Sheriff Dodoo, MD, Cardiovascular Disease Fellow
Cardiovascular disease (CVD) accounts for the significant cause of morbidity and mortality for women in the United States and worldwide. Over a third of women die from CVD, and 45% of whom are over age 20 years ( 1 ).
The American College of Cardiology (ACC) and American Heart Association (AHA) recently published its updated guideline recommendations in for the primary prevention of cardiovascular disease in women (2). This effort highlights measures that can be implemented to evaluate and prevent sex-related risk factors, including, pregnancy related events, as well as hypertension, diabetes mellitus, dyslipidemia. Sex-related risk factors pertaining to pregnancy have been shown to increase Cardiovascular disease burden in women. As we celebrate and commemorate heart health month, there is the need to throw light on these risk factors and health related conditions that put women at increased risk of cardiovascular mortality and morbidity.
Pregnancy Related Conditions that Increase Future Risk of CVD
Adverse pregnancy related outcomes occur in 15% of all pregnancies and these are associated with a 2.5-fold risk of future CVD ( 3 ). Risk of cardiovascular disease in pregnancy and its attendant future cardiovascular illnesses have been a subject of intense research to find way by which these risks can be mitigated, if not eliminated. Current paradigm accounting for these risks, especially in pregnancy, include placental vascular endothelial dysfunction. This is known to be an early indicator of future cardiometabolic risk ( 4 ). The American College of Obstetrics and Gynecology recommends that women with adverse pregnancy related outcomes and those with these cardiovascular risk factors undergo cardiovascular risk evaluation within 3 months postpartum ( 5 ). These adverse pregnancy related outcomes and risk factors include hypertensive disorders of pregnancy (chronic hypertension, gestational hypertension preeclampsia, eclampsia, and HELLP syndrome), gestational diabetes, intrauterine growth retardation, preterm birth, placental abruption, pregnancy related obesity, sleep disorders in pregnancy, and, advanced maternal age. Those with these risk factors are encouraged to see obstetrics and gynecology providers for cardiovascular risk screening 3 months postpartum (5). This evaluation will include obtaining medical history, smoking history, physical activity, breast-feeding, prior history of hypertension, diabetes, hyperlipidemia and a history of first-degree family history of cardiovascular disease. Physical examination during this visit will include measurement of blood pressure and resting heart rate, body mass index and weight circumference. Laboratory investigations for fasting lipid panel, blood sugar, urine protein: Creatinine ratio will be undertaken. These will help to risk stratify these women in order to provide clinical care that would go in the long way to reduce the inherent risk of future cardiovascular mortality and morbidity.
The 2017 ACC/AHA guidelines for the prevention, detection, evaluation, and management of high BP provides very limited gender-neutral guidance in the management of hypertension. However, this practice guideline sheds some light on hypertension during pregnancy ( 6 ). There are certain gender specific considerations in the epidemiology, evaluation, and management of hypertension in women. Some common risk factors for hypertension in women include: obesity, sedentary lifestyle, increased salt consumption, diabetes mellitus, and alcohol consumption (i.e., >1 alcoholic drink/day). Of these, obesity has the highest association with the incidence of hypertension among women ( 7 ). The possible explanation includes the up-regulation of renin-angiotensin receptors in the post-menopausal period, and hence salt restriction has been shown to be beneficial in reducing the risk of hypertension. Indeed, reducing salt consumption is associated with reduction in systolic BP in women with and without a history of hypertension ( 8 ). The 2017 ACC/AHA guidelines recommend to ideally limit sodium intake to <1,500 mg/day or at least aim for a 1,000 mg/day reduction, and to enhance the intake of potassium from foods to at least 3,500 to 5,000 mg/day ( 7 ); however, there is no specific recommendations based on sex.
Attention needs to be given to the possible presence of secondary causes of hypertension among young women. In particular, women account for >90% of cases of fibromuscular dysplasia, a condition that affects 3.3% of the general population ( 9 ). The use of hormonal contraceptive can also result in an increase in BP, particularly among women with chronic hypertension. Pre-menopausal women needing antihypertensive therapy also require education on potential teratogenicity of these medications, particularly if receiving angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or mineralocorticoid receptor antagonists ( 10 ).
The 2017 ACC/AHA guideline recommends out-of-office monitoring of BP for confirmation and management of hypertension regardless of gender ( 7 ). Notably, studies suggested that post-menopausal women are likely to experience a non-dipping nighttime BP phenomenon (defined as <10% reduction in nighttime BP) ( 11). This effect likely explains the higher incidence of cardiovascular events attributed to nocturnal BP observed in women compared with men ( 12 ), suggesting that women might derive more benefit from BP control using out- of- office BP monitoring when compared with conventional one time BP monitoring.
Based on the findings of the SPRINT (Systolic Blood Pressure Intervention Trial), the 2017 ACC/AHA guideline recommends a therapeutic BP target of 130/80 mm Hg irrespective of sex (13). Despite the higher prevalence of hypertension among women, SPRINT sadly enrolled only 36% women (13). This may have accounted for women having lower cardiovascular risk than men in this landmark trial( 13). Two analyses for the sex-specific differences between an intensive BP-lowering strategy versus a standard BP-lowering strategy from SPRINT were conducted ( 14 , 15 ). One showed that women and men derive similar benefit from an intensive BP-lowering strategy ( 14 ), whereas the other analysis showed that women do not benefit from an intensive BP-lowering strategy after matching the baseline differences in both groups ( 15 ). Collectively, this suggests that the BP targets in women remains not well established even after the results of the SPRINT trial ( 15 ).
Randomized trial data suggest that there is no large difference between women and men in cardiovascular outcomes based on the antihypertensive regimen ( 16 ), but it suggests that women might experience more side effects from antihypertensive medication with compared to men( 16 , 17 ). Perhaps thiazide diuretic agents are only clearly beneficial agent in older women due to their effect in reducing calcium excretion and preventing osteoporosis (18 ).
Diabetes mellitus (DM) is projected to affect over 26 million people in the United States, of which 12.8 million are women, with the vast majority having type 2 DM ( 1 ). There are significant gender disparity in the prevalence of type 2 DM, as well as sex differences in CVD outcomes over a lifetime.
Over a lifetime, girls have a higher rates of type 2 DM in youth, whereas men have higher rates during midlife, with similar incidence between men and women at later stages in life ( 19 ). The possible pathophysiology of sex difference may be due to sex differences in insulin resistance during adolescence and midlife, with young females having higher rates of insulin resistance from early childhood to puberty ( 19 ). These findings of early-onset of DM in female patients, which translates into longer duration of disease throughout their lifetime. This finding was corroborated by the recent finding in the Swedish Heart Registry that people diagnosed with type 2 DM before the age of 40 years have increased CVD mortality( 20 ).
Diabetes increases the risk of having an MI or stroke by 2-fold ( 19 ). In the presence of type 2 DM, the absolute rate difference between the sexes is significantly diminished, although not fully eliminated ( 21 , 22 ). The cardioprotection that occurs in pre-menopausal women is thus significantly diminished with diabetes. A recent meta-analysis of over 5 million patients found that the pooled relative risk for CVD mortality in patients with DM was 2.42 in women (95% CI: 2.10 to 2.78) and 1.86 (95% CI: 1.70 to 2.03) in men ( 23 ). There also appears to be increased risk of CVD mortality in women with DM compared with men (relative risk: 1.30; 95% CI: 1.13 to 1.49; p < 0.001) in this pooled analysis( 23 ). Recently, the Atherosclerosis Risk In Communities study found DM was a stronger predictor for CVD morbidity as well as CVD mortality among African-American women than among African-American men ( 24 ). These findings were similar to the disparities seen in white male and female patients ( 24 ). In addition to atherosclerotic events, having DM increased the incidence of congestive heart failure. In the UK biobank study of 468,941 patients, women with type 2 DM had significantly higher rates of incidence of heart failure (HR: 1.73; 95% CI: 1.34 to 2.24; p < 0.0001) as well as heart failure mortality (HR: 1.92; 95% CI: 1.25 to 2.94; p = 0.003) compared with men ( 25 ). Last, DM increases the risk of cancer death by 26% in women (95% CI: 1.16 to 1.36) and by 29% in men (95% CI: 1.18 to 1.42) ( 23 ).
There appears to be gender differences in response to therapeutic options for DM. For instance, whereas glucagon-like peptide-1 receptor agonists have better glycemic control among men than women, women had more weight loss ( 26 ). There is better glycemic reduction in obese women to thiazolidinediones, whereas nonobese men respond better to sulfonylureas ( 26 , 27 ). Reassuringly, the EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) study, which showed reduction in cardiovascular mortality in diabetic patients treated with the sodium glucose cotransporter 2 inhibitor empagliflozin, showed no significant sex differences in benefit with the drug ( 28 ).
Despite this sex specific difference in response to diabetic medications, all patients with DM require aggressive risk factor reduction. Nonetheless, women are often underdiagnosed and undertreated compared with men ( 29 , 30 ).
Blood Cholesterol Management in Women
Despite recent advancements in cholesterol-lowering therapy, women are less likely to receive statin therapy, the guideline standard of care in patients with dyslipidemia, compared with men. They are also more likely to decline and less likely to continue therapy ( 31 ). The 2018 AHA/ACC multisociety guideline on the management of blood cholesterol and the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease emphasize the importance of lipid management for reduction of atherosclerotic cardiovascular disease (ASCVD) risk and include some sex-specific risk-enhancing factors to help further identify women at increased ASCVD risk (2, 31). In addition to lifestyle interventions with diet, exercise, and weight loss, the guidelines recommend statin therapy as the mainstay treatment in 4 groups of patients: Clinical ASCVD, severe hypercholesterolemia (low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), diabetes mellitus in adults (age 40 to 75 years), primary prevention in adults age 40 to 75 years at high risk (≥20%) and some adults at intermediate risk (≥7.5% to <20%) or borderline risk (5% to <7.5%) based on the presence of risk enhancers, the presence of an elevated coronary artery calcium score if measured, and provider-patient risk discussion.
The benefit of statin therapy has been widely accepted for reduction of CVD events for secondary prevention in both sexes; however, the role of statin therapy for primary prevention in women has been debated over the past decade. This controversy stemmed in part from a lack of robust data on the efficacy of statins for primary prevention in women, as under-representation of women in randomized controlled trials left studies underpowered to adequately analyze outcomes by sex. In addition, early meta-analyses of statin therapy for primary prevention yielded conflicting data, with some studies showing no significant reduction in mortality or cardiovascular events in women (34 ). Since the Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update ( 33 ), 2 larger meta-analyses including over 40,000 women have demonstrated a similar benefit of statin therapy in women and men for both primary and secondary prevention, and this benefit was seen in both sexes across all levels of risk in primary prevention studies ( 35 , 36). Although no significant sex differences in adverse effects were identified in these meta-analyses, few statin trials reported adverse drug reactions by sex. Despite a paucity of randomized trial data, international consensus statements recognized female sex as a risk factor for statin-associated muscle symptoms ( 37 , 38 ). In patients with statin-associated muscle symptoms, careful review of concomitant medications and detailed history should be taken to understand factors that may contribute to statin side effects ( 37 , 38 ). Change in statin (hydrophilic vs. lipophilic) as well as intermittent statin dosing can be used to help overcome some of the muscle symptoms associated with statins ( 39 ).
There are currently no sex-specific guidelines for the management of blood cholesterol with statin therapy. Statins reduce cardiovascular events and all-cause mortality regardless of sex, and should be considered at recommended doses in women who meet criteria for 1 of the 4 guideline-recommended patient populations
Women have different manifestations of CVD, and studies have shown gender disparities in CVD risk factors and response to therapy. Additionally, unique aspects that pertain to women, such as pregnancy-associated conditions, as well as, traditional risk factors that increase future CVD events, need to be considered when treating women. Knowledge of updated guideline recommendations are crucial in the efforts to curbs the rising prevalence in CVD in women.
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- Whelton P.K., Carey R.M., Aronow W.S., et. al.: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71: pp. 2199-2269.
- Wenger N.K., Arnold A., Bairey Merz C.N., et. al.: Hypertension across a woman’s life cycle. J Am Coll Cardiol 2018; 71: pp. 1797-1813.
- Sacks F.M., Svetkey L.P., Vollmer W.M., et. al., for the DASH-Sodium Collaborative Research Group: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344: pp. 3-10
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- Routledge F.S., McFetridge-Durdle J.A., Dean C.R.: Stress, menopausal status and nocturnal blood pressure dipping patterns among hypertensive women. Can J Cardiol 2009; 25: pp. e157-e163.
- Boggia J., Thijs L., Hansen T.W., et. al.: Ambulatory blood pressure monitoring in 9357 subjects from 11 populations highlights missed opportunities for cardiovascular prevention in women. Hypertension 2011; 57: pp. 397-405.
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- Foy C.G., Lovato L.C., Vitolins M.Z., et. al.: Gender, blood pressure, and cardiovascular and renal outcomes in adults with hypertension from the Systolic Blood Pressure Intervention Trial. J Hypertens 2018; 36: pp. 904-915.
- Ochoa-Jimenez R., Viquez-Beita K., Daluwatte C., et. al.: Sex differences of patients with systemic hypertension (from the Analysis of the Systolic Blood Pressure Intervention Trial [SPRINT]). Am J Cardiol 2018; 122: pp. 985-993.
- Turnbull F., Woodward M., Neal B., et. al.: Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J 2008; 29: pp. 2669-2680.
- Os I., Franco V., Kjeldsen S.E., et. al.: Effects of losartan in women with hypertension and left ventricular hypertrophy: results from the Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2008; 51: pp. 1103-1108
- Puttnam R., Davis B.R., Pressel S.L., et. al.: Association of 3 different antihypertensive medications with hip and pelvic fracture risk in older adults: secondary analysis of a randomized clinical trial. JAMA Intern Med 2017; 177: pp. 67-76.
- Huebschmann A.G., Huxley R.R., Kohrt W.M., et. al.: Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course. Diabetologia 2019; 62: pp. 1761-1772.
- Sattar N., Rawshani A., Franzen S., et. al.: Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risk: Findings from the Swedish National Diabetes Registry. Circ 2019; 139: pp. 2228-2237.
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- Prospective Studies Collaboration, Asia Pacific Cohort Studies Collaboration: Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980,793 adults from 68 prospective studies. Lancet Diabetes Endocrinol 2018; 6: pp. 538-546.
- Wang Y., O’Neil A., Jiao Y., et. al.: Sex differences in the association between diabetes and risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality: a systematic review and meta-analysis of 5,162,654 participants. BMC Med 2019; 17: pp. 136.
- George K.M., Selvin E., Pankow J.S., et. al.: Sex differences in the associations of diabetes with cardiovascular disease outcomes among African-American and white participants in the Atherosclerosis Risk In Communities Study. Am J Epidemiol 2018; 187: pp. 403-410.
- Sillars A., Ho F.K., Pell G.P., et. al.: Sex differences in the association of risk factors for heart failure incidence and mortality. Heart 2020; 106: pp. 203-212.
- Anichini R., Cosimi S., Di Carlo A., et. al.: Gender difference in response predictors after 1-year exenatide therapy twice daily in type 2 diabetic patients: a real world experience. Diabetes Metab Syndr Obes 2013; 6: pp. 123-129.
- Dennis J.M., Henley W.E., Weedon M.N., et. al.: MASTERMIND Consortium Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: a framework for evaluating stratification using routine clinical and individual trial data. Diabetes Care 2018; 41: pp. 1844-1853.
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- Peters S.A.E., Muntner P., Woodward M.: Sex differences in the prevalence of, and trends in, cardiovascular risk factors, treatments, and control in the United States, 2001-2016. Circulation 2019; 139: pp. 1025-1035.
- Wright A.K., Kontopantelis E., Emsley R., et. al.: Cardiovascular risk and risk factor management in type 2 diabetes:a population-based cohort study assessing sex disparities. Circulation 2019; 139: pp. 2742-2753.
- Nanna M.G., Wang T.Y., Xiang Q., et. al.: Sex differences in the use of statins in community practice. Circ Cardiovasc Qual Outcomes 2019; 12:
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- Mosca L., Benjamin E.J., Berra K., et. al.: Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. J Am Coll Cardiol 2011; 57: pp. 1404-1423
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- Kostis W.J., Cheng J.Q., Dobrzynski J.M., et. al.: Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59: pp. 572-582.
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- Stroes E., Thompson P., Corsini A., et. al.: Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J 2015; 36: pp. 1012-1022.
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Learn more about the Cardiovascular Disease Fellowship program at Northeast Georgia Medical Center!