Sex Differences in Cardiometabolic Disorders
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Sex differences in cardiometabolic risk factorsObesity. According to the World Health Organization (WHO), in 2018 11 % of men and 15% of women worldwide above 18 years of age were obese (BMI ≥30 kg/m2) when assessed by body mass index (BMI). Worldwide, the prevalence of obesity has tripled since 1975. The National Health and Nutrition Examination Survey (NHANES) from 2013–2014 in the United States reported higher prevalence of obesity in women than in men (40.5 vs. 35.2%)10 (Table 1). While the obesity prevalence in women steadily increased in the period 1980–2014, no further increase was observed in men after 200610. In NHANES, obe-sity was more prevalent in subjects of Hispanic origin in both sexes, in current smoking men, and in women with less than high school edu-cation10. Data from the European Social Survey Round 7, performed in 20 European countries, found on average 15.9% (range 11–20%) of both women and men to be obese (Table 1)11. In both sexes, obe-sity was more common in older subjects compared to middle-aged and younger subjects11. Furthermore, regional differences in obesity prevalence were demonstrated; obesity prevalence was highest in the United Kingdom and East European countries, and lower in Central and Northern European countries11.Sex differences in body fatness and regional adipose tissue distri-bution are well documented12. Women are generally characterized by greater body fat mass and preferential accumulation of adipose tissue in the gluteofemoral region, whereas men are more prone to abdominal fat deposition, particularly around the abdominal internal organs, referred to as visceral obesity13–15. In the Jackson Heart Study, 55% of both sexes were obese (Table 1)15. Women had higher subcutaneous adipose mass than men (2,659 vs. 1,730 cm3), while men had higher visceral adipose mass than women (873 vs. 793 cm3), measured by computed tomography15. Visceral adipose mass was associated with higher odds ratios for hypertension, dia-betes and metabolic syndrome than subcutaneous adipose mass in both sexes15, reflecting the higher metabolic activity of visceral compared to subcutaneous fat. The association of visceral adipose mass with prevalent hypertension and metabolic syndrome differed between women and men (odds ratios 1.62 [95% confidence inter-vals 1.4–1.9] in women vs. 1.55 [1.3–1.8] in men for hypertension and 3.34 [2.8–4.0] in women vs. 3.46 [2.8–4.3] in men for metabolic syndrome, both P< 0.001 for sex interaction) after multivariable adjustment, while no sex difference in the association with preva-lent diabetes was demonstrated
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Hypertension.
According to the WHO, in 2015 one in four men and one in five women worldwide had hypertension, identified as a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg. In the United States, the hypertension preva-lence has remained the same among adults since 1999, on average 30.2% in men and 27.7% in women (P< 0.05 between sexes)16. In the NHANES survey in 2015–2016, men had a higher prevalence of hypertension than women among adults aged 18–39 (9.2 vs. 5.6%) and 40–59 years (37.2 vs. 29.4%), while hypertension was more common in women among adults aged 60 years and over (66.8 vs. 58.5%)16. In older subjects, isolated systolic hypertension is the most common type of hypertension in both sexes, pointing to the importance of arterial stiffening and aging for development of hypertension17. Obesity is generally associated with a threefold higher prevalence of hypertension compared to that in normal weight subjects3.
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Sex differences in preclinical cardiometabolic diseaseDiagnosis of preclinical cardiac disease. Preclinical cardiac disease
refers to structural and/or functional changes in the heart in asymp-tomatic subjects that precede incident morbid cardiometabolic events (Box 1)31. Preclinical cardiac disease may be diagnosed by non-inva-sive cardiac imaging methods such as electrocardiography, echocar-diography, cardiac magnetic resonance imaging (CMR) or cardiac computed tomography. Echocardiography is by far the most utilized imaging method based on its high availability and prognostically vali-dated measures of cardiac structure and function32–35. However, com-plementary information may be obtained by these different methods.Impact of cardiometabolic risk factors on prevalent preclini-cal cardiac disease. Cardiometabolic risk factors such as obesity, hypertension, T2DM and metabolic syndrome are all associated with increased prevalence and incidence of preclinical cardiac dis-ease32,33,35–39. Obesity promotes preclinical cardiac disease through a number of hemodynamic and non-hemodynamic effects, includ-ing combined pressure and volume overload and biological actions in visceral adipose tissue40. A number of these changes are sexu-ally dimorphic. In the Fat-Associated Cardiovascular Dysfunction (FATCOR) study in Norwegian middle-aged subjects with increased BMI and without known coronary artery disease, preclinical cardiac disease was diagnosed by echocardiography in 77% of women and 62% of men (P< 0.01 between sexes) (Table 1)36. The type of pre-clinical cardiac disease differed by sex: a dilated left atrium was more prevalent in women while left ventricular hypertrophy (LVH) was more prevalent in men (Box 1)36. Also, in older patients with mod-erate hypertension participating in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study undertaken in the United States and Northern Europe, left atrial dilatation was more common in women, found in 56% of women vs. 38% in men (P< 0.01 between sexes) (Table 1)41. In the LIFE study, women had a signifi-cantly higher prevalence of LVH both at baseline (80% in women vs. 70% in men) and after 4.8 years of systematic antihypertensive treat-ment (50% in women vs. 34% in men, P< 0.001 between sexes)42. Obesity was identified as the main factor associated with lack of LVH regression. In the American Strong Heart Study, LVH was also more common in women than in men (36 vs. 23%, P< 0.001 between sexes)43. At a four-year follow-up examination, regression of LVH was rare, seen in only 3% of men and 10% of women (P< 0.0001 between sexes). Furthermore, new-onset LVH was diagnosed in a comparable 14% of men and 15% of women43. Higher BMI and uri-nary albumin/creatinine ratio were identified as the most important confounders of lack of LVH regression in the Strong Heart Study in both sexes43. In another publication from the same cohort, obesity assessed by fat mass and waist/hip ratio was associated with higher left ventricular mass in women, but not in men44. In treated hyper-tensive patients in the prospective Italian Campania Salute Network project, new-onset LVH was seen in 21% of people during 16 years of follow-up, and particularly more common in women than men and in obese people (Table 1)45. Despite the higher prevalence of LVH, several studies in hypertension have reported that women have bet-ter left ventricular systolic function (Box 1)42,46. In the Strong Heart Study, reduced left ventricular systolic function was more common in obese men compared to obese women (6.2 vs. 2.9%, P< 0.001), independent of the co-incidence of other cardiometabolic risk fac-tors such as hypertension and diabetes47.We recently demonstrated in the Campania Salute Network project that women with treated, uncomplicated hypertension had a 35% lower risk of major cardiovascular events than their male coun-terparts (P< 0.01 for sex interaction)33. However, when hyperten-sion was complicated by LVH, this sex difference in cardiometabolic risk disappeared33. Taken together, these reports demonstrate that LVH is more common and less modifiable in women. Furthermore, when T2DM or LVH is present in women, their risk for cardiometa-bolic disease is similar to that observed in men
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Review ARticle | FOCUSNaTure MediciNereview and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia57, 1542–1551 (2014). 8. EUGenMed Cardiovascular Clinical Study Group et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur. Heart J.37, 24–34 (2016). 9. Sharashova, E. et al. Long-term blood pressure trajectories and incident atrial fibrillation in women and men: the Tromso Study. Eur. Heart J. (2019). 10. Flegal, K. M., Kruszon-Moran, D., Carroll, M. D., Fryar, C. D. & Ogden, C. L. Trends in obesity among adults in the United States, 2005 to 2014. JAMA315, 2284–2291 (2016). 11. Marques, A., Peralta, M., Naia, A., Loureiro, N. & de Matos, M. G. Prevalence of adult overweight and obesity in 20 European countries, 2014. Eur. J. Public Health28, 295–300 (2018). 12. Mauvais-Jarvis, F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol. Sex. Differ.6, 14 (2015). 13. Fox, C. S. et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation116, 39–48 (2007). 14. Despres, J. P. et al. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study. Arterioscler. Thromb. Vasc. Biol.20, 1932–1938 (2000). 15. Liu, J. et al. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J. Clin. Endocrinol. Metab.95, 5419–5426 (2010). 16. Fryar, C.D., Ostchega, Y., Hales, C.M., Zhang, G. & Kruszon-Moran, D. Hypertension prevalence and control among adults: United States, 2015–2016. NCHS Data Brief, 1–8 (2017). 17. Scuteri, A. et al. Longitudinal perspective on the conundrum of central arterial stiffness, blood pressure, and aging. Hypertension64, 1219–1227 (2014). 18. Jackson, C. A., Dobson, A., Tooth, L. & Mishra, G. D. Body mass index and socioeconomic position are associated with 9-year trajectories of multimorbidity: a population-based study. Prev. Med.81, 92–98 (2015). 19. 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 (2015). 20. Pelletier, R. et al. Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young? J. Am. Coll. Cardiol.67, 127–135 (2016). 21. Pelletier, R., Ditto, B. & Pilote, L. A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome. Psychosom. Med.77, 517–526 (2015). 22. Cho, N. H. et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract.138, 271–281 (2018). 23. Al-Salameh, A., Chanson, P., Bucher, S., Ringa, V. & Becquemont, L. Cardiovascular disease in type 2 diabetes: a review of sex-related differences in predisposition and prevention. Mayo Clin. Proc.94, 287–308 (2019). 24. Lyon, A., Jackson, E. A., Kalyani, R. R., Vaidya, D. & Kim, C. Sex-specific differential in risk of diabetes-related macrovascular outcomes. Curr. Diab. Rep.15, 85 (2015). 25. Juutilainen, A. et al. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care27, 2898–2904 (2004). 26. O’Neill, S. & O’Driscoll, L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes. Rev.16, 1–12 (2015). 27. Regitz-Zagrosek, V., Lehmkuhl, E. & Mahmoodzadeh, S. Gender aspects of the role of the metabolic syndrome as a risk factor for cardiovascular disease. Gend. Med.4(Suppl. B), S162–S177 (2007). 28. Moore, J. X., Chaudhary, N. & Akinyemiju, T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev. Chronic Dis.14, E24 (2017). 29. Resnick, H. E. et al. Metabolic syndrome in American Indians. Diabetes Care25, 1246–1247 (2002). 30. Huxley, R., Barzi, F. & Woodward, M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ332, 73–78 (2006). 31. Devereux, R. B. & Alderman, M. H. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation88, 1444–1455 (1993). 32. Gerdts, E. et al. Left atrial size and risk of major cardiovascular events during antihypertensive treatment: losartan intervention for endpoint reduction in hypertension trial. Hypertension49, 311–316 (2007). 33. Gerdts, E. et al. Left ventricular hypertrophy offsets the sex difference in cardiovascular risk (the Campania Salute Network). Int. J. Cardiol.258, 257–261 (2018). 34. Lang, R. M. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr.28, 1–39.e14 (2015). 35. de Simone, G. et al. Does information on systolic and diastolic function improve prediction of a cardiovascular event by left ventricular hypertrophy in arterial hypertension? Hypertension56, 99–104 (2010). 36. Halland, H. et al. Sex differences in subclinical cardiac disease in overweight and obesity (the FATCOR study). Nutr. Metab. Cardiovasc. Dis.28, 1054–1060 (2018). 37. Halland, H. et al. Effect of fitness on cardiac structure and function in overweight and obesity (the FATCOR study). Nutr. Metab. Cardiovasc. Dis.29, 710–717 (2019). 38. de Simone, G. et al. Target organ damage and incident type 2 diabetes mellitus: the Strong Heart Study. Cardiovasc. Diabetol.16, 64 (2017). 39. Bella, J. N. et al. Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study). Am. J. Cardiol.87, 1260–1265 (2001). 40. de Simone, G., Mancusi, C., Izzo, R., Losi, M. A. & Aldo Ferrara, L. Obesity and hypertensive heart disease: focus on body composition and sex differences. Diabetol. Metab. Syndr.8, 79 (2016). 41. Gerdts, E. et al. Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Hypertension39, 739–743 (2002). 42. Gerdts, E. et al. Gender differences in left ventricular structure and function during antihypertensive tre
Review ARticle | FOCUSNaTure MediciNereview and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia57, 1542–1551 (2014). 8. EUGenMed Cardiovascular Clinical Study Group et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur. Heart J.37, 24–34 (2016). 9. Sharashova, E. et al. Long-term blood pressure trajectories and incident atrial fibrillation in women and men: the Tromso Study. Eur. Heart J. (2019). 10. Flegal, K. M., Kruszon-Moran, D., Carroll, M. D., Fryar, C. D. & Ogden, C. L. Trends in obesity among adults in the United States, 2005 to 2014. JAMA315, 2284–2291 (2016). 11. Marques, A., Peralta, M., Naia, A., Loureiro, N. & de Matos, M. G. Prevalence of adult overweight and obesity in 20 European countries, 2014. Eur. J. Public Health28, 295–300 (2018). 12. Mauvais-Jarvis, F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol. Sex. Differ.6, 14 (2015). 13. Fox, C. S. et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation116, 39–48 (2007). 14. Despres, J. P. et al. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study. Arterioscler. Thromb. Vasc. Biol.20, 1932–1938 (2000). 15. Liu, J. et al. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J. Clin. Endocrinol. Metab.95, 5419–5426 (2010). 16. Fryar, C.D., Ostchega, Y., Hales, C.M., Zhang, G. & Kruszon-Moran, D. Hypertension prevalence and control among adults: United States, 2015–2016. NCHS Data Brief, 1–8 (2017). 17. Scuteri, A. et al. Longitudinal perspective on the conundrum of central arterial stiffness, blood pressure, and aging. Hypertension64, 1219–1227 (2014). 18. Jackson, C. A., Dobson, A., Tooth, L. & Mishra, G. D. Body mass index and socioeconomic position are associated with 9-year trajectories of multimorbidity: a population-based study. Prev. Med.81, 92–98 (2015). 19. 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 (2015). 20. Pelletier, R. et al. Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young? J. Am. Coll. Cardiol.67, 127–135 (2016). 21. Pelletier, R., Ditto, B. & Pilote, L. A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome. Psychosom. Med.77, 517–526 (2015). 22. Cho, N. H. et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract.138, 271–281 (2018). 23. Al-Salameh, A., Chanson, P., Bucher, S., Ringa, V. & Becquemont, L. Cardiovascular disease in type 2 diabetes: a review of sex-related differences in predisposition and prevention. Mayo Clin. Proc.94, 287–308 (2019). 24. Lyon, A., Jackson, E. A., Kalyani, R. R., Vaidya, D. & Kim, C. Sex-specific differential in risk of diabetes-related macrovascular outcomes. Curr. Diab. Rep.15, 85 (2015). 25. Juutilainen, A. et al. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care27, 2898–2904 (2004). 26. O’Neill, S. & O’Driscoll, L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes. Rev.16, 1–12 (2015). 27. Regitz-Zagrosek, V., Lehmkuhl, E. & Mahmoodzadeh, S. Gender aspects of the role of the metabolic syndrome as a risk factor for cardiovascular disease. Gend. Med.4(Suppl. B), S162–S177 (2007). 28. Moore, J. X., Chaudhary, N. & Akinyemiju, T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev. Chronic Dis.14, E24 (2017). 29. Resnick, H. E. et al. Metabolic syndrome in American Indians. Diabetes Care25, 1246–1247 (2002). 30. Huxley, R., Barzi, F. & Woodward, M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ332, 73–78 (2006). 31. Devereux, R. B. & Alderman, M. H. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation88, 1444–1455 (1993). 32. Gerdts, E. et al. Left atrial size and risk of major cardiovascular events during antihypertensive treatment: losartan intervention for endpoint reduction in hypertension trial. Hypertension49, 311–316 (2007). 33. Gerdts, E. et al. Left ventricular hypertrophy offsets the sex difference in cardiovascular risk (the Campania Salute Network). Int. J. Cardiol.258, 257–261 (2018). 34. Lang, R. M. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr.28, 1–39.e14 (2015). 35. de Simone, G. et al. Does information on systolic and diastolic function improve prediction of a cardiovascular event by left ventricular hypertrophy in arterial hypertension? Hypertension56, 99–104 (2010). 36. Halland, H. et al. Sex differences in subclinical cardiac disease in overweight and obesity (the FATCOR study). Nutr. Metab. Cardiovasc. Dis.28, 1054–1060 (2018). 37. Halland, H. et al. Effect of fitness on cardiac structure and function in overweight and obesity (the FATCOR study). Nutr. Metab. Cardiovasc. Dis.29, 710–717 (2019). 38. de Simone, G. et al. Target organ damage and incident type 2 diabetes mellitus: the Strong Heart Study. Cardiovasc. Diabetol.16, 64 (2017). 39. Bella, J. N. et al. Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study). Am. J. Cardiol.87, 1260–1265 (2001). 40. de Simone, G., Mancusi, C., Izzo, R., Losi, M. A. & Aldo Ferrara, L. Obesity and hypertensive heart disease: focus on body composition and sex differences. Diabetol. Metab. Syndr.8, 79 (2016). 41. Gerdts, E. et al. Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Hypertension39, 739–743 (2002). 42. Gerdts, E. et al. Gender differences in left ventricular structure and function during antihypertensive tre
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