The Gamut of Coronary Artery Disease in Indian Women

INTRODUCTION

In the present scenario, coronary artery disease (CAD) is the leading cause of death among women. It is the cause of death for one in three women every year, killing approximately one woman every minute. Majority of women (90%) suffering from CAD have one or more risk factors for CAD in their parents.^[1] Coronary heart disease (CHD) continues to be prime killer and crippler in India – this was commented way back in 1995 in a chapter titled^[2] “Coronary Artery Disease in Indian Women Change the Gender Bias” by me. The incidence of CAD in India increased from 1.05% in 1960 to 9.67% in 1995. The greatest rise was seen in men below 40 years and women below 50 years.^[3] Mortality from CAD was also high in Indian men and women (36% and 46% higher, respectively) compared to general population in England. The incidence of CAD according to the WHO will be doubled by the year 2020 thus making CAD as the leading cause of death among men and women.

Sadly, the prediction of 1995 has already come true in 2021. The article titled “Gender differences in South Indians with premature CAD (<40 years) – Insights from the PCAD registry” states – “Nearly one-third of all fatalities are caused by CAD, which is also the major cause of morbidity and mortality in both sexes.”^[4] It accounts for higher death rate in women, regardless of their race or ethnicity.^[5] CAD being an epidemic today among Indians is nearly doubling in the incidence compared to the Americans and several fold higher than other Asians.^[6] Indian ethnicity is now considered a risk factor by itself.^[7] According to statistics, there has been a rise in proportionate cardiovascular disease (CVD) mortality, with 20.6%, 21.4%, 24.3%, 27.5%, 29.0% of deaths occurring in 1990, 1995, 2000, 2005, and 2013, respectively.^[8] According to the Registrar General of India, CAD accounted for 26.9% of all medically certified fatalities in 2015 and, circulatory system disorders representing one-third of these deaths.^[9] In India, the average age of the first myocardial infarction (MI) has dropped by 20 years. Half of all MI occur in people under the age of 50 and 25% under the 40 years of age. It has been determined that age-standardized values for the number of disability-adjusted life years lost as a result of CAD per 1000 people in India are triple times higher than in industrialized countries.

Indians have “Malignant CAD” – severe and extensive coronary atherosclerosis affecting young individuals (≤45 years in men and ≤50 years in women) with very low burden of established risk factors. It is important to analyze gender differences in risk factors, clinical presentation, and angiographic profile in Indian youth from the on-going premature CAD registry which is very important. Hence, awareness of the whole gamut of CHD is of paramount importance to prevent CHD in Indian women.

FRAMINGHAM HEART STUDY: TRUTH AND MYTH

The concepts and fundamentals that women are less affected by CAD came from landmark Framingham Heart Study (FHS).^[10] The study began in 1948 with 5209 adult subjects from Framingham and is now on its third generation of participants. The pathophysiology of cardiac disease occurs from the results of FHS studies. The risk of traditional risk factors such as hypertension, diabetes mellitus, and tobacco consumption is similar for both sexes. Menopause was found to increase the risk of CAD in women and psychosocial factors found to affect women. This misleads physicians that younger women are immune to CAD due to hormonal protection and chest pain in women is largely due to psychological stress. This is the root cause for major gender bias in CAD. Prognosis of Framingham women with angina was more favorable than that of men. While 75% of the men with angina developed acute MI within 5 years, only half of women with angina developed infarction in Framingham study, which made things even worse and created gender bias.

EPIDEMIOLOGY AND PREVALENCE OF CAD AMONG INDIAN WOMEN

Epidemiologic and clinical research shows important gender differences in the prevalence, presentation, risk factors, management, and outcomes of CAD patients. Indian adults’ prevalence of CAD grew from 1960 to 1995 from 2% to 4% and 3% to 10% in rural and urban Indians, respectively, with rates comparable to men.^[11] In a rural community in central India, the prevalence of CAD in those over 60 years old was 51.3/1000, with nearly equal sex distribution, and hypertension was shown to be the only risk factor.^[11] CAD incidence was higher in women and more deaths are seen due to heart disease than breast cancer. Heart disease in women accounts to more than 40% of all deaths. Since 1984, more women than men have died every year from CAD.^[12] Higher mortality and worse prognosis are seen in women after acute cardiovascular events be it CHD, stroke, heart failure, or aortic diseases. Sex-specific differences in pathophysiology, prevalence, and impact of CVD risk factors may explain the high cardiovascular mortality rates in women. As CAD is a leading cause of death in post-menopausal women than all cancers combined,^[13] very few studies in India have addressed the problems of CAD among Indian women.

GENDER DIFFERENCES AND BIAS

At first presentation, women with CAD are older than men and have more cardiovascular risk factors.^[14,15] CAD remained the leading cause of death for women over the age of 65 despite developing 7–10 years later in women than in men. According to statistics from the National Health and Nutrition Examination Survey, midlife women (aged 35–54) have a higher prevalence of MI than older males over the past two decades.^[16] According to the European Heart Survey report on stable angina pectoris, much less women are referred for functional testing for ischemia and less likely to undergo diagnostic angiograms and interventional procedures as compared with men^[2] due to the different clinical presentation in women. Under-recognition of heart disease also leads to less aggressive therapeutic approaches and a smaller proportion of female participants in clinical trials.

DIFFERENCES IN PATHOPHYSIOLOGY

MI with non-obstructive coronary arteries reported between 5.9% and 11% is much more common presentation in women, especially younger and non-white patients.^[17,18] Angiographically normal coronaries in a young women presenting with acute coronary artery syndrome (ACS) are attributed to coronary microvascular dysfunction by aberrant inflammatory responses, low endogenous estrogen levels, coagulation disorders, and endothelial reactivity.^[19] Increased pain perception in women could probably explain the abnormal atypical persistent cardiac pain in them.^[20] Epicardial atherosclerosis and microvascular dysfunction relationship is still unclear.

Estrogens have a regulating effect on coagulant system, lipids, and the inflammatory markers. They have a direct vasodilatory effect on the vessel wall.^[21] Women can exhibit subclinical atherosclerosis signs as shown by intima-media thickness measurements even before menopause, particularly in the presence of coronary risk factors.^[22] Flow-mediated vaso-reactivity decreases with progression of time following menopause. Atherosclerotic plaque composition evolves into more vulnerable lesions with menopause.

Do women have a specific Genetic code? Women’s MI has been linked to stromelysin-1, a member of the matrix metalloproteinase family of enzymes implicated in plaque rupture and plasminogen activator inhibitor-1.^[23] Recent research has identified due to MEF2A’s high expression in the endothelium and its role in the development of CAD and MI, it hypothesizes endothelial dysfunction as an early trigger for MI and CAD. The available genome-wide association studies do not show any sex bias.

RISK FACTORS

The so called traditional risk factors (tobacco use, unhealthy diet, obesity, physical inactivity, hypertension, diabetes, hyperlipidemia, and harmful use of alcohol) have been identified as cause of CAD and stroke in both genders.

DIABETES MELLITUS

According to the National Cholesterol Education Program Adult Treatment Panel III, diabetes is an analogous CAD risk factor.^[31] Compared to men, it is a substantially bigger risk factor for CAD in women. Women with diabetes experience CAD twice as frequently as those without. It is associated with three- to seven-fold higher incidence of CAD and two- to three-fold higher risk of death rate in men. Women who have diabetes are more likely to have heart failure (eight-fold vs. four-fold) compared to men. Diabetes eliminates the protective effects of estrogens and predisposes to premature CAD.^[32]

DYSLIPIDEMIA

Compared to premenopausal women, postmenopausal women have worse lipid profiles. When compared to premenopausal women of the same age, menopausal women had levels of total cholesterol (TC) and low-density lipoprotein (LDL) that were 0.2–0.4 and 0.1–0.3 mmoL/l higher, respectively, according to a cross-sectional research of 63,466 women, aged 18–65. Postmenopausal women had smaller LDL particle size. There was no significant change in VLDL or high-density lipoprotein (HDL) concentrations. Thus, both chronological aging and menopause predispose to dyslipidemia. A lifetime risk of developing CAD is increased by 50–60% with a 20% increase in TC level.^[33]

Low HDL is a potent predictor of CADI women after onset of 65 years. Indian women have very low levels of HDL than other ethnic groups which parallel their high rates of CAD.^[34] In the CADI study,^[35] 70% of Indian women had HDL level <50 mg/dL. HDL-c level <35 mg/dL confers an eight-fold higher CAD risk.^[36]

• TC/HDL ratio more than 5 is the single best predictor of CAD in both men and women and is seen in 25% of industrial and 32% of urban Indian women^[37]

• Compared to men, women have a higher propensity for CAD when their TG levels are high. In addition, a TG level increase of 90 mg/dL increases the risk of CAD in women by 75% as opposed to 30% in males.^[38]

Due to their low HDL, and high TG, and small dense LDL levels, Indian men and women are hence more vulnerable to CAD.^[39]

NOVEL RISK FACTORS

Depression and other psychosocial factors

Majority of women have psychological stress, due to rapid urbanization and nuclear families, the incidence has increased in both working women and housewives. Stress-induced release of catecholamine causes acceleration of heart rate, blood pressure, vasoconstriction, leading to demand-supply mismatch which contributes to ischemia. Depression and panic disorders^[42,43] in women with CAD have adverse effects in terms of morbidity and mortality. Timely, recognition and treatment of mental stress can avoid CAD and its poor outcomes. Although chest pain and tachycardia can be features of depression and anxiety in women, physicians should access these symptoms and not diagnose this as a psychogenic origin without thorough investigations [Figure 1].

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Figure 1:

Pathophysiologic mechanisms of MINOCA and INOCA.

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AUTOIMMUNE DISEASES

Autoimmune diseases such as rheumatoid arthritis and SLE are more common in women predisposing to increased cardiovascular morbidity and mortality due to accelerated atherosclerosis seen in young women.

RISK FACTORS UNIQUE TO WOMEN

Some risk factors are specific to women – (1). Primary ovarian insufficiency, (2). pregnancy-induced hypertension, (3). pre-eclampsia, (4). gestational diabetes mellitus, (5). preterm birth, and (6). polycystic ovary syndrome and menopause.^[44]

CAD IN PREGNANCY

Ischemic heart disease in pregnancy is rare, 2.8 and 6.2/100,000 deliveries. Incidence is on a rise due to advanced maternal age with its associated medical comorbidities. Pregnancy itself seems to be a risk factor for AMI, although the exact mechanisms are not clear. AMI in pregnancy should be investigated in the same manner as in the non-pregnant population. Maternal morbidity following AMI is high due to increased rates of heart failure, arrhythmia, and cardiogenic shock during pregnancy.^[4]

SPONTANEOUS CORONARY ARTERY DISSECTION (SCAD)

SCAD is a rare cause of ACS (0.1–4%) and sudden cardiac death (0.4%) and is seen in 0.2–1.1% of coronary angiograms in the general population.^[46] SCAD is the most common non-atherosclerotic cause of CAD in young women, accounting for 24% of MI, according to Douglas PS et al.,^[48] who analyzed coronary angiograms of women under 50 from 2009 to 2011.^[48]

CLINICAL PRESENTATION AND NON-INVASIVE TESTING

Women are less reliable than men when it comes to the clinical manifestation of CAD and non-invasive diagnostic testing, particularly in the age range under 55 when the prevalence of CAD is still low.^[48-50]

Women have chest pain syndromes more frequently than males do, and they are less often linked to atherosclerosis in the large epicardial coronary arteries.^[51] These women have a 4 times higher chance of re-hospitalization and repeat angiograms during the next 180 days, as well as a two-fold increased risk of cardiac event over the course of 5–7 years. A defined clinical event like MI is less common in women. Apart from chest pain, women have symptoms such as nausea, sweating, vomiting, pain in the neck, jaw, throat, abdomen, or back more than men. The classification of typical angina would miss 65% of women with CAD (according to WISE) study and is labeled as non-ischemic chest pain. Furthermore, several causes of non-cardiac chest pain can mimic the discomfort that is related with MI. The implication is that traditional diagnostic methods are not optimal for women and assessment and diagnosis should be based on the importance of risk factor profile at presentation [ Chart 1].

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Chart 1

The mechanism of ischemia occurring due to stress.

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ELECTROCARDIOGRAPHY

While women exhibit tachycardia at rest and a longer QT interval, there are no gender-specific criteria for ECG interpretation.

An ECG showing a 15–20 leftward axis deviation during pregnancy indicates that the heart rotates to the left. Shifts that are frequently observed include transient ST/T wave changes, attenuated Q waves in lead aVF, Q waves and inverted T waves in lead III, and inverted T waves in V1, V2, and infrequently V3. These could resemble structural cardiac problems such as LV hypertrophy.

EXERCISE TESTING

Non-specific ECG changes at rest, lower exercise capacity, and smaller vessel size contribute to the lower sensitivity and specificity of non-invasive testing in women.^[49] It has been observed that endogenous estrogen might cause ECG abnormalities in young women that mimic ischemia. For treadmill exercise assessment, normograms specifically for women have been developed. A limited capacity for exercise in both symptomatic and asymptomatic women is a reliable indicator of 5-year mortality. By evaluating the angina history, estrogen status, and presence of the main CHD risk factors, accuracy in the diagnostic capability of exercise testing in women can be further improved.^[52]

HOLTER MONITORING

Holter monitoring is a reliable indicator of arrhythmias and should be used in individuals who have a history of palpitations or VT, AF, or paroxysmal or persistent arrhythmias.

CORONARY ANGIOGRAM

Men typically have a plaque in major epicardial vessels, but the plaque in women more commonly is in the smallest blood vessels, known as the microvasculature. ACS with angiographically “normal” coronaries is more common in young women than men (41 vs. 8% in CASS study). This coronary microvascular dysfunction is assumed to be related to endothelial reactivity, low endogenous estrogen levels, coagulation disorders, and abnormal inflammation.^[53] In addition, abnormal cardiac nociception attributes to persistent chest pain in women. Thus, the symptoms of microvascular dysfunction result in objective signs of ischemia, which is addressed as micro vascular angina pectoris. It is yet unclear how epicardial atherosclerosis and microvascular dysfunction are related. This syndrome has a less favorable prognosis and frequently requires hospital stays and coronary angiograms.^[54,55] The prognosis is worse in women and these should be treated aggressively to prevent future CHD events as a priority.

ACUTE CORONARY SYNDROMES IN WOMEN

The symptoms of chest pain in ST-elevation MI (STEMI) are similar in men and women, but women tend to have more concurrent vaso-vegetative symptoms, which might obscure the symptoms of chest pain, and less significant ST-T elevations at admission, particularly in younger patients.^[56,57] Unstable angina pectoris and non-STEMI are frequently misdiagnosed in women under the age of 55 at the emergency department.^[57] Women with ACS tend to be older and have more risk factors clustered together, which may increase their mortality risk.^[58] It is commonly recognized that women have more diffuse and less extensive obstructive CAD than men, and that their event rates are also greater. In both genders, altogether management is the same.

A major area of concern is STEMI during pregnancy. Management relies on PCI. Thrombolysis can be a last resort, as recombinant tissue plasminogen activator is advised in non-pregnant individuals, because it does not cross the placenta but may result in bleeding complications (sub-placental bleeding). Catheterization procedures during pregnancy must follow the “as low as reasonably achievable” principle to minimize radiation exposure. Maneuvers that should be implemented are: (i) echo guidance whenever feasible; (ii) Anteroposterior projections; (iii) minimize fluoroscopy time; (iv) avoid direct radiation of the abdominal region; (v) source of radiation as far as possible from patient; (vi) collimate as tightly as possible to the area of interest; (vii) low-dose fluoroscopy; and (viii) utilize an experienced cardiologist.^[53] The radiation exposure to the fetus can be somewhat reduced by abdominal shielding, but the presence of lead in the primary beam’s field may have the opposite effect by increasing scattered radiation. However, shielding should not interfere with an optimal intervention. Assessing potential impacts on the fetus in the future is made easier by tracking and recording radiation exposure.^[54]

MORTALITY RATES IN WOMEN

Data from the FHS showed that CVD mortality has declined among women with diabetes; however, overall mortality has not declined. Thus diabetes is a greater risk factor for CVD mortality in women.^[59-61] Mortality after CABG is higher in women especially in the young, after adjustment for risk factors.^[62] Associated comorbidities, smaller vessels, need of urgent procedures in women, and the presence of hypertensive heart disease contribute to this. Bleeding complications are higher after PCI in women, especially when glycoprotein IIb/IIIa inhibitors are used.^[63] In a meta-analysis of 11 randomized ACS trials, no differences were found in the efficacy and safety of clopidogrel between men and women.^[64] Sex-based differences in 30-day mortality in ACS are based on atypical clinical presentation and the severity of angiographically documented disease.

LIFESTYLE MODIFICATION

The present hour requires preventive strategies to combat this epidemic. Education, self-awareness in women, and timely recognition of CAD in women with lifestyle modifications and timely intervention result in better outcomes.

CONCLUSION

CAD in India is like an epidemic which is escalating. Women are at higher risk for cardiac events with respect to traditional risk factors including dyslipidemia, hypertension, diabetes, and smoking. Menopause, pregnancy complications, inflammation, anemia, migraines, and depression are important sex-specific novel risk factors for CVD, and it is important that clinicians should be aware of these risks to design strategies for prevention. Pregnancy offers a unique opportunity and window to screen otherwise healthy women who are at an increased risk of CVD in the future. Indian women have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD, yet lag timely intervention. There is dire need to promote primordial, primary, and secondary prevention strategies. Primordial strategies such as promotion of healthy dietary habits, physical activity, and smoking/tobacco cessation should prevent risk factors from occurring in the first place. To reduce the risk of overt CHD, primary prevention focuses on screening and better risk factor management. Morbidity can be avoided through effective secondary prevention and better acute and chronic event management. Excellent quality secondary and tertiary care will reduce morbidity and mortality as women are the strongest roots of a healthy society. Multicentric trials dedicated to women are the need of hour to prevent the disease.