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Sex and gene regulation in cardiovascular health and disease
No full textThe biological differences between males and females encompass different sex chromosomes and differing sex hormones. These differences contribute to sex differences in the development of disease. Typical examples are the higher prevalence of non-reproductive cancers in males, and the higher prevalence of auto-immunity in females. Another example are the sex differences in cardiovascular diseases driven by atherosclerosis. Despite the differences in atherosclerosis in which females develop more often stable plaques as compared to males with more unstable plaques, we lack knowledge about female biology in atherosclerosis. This is because the majority of biomedical research has been performed in male patients, male animals, and male cells. Using a systematic review, we show that sex stratification is scarce in cardiovascular epigenetics. Next, we determined how sex influenced gene regulation by integrating DNA methylation and RNA-sequencing data of the atherosclerotic plaque. The sex differential genes suggest that smooth muscle cells in the plaque are heavily subject to sex differences as underlined by deconvolution analyses, regulatory linkage, RNA-sequencing and single-cell RNA-sequencing. Systems biology approaches have been successfully used to find novel disease targets, such as for coronary artery disease. However, these studies also mainly use predominantly male populations. We generated sex-specific gene regulatory networks of atherosclerosis and determined that female key drivers of atherosclerosis are involved in smooth muscle cell phenotype switching, as compared to the more immune system biology from male samples. It shows that completely different biology erupts when we study male and female tissues separately, but in equal numbers. Male biology in atherosclerosis seems to center around inflammation, whereas female biology seems to converge on the smooth muscle cell. To determine whether sex differences exist within cell types, we generated RNA-sequencing data from endothelial cells from new-born twins and adults. We found that genes that are differentially expressed between the sexes at birth and in the adult stage are enriched for coronary artery disease genes. Many biological sex differences are described also in healthy tissue from different organs all over the human body, since a body-wide analysis on 24 tissues in this thesis found that the gene activity of 20.1% of the 13,787 studies genes are affected by sex. We may also use information generated from sex-specific diseases and risk factors to detect novel biology that may be important for both sexes, for example, we used RNA-sequencing data of platelets of women with former preeclampsia to detect biology important for accelerated atherosclerosis that may inform about processes in men as well. Lastly, we postulate conjectures about sex chromosomal genes and how these may influence sex-bias in disease, and conclude that attention to sex chromosomal genes is warranted. This dissertation shows that sex is an important player in cardiovascular health and disease, in which sex affects the genetic material and the regulation thereof in multiple ways. By studying sex differences standardly, we discover biology that until now has remained hidden in all the biology based on males. This knowledge may contribute to new findings important for both males and females
Safety and efficacy of cardiovascular medication in women and men; the added value of clinical care data
No full textWomen and men are different. This may seem obvious, but cardiovascular research too often treats women and men as interchangeable. Due to this, there is a lack of sex-specific knowledge about optimal treatment for patients suffering from cardiovascular diseases such as heart failure. Sex differences in pharmacokinetics and – dynamics can affect how women react to cardiovascular medication compared with men, supporting the idea of sex-specific approaches to treatment. However, women remain underrepresented in clinical heart failure trials and thus data on safety and efficacy of heart failure medication in women is scarce. This thesis explores whether clinical care data can close this evidence gap.
Clinical care data comprise electronic patient records, which better reflect the patient population seen in daily care than for example clinical trials. This means that women are properly represented in these data, creating opportunities for sex differences research. Using a large clinical care dataset, we show that women more often stop their cardiovascular medication due to adverse drug reactions than men. In addition, women report different adverse drug reactions than men for the same medication types. We also show that the optimal dosage of heart failure medication may be lower for women compared with men. Women treated with ≤50% of the guideline-recommended dose had a lower mortality risk than those treated with higher doses, an effect that was not seen in men. Lastly, we show that primary prevention statins reduce mortality risk more strongly in women than in men, taking away remaining doubts surrounding the effectiveness of statins in women free of cardiovascular disease.
However, it remains debatable whether clinical care data alone are sufficient to completely close existing evidence gaps as these data have their own inherent limitations. The last chapter of this thesis discusses how these limitations can affect the quality of clinical care data-based research, and how researchers can mitigate these effects via statistical and methodological techniques. We conclude that clinical care data are and will remain an important source of information for sex differences research, as current and future efforts aimed at quality improvements will only reduce the size and effect of any inherent limitations that these data have
Plaque Myofibroblasts: a focus into sex-related mechanisms of atherosclerosis: Combining computational and experimental insights
No full textCardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with projections indicating significant increases in prevalence by 2060 due to lifestyle changes and rising obesity rates. By 2060, ischemic heart disease is expected to rise by 31.1%, heart failure by 33.0%, myocardial infarction by 30.1%, and stroke by 34.3% compared to 2025. While both sexes will experience these trends, men are anticipated to have a higher prevalence of ischemic heart disease and myocardial infarction. In Europe, however, CVD poses a greater mortality risk for women, highlighting the importance of understanding sex-specific variations in the disease.
Atherosclerosis, the primary cause of CVD, leads to conditions such as myocardial infarction and stroke through mechanisms like plaque rupture and plaque erosion. Plaque rupture involves the breaking of a thin fibrous cap over a lipid-rich core, causing blood clots that can trigger acute events. Plaque erosion results in clot formation directly on the arterial wall without rupture. Historically, research has focused on plaque rupture due to its higher prevalence, leading to a one-size-fits-all approach that overlooks differences in plaque composition between sexes and the rising occurrence of non-ST-segment elevation myocardial infarction (NSTEMI), which is more associated with plaque erosion.
The male-centric focus in medical research has created a significant gap in understanding how CVD manifests and progresses in women. Women often develop atherosclerosis later in life and exhibit less pronounced and more diverse symptoms, complicating diagnosis and treatment. Even when included in studies, the lack of sex-stratified analyses prevents the identification of crucial differences that could inform more effective, sex-specific medical strategies. Early gene regulatory network (GRN) studies in coronary artery disease typically analyzed tissues from male patients, limiting the applicability of findings to female biological processes.
This thesis addresses the critical gap in understanding sex-specific cellular mechanisms within atherosclerotic plaques. An innovative method was developed to isolate smooth muscle cell (SMC)-derived plaque myofibroblasts from atherosclerotic tissues of both male and female donors. These cells were examined for their responses to environmental triggers known to accelerate atherosclerotic disease development, compared to contractile SMCs. The study investigated how these myofibroblasts contribute to plaque stability and progression, providing insights into cellular behaviours that differ between sexes.
In addition to the experimental work, in vitro findings were integrated with in silico analyses of GRNs to uncover sex-specific mechanisms influencing disease progression. Key driver genes within these GRNs were identified in primary myofibroblasts, shedding light on differential gene expression patterns between men and women in atherosclerosis. This approach validated the existence of discovered GRNs and their role in sex-specific determinants of disease deterioration.
By combining novel cellular models with computational analyses, this research enhances the understanding of sex-specific determinants in atherosclerotic plaque development and progression. The findings challenge the traditional one-size-fits-all approach and underscore the necessity of fine-tuning and sex-stratifying studies in CVD research. This work lays the groundwork for developing more effective, personalized medical interventions for both men and women, ultimately contributing to improved outcomes in the management of cardiovascular disease
Carotid artery imaging and cardiovascular disease risk
No full textPart 1 of this thesis focuses on echogenicity of the carotid artery. This measure represents the color of the intima-media complex on ultrasound images. Echolucent vascular walls appear dark, echodense vascular walls light. We showed in a group of young adults that higher age, BMI, systolic blood pressure, triglycerides and carotid intima media thickness (CIMT) were associated with a lower grey-scale median (GSM) and thus a more echolucent carotid artery wall. Higher HDL-cholesterol and male sex were associated with a higher GSM and thus a more echodense carotid artery wall. Lower GSM was associated with a higher estimated cardiovascular disease risk. Furthermore, we showed that in a cohort of elderly men that when the population was split into thirds of GSM, individuals in the highest third had (independent of cardiovascular risk factors and CIMT) a significantly higher risk of all-cause mortality and cardiovascular mortality compared to those with a GSM in the lowest third.
Part 2 of this thesis focuses on CIMT, both in association with risk factors and disease and as a possible marker to improve cardiovascular risk prediction. Ethnicity appeared to slightly but significantly modify the associations between risk factors and CIMT and cardiovascular events. This has possible implications for the development of cardiovascular risk prediction models. In a population of adults under 45 years of age, we found that age, sex, diastolic blood pressure, body mass index, total cholesterol and high-density lipoprotein cholesterol were associated with higher CIMT. Furthermore, higher CIMT was independently associated with increased risk of first-time myocardial infarction or stroke in this population. We did not find clinically relevant incremental prognostic value, either for measuring mean common CIMT in individuals with hypertension, or for measuring CIMT in the internal carotid artery and/or the carotid bulb in the general population.
Part 3 of this thesis focuses on vascular age and on the comparison of prediction models. First, we conducted a review of the literature to explore published concepts, definitions and clinical applications of vascular age. Vascular age is the expression of cardiovascular disease risk in years instead of a percentage. Despite sharing a common name, various studies have proposed distinct ways to define and measure vascular age. While we were unable to examine the effect of using vascular age in the communication of risk, we did examine the claim of vascular age as a way to improve risk prediction. We applied four methods of determining vascular age (two based on existing risk scores and two based on CIMT) to a study population representing the general population. Irrespective of definition vascular age does not improve cardiovascular risk prediction.
Finally, we examined the metrics used to calculate incremental prognostic value of prediction models. We did this by calculating several incremental value statistics for biomarkers currently used in risk predictions and clinical practice, when they were added as ‘new biomarker’ to the remaining set. Most of these biomarkers seem to show little benefit in risk prediction when using current metrics that test added value of novel biomarkers
A Sex-Specific View On Coronary Vascular Disease
No full textIn coronary artery disease atherosclerosis, i.e., local thickening of the vessel wall, occurs in the cardiac arteries. If the heart (temporarily) does not get enough oxygen due to impaired blood supply, this results in complaints, mainly chest pain or discomfort. We showed that the specific chest pain complaint characteristics help to diagnose coronary artery disease well in both sexes. Interestingly, the value of specific complaints was slightly different for women and men. We also showed that women tend to have less calcified coronaries when suffering from the same degree of coronary artery disease as men. Finally, we focused specifically on women and men with symptoms suggestive for myocardial ischemia with (near) normal coronaries. We demonstrated that most of these patients remain symptomatic in the years following their diagnostic coronary angiography appointment. In addition, they had a higher healthcare consumption than the general population, for both cardiac and psychological complaints. Thus, we concluded that only focusing on obstructed coronaries is not enough to evaluate coronary artery disease in these patients and we should pay attention to these patients after the coronary angiography. In the light of the evidence presented in this thesis, along with other supporting literature, the “one size fits all” approach in which women and men are evaluated similarly no longer seems suitable; a clinician should evaluate his or her patients through sex-colored glasses, supported by a specific guideline for each sex
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Coronary Artery Disease: Ethnicity, Sex and Risk Prediction
No full textDespite major advances in prevention and treatment, cardiovascular disease is still the leading cause of death around the globe. In particular, coronary artery disease (CAD) has become a disease of men and women of all ethnicities.
In the first part of this thesis we examined ethnic differences in CAD risk factors, CAD biomarkers and CAD severity. From a systematic literature review we found profound differences in CAD biomarkers between Asians and Whites in the general population (mainly inflammatory markers and markers of glucose metabolism) with a most hazardous profile among South Asians and more benign profiles in Japanese and Chinese. Then, in a general population cohort we found inter-ethnic differences in the relation of the Framingham risk factors with carotid intima-media thickness and the occurrence of cardiovascular events. These small, but significant differences might prove to be important when implementing global prevention strategies.
In the multi-ethnic United Coronary Biobank (UNICORN) we found that severity of CAD differed by ethnicity and that CAD risk factors related with CAD severity in an ethnicity-specific manner. Also our data suggested that different biomarker cut-offs might be indicated for certain ethnic groups. The SYNTAX score, which quantifies CAD severity, differed significantly among Asian and White patients undergoing percutaneous coronary intervention for stable CAD or myocardial infarction. SYNTAX scores were particularly high in Malays, who might also have poorer survival after myocardial infarction.
By combining Swedish and Singporean heart failure cohorts we found that electrocardiographic QRS-prolongation occured in heart failure in both Asians and Whites. But with deterioration of the ejection fraction QRS-prolongation was more extreme in Asians than Whites. QRS-prolongation was associated with poorer outcome in both Asians and Whites, but different cut-offs might need to be considered.
In the second part of this thesis we addressed sex differences in CAD. Women with stable complaints had less severe CAD than men upon angiography. However, women who presented with myocardial infarction or who happened to have multi-vessel disease upon angiography were found to have a poorer prognosis than men.
Women, regardless of the indication for angiography or the severity of CAD, reported worse health-related quality of life (HRQOL) than men. Paradoxically, the lower HRQOL in women conferred less risk of future adverse events than for men. Importantly, people who did not respond to the HRQOL questionnaire had the poorest survival, indicating an important non-response bias.
In the final part of this thesis we discuss the predictive potential of hematological parameters. Hematological parameters are measured on a very regular basis for many purposes. But these parameters are overlooked as CAD biomarkers. Among leukocyte parameters we found that the monocyte-to-lymphocyte ratio (MLR) is capable of improving prediction of mortality in addition to clinical characteristics. And when considering all hematological parameters the red cell distribution width (RDW) showed to improve prediction of mortality and adverse events after coronary angiography, superiorly to high-sensitivity troponin and NT-pro brain natriuretic peptide. Measuring MLR and RDW is inexpensive and in many cases these parameters are readily available
Left Ventricular Diastolic Dysfunction towards a HELPFul role for biomarkers
No full textIn this thesis the trend over the last two decades of improved survival after a first hospitalisation for heart failure is shown in the Netherlands for both men and women. Furthermore it is shown that there is a relation between diabetes and stiffening of the heart, as well as heart failure, in both men and women. To evaluate the diagnostic and prognostic value of biomarkers in men and women with stiffening of the heart the HELPFul study was started. The rationale and design of this study is further explained in the this thesis. In this thesis the value of diagnostic models for heart stiffening and heart failure with preserved ejection fraction is tested and found to be reasonably effective. The role of worsening of the kidney function is examined, but after correction for potential confounders there was no longer a significant relationship with left ventricular diastolic dysfunction. In the different projects in this thesis large heterogeneity in between studies and in the definition of sitffening of the heart (left ventricular diastolic dysfunction) is found. These problems require further attention in the future if the these fields are to develop further. A individual patient data meta-analysis might be a solution to develop a new definition for left ventricular diastolic dysfunction
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