Impact of sex on clinical outcome in early Multiple Sclerosis.

BACKGROUND: Previous evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are lacking. We aim to quantify the impact of sex on clinical outcomes in early-stage RRMS. METHODS: Utilizing prospective cohort data, we assessed the impact of biological sex on time-to-relapse, disability progression (Expanded Disability Status Scale [EDSS]), extremity function (Nine-Hole Peg Test, Timed-25-food walk test), cognition (Paced Auditory Serial Addition Test, Symbol Digit Modalities Test), quality-of-life (Hamburg Quality of Life Questionnaire in Multiple Sclerosis, Short-Form-36), fatigue (Fatigue Severity Scale, Fatigue Scale for Motor and Cognitive functions), and depression (Beck Depression Inventory-II) in clinically isolated syndrome (CIS) or RRMS patients. Inclusion was within 12 months of symptom onset. Linear, negative binomial, mixed, and Cox models estimated male vs. female effects at the four-year follow-up including baseline-to-follow-up course. RESULTS: We included 149 patients (65.1 % female). Eighty-five completed four-year follow-up. No sex differences in time-to-relapse emerged (HR = 0.91;95 %CI = 0.53-1.58). Males had no increased risk of EDSS worsening (OR = 0.75;95 %CI = 0.21-2.35) compared to females. Similarly, minor/no sex differences emerged in other outcomes. CONCLUSIONS: Four years after first manifestation, neither disease activity (disability progression and relapse rate) nor patient-reported outcomes showed sex-related disparities in this early-MS-cohort. GOV IDENTIFIER: NCT01371071.

[Update of the ESC guidelines 2018 on cardiovascular diseases during pregnancy : Most important facts]. / Update 2018 der ESC-Leitlinie zu kardiovaskulären Erkrankungen in der Schwangerschaft : Die wichtigsten Fakten.

Heart diseases are the most common cause of maternal death during pregnancy in Western countries. The current ESC guidelines 2018 for the management of cardiovascular diseases during pregnancy is a guide for any physician facing the challenge of caring for pregnant women with cardiovascular diseases. Among the new concepts compared to 2011, are recommendations to classify maternal risk due to the modified World Health Organization (mWHO) classification, introduction of the pregnancy heart team, guidance on assisted reproductive therapy, specific recommendations on anticoagulation for low-dose and high-dose requirements of vitamin K antagonists and the potential use of bromocriptine in peripartum cardiomyopathy. The Food and Drug Administration (FDA) categories A-D and X should no longer be used. Therefore, the table of drugs was completed with detailed information from animal and human studies on maternal and fetal risks. The new findings on specific heart diseases are presented in detail in the respective chapters.

[Gender and cardiovascular diseases : Why we need gender medicine]. / Geschlecht und Herz-Kreislauf-Erkrankungen : Warum wir Gendermedizin brauchen.

Gender medicine is concerned with the question of why diseases are expressed differently in the genders. It takes differences between men and women into account, which are often neglected by traditional medicine. Sex differences can also be found in cardiovascular diseases; therefore, risk factors for cardiovascular diseases have a different significance depending on the sex. Diabetic diseases tend to promote the occurrence of coronary heart disease (CHD) more strongly in women than in men. Myocardial infarctions affect women 10 years later than men and young women are often treated too late, possibly because myocardial infarction is consider to be a "male disease". The number of cases of coronary syndrome is significantly increasing, particularly in young women. Some of the diseases which predominantly occur in women are takotsubo cardiomyopathy, microcirculation disorders and spontaneous coronary artery dissection. Pharmacological treatment of CHD is principally the same in men and women but attention must be paid to differences in the pharmacokinetics of important drugs. Coronary dilatation has comparable effects in both men and women but more complications occur in women. Cardiac failure with impaired left ventricular systolic function affects more men than women in the Western world but the opposite is true for cardiac failure with preserved left ventricular ejection fraction. Hypertrophic and dilatative cardiomyopathies are more frequent in men. Many of the drugs used to treat cardiac failure have different actions in men and women. Too little attention is paid to the pharmacokinetics and pharmacodynamics in women when testing active agents; however, awareness of the differences that need to be considered is growing.

[Sex and gender differences in pharmacotherapy]. / Geschlechterunterschiede in der Pharmakotherapie.

Many drugs have act differently in women and men. Biological differences between women and men lead to sex differences in pharmacokinetics, i.e., in drug absorption, distribution in tissues, metabolism by liver enzymes, and excretion via the kidney and intestine. In addition there are sex differences in pharmacodynamics, leading to a different efficacy of drugs in women and men. The biological differences between women and men may be caused by sex-specific gene expression, by sex-specific epigenetic modifications, and finally by the effect of sex hormones. In addition, gender plays a role in drug efficacy as a sociocultural dimension that may lead to differences between women and men. Frequently drugs are only tested on animals of one sex and thereby optimized for one sex. This is based on the notion that sex differences are not important for clinical drug effects. Furthermore, to date, sex and gender differences have been underestimated in clinical studies, and phase III studies were not prospectively designed to assess sex differences in drug effects. In addition, women and men use drugs differently with respect to compliance, adherence, and self-medication with over-the-counter drugs. Further, it is known that male and female physicians treat women and men as patients differently. In conclusion, drug therapy is not yet optimized for both genders. However, there is increasing awareness that differences between women and men should be respected in order to provide optimal drugs in optimal doses for both genders.

Gender-specific predictors of early mortality after coronary artery bypass graft surgery.

BACKGROUND: Female gender is a risk factor for early mortality after coronary artery bypass graft surgery (CABG). Yet, the causes for this excess mortality in women have not been fully explained. OBJECTIVES: To analyse gender differences in early mortality (30 days post surgery) after CABG and to identify variables explaining the association between female gender and excess mortality, taking into account preoperative clinical and psychosocial, surgical and postoperative risk factors. METHODS: A total of 1,559 consecutive patients admitted to the German Heart Institute Berlin (2005-2008) for CABG were included in this prospective study. A comprehensive set of prespecified preoperative, surgical and postoperative risk factors were examined for their ability to explain the gender difference in early mortality. RESULTS: Early mortality after CABG was higher in women than in men (6.9 vs. 2.4 %, HR 2.91, 95 % CI 1.70-4.96, P < 0.001). Women were older than men (+4.7 years, P < 0.001), had lower self-assessed preoperative physical functioning (-16 points on a scale from 0 to 100, P < 0.001), and had higher rates of postoperative low cardiac output syndromes (6.6 vs. 3.3 %, P = 0.01), respiratory insufficiency (9.4 vs. 5.3 %, P = 0.006) and resuscitation (5.2 vs. 1.8 %, P = 0.001). The combination of these factors explained 71 % of the gender difference in early mortality; age and physical functioning alone accounted for 61 %. Adjusting for these variables, HR for female gender was 1.36 (95 % CI 0.77-2.41, P = 0.29). CONCLUSIONS: Age, physical function and postoperative complications are key mediators of the overmortality of women after aortocoronary bypass surgery. Self-assessed physical functioning should be more seriously considered in preoperative risk assessment particularly in women.

Implementation of pharmacotherapy guidelines in heart failure: experience from the German Competence Network Heart Failure.

AIM: To evaluate the implementation of current pharmacotherapy guidelines of heart failure and to identify factors associated with high pharmacotherapy guideline adherence in heart failure patients. METHODS AND RESULTS: We pooled data from seven studies performed in the context of the German Competence Network Heart Failure selecting patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) <45% (n = 2,682). The quality of pharmacotherapy was evaluated by calculating the guideline adherence indicator (GAI), which considers three (GAI-3) or five (GAI-5) of the recommended heart failure substance classes and accounts for respective contraindications. GAI-3 was categorized as perfect (GAI = 100%: 71% of the cohort), medium (GAI = 50-99%: 22%), and poor adherence (GAI <50%: 7%). In ordinal regression, the following factors were positively associated with perfect adherence: history of revascularization (odds ratio 1.59, 95% confidence interval 1.27-1.98), prior ICD implantation (2.29, 1.76-2.98), and LV ejection fraction <30% (1.45, 1.19-1.76), whereas age (per 10 years; 0.82, 0.77-0.89), NYHA III/IV (0.15, 0.12-0.18), unknown duration of heart failure (0.69, 0.53-0.89), and antidepressant medication (0.61, 0.42-0.88) were negatively associated with perfect adherence. Better GAI-3 at baseline predicted favorable changes of LV ejection fraction and end-diastolic diameter after 1 year. One-year mortality risk was closely related to GAI-3 in both groups of NYHA functional class I/II (excellent vs. poor GAI-3: 7.2 vs. 14.5%, log rank = 0.004) and class III/IV (13.5 vs. 21.5%, log rank = 0.005). CONCLUSIONS: This large pooled analysis showed that a high level of guideline adherence is achievable in the context of clinical studies. Those receiving and tolerating optimal pharmacotherapy experience a better prognosis. Nevertheless, the implementation of heart failure medication needs further improvement in female and elderly patients, especially those in NYHA functional class >II and patients with LVEF ≥30%.

eNOS phosphorylation and translocation are altered in male but not female mice by increased activation of the Gαq protein.

Little is known about sex-dependent physiological and pathophysiological differences in cardiac endothelial nitric oxide synthase (eNOS) expression and activation. Therefore, we investigated cardiac morphology and eNOS protein expression, including its translocation-dependent activation and phosphorylation, in cardiac tissue of male and female wild-type mice and transgenic heart-failure mice having a cardiac-specific, 5-fold overexpression of the Galphaq protein. In addition, we measured calcineurin protein expression. Heart-to-body weight ratio was increased in Galphaq mice. Female wild-type mice showed higher eNOS protein expression and activation (translocation and phosphorylation) than did wild-type males. In cardiac tissue of Galphaq mice, these sex-dependent differences remained or were enhanced. Protein expression of the catalytic subunit calcineurin A, which has been shown to dephosphorylate eNOS, was higher in wild-type males than in wild-type females. These differences were increased in the Galphaq mice model. We conclude that sex differences exist in cardiac eNOS protein expression and phosphorylation. Increased activation of the Galphaq protein appears to alter eNOS protein expression and phosphorylation only in males.

[Gender differences in psychopharmacology]. / Geschlechterunterschiede in der neuropsychiatrischen Pharmakotherapie.

At least half of all patients with psychiatric disorders are female. Depressive disorders occur twice as often in women than in men. Despite the need for a gender-specific approach in treating psychiatric disorders, little is known about gender issues in psychopharmacology. It has been recognized that women respond better than men to serotonin-modulating substances but that this effect is reversed after menopause. Furthermore, women develop gynecological complications under medication with certain psychopharmacological agents which calls the use of these drugs into question. Side effects such as weight gain, hyperglycemia, cardiac arrhythmias, and sexual dysfunction also occur more frequently in women than in men. Pregnancy is a particularly sensitive aspect. The risk that a mother with a psychiatric disorder could relapse if the drug is discontinued has to be weighed against the risk of the child being born with an anomaly or developing prenatal complications.

[Sex differences in cardiovascular drug targeting]. / Geschlechterunterschiede in der kardiovaskulären Pharmakotherapie.

Women and men differ in drug needs and drug metabolism. Usually women are smaller and lighter and have a higher body fat percentage and lower kidney function. Primary drug-metabolizing enzymes in the intestinal wall and liver, which are part of the cytochrome P450 family, have different activities in men and women. Their substrates (beta-blockers, blockers of calcium channels such as nifedipine and verapamil, cyclosporine, and many others) are metabolized differently. Sex differences were observed after administration of digitalis, which is often overdosed in women. Furthermore, beta-blockers are found at higher plasma levels in women and ACE inhibitors cause more side effects in women than in men. In women, acetylsalicylic acid provides effective primary prophylaxis against stroke but not myocardial infarction. In men, these drugs have opposite effects. Anticoagulants and thrombolytics often lead to bleeding complications in women, QT prolonging drugs produce more frequently arrhythmia. It is therefore very important to control drugs following approval and to look out for these differences between men and women.

[Anticoagulation and thrombophilia in pregnancy]. / Antikoagulation und Gerinnungsstörungen in der Schwangerschaft.

A review of coagulation disturbances during pregnancy and the current management of the anticoagulated patient with heart valve prostheses, atrial fibrillation, and thromboembolic events is presented. All patients with mechanical heart valve prostheses require life-long oral anticoagulation with coumarin or one of its derivatives. Recommendations for the treatment and prevention of thromboembolic events are discussed. The advantages and disadvantages of three different treatment approaches to anticoagulation during pregnancy are discussed and recommendations for the management in different situations are outlined with delineation of specific risks for the mother and the fetus.

[Heart failure--are there gender aspects?]. / Herzinsuffizienz--geschlechtsspezifische Aspekte?

Gender differences in the syndrome of heart failure (HF) occur in etiology and pathophysiology, in the clinical presentation and course of the syndrome. In addition, gender specific treatment responses and gender associated differences in the behavior of treating physicians are found. Hypertension and diabetes play a major role as causes of HF in women and both interact in their pathophysiology with the renin angiotensin system (RAS). Modulation of the RAS by estrogens explains specific differences between pre- and postmenopausal women and men. Myocardial growth processes and myocardial calcium handling are differentially regulated in female and male myocytes. Myocardial remodeling with age and as a consequence of mechanical load differs in women and men. For yet unknown reasons, HF with preserved systolic function seems to be more frequent in women than in men and the clinical course of systolic failure is different in both genders.

[Implications of gender-specific aspects in the therapy of cardiovascular diseases]. / Therapeutische Implika- tionen gender-spezifischer Aspekte von Herzkrankheiten.

In cardiovascular diseases e.g. heart failure and coronary artery disease gender differences are evident in etiology, pathophysiology, clinical presentation, prognosis and response to treatment. Diabetes and hypertension are the major risk factors in women. Mechanisms leading to apparent diabetes or its clinical pre-stage are different in women and men and according to this result in different therapeutic implications. Diastolic heart failure is more frequent in women and effects and side effects of important groups of active pharmaceutical substances are, at least to some extent, different. Atrial fibrillation and ventricular arrhythmia differ in frequency of occurrence; drug induced tachycardia with QT interval prolongation is particularly frequent in women. Underlying pathomechanisms responsible for gender differences in pharmacotherapy are on the one hand differences in pharmacokinetic mechanisms. Particularly drugs which are metabolised via cytochrome P 450 CYP 3A pathway show different kinetics in women and men. In addition, important differences are evident in pharmocodynamics caused by effects of sex steroid hormones or products of X-chromosomal genes. The evidence of estrogen and testosterone receptors in cardiomyocytes and the vascular system, interaction of sex steroid hormones with cellular pathways and the role of X-chromosomal genes are the focus of basic research. Interactions of sex steroid hormone receptors with other nuclear receptors e.g. PPARs ("peroxisome proliferator-activated receptors") are another important underlying mechanism. The knowledge of different pharmacokinetic mechanisms has to be taken into consideration in pharmacotherapy of cardiovascular diseases, for example by adjustment of drug dosages in women, necessary in different groups of pharmaceutical substances or in the long run, gender differences in effects and side effects of drugs. In drug development both aspects have to be considered. There is more than one good reason to intensify basic and clinical research and research on health care on gender differences in cardiovascular diseases.

Gender differences in the metabolic syndrome and their role for cardiovascular disease.

Women live longer than men and develop cardiovascular disease (CVD) at an older age. The metabolic syndrome represents a major risk factor for the development of CVD, and gender differences in this syndrome may contribute to gender differences in CVD. In recent years, the metabolic syndrome has been more prevalent in men than in women. Prevalence is increasing and this increase has been steeper in women, particularly in young women, during the last decade. The contributions of the different components of the metabolic syndrome differ between genders and in different countries. In a recent survey in Germany, 40% of the adult population had been diagnosed with disturbed glucose tolerance or type 2 diabetes. Undiagnosed diabetes was more frequent in men than in women, and risk factors for undiagnosed diabetes differed between the sexes. Worldwide, in individuals with impaired glucose tolerance, impaired fasting glucose was observed more frequently in men, whereas impaired glucose tolerance occurred relatively more often in women. Lipid accumulation patterns differ between women and men. Premenopausal women more frequently develop peripheral obesity with subcutaneous fat accumulation, whereas men and postmenopausal women are more prone to central or android obesity. In particular, android obesity is associated with increased cardiovascular mortality and the development of type 2 diabetes. Visceral adipocytes differ from peripheral adipocytes in their lipolytic activity and their response to insulin, adrenergic and angiotensin stimulation and sex hormones. Visceral fat is a major source of circulating free fatty acids and cytokines, which are directly delivered via the portal vein to the liver inducing insulin resistance and an atherogenic lipid profile. Inflammation increases cardiovascular risk particularly in women. A relatively greater increase in cardiovascular risk by the appearance of diabetes in women has been reported in many studies.Thus, the presently available data suggest that the pathophysiology of the metabolic syndrome and its contribution to the relative risk of cardiovascular events and heart failure show gender differences, which might be of potential relevance for prevention, diagnostics, and therapy of the syndrome.

Gender aspects in heart failure. Pathophysiology and medical therapy.

Gender differences in the syndrome of heart failure (HF) occur in etiology and pathophysiology and lead to differences in the clinical presentation and course of the syndrome. In addition, gender specific treatment responses and gender associated differences in the behavior of treating physicians are found. Hypertension and diabetes play a major role as causes of HF in women and both interact in their pathophysiology with the renin angiotensin system (RAS). Modulation of the RAS by estrogens explains specific differences between pre- and post-menopausal women and men. Myocardial growth processes and myocardial calcium handling are differentially regulated in female and male myocytes. Myocardial remodeling with age and as a consequence of mechanical load differs in women and men. For yet unknown reasons, HF with preserved systolic function seems to be more frequent in women than in men and the clinical course of systolic HF is different in both genders. Medical therapy in heart failure has usually not been specified according to gender and gender specific analysis has been neglected in most large survival trials. Only a post-hoc analysis of gender differences led to the recognition of increased mortality with digitalis therapy in women. Single studies on angiotensin converting enzyme inhibitors (ACEI) or beta-receptor blockers did not reach significant end points in women whereas meta-analyses showed overall positive effects. Side effects of ACEI are more common and pharmacokinetics of beta-blockers are different in women. Angiotensin receptor blockers (ARB) are equally well tolerated in women and men. RAS inhibition may be particularly advantageous in postmenopausal women in whom the natural modulation of the RAS by estrogens is lost.