- Email: [email protected]
Editorial commentary: Dissecting the gender differences in nonobstructive coronary artery disease: How do we bridge the gap?
Author’s Accepted Manuscript Dissecting the gender differences in nonobstructive coronary artery disease. How do we bridge the gap? Ramzi Y. Khamis www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(16)30139-6S1050-1738(16)30110-4 http://dx.doi.org/10.1016/j.tcm.2016.09.003 TCM6339
To appear in: Trends in Cardiovascular Medicine Accepted date: 8 Cite this article as: Ramzi Y. Khamis, Dissecting the gender differences in nonobstructive coronary artery disease. How do we bridge the gap?, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2016.09.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dissecting the gender differences in nonobstructive coronary artery disease. How do we bridge the gap?
Dr. Ramzi Y Khamis MB ChB MRCP PhD FESC National Heart and Lung Institute Imperial College London [email protected]
Ever since Charles Darwin published a book Entitled ‘The Descent Of Man, and Selection in Relation to Sex’, a brilliant follow-up from his seminal book ‘the Origin of Species’, commentators have identified the need to study gender differences in relation to biology and pathology1. It has now become inevitable to focus on gender difference in coronary artery disease (CAD) and its sequelae, as there is mounting evidence showing gender disparities in outcomes, with women fairing differently, depending on the clinical scenario2. The paradigm shift in thinking about women and men having different pathophysiological factors and processes contributing to cardiovascular events in what is termed ‘nonobstructive CAD’ is presented in a tour de force review by T K Paul et al in this issue of the journal3. The major questions that are being addressed in this review relate to the different factors that may lead to adverse cardiovascular events in women in the absence of angiographically obstructive coronary disease. The reviewers challenge the notion that ‘nonobstructive CAD’ is a female-specific problem, and present the notion that there is a diagnostic gap in the modalities used to investigate all patients presenting with chest pain. Certainly, evidence suggests that women with chest pain symptoms and ischemia by non-invasive testing but no obvious coronary obstruction still suffer an increased risk of major adverse cardiovascular events (MACE). Whether this is related to pathophysiological factors or treatment bias remains to be answered4.
The hypothesis that women and men have different plaque pathophysiology is gathering more wind in its sails5. Pathological studies suggest that women have more plaque erosions than men, whilst population data show a disparity in clinical outcome5,6. Yet, the basic science aspects of gender interaction with elements of CAD are understudied, and have not received enough attention from
the basic science cardiovascular community despite clinical data suggesting significant differences in plaque characteristics and response to treatment7,8. Plaque vulnerability is one of those major factors to be considered. With the advent of modern intravascular imaging technology, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), we now have better tools to determine plaque morphology in symptomatic populations. However, we still do not have the tools to study plaque biology in vivo, and therefore we eagerly await the development of novel molecular imaging techniques that may go some way to answering these questions9. The review also highlights gender differences in fractional flow reserve (FFR) cut offs. This is a really important topic, and we hope that future studies in coronary physiology will include enough female patients to establish formal cut offs in order to answer this question adequately10. Furthermore, recent biomarker studies have shown that women may benefit from being studied with more sensitive assays11,12. This may present better risk reclassification in the acute situation. Our own work on a stable non-symptomatic population showed a suggestion that women may have a more favorable immunoglobulin profile, which could in turn contribute to a delay in developing established atherosclerosis 13. Clearly, this is a fertile ground for further gender-focused research, as most of the research signals are extrapolated from studies not powered to answer gender specific questions. Whether microvascular function or endothelial function are affected by systematic hormonal factors, or other factors that are more prevalent in women, such as smaller vessel size, remains to be answered. It is very interesting that the authors highlight significant differences in outcome in women with nonobstructive disease and reduced hyperemic response to adenosine. It may be that conventional coronary angiography is the wrong test to rely on when deciding on risk in the symptomatic population, and novel techniques that combine serology with intravascular
imaging as well as dynamic physiological testing need to be considered when faced with asymptomatic women with unobstructed coronaries. Another important factor is treatment bias. We tend to underestimate risk in women. This pattern also applies when referring for further investigations and invasive studies. The fact that women underestimate their own risk also plays a part in the physician/ patient interaction14. Therefore clearer pathways need to be determined that cater to both genders in terms of appropriate investigations. The lack of gender-tailored studies that investigate the effects of different pharmacological targets is also an issue. It is surprising that there is still little research on the potential biological targets that the menopause could exert on the pathology of atherosclerosis, but hopefully more work is underway in this field. 15 This review demonstrates clearly that the classical paradigm of a normal angiogram translating into a reassuring discussion about the absence of risk is flawed. We hope that there will be a drive to undertake serious translational work where gender disparities in pathophysiology, natural history of the disease, and pharmacology are explored in a rigorous scientific manner, thus leading to treatments that are tailored to women. Furthermore, serious efforts need to be made in clinical trial design to allow for more recruitment of women, and to provide enough power to answer gender related questions. The real challenge for the future is to try to abandon the classical definitions that are modality dependent, such as ‘nonobstructive coronary disease’. The panacea of cardiovascular medicine is to be able to identify the vulnerable patient, and furthermore to be able to pinpoint the pathophysiological causes of this vulnerability and target them specifically with tailored therapies. There is much work to do in the field, which is elegantly highlighted by Paul et al in this issue of the journal3.
References 1 2 3 4
5
6
7 8
9 10 11
12
13
14
15
Goodman, N. The Descent of Man and Selection in Relation to Sex. J Anat Physiol 5, 363-372 (1871). Khamis, R. Y., Ammari, T. & Mikhail, G. W. Gender differences in coronary heart disease. Heart 102, 1142-1149, doi:10.1136/heartjnl-2014-306463 (2016). Tracy, P., Kaartiga, S. & Joshua, S.-M. (2016). Gulati, M. et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 169, 843-850, doi:169/9/843 [pii]10.1001/archinternmed.2009.50 [doi] (2009). Falk, E., Nakano, M., Bentzon, J. F., Finn, A. V. & Virmani, R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J 34, 719-728, doi:10.1093/eurheartj/ehs411 (2013). Tan, Y. C. et al. Gender differences in outcomes in patients with acute coronary syndrome in the current era: A review. Eur Heart J Acute Cardiovasc Care, doi:10.1177/2048872615610886 (2015). Puri, R., Nissen, S. E. & Nicholls, S. J. Statin-induced coronary artery disease regression rates differ in men and women. Curr Opin Lipidol, doi:10.1097/mol.0000000000000195 (2015). Lansky, A. J. et al. Gender and the extent of coronary atherosclerosis, plaque composition, and clinical outcomes in acute coronary syndromes. JACC Cardiovasc Imaging 5, S62-72, doi:10.1016/j.jcmg.2012.02.003 (2012). Jaffer, F. A. & Verjans, J. W. Molecular imaging of atherosclerosis: clinical state-of-the-art. Heart 100, 1469-1477, doi:10.1136/heartjnl-2011-301370 (2014). Li, J. et al. Sex-related differences in fractional flow reserve-guided treatment. Circ Cardiovasc Interv 6, 662-670, doi:10.1161/circinterventions.113.000762 (2013). Motiwala, S. R., Sarma, A., Januzzi, J. L. & O'Donoghue, M. L. Biomarkers in ACS and heart failure: should men and women be interpreted differently? Clin Chem 60, 35-43, doi:10.1373/clinchem.2013.202531 (2014). Shah, A. S. et al. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. BMJ 350, g7873, doi:10.1136/bmj.g7873 (2015). Khamis, R. Y. et al. High Serum Immunoglobulin G and M Levels Predict Freedom From Adverse Cardiovascular Events in Hypertension: A Nested Case-Control Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. EBioMedicine, doi:10.1016/j.ebiom.2016.06.012 (2016). Oertelt-Prigione, S. et al. Cardiovascular risk factor distribution and subjective risk estimation in urban women--the BEFRI study: a randomized cross-sectional study. BMC Med 13, 52, doi:10.1186/s12916-015-0304-9 (2015). Feldman, R. D. Heart Disease in Women: Unappreciated Challenges, GPER as a New Target. Int J Mol Sci 17, doi:10.3390/ijms17050760 (2016).
PII: DOI: Reference:
S1050-1738(16)30139-6S1050-1738(16)30110-4 http://dx.doi.org/10.1016/j.tcm.2016.09.003 TCM6339
To appear in: Trends in Cardiovascular Medicine Accepted date: 8 Cite this article as: Ramzi Y. Khamis, Dissecting the gender differences in nonobstructive coronary artery disease. How do we bridge the gap?, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2016.09.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dissecting the gender differences in nonobstructive coronary artery disease. How do we bridge the gap?
Dr. Ramzi Y Khamis MB ChB MRCP PhD FESC National Heart and Lung Institute Imperial College London [email protected]
Ever since Charles Darwin published a book Entitled ‘The Descent Of Man, and Selection in Relation to Sex’, a brilliant follow-up from his seminal book ‘the Origin of Species’, commentators have identified the need to study gender differences in relation to biology and pathology1. It has now become inevitable to focus on gender difference in coronary artery disease (CAD) and its sequelae, as there is mounting evidence showing gender disparities in outcomes, with women fairing differently, depending on the clinical scenario2. The paradigm shift in thinking about women and men having different pathophysiological factors and processes contributing to cardiovascular events in what is termed ‘nonobstructive CAD’ is presented in a tour de force review by T K Paul et al in this issue of the journal3. The major questions that are being addressed in this review relate to the different factors that may lead to adverse cardiovascular events in women in the absence of angiographically obstructive coronary disease. The reviewers challenge the notion that ‘nonobstructive CAD’ is a female-specific problem, and present the notion that there is a diagnostic gap in the modalities used to investigate all patients presenting with chest pain. Certainly, evidence suggests that women with chest pain symptoms and ischemia by non-invasive testing but no obvious coronary obstruction still suffer an increased risk of major adverse cardiovascular events (MACE). Whether this is related to pathophysiological factors or treatment bias remains to be answered4.
The hypothesis that women and men have different plaque pathophysiology is gathering more wind in its sails5. Pathological studies suggest that women have more plaque erosions than men, whilst population data show a disparity in clinical outcome5,6. Yet, the basic science aspects of gender interaction with elements of CAD are understudied, and have not received enough attention from
the basic science cardiovascular community despite clinical data suggesting significant differences in plaque characteristics and response to treatment7,8. Plaque vulnerability is one of those major factors to be considered. With the advent of modern intravascular imaging technology, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), we now have better tools to determine plaque morphology in symptomatic populations. However, we still do not have the tools to study plaque biology in vivo, and therefore we eagerly await the development of novel molecular imaging techniques that may go some way to answering these questions9. The review also highlights gender differences in fractional flow reserve (FFR) cut offs. This is a really important topic, and we hope that future studies in coronary physiology will include enough female patients to establish formal cut offs in order to answer this question adequately10. Furthermore, recent biomarker studies have shown that women may benefit from being studied with more sensitive assays11,12. This may present better risk reclassification in the acute situation. Our own work on a stable non-symptomatic population showed a suggestion that women may have a more favorable immunoglobulin profile, which could in turn contribute to a delay in developing established atherosclerosis 13. Clearly, this is a fertile ground for further gender-focused research, as most of the research signals are extrapolated from studies not powered to answer gender specific questions. Whether microvascular function or endothelial function are affected by systematic hormonal factors, or other factors that are more prevalent in women, such as smaller vessel size, remains to be answered. It is very interesting that the authors highlight significant differences in outcome in women with nonobstructive disease and reduced hyperemic response to adenosine. It may be that conventional coronary angiography is the wrong test to rely on when deciding on risk in the symptomatic population, and novel techniques that combine serology with intravascular
imaging as well as dynamic physiological testing need to be considered when faced with asymptomatic women with unobstructed coronaries. Another important factor is treatment bias. We tend to underestimate risk in women. This pattern also applies when referring for further investigations and invasive studies. The fact that women underestimate their own risk also plays a part in the physician/ patient interaction14. Therefore clearer pathways need to be determined that cater to both genders in terms of appropriate investigations. The lack of gender-tailored studies that investigate the effects of different pharmacological targets is also an issue. It is surprising that there is still little research on the potential biological targets that the menopause could exert on the pathology of atherosclerosis, but hopefully more work is underway in this field. 15 This review demonstrates clearly that the classical paradigm of a normal angiogram translating into a reassuring discussion about the absence of risk is flawed. We hope that there will be a drive to undertake serious translational work where gender disparities in pathophysiology, natural history of the disease, and pharmacology are explored in a rigorous scientific manner, thus leading to treatments that are tailored to women. Furthermore, serious efforts need to be made in clinical trial design to allow for more recruitment of women, and to provide enough power to answer gender related questions. The real challenge for the future is to try to abandon the classical definitions that are modality dependent, such as ‘nonobstructive coronary disease’. The panacea of cardiovascular medicine is to be able to identify the vulnerable patient, and furthermore to be able to pinpoint the pathophysiological causes of this vulnerability and target them specifically with tailored therapies. There is much work to do in the field, which is elegantly highlighted by Paul et al in this issue of the journal3.
References 1 2 3 4
5
6
7 8
9 10 11
12
13
14
15
Goodman, N. The Descent of Man and Selection in Relation to Sex. J Anat Physiol 5, 363-372 (1871). Khamis, R. Y., Ammari, T. & Mikhail, G. W. Gender differences in coronary heart disease. Heart 102, 1142-1149, doi:10.1136/heartjnl-2014-306463 (2016). Tracy, P., Kaartiga, S. & Joshua, S.-M. (2016). Gulati, M. et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 169, 843-850, doi:169/9/843 [pii]10.1001/archinternmed.2009.50 [doi] (2009). Falk, E., Nakano, M., Bentzon, J. F., Finn, A. V. & Virmani, R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J 34, 719-728, doi:10.1093/eurheartj/ehs411 (2013). Tan, Y. C. et al. Gender differences in outcomes in patients with acute coronary syndrome in the current era: A review. Eur Heart J Acute Cardiovasc Care, doi:10.1177/2048872615610886 (2015). Puri, R., Nissen, S. E. & Nicholls, S. J. Statin-induced coronary artery disease regression rates differ in men and women. Curr Opin Lipidol, doi:10.1097/mol.0000000000000195 (2015). Lansky, A. J. et al. Gender and the extent of coronary atherosclerosis, plaque composition, and clinical outcomes in acute coronary syndromes. JACC Cardiovasc Imaging 5, S62-72, doi:10.1016/j.jcmg.2012.02.003 (2012). Jaffer, F. A. & Verjans, J. W. Molecular imaging of atherosclerosis: clinical state-of-the-art. Heart 100, 1469-1477, doi:10.1136/heartjnl-2011-301370 (2014). Li, J. et al. Sex-related differences in fractional flow reserve-guided treatment. Circ Cardiovasc Interv 6, 662-670, doi:10.1161/circinterventions.113.000762 (2013). Motiwala, S. R., Sarma, A., Januzzi, J. L. & O'Donoghue, M. L. Biomarkers in ACS and heart failure: should men and women be interpreted differently? Clin Chem 60, 35-43, doi:10.1373/clinchem.2013.202531 (2014). Shah, A. S. et al. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. BMJ 350, g7873, doi:10.1136/bmj.g7873 (2015). Khamis, R. Y. et al. High Serum Immunoglobulin G and M Levels Predict Freedom From Adverse Cardiovascular Events in Hypertension: A Nested Case-Control Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. EBioMedicine, doi:10.1016/j.ebiom.2016.06.012 (2016). Oertelt-Prigione, S. et al. Cardiovascular risk factor distribution and subjective risk estimation in urban women--the BEFRI study: a randomized cross-sectional study. BMC Med 13, 52, doi:10.1186/s12916-015-0304-9 (2015). Feldman, R. D. Heart Disease in Women: Unappreciated Challenges, GPER as a New Target. Int J Mol Sci 17, doi:10.3390/ijms17050760 (2016).