106
Letters to the Editor
JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 1, 2014 JANUARY 2014:101–8
One pitfall of reporting response is the phenomenon of “regression to the mean.” If enrollment requires a measurement below a certain threshold, using a test with an element of variability, such as LVEF, a measurement taken on 1 particular day might be lower than the patients’ true average value. When the test is repeated (after the intervention), the measurement is likely to have risen closer to the patients’ true average. This may give the false impression of a therapeutic improvement. Unless there is a control group for comparison, a reader may be misled into thinking that an intervention is effective. Describing an intervention as “effective” should be reserved for the findings of randomized controlled trials where there is a significant difference between the intervention and control groups. The terms “outcome,” “response,” and “effect” are sometimes used interchangeably in imaging research. We suggest simple definitions to facilitate clear communication and avoid misinterpretation of findings and even of study design. Sonia Bouri, MBBS, BSc,* Zachary I. Whinnett, PhD, Graham D. Cole, MA, MB, BChir, Charlotte H. Manisty, MBBS, PhD, John G. Cleland, MD, PhD, Darrel P. Francis, MA *Dr. Sonia Bouri, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59-61 North Wharf Road, London W2 1LA, United Kingdom. E-mail:
[email protected] http://dx.doi.org/10.1016/j.jcmg.2013.11.001 Please note: Drs. Whinnett (FS/13/44/30291) and Cole (FS/12/12/29294) and Professor Francis (FS/10/038) are supported by grants from British Heart. Professor Cleland has received speakers’ honoraria from Medtronic, Biotronik, and Sorin; and a research grant from Sorin. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Qualitative Characterization of Adipose Tissue by MDCT We read with great interest the paper by Rosenquist et al. (1) published recently in iJACC. The analysis performed on a large cohort drawn from the Framingham Heart Study implies that lower multidetector computed tomography (MDCT) attenuation of subcutaneous adipose tissue and visceral adipose tissue is associated with an adverse cardiometabolic risk profile. We would like to reflect on 2 aspects of the published data. First, although imaging of adipose tissue by MDCT offers relatively high resolution and reproducibility and has increasingly been used as a research tool, the methodology of computed tomography fat volume calculations has never been validated. Measurements are based on an arbitrary attenuation range (Hounsfield units), which is not set uniformly across the literature. Such attenuation-based identification may lead to the parts of adipose tissue with the lowest and highest attenuation being left unaccounted for. Furthermore, attenuation relies substantially on computed tomography scan parameters, especially tube voltage (kV), and also on patients’ characteristics. Tube voltage is often set differently for lean and obese patients. All of these factors may lead to a systematic bias in interpretation of a study such as that by Rosenquist et al. (1). Scan parameters applied in the reported cohort were not mentioned in the paper.
Second, we know from basic research studies that adipose tissue may display either an unfavorable or a favorable metabolic profile (endocrine and paracrine) depending on its location and metabolic status (2). As an example, epicardial adipose tissue in patients with coronary artery disease as opposed to patients without this disease showed intense leukocyte infiltration, thickened interlobular septa, and increased neovascularization (3). All of these elements are more radiodense than lipid-laden adipocytes and thus may lead to higher, rather than lower, MDCT attenuation of adipose tissue with a proinflammatory and proatherosclerotic metabolic profile. Results of our clinical study corroborate this hypothesis (4). Furthermore, as noted by Rosenquist et al. (1), lower attenuation of subcutaneous adipose tissue and visceral adipose tissue was correlated with fat volume because larger, lipid-laden adipocytes are less attenuating. In such circumstances, in a retrospective, cross-sectional study, it may be difficult to distinguish the effects of fat volume from those of its attenuation. Thus, it would be interesting to see how the attenuation correlated with cardiometabolic risk factors within subgroups with similar fat volumes. To summarize, the study by Rosenquist et al. (1) adds significantly to the growing body of evidence on the research and clinical role of MDCT-derived characterization of adipose tissue. However, further research efforts to eliminate the aforementioned limitations are warranted. Longitudinal designs, histopathology references, methodological improvements, standardization of MDCT fat measurements, and prospective methods of accounting for the established confounding factors in adipose tissue attenuation and volume measurements should be clarified to further develop this new, fascinating area of research. Radoslaw Pracon, MD, PhD,* Mariusz Kruk, MD, PhD, Marcin Demkow, MD, PhD *Department of Coronary and Structural Heart Diseases, 42 Alpejska Street, Institute of Cardiology, 04-628 Warsaw, Poland. E-mail:
[email protected] http://dx.doi.org/10.1016/j.jcmg.2013.05.019 REFERENCES
1. Rosenquist KJ, Pedley A, Massaro JM, et al. Visceral and subcutaneous fat quality and cardiometabolic risk. J Am Coll Cardiol Img 2013;6:762–71. 2. Bays HE. Adiposopathy: is “sick fat” a cardiovascular disease? J Am Coll Cardiol 2011;57:2461–73. 3. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460–6. 4. Pracon R, Kruk M, Kepka C, et al. Epicardial adipose tissue radiodensity is independently related to coronary atherosclerosis. A multidetector computed tomography study. Circ J 2011;75:391–7.
Myocardial Extracellular Volume Measurement by Cardiac Magnetic Resonance Measuring myocardial extracellular volume (ECV) with cardiovascular magnetic resonance is achieving increasing importance because it allows quantification of diffuse fibrosis not detectable with conventional late gadolinium enhancement techniques. However, the conditio sine qua
Letters to the Editor
JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 1, 2014
107
JANUARY 2014:101–8
non to accurately measure myocardial ECV consists of achievement of a steady-state equilibrium of gadolinium-based contrast agent between plasma and the cardiac interstitium. Currently, this requires a rather complicated and time-consuming protocol, which hinders the largescale clinical application of this technique. In a recent issue of iJACC, White et al. (1) wrote a seminal paper validating a bolus-only (pseudoequilibrium) technique to estimate the ECV in a wide range of cardiac diseases, with different degrees of extracellular matrix expansion, by comparing it against both a previously validated equilibrium (infusion) technique and histology. In particular, they demonstrated that a pseudo-equilibrium protocol (15 min after a 0.1 mmol/kg gadolinium bolus) yielded ECV estimates comparable to those obtained with the equilibrium protocol (0.1 mmol/kg bolus þ 0.011 mmol/kg/min gadolinium infusion), even though the former overestimated myocardial ECV in case of an important expansion of cardiac interstitium (i.e., ECV >0.4, as in the case of amyloid deposition or fibrotic scars). Moreover, both techniques showed very tight correlation with the histologically determined collagen volume fraction. Overall, the paper by White et al. (1) paves the way for clinical studies on cardiac interstitium remodeling and for further methodological studies exploring gadolinium contrast kinetics with particular regard to diseases with extreme ECV expansion. In previous work, Flett et al. (2) provided evidence on how the equilibrium can be reached with a constant gadolinium infusion (0.1 mmol/kg þ 0.0011 mmol/kg/min gadolinium) in patients with aortic stenosis or hypertrophic cardiomyopathy. They acquired T1 values every 5 min and demonstrated that the ECV remained constant over time and correlated with histology. Another group (3) validated a different pseudo-equilibrium technique (12 to 50 min after 0.2 mmol/kg gadolinium bolus) against a different equilibrium technique (0.1 mmol/kg bolus þ 0.0017 mmol/kg/min gadolinium infusion) in healthy volunteers, again by acquiring T1 values every 5 min and demonstrating that ECV remained constant. Conversely, little is known about gadolinium kinetics in cardiac amyloidosis, which is characterized by marked interstitial expansion and fast gadolinium accumulation but also very rapid gadolinium washout from both the myocardium and the blood pool (4). In the current paper (1), T1 acquisitions were performed only 15 min after bolus and during infusion, with no serial T1 acquisitions to demonstrate a blood– myocardium steady-state equilibrium. Moreover, the histological validation provided by the authors was limited to patients with aortic stenosis undergoing valve replacement or patients with hypertrophic cardiomyopathy undergoing septal myectomy (1,2). Histological validation of equilibrium or pseudo-equilibrium techniques is still lacking for cardiac disease with ECV >0.4, such as in cardiac amyloidosis, in which interstitial remodeling may be ascribed to disparate mechanisms (including myocyte necrosis, amyloid deposition, and scarring). Finally, we agree with the authors (1) that further technical development is required before a bolus-only protocol for ECV measurement becomes clinically available. This protocol should account for all potentially relevant parameters (contrast delivery rate, dose, agent, and acquisition timing) and be validated for diverse cardiac pathologies. Andrea Barison, MD, PhD,* Giovanni Donato Aquaro, MD, Pier Giorgio Masci, MD *Fondazione “G. Monasterio” CNR–Regione Toscana, Via Moruzzi, 1–56124 Pisa, Italy. E-mail: [email protected] http://dx.doi.org/10.1016/j.jcmg.2013.06.009
REFERENCES
1. White SK, Sado DM, Fontana M, et al. T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique. J Am Coll Cardiol Img 2013;6:955–62. 2. Flett AS, Hayward MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation 2010; 122:138–44. 3. Schelbert EB, Testa SM, Meier CG, et al. Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus. J Cardiovasc Magn Reson 2011;13:16. 4. Emdin M, Aquaro GD, Pugliese NR, et al. Myocardial gadolinium kinetics evaluation at magnetic resonance imaging for the diagnosis of cardiac amyloidosis. J Am Coll Cardiol 2013;61 Suppl 10: E1237.
R E P L Y : Myocardial Extracellular Volume Measurement by Cardiac Magnetic Resonance We thank Dr. Barison and colleagues for their interest in our paper (1). Extracellular volume fraction (ECV) has promise as an important future imaging biomarker but can be measured by a number of different T1 mapping techniques (2,3). The primary aim of our study was to support the concept that a sufficient dynamic (or “pseudo”) equilibrium exists with delay after a bolus of contrast, such that an infusion-maintained steady state is not necessary (1). By removing the need for this cumbersome, timeconsuming intervention (4), this method would expand the clinical applicability of ECV quantification into routine study. We confirmed that this approach is valid in the majority of clinical patients who might be encountered in a clinic, but perhaps not all. The development of new imaging biomarkers requires multifaceted technical development, including correlation or “calibration” with histology, clinical correlates (e.g., left atrial size), and hard clinical outcomes. As Dr. Barison and colleagues rightly stress, no histological correlations are yet available in “high ECV” diseases, in particular, cardiac amyloidosis. Hopefully, this is within sight, but histological quantification has thus far proved challenging because tissue stains have not adequately separated myocytes from amyloid protein and fibrosis. Other methods, however, may be helpful. Dr. Barison and colleagues point out that contrast behavior is abnormal in other ways in amyloid. The behavior of contrast may reflect myocardial wash-in/wash-out kinetics and total potential accumulation (volume of distribution), but other factors are at play. The decay curve of gadolinium-diethylenetriaminepentaacetic acid in the blood is multiexponential: first dominated by redistribution in blood, then by distribution with slow and fast exchange compartments in the body, and later by renal elimination. These factors may be altered in AL and ATTR amyloidosis. In AL amyloidosis in particular, there may be large accumulations (in kilograms) of amyloid deposits in the liver, spleen, tongue, and other soft tissues of the body. Scrutiny of contrast behavior may therefore provide additional insights. What is the correct ECV in amyloidosis? We found that the ECV measured using the bolus-only method was consistently higher than that determined by using the infusion method. Although the infusion technique is theoretically superior, our global
Letters to the Editor
JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 1, 2014 JANUARY 2014:101–8
One pitfall of reporting response is the phenomenon of “regression to the mean.” If enrollment requires a measurement below a certain threshold, using a test with an element of variability, such as LVEF, a measurement taken on 1 particular day might be lower than the patients’ true average value. When the test is repeated (after the intervention), the measurement is likely to have risen closer to the patients’ true average. This may give the false impression of a therapeutic improvement. Unless there is a control group for comparison, a reader may be misled into thinking that an intervention is effective. Describing an intervention as “effective” should be reserved for the findings of randomized controlled trials where there is a significant difference between the intervention and control groups. The terms “outcome,” “response,” and “effect” are sometimes used interchangeably in imaging research. We suggest simple definitions to facilitate clear communication and avoid misinterpretation of findings and even of study design. Sonia Bouri, MBBS, BSc,* Zachary I. Whinnett, PhD, Graham D. Cole, MA, MB, BChir, Charlotte H. Manisty, MBBS, PhD, John G. Cleland, MD, PhD, Darrel P. Francis, MA *Dr. Sonia Bouri, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59-61 North Wharf Road, London W2 1LA, United Kingdom. E-mail:
[email protected] http://dx.doi.org/10.1016/j.jcmg.2013.11.001 Please note: Drs. Whinnett (FS/13/44/30291) and Cole (FS/12/12/29294) and Professor Francis (FS/10/038) are supported by grants from British Heart. Professor Cleland has received speakers’ honoraria from Medtronic, Biotronik, and Sorin; and a research grant from Sorin. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Qualitative Characterization of Adipose Tissue by MDCT We read with great interest the paper by Rosenquist et al. (1) published recently in iJACC. The analysis performed on a large cohort drawn from the Framingham Heart Study implies that lower multidetector computed tomography (MDCT) attenuation of subcutaneous adipose tissue and visceral adipose tissue is associated with an adverse cardiometabolic risk profile. We would like to reflect on 2 aspects of the published data. First, although imaging of adipose tissue by MDCT offers relatively high resolution and reproducibility and has increasingly been used as a research tool, the methodology of computed tomography fat volume calculations has never been validated. Measurements are based on an arbitrary attenuation range (Hounsfield units), which is not set uniformly across the literature. Such attenuation-based identification may lead to the parts of adipose tissue with the lowest and highest attenuation being left unaccounted for. Furthermore, attenuation relies substantially on computed tomography scan parameters, especially tube voltage (kV), and also on patients’ characteristics. Tube voltage is often set differently for lean and obese patients. All of these factors may lead to a systematic bias in interpretation of a study such as that by Rosenquist et al. (1). Scan parameters applied in the reported cohort were not mentioned in the paper.
Second, we know from basic research studies that adipose tissue may display either an unfavorable or a favorable metabolic profile (endocrine and paracrine) depending on its location and metabolic status (2). As an example, epicardial adipose tissue in patients with coronary artery disease as opposed to patients without this disease showed intense leukocyte infiltration, thickened interlobular septa, and increased neovascularization (3). All of these elements are more radiodense than lipid-laden adipocytes and thus may lead to higher, rather than lower, MDCT attenuation of adipose tissue with a proinflammatory and proatherosclerotic metabolic profile. Results of our clinical study corroborate this hypothesis (4). Furthermore, as noted by Rosenquist et al. (1), lower attenuation of subcutaneous adipose tissue and visceral adipose tissue was correlated with fat volume because larger, lipid-laden adipocytes are less attenuating. In such circumstances, in a retrospective, cross-sectional study, it may be difficult to distinguish the effects of fat volume from those of its attenuation. Thus, it would be interesting to see how the attenuation correlated with cardiometabolic risk factors within subgroups with similar fat volumes. To summarize, the study by Rosenquist et al. (1) adds significantly to the growing body of evidence on the research and clinical role of MDCT-derived characterization of adipose tissue. However, further research efforts to eliminate the aforementioned limitations are warranted. Longitudinal designs, histopathology references, methodological improvements, standardization of MDCT fat measurements, and prospective methods of accounting for the established confounding factors in adipose tissue attenuation and volume measurements should be clarified to further develop this new, fascinating area of research. Radoslaw Pracon, MD, PhD,* Mariusz Kruk, MD, PhD, Marcin Demkow, MD, PhD *Department of Coronary and Structural Heart Diseases, 42 Alpejska Street, Institute of Cardiology, 04-628 Warsaw, Poland. E-mail:
[email protected] http://dx.doi.org/10.1016/j.jcmg.2013.05.019 REFERENCES
1. Rosenquist KJ, Pedley A, Massaro JM, et al. Visceral and subcutaneous fat quality and cardiometabolic risk. J Am Coll Cardiol Img 2013;6:762–71. 2. Bays HE. Adiposopathy: is “sick fat” a cardiovascular disease? J Am Coll Cardiol 2011;57:2461–73. 3. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460–6. 4. Pracon R, Kruk M, Kepka C, et al. Epicardial adipose tissue radiodensity is independently related to coronary atherosclerosis. A multidetector computed tomography study. Circ J 2011;75:391–7.
Myocardial Extracellular Volume Measurement by Cardiac Magnetic Resonance Measuring myocardial extracellular volume (ECV) with cardiovascular magnetic resonance is achieving increasing importance because it allows quantification of diffuse fibrosis not detectable with conventional late gadolinium enhancement techniques. However, the conditio sine qua
Letters to the Editor
JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 1, 2014
107
JANUARY 2014:101–8
non to accurately measure myocardial ECV consists of achievement of a steady-state equilibrium of gadolinium-based contrast agent between plasma and the cardiac interstitium. Currently, this requires a rather complicated and time-consuming protocol, which hinders the largescale clinical application of this technique. In a recent issue of iJACC, White et al. (1) wrote a seminal paper validating a bolus-only (pseudoequilibrium) technique to estimate the ECV in a wide range of cardiac diseases, with different degrees of extracellular matrix expansion, by comparing it against both a previously validated equilibrium (infusion) technique and histology. In particular, they demonstrated that a pseudo-equilibrium protocol (15 min after a 0.1 mmol/kg gadolinium bolus) yielded ECV estimates comparable to those obtained with the equilibrium protocol (0.1 mmol/kg bolus þ 0.011 mmol/kg/min gadolinium infusion), even though the former overestimated myocardial ECV in case of an important expansion of cardiac interstitium (i.e., ECV >0.4, as in the case of amyloid deposition or fibrotic scars). Moreover, both techniques showed very tight correlation with the histologically determined collagen volume fraction. Overall, the paper by White et al. (1) paves the way for clinical studies on cardiac interstitium remodeling and for further methodological studies exploring gadolinium contrast kinetics with particular regard to diseases with extreme ECV expansion. In previous work, Flett et al. (2) provided evidence on how the equilibrium can be reached with a constant gadolinium infusion (0.1 mmol/kg þ 0.0011 mmol/kg/min gadolinium) in patients with aortic stenosis or hypertrophic cardiomyopathy. They acquired T1 values every 5 min and demonstrated that the ECV remained constant over time and correlated with histology. Another group (3) validated a different pseudo-equilibrium technique (12 to 50 min after 0.2 mmol/kg gadolinium bolus) against a different equilibrium technique (0.1 mmol/kg bolus þ 0.0017 mmol/kg/min gadolinium infusion) in healthy volunteers, again by acquiring T1 values every 5 min and demonstrating that ECV remained constant. Conversely, little is known about gadolinium kinetics in cardiac amyloidosis, which is characterized by marked interstitial expansion and fast gadolinium accumulation but also very rapid gadolinium washout from both the myocardium and the blood pool (4). In the current paper (1), T1 acquisitions were performed only 15 min after bolus and during infusion, with no serial T1 acquisitions to demonstrate a blood– myocardium steady-state equilibrium. Moreover, the histological validation provided by the authors was limited to patients with aortic stenosis undergoing valve replacement or patients with hypertrophic cardiomyopathy undergoing septal myectomy (1,2). Histological validation of equilibrium or pseudo-equilibrium techniques is still lacking for cardiac disease with ECV >0.4, such as in cardiac amyloidosis, in which interstitial remodeling may be ascribed to disparate mechanisms (including myocyte necrosis, amyloid deposition, and scarring). Finally, we agree with the authors (1) that further technical development is required before a bolus-only protocol for ECV measurement becomes clinically available. This protocol should account for all potentially relevant parameters (contrast delivery rate, dose, agent, and acquisition timing) and be validated for diverse cardiac pathologies. Andrea Barison, MD, PhD,* Giovanni Donato Aquaro, MD, Pier Giorgio Masci, MD *Fondazione “G. Monasterio” CNR–Regione Toscana, Via Moruzzi, 1–56124 Pisa, Italy. E-mail: [email protected] http://dx.doi.org/10.1016/j.jcmg.2013.06.009
REFERENCES
1. White SK, Sado DM, Fontana M, et al. T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique. J Am Coll Cardiol Img 2013;6:955–62. 2. Flett AS, Hayward MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation 2010; 122:138–44. 3. Schelbert EB, Testa SM, Meier CG, et al. Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus. J Cardiovasc Magn Reson 2011;13:16. 4. Emdin M, Aquaro GD, Pugliese NR, et al. Myocardial gadolinium kinetics evaluation at magnetic resonance imaging for the diagnosis of cardiac amyloidosis. J Am Coll Cardiol 2013;61 Suppl 10: E1237.
R E P L Y : Myocardial Extracellular Volume Measurement by Cardiac Magnetic Resonance We thank Dr. Barison and colleagues for their interest in our paper (1). Extracellular volume fraction (ECV) has promise as an important future imaging biomarker but can be measured by a number of different T1 mapping techniques (2,3). The primary aim of our study was to support the concept that a sufficient dynamic (or “pseudo”) equilibrium exists with delay after a bolus of contrast, such that an infusion-maintained steady state is not necessary (1). By removing the need for this cumbersome, timeconsuming intervention (4), this method would expand the clinical applicability of ECV quantification into routine study. We confirmed that this approach is valid in the majority of clinical patients who might be encountered in a clinic, but perhaps not all. The development of new imaging biomarkers requires multifaceted technical development, including correlation or “calibration” with histology, clinical correlates (e.g., left atrial size), and hard clinical outcomes. As Dr. Barison and colleagues rightly stress, no histological correlations are yet available in “high ECV” diseases, in particular, cardiac amyloidosis. Hopefully, this is within sight, but histological quantification has thus far proved challenging because tissue stains have not adequately separated myocytes from amyloid protein and fibrosis. Other methods, however, may be helpful. Dr. Barison and colleagues point out that contrast behavior is abnormal in other ways in amyloid. The behavior of contrast may reflect myocardial wash-in/wash-out kinetics and total potential accumulation (volume of distribution), but other factors are at play. The decay curve of gadolinium-diethylenetriaminepentaacetic acid in the blood is multiexponential: first dominated by redistribution in blood, then by distribution with slow and fast exchange compartments in the body, and later by renal elimination. These factors may be altered in AL and ATTR amyloidosis. In AL amyloidosis in particular, there may be large accumulations (in kilograms) of amyloid deposits in the liver, spleen, tongue, and other soft tissues of the body. Scrutiny of contrast behavior may therefore provide additional insights. What is the correct ECV in amyloidosis? We found that the ECV measured using the bolus-only method was consistently higher than that determined by using the infusion method. Although the infusion technique is theoretically superior, our global
