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Sumario Vol. 42 - Nº 3 Julio - Septiembre 2013

Differences in the Presentation and Diagnosis
of Coronary Artery Disease in Women

Jorge Camilletti A, Monica Redolatti, Juan Erriest

Hospital Italiano de La Plata.
Servicio de Cardiologia. Unidad de Medicina Nuclear
Calle21 Nº 525. (CP 1900) La Plata, Buenos Aires
E mail

Recibido 07-FEB-2013 – ACEPTADO despues de revision el 21-MARZO-2013.

The authors declare not having a conflict of interest.

Rev Fed Arg Cardiol. 2013; 42(3): 182-188


Print version Imprimir sólo la columna central

 

 

RESUMEN

Introducción: La enfermedad coronaria (EC) en la mujer constituye la causa de mortalidad más frecuente de los países desarrollados. Diferencias en el sexo en cuanto a las formas de presentación, diagnóstico y tratamiento de la EC se han puesto de manifiesto en los últimos trabajos, que nos alerta de una disociación entre el riesgo percibido y el real.
Objetivos: El objetivo de este trabajo es analizar las características de la población estudiada según el sexo, correlacionar la sintomatología previa al estudio y los resultados de la prueba ergométrica graduada (PEG), con la perfusión miocárdica y evaluar el impacto de los resultados positivos en la perfusión miocárdica mediante scores de riesgo en cuanto a la indicación de cinecoronariografía (CCG)
Método: Se realizó un análisis retrospectivo de pacientes remitidos a la Sección de Medicina Nuclear para realizarse un estudio de perfusión miocárdica SPECT (EPM), se dividió a la población según el sexo y se evaluó el motivo de consulta: asintomáticos, dolor torácico no característico (DTI) y dolor típico (DT); los factores de riesgo cardiovasculares, los resultados de la PEG, y los resultados del EPM. Se realizó un seguimiento a 2 meses de aquellas pacientes con EPM (+) en cuanto a la indicación de CCG.
Resultados: Se incluyeron 700 pacientes, hombres n 456 (66%); mujeres n 244 (34%) p: 0.0001; no se encontraron diferencias significativas entre sexos en HTA, tabaquismo y diabetes; dislipémicos hombres n 241 (53%) vs mujeres n 158 (65%) p=0.003; Asintomáticos hombres n 243 (54%) vs mujeres n 76 (31%), p=0.0001; DTI hombres n123 (26%) vs mujeres n 120 (49%), p 0.0001; DT hombres n 90 (20%)  vs mujeres n 48 (20%), p ns. La PEG fue positiva en 127 hombres (27%) y 59 mujeres (24%), p ns; mientras que la misma resultó negativa en 329 hombres (73%) y 185 mujeres (76%), p ns. Los EPM fueron positivos en 242 pacientes; 187 (77%) hombres Vs 55 (23%) mujeres p: 0.0001. Cuando comparamos la presentacion clinica y EPM positivo no encontramos diferencia significativa entre ambos sexos. Posteriormente evaluamos a los pacientes con PEG positiva y EPM positivo donde encontramos 127 hombres (68%) y sólo en 25 mujeres (45%), p 0.003; luego comparamos PEG negativa y EPM positivo encontramos 60 hombres (32%) y 30 mujeres (54%), p 0.005.  
Del total de las mujeres evaluadas el 22% (n 55) presentó EPM (+), de las cuales el 13% (n 11) se realizó CCG; dentro de este grupo se indicó CCG a las pacientes con SDS >5 (moderado-alto riesgo); 4 p (27%) vs 11 p (73%) que no fueron a CCG p: 0.03.
Conclusiones: Las pacientes de sexo femenino son derivadas con menor frecuencia que los hombres, para la evaluación de EC en nuestro servicio. El síntoma de consulta más frecuente en la mujer es el DTI. El dolor precordial típico y la PEG positiva en las mujeres no son buenos predictores de isquemia miocárdica según los estudios de perfusión comparado con la población masculina. Las mujeres presentan una baja tasa de indicación de estudios angiográficos.

Palabras clave: Enfermedad Coronaria. Mujer. Gammagrafía de perfusión. Prueba Ergométrica.
SUMMARY

Introduction: Coronary heart disease (CHD) in women is the most common cause of death in developed countries. Sex differences in terms of clinical presentation, diagnosis and treatment of CHD have been shown in recent work, which alerts us to a dissociation between perceived and real risk.
Objectives: The aim of this study is to analyze the characteristics of the study population by gender, previous symptoms correlate to the study and the results of stress testing (PEG) with myocardial perfusion and to assess the impact of positive results myocardial perfusion by scores of risk as the indication of coronary angiography (CCG).
Methods: A retrospective analysis of patients referred to the Section of Nuclear Medicine for a study of myocardial perfusion SPECT (EPM), the population was divided according to sex and assessed the reason for visit: asymptomatic, uncharacteristic chest pain ( DTI) and typical pain (DT), the cardiovascular risk factors, the results of the PEG, and the results of EPM Were followed up to 2 months for those patients with EPM (+) as the indication of CCG.
Results: 700 patients were included. Men n 456 (66%) female n 244 (34%) p: 0.0001; no significant differences between sexes in high blood pressure, smokers and diabetics; dyslipidemia men n=241 (53%) vs female n 158 (65%) p=0.003; Asymptomatic men n 243 (54%) vs. 76 female n (31%), p = 0.0001; DTI men n 123 (26%) vs female n 120 (49 %), p 0.0001, DT men n 90 (20%) vs female n 48 (20%), p ns. The PEG was positive in 127 men (27%) and 59 women (24%), p ns, while it was negative in 329 men (73%) and 185 women (76%), p ns. The EPM were positive 242 patients; 187 (77%) men Vs 55 (23%) women p: 0.0001. When we compared the clinical presentation and positive EPM we found no significant difference between the sexes. Subsequently evaluated patients with positive PEG; EPM was also positive in 127 men (68%) and only 25 women (45%), p 0.003, then compared PEG positive and negative EPM find 60 men (32%) and 30 female (54 %), p 0.005.Of all women screened, 22% (n 55) showed EPM (+), of which 13% (n 11) was CCG; within this group, CCG was prescribed mainly to patients with SDS> 5 (moderate -high risk), 4 p (27%) vs 11 p (73%) that were not at CCG p: 0.03.
Conclusions: Female patients are referred less often than men for the evaluation of CAD in our service. The most frequent symptom in women is the DTI. The typical chest pain and positive PEG women are not good predictors of myocardial ischemia as perfusion studies compared to the male population. Women have a low rate of angiographic indication.

Key words: Coronary Disease. Female. Perfusion scan. Exercise stress test.

 

INTRODUCTION
Currently, coronary artery disease (CAD) in women is the most frequent cause of mortality in developed countries, even exceeding all forms of cancer, and its impact on overall mortality is greater in women than in men. CAD as a cause of death in women has increased in spite of the advancements in its diagnosis and treatment. This presents us with the existence of an underestimation by physicians of the significance of CAD in the female population, especially at a young age [1].

The last figures published in USA indicate that 500,000 women suffer acute myocardial infarction yearly and 250,000 die by CAD every year. Besides, because of the increase in the population aging, the number of women that die yearly of cardiovascular causes is increased year after year. Probably because the belief persists that cardiovascular disease is a male pathology, women themselves do not perceive the magnitude of the problem they are facing, and this entails a somehow inefficient approach, being underdiagnosed and with incomplete treatments because of the bias that women present a lower prevalence. Identifying the symptoms of CAD in women may be very complex and may lead to an unwanted delay in therapeutic management. There is evidence that the female population has different characteristics both in the way of clinical presentation of CAD, with a greater proportion of atypical angor, and also differences in the stress test response [2,3].

Although prevention campaigns have been made as “Go Red” and “Red Dress”, only 55% of women in the last surveys acknowledged cardiovascular diseases as the first cause of death and only 15% really perceived this as a significant risk for their health [4].

Although the mortality rate of cardiovascular etiology has declined over the last 20 years in the group of men, such phenomenon has not been observed in the female gender.

Currently, we don’t have concrete data available about our population, and the aim of our work is making a contribution in this field. For these reasons, the goal of this paper is analyzing the form of presentation of CAD, associated risk factors, ways to evaluate it, graded exercise test (GXT), myocardial perfusion imaging (MPI), and coronary angiography (CAG) and whether there are really differences in relation to gender [5].

 

MATERIAL AND METHODS
A retrospective analysis was made on 700 patients sent to the Nuclear Medicine Section of the Hospital Italiano of the city of La Plata, with known or suspected CAD, to undergo a gated spect myocardial perfusion study.

They were questioned about the presence of precordial pain. We defined the symptomatic patients as those that presented typical precordial pain (TP) (“substernal pain caused by strain or emotional stress that is relieved with rest or nitroglycerin”) or non-typical chest pain (NTP) (“pain that does not meet one or more of the 3 requirements mentioned when defining TP”) and asymptomatic as those that were free from symptoms. We considered classical risk factors for CAD: hypertension, diabetes, hypercholesterolemia, inherited and familial history, smoking, sedentarism and obesity.

The population was divided according to gender, cardiovascular risk factors were analyzed, the reason for the visit and the results of noninvasive tests (GXT and MPI).

Finally, a follow-up at 2 months was made in those female patients with positive MPI for ischemia and we investigated whether the family doctor had requested a CAG.


Tc99m-MIBI gated myocardial perfusion spect study
A gated spect myocardial perfusion study was conducted in stress and rest, or else in pharmacological stress with dipyridamole in those patients with complete LBBB, in those incapable of performing a physical strain or in those carriers of permanent pacemaker. To perform the pharmacological stress, 0.56 mg/Kg of dipyridamole were administered in an IV infusion over 4 minutes. Sestamibi-Tc99m was used as radiotracer.

Exercise was made in an ergometer bicycle. Antianginal drugs (beta blockers, calcium blockers and nitrates) were suspended for 96 hours before the study. At the peak of exercise, 10-12 mCi of MIBI-Tc99m were injected intravenously, continuing with the challenge for an additional minute. GXT was considered positive when the patients presented angina or ST segment depression of 2 mm or more in any of the ECG leads. The perfusion images of exercise were acquired within 5-10 minutes of having completed it. Two hours later, a second dose of MIBI-Tc99m was injected (25-35mCi) to get the rest images.

Acquisition and processing
The images were obtained in a Picker Prism 2000 XP double-head gamma camera. Sixty projections were acquired with a 64 by 64 matrix, in a 180º elliptical orbit. The time of projection was 35 seconds in the stress test and 20 seconds in rest. A 20% window of symmetrical energy was used on the 140 Kev photopeak. In prefiltering, a Butterworth filter was applied, with a slice of 0.21 cycles per pixel and order of 5. The reconstruction of the cross-sectional slices was 2.5 mm with the filtered backprojection method and a ramp filter. The images were acquired in a synchronized (gated) way with the R wave of the electrocardiogram of the patient. The data were processed with the QGS software (Quantitative Gated Spect, Cedars Sinai Medical Center, Los Angeles, California). Left ventricular ejection fraction (LVEF), end systolic volume (ESV) and end diastolic volume (EDV) were obtained automatically.

Analysis of perfusion images
A semi-quantitative visual interpretation was made of the tomographic perfusion images, both in rest and in stress, using a model that divides the left ventricle into 17 segments. A score was assigned to each segment, using a 5 point score: 0= normal; 1= mild reduction; 2= moderate reduction; 3= severe reduction and 4= absence of radioactive tracer uptake.

It was estimated:

  • Summed stress score (SSS), which is defined as the sum of the points assigned to each of the segments in which the left ventricle was divided in the stress images, representing the perfusion in the peak of exercise. Summed rest score (SRS), defined as the sum of the points assigned to the segments in the images obtained in rest, representing the perfusion in this condition.
  • Summed difference score (SDS), expressing the difference between SSS and SRS, representing the degree of reversibility and thus, of myocardial ischemia.


Follow-up of patients:
the clinical follow-up consisted of personal interviews, contact by phone or through the family doctor, to learn whether the patients had been evaluated by coronary angiography (CAG). The average time of follow-up was 2 months [5,6].


Statistical analysis
The comparisons between groups of patients were made by the student’s t-test forcontinuous variables and the x2 test for categorical variables.

Continuous variables were expressed as averages +/- standard deviation. The differences between proportions were analyzed with the corresponding test (comparison of two proportions). In all of the cases, a p value lower or equal to 0.05 was considered statistically significant.

RESULTS
A total of 700 patients were studied, 456 males (66%), 244 females (34%), p=0.0001, the average age was 62±10 years in men vs. 64±10 years in women, p=NS.

About risk factors, the following results were found: hypertension 288 men (63%) vs. 168 women (68%), p=NS. Dyslipidemia 241 men (53%) vs. 158 women (65%), p=0.003; smoking 94 men (21%) vs. 36 women (15%), p=NS; diabetes 103 men (23%) vs. 51 women (21%), p=NS, obesity 243 men (54%) vs. 141 women (58%), p=NS.

As to the stress used in the perfusion study, in the case of the female gender 85% of the patients made a physical effort, and 15% underwent pharmacological stress. When analyzing physical stress, we observed that 70% reached a strain equal or higher than 5 Mets, while the remaining 30% did not reach the pre-established goal.

When we analyzed the results of the GXT, we obtained values without significant differences in both genders. Ergometer test was positive in 127 men (27%) and 59 women (24%), p=NS; while it was negative in 329 men (73%) and 185 women (76%), p=NS. (Table 1).

 

Men

Women

P

 

Men

Women

p

GXT  +

127 (27%)

59 (24%)

NS

GXT +MPI +

127 (68%)

25 (45%)

   0.003

GXT  -

329 (73 %)

185 (76%)

NS

GXT -MPI +

60 (32%)

30 (54%)

   0.005

GXT: Graded exercise test. NS: Non-significant. MPI: Myocardial perfusion imaging.

Table 1.Correlation of noninvasive studies for the diagnosis of CAD. Men vs. women.

The myocardial perfusion study was positive in 242 patients: 187 men (77%) vs. 55 women (23%), p=0.0001, with no significant differences being verified in relation to the risk scores and ejection fraction between both genders. (Table 2).

 

Men

Women

p

SSS

7 ± 8

2.5 ± 6

NS

SRS

5.6 ± 8

2.5 ± 6

NS

SDS

4 ± 5.5

3 ± 6

NS

EF %

50 ± 11

264 ± 7

NS

SSS: Summed stress score; SRS: Summed rest score; SDS: Summed difference score; EF: Ejection fraction.

Table 2. Perfusion scores and EF of the evaluated population with myocardial perfusion study. Men vs. women.

About the form of presentation of the symptoms, 243 patients of the male gender (54%) vs. 76 patients of the female gender (31%), p=0.0001, did not present symptoms of CAD (asymptomatic); uncharacteristic chest pain 123 men (26%) vs. 120 women (49%), p=0.0001, typical chest pain 90 men (20%) vs. 48 women (20%), p=NS. Thus, we can say that the atypical forms of presentation are more frequent in the female gender.

When we correlate the forms of clinical presentation in relation to the positive perfusion studies for ischemia, there were no significant differences in the groups of patients between men and women, so we can state the symptom of precordial pain is not a good indicator of ischemia in both genders. (Table 3).

 

Men

Women

P

 

Men

Women

P

Asymptomatic

243 (54%)

76 (31%)

0.0001

Asymptomatic MPI +

79 (42%)

15 (27%)

NS

NTP

123 (26%)

120 (49%)

0.0001

NTP
MPI +

41 (22%)

17 (30%)

NS

TP

90 (20%)

48 (20%)

NS

TP
MPI +

67 (36%)

23 (41%)

NS

NTP: Non-typical chest pain; TP: Typical precordial pain; MPI: Myocardial perfusion imaging.

Table 3. Correlation between the form of presentation of CAD and the results of the myocardial perfusion test. Men vs. women.

We analyzed the results of positive GXT where Spect was also positive in 127 men (68%) and only 25 women (45%), p=0.003.

Subsequently we compared the group of patients with negative GXT and positive Spect, where 60 men (32%) and 30 women (54%), p=0.005, presented ischemia in MPI. Thus, we can say by our results that there is a greater correlation between positive noninvasive studies (GXT and Spect) in the male gender in regard to their usefulness to detect the prevalence of myocardial ischemia. (Table 1).

From the total of 244 patients of the female gender evaluated with MPI, 22% presented a positive result (n=55), we followed this group for two months to analyze the degree of frequency of indication of CAG, and we observed that 13% (n=11) were sent to CAG, while 87% (n=44) were not, p=0.0001.

Finally, we analyzed whether there was a relation between the indication of the hemodynamic study and the stratified risk by positive MPI; we used the Summed Difference Score (SDS) to evaluate in this case the ischemic amount and the risk of events (death and acute myocardial infarction); in 15 patients we obtained SDS >5 (moderate – high risk), from them 4 patients (27%) were submitted to undergo CAG and the 11 remaining patients (73%) were not, p=0.03. When evaluating the group of patients with SDS considered of low risk (SDS <5), from the 40 patients included only 6 of them (15%) were evaluated by coronary angiography and 34 (85%) were not, p=0.0001. (Figure 1).

Figure 1. Relation between the indication of hemodynamic study and the risk stratified by positive MPI (summed difference score >5 or <5).

 

DISCUSSION
Currently, scientific evidence shows us that cardiovascular prevention in women should start at an early age, not only after menopause or at the time when symptoms appear [1,2].

Currently, underdiagnosis and a poor treatment of CAD in women are attributed to different factors, including differences as to epidemiology and prevalence, age of onset of symptoms, etiology and forms of presentation. Other factors to be considered are body size and the coronary arteries, menopause and hormonal state, myocardial response to aging, sensibility of the different diagnostic methods, physiological response to exercise and forms of communication of the symptoms [3,4,5].

There is a great difference first in regard to the form of presentation of CAD with greater prevalence of atypical symptoms including dyspnea, tiredness, pain mentioned as dyspepsia, nausea, syncope or just sweating. In our work, this proved, since 49% of the women evaluated with MPI mentioned uncharacteristic pain as the most frequent symptom [6,7].

About this, in women, an advanced age, a lower level of physical activity and a greater prevalence of diabetes and other co-morbidities contribute to a greater presence of silent ischemia and symptoms such as dyspnea in regard to the presentation of CAD. Besides, women usually consult later the emergency services in comparison to men when they suffer coronary symptoms, both acute and chronic. Because of this very delay, the diagnosis of many coronary syndromes is dismissed, resulting in a lower therapeutic indication and thus, a greater morbi-mortality rate [8,9,10].

In regard to the screening of CAD, the results of our work correspond to those published, where an underuse of diagnostic methods in women is denounced, thus proving the lower indication of myocardial perfusion study in the group of patients that do not present symptoms, but do present cardiovascular risk factors; from a total of 319 asymptomatic patients evaluated, 54% belong to the male gender (n=243) and 31% to the female gender (n=76); p=0.0001 [3,11,12].

About the usefulness of the different diagnostic methods to evaluate CAD, the appearance of false positive or non-diagnostic results is more likely in women in ergometer tests, caused by a lower pre-test probability of presenting the disease, poor exercise capacity and higher probability of presenting basal anomalies of repolarization in ECG. The average sensibility and specificity of the test in them is 61% and 69% [10,13,19].

In our work, when we analyzed positive GXT, we did not find significant differences between both population groups, 27% for men and 24% for positive GXT for women. When we correlated these results with the myocardial perfusion study, this was positive in 68% of men and 45% of women. These results show once again, that the ergometer test presents a scant sensibility and specificity in women. We have observed in our work in regard to the stress used in the diagnostic tests, that 70% of the group of female patients reached 5 Mets or more, thus 30% of the patients did not reach an intermediary workload. If we compare these results with the indication of pharmacological stress, only 15% of the perfusion tests indicated in women were made with pharmacological challenge, representing an underuse of this method, and thus an incomplete evaluation in this group of patients.

When we analyze negative GXT with positive MPI, we observe a greater rate in women 54% in regard to women 32%, we can say by our results that positive GXT in women is not a good predictor of myocardial ischemia according to perfusion studies compared with the male population.

For these reasons, in the group of women with intermediary risk of CAD, the use of noninvasive studies, such as stress echocardiography and myocardial perfusion studies have proven especially usefully, when discriminating with a high level of safety the patients that require an invasive study. Stress echo shows a high sensibility for the diagnosis of CAD in women, but requires the patient to have a good acoustic window [14,15].

The myocardial perfusion study has shown an independent predictor for significant coronary events, specifically the presence, size and extension of perfusion defects is the most powerful predictor of cardiac events (infarction, need to revascularize and death by cardiovascular origin) in the future, but there are two problems of significant interpretation: a) women have smaller hearts than men, which causes small defects in the radiotracer uptake to be in the inferior limit of the resolution of the detector, and b) attenuation defects by the presence of mammary tissue [16,17].

As to completing the evaluation with invasive studies, we have observed an underuse of the hemodynamic study to evaluate CAD in women. We observed in our work that from the female patients with SDS of higher risk (SDS >5), only 27% were evaluated by coronary angiography [12,15,18].

In the bibliography published, several studies have shown that the female gender is an independent predictor with a lower chance of evaluation with coronary angiography in comparison to the male gender, regardless of risk factors or degree of severity of suspected CAD; this is reflected by a lower degree of revascularization (both by angioplasty and by surgery) in this population group. However, once cardiac catheterization is made, the subsequent revascularization presents similar rates between men and women, thus proving a bias in the initial diagnosis; not so in the subsequent therapy, which is based in the type of coronary lesions regardless of the gender of the patient [1,2,19].

All these issues in relation to the female gender are also reflected in the clinical protocols of the CAD study, where in general, they have a lower proportion of women or only include men. There are scant works focused only in the female population. The interest in this group is more recent, since a growing increase has been observed in the rate of deaths by CAD in women [3,11,20].

Much has been advanced in regard to this topic when the results of the large studies were published, which add an enough number of women to show the differences.

It was considered that women were protected from this pathology by the presence of female hormones during their fertile stage, later the great usefulness of hormone replacement therapy was accepted between other reasons, to continue with the cardiovascular protection. These statements were strongly refused, especially in the results of the WHI (Women’s Health Initiative) and the HERS (Heart and Estrogen/Progestin Replacement Study). The WHI study enrolled 16,608 women, randomized to receive standard hormone replacement therapy or placebo and had to be suspended in an average of 5.2 years of follow-up (originally scheduled for 8.5 years) due to an excess of incidence of breast cancer, stroke and pulmonary embolism. In the HERS I and II studies, which enrolled post-menopausal women, by the end of 4 years of follow-up, there were no significant differences for coronary events between both groups. Both studies show not just that hormone replacement therapy in women is not cardioprotective, but that it might even increase the risk of coronary events [3,9,10,21]. We should remember that women with chest pain have a greater risk of cardiovascular events [22].

To conclude, we should mention that there is not a clear explanation for these differences between men and women; factors such as the lower caliper of epicardial vessels and the microvascular vasculature, the increase of arterial rigidity suggesting a greater fibrosis and an alteration of arterial vascular remodeling, diffuse atherosclerotic disease and a greater endothelial dysfunction have been proposed as factors for example [16,17]. All these reasons make the diagnosis of CAD in women difficult, in comparison to men.

Women with chest pain are a group of patients in whom it would be appropriate to focus efforts to reduce morbi-mortality and to improve the quality of life of this population [22].

A change in the attitude of the different health care environments is necessary to enable an earlier diagnosis of CAD in women and thus increase the appropriate use of diagnostic and therapeutic procedures in them, in a proportion to the severity of the symptoms they present.

 

CONCLUSIONS
Female patients with suspicion of CAD are referred, as these results show, with a lower frequency than men to undergo MPI for the evaluation of CAD. The most frequent symptoms of for consultation are NTP, typical precordial pain and positive ergometer test in women, which are not good predictors of myocardial ischemia compared with the male population, and the rate of referral to angiographic studies, when MPI are positive is low, less than in males.

The population of evaluated women in this study presents particular characteristics both in its clinical presentation and in the diagnostic and therapeutic procedures indicated to treat CAD.

 

REFERENCES

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Publication: September 2013

 
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