1. Introduction: Coronary artery disease (CAD) is the commonest heart disease in present scenario and it is one of the leading causes of morbidity and mortality worldwide, with the heaviest burden in developing countries including India. Diabetes as a whole increases cardiovascular disease (CVD) risk 2-4 fold compared with the non-diabetic general population – a risk level that may compare with that of non-diabetic people who have already suffered a myocardial infarct . Many people think of CAD as primarily a problem of men, perhaps because men have more than twice the total incidence of cardiovascular morbidity and mortality than women between the ages of 35-84 . The explanation for the sex difference in CAD is a “cardio-protective” effect of oestrogen hormone present in premenopausal women, which causes improvement of the lipid profile and implicates a direct vasodilatory effect, and perhaps due to other contributing factors .
However, many studies have reported that the premenopausal protection against coronary heart disease seen in healthy women is lost in those with diabetes . Women with diabetes mellitus have twice the risk of myocardial infarction as compared to non-diabetic women and possess the same risk of a myocardial infarction as a non-diabetic male of the same age . In fact, the increased risk of CVD associated with diabetes appears to be biased with gender too but opposite to the non-diabetic population as observational studies showed diabetic women are at higher risk of CVD then diabetic men. Cardiovascular mortality rates were found to be 3-7 folds higher in diabetic women than non-diabetic women, as compared to 2-4 folds higher in diabetic men than in non-diabetic men . WHO study group mentioned in their technical report series 1985 (page 727) that women with diabetes not only are at greater risk for CAD, but also experience more adverse outcomes following an event of myocardial infarction (MI), both early (28 days) (22 vs 14 %) and late (2 years) (28.9 vs 19.6 %) mortalities are greater in women than in men with diabetes.
2. Chest pain as presenting symptom: In women establishing the diagnosis of CAD remains problematic and this is, in part, due to the relatively high prevalence of chest pain in women in the absence of significant epicardial coronary artery stenosis . Over 50% of women may have angina pectoralis as their first symptoms . One of the initial studies to recognize the diagnostic value of angina in women was the Coronary Artery Surgery Study (CASS) and they found 72% of the women with definite angina and 36% of the women with probable angina were having significant coronary disease, defined as at least 70% coronary artery stenosis . In the study “Hysterectomy Enhances the Risk of Coronary Artery Disease in Type 2 Diabetic Women in Premenopausal Age Group” published in the Journal of Medical Science and Clinical Research, the author found during a sub-analysis as expected angina was more common in subjects with CAD in both premenopausal and postmenopausal group. It was observed 59% of women presented with angina and out of them 54% had CAD defined by exercise treadmill ECG testing.
3. Age: Among type 1 diabetes the risk of CAD increases rapidly after the age of 40; by 55 years of age, 35% diabetic men and women died from a coronary event, compared with 8% of men and only 4% of women in the general population . In the mentioned study  by the author even among type 2 diabetic women, during univariate analysis of premenopausal CAD (age 44.2 ± 2.9) and postmenopausal CAD (age 54.4 ± 4.8) group, higher age too was significantly associated in both the group. Further in premenopausal CAD group, age was more significant and independent risk factor during multiple logistic regression analysis with odds ratio 1.24 and p value 0.44.
4. Family history of Ischemic heart disease (IHD): Genetic factors are an important determinant of IHD risk in both men and women and no gender bias has been reported so far. As per Mayo Clinic report positive family history of heart disease is associated with a higher risk of coronary artery disease, especially if a close relative developed heart disease at an early age. They further mentioned the risk is highest if subject`s father or a brother was diagnosed with heart disease before age 55 or mother or a sister developed it before age 65. A case-control study  was conducted in Italy during 1995-1999 on 378 men and 129 women with a first nonfatal acute myocardial infarction (AMI), and 297 male and 181 female controls in a hospital for selected acute conditions. Odds ratios (OR) of AMI according to family history of IHD were estimated using unconditional logistic regression, adjusting for other AMI risk factors and family size. The overall OR for those having > or =1 first-degree relatives with IHD were 2.1, and 3.8 for > or =2 relatives. The OR for those with an affected parent or sibling was similar. Further they came to the conclusion that family history of IHD is an independent risk factor for AMI, and intervention on modifiable risk factors may be beneficial also in those with a family history of the disease. Similar observation found in the mentioned study  by the author, family history of IHD was significantly and independently associated with comparatively over aged 58 postmenopausal CAD women (age 54.4 +/- 4.8 years), during multiple logistic regression analyses with odds ratio (OR) 3.38 and P value 0.028.
5. Hypertension: History of hypertension, duration of hypertension and uncontrolled blood pressure all were significant during univariate analysis in postmenopausal CAD in the mentioned study  by the author. The probable explanation might be women have a higher incidence of hypertensive heart disease and common causes of hypertension, such as renovascular hypertension due to fibromuscular dysplasia, are more common in women than in men [11, 12]. Among those uncontrolled hypertension was more significantly and independently associated with postmenopausal CAD women during multiple logistic regression analysis with odds ratio 0.31 and p value 0.011. In UKPDS, type 2 diabetes was more likely to be associated with elevations in both systolic and diastolic blood pressure (BP) in women (45%) then in men (32%) and also showed that hyperglycemia and hypertension exert additive (but not synergistic) effects and with tight BP control myocardial infarction (MI) was reduced by 21% (but this did not reach statistical significance, p = 0.13). From all references it can be hypothesized that uncontrolled hypertension is very vulnerable among type 2 diabetic women, may be particularly in postmenopausal type 2 diabetic women among all hypertension related issues like history of hypertension, duration of hypertension and uncontrolled hypertension.
6. HDL cholesterol: The Framingham study was the first to demonstrate the association of low HDL cholesterol levels with CAD . Studies have shown that for every 1 mg decrease in HDL cholesterol the risk for heart disease increased by 2% in men and 3% in women [14, 15]. In fact, decreased HDL cholesterol levels are a stronger predictor of risk in women than in men [16, 17]; elevated LDL cholesterol levels, a strong predictor of atherosclerotic heart disease in men, do not contribute as strong a risk factor for CAD as low HDL cholesterol levels in women who do not have established clinical coronary disease [18, 19]. In the mentioned study  by the author, it was found that during univariate analysis low HDL cholesterol levels too were significantly associated with both premenopausal and postmenopausal CAD, however during multiple logistic regression analysis low HDL cholesterol was further significantly and independently associated as risk factor with young premenopausal CAD with odds ratio 0.914 and p value 0.046. LDL cholesterol was not significant in CAD in this study.
7. Triglyceride: Elevated triglyceride levels also appear to be an independent predictor of coronary disease in older women . Even, in the mentioned study  by the author, triglycerides were significantly and independently associated with postmenopausal CAD women vs postmenopausal without CAD women, during multiple logistic regression analyses [odds ratio = 1.008, p value = 0.034], though mean triglycerides were high in all study subjects and the possible explanations might be poor glycaemic control in the study subjects.
8. Albuminuria: The presence of albuminuria is a powerful predictor of renal and cardiovascular risk in patients with T2DM and hypertension without any gender bias. An analysis of 3,498 patients with diabetes and 5,545 patients without diabetes in the Heart Outcomes Prevention Evaluation (HOPE) study found that microalbuminuria increased the adjusted relative risk (RR) of major cardiovascular events (RR 1.83, 95% CI 1.64–2.05) (19). Participants with diabetes had a RR of 1.97 (95% CI 1.68–2.31) and those without diabetes had an RR of 1.61 (95% CI 1.36–1.90). Microalbuminuria may also be a risk factor for more severe or advanced cardiovascular disease as well. The 330 patients who underwent coronary angiography were divided into groups based on the presence or absence of diabetes and the presence or absence of microalbuminuria (20). Diabetic patients with microalbuminuria had a higher prevalence of three-vessel coronary artery disease compared with those without microalbuminuria (75 vs. 42%). This relationship was also seen in those patients studied without diabetes and with or without microalbuminuria (39 vs. 20%). In addition, multiple studies have shown that decreasing the level of albuminuria by rennin angiotensin system (RAS) blocked drugs reduce the risk of adverse renal and cardiovascular outcomes. The pathophysiology is not definitively known, but is hypothesized to be related to endothelial dysfunction, inflammation, or possibly abnormalities in the renin-angiotensin-aldosterone system. Albuminuria was not statistically significant in the mentioned study  by the author might be because of its predominant presence of 22% to 45% in all the four sub groups consisting without and with CAD premenopausal and without and with CAD postmenopausal groups, however in both CAD positive premenopausal and postmenopausal group albuminuria was more predominantly present supporting the recent findings as discussed earlier.
9. Glycaemic control and duration of diabetes: There are not much report regarding gender bias in glycaemic control and CVD outcome, even dysglycaemia, uncontrolled glycaemia or duration of diabetes which one has more impact in CVD outcome is highly debatable. However, there is some evidence from prospective studies that more intensive treatment of blood glucose in newly diagnosed T2DM patients irrespective of gender bias may reduce long-term CVD rates. For instance, in the UKPDS trial, a 16% reduction in CVD events in the intensive glycaemic control arm was noted, but did not reach statistical significance. However, after 10 years of follow-up, patients randomized to intensive glycaemic control showed a significant long-term reduction in MI , virtually supporting the concept of metabolic memory in diabetes.
However, more recent large trials like ACCORD, ADVANCE and VADT [23-25] suggested no significant reduction in CVD, or even a higher risk of death, with intensive glycaemic control in patients who had long duration of T2DM as compared to those on UKPDS. In the ACCORD Study, tight control did not yield protection against CVD, mainly in those with advanced diabetes, known history of severe hypoglycaemia, and advanced atherosclerosis. Of note, all these trials were conducted in participants with more long-standing T2DM (mean duration 8–11 years) and either known CVD or multiple cardiovascular risk factors . For example, the ACCORD trial involved persons who had T2DM for a median of 10 years . Here in the mentioned study  by the author overall glycaemic control in all subject women were very poor as reflected by HbA1c > 8.5%, might be that’s the reason glycaemic control was non-significant in any arm of the study during analysis. However higher duration of diabetes 8.8 +/- 5.7 years and 10.7 +/- 6 years in postmenopausal women without CAD and CAD positive group respectively were significant (p value < 0.05) comparing with lower duration of diabetes 6.1 +/- 4.3 years in premenopausal without CAD group.
In future we require more prospective long-term clinical trials to confirm the hypothesis that higher duration of diabetes (with median cut off point might be 10 year or so) with poor glycaemic control is vulnerable for macrovascular complications in T2DM, however early intensification of treatment to achieve intensive glycaemic control in the initial period might be helpful in significant long-term CVD risk reduction, supporting the concept of metabolic memory.
10. Sedentary lifestyle and obesity: Obesity and sedentary lifestyle are parallel, interrelated epidemics in the United States that contribute to increased risk of CAD. Regular physical exercise remains a cornerstone of the primary prevention of CAD and of the management of overweight diabetic patients. Lack of exercise has been linked to 7-12% of CAD cases . However few studies have assessed the prospective relationship of sedentary lifestyle and CAD in over-aged women. Rebecca Seguin, PhD, lead author and assistant professor in the division of nutritional sciences at Cornell University, analysed the connection between a sedentary lifestyle and mortality risks of 92,234 postmenopausal women 50 to 79-years-old during 1993 to 1998 in the Women’s Health Initiative Study and found that older women who spend a majority of their day sitting or lying down were at increased risk for cardiovascular disease, coronary heart disease, cancer and death as it was published in the American Journal of Preventive Medicine. Similar observation was found in the mentioned study  by the author. Here sedentary lifestyle was significantly and independently associated with over-aged postmenopausal CAD women (age 54.4 +/- 4.8 years) during multiple logistic regression analysis with odds ratio (OR) 0.281 with p value 0.011.
11. Cigarette smoking: It remains the leading preventable cause of CHD in both men and women. The magnitude of excess risk, a twofold to fourfold elevation, is similar in both women and men . Considering social argument in the mentioned study by the author cigarette smoking related question is avoided by the study questioner.
12. Hysterectomy in premenopausal women: There are not many reports regarding role of hysterectomy as an associated risk factor for CAD in women. Univariate analysis in the study  by the author, “Hysterectomy Enhances the Risk of Coronary Artery Disease in Type 2 Diabetic Women in Premenopausal Age Group” published in the Journal of Medical Science and Clinical Research, showed that hysterectomy was significantly associated with CAD of both premenopausal and postmenopausal groups. Further during multiple logistic regression analysis where independent variables were age, body mass index, duration of diabetes, glycosylated haemoglobin, family history of IHD, history of hypertension, uncontrolled hypertension, albuminuria, hysterectomy, triglyceride, HDL cholesterol, LDL cholesterol, physical activity and diet, hysterectomy was found to be strongly and independently associated only with premenopausal CAD with odds ratio 7.73 and p value 0.016.
The large-scale epidemiological studies have shown that restoration of the premenopausal hormones with hormone replacement therapy (HRT) is associated with 30% to 50% reduction in death from cardiovascular disease [29-31]. However based on the results of the Heart and Oestrogen / Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) study, HRT is not recommended for any women with or without diabetes, as a therapeutic strategy for primary or secondary prevention of CAD [32, 33]. Several trials form the basis for the current American Heart Association / American College of Cardiology (AHA / ACC) recommendation that HRT does not play a role in the primary prevention of CAD; however, for women who presently take oestrogen compounds, there is no benefit to discontinue this therapy . Confounding clinical decisions regarding the initiation of HRT is a recently published study from Heart and Oestrogen / Progestin Replacement study (HERS) in which HRT reduced the incidence of diabetes by 35% .
However, study  observations support the risk enhancement by hysterectomy, but those are insufficient to recommend the use of hormones for prevention of either diabetes or CAD. Results from Women’s Health Initiative (WHI) study regarding the use of oestrogen replacement therapy (ERT) alone in hysterectomized women have not yet been published, and there are no prospective data to guide healthcare providers in advising in favour of or against this therapy . The mechanisms by which diabetes abolishes the cardiovascular protective effects of female sex hormones are not well understood. However, one recently described mechanisms involves the interaction between hyperglycemia and oestradiol in regulation of endothelial cell ‘NO’ (nitric oxide) production; where hyperglycaemia reduces the oestradiol mediated production of ‘NO’ from vascular endothelial cells, which may contribute to the accelerated atherosclerosis in diabetic women [37, 38].
13. Conclusion: Many still believe that CVD is not a real problem for women, though it is estimated that 1 in 2 women will eventually die of heart disease or stroke in America, compared with 1 in 25 death from breast cancer . Two thirds of sudden deaths due to CHD in women in the Framingham Heart Study occurred in those with no previous symptoms of disease compared with about half the sudden deaths in men . Primary prevention is likely to be the only practical solution, as in many cases women approach for treatment either late or never! However, more information from prospective long-term clinical trials targeted to answer the questions regarding the loss of premenopausal protection of CAD in diabetes and the optimal treatment strategies for both premenopausal and postmenopausal diabetic women with CAD will help to guide therapy in the future.
1. Peter J et al. Cardiovascular disease and diabetes. In: John C. Pickup, Gareth Williams (eds): Text book of diabetes 2, 3rd Edn, Blackwell science ltd 2003; 56.1 – 56.24.
2. Anthony L. Komaroff et al. Women’s health. In: Anthony s. Fanci et al (eds): Harrison’s principles of internal medicine, 14th Edn, the McGraw – Hill Companies 1998; 1: 21 – 24.
3. Castelli WP. Cardiovascular disease in women. Am J Obstet Gynaecol 1988; 158: 1553 – 1567.
4. Mosca L et al. Guide to preventive cardiology for women. AHA / ACC Scientific statement consensus panel statement. Circulation 1999; 99: 2480 – 2484.
5. Jane A. Leopold et al. Women and acute coronary syndromes. In: Christopher P. Cannon (eds): Management of acute coronary syndromes; 2nd edn; Totowa NJ, Humana Press 2003: 569 – 602.
6. Lenner DJ et al. Pattern of coronary heart disease morbidity and mortality in the sexes: a 26 year follow up of the Framingham population. Am Heart J 1986; 111: 383 – 390.
7. Chaitman BR et al. Angiographic prevalence of high risk coronary artery disease in patients subsets (CASS). Circulation 1981; 64: 360 – 367.
8. Ghosh B. Hysterectomy Enhances the Risk of Coronary Artery Disease in Type 2 Diabetic Women in Premenopausal Age Group. In: Journal of Medical Science and Clinical Research, an Official Publication of IGM publication e-ISSN NO: 2347-176X; 2014 Nov; vol 2,issue 11:2985-2995.
9. Krolewski AS et al. Magnitude and determinants of coronary artery disease in juvenile – onset, insulin dependent diabetes mellitus. Am J Cardiol 1987; 59: 750 – 755.
10. Bertuzzi M et al. Family history of ischemic heart disease and risk of acute myocardial infarction. Prev Med. 2003 Sep;37(3):183-7
11. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703 – 713.
12. Kannel WS. Hypertension, hypertrophy and the occurrence of cardiovascular disease. Am J Med Sci 1991; 302: 199 –204.
13. Castell WP et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986: 256; 2835 – 2838.
14. Kwiterovick PO Jr. The antiatheogenic role of high density lipoprotein cholesterol. Am J Cardiol 1998; 82: 13s – 21s.
15. Gordon DJ et al. High density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79: 8 – 15.
16. Miller VT. Lipids, lipoproteins, women and cardiovascular disease. Atherosclerosis 1994; 108 (suppl.): S73 – S82.
17. Braunwald E. Cardiovascular disease in women. In: EB, ed. Heart Disease: A Text book of Cardiovascular Medicine. 5th ed. WB Saunders, Philadelphia, 1997; 1704 – 1714.
18. Bass KM et al. Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med 1993; 153: 2209 – 2216.
19. Walsh JM, Grady D. Treatment of hyperlipidemia in women. JAMA 1995; 274: 1152 – 1158.
20. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421–426
21. Sukhija R, Aronow WS, Kakar P, Garza L, Sachdeva R, Sinha A, Mehta JL: Relation of microalbuminuria and coronary artery disease in patients with and without diabetes mellitus. Am J Cardiol 2006;98:279–281
22. Holman RR, Paul SK, et al: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008, 359:1577-1589.
23. Gerstein HC, Miller ME, et al: Action to Control Cardiovascular Risk in Diabetes Study Group: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008, 358:2545-2559.
24. Patel A, MacMahon S, Chalmers J, et al: ADVANCE Collaborative Group: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008, 358:2560-2572.
25. Duckworth W, Abraira C, et al: VADT Investigators: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009, 360:129-139.
26. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EAM, Howard BV, Kirkman MS, Kosiborod M, Reaven P, Sherwin RS, American Diabetes Association, American College of Cardiology Foundation, American Heart Association: Intensive glycaemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009, 32(1):187-192.
27. Lee IM, Shiroma EJ, Lobelo F, et al (July 2012). “Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy”. Lancet 380 (9838): 219–29.
28. Hays JT, Hurt RD, Dale LC. Smoking cessation. In: Manson JE, Ridker PM, Gaziano JM, Hennekens CH, eds. Prevention of Myocardial Infarction. New York, NY: Oxford University Press; 1996:99-129.
29. Ross RK et al. Menopausal estrogen therapy and protection from death from IHD. Lancet 1981; 1: 858 – 860.
30. Beard CM et al. The Rochester Coronary Heart Disease Project: effect of cigarette smoking, hypertension, diabetes and steroidal estrogen use on coronary heart disease among 40 – 59 year old women, 1960 – 1982. Mayo Clin Proc 1989; 64: 1471 – 1480.
31. Bush TL et al. Cardiovascular mortality and non-contraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow up study. Circulation 1987; 75: 1102 – 1109.
32. Hulley S et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post menopausal women. JAMA 1998; 280: 613- 650.
33. Writing Group for the Women’s Health Initiative: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321 – 333.
34. Ryan TJ et al. 1999 update: ACC / AHA guidelines for the management of patients with acute myocardial infarction. A report of the ACC / AHA Task Force on Practice Guidelines (committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999; 34: 890 – 911.
35. Kanaya AM et al. Glycaemic effects of postmenopausal hormonal therapy. The Heart and Estrogen / Progestin Replacement Study: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138: 1 – 9.
36. Glory Koerbel et al. Coronary heart disease in women with diabetes. Diabetes spectrum (Asian edition): vol 3; number 1; 2004: 10 – 16.
37. Bakris GL et al. Analogy between endothelial / mesangial cell and endothelial / vascular smooth muscle cell interactions: role of growth factors and mechanotransduction. In: Sowers JR (eds): Endocrinology of the vasculature; Totowa NJ, Humana press 1996; 341 – 355.
38. Sowers JR et al. Risk factors for arterial disease in diabetes: hypertension. In: Tooke JE (eds): Diabetic Angiopathy; London, UK, Arnold Publisher 1999; 45 – 63.
39. American Heart Association. 1997 Heart and Stroke Facts: Statistical Update. Dallas, Tex: American Heart Association; 1996.
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