Why gender is a crucial — but overlooked — factor in heart disease

by Vera Regits-Zagrosek, MD for Elsevier:In most European countries, women with myocardial infarction come much later to emergency departments than men. Once in the hospital, they are diagnosed later than men. Diagnosis does not always lead to a positive result, and syndromes specific to women are frequently missed.Women are also later treated later than men, they are treated less intensively, and they receive less medication and information when they are sent home. If they do receive drugs, they face a greater chance of having adverse effects and inadequate dosing than men. While the situation has improved over the last few years in most European countries, the problem still persists.Moreover, it’s a problem that plagues many other diseases. Other common diseases with gender differences include diabetes, renal and endocrine disorders, cancer, and inflammatory and metabolic diseases.Therefore, we do need gender sensitive lenses in all medical disciplines – and we need one discipline that makes and provides the lenses to others.6 problems that plague cardiovascular care for womenA variety of issues have been preventing women from getting better care and treatment for heart disease. They include:

• Lack of awareness. Women and their doctors are not well aware that cardiovascular diseases are the most frequent causes of death in women. Women are often not tuned to complain on the same few lead symptoms of myocardial infarction as men. They are often more sensitive and mention many more bodily problems and complaints then men, and this confuses the doctors in charge. On the other hand, men underestimate psychosocial causes of disease, such as depression and stress.
• Lack of knowledge among doctors. Women do frequently have a different underlying patho­physiology then men. Women with an acute coronary syndrome – in men most frequently caused by rupture of an atherosclerotic plaque – may have stress-induced heart disease, they may have dissections (longitudinal ruptures in the walls of arteries), they may have functional disorders of the coronary arteries such as spasms, or they may have disturbances of the microcirculation. This diversity of disease mechanisms leads to symptoms that deviate from the straightforward picture in men – different localization, different triggers of pain, different time course and render diagnosis of the underlying problem difficult.
• Pathophysiology of women- and men-specific cardiovascular syndromes is poorly understood. There is a lack of research, a lack of research funding, a lack of animal models and a lack of researchers that understand these problems. Estrogen and estrogen receptors and testosterone in men do their best to drive the cardiovascular system into specific directions in both genders and make it sensitive to specific risks and stress factors. Activation of the coagulation system, of the immune system and myocardial and vascular function and growth occurs in a gender specific manner. Stress-induced heart disease may occur as adrenergic overstimulation in women, when the hormonal brake on catecholamine function in the myocardioum is lost after menopause. Coronary dissections may occur because of overstimulation with sexual hormones in pregnancy. The functional disorders of the coronary arteries, such as spasms or disturbances of the microcirculation, may arise as a consequence of the disturbed interaction of estrogen with the vasoprotective nitric oxide system, which is probably more pronounced in women than in men. Heart failure develops with different clinical characteristics in women and men, with more diastolic failure (defects in relaxation) in women, more systolic failure (defects in pump function) in men. In men, poorly understood syndromes include sudden death in younger athletes (about 90 percent of whom are men), and the mechanisms are poorly understood.
• Lack of gender-sensitive diagnosis strategies. Standards of diagnosis are often insufficient in women: spasms are only detected if specific trigger substances that are not included in routine diagnosis (for example, acetylcholine) are injected, and disorders of the microcirculation need specific imaging approaches. Exercise testing is less sensitive in women than in men, and the more expensive imaging modalities that can show under perfusion of a given myocardial area are not always available, and doctors may not be aware when they need to use them. This may be one of the reasons the standard angiographic approach leads to much more negative investigations in women than in men, best documented in the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) study.
• Use of therapies and therapeutic outcomes also differ between genders. Women have a higher mortality after a myocardial infarction than men. They have more bleeding complications after percutaneous interventions (PCI). They have a higher mortality after aorto-coronary bypass surgery. Women have better effects with the more expensive re-synchronization therapy, but this expensive therapy is less frequently used in women.
• Drugs are less well adapted for women than for men, and female-specific drugs may not be detected since more than 80 percent of animal research in cardiology is done in male rodents. Sex differences in survival have been shown for experimental drugs. A number of cardiovascular drugs do have more adverse effects in women than in men. More arrhythmia with QT prolongation, more bleeding complications, more adverse effects of digoxin and more adverse effects of lipid lowering drugs have been reported. Furthermore, woman receive less effective drugs after a myocardial infarction. They also receive less counseling in particular for lifestyle, rehabilitation and sexual life.

How to apply a gender lens to all medical careTo overcome these problems, it’s crucial to apply a gender-sensitive lens to all medical care. Coronary artery disease is just one example. Gender differences impact many other medical areas, including oncology, nephrology and endocrinology. Therefore, we do need gender sensitive lenses in all medical disciplines – and we need one discipline that makes and provides the lenses to others.Providing gender lenses means providing gender-sensitive tools and methods, largely disease independent, as lenses are independent of the objects they perceive. Here’s how to achieve that:

• Use male and female animals in drug development. Develop gender-sensitive animal models, for example, with gonadektomie and hormones substitution at the right time points, genetic modification of sex hormone receptors and their downstream effectors, sex specific agonists and antagonists.
• Analyze the pathomechanisms behind sex differences in animal models and in cell cultures. Document the sex of your cells. Conclusions will be applicable to many diseases since general events like cell death and survival, proliferation, immune response and energy metabolism are sex-specific and play a role everywhere.
• Provide information on gender sensitive risk factors in the human by well-designed epidemiological studies, and analyze interaction of gender and age. Elaborate risk factors that play a specific role in one sex include sex hormone status, sexual function, number of children (in both), number of stillbirths in women, education, socioeconomic status, nutrition, stress, environmental factors, and awareness of major risk factors.
• Provide information on gender sensitive disease manifestation and symptoms. Make sure doctors understand these.
• Develop gender-sensitive diagnostic tools and gender-sensitive treatments. The latter shall start early in drug development, and translation should be kept in mind.
• Include sufficient numbers of women and men in clinical studies. Develop tools for gender analysis and study design that does not just require doubling of all numbers.

How to design the gender lensA variety of factors can encourage more and better research in gender medicine:

• Interdisciplinary study teams. Training in knowledge on the basis of sex and gender differences – at genetic, epigenetic, molecular, pharmacological, psychological, and sociological level.
• Training opportunities for researchers, systematic teaching for students to attract the best.
• Career opportunities for researchers – no qualified researchers will go in areas without it.
• Scientific exchange – to implement cross sectional studies.
• Funding.
• Awareness among policy makers.

Advancing the field of gender medicineOrganization of gender medicine (GM) is crucial for its success. Institutes of gender medicine are needed to drive scientific progress in GM, since scientific achievements always require the development of scientific aims, hypotheses and methods – that is, all elements of good mechanistic research. Mechanistic research can be done in the field of biology, genetics and physiology, and also in the field of psychosocial and socioeconomic determinants of health. These elements can then be exported to other disciplines where gender research functions as a cross-sectional element. If these mechanistic core elements that are developed in the institutes of gender medicine are not available, sex and gender research will be limited to “head counting” – comparing numbers of women and men without adequate consideration of sex- and gender-specific confounders and understanding of mechanisms.In addition, risk factors that play a specific role in one sex should be included in major databases and registries. These include sex hormone status, sexual function, number of children (in women and men), number of stillbirths in women, education, socioeconomic status, nutrition, stress, mental health factors, environmental factors, and awareness of major risk factors.Source: http://bit.ly/2oucaSt