Myocardial tissue characteristics undoubtedly differ by gender but not age

Myocardial tissue characteristics undoubtedly differ by gender but not age This editorial refers to ‘Myocardial native T1 and extracellular volume with healthy ageing and gender’, by S. Rosmini et al., pp. 615--621. Myocardial tissue characterization with native T1 and extracellular volume Cardiovascular magnetic resonance (CMR) applications transcend traditional assessments of the left ventricle related to morphology and function, such as mass, volumes, strain, and ejection fraction, all of which inherently lack aetiological specificity. Newer capabilities such as CMR with T1 parametric mapping permit characterization of innate myocardial tissue characteristics related to its composition, distinct abnormalities of which may implicate specific disease pathways. When combined with the clinical context, CMR tissue characterization emerges as a powerful non-invasive diagnostic tool. Two quantitative parameters attract particular attention: (i) native T1, the exponentiated time constant describing the recovery of longitudinal magnetization (spin–lattice relaxation) and (ii) extracellular volume (ECV), a measure of the volume percent of the myocardial interstitium which includes the intramyocardial vasculature. Both parameters can be encoded into every pixel and colour coded on an image to yield parametric maps for quick visual appraisal of the spatial distribution of the parameter. Assuming correct implementation of scanning protocols, ECV and native T1 provide the clinician with robust tools to detect disease that otherwise might prove challenging to diagnose. Native T1 reflects aggregate myocardial disease involving either the myocyte, interstitium (including the myocardial vasculature), or both, without use of gadolinium based contrast agents, whereas ECV quantifies the extracellular space which expands with interstitial disease. ECV effectively dichotomizes the myocardium into its cellular and interstitial compartments. Low native T1 indicates specific disease processes such as myocardial siderosis1 or Fabry’s disease,2,3 which may appear in the setting of systolic dysfunction or left ventricular (LV) hypertrophy, respectively. Other common conditions such as myocardial fibrosis increase both ECV and native T1, although ECV appears to be the more robust measure, leveraging gadolinium contrast as an extracellular space marker.4 Cardiac amyloidosis yields especially high values for both parameters.5 Active inflammation and oedema also can increase both parameters. Misconceptions of aging promoting myocardial fibrosis Given the relevance of these techniques, how they change across gender and age in those without disease becomes an important issue. In this issue of EHJCI, Rosmini et al.6 measured myocardial native T1 and ECV in 94 healthy volunteers with no history or symptoms of cardiovascular disease or diabetes, with a mean age of 50 ± 14 years (range 20–76), They report that in the state of ostensible health, ‘gender influences native myocardial T1 and ECV with women having a higher native T1 and ECV compared to males’. Furthermore, they find no elevations in myocardial native T1 or ECV with increasing age which refutes misconceptions that aging alone promotes myocardial fibrosis. Methodological rigour and flawless execution distinguish this work. We applaud the authors, especially the ‘curators’ of the various simultaneously emerging ‘best available’ techniques, for working together to characterize myocardial composition in triplicate using three different T1 pulse sequences for each study participant. This cooperative effort to repeatedly examine myocardial differences benefits the field greatly and increases the scientific impact of this work. The careful prospective recruitment focusing on health also adds confidence in the work. We particularly appreciate the authors’ data regarding the absence of associations between CMR myocardial fibrosis measures and aging. With the passage of time, the authors’ work indicates that one is not condemned to the inevitable development of myocardial fibrosis. While the regulation and treatment of myocardial fibrosis remain poorly understood,4 escaping this fate remains important because myocardial fibrosis—defined as disproportionate accumulation of excess collagen in the myocardial interstitium (i.e. increased concentration)—associates with mortality,7 hospitalization for heart failure,8 and sudden cardiac death, indeed representing ‘vulnerable interstitium’.9 So, while the ageing heart develops LV concentric remodelling manifest by increasing LV mass and mass to volume ratios, smaller end-diastolic volumes, and increased torsion,10 the authors meticulous work indicates that myocardial fibrosis does not appear to contribute significantly to this age-related LV remodelling, regardless of the T1 mapping technique or parameter one chooses to employ. Importantly, prior data from Multi-Ethnic Study of Atherosclerosis (MESA) suggest that concentric LV remodelling appears to be modifiable with control of risk factors and blood pressure.10 Prior MESA data also indicate trivial relationships between age and ECV myocardial fibrosis measures (R2 = 0.02) in their population with prevalent hypertension and diabetes.11 Despite misconceptions of aging promoting myocardial fibrosis, no ‘antifibrosis’ intervention appears warranted solely because we age. Gender differences in the left ventricle Regarding gender, the authors work also confirms prior observations that ostensibly healthy women fundamentally have higher ECV than men.11,12 As the authors note, these differences appear real since MESA data with higher prevalence of risk also observed higher ECV in women.11 The ultimate meaning of these differences remain unclear at this time. We believe that outcomes data are essential to adjudicate two radically different potential scenarios: (i) gender simply introduces benign differences in tissue composition that do not associate with increased risks or (ii) gender differences in tissue composition actually indicate ‘disease’, conferring greater risk in women. Until, we learn how women with higher ECV fare, one cannot distinguish these scenarios. The latter scenario, however, remains plausible since women appear to have greater risks of heart failure with preserved ejection fraction (HFpEF). Furthermore, elevated ECV appears prevalent and associates with outcomes in HFpEF.13 Future work Going forward, the authors’ work highlights the importance of adjusting for gender differences in future work employing T1 mapping and ECV, regardless of technique. The elevations in both baseline native T1 and ECV in women compared to men in all T1 pulse sequences provide compelling evidence that statistical modelling must account for these differences in future studies. The baseline differences also raise the possibility of interactions between gender and other variables in further analyses. Indeed, response to exposures or interventions may vary by gender. As such, the authors data will inform future work and represent a significant contribution to the field. Funding C.A.M is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research, UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. C.A.M has received research support from Roche and Guerbet. Conflict of interest: E.B.S. has accepted contrast material from Bracco Diagnostics for research purposes and has served on advisory boards for Merck and Bayer. References 1 Sado DM , Maestrini V , Piechnik SK , Banypersad SM , White SK , Flett AS et al. Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload . J Magn Reson Imaging 2015 ; 41 : 1505 – 11 . Google Scholar CrossRef Search ADS PubMed 2 Sado DM , White SK , Piechnik SK , Banypersad SM , Treibel T , Captur G et al. Identification and assessment of anderson-fabry disease by cardiovascular magnetic resonance noncontrast myocardial t1 mapping . Circ Cardiovasc Imaging 2013 ; 6 : 392 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Thompson RB , Chow K , Khan A , Chan A , Shanks M , Paterson I et al. T1 mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex . Circ Cardiovasc Imaging 2013 ; 6 : 637 – 45 . Google Scholar CrossRef Search ADS PubMed 4 Schelbert EB , Sabbah HN , Butler J , Gheorghiade M. Employing extracellular volume cardiovascular magnetic resonance measures of myocardial fibrosis to foster novel therapeutics . Circ Cardiovasc Imaging 2017 ; 10 : e005619. Google Scholar CrossRef Search ADS PubMed 5 Banypersad SM , Fontana M , Maestrini V , Sado DM , Captur G , Petrie A et al. T1 mapping and survival in systemic light-chain amyloidosis . Eur Heart J 2015 ; 36 : 244 – 51 . Google Scholar CrossRef Search ADS PubMed 6 Rosmini S , Bulluck H , Gabriella C , Treibel TA , Abdel-Gadir A , Bhuva AN et al. Myocardial native T1 and extracellular volume with healthy ageing and gender . Eur Heart J Cardiovasc Imaging 2018 ; 19 : 615 -- 21 . 7 Wong TC , Piehler K , Meier CG , Testa SM , Klock AM , Aneizi AA et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality . Circulation 2012 ; 126 : 1206 – 16 . Google Scholar CrossRef Search ADS PubMed 8 Schelbert EB , Piehler KM , Zareba KM , Moon JC , Ugander M , Messroghli DR et al. Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage . J Am Heart Assoc 2015 ; 4 : e002613. Google Scholar CrossRef Search ADS PubMed 9 Tamarappoo BK , John BT , Reinier K , Teodorescu C , Uy-Evanado A , Gunson K et al. Vulnerable myocardial interstitium in patients with isolated left ventricular hypertrophy and sudden cardiac death: a postmortem histological evaluation . J Am Heart Assoc 2012 ; 1 : e001511. Google Scholar CrossRef Search ADS PubMed 10 Yoneyama K , Donekal S , Venkatesh BA , Wu CO , Liu CY , Souto Nacif M et al. Natural history of myocardial function in an adult human population: serial longitudinal observations from MESA . JACC Cardiovasc Imaging 2016 ; 9 : 1164 – 73 . Google Scholar CrossRef Search ADS PubMed 11 Liu CY , Liu YC , Wu C , Armstrong A , Volpe GJ , van der Geest RJ et al. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis) . J Am Coll Cardiol 2013 ; 62 : 1280 – 7 . Google Scholar CrossRef Search ADS PubMed 12 Piechnik SK , Ferreira VM , Lewandowski AJ , Ntusi NA , Banerjee R , Holloway C et al. Normal variation of magnetic resonance T1 relaxation times in the human population at 1.5 T using ShMOLLI . J Cardiovasc Magn Reson 2013 ; 15 : 13. Google Scholar CrossRef Search ADS PubMed 13 Schelbert EB , Fridman Y , Wong TC , Abu Daya H , Piehler KM , Kadakkal A et al. Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: association with baseline disease severity and subsequent outcome . JAMA Cardiol 2017 ; 2 : 995 – 12 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Myocardial tissue characteristics undoubtedly differ by gender but not age

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jey057
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Abstract

This editorial refers to ‘Myocardial native T1 and extracellular volume with healthy ageing and gender’, by S. Rosmini et al., pp. 615--621. Myocardial tissue characterization with native T1 and extracellular volume Cardiovascular magnetic resonance (CMR) applications transcend traditional assessments of the left ventricle related to morphology and function, such as mass, volumes, strain, and ejection fraction, all of which inherently lack aetiological specificity. Newer capabilities such as CMR with T1 parametric mapping permit characterization of innate myocardial tissue characteristics related to its composition, distinct abnormalities of which may implicate specific disease pathways. When combined with the clinical context, CMR tissue characterization emerges as a powerful non-invasive diagnostic tool. Two quantitative parameters attract particular attention: (i) native T1, the exponentiated time constant describing the recovery of longitudinal magnetization (spin–lattice relaxation) and (ii) extracellular volume (ECV), a measure of the volume percent of the myocardial interstitium which includes the intramyocardial vasculature. Both parameters can be encoded into every pixel and colour coded on an image to yield parametric maps for quick visual appraisal of the spatial distribution of the parameter. Assuming correct implementation of scanning protocols, ECV and native T1 provide the clinician with robust tools to detect disease that otherwise might prove challenging to diagnose. Native T1 reflects aggregate myocardial disease involving either the myocyte, interstitium (including the myocardial vasculature), or both, without use of gadolinium based contrast agents, whereas ECV quantifies the extracellular space which expands with interstitial disease. ECV effectively dichotomizes the myocardium into its cellular and interstitial compartments. Low native T1 indicates specific disease processes such as myocardial siderosis1 or Fabry’s disease,2,3 which may appear in the setting of systolic dysfunction or left ventricular (LV) hypertrophy, respectively. Other common conditions such as myocardial fibrosis increase both ECV and native T1, although ECV appears to be the more robust measure, leveraging gadolinium contrast as an extracellular space marker.4 Cardiac amyloidosis yields especially high values for both parameters.5 Active inflammation and oedema also can increase both parameters. Misconceptions of aging promoting myocardial fibrosis Given the relevance of these techniques, how they change across gender and age in those without disease becomes an important issue. In this issue of EHJCI, Rosmini et al.6 measured myocardial native T1 and ECV in 94 healthy volunteers with no history or symptoms of cardiovascular disease or diabetes, with a mean age of 50 ± 14 years (range 20–76), They report that in the state of ostensible health, ‘gender influences native myocardial T1 and ECV with women having a higher native T1 and ECV compared to males’. Furthermore, they find no elevations in myocardial native T1 or ECV with increasing age which refutes misconceptions that aging alone promotes myocardial fibrosis. Methodological rigour and flawless execution distinguish this work. We applaud the authors, especially the ‘curators’ of the various simultaneously emerging ‘best available’ techniques, for working together to characterize myocardial composition in triplicate using three different T1 pulse sequences for each study participant. This cooperative effort to repeatedly examine myocardial differences benefits the field greatly and increases the scientific impact of this work. The careful prospective recruitment focusing on health also adds confidence in the work. We particularly appreciate the authors’ data regarding the absence of associations between CMR myocardial fibrosis measures and aging. With the passage of time, the authors’ work indicates that one is not condemned to the inevitable development of myocardial fibrosis. While the regulation and treatment of myocardial fibrosis remain poorly understood,4 escaping this fate remains important because myocardial fibrosis—defined as disproportionate accumulation of excess collagen in the myocardial interstitium (i.e. increased concentration)—associates with mortality,7 hospitalization for heart failure,8 and sudden cardiac death, indeed representing ‘vulnerable interstitium’.9 So, while the ageing heart develops LV concentric remodelling manifest by increasing LV mass and mass to volume ratios, smaller end-diastolic volumes, and increased torsion,10 the authors meticulous work indicates that myocardial fibrosis does not appear to contribute significantly to this age-related LV remodelling, regardless of the T1 mapping technique or parameter one chooses to employ. Importantly, prior data from Multi-Ethnic Study of Atherosclerosis (MESA) suggest that concentric LV remodelling appears to be modifiable with control of risk factors and blood pressure.10 Prior MESA data also indicate trivial relationships between age and ECV myocardial fibrosis measures (R2 = 0.02) in their population with prevalent hypertension and diabetes.11 Despite misconceptions of aging promoting myocardial fibrosis, no ‘antifibrosis’ intervention appears warranted solely because we age. Gender differences in the left ventricle Regarding gender, the authors work also confirms prior observations that ostensibly healthy women fundamentally have higher ECV than men.11,12 As the authors note, these differences appear real since MESA data with higher prevalence of risk also observed higher ECV in women.11 The ultimate meaning of these differences remain unclear at this time. We believe that outcomes data are essential to adjudicate two radically different potential scenarios: (i) gender simply introduces benign differences in tissue composition that do not associate with increased risks or (ii) gender differences in tissue composition actually indicate ‘disease’, conferring greater risk in women. Until, we learn how women with higher ECV fare, one cannot distinguish these scenarios. The latter scenario, however, remains plausible since women appear to have greater risks of heart failure with preserved ejection fraction (HFpEF). Furthermore, elevated ECV appears prevalent and associates with outcomes in HFpEF.13 Future work Going forward, the authors’ work highlights the importance of adjusting for gender differences in future work employing T1 mapping and ECV, regardless of technique. The elevations in both baseline native T1 and ECV in women compared to men in all T1 pulse sequences provide compelling evidence that statistical modelling must account for these differences in future studies. The baseline differences also raise the possibility of interactions between gender and other variables in further analyses. Indeed, response to exposures or interventions may vary by gender. As such, the authors data will inform future work and represent a significant contribution to the field. Funding C.A.M is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research, UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. C.A.M has received research support from Roche and Guerbet. Conflict of interest: E.B.S. has accepted contrast material from Bracco Diagnostics for research purposes and has served on advisory boards for Merck and Bayer. References 1 Sado DM , Maestrini V , Piechnik SK , Banypersad SM , White SK , Flett AS et al. Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload . J Magn Reson Imaging 2015 ; 41 : 1505 – 11 . Google Scholar CrossRef Search ADS PubMed 2 Sado DM , White SK , Piechnik SK , Banypersad SM , Treibel T , Captur G et al. Identification and assessment of anderson-fabry disease by cardiovascular magnetic resonance noncontrast myocardial t1 mapping . Circ Cardiovasc Imaging 2013 ; 6 : 392 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Thompson RB , Chow K , Khan A , Chan A , Shanks M , Paterson I et al. T1 mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex . Circ Cardiovasc Imaging 2013 ; 6 : 637 – 45 . Google Scholar CrossRef Search ADS PubMed 4 Schelbert EB , Sabbah HN , Butler J , Gheorghiade M. Employing extracellular volume cardiovascular magnetic resonance measures of myocardial fibrosis to foster novel therapeutics . Circ Cardiovasc Imaging 2017 ; 10 : e005619. Google Scholar CrossRef Search ADS PubMed 5 Banypersad SM , Fontana M , Maestrini V , Sado DM , Captur G , Petrie A et al. T1 mapping and survival in systemic light-chain amyloidosis . Eur Heart J 2015 ; 36 : 244 – 51 . Google Scholar CrossRef Search ADS PubMed 6 Rosmini S , Bulluck H , Gabriella C , Treibel TA , Abdel-Gadir A , Bhuva AN et al. Myocardial native T1 and extracellular volume with healthy ageing and gender . Eur Heart J Cardiovasc Imaging 2018 ; 19 : 615 -- 21 . 7 Wong TC , Piehler K , Meier CG , Testa SM , Klock AM , Aneizi AA et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality . Circulation 2012 ; 126 : 1206 – 16 . Google Scholar CrossRef Search ADS PubMed 8 Schelbert EB , Piehler KM , Zareba KM , Moon JC , Ugander M , Messroghli DR et al. Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage . J Am Heart Assoc 2015 ; 4 : e002613. Google Scholar CrossRef Search ADS PubMed 9 Tamarappoo BK , John BT , Reinier K , Teodorescu C , Uy-Evanado A , Gunson K et al. Vulnerable myocardial interstitium in patients with isolated left ventricular hypertrophy and sudden cardiac death: a postmortem histological evaluation . J Am Heart Assoc 2012 ; 1 : e001511. Google Scholar CrossRef Search ADS PubMed 10 Yoneyama K , Donekal S , Venkatesh BA , Wu CO , Liu CY , Souto Nacif M et al. Natural history of myocardial function in an adult human population: serial longitudinal observations from MESA . JACC Cardiovasc Imaging 2016 ; 9 : 1164 – 73 . Google Scholar CrossRef Search ADS PubMed 11 Liu CY , Liu YC , Wu C , Armstrong A , Volpe GJ , van der Geest RJ et al. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis) . J Am Coll Cardiol 2013 ; 62 : 1280 – 7 . Google Scholar CrossRef Search ADS PubMed 12 Piechnik SK , Ferreira VM , Lewandowski AJ , Ntusi NA , Banerjee R , Holloway C et al. Normal variation of magnetic resonance T1 relaxation times in the human population at 1.5 T using ShMOLLI . J Cardiovasc Magn Reson 2013 ; 15 : 13. Google Scholar CrossRef Search ADS PubMed 13 Schelbert EB , Fridman Y , Wong TC , Abu Daya H , Piehler KM , Kadakkal A et al. Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: association with baseline disease severity and subsequent outcome . JAMA Cardiol 2017 ; 2 : 995 – 12 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Apr 10, 2018

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