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Cardiovascular disease - more attention required for women

Cardiovascular disease (CVD) is by far the leading cause of death in industrial countries. However, there are significant differences by continent/region, and even more so in terms of gender. There have also been some major recent changes in the evolution of CVD, compared to another major source of mortality - cancer. Once again here, there are some female-specific factors of interest.

 

The US and Europe
For Europe as a whole, latest figures from the World Health Organization (WHO) show CVD accounting for 45percent of deaths, approximately the same level as the US, where the figure is 44percent.
Cancer is the second largest cause of death in both the US and Europe. However, a significant margin separates its mortality impact from CVD.
There are also differences between the US and Europe in the relative impact of CVD versus cancer. In the former, cancer accounts for 32percent of deaths (or almost three-fourths of that from CVD). In Europe, the share of cancer is less than half CVD deaths. The WHO data cover 52 countries in Europe, including all members of the European Union (EU).

A man's illness ?
Traditionally, heart disease was thought of as a man's' illness, although approximately the same number of women and men died each year of heart disease in the US and the EU.
Indeed, gender issues in CVD deaths are significant, both in the US and Europe. Although a higher number of males die in the US from CVD as compared to females, the share of CVD as a cause of death is only slightly higher in American women (44.3percent vs. 43.4percent).
In Europe, the gap is far more dramatic, with CVD accounting for 51percent of deaths among women and 42percent among men.

Cancer replaces CVD as leading cause of death in northern/western Europe
There are nevertheless considerable divergences across European countries in CVD mortality as well as in recent changes in death rates due to CVD.
In ten advanced EU countries, more men now die from cancer than CVD. These countries are Belgium, Denmark, France, Italy, Luxembourg, the Netherlands, Portugal, Slovenia, Spain, and the UK. The case is the same for an EU non-member, Norway. Conversely, the highest numbers of deaths from CVD tend to be seen in Eastern European countries.
In much of Europe, however, latest WHO data show more than double the number of deaths from CVD compared with cancer, in women. 15 countries in this group report CVD causing more than four times the number of deaths in women as cancer, compared to only 6 for men.
Meanwhile, death rates from CVD have declined in all countries over the past ten years. However, in some countries, women have seen a relatively lower fall than men in age standardized mortality rates, over the period. These include Luxembourg (50percent for men vs. 42percent for women), the Netherlands (39percent vs. 32percent) and Sweden (31percent vs. 26percent), and to some extent Ireland, Italy and Switzerland.

Raising awareness
One immediate priority for health professionals and policy makers is to raise awareness about CVD and women. Currently, Red Day', Go Red for Women' and Women at Heart' campaigns by professional societies and patient groups in the US and Europe have sought to boost awareness further, and do this faster.
The reasons for this are evident. In the US, just over half of women surveyed recognize heart disease as their Number 1 killer, according to a 12-year follow-up study published in 2010 in Circulation: Cardiovascular Quality Outcomes'.
Nevertheless, the situation had improved significantly compared to the baseline year of 1997 when only 30 percent identified heart disease as the leading killer of women, with 35 percent believing that cancer took this role.
The situation is worse in parts of Europe. In Ireland, for example, a recent Irish Heart Foundation report showed that less than one in 5 Irish women knew CVD as being the leading cause of female mortality.

CVD protection in younger women
The reasons for believing CVD was a man's' disease (as mentioned above) were not simply hearsay. Women are protected by their hormones against CVD during their child-bearing years. However, this protection is lost as soon as they enter menopause. The net result is that women tend to get CVD at an age about 10 years more than men.
To complicate matters, CVD symptoms in women are sometimes different from those in men. This adds to under-recognition of heart disease in women. For example, heart attack symptoms in women such as chest pain can be less profound than in men. Women may only feel an uncomfortable pressure in the chest centre which occurs sporadically or lasts a few minutes, or experience pain in one or both arms, their neck, back or stomach, along with shortness of breath and accompanied by a cold sweat, nausea, vertigo and weakness. Moreover, it has also been established that women have a higher prevalence of silent ischemia and of unrecognized myocardial infarction than men.
As a result, both women and physicians need to be trained to recognize female-specific symptoms.

HRT and CVD risks
One of the beliefs which has endured for several decades is that the estrogen drop during menopausal transition induces increased post-menopausal CVD risk in women, probably through harmful changes in CVD risk factors. One of the findings supporting this conclusion was that women who reached menopause before the age of 40 had a two-year lower life expectancy than women with a normal or late menopause.
Indeed, circulating estrogens do have a regulating effect on several metabolic factors, such as lipids, inflammatory markers, and the coagulation system.
This was the reason for the popularity of Hormone Replacement Therapy (HRT), or exogenous estrogens. Until recently, HRT was recommended for use in post-menopausal women to limit CVD risk. The hypothesis was supported by several observational studies, but could not be conclusively proved in large randomized trials. Instead, HRT was shown to increase CVD event rate in older (>60 years) post-menopausal women. As a result, clinicians now recommend a careful evaluation of the risk/benefit of HRT replacement for preventing CVD, and the use of HRT has declined.

Concurrent risk factors for women
Other, concurrent risk factors include hypertension, hypercholesterolemia, hypertriglyceridemia and metabolic syndrome. These increase in women over the age of 45, or a few years before menopause.
For example, systolic blood pressure rises steeply in older women compared with men. Hypertension is associated strongly with a higher prevalence of left ventricular hypertrophy and diastolic heart failure (HF). Studies have shown that even borderline hypertension (less than 14/9 cm Hg) causes more cardiovascular complications in females than in men.
At younger age, the prevalence of hypercholesterolemia is lower in women than men, but at over 65 years age, mean LDL-cholesterol levels are higher in women. Hypertriglyceridemia and low HDL-C levels are far more important risk factors for CVD in women than for men, as discussed below.

Type 2 Diabetes
Nevertheless, of the biggest areas of concern is Type 2 diabetes mellitus, which poses a much higher greater risk for cardiovascular complications in women than in men.
One meta-analysis of 37 prospective cohort studies published in the British Medical Journal' in December 2006 found mortality risk to be 50percent higher in women with diabetes compared with men. In addition, it has been shown that Type 2 diabetes is a potent, independent risk factor for heart failure in women. However, this cannot be fully explained by coexisting cardiovascular risk factors or previous myocardial infarctions.

Lifestyle factors
Lifestyle changes also play a role. Obesity, for example, is a major CVD risk factor. It is more prevalent in men under the age of 45, but has begun to increase with advancing age in women, reducing the gap with time, and often reversing it in older women. This was one of the findings of a report called European Heart Health Strategy: Red Alert on Women's Hearts', published in 2009 by the EuroHeart Project, funded by the EU Commission and conducted jointly by the European Heart Network (EHN) and the European Society of Cardiology (ESC).

Women and clinical trials
The case of HRT, where findings from large randomized trials reversed those of observational studies, has brought another priority to the forefront, namely to increase the presence of women in CVD clinical trials.
The EU-funded EuroHeart project (see above) found women to be under-represented in many trials, even where important gender differences are present within most areas of heart disease. The proportion of women enrolled was 27-41percent, even though the female prevalence of clinical conditions under study in the general population was similar for both men and women.
The case in the US is similar, in spite of a legal requirement that research funded by tax receipts must include women and minority groups. One study found that trials by the National Heart Lung and Blood Institute, attached to the National Institutes of Health (NIH), enrolled 38percent women for the years 1965-1998. This fell further to 27percent in 1997-2006. Furthermore, only 13 of 19 studies analysed gender differences.

Apart from the traditional belief that CVD was a man's' disease, some experts believe that cost may also have been a consideration in under-recruitment of women, whose hormonal fluctuations tend to complicate pharmacokinetic and pharmacodynamic analysis.
Nevertheless, given the growing burden of CVD in middle-aged women relative to men, it is evident that greater gender-specific cardiovascular research is required to adapt existing guidelines for better cardiovascular health in women.

Pregnancy as stress test for future CVD
There is intriguing evidence that pregnancy might be a useful stress-test' for future CVD risk. Hypertensive disorders in pregnancy have been shown to be predictors for CVD events in later life. Impaired glucose tolerance and gestational diabetes in pregnancy are also female-specific risk factors for the development of diabetes and metabolic syndrome in young women.
One of the conditions under close scrutiny is pre-eclampsia, which is characterized by high blood pressure and large amounts of protein in the urine. Although the etiology of pre-eclampsia has yet to be established with certainty, the hyperlipidemia of normal pregnancy (elevated total cholesterol and triglycerides) becomes more extreme in women developing the condition. The sharp growth in triglycerides leads to increased production of LDL (up to 3-4 times more than in a normal' pregnancy), along with reduced HDL-C. Together, this contributes to endothelial dysfunction.
One ongoing trial at Brigham and Women's Hospital in Massachusetts seeks to demonstrate an association between pre-eclampsia during pregnancy and altered blood vessel function and abnormal hormone levels in later life. The trial, known as Preeclampsia: A Marker for Future Cardiovascular Risk in Women' commenced in 2012. Its results are expected to be published in the near future.


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