Current Pharmaceutical Design - Volume 22, Issue 25, 2016

Background: The incidence of acute coronary syndrome is reported to be higher for males than females, yet clinical outcomes following acute myocardial infarction are worse among females. Information about acute coronary syndrome outcomes is obtained from randomised and cohort data. However, randomised controlled trials which are designed to evaluate the efficacy of clinical interventions often have limited external validity, and observational studies which draw inferences from the effect of an exposure whilst being more generalizable are limited by confounding. Methods: We undertook a structured literature review of research manuscripts published between 2000 and 2015 to examine whether reported sex-dependent outcomes following acute coronary syndrome differed between randomised control trials and observational registries. Results: Of 56 manuscripts, we found consistency between the two types of study designs – each type of study describing worse clinical outcomes for females with acute coronary syndrome. We also found a reduction in the use of guideline recommended therapy in females. Conclusion: Further research is needed to understand at a mechanistic and health services level why such a discrepancy in clinical outcomes exists.

Ischemic heart disease remains a leading cause of morbidity and mortality in industrialized nations, and contributes substantially to healthcare expenditure worldwide. As the evidence base in acute coronary syndromes (ACS) has expanded dramatically over decades, longitudinal data demonstrate improvements in risk factor modification, organization of healthcare systems, and disease management that have substantially attenuated the adverse prognosis of both ST-segment elevation myocardial infarction (STEMI) and non-STsegment elevation ACS (NSTE-ACS). Nevertheless, discrepancies remain between genders, and women with ACS often sustain worse outcomes than men. In this review, we focus on the gender and sex-specific commonalities and differences in the pathophysiology, clinical presentations, diagnosis, and risk stratification of ACS. We highlight available data on the interactions between gender and efficacy of current pharmacological and interventional treatment for NSTE-ACS and STEMI. We also examine gender differences in the trends of clinical outcomes, and possible mechanisms that account for persistent care gaps where future efforts can be directed.

Background: Cardiovascular disease (CVD) despite the advances in medical management keeps on as the primary cause of morbidity and mortality for both genders in Western societies. Sex differences though modify the clinical picture as well as the effectiveness of treatment. Methods and Results: In this literature review article we searched publications in Englishlanguage on MEDLINE and the Cochrane Database from the beginning of the databases to January 2016. Among the specific key words and phrases we used were Diabetes Mellitus; Gender; Coronary artery disease; Stroke and Cardiovascular disease. Various studies have found that diabetic women have increased risk of coronary heart disease than their male counterparts; however, further research into this field has questioned this finding and there is much controversy among many researchers. Women have a different risk factor profile, are usually treated less effectively than men, and have a variance in the levels of sex hormones throughout their life which complicate the study and understanding of the mechanisms involved in insulin resistance, diabetes mellitus and cardiovascular risk profile. Conclusion: The connection between diabetes mellitus and cardiovascular disease is variable according to gender and further studies are needed to elucidate the lenient differentiations in gender specific hormones, risk factor profile, and therapeutic implications between genders.

Background: The debate on whether sex-specific predictive models improve risk stratification after myocardial infarction is ongoing. Methods: This review summarises the current clinical knowledge on sex-specific differences in post-infarction risk stratification parameters. Particular focus is given to electrocardiographic risk factors and indices of cardiac autonomic status. Results: Differences in the underlying pathophysiology between men and women are known. However, clinical findings often lead to uncertain conclusions for a number of risk predictors including, among others, resting heart rate, heart rate variability, heart rate turbulence, QT interval duration, and QRS-T angle. The review links recent findings in prognostic parameters with successful approaches in sex-specific non-invasive risk stratification. Conclusion: Disparities are described in the current clinical opinions on the relevance of investigated parameters in women and possible directions for further research in the field are given.

Background: The autonomic nervous system (ANS) is a key regulator of the cardiovascular system. The two arms of the ANS, sympathetic and parasympathetic (vagal) have co-regulatory effects on cardiac homeostasis. ANS modulation and dysfunction are also believed to affect various cardiac disease states. Over the past decade, there has been increasing evidence suggesting gender differences in ANS activity. Methods: In multiple previous studies, ANS activity was primarily assessed using heart rate variability, muscle sympathetic nerve activity, coronary blood flow velocity, and plasma biomarkers. Heart rate variability is a non-invasive measure, which can be analyzed in terms of low frequency and high frequency oscillations, which indicate the sympathetic and parasympathetic tone, respectively. These measures have been studied between women and men in states of rest and stress, and in cardiac disease. Conclusion: Studies support the concept of a significant gender difference in ANS activity. Further studies are indicated to elucidate specific differences and mechanisms, which could guide targeted therapy of various cardiovascular disease states.

Background: Cardiovascular disease has been the leading cause of death in both sexes in developed countries for decades. In general, men and women share the same cardiovascular risk factors. However, in recent trials including both men and women sexspecific analyses have raised awareness of sex differences in cardiovascular risk factors due to both biological and cultural differences. Results: Women experience their first myocardial infarction (MI) 6-10 years later than men and a protective effect of their natural estrogen status prior to menopause has been suggested. Female sex hormones have been associated with a less atherogenic lipid profile and a more healthy fat distribution. These differences are attenuated following menopause. Regarding life style the prevalence of smoking is highest in men but female smokers have a relatively higher cardiovascular risk than male smokers. Men are more physically active than women while women have healthier dietary habits. Genetic factors also affect cardiovascular risk but no sex differences have been seen. Increased cardiovascular risk attributed to psychosocial distress is similar in men and women, but since women are more prone to psychosocial distress their burden of disease is greater. Compared with a healthy population the relative risk of MI in a diabetic population is higher in women than in men. No sex difference exists in the prevalence of hypertension but it has an earlier onset in men. Conclusion: Sex differences in cardiovascular risk are becoming more apparent and paying attention to this is pivotal when addressing risk factors in preventive efforts.

Background: Psychosocial risk factors such as stress and psychiatric disorders are known to have negative impacts on health outcomes, but their effects on ischemic heart disease, particularly in women, remain to be fully understood despite contributing to one-third of the population attributable risk in acute myocardial infarction. Methods: The impact of stress, social isolation, low socioeconomic status, hostility and anger, and stress-related psychiatric disorders on cardiovascular outcomes and the potential mechanisms that underlie their association with ischemic heart disease, with a focus on women, is evaluated. Online search of relevant terms, including the aforementioned risk factors, women, and ischemic heart disease, was utilized to find recent and pertinent trials. Results: Psychosocial risk factors increase cardiovascular risk in both women and men. However, current literature points to a greater degree of adverse cardiovascular events in women who experience these risk factors than in men, but the literature is not as well-defined as the data regarding traditional risk factors and cardiovascular disease. Conclusion: Dedicated study of the sex differences in ischemic heart disease incidence and recurrence, including the impact of psychosocial risk factors, is warranted for the development of appropriate gender-specific diagnostic testing and treatment options in heart disease.

Background: Silent myocardial ischemia is a recognized but suboptimally studied condition in patients with and without known coronary artery disease. Limited work has focused on the association between silent myocardial ischemia and future prognosis however the majority of these analyses have focused mostly on male cohorts. As signs and symptoms of myocardial ischemia are known to be different in women, it is important to discuss and highlight any differences in association between silent myocardial ischemia and adverse cardiovascular outcomes based on gender. Methods: The aim of this review is to summarize the current literature available discussing silent myocardial ischemia and potential gender differences. We searched English language studies on PUBMED and the Cochrane Database of Systematic Reviews from the database start dates to November 2015. Conclusion: As data on the presence of silent myocardial ischemia in women is limited, whether a differential association based on gender between this condition and cardiovascular prognosis remains unknown. Future studies should target women especially those without epicardial coronary disease and suspected coronary microvascular dysfunction.

Not all acute coronary syndromes (ACS) exhibit the classic symptoms of chest pain. The diagnosis of ACS in patients without typical chest pain is often challenging. These patients are at increased risk for delayed or incorrect diagnosis, less aggressive treatment and high in-hospital mortality. The association between diabetes mellitus and absence of chest pain in ischemic heart disease is established. As well, it is known that women, more frequently than men, have atypical presentation. However, there is a lack of standardization in characterizing the population of patients with ACS and atypical presentation. The identification of other factors influencing and/or related with the absence of chest pain in ACS could be helpful for patients’ outcomes. The object of our study was to examine the current literature on the clinical features, other than female gender and diabetes, associated with the atypical presentation of ACS. We found that patients with non-ST-elevation ACS more frequently than patients with ST-elevation myocardial infarction have atypical presentation. Atypical symptoms in aged population are common both among female and male. Subjects with history of comorbidities, specifically heart failure, chronic kidney disease, chronic obstructive pulmonary disease and stroke are less likely to report chest pain as chief complain of ACS.

Background: Ischemic heart disease (IHD) is the most important cause of mortality worldwide. Although the awareness of cardiovascular risk factors and IHD in women has increased over the last decades, mortality rates are still higher in women than in men. Among traditional cardiovascular risk factors, hypertension is associated with a greater risk for IHD in women as compared to men. Methods: In this review, discuss gender differences in epidemiology and pathophysiology of hypertension and its impact on the incidence and outcomes of IHD in women. We also, discuss some “women conditions” such as hypertensive disorders in pregnancy (HDP) and polycystic ovarian syndrome (PCOS). Even though this is not a systematic review, English-language studies on MEDLINE and the Cochrane Database of Systematic reviews were searched for consultation and analysis. Results: Hypertension display different epidemiological patterns in men and women. Studies have shown that hypertension has a different proatherogenic effects in men and women. Hypertension has a direct effect on microcirculation, but estrogens have a protective role in this regard in premenopausal women. However, after the decline in estrogen levels, women are exposed to the same cardiovascular risk as males. Postmenopausal women exhibit a greater burden of cardiovascular risk factors, which together with microvascular dysfunction and smaller and stiffer arteries conducts to the worse prognosis observed in women with IHD. “Women specific conditions” such as HDP and PCOS affects 10% of pregnant women and women in reproductive age, respectively. These conditions are associated with increased risk of hypertension and IHD later in life. Although women are more aware of their hypertension, cardiovascular mortality is higher in hypertensive women with comorbid IHD. Yet these gender disparities in outcomes seem to be attenuated with effective therapy. Conclusion: The pathophysiology of IHD is gender specific, women with ischemic symptoms presenting less often with coronary obstructive disease, and more frequently with dysfunction of the coronary microcirculation. Optimal control of hypertension could attenuate gender related differences in mortality in this population.

Background: There are no ready explanations for differences in ischemic heart disease incidence between women and men under an epidemiological perspective. However, when myocardial infarction occurs, there are more likely individuals who happen to die. Methods: This review from a more recent literature was performed for a two-fold purpose, to describe gender wise: a) the role of classical and novel factors defined to evaluate coronary artery disease (CAD) risk and mortality, aimed at assessing applicability and relevance for primary and secondary prevention; b) the differences in northern versus southern European Countries in risk factors and CAD mortality. Results: Age-related risk patterns differ in men and women. It is uncertain whether standard factors may index CAD risk, including mortality, in different ways and/or whether specific factors might be targeted gender-wise. A list might be compiled: HDL-cholesterol levels, higher in pre-menopausal women than in men, are more strictly related to CAD; high triglycerides and Lp(a) have a similar relationship; HDL-cholesterol levels have an inverse relation with CAD incidence and mortality. The role of statins is not completely defined in primary prevention for women. However, in secondary prevention statins are equally effective in both genders. Weight and glycemic control are effective to reduce cardiovascular disease (CVD) mortality in women from middle to older age. Similarly, CVD mortality in women, from middle to older age, might be reduced by controlling blood pressure, particularly among diabetic or over weighted women. Renal dysfunction, either defined by UAE or eGFR or both may usefully predict primary CVD incidence and risk in both genders. In secondary prediction, kidney dysfunction predicts sudden death in women when left ventricular ejection fraction is also evaluated. Serum uric acid that normally increases with age, differentiates gender-related CVD incidences with a peculiar importance in women as compared to men. There has been much interest to investigate loss of ovarian function in explaining age-related differences between genders. More recently, some emphasis has been laid on the loss of ovarian function-related iron stores. There are subgroups of women as those with mitral valve prolapse and increased circulating levels of catecholamines in whom QT interval, physiologically longer in women than men, may be an arrhythmogenic risk index. However, no large population-based studies were ever conducted to assess this. Therefore, in the future, it will be important to implement risk score instruments (charts and softwares) in women using novel parameters, and among these inflammatory markers and reproductive hormones and serum uric acid. The important results of the WHO MONICA Project confirmed the northern versus southern European gradient in both men and women, for death rates and the proportion of all deaths from cardiovascular causes (including CAD, stroke and other CVD causes). The coronary event rate was initially as high as 1, 000 per 100, 000 inhabitants in Finland and less than 1 fifth of that in Spain with the corresponding figures in women of 200 and 30, respectively. Conclusion: No doubt might still exist that all efforts need be undertaken for both men and women, for health and prolongation of life to effectively treat common risk factors such as cigarette consumption, high blood pressure, cholesterol levels and physical inactivity by also paying attention to optimal diet.

Background: There is conflicting evidence regarding the benefit of an early invasive strategy vs. a conservative strategy in women with non-ST-elevation acute coronary syndrome (NSTE-ACS). Methods: We searched English-language studies on MEDLINE and the Cochrane Database of Systematic Reviews from 2000 to December 2015. Results from major available studies and meta-analysis comparing outcomes of an early invasive strategy vs. a conservative strategy or medical therapy vs. revascularization in women with NSTE-ACS were considered. Results: Available data on the comparative effectiveness and safety of different management strategies in NSTE-ACS women derive from observational registries and pre-specified gender sub-analyses of randomized trials comparing early routine invasive with a selective invasive strategy. While some post-hoc analysis of randomized trials showed that an early invasive strategy did not reduce the risk of future events among women, in contrast to its beneficial effect in men, others showed similar benefits of a routine early invasive vs. a conservative strategy in men and women. Several important differences between these trials may explain the lack of benefits from a routine invasive strategy compared with a conservative strategy. Overall evidence showed better outcomes with a routine invasive strategy, especially for women at higher risk and those with positive biomarkers. Differently, women with negative biomarkers and those at lower risk appeared to benefit most from a conservative approach. Conclusion: The benefit of an early invasive strategy is restricted to women at higher risk. Further research is warranted to define the optimal management of women with NSTE-ACS.

Background: Ischemic heart disease is the major cause of death in women. Men and women have many similarities in relation to cardiovascular risk factors, but they differ in the pathophysiology, clinical presentation and outcomes in the setting of coronary artery disease and myocardial ischemia. Over the last years, due to innovative imaging technologies and more specific diagnostic strategies, increasing number of clinical studies report on specific-gender characteristics on plaque composition and burden, associated to acute coronary syndromes, and also on coronary vascular dysfunction as a major cause of clinical symptoms in women with apparently normal arteries. Methods: Here we performed a review of the literature focused on atheroma burden in women that includes information provided in original articles (basic and clinical oriented), cohort studies, trial and registry data, metaanalysis and other systematic reviews. Results and Conclusions: The Studies published over the last 30 years provide a new view about the pathophysiology and presentation of ischemic heart disease in women. However, many questions remain to be addressed by future research. The mechanisms behind the delay on disease presentation in women over the fertile period and the paradoxical fact that young women have more adverse outcomes after an ischemic event need to be identified. A better understanding of these issues is expected to derive in better strategies for prevention and management of ischemic heart disease in women.

Background: A substantial part of literature has been centered on sex differences in the clinical aspects of ischemic heart disease (IHD). Many reports have documented differences in the presentation and risk profile between women and men. Such differences drive sex-related inequalities in the referral and treatment of IHD. Yet data are insufficient to clarify the reasons for such disparities. The objective of this review is to analyze the main gender differences regarding symptoms, diagnosis, and risk stratification of coronary heart disease in order to identify “gaps” in existing literature that need to be addressed in future research efforts. Methods: We searched English-language studies on MEDLINE and the Cochrane Database of Systematic Reviews from the database start dates to January 2016. Evidence synthesis was based on cohort studies, registry data, and clinical trial data. Results: Women do not often participate in clinical studies. In a number of articles, authors have questioned how the "white male” came to be the prototype of the human research subject. Consequently although many reports continue to describe differential treatment based on patients’ sex, the extent to which such inequalities are due to true sex differences in pathophysiology or whether they reflects inaccuracy in risk stratification is unclear. Conclusion: Today, even the best database is incapable in and of itself of supplying answers to the question of whether women are being treated less compared with men by the medical community.