Ischemic heart disease remains one of the most leading causes of death and disability worldwide [1]. It is most frequently caused by atheromatous plaque that limits blood flow in the epicardial coronary artery disease (CAD) [2]. Angina is usually the predominant symptom of IHD [2]. IHD is the leading cause of mortality of both men and women accounting for over one third of total deaths [3]. It accounts for 1 out of 3 women death regardless of the race or ethnicity and the annual mortality rate from CAD is high [4]. Ischemic heart disease can be categorized as acute or chronic, it can be due to obstructive and non – obstructive CAD [5]. For many decades, IHD research has focused primarily on men, thus leading to underappreciation of sex difference from etiologic, diagnostic, and therapeutic perspective [6]. The worldwide INTERHEART Study, a large cohort study of more than 52000 individuals with myocardial infarction (MI), have revealed that women have their first presentation of CAD approximately 10 years later than men, most commonly after menopause [7]. Despite this delay in onset, mortality is increasing more rapidly amongst women than men [8]. Women have worse prognosis than men after MI, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Women are more likely than men to die after a first MI, and for survivors, there is higher risk of recurrent MI, heart failure (HF) or death [8]. In Framingham heart study, the one-year mortality following MI was 44% in women vs. 27% in men [9].The overall short term and long-term CAD mortality following MI are about 40% higher in women after adjustment for age and other risk factors [9] Despite their excess risk, women are only half as likely as men to receive aspirin, beta-blockers, or thrombolytic therapy or to be referred for revascularization procedure [9]. In general, woman’s blood vessels are smaller and narrower than men. The muscular walls of a woman’s heart are also thinner [10]. Women undergo hormonal changes throughout their lifespan starting from menarche to menopause and including pregnancy, many of these biological changes may affect the vulnerability of women for IHD [11].Before menopause, estrogen increases high density lipoprotein (HDL) and modifies coronary vasodilation through endothelial nitric oxide synthase activation [12] while progesterone has cardio-depressive effect by modulation of calcium handlining and after menopause, drop in estrogen level leading to raising in CAD risk [13].  Biological variances among women and men are called sex differences in the cardiovascular system are as a result of differences in gene expression from the sex -chromosomes, which may be further modified by sex differences in hormones, resulting in sex unique gene expression and function ^[14]. There is a trend suggests that environmental or behavioral causes of sex differences in outcomes may be more important than biological ones ^[15]. The effects of aging, dyslipidemia, diabetes Mellitus (DM), hypertension (HT) and cigarette smoking, among other risk factors, promote the sequelae of endothelial dysfunction, inflammation, and atheromatous plaque deposition in women, as well as men [16]. The five risk factors mentioned above are all well- known traditional risk factors and their correlation to pathophysiology of CAD has been well documented [16]. Several novel risk markers have been identified over the past 10 years, which include new forms of lipid particles, metabolites, hemostatic factors, and inflammatory markers. [16]. Women are about 10 years older than men at first manifestation of CAD [17]. Women lose this 10-year advantage if they smoke, have diabetes, or had premature menopause. Prevalence of CAD is higher in men prior to forth decade of life. During sixth decade it equalizes and subsequently it becomes greater in women [17].  Postmenopausal increase in the risk of CAD is related to a higher incidence of HT, DM, dyslipidemia & obesity[18] .Family history of CAD in a sister is associated with 12-fold higher risk vs. 6-fold for a brother & 3-fold for a parent[19]. Asian Indian women are at increased risk for development of CAD[20] . Hypertension confers a 4-fold higher risk of CAD in women vs. 3-fold in men [21]. Women have 15 % higher prevalence of HT than in men, women with HT are more under treatment & have poor control than men[22] . Diabetes is a stronger risk factor for CAD in women than in men [23]. Many studies observed a rise in triglyceride & low density lipoprotein cholesterol with menopause[24] .Obesity is associated with increased risk of HT, DM, dyslipidemia, and CAD. Body mass index (BMI) is now accepted as the single best measure of obesity [25]. In the 16- years data from the Nurses’ Health Study, CAD mortality was 4-fold lower in lean (BMI < 21) than in obese women [26]. Due to its anti-estrogenic effects, smoking quadruples the risk of MI in young premenopausal women. It is a strong risk factor in women than in men. The risk of CAD begins to decline within months of cessation of smoking and disappears within 3–5 years [27]. CAD has now become a disease of the poor in rich countries and of the rich in poor counties. Women with a less than a high school education have a 30– 50% higher CAD mortality than those with higher education. Depression, high hostility, low social support, and low education level are associated with CAD. Depression, which is twice as common among women relative to men, is a relatively consistent predictor of both incident and recurrent IHD among women and it was a risk factor for progression of coronary calcification in midlife women. Stress is associated with increased risk of IHD incident, MI, and mortality following a cardiac event by increasing platelets aggregation, inflammation, and autonomic nervous system dysregulation [28-31]. IHD accounts for <2% of CVD in pregnancy. ACS is 3 to 4 times more likely to affect women during pregnancy than similarly aged, non-pregnant women [32]. ACS can affect women at any stage during their pregnancy, though it is most common in the late third trimester and early post-partum period [32-36]. Angina is the most frequent initial and subsequent manifestation of IHD in women. Women have a more diverse symptom presentation than men, with prominent anginal equivalents, symptoms are more often precipitated by emotional or mental stress. Compared with men, women tend to have symptoms more often when resting, or even when asleep [37,38]. Women are more likely than men to have non-obstructive CAD^, which includes coronary microvascular dysfunction (CMD), vasomotor abnormalities, myocardial bridge, spontaneous coronary artery dissection (SCAD), stress cardiomyopathy [39], plaque erosion and subsequent thrombosis [40]. Even in patients with normal coronary angiography, intravascular ultrasound (IVUS) confirms the presence of atherosclerosis in the vast majority [41]. CMD can be investigated by coronary reactivity test and functional assessment of coronary flow reverse (CFR) [42] (either invasive by angiography or non – invasive by cardiac magnet resonance (CMR), coronary computed tomography angiogram (CCTA), and positron emission tomography (PET) scan) [43]. Diminished CFR <1.9 indicate vascular abnormality and CMD [44]. CMD can be further evaluated by thorough investigation of coronary artery response to vasoactive substance including adenosine and acetylcholine to determine if there is endothelial – dependent dysfunction (decreased coronary flow with intracoronary acetylcholine) or endothelial independent dysfunction (decreased coronary flow with adenosine) [45-47].The aim of the study was to determine the clinical profile of IHD in women and their risk factors, coronary angiographic profile, and short-term outcomes.

This study is a subgroup analysis of patients included in prospective multicenter hospital-based registry of cardiovascular disease (CVD) in women (the registry in its pilot phase and is the first study that focusing the light on IHD, HF, arrythmias and valvular heart diseases in Iraqi female patients). The target population of this study was female patient aged 18 years or older admitted for diagnosis of ACS or who suspected to have CCS and referred for elective coronary angiography in the following hospitals: Ibn Al-bitar Cardiac Center, Iraqi Center for Heart Diseases, Baghdad Heart Center, Al-Basrah Cardiac Hospital and Azadi Heart center (Duhok) Excluded criteria was patient declination to participate in the study. The study was conducted during the period from 1^st of January 2022 to the 1^st of January 2023. The data was collected by a well-structured questionnaire and entered through a google form. Collected data include:

Part 1: Demographic questions.

Part 2: History and clinical examinations {including BMI; dividing the weight(kg) by the square height (meter)}

Part 3: In hospital investigations (Renal function test, cardiac enzymes, lipid profile, complete blood count (CBC), electrocardiogram (ECG), treadmill exercise ECG, Echocardiographic study, CCTA and coronary angiography).

Part 4: In hospital treatments (including conservative medical therapy and interventional therapy)

Part 5: Follow up 1 month outcome by telephone conversations asking about their compliance to medications and healthy lifestyle, or if they developed any complications following discharge to home or any rehospitalization for any new cardiac event or intervention.

The collated data was introduced into Microsoft excel 2016 and after purification, the data loaded into SPSS version 26 statistical program. Tables and graphics were used to display descriptive statistics. The chi-square test was used to find out the significance of association between related categorical variables. P value less than 0.05 was considered as a discrimination point of significancy .

This prospective study included 123 hospitalized patients, 91 (74%) were elective admissions and 32 (26%) were emergency admissions. The mean age of studied patients was 60 ± 9.8 years. Table 1: - displayed that 48 (87.3%) of patients aged more than 60 years had IHD, which was significantly higher than that of aged 40-60 year 47 (81%), and <40 year 4 (40%). P value = 0.002. A significant association was noticed between primary education level and getting IHD 84(85.7%) in comparison with secondary 12(57.1%) and university level of education 3(75%). P value = 0.011. No significant associations were noticed between social status, job, income of patient and rate of IHD. P Value > 0,05 in all conditions.

Table 1: Distribution of demographic and social variables according to IHD

Table 2: - showed that the rate of IHD among diabetic patients was significantly higher than that of non-diabetic 74(88.1%) vs 25(64.1%). P value = 0.002., Patients who had menopause had a higher rate of IHD 88 (84.6%) in comparison with those who were not 11 (57.9%). P value= 0.007. Patients with family history of IHD had a higher rate of IHD 48(90.6%) in comparison with those who are not 51(72.9%). P value = 0.014. The rate of IHD among patients with hyperlipidemia 58(87.9%) was significantly higher than that of non- hyperlipidemia patients 41(71.9%). P value = 0.026. Smokers had a higher rate of IHD (100%) than non-smokers (77.9%). No significant associations were noticed between hypertension, gestational diabetes, recent stress, COVID19 and getting IHD. P value>0.05% in all conditions.

Table 2:  Distribution of clinical characteristics according to IHD

Table 3: - displayed that regional wall motion abnormality (RWMA) was found in 39(45%) of patients with IHD. (NB: echocardiography was done for 111 patients)

Table 3: Distribution of studied patients according to echocardiographic variables

Figure 1: - showed that [20] 23 % of patients who were diagnosed with IHD had HF with reduced EF.

Figure 1: Percentage of patients with IHD who had HF with reduced EF.

Table 4: - showed that 26(21.13%) of patients didn’t underwent any procedure, coronary catheterization done in 97(78.86%) in whom 80(82.5%) were underwent diagnostic coronary angiography, 17(17.5%) PCI (from which 23.5% was primary PCI) and 2(1.6%) were underwent CABG. (NB: same patient may undergo diagnostic coronary angiography and PCI or CABG)

Table 4: Procedures during hospitalization

Figure 2: - showed that from total number of cases who undergone coronary catheterization, [24]25 % revealed normal coronaries.

Figure 2: percentage of normal coronaries from total coronary catheterization 

Table 5: - showed that right coronary artery (RCA) 9 (41%) and left anterior descending artery (LAD) 8(36.5%) were the most common coronary arteries that were revascularized, followed by Left circumflex artery (LCX) 2(9%), left main coronary artery (LMCA)2(9%), and the least revascularized one was ramus intermedius 1(4.5%). (NB: more than one vessel may be revascularized for the same patient)

Table 5: Distribution of PCI according to the target vessels revascularization

Figure 3: - showed that coronary interventions were not performed for 26 (81%) of patients with ACS.

Figure 3:distribution of patients with ACS according to coronary interventions

Table 6: - showed that 67(54.5%) of patients had CCS, 32 (26%) had ACS, and 24 (19.5%) of patients had normal coronary arteries.

Table 6: Distribution of patients according to final diagnosis

Figure 4: - showed that from total ACS cases,  unstable angina (UA) was 12 (37 %), non-ST elevation myocardial infarction (NSTIMI) was 12 (37 %) and ST elevation myocardial infarction ( STEMI) was 8 (26%).

Figure 4:  Distribution of patients according to pattern of ACS

Figure 5: - revealed that 101(82%) of patients did not develop any complication during hospitalization, 22(18%) developed HF, 8(6.5%)  developed cardiogenic shock, 4(3.3%) developed arrhythmias and 4(3.3%) died.

Figure 5: complications during hospitalization

Table 7: - showed that after one month follow up, in 80(85%) of patients no complications appeared, while 12(12.8%) patients needed hospitalization for new cardiac events (including MI, HF exacerbation, arrythmia, shock and coronary intervention), and only 2 (2.1%) of patients were died.(NB: only 94 patients were achievable)

Table 7: one-month outcome (N=94 patients)

Figure 6: - showed that the total number of patient mortality in the current study was 6 (5%) patients, among them 4(67%) died during index hospitalization and 2(33%) died during one month follow up period.

Figure 6: Distribution of death according to timeline

Figure 7: - showed that 6(19 %) of patients with ACS were died. 

Figure 7: Percentage of death among patients 

This is the first multicenter hospital-based registry focused on the pattern of IHD among women in Iraq. It shown that the major risk factors contributing to the development of IHD in women were old age, DM, menopause, family history of IHD, low education level, hyperlipemia and smoking. It’s known that women with menopause are at increased risk of IHD due to hormonal changes leading to a higher incidence of hypertension, diabetes, dyslipidemia, and obesity. [18] The current study showed a significant association between the age of more than 60 years old and the development of IHD, and this finding agrees with the results of LA Pathak et al study in which the most prevalent age group for IHD was (60-80) years [27]. Diabetes was also significantly associated with IHD, and this result is consistent with that of Mohammed MA et al study [48], and LA Pathak et al study [27], which showed association between IHD development and HT, DM, and hyperlipidemia. Moreover, in our study IHD was more common in patients with family history of IHD, and this is similar to the results of Abdul Rashid N. et al study which also found significant association between IHD and family history of IHD [49]. In addition , this study revealed a significant relationship between IHD & level of education of the participants which is highest in primary level of education , a comparative study of the relationship between unemployment & self-reported health in 23 European countries also resulted in a potential association of increased CAD burden with low level of education [50]. Another major risk factor in our study was hyperlipidemia, similarly Mohammed AM et al study found that dyslipidemia is one of the most prevalent risk factors for IHD [48]. We found that IHD is higher in smoker patients. Muhammed AM et al study also reported that smoker is a risk factor for IHD [48].  Although it is well known that HT is a risk factor for IHD, surprisingly our study did not report such a significant association in women, and this is probably related to the small sample size and being a pilot study. In contrast to LA Pathak et al study and Muhammed AM et al, both studies showed positive correlation between IHD and HT [27,48]. Also, the current study found that there was no significant association between IHD and gestational diabetes, this result was differed from the study of Naderi S et al and American College of Obstetricians and Gynecologists Presidential Task Force which showed that gestational diabetes and hypertensive disorder of pregnancy, have been associated with increased risk of IHD and cardiovascular mortality [51-52],the differences in the results may also be related to the small sample size. Additionally, there was no association between IHD and recent stress, this result is against the result of Low CA et al meta-analysis study [53], which documented a significant association between psychological factors and the development of IHD for women. The discrepancy between the results may be explained by the study population in Low CA et al study which included patients with both acute and chronic history of psychological disorders and risk factors .  Regarding the relationship between IHD and use of oral contraceptive pills, only two patients were used contraceptive pills, therefore, statistical analysis cannot be conclusive. Results of an international, multicenter, case-control study of WHO showed that contraceptive usage in healthy women, does not represent a major risk factor for IHD in the absence of other risk factor ^[54]. The present study showed that about one-quarter of patients who diagnosed with IHD had HF with reduced EF% and this is somewhat consistent with the result of LA Pathak et al study [27], who showed that (32%) of echocardiographic findings of women with IHD had decreased EF. Our study also revealed that RWMA was found in about one-half of the patients with IHD. Among other findings of the current study, coronary catheterizations were done in three-quarters of patients, from those two-thirds were diagnostic coronary angiography and less than one-fifth were PCI (from which less than one-quarter were primary PCI), while only 1.6% underwent CABG. It also showed that about one-fifth of patients with ACS underwent coronary angiography, two-third of the later patients underwent PCI, unlike Sarma et al study, in which two-thirds of the patients with ACS underwent coronary angiography and one-half of the patients underwent PCI [55]. Moreover, about one-quarter of cases who underwent coronary catheterization had normal coronaries, which is consistent with results of Lee BK et al study [56] that found among patients with angina, more than 20 % have no angiographic evidence of IHD. Mohammad AM et al study [48] also revealed that angiographic analysis showed a normal angiogram in 29.3%. Other finding in the current study reported RCA and LAD as the most common coronary artery that was revascularized followed by LCX, LMCA, and the least revascularized one was ramus intermedius. These results were similar to that of Entezarjou et al study, which observed that women patients had higher RCA involvement [57], while Mohammed AM et al study showed LAD involvement constituted the highest percentage in both men and women and was followed by very close percentage for RCA and LCX [48]. Our study showed that among patients who admitted with IHD was mainly diagnosed with CCS, while STEMI diagnosis was the least. Ahmed F. et al study showed the opposite finding, and this may be related to the period of our data collection in which the number of patients with CCS was more than patients with ACS[58] . During hospitalization, we found that about one-fifth of the total patients developed HF with reduced EF and very small number of patients developed serious complication including arrhythmia, cardiogenic shock, and death. Regarding the outcomes after one month follow up, less than one-fifth of patients needed re-hospitalization for new cardiac events, and few numbers of patients were died. In Sawano et al. study, similar results were found, in which one-month rehospitalization related to cardiac events and mortality were less than 5% and less 1%, respectively [59]. In Manzi et al study, also cardiovascular mortality was 4.1% [60]. Finally, the current study reported the total number of deaths was six (5%) patients, all of them were diagnosed as ACS, among them two-thirds died during initial hospitalization and one-third at one month follow up period. 

Main obstacles and limitations of our study:

1-Small sample size and short follow-up time due to time and logistic constraint, however it is an ongoing study. 2-It is conducted in tertiary centers. 3-Lacking advanced facilities to detect IHD in those with normal coronary angiography.

This study showed that the most significant contributing factors for development of IHD in women were old age, diabetes, menopause, and family history of IHD. About one-quarter of patients who were diagnosed with IHD had developed HF with reduced EF, moreover, about one-quarter of patients who underwent coronary catheterization had normal coronaries, the most common revascularized coronary artery was RCA and LAD, and among patients with ACS, coronary catheterizations were done in about one-fifth of them. Two-thirds of total mortality occurred during index hospitalization while one-third occurred throughout one month follow up period.

RECOMMENDATIONS:

There is a knowledge gap in prevention and treatment of IHD in women, so future research needs to be more directed toward risk factors which are specific or more common in women. Future larger studies with longer follow up duration and studies that involve comparison with male patients are needed in Iraq to identify the underlying causes of IHD rather than obstructive CAD, using advanced investigational modalities including non-invasive (CMR, CCTA and PET) and invasive (IVUS, Functional assessment and coronary reactivity test) investigations.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the University of Baghdad, Baghdad Heart Center.