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Gender Related Differences in the Risk Profile, Comorbidities and Prognostic Indicators of Patients with Acute Coronary Syndrome

 

Nia Emilova1, S. Denchev2, M. Gospodinova2, S. Dimitrov3, Т. Kundurdjiev4

1 Clinic of Cardiology, University Hospital „Аlexandrovska”, Sofia

2 Clinic of Cardiology, Medical Institute of the Ministry of Internal Affairs, Sofia

3 Department of Invasive Cardiology, MHAT Hristo Botev”, Vratza

4 Faculty of Public Health, Medical University, Sofia

 

Summary

Purpose: We aimed to investigate the significance of gender-related contrasts concerning the risk profile, comorbidities and prognostic indicators of patients with acute coronary syndrome.

Material and methods: The study group included 259 patients (144 men, 55,6% and 115 women, 44,4%) with diаgnosed acute coronary syndrome (ACS), admitted to University Hospital Alexandrovska”, Sofia. Data about risk factors for atherosclerosis, noncardiac chronic disease, type of presenting symptoms were collected through clinical exam. The echocardiographic indices of left ventricular systolic function (ejection fraction and end-systolic volume) were obtained with 2D - mode echocardiography. The coronary disease severity was assessed by calculating SYNTAX scores in those patients with performed selective coronary angiography. The frequency of adverse events for a period of one year was registered.

Results: Women were significantly older (69,5±10,9 vs 62±13,2 years, p<0,0001), had more frequently аrterial hypertension (96,5% vs 84%, p=0,001) and comorbidities (55% vs 33,3%, p=0,001). Smoking was more prevalent among male patients (66,2% vs 20,9%, p<0,0001). Atypical angina was encountered with similar frequency among female and male patients (22,2% vs 32,2%, p=0,089). The incidence of obstructive coronary disease (90,1% vs 76,6%, p=0,005) and acute myocardial infarction with persistent ST elevation were higher in the examined male group (65% vs 35%, p=0,008). In contrast to women, more subsequent percutaneous interventions (32,4% (n=35) vs 19,1% (n=17), p=0,037) and rehospitalisations (57% (n=61) vs 40% (n=36), p=0,022) were observed in the male group during follow-up.

Conclusion: Specific for male gender association with more extensive obstructive coronary atherosclerosis is observed in our study despite the lower coronary risk factor burden and fewer baseline comorbidities. The sex-based difference regarding risk for adverse cardiovascular outcome is dependent on the higher frequency of obstructive coronary atherosclerosis and left ventricular systolic dysfunction among male patients.

Кеy words: аcute coronary syndromes, prognostic indicators, sex

Address for correspondence: Nia Emilova, University Hospital „Аlexandrovska”, 1 Georgi Sofiiski” Str, 1421, Sofia; e-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Introduction

The social and ecomonic significance of cardiovascular disease in Europe is expanding during the last decades because of accumulation and poor control of cardiovascular risk factors. A report of World Health Organisation states that coronary heart disease along with cancer and stroke are leading causes of death in women as they are in men (16). Still there are unexplained sex-based differences concerning the clinical outcome following acute coronary syndrome (ACS) (18).

Purpose

We aimed to investigate the significance of the sex-based contrasts in the risk profile, comorbidities and prognostic indicators of patients with acute coronary syndrome.

 

Materials and methods

The study group included 259 patients (144 men, 55,6% and 115 women, 44,4%) with diаgnosed acute coronary syndrome admitted to University Hospital Alexandrovska” between July 2011 and May 2014. Information about atherosclerotic risk factors, atypical symptoms at presentation, echocardiographic indices (ejection fraction, EF and end-systolic volume, ESV), coronary disease severity and the frequency of new major adverse events (ischaemic-driven rehospitalisations, revascularisations, ACS, transient ischaemic attacks, strokes and all-cause deaths) as combined endpoint for a period of one year was gathered (table 1).

 

Table 1. Demographic profile, atherosclerotic risk factors, SYNTAX scores, indices characterising left ventricular systolic function in acute phase and sixth months after ACS

Group/variable

Patients with ACS

 

Men with ACS

 

Women with ACS

Sex n (%)

259 (100)

144 (55,6)

115 (44,4)

Age (years)

65,3 ± 13,2

62,0 ± 13,2

69,5 ± 10,9

Arterial hypertension

n (%)

232 (89,6)

121 (84)

111 (96,5)

Diabetes mellitus n (%)

89 (34,4)

50 (34,7)

39 (33,9)

Dyslipidemia n (%)

185 (71,7)

102 (70,8)

83 (72,8)

Smoking n (%)

118 (45,9)

94 (66,2)

24 (20,9)

SYNTAX score

13 ± 10

15 ± 10

12 ± 10

Nonobstructive coronary athesrosclerosis n (%)

31 (18,2)

11 (10,8)

20 (27,1)

Single vessel disease n (%)

38 (20,3)

21 (20,6)

17 (20)

Two vessel disease n (%)

53 (28,3)

38 (37,3)

15 (17,6)

Three vessel disease n (%)

62 (33,2)

32 (31,4)

30 (35,3)

EF1, %

53,5 ± 11,0

52,6 ± 9,8

54,7 ± 12,2

ESV1 index, ml

33,1 ± 16,5

34,7 ± 16,1

30,0 ± 17,1

EF2, %

55,3 ± 10,0

53,8 ± 9,7

57,4 ± 11,8

ESV2 index, ml

35,6 ± 18,7

38,3 ± 19,0

31,0 ± 17,7

Legend: EF 1 и EF 2ejection fractions in acute phase and six months following the acute event; ESVindex1 и ESVindex2 – indices of end-systolic volumes during the index hospitalisation and at sixth month

All patients provided written informed consent to participate in the study which was approved by the hospital ethics committee and complied with the Declaration of Helsinki.

 

Clinical methods

Medical history and physical examination were the clinical methods used. A part of the information particularly during the follow-up was obtained by telephone interview.

The diagnoses acute coronary syndrome, ACS without ST elevation (NSTEMI) and ACS with persistent ST elevation (STEMI) were made based on the criteria of the European Society of Cardiology (13). Details about traditional atherosclerotic risk factors were collected. Arterial hypertension was diagnosed according to the clinical guidelines of the European Society of Hypertension and European Society of Cardiology (15). The recommendations of the International Diabetes Federation were followed while diagnosing diabetes mellitus (4). Patients were considered as having dyslipidemia when their serum lipid concentrations were abnormal compared to the values recommended for individuals with low cardiovascular risk as defined by the European Society of Cardiology and European Atherosclerosis Society (17). Renal insufficiency was acknowledged in cases of permanently decreased creatinine clearance (< 60 ml/min) in line with criteria of Inernational Society of Nephrology (22).

 

Echocardiography and selective coronary angiography

The echocardiographic study was performed with ultrasound diagnostic instruments Аloka ProSound 10 (Hitachi Aloka Medical) and Sonos 5500 (Hewlett-Packard) using 2,5 – 4 МHz transducer. The modified Simpson method and heart imaging in apical four and two chamber views were applied for evaluation left-ventricular ejection fraction and end-systolic volume. The results of the measurements in both views were averaged (14).

Cardiac catheterization and selective coronary angiography (SCA) were performed via femoral or radial approach using Simens Coroscop Plus and Philips Alura XP 20 imaging systems. Visual assessment and quantitative coronary angiography (QCA) were the methods exploited for coronary atherosclerotic lesions quantification. The extent and severity of coronary disease were assessed by means of SYNTAX score calculation for each patient who had SCA performed.

 

Statistical analysis

The variables distribution was analysed using Shapiro-Wilk test for samples of less than 20 cases, otherwise Kolmogorov-Smirnov test was utilized. The characteristics of male and female patients were compared with the use of nonparametric (χ2 test, Fisher exact tests, Mann-Whitney U test) and parametric (Students t-test for independent samples) methods. The association of risk indicators with adverse events incidence during follow-up was performed using univariate and multivariate regression analyses. Null hypothesis was rejected when P value was lower than 0,05. Statistical analysis was performed with SPSS version 19 (Statistical Package for Social Science, Chicago, IL, USA) for Windows.

 

 

Results

In the examined patient group women were substantially older (69,5±10,9 vs 62±13,2 years, p<0,0001). Smoking was the other risk factor with significantly different distribution in relation with gender (66,2% vs 20,9%, p<0,0001). Higher incidence of systemic hypertension was observed among female patients with ACS (96,5% vs 84%, p=0,001) (figure 1).

Figure 1. Traditional atherosclerotic risk factors in patients with ACS – sex-based differences

 

Several noncardiac pathologic conditions (chronic renal disease, anemia, cerebrovascular disease, depression) were found to prevail substantially in the female group (55% vs 33,3%, p=0,001). Among these disorders amenia (35,2% vs 19,6%, p=0,008) and depression (8,7% vs 2,1%, p=0,021) separately were commonly encountered in female patients in contrast to men.

The rate of reported at presentation atypical symptoms were higher in the female group (32,2% vs 22,2%, p=0,089). Significantly more cases of obstructive coronary atherosclerosis (more than one coronary stenosis > 50%) were registered among male patients (90,1% vs 76,6%, p=0,005) and they had greater atherosclerotic burden than women (15±10 vs 12±10, p=0,030). Our analysis show related to sex distinctions regarding the history of previous myocardial infarction (24,3% vs 17,4%, p=0,221) and revascularisation procedures (percutaneous coronary interventions, PCI and aorto-coronary bypass surgery, ACB) - 16% vs 12,2%, p=0,475. Women with ACS were found to present less frequently with STEMI compared to men (35% vs 48%, p=0,008) (fig. 2 и 3).

 

Figure 2. Types of ACS - frequency among male patients

Legend: NSTEMI – acute coronary syndrome without persistent ST elevation; STEMI – acute myocardial infarction with persistent ST elevation

Figure 3. Types of ACSfrequency among female patients


Legend: NSTEMI – acute coronary syndrome without persistent ST elevation; STEMI – acute myocardial infarction with persistent ST elevation

The frequency of heart failure Killip > II class during the index hospitalisation for ACS was comparable between the examined male and female patients (16% vs 8%, p=1,000), in spite of the significantly lower frequency of abnormal left ventricular systolic function in the female group (40,3% vs 27,8%, p=0,049).

Depending on the type of ACS several disparities with regard to clinical characteristics were observed (table 4). In the male group STEMI tended to be the first presentation of coronary disease, occurred at relatively young age (men with NSEMI vs STEMI - 65,4±14 vs 58,9±11,7 years, p=0,045) when coronary atherosclerosis had already advanced to obstructive disease (obstructive coronary atherosclerosis among men with NSTEMI vs STEMI - 85,3% vs 94,6%, p=0,091).

Tаble 4. Differences in the frequency of clinical characteristics consistent with the ACS type

of male and female patients

 

Patient group

Men

 

 

Women

 

 

 

NSTEMI

STEMI

P-value

NSTEMI

STEMI

P-value

Age, years

65,4±14

58,9±11,7

0,045

68,7±10,4

71,1±11,7

NS

Arterial hypertension

n (%)

92,9

75,7

0,006

97,3

95

NS

Diabetes mellitus

n (%)

31,4

37,8

NS

34,7

32,5

NS

Dyslipidemia n (%)

71,4

70,3

NS

75,7

67,5

NS

Smoking n (%)

61,4

70,8

NS

18,7

25

NS

Chronic renal disease

n (%)

18,6

10,8

NS

18,7

25,6

NS

Аnemia n (%)

21,9

17,6

NS

30,8

42,5

NS

Depression n (%)

1,4

2,7

NS

10,7

5

NS

CVD n (%)

14,3

6,8

NS

8

10

NS

Co-morbidities n (%)

38,6

28,4

NS

53,6

57,5

NS

Prior MI n (%)

35,7

13,5

0,003

22,7

7,5

NS

Prior ACB/PCI n (%)

24,3

8,1

0,011

17,3

2,5

0,032

LV systolic dysfunction

n (%)

40

40,5

NS

14,7

52,5

0,0001

Obstructive coronary

athersoclerosis n (%)

85,3

94,5

NS

69,9

91,2

0,015

Legend: CVD – cerebrovascular disease; MI – myocardial infarction; PCI – percutaneous coronary intervention; ACB – aorto-coronary bypass surgery; LV systolic dysfunction – left ventricular systolic dysfunction

Sex related contrasts in the groups of NSTEMI and STEMI are presented on table 5. They were statistically significant only in the STEMI group. Women were older (71,1±11,7 vs 58,9±11,7 years, p<0,0001). The incidence of arterial hypertension (95% vs 75,7%, p=0,010), anemia (42,5% vs 17,6%, p=0,007) and noncardiac pathologic conditions (57,5% vs 28,4%, p=0,002) were more frequently observed in this group. The abnormal left ventricular systolic function (85,3% vs 69,9%, p=0,043) and obstructive coronary atherosclerosis (40% vs 14,7%, p=0,001) were irregularly distributed among younger patients - those with NSTEMI, with substantially higher incidence among male patients. Smoking was the only risk factor with male specific predominance independent of the ACS type (61,4% vs 18,7%, p<0,0001 for NSTEMI; 79,8% vs 25%, p<0,0001 for STEMI) (table 5).

Table 5. Clinical characteristics - sex-based contrasts in patients with NSTEMI and STEMI


Patient group

NSTEMI

 

 

STEMI

 

 

 

Men

Women

P-value

Men

Women

P-value

Age, years

65,4±14,0

68,7±10,4

NS

58,9±11,7

71,1±11,7

0,0001

Arterial hypertension

n (%)

92,9

97,3

NS

75,7

95

0,010

Diabetes mellitus

n (%)

31,4

34,7

NS

37,8

32,5

NS

Dyslipidemia n (%)

71,4

75,7

NS

70,3

67,5

NS

Smoking n (%)

61,4

18,7

0,0001

79,8

25

0,0001

Chronic renal disease

n (%)

18,8

18,7

NS

10,8

25,8

0,058

Anemia n (%)

21,9

30,8

NS

17,6

42,5

0,007

Depression n (%)

1,4

16,7

0,034

2,7

5

NS

CVD n (%)

14,3

8,0

NS

6,8

10

NS

Co-morbidities n (%)

38,6

53,6

NS

28,4

57,5

0,002

Prior MI n (%)

35,7

22,7

NS

13,5

7,5

NS

Prior ACB/PCI n (%)

24,3

17,3

NS

8,1

2,5

NS

LV systolic

dysfunction n (%)

40

14,7

0,001

40,5

52,5

NS

Obstructive coronary

atherosclerosis n (%)

85,3

69,9

0,043

94,5

91,2

NS

Legend: CVD – cerebrovascular disease; MI – myocardial infarction; PCI – percutaneous intervention; ACB – aorto-coronary bypass surgery; LV systolic dysfunction – left ventricular systolic dysfunction

Men underwent more frequently repeated revascularisations in the first year following ACS (32,4% (n=35) vs 19,1% (n=17), p=0,037). Appreciably higher incidence of rehospitalisations was detected also among male patients (57% (n=61) vs 40% (n=36), p=0,022). The results for both sexes did not differ significantly in relation to hospitalization rate at the end of the first year following the index event (61,1% (n=66) vs 52,2% (n=47), p=0,249). We recorded more cases of all cause death during the follow-up in the female group (men vs women - 5% vs 9,9%).

The results of univariate analysis showed that diabetes mellitus, chronic renal disease, greater SYNTAX scores, left ventricular systolic dysfunction in the male group and dyslipidemia (OR 0,125; 95 % 0,016-0,999; p=0,050) among women were significant indicators of the risk for subsequent percutaneous coronary interventions a year after ACS (table 6). While the risk for recurrent adverse events in male group was determined mainly by the contractile myocardial function at the time of ACS (OR 0,425; 95% CI 0,186-0,970; p=0,049) and atypical angina symptoms (OR 0,124; 95% CI 0,027-0,564; p=0,007), among the examined women the same risk was dependent on the degree of coronary atherosclerotic burden (ОR 1,071; 95% 1,018-1,127; р=0,008) and diabetes mellitus incidence (OR 0,390; 95% 0,153-0,996; р=0,049).

Table 6. Prognostic variables for the risk of revascularisation after ACS


Revascularistions

Following ACS (men)

Eднофакторен анализ

ОR (95%CI)

P-value

Age

1,033 (1,001-1,066)

0,045

Arterial hypertension

0,656 (0,195-2,203)

NS

Diabetes mellitus

2,661 (1,097-6,455)

0,030

Dyslipidemia

0,785 (0,306-2,014)

NS

Smoking

1,043 (0,445-2,448)

NS

SYNTAX score

1,045 (1,000-1,093)

0,050

Left ventricular

dysfunction

0,307 (0,133-0,708)

0,006

Anemia

0,738 (0,243-2,238)

NS

Chronic renal disease

0,224 (0,074-0,680)

0,008

Comorbidities

0,938 (0,276-1,478)

NS

EF1

0,893 (0,844-0,945)

0,0001

EF2

0,908 (0,846-0,976)

0,009

Аtypical symptoms

of ischaemia

0,346 (0,130-0,940)

0,033

 

Multivariable regression analysis demonstrated that diabetes mellitus is significant independent predictor of the revascularization risk (OR 13,379; 95% CI 1,276-140,265; p=0,031). Age (OR 1,051; 95% CI 1,014-1,089; p=0,006) and atypical angina (OR 1,143; 95% CI 1,084-1,089; p=0,015) were associated with the rate of complications as a composite endpoint during one-year follow up.

Discussion

The obtained results indicate the existence of characteristic for the patient sex incidence of ACS risk factors. According to our data women experience acute coronary event nearly six years later than men, smoking is more prevalent among male patients. Similar related to sex contrasts in the setting of acute coronary disease have already been reported (1,2,7,11). In most countries smoking as a risk factor for atherosclerosis imposes substantial burden on society and economics (7).

Female patients with ACS are less prone to development of left ventricular systolic dysfunction, have higher frequency of nonobstructive coronary atherosclerosis and noncardiac pathology. Depression and anemia separately were more commonly encountered in the female group. Previous studies confirm the observed differences (2,3,6,8,9,12,16,21). However, the disparity between age and co-morbidities on one hand and less severe cardiovascular involvement of female ACS patients is difficult for interpretation. The comparison of pesenting clinical characteritics between men and women according to the type of ACS suggested sex-based disparities mainly among oldest patients - those with STEMI. Among female patients coronary disease is diagnosed later in life, at the time of nonobstructive coronary atherosclerosis and in its most common acute form - NSTEMI, have less severe presentation and relatively favourable prognosis. While gradual and delayed course of the disease can be seen among female patients we demonstrate typical for male sex more aggressive progression of coronary disease with higher rates of STEMI, revascularization procedures at younger age. These observations are supported by the results of pathologic studies (11). Data obtained by studying dyslipidemias in male and female coronary disease patients (not presented here) had indicated a significant protective effect of higher levels of HDL in female patients - less severe coronary atherosclerosis among women with higher plasma HDL. The effect of dyslipidemia was insignificant in the examined male group, due perhaps to more powerful risk factors (smoking).

Higher incidence of adverse events were recorded in the male group. The severity of atherosclerotic coronary burden was the only clinical feature that explained substantially the unfavourable outcome in both sexes. The observation that most clinical charcteristics at presentation had only male specific prognostic significance following ACS contradicted prior data. CURE, CRUSADE, FRISC II, RITA -3, SWEDEHEART studies have showed that there is interaction of sex, the type of ACS and treatment strategy, other risk indicators (high TIMI score, increased hsTnT). In summerised fashion, this interaction is related to increased risk of adverse events among female patients (5,6,9,10,21,23). The substantial number of male specific indicators with negative prognostic significance after ACS emerging from our analysis could also indicate the existence of intrinsic protective mechanisms impeding the progression of coronary atherosclerosis in female patients (8, 11, 20, 24).

The underestimation of angina symptoms and the undertreatment of coronary disease in female patients imposes substantial risk for adverse events according to CURE, CRUSADE, OASIS-WSS (6,9,10,19,21). Contrary to larger studies our analysis demonstrated an unusual association characteristic for male patients in Bulgaria - between the atypical symptoms of ischaemia and unfavourable prognosis after ACS. Further regional investigations are necessary to prove this result and also to serve as a basis for local strategies for coronary disease secondary prophylaxis.

 

Conclusion

Specific for male gender association with more extensive obstructive coronary atherosclerosis is observed in our study despite the lower coronary risk factor burden and fewer baseline comorbidities. The sex-based difference regarding risk for adverse cardiovascular outcome is dependent on the higher frequency of obstructive coronary atherosclerosis and left ventricular systolic dysfunction among male patients.

 

 

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