Sex Differences in Hypertension: Related to Genes, Jean Sizes, and Salt Sensitivity?

Abstract

HomeHypertensionVol. 79, No. 1Sex Differences in Hypertension: Related to Genes, Jean Sizes, and Salt Sensitivity? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBSex Differences in Hypertension: Related to Genes, Jean Sizes, and Salt Sensitivity? Michael E. Hall and John E. Hall Michael E. HallMichael E. Hall Correspondence to: Michael E. Hall, Associate Division Director of Cardiovascular Diseases, Director of Clinical and Population Studies, Mississippi Center for Clinical and Translational Research, University of Mississippi Medical Center, Jackson, MS, 39216. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5733-1025 From the Department of Medicine (M.E.H.), University of Mississippi Medical Center. Department of Physiology and Biophysics (M.E.H., J.E.H.), University of Mississippi Medical Center. Search for more papers by this author and John E. HallJohn E. Hall https://orcid.org/0000-0001-9867-5855 Department of Physiology and Biophysics (M.E.H., J.E.H.), University of Mississippi Medical Center. Search for more papers by this author Originally published8 Dec 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.18425Hypertension. 2022;79:47–49This article is a commentary on the followingFemale Sex and Angiotensin-Converting Enzyme (ACE) Insertion/Deletion Polymorphism Amplify the Effects of Adiposity on Blood PressureIn this issue of Hypertension, Chiriacò et al1 report the associations of adiposity with blood pressure (BP) and incident hypertension while adjusting for lifestyle and metabolic factors in the Relationship between Insulin Sensitivity and Cardiovascular disease cohort that included 1211 normotensive European participants (ages 30–60 years) with 3.3 years of follow-up. Further, they assessed the impact of sex and ACE (angiotensin-converting enzyme) gene insertion/deletion polymorphisms on the relationships between adiposity, BP, and hypertension.See related article, pp 36–46Waist circumference (WC) and body mass index were significantly associated with mean arterial pressure after adjusting for traditional risk factors including age, lifestyle, and metabolic factors, and this relationship was stronger in women than in men and in those with the ACE II and ID genotypes. They also observed that a 5 cm larger WC was associated with incident hypertension in women, but not men, and in those with the ACE II genotype. Overall, they concluded that the hypertensive effect of central adiposity is more pronounced in women than in men as well as in people with the ACE II gene polymorphism. They also suggest that salt sensitivity of BP may play an important role in these relationships.Not surprisingly, Chiriacò et al demonstrated a stronger relationship between WC, a marker of central/visceral adiposity, and BP compared with body mass index. This observation reinforces other studies indicating that visceral adipose tissue surrogates are better predictors of hypertension than body mass index which does not differentiate lean muscle, fat distribution, or type of adipose tissue (visceral versus subcutaneous). It is important to note that the population studied by Chiriacò et al was normotensive at baseline without major cardiometabolic derangements or use of cardiovascular medications which have confounded many previous investigations of these associations. They also provide evidence that menopause amplifies the relationship between WC and risk of incident hypertension in women.Insertion/deletion polymorphisms in the ACE gene have been associated with hypertension, obesity, and metabolic disorders including insulin resistance and impaired glucose tolerance.1,2 Activation of the renin-angiotensin-aldosterone system involves ACE activity which converts angiotensin I to angiotensin II and inactivates vasodilators including bradykinin. The ACE DD homozygote polymorphism has previously been associated with hypertension and cardiovascular diseases while the ACE II homozygote polymorphism has been associated with a more favorable cardiometabolic profile, but it has also been associated with greater salt sensitivity of BP.3 Consistent with the latter observations, Chiriacò et al’s findings support the hypothesis that the ACE II gene polymorphism is associated with a higher risk of hypertension in women, possibly due to greater salt sensitivity. Thus, they speculate that the ACE II gene polymorphism may amplify the BP effect of visceral fat in women who may be more fat-sensitive ultimately due to greater salt sensitivity. Although difficult to precisely define, salt sensitivity generally describes a significant increase in BP when salt intake is increased and has been reported in patients with obesity, hypertension, older age, and kidney disease.4Many studies have provided compelling evidence that excess visceral fat is strongly associated with cardiometabolic diseases including hypertension. Visceral fat may contribute to hypertension through several mechanisms including: (1) activation of the renin-angiotensin-aldosterone system, (2) activation of the sympathetic nervous system, and (3) physical compression of the kidneys by intraabdominal and perinephric fat.5 Each of these mechanisms contributes to increased renal sodium reabsorption and potentially salt sensitivity of BP (Figure).Excessive renin-angiotensin-aldosterone system activation, or inability to effectively modulate its activity, is an important cause of BP salt sensitivity.4 Another major cause of salt-sensitive hypertension is kidney injury or loss of functional nephrons which may occur when visceral obesity is sustained over many years.5In the present study, the ACE II genotype was associated with increased risk of central adiposity-mediated hypertension. Chiriacò et al hypothesized that increased salt sensitivity related to this genotype may be due to increased plasma levels of aldosterone, especially in obese women. Visceral obesity has been reported to increase plasma aldosterone which could contribute to salt sensitivity.5 Unfortunately, plasma aldosterone was not measured in the Relationship between Insulin Sensitivity and Cardiovascular cohort so this hypothesis is speculative. Excessive activation of the MR (mineralocorticoid receptor), independent of elevated aldosterone levels, may also contribute to increased renal sodium reabsorption and BP salt sensitivity in obesity.4,5 However, the impact of sex differences on the role of MR activation as a mediator of salt sensitivity remains unclear. Some clinical trial results suggest MR antagonists may be more effective at lowering BP in women compared with men.6 In contrast, data from the more recent TOPCAT trial did not show any significant sex differences in BP-reducing effect of the MR antagonist spironolactone.7 Regardless, MR antagonists are effective at lowering BP in patients with resistant hypertension and most of these patients are overweight or obese.Men typically have more visceral adiposity and greater risk for hypertension, while premenopausal women often have more subcutaneous adipose tissue and lower prevalence of hypertension. However, after menopause, women develop more visceral adiposity and have greater risk for hypertension compared with premenopausal women. Clinical and epidemiological studies suggest that salt sensitivity may be more common in postmenopausal women compared with men.8 Surgical menopause (hysterectomy-oophorectomy) was associated with BP salt sensitivity in normotensive women and salt-sensitive women had higher waist/hip ratios.9 Chiriacò et al observed a larger WC in menopausal women associated with higher risk of incident hypertension. Increased salt sensitivity in women has been linked to inappropriate aldosterone production and MR activation which may be due to increased visceral fat after menopause.10Strengths of the study by Chiriacò et al include a large, well-phenotyped cohort with genetic data and longitudinal follow-up. Importantly, at baseline, participants were normotensive and not on antihypertensive therapies (eg, diuretics and renin-angiotensin-aldosterone system blockers) which can confound assessment of these associations with incident hypertension. There are several important limitations to note. While this study had fairly comprehensive measures of metabolic and lifestyle factors coupled with genetic data, there were no data on important factors which impact salt sensitivity of BP. The most notable missing factor is assessment of sodium intake. Many cohort studies are limited to dietary recall data which generally underestimate sodium intake. Ideal assessment of sodium intake would include at least one measurement of 24-hour urinary sodium excretion although adequate urine collections in large cohort studies can be challenging. There was also no assessment of renal function. Recognizing the limitations of estimated glomerular filtration rate as a measure of kidney function specifically in obesity, this measurement would at least have provided some assessment of the potential impact of kidney dysfunction on the findings. Previous studies suggest that obesity is associated with kidney dysfunction and injury even after adjusting for diabetes and hypertension.11 Also, the participants were White and it is unclear if similar associations would be observed in other racial/ethnic groups (eg, Black adults) who may be at even greater risk for adiposity-related changes in BP and salt sensitivity.Chiriciao et al have shed light on how sex and genetics may modulate the strong relationship between adiposity and BP. More direct studies of the potential impact that female sex and genetic polymorphisms have on obesity-mediated salt sensitivity and hypertension are warranted. However, while these factors may help identify people at higher risk for developing hypertension and subsequent cardiovascular diseases, effective prevention, and treatment strategies are available. Almost all patients should be counseled on the BP risks related to excess weight gain and excess sodium intake regardless of sex or genetics.Download figureDownload PowerPointFigure. Visceral adiposity increases the risk of hypertension through several mechanisms including: (1) activation of the renin-angiotensin-aldosterone system (RAAS), (2) activation of the sympathetic nervous system, and (3) physical compression of the kidneys. Potential factors that may modulate sex differences in the relationship between visceral adiposity and hypertension include salt sensitivity which may be amplified in women due to genetic factors (eg angiotensin-converting enzyme, ACE [angiotensin-converting enzyme], gene polymorphisms), hormonal factors related to menopause, and activation of the mineralocorticoid receptor.Article InformationSources of FundingThe authors recieve grant funding from the National Institutes of Health, National Institute of General Medical Sciences (P20GM104357 and U54115428), and the National Institutes of Diabetes and Digestive and Kidney Diseases (K08DK099415, R01DK121411, and R01DK121748).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the American Heart Association.For Sources of Funding and Disclosures, see page 49.Hypertension is available at www.ahajournals.org/journal/hypCorrespondence to: Michael E. Hall, Associate Division Director of Cardiovascular Diseases, Director of Clinical and Population Studies, Mississippi Center for Clinical and Translational Research, University of Mississippi Medical Center, Jackson, MS, 39216. Email [email protected]edu