Cardiovascular diseases (CVDs) affect women and men differently, with variations between the sexes in the age at which CVDs manifest and their impact on survival. Diabetes and hypertension are more severe risk factors for CVD in women and sudden death is more frequent in men. It is important that those involved in disease treatment and drug discovery and development are aware of these differences.
Differences in the clinical presentation of coronary artery disease are of particular relevance, as they could contribute to a delay in the diagnosis of CVD in women. Women present less frequently with typical exercise angina, and the sensitivity and specificity of diagnostic procedures in women are different from in men.
Receptors for the sexual hormones oestrogen, progesterone and androgen (ERs, PRs and ARs, respectively) mediate sex-specific effects in the cardiovascular system. These receptors act by genomic and non-genomic mechanisms. The two known oestrogen receptors, ERα and ERβ, modulate myocardial gene expression, hypertrophic and apoptotic signalling, ion channels, metabolism and function; vascular ERs exert vasoprotective effects, including fast vasodilation via nitric oxide, reduction of leukocyte adhesion and inhibition of vascular smooth-muscle-cell proliferation.
Drugs commonly used to treat CVD include digitalis, angiotensin-converting enzyme inhibitors, beta-blockers, aspirin and anti-arrhythmic drugs. However, these drugs have gender-specific side effects, and the incidence of these side effects is higher in women; in particular, QT-interval-prolonging drugs cause more life-threatening arrhythmia in women.
There are several differences between women and men in drug pharmacokinetics. These include drug absorption and metabolism, and are frequently related to the cytochrome P450 system. Because lower numbers of women patients are included in cardiovascular trials, there is a lack of safety and efficacy data in women.
There is considerable knowledge of the role of gender in CVD and its treatment, and so a systematic search for gender-related differences in the pharmacodynamics and pharmacokinetics of drugs should be integrated into all phases of drug development, from preclinical studies through Phase I and II testing to large-scale clinical trials.
The manifestations of cardiovascular diseases differ between men and women, as do outcomes after therapeutic interventions. It is important that those involved in drug discovery and development, as well as disease treatment, are aware of these differences because such variations are likely to have an increasing role in therapeutic decisions in the future. Here, I review gender differences in the most frequent cardiovascular diseases and their underlying sex-dependent molecular pathophysiology, and discuss gender-specific effects of current cardiovascular drugs and the implications for novel strategies for drug development.
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I thank S. Brokat for help with Figure 1, S. Eder and S. Mahmoodzadeh for Figure 2, E. Lehmkuhl for literature research and evaluation and A. M. Gale, Editor in the Life Sciences, for editorial assistance. My warm thanks go to M. Prescott, Novartis, New Jersey, USA, for many fruitful discussions and suggestions and to E. Zagrosek for very helpful thoughts. The support of the Deutsche Forschungsgemeinschaft, the BMBF (Competence Network Heart Failure) and the Centre for Gender in Medicine (GiM) in Berlin, Germany, is gratefully acknowledged. I also would like to acknowledge the work of many authors whose original work, due to space restrictions, could not be referenced and had to be quoted as being discussed in earlier reviews.
The author declares no competing financial interests.
- QT interval
The QT interval represents the time for electrical activation and inactivation of the ventricles, the pumping chambers of the heart. Prolongation of the QT interval can result in potentially lethal arrhythmias (some of which are known as torsades de pointes).
A narrowing of the coronary arteries, frequently as a result of arteriosclerosis, that leads to the chest pains known as angina pectoris.
The use of ultrasound to image structural and functional abnormalities of the heart.
- Cardiac catheterization
A procedure in which a catheter is introduced into the heart and contrast material is injected to visualize the right and left ventricles, as well as the coronary arteries.
- Myocardial hypertrophy
Physiological (pregnancy, training) or pathological growth of the myocardium. Pathological myocardial hypertrophy is a major risk factor for heart failure.
- Diastolic heart failure
A condition in which the heart contracts normally, but the ventricle does not distend correctly and so filling of the heart is impaired.
- Systolic heart failure
A condition in which inadequate contraction of the heart leads to reduced cardiac output.
- Autosomal dominant
A mode of inheritance that requires that the mutation of a single gene be present on either of the paternally and maternally derived alleles for the clinical phenotype to be expressed.
- Population-attributable risk
The percentage of risk that can be attributed to a given risk factor in a population.
- Android obesity
Obesity typically seen in males, which is characterized by visceral fat accumulation.
A deficiency of sodium in the blood.
A deficiency of potassium in the blood.
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Regitz-Zagrosek, V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 5, 425–439 (2006). https://doi.org/10.1038/nrd2032
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