Myocardial Extracellular Volume Fraction Adds Prognostic Information Beyond Myocardial Replacement Fibrosis.

BACKGROUND: Cardiac magnetic resonance techniques permit quantification of the myocardial extracellular volume fraction (ECV), representing a surrogate marker of reactive interstitial fibrosis, and late gadolinium enhancement (LGE), representing replacement fibrosis or scar. ECV and LGE have been independently linked with heart failure (HF) events. In deriving ECV, coronary artery disease type LGE, but not non-coronary artery disease type LGE, has been consistently excluded. We examined the associations between LGE, global ECV derived from myocardial tissue segments free of any detectable scar, and subsequent HF events. METHODS: Mid short-axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from only segments without LGE. ECV was considered elevated if >30%, the upper 95% bounds of a reference group without known cardiac disease (n=28). Patients were divided into 4 groups by presence of elevated ECV and of any LGE. Subsequent HF hospitalization and any death were ascertained. Their relationship with ECV was examined separately and as a composite with Cox proportional hazard models. RESULTS: Of 1604 serial patients with T1 maps, 1255 were eligible after exclusions and followed over a median 26.3 (interquartile range, 15.9-37.5) months. Patients with elevated ECV had increased risk for death (hazard ratio [HR] 2.45 [95% CI, 1.76-3.41]), HF hospitalization (HR, 2.45 [95% CI, 1.77-3.40]), and a combined end point of both outcomes (HR, 2.46 [95% CI, 1.94-3.14]). After adjustments for covariates including LGE, the relationship persisted for death (HR, 1.82 [95% CI, 1.28-2.59]), hospitalization (HR, 1.60 [95% CI, 1.12-2.27]), and combined end points (HR, 1.73 [95% CI, 1.34-2.24]). CONCLUSIONS: ECV measures of diffuse myocardial fibrosis were associated with HF outcomes, despite exclusion of replacement fibrosis segments from their derivation and even among patients without any scar. ECV may have a synergistic role with LGE in HF risk assessment.

Four-dimensional flow cardiovascular magnetic resonance in aortic dissection: Assessment in an ex vivo model and preliminary clinical experience.

OBJECTIVE: Four-dimensional flow cardiovascular magnetic resonance may improve assessment of hemodynamics in patients with aortic dissection. The purpose of this study was to evaluate the feasibility and accuracy of 4-dimensional flow cardiovascular magnetic resonance assessment of true and false lumens flow. METHODS: Thirteen ex vivo porcine aortic dissection models were mounted to a flow loop. Four-dimensional flow cardiovascular magnetic resonance and 2-dimensional phase-contrast cardiovascular magnetic resonance measurements were performed, assessed for intraobserver and interobserver variability, and compared with a reference standard of sonotransducer flow volume measurements. Intraobserver and interobserver variability of 4-dimensional flow cardiovascular magnetic resonance were also assessed in 14 patients with aortic dissection and compared with 2-dimensional phase-contrast cardiovascular magnetic resonance. RESULTS: In the ex vivo model, the intraobserver and interobserver measurements had Lin's correlation coefficients of 0.98 and 0.96 and mean differences of 0.17 (±3.65) mL/beat and -0.59 (±5.33) mL/beat, respectively; 4-dimensional and sonotransducer measurements had a Lin's concordance correlation coefficient of 0.95 with a mean difference of 0.35 (±4.92) mL/beat, respectively. In patients with aortic dissection, the intraobserver and interobserver measurements had Lin's concordance correlation coefficients of 0.98 and 0.97 and mean differences of -0.95 (±8.24) mL/beat and 0.62 (±10.05) mL/beat, respectively; 4-dimensional and 2-dimensional flow had a Lin's concordance correlation coefficient of 0.91 with a mean difference of -9.27 (±17.79) mL/beat because of consistently higher flow measured with 4-dimensional flow cardiovascular magnetic resonance in the ascending aorta. CONCLUSIONS: Four-dimensional flow cardiovascular magnetic resonance is feasible in patients with aortic dissection and can reliably assess flow in the true and false lumens of the aorta. This promotes potential future work on functional assessment of aortic dissection hemodynamics.

Left ventricular function in patients with hypertrophic cardiomyopathy and its relation to myocardial fibrosis and exercise tolerance.

We sought to determine the relation between myocardial extracellular volume (ECV), left ventricular (LV) diastolic function, and exercise tolerance in patients with hypertrophic cardiomyopathy (HCM). Forty five HCM patients with an ejection fraction >50% and no previous septal reduction therapy underwent imaging by CMR and transthoracic echocardiography. CMR was used to quantify LV volumes, mass, EF, LA volumes, scar burden, pre and post contrast T1 relaxation times and ECV. Echocardiography was used to measure outflow tract gradients, mitral inflow and annular velocities, circumferential strain, systolic, early and late diastolic strain rates. Exercise duration and peak oxygen consumption were noted. HCM patients had increased native T1 relaxation time and ECV vs. controls [ECV controls: 24.7 (23.2-26.4) vs. HCM: 26.8 (24.6-31.3)%, P = 0.014]. Both parameters were significantly associated with LV diastolic dysfunction, circumferential strain, diastolic strain rate and peak oxygen consumption (r = -0.73, P < 0.001). Compared to controls, HCM patients have significantly longer native T1 relaxation time and higher ECV. These structural changes lead to worse LV global and segmental diastolic function and in turn reduced exercise tolerance.

Detection of LA and LAA Thrombus by CMR in Patients Referred for Pulmonary Vein Isolation.

OBJECTIVES: The goal of this study was to evaluate the diagnostic performance of a comprehensive, multicomponent cardiac magnetic resonance (CMR) study for assessment of left atrial (LA) and left atrial appendage (LAA) thrombus. BACKGROUND: Pre-operative evaluation for pulmonary vein isolation (PVI) typically requires tomographic imaging to define pulmonary venous anatomy and transesophageal echocardiogram (TEE) to assess for the presence of LA/LAA thrombus. CMR is increasingly being used to define pulmonary venous anatomy before PVI. Limited data are available on the utility of a multicomponent CMR protocol in assessing LA/LAA thrombus. METHODS: We studied patients who underwent multicomponent CMR for evaluation of pulmonary venous anatomy before PVI and underwent TEE within 7 days. LA and LAA thrombi were evaluated by using CMR as follows: 1) cine-CMR; 2) contrast-enhanced magnetic resonance angiography; and 3) equilibrium phase delayed enhancement (DE) CMR with a long inversion time (TI) of 600 ms (long TI DE-CMR). Components of the CMR study were evaluated for diagnostic performance for detection of LA or LAA thrombus using TEE as the reference standard. RESULTS: During the study period, 261 patients were assessed. The median CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 2, and 73.6% of patients were undergoing anticoagulation therapy. CMR and TEE were performed within 1.3 ± 2.3 days. LA/LAA thrombi were discovered in 9 patients (3.5%) by using TEE. Among the CMR techniques performed, long TI DE-CMR had the highest diagnostic accuracy (99.2%), sensitivity (100%), and specificity (99.2%), followed by contrast-enhanced magnetic resonance angiography (accuracy 94.3%; sensitivity 66.7%; and specificity 95.2%) and cine-CMR (accuracy 91.6%; sensitivity 66.7%; and specificity 92.5%). CONCLUSIONS: In patients referred for PVI, CMR could be a single complete diagnostic study for assessment of pulmonary venous anatomy as well as presence of LA/LAA thrombi, thus reducing the number of pre-operative tests before PVI. Long TI DE-CMR has the best diagnostic performance and should be used for the detection of LA/LAA thrombi.

Important advances in technology and unique applications related to cardiac magnetic resonance imaging.

Cardiac magnetic resonance has become a well-established imaging modality and is considered the gold standard for myocardial tissue viability assessment and ventricular volumes quantification. Recent technological hardware and software advancements in magnetic resonance imaging technology have allowed the development of new methods that can improve clinical cardiovascular diagnosis and prognosis. The advent of a new generation of higher magnetic field scanners can be beneficial to various clinical applications. Also, the development of faster acquisition techniques have allowed mapping of the magnetic relaxation properties T1, T2, and T2* in the myocardium that can be used to quantify myocardial diffuse fibrosis, determine the presence of edema or inflammation, and measure iron within the myocardium, respectively. Another recent major advancement in CMR has been the introduction of three-dimension (3D) phase contrast imaging, also known as 4D flow. The following review discusses key advances in cardiac magnetic resonance technology and their potential to improve clinical cardiovascular diagnosis and outcomes.

ASSESSMENT OF TISSUE OPTICAL CLEARING AS A FUNCTION OF GLUCOSE CONCENTRATION USING OPTICAL COHERENCE TOMOGRAPHY.

One of the major challenges in imaging biological tissues using optical techniques, such as optical coherence tomography (OCT), is the lack of light penetration due to highly turbid structures within the tissue. Optical clearing techniques enable the biological samples to be more optically homogeneous, allowing for deeper penetration of light into the tissue. This study investigates the effect of optical clearing utilizing various concentrations of glucose solution (10%, 30%, and 50%) on porcine skin. A gold-plated mirror was imaged beneath the tissue and percentage clearing was determined by monitoring the change in reflected light intensity from the mirror over time. The ratio of percentage clearing per tissue thickness for 10%, 30% and 50% glucose was determined to be 4.7 ± 1.6% mm(-1) (n = 6), 10.6 ± 2.0% mm(-1) (n = 7) and 21.8 ± 2.2% mm(-1) (n = 5), respectively. It was concluded that while higher glucose concentration has the highest optical clearing effect, a suitable concentration should be chosen for the purpose of clearing, considering the osmotic stress on the tissue sample.

Monitoring of glucose permeability in monkey skin in vivo using Optical Coherence Tomography.

Topical trans-dermal delivery of drugs has proven to be a promising route for treatment of many dermatological diseases. The aim of this study is to monitor and quantify the permeability rate of glucose solutions in rhesus monkey skin noninvasively in vivo as a primate model for drug diffusion. A time-domain Optical Coherence Tomography (OCT) system was used to image the diffusion of glucose in the skin of anesthetized monkeys for which the permeability rate was calculated. From 5 experiments on 4 different monkeys, the permeability for glucose-20% was found to be (4.41 +/- 0.28) 10(-6) cm/sec. The results suggest that OCT might be utilized for the noninvasive study of molecular diffusion in the multilayered biological tissues in vivo.

Effect of temperature on permeation of low-density lipoprotein particles through human carotid artery tissues.

Quantification of the diffusion of small molecules and large lipid transporting lipoproteins across arterial tissues could be useful in elucidating the mechanism(s) of atherosclerosis. Optical coherence tomography (OCT) was used to determine the effect of temperature on the rate of diffusion of glucose and low-density lipoproteins (LDL) in human carotid endarterectomy tissue in vitro. The permeability rate for glucose was calculated to be (3.51 +/- 0.27) x 10(-5) cm/s (n = 13) at 20 degrees C, and (3.70 +/- 0.44) x 10(-5) cm/s (n = 5) at 37 degrees C; for LDL the rate was (2.42 +/- 0.33) x 10(-5) cm/s (n = 5) at 20 degrees C and (4.77 +/- 0.48) x 10(-5) cm/s (n = 7) at 37 degrees C, where n is the number of samples. These results demonstrate that temperature does not significantly influence the permeation of small molecules (e.g. glucose), however, raising the temperature does significantly increase the permeation of LDL. These results provide new information about the capacity of an atherogenic lipoprotein to traverse the intimal layer of the artery. These results also demonstrate the potential of OCT for elucidating the dynamics of lipoprotein perfusion across the arterial wall.

Differential permeability rate and percent clearing of glucose in different regions in rabbit sclera.

Imaging of biological tissues with optical coherence tomography (OCT) poses a great interest for its capability to noninvasively outline subsurface microstructures within tissues. However, a major limitation for many optical imaging techniques is inadequate depth penetration of light in turbid media, which is bounded to just a few millimeters. There have been several attempts to improve light penetration depth in biological tissues, including application of different tissue optical clearing methods. In this study, an aqueous solution of glucose (40%) is added to rabbit sclera in vitro, where depth-resolved permeability coefficients and optical clearing are calculated with OCT. The permeability rate in regions in the upper 80- to 100-microm region is found to be different from that of regions in the deeper 100-microm region: (6.01+/-0.37)x10(-6) cmsec and (2.84+/-0.68)x10(-5) cmsec, respectively. A difference in percent clearing is also noted. Optical clearing of the upper region is about 10% and increased to 17 to 22% in the one beneath. These results demonstrate the capability of OCT-based methods to not only measure the diffusion rate and optical clearing of a tissue, but also its ability of functional differentiation between layers of epithelial tissues.

Permeability of hyperosmotic agent in normal and atherosclerotic vascular tissues.

Noninvasive cardiovascular imaging could lead to the early detection and timely treatment of complex atherosclerotic lesions responsible for major cardiovascular events. Recent investigations have suggested that optical coherence tomography (OCT) is an ideal diagnostic tool due to the high resolution this technology achieves in discriminating the different features of atherosclerotic lesions based on structural imaging. We explore the capability of OCT for functional imaging of normal and atherosclerotic aortic tissues based on time- and depth-resolved quantification of the permeability of biomolecules through these tissues. The permeability coefficient of 20% aqueous solution of glucose was found to be (6.80+/-0.18)x10(-6) cms in normal aortas and (2.69+/-0.42)x10(-5) cms in aortas with atherosclerotic disease. The results suggest that this new OCT functional imaging method-the assessment of the permeability coefficients of various physiologically neutral biomolecules in vascular tissues-could assist in early diagnosing and detecting the different components of atherosclerotic lesions.

Nondestructive quantification of analyte diffusion in cornea and sclera using optical coherence tomography.

PURPOSE: Noninvasive functional imaging, monitoring, and quantification of analytes transport in epithelial ocular tissues are extremely important for therapy and diagnostics of many eye diseases. In this study the authors investigated the capability of optical coherence tomography (OCT) for noninvasive monitoring and quantification of diffusion of different analytes in sclera and cornea of rabbit eyes. METHODS: A portable time-domain OCT system with wavelength of 1310 +/- 15 nm, output power of 3.5 mW, and resolution of 25 mum was used in this study. Diffusion of different analytes was monitored and quantified in rabbit cornea and sclera of whole eyeballs. Diffusion of water, metronidazole (0.5%), dexamethasone (0.2%), ciprofloxacin (0.3%), mannitol (20%), and glucose solution (20%) were examined, and their permeability coefficients were calculated by using OCT signal slope and depth-resolved amplitude methods. RESULTS: Permeability coefficients were calculated as a function of time and tissue depth. For instance, mannitol was found to have a permeability coefficient of (8.99 +/- 1.43) x 10(-6) cm/s in cornea and (6.18 +/- 1.08) x 10(-6) cm/s in sclera. The permeability coefficient of drugs with small concentrations (where water was the major solvent) was found to be in the range of that of water in the same tissue type, whereas permeability coefficients of higher concentrated solutions varied significantly. CONCLUSIONS: Results suggest that the OCT technique might be a powerful tool for noninvasive diffusion studies of different analytes in ocular tissues. However, additional methods of OCT signal acquisition and processing are required to study the diffusion of agents of small concentrations.

Depth-resolved monitoring of glucose diffusion in tissues by using optical coherence tomography.

We demonstrate the capability of the optical coherence tomography (OCT) technique for depth-resolved monitoring and quantifying of glucose diffusion in fibrous tissues (sclera). The depth-resolved and average permeability coefficients of glucose were calculated. We found that the glucose diffusion rate is not uniform throughout the tissue and is increased from approximately 2.39+/-0.73 x 10(-6) cm/s at the epithelial side to 8.63+/-0.27 x 10(-6) cm/s close to the endothelial side of the sclera. Results demonstrated that the OCT technique is capable of depth-resolved monitoring and quantification of glucose diffusion in sclera with a resolution of approximately 40 mum.