Long-term results of coronary artery bypass grafting in women under 45 years of age

Introduction

Early prophylaxis, proper diagnostics and effective treatment concordant with the latest guidelines contributed to the current reduction in cardiovascular mortality rate. Although ischemic heart disease (IHD) is more prevalent in men, especially in middle-aged ones, cardiovascular diseases cause higher mortality among women than in men. Even doctors do not always notice a problem of IHD in women as clearly as they do in men and clinical trials also consider a proportionally lower number of women than men or they are based only on a male population [1]. Prevalence of IHD in pre-menopausal women is relatively low. Each year in the USA, acute myocardial infarct (AMI) is diagnosed in approximately 123 000 men and in 3 000 women less than 45 years of age [2]. It is probably caused by a protective action of female hormones on the cardiovascular system. Due to low prevalence of IHD in young women, the rate of coronary artery bypass grafting (CABG) performed in that population is low and it is followed by a small number of publications on this issue. The issue of whether the female gender itself should be treated as an independent predictor of higher operative mortality (both early and long-term one) after CABG is not ultimately resolved. However, female gender as one of the factors included in multivariate analysis is associated with statistically higher operative mortality [3]. There is no doubt that the age of the patient is a factor strongly correlated with the intensity of atheromatous lesions in coronary arteries. According to the Framingham Study [4], in the third decade of life the morbidity rate of IHD for the male gender is about seven to one in comparison with the female gender. It decreases progressively with age and reaches equality in the seventh decade of life.

Material and methods

From 1990 to 1999, 58 women aged 27 to 45 (mean 41.5 ±3.5) years were discharged from our hospital after CABG. The duration of ailments from the first episode of angina pectoris to CABG was 26 months ±26. The follow-up averaged 17.5 years ±2.5. The survival curve and free of cardiac events curve (PCI, hospitalization because of angina) were constructed.

All procedures were performed on a cardiopulmonary bypass with cold crystalloid cardioplegic solution for protecting the heart. The mean rate of grafts per patient was 2.6 ±1.1 and revascularization completeness was 91.4% (53 patients). The left internal mammary artery (LIMA) was used in 56 (96.5%) cases.

CCS and NYHA class and professional activity were evaluated before and 5 and 10 years post operation. Before the operation 84.5% of patients were classified in CCS class III or IV and 43% in NYHA class III. 74% of patients had a history of myocardial infarction and 29.3% underwent emergency CABG due to unstable angina. Single vessel disease was seen in 22.4% of patients, double vessel one in 24.1% and triple vessel in 46.5%. Left main stenosis was observed in 17.2% of patients. Mean body surface area (BSA) was 1.78 m2 and 69% had BSA below 1.8 and 24% below 1.6 m2. During the follow-up period the ECG exercise test was also performed in all of the patients.

Risk factors of CAD and clinical status before CABG are presented in Table I. These factors included cigarette smoking continuation, total cholesterol (chol) level higher than 200 mg% and triglyceride (TG) level higher than 180 mg%, body mass index (BMI) higher than 26, diabetes mellitus (DM) glucose > 120 mg% or medications, arterial hypertension (HA) > 160/90 and family history (FH) – IHD in relatives before 55 years of age. A similar comparison was also made concerning effect of complete and incomplete myocardial revascularization on clinical state of the patients during the follow-up period. The data on patients’ clinical state were then pooled with risk factors of IHD to which this population was exposed during the follow-up period.

Statistical analysis

Continuous variables are presented as mean values ± standard deviation. Survival curves were drawn using Kaplan-Meier analysis. The statistical analysis of differences in variables occurrence in the compared groups was made using χ2 independency test with Yates’ amendment (for two groups). The results of the test for which probability of error (p) was lower than 0.05 were considered statistically significant.

Results

The overall survival of patients discharged from the hospital during the follow-up period is presented in Figure 1. Five, ten and fifteen year survival rates were 88%, 81.5%, 66% respectively. There were 10 late deaths (4 non-cardiac), and the fate of 2 patients is unknown. Angina free and coronary events free survival 5, 10 and 15 years post surgery was 66%, 57%, 36.5% respectively (Figure 2). During the 17.5 years of observation none of the patients needed reoperation.

The results of follow-up examination revealed a significant improvement of the clinical state. The mean CCS class was 3.24 +/- 0.85, 5 years after CABG 1.48 +/-0.71, 10 years after 1.7 +/- 0.77. Mean NYHA class 2.51 +/-0.58, 1.78 +/- 0.67 and 1.65 +/- 0.63 respectively. ECG exercise test performed 5 years after the operation was negative in 57% of patients and in 31% it remained positive. Most ECG curve changes were localized in the inferior wall region, which is not specific for women. On ECHO examinations, there was no significant improvement in the left ventricular function. The mean left ventricular ejection fraction before and 5 years after the operation was 57 ±10 vs 55 ±10 (p = ns). There was no significant decline in exposure to IHD risk factors (chol, TG, BMI, DM, HA, FH) after the operation. Postoperatively, the most significant changes were observed in cigarette smoking. It should be emphasized that 94.8% of patients were smokers before CABG. Although 5 years after the operation 7 (13%) patients were still smoking, nobody did 10 and 15 years after the surgery. It must be noted that approximately 22% (13) of patients had a complicated endpoint, including death, myocardial infarction, rehospitalization, within the first 3 years post operation. 11 of them were those who returned to smoking. CCS III or IV and NYHA II or IV complaints were significantly more frequent than in the non-smoking population (P values respectively lower than 0.01 and 0.001). In ECG exercise test a positive correlation was found between lower effort tolerance (in METs) and continuation of smoking after the operation (p < 0.05). Postoperative continuation of cigarette smoking was also significantly correlated with angina recurrence (p < 0.03). The whole comparison is presented in Table II.

A comparison between the patients’ clinical state and completeness of revascularization was also performed. This analysis showed a significant effect of complete vs. incomplete revascularization on classifications according to CCS (p < 0.01) and NYHA (p < 0.01). Among 12 women qualified for repeat coronary angiography during the follow-up period, due to angina recurrence, there were 9 patients who did not cease cigarette smoking after the operation. In all of them, progression of atheromatous lesions in coronary arteries was found. In 4 of those patients percutaneous coronary intervention (PCI) was performed in the left anterior descending (LAD) artery (in 2 cases) or in the right coronary artery (RCA). Three other patients were qualified for medical treatment because there was no technical possibility for PCI. In 3 non-smoking women referred for repeat coronary angiography after CABG no progression of atheromatosis either in native vessels or in grafts was observed in 2 patients. In these cases only a vasospasm of the coronary artery was found. The third of the patients had progression of the disease and required PCI in the RCA.

Before the operation 15.5% (9) of patients were in the menopause and 5 years post CABG menopause before 45 years of age appeared in 39.7% (23) of cases. Before CABG 74% of women worked and only 34.5% remained employed after the operation. Despite improvement of clinical condition, professional activity decreased especially among patients with elementary education.

Discussion

The outcome of CABG in young women is worse in comparison with young men [5, 6]. Hogue et al. [7], analyzing 30-day survival after CABG, found that women younger than fifty had a mortality rate threefold higher, and women between fifty and seventy twofold higher than men at the same age. Generally, women are a group of patients which demands special care and more intensive treatment, both pre- and postoperatively.

In order to assess early postoperative mortality in women, with special regard to female patients below 50 years of age, Vaccarino et al. [5] analyzed 51 000 patients who underwent CABG. In the subset of patients under 50 years of age, comprising 5024 subjects, women constituted 22.5%. Overall mortality in women was 1.8-fold higher than in men. The highest mortality in female patients in comparison with the male population was observed in “the youngest” group below 50 years of age. This study, comprising one of the most numerous subsets of young patients who underwent CABG, shows that together with successive decades of life, in-hospital mortality of women in comparison with men diminishes and trends towards equality. Similar findings were reported by Regitz-Zagrosek et al. [6]. Risk of death for women in comparison with men decreases together with age and in older patients is nearly the same. Operative mortality after CABG in the population of patients aged 50 or younger was from 3.04 to 2.36-fold higher than in men [5, 6, 8].

According to Vaccarino et al. [5] and Regitz-Zagrosek et al. [6], female patients referred for CABG in comparison with male patients had a bigger burden of preoperative risk factors. Compared with men, more women were in functional class III or IV according to the Canadian Cardiovascular Society (CCS). They were also more often operated on in a non-elective way. Postoperative morbidity rate also indicates that women at pre-menopausal and menopausal age, in comparison with men below 50 years, have worse prognosis after CABG. In this age group, Vaccarino et al. [5] observed statistically more postoperative complications in women than in men. It should be emphasized that female gender in comparison with male gender was the most unfavorable predictor of outcome after CABG in patients below 50 years of age.

The protective effect of estrogens on the cardiovascular system is well known, as is the correlation between menopausal age and the risk of IHD development. Bilateral ovariectomy in pre-menopausal women also results in a rapid fall of estrogen level and in consequence in the increase of IHD prevalence [9].

In the study comparing a subset of women with a history of MI and angiographic evidence of coronary artery atheromatosis with a subset of women free of IHD, a lower level of dehydroepiandrosterone (DHEA) was found in the first subset. DHEA is a hormone believed to have some anti-atheromatous properties [10].

Anovulatory cycles and hyperandrogenism are features of polycystic ovary syndrome. It is a major problem of not properly diagnosed women, simultaneously burdened with other risk factors of IHD such as dyslipidemia, visceral obesity, arterial hypertension or glucose intolerance. The risk of IHD in this population of women is 4 to 11-fold higher than in healthy women [11].

Expression of the estrogen receptors (ERs) in smooth muscle cells of the coronary arteries is higher in the atheromatosis free vessels. The correlation between ER expression and the absence of atheromatous plaques has the highest statistical significance in pre-menopausal women. Smooth muscle cells of the arteries of healthy women showed expression of ERs in more than 83% of cases [12]. It means that there must be another beneficial effect of estrogens, acting directly on the vascular wall. In pre-menopausal women, plaque erosion is observed more frequently than in men of the same age. In patients younger than 50 referred for CABG, unstable IHD was more prevalent among women than among men [5, 6].

A premature manifestation of IHD in patients with a positive family history of cardiovascular diseases may suggest a genetic background of the atherosclerosis development in coronary arteries. A lack of estrogens’ protective properties on the cardiovascular system in pre-menopausal women may result from polymorphism of the ER gene. The allelic sequence of c.454-397CC in intron 1 of gene ESR1 is burdened with 3-fold higher risk of myocardial infarction than the sequence of c.454-397TT/CT [13].

Diabetes mellitus is diagnosed significantly more frequently in young women than in young men referred for CABG [14]. Obesity is another risk factor of IHD that is more common among young women. Young and obese women often present with some abnormalities associated with the effects of estrogens, e.g. infertility and dysmenorrhea [15]. In such a case, dysfunction of ERs both in adipocytes and in endothelial cells may be associated with abnormal transcription pathways which do not signal proper vascular protection.

Lipoprotein (α) [Lp (α)] was found to be an extremely strong predictor of premature development of IHD and its serum level seems to be at least partially dependent on genes. Among women with a level of Lp (α) higher than 30 mg/dl, the risk of hospitalization due to acute coronary syndrome is 5-fold higher in pre-menopausal women and 2.4-fold higher in post-menopausal women, in comparison with women in whom the level of Lp (α) is lower than 6 mg/dl [16].

The higher relative mortality rate of women after CABG may also result from technical problems which can occur during the operation. Smaller diameter and more tortuous course of the coronaries may result in some technical problems for the surgeon during graft anastomosis, which may affect postoperative outcomes. Early postoperative mortality increases with diminishing of the coronary artery diameter, and this phenomenon is better seen in women than in men [17]. Nishida et al. [18] found the advantage of arterial grafts in comparison to venous grafts in patients with coronaries of small diameter. Some authors report that the use of arterial grafts is less common in women than in men, and this fact, according to the observations of Nishida et al. [18], may contribute to worse prognosis in female gender subsets. It should be emphasized that according to Sheifer et al. [19], women have smaller coronary vessels than men, regardless of body surface area.

Another risk factor is addiction to nicotine. The rate of subjects addicted to nicotine is higher in men, but it is the population of women, especially young ones, in whom the adverse trend towards an increased number of smokers is observed. Smoking in combination with use of oral contraceptives significantly enhances the development of IHD and aggravates its course in the subset of young women. Smoking accelerates menopause, and thus the moment when a decrease of plasma estrogen level is observed. Addiction to nicotine probably does not affect atheromatous plaque rupture, but it significantly promotes the development of plaque erosion [20].

Conclusions

Angina pectoris exacerbation, the high percentage of post-MI patients and the significant number of accompanying risk factors place this group among the populations at very high risk of mortality.

Of immense benefit to the study group is giving up cigarette smoking. The study shows unequivocally that the continuation of smoking after CABG is associated with ischaemic disease progression and clinical deterioration, as clearly seen in the first 3 years after surgery.

Despite improvement of clinical condition, professional activity decreased, especially among patients with elementary education. Not undertaking a job after the surgery was also a result of the adverse conditions in the labor market for women in the 1990s, which was associated with political transitions and high unemployment.

The relief of angina symptoms improves the quality of life, but the generally understood socioeconomic situation significantly reduces the possibility of returning to the same level of active life after cardiac surgery.

References

1. Meinert CL, Gilipin AK, Unalp A, Dawson C. Gender representation in trials. Control Clin Trials 2000; 21: 462-475.

2. Enas AE. Lipoprotein(a) as a determinant of coronary heart disease in young women: a stronger risk factor than diabetes? Circulation 1998; 27: 293-295.

3. O’Rourke DJ, Malenka DJ, Olmstead EM, et al. Improved in-hospital mortality in women undergoing coronary artery bypass grafting. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2001; 71: 507-511.

4. Castelli WP. Epidemiology of coronary heart disease in the Framingham Study. Am J Med 1984; 76: 4-13.

5. Vaccarino V, Abramson JL, Veledar E, Weintraub W. Sex differences in hospital mortality after coronary artery bypass surgery. Evidence for a higher mortality in younger women. Circulation 2002; 105: 1176-1181.

6. Regitz-Zagrosek V, Lehmkuhl E, Hocher B, Goesmann D, Lehmkuhl HB, Hausmann H, Hetzer R. Gender as a risk factor, not in old, women undergoing coronary artery bypass grafting. J Am Coll Cardiol 2004; 44: 2413-2414.

7. Hogue CW Jr, Barzilai B, Pieper KS, Coombs LP, DeLong ER, Kouchoukos NT, Dávila-Román VG. Sex differences in neurological outcomes and mortality after cardiac surgery. A Society of Thoracic Surgery National Database report. Circulation 2001; 103: 2133-2137.

8. Humphries KH, Gao M, Pu A, Lichtenstein S, Thompson CR. Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991-2004). J Am Coll Cordiol 2007; 49: 1552-1558.

9. Colditz GA, Willett WC, Stampfer MJ. Menopause and risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-1110.

10. Słowińska-Srzednicka J, Malczewska B, Srzednicki M, Chotkowska E, Brzezińska A, Zgliczyński W, Ossowski M, Jeske W, Zgliczyński S, Sadowski Z.

Hyperinsulinaemia and decreased plasma levels of dehydroepiandrosterone sulfate in premenopausal women with coronary heart disease.

J Intern Med 1995; 237: 465-472.

11. Dahlgren E, Janson PO, Johansson S, Lapidus L, Odén A. Polycystic ovary syndrome and risk for myocardial infarction: evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 1992; 71: 599-604.

12. Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994; 89: 1501-1510.

13. Shearman AM, Cupples LA, Demissie S. Association between estrogen alpha gene variation and cardiovascular disease. JAMA 2003; 5: 2263-2270.

14. Di Carli MF, Afonso L, Campisi R, Ramappa P, Bianco-Batlles D, Grunberger G,

Schelbert HR. Coronary vascular dysfunction in premenopausal women with diabetes mellitus. Am Heart J 2002; 144: 711-718.

15. Kortelainen ML, Huttunen P. Expression of estrogen receptors in the coronary arteries of young and premenopausal women in relation to central obesity. Int J Obes Relat Metab Disord 2004; 28: 623-627.

16. Orth-Gomer K, Mittleman MA, Schenck-Gustafsson K. Liporotein(a) as a determinant of coronary heart disease in young women. Circulation 1997; 21: 329-334.

17. Ramstrom J, Lund O, Cadavid E, Thuren J, Oxelbark S, Henze A. Multiarterial coronary artery bypass grafting with special reference to small vessel disease and results in women. Eur Heart J 1993; 14: 634-639.

18. Nishida H, Nakajima M, Ihashi K, Sato M, Shiikawa A, Endo M, Koyanagi H.

Effects of smaller physical size on complex arterial grafting in coronary artery operations. Ann Thorac Surg 1996; 62: 733-736.

19. Sheifer SE, Canos MR, Weinfurt KP, Arora UK, Mendelsohn FO, Gersh BJ, Weissman NJ. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000; 139: 649-653.

20. Burke AP, Farb A, Malcolm GT, Liang Y, Smialek J, Virmani R. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998; 97: 2110-2116.