy (NIRS) [18-21], single photon emission computed tomography [22] and CMR [23-25]. The NIRS is also a widely used research tool due to portability and low cost. It has excellent temporal resolution, is less prone to artifacts from subject motion, and allows simultaneous monitoring of relative changes in tissue blood flow and oxygenation. However, the spatial resolution of NIRS is limited and it can only target the capillary bed in relatively superficial tissues. Further, the modality is susceptible to large inter-subject variations in the tissue response to light, which depends on skin color, body fat and muscle layers. CMR flow velocimetry [23,24] has been shown to provide high spatial and temporal resolution during post-occlusion hyperemia in the femoral artery of PAD patients and healthy subjects at 1.5T. The method requires spatially-selective RF pulses which are not widely available and migration to systems with higher field strength may be challenging due to increased field in homogeneity. Alternatively, microvascular function can be assessed by quantifying postocclusive perfusion with arterial spin labeling (ASL) in calf muscle [26]. The ASL-approach is model-dependent, and the temporal and spatial resolutions are limited. Here, we designed, implemented and evaluated an integrated CMR protocol that captures quantitative markers of vascular reactivity in the lower extremity and the aortic arch in a single examination. The markers include parameters derived from post-occlusive blood flow velocity and oxygenation levels (HbO2) in the femoral vessels at high temporal resolution, and pulse-wave velocity for assessing the stiffness of the aortic arch. (...truncated)