Challenges and Opportunities in Obstetrics & Gynecology
Sex differences of angiotensin-converting enzyme inhibitors in blood pressure lowering and cardiac remodeling: a systematic review and meta-analysis
Sophie A.J.S. Laven, MD, Zenab Mohseni-Alsalhi, MSc, Eveline M. van Luik, MD, Maud A.M. Vesseur, MD & Esmée W.P. Vaes, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands;
Daniek A.M. Meijs, MD & Nick Wilmes, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Intensive Care Medicine, Maastricht University Medical Center + (Maastricht UMC+), the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands;
Sander de Haas, MSc, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands;
Marc E.A. Spaanderman, MD, PhD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Obstetrics and Gynecology, Radboud University Medical Center, the Netherlands;
Chahinda Ghossein-Doha, MD, PhD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Intensive Care Medicine, Maastricht University Medical Center + (Maastricht UMC+), the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Department of Cardiology, Maastricht University Medical Center (MUMC+), the Netherlands;
Abstract
Objectives: Hypertension is the leading risk factor for cardiovascular disease. While treatment of high blood pressure is essential in cardiovascular disease prevention or slowing it down once cardiovascular disease occurred, it is assumed that pharmacological effectiveness may be hampered by sex differences. The aim is to evaluate sex-stratified effects for angiotensin-converting-enzyme inhibitors (ACEIs) on blood pressure and cardiac function in hypertensive participants.
Methods: A systematic review and meta-analysis were performed for studies on ACEIs from 1945 to May 2020. Studies had to present both baseline and follow-up measurements of the interested outcome variables and present sex stratified data. Mean differences were calculated using a random-effects model. 45 studies with 976 participants were used in this review.
Results: In females as compared to males, systolic blood pressure decreased by 19.9 mmHg (95% CI, -26.8; -13.0) vs. 15.1 mmHg (95% CI, -19.5; -10.8), diastolic blood pressure by 14.5 mmHg (95% CI, -17.2; -11.8) vs. 8.5 mmHg (95% CI, -11.4; -5.7), heart rate by -3.5 bpm (95% CI, -6.1; -0.9) vs. -2.5 bpm (95% CI, -4.8; -0.2). Only diastolic blood pressure lowered significantly more in females as compared to males. Left ventricular ejection fraction increased by 2.3% (95% CI, 0.8; 3.7) vs. 1.5% (95% CI, 0.6; 2.3), but without reaching statistical significance.
Conclusion: Although hypertensive treatment effects of ACEIs are comparable between sexes, diastolic blood pressure response is stronger in females, which may guide treatment choices in systolic or diastolic hypertension. It may be that other pharmacological different antihypertensive compounds show sex-specific differences in effectiveness.
Sophie AJS Laven, MD, Zenab Mohseni-Alsalhi, MSc, Esmée W. P. Vaes, MD, Eveline M van Luik, MD, Maud AM Vesseur, MD, & Sander de Haas, MSc, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands
Daniek AM Meijs, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Intensive Care Medicine, Maastricht University Medical Center + (Maastricht UMC+), the Netherlands
Nick Wilmes, MD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands
Chahinda Ghossein-Doha, MD, PhD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Cardiology, Maastricht University Medical Center (MUMC+), the Netherlands
Marc EA Spaanderman, MD, PhD
Department of Obstetrics and Gynecology, Maastricht University Medical Center (MUMC+), the Netherlands; Department of Obstetrics and Gynecology, Radboud University Medical Center, the Netherlands
Abstract
Background: Hypertension is the leading risk factor for cardiovascular disease (CVD) in females. While treatment of high BP is essential in the global prevention strategies of CVD it is assumed that effectiveness of pharmacological treatment may be different across sexes.
Objective: The aim of this systematic review and meta-analysis was to evaluate sex-stratified effects for angiotensin receptor blockers (ARBs) on blood pressure (BP), heart rate and cardiac function in female compared to male hypertensive individuals.
Design and methods: We performed a series of systematic reviews and meta-analysis after we systematically searched PubMed and EMBASE for studies evaluating the effects of the five major groups of antihypertensive medication from 1945 to May 2020. We included randomized control trials and observational studies in humans (≥18 years) investigating Beta-blockers (BB), angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and diuretics. In this study we analysed data on ARB’s. Studies had to present both baseline and follow-up measurements of at least one of the outcome variables of interest and present their data in a sex-stratified manner. Data on BP, heart rate and cardiac function were retrieved from studies. Mean differences between baseline and follow-up were calculated using a random-effects model. Intervention effect was assessed for the acute (0-14 days), subacute (15-30 days) and chronic (>31 days) phase.
Results: The search strategy resulted in 73,867 hits. After first screening based on title and abstract, 15,130 articles were suitable for full text screening. After excluding all studies that matched our exclusion criteria, 205 studies were eligible for analysis for the five antihypertensive drugs. Studies investigating ARB´s (n=17) were used in this review. ARB decreased BP significantly but comparably in both female and male; systolic BP -18.2 mmHg (95% CI, -24.8; -11.5) vs -20.1 mmHg (95% CI, -26.7; -13.6) and diastolic BP -11.6 mmHg (95% CI, -14.7; -8.4) vs -12.3 mmHg (95% CI, -16.4; -8.1). Left ventricular ejection fraction (LVEF) did not change significantly in either group. Left ventricle (LV) mass was only reported in males and did not change statistically significant -11.8 g (95% CI, -25.6; 1.9).
Conclusion: ARB’s decreased BP in both female and male hypertensive patients substantially but comparably.
Katharine Linder, MD, Rachel Watson, MD, Keely Ulmer, MD, David Bender, MD, Michael J Goodheart, MD, Eric Devor, PhD & Jesus Gonzalez Bosquet, MD, PhD
Abstract
Objective: Early detection of ovarian cancer could lead to improved survival rates, however no method has reliably been able to predict ovarian cancer. The aim of this study is to determine if processing alternative splicing data from high grade serous ovarian cancer patients using machine learning analytics will discriminate high grade serous ovarian cancer from normal fallopian tube samples. The ultimate goal would be to have a model that can predict high grade serous ovarian cancer with a blood test.
Methods: This is a case-control study of patients with confirmed high grade serous ovarian cancer and those undergoing salpingectomy for benign indications. RNA-sequencing was performed on all samples. RNA-sequence data was then put into Deep-learning augmented RNA-seq analysis of transcript splicing software suite. Deep-learning augmented RNA-seq analysis of transcript splicing created a model of differential alternative splicing aimed to discriminate between high grade serous ovarian cancer and normal fallopian tube. DEXSeq analysis was used to determine exon-based expression. Initial results with both analytics were then modelled with multivariate lasso regression to create prediction models (performance determined by area under the curve and 95% CI). Models created were the validated using The Cancer Genome Atlas data sets.
Results: One hundred and twelve high grade serous ovarian cancer and 12 benign samples were successfully sequenced. Deep-learning augmented RNA-sequencing analysis of transcript splicing identified 998 unique differentially expressed exons between high grade serous ovarian cancer and controls. Multivariate lasso regression analysis identified several exons that predicted high grade serous ovarian cancer with high performance. Specifically, ENSG00000182512:E001 from gene GLRX5 was highly predictive of high grade serous ovarian cancer with an area under the curve of 100%.
Conclusions: Application of machine learning analytics to exon differential expression, most likely due to alternative splicing, predicted high grade serous ovarian cancer with high performance. These results were validated in an independent dataset of cases and controls. Differential exon expression from cell-free RNA potentially could be used for early diagnosis of high grade serous ovarian cancer.
Min Luo, M.D. & Xianjun Cai, M.D.
Department of Obstetrics and Gynecology, Ningbo No. 7 Hospital, Ningbo, Zhejiang 315200, China
Xishi Liu, M.D., Ph.D.
Dept. of Gynecology, Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China
Dingmin Yan
Fudan University
Sun-Wei Guo, M.D., Ph.D.
Research Institute, Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China
Abstract
So far, the pressing need for the development of non-hormonal therapeutics for endometriosis has been unfulfilled. In light of the evidence that platelets play important roles in the development of endometriosis and that tetramethylpyrazine has therapeutic potential, we tested the hypothesis that tetramethylpyrazine can induce cellular senescence in endometriotic lesions, hindering fibrogenesis in mice with induced deep endometriosis and that the combined use of tetramethylpyrazine and sodium tanshinone IIA sulfonate may have a synergistic effect. We induced deep endometriosis in 32 female Balb/C mice, and then randomly divided mice into equal-sized four groups: low- and high-dose tetramethylpyrazine, low-dose tetramethylpyrazine plus low-dose tanshinone IIA sulfonate and inert vehicle control. After two weeks of treatment, their lesion tissues were removed and procured. All lesions were weighed, and lesion fibrosis was quantitated by Masson trichrome staining. In addition, cellular senescence in lesions was evaluated by senescence-associated β-galactosidase, along with immunohistochemistry analyses of p53, Salvador 1, cellular communication network factor 1, hyaluronan synthase 2, surviving and granulocyte-macrophage colony stimulating factor and other markers. We found that tetramethylpyrazine treatment significantly decreased lesion weight, arrested lesional progression and ameliorated pain behaviour ostensibly via inducing senescence by p53 activation, and induction of Salvador 1 and cellular communication network factor 1 while suppressing hyaluronan synthase 2, survivin and granulocyte-macrophage colony stimulating factor, resulting in increased apoptosis and reduced lesional infiltration of alternatively activated macrophages. Tetramethylpyrazine treatment also significantly reduced the plasma concentration of P-selectin and hyaluronic acid, possibly leading to reduced lesional platelet aggregation. Thus, we conclude that tetramethylpyrazine holds the promise as therapeutics for treating endometriosis, but the tetramethylpyrazine plus tanshinone IIA sulfonate did not further enhance the therapeutic effect. These results further underscore the notion that induced senescence may play an antifibrotic role in endometriosis, and activating the senescence pathway, through treatment with tetramethylpyrazine or other similar drugs, may be a novel avenue for treating endometriosis.
Yi Liang Lee, MD
Tri-Service General Hospital, Neihu, Taipei, Taiwan, ROC.
Yin-Shium Bai, MPhil. PhD candidate
Department of Obstetrics and Gynecology, Kang Ning Hospital, Neihu, Taipei, Taiwan, ROC; National Defense Medical Center, Neihu, Taipei, Taiwan, ROC.
Chang Sheng Yin, MD
Department of Obstetrics and Gynecology, Kang Ning Hospital, Neihu, Taipei, Taiwan, ROC; National Defense Medical Center, Neihu, Taipei, Taiwan, ROC.
Abstract
Background: Treatment for patients with symptomatic adenomyosis has been mainly by hysterectomy. The aim of this 5-year observational study was to assess the feasibility of Hysteroscopic Endomyometrium Resection with concomitant Insertion of LNG-IUD for symptomatic adenomyosis.
Methods: From May 2015 and December 2022, a group of 36 women with symptomatic adenomyosis underwent this combined modality treatment at a community hospital. The core outcomes of the study were effective rate of dysmenorrhea, menorrhagia, secondary outcomes as hysterectomy, IUD expulsion, or premature removal, repeated the procedures.
Results: The study followed the progress of 36 women, aged 42.9±4, over a period of five years. The procedures were performed safely, and no complications were observed. The total successful rate of amenorrhea was 27 of 36 (75%). For the Pain Control, the intervention led to a significant reduction in pain scores, with the mean pain score decreasing by approximately 63.4% (95% CI: -64.3% to -62.5%). For the Blood Loss, with the mean blood loss decreasing by approximately 75.77% (95% CI: 32.93% to 118.61%). The study also showed reduced CA-125 level, reduction in uterine length and volume, about 70% of patients reported being very satisfied and satisfied of this combined treatment.
Conclusion: We demonstrated this combined modality is feasible and safe for treatment of symptomatic adenomyosis.
Kenneth Blum
Mark S Gold
Jean Lud Cadet
Marjorie C. Gondre-Lewis
Thomas McLaughlin
Eric R Braverman
Igor Elman
B. Paul Carney
Rene Cortese
Tomilowo Abijo
Debasis Bagchi
John Giordano
Catherine A. Dennen
David Baron
Panayotis K Thanos
Diwanshu Soni
Milan T. Makale
Miles Makale
Kevin T. Murphy
Nicole Jafari
Keerthy Sunder
Foojan Zeine
Mauro Ceccanti
Abdalla Bowirrat
Rajendra D. Badgaiyan
Abstract
Addiction, albeit some disbelievers like Mark Lewis [1], is a chronic, relapsing brain disease, resulting in unwanted loss of control over both substance and non- substance behavioral addictions leading to serious adverse consequences [2]. Addiction scientists and clinicians face an incredible challenge in combatting the current opioid and alcohol use disorder (AUD) pandemic throughout the world. Provisional data from the Centers for Disease Control and Prevention (CDC) shows that from July 2021-2022, over 100,000 individuals living in the United States (US) died from a drug overdose, and 77,237 of those deaths were related to opioid use [3]. This number is expected to rise, and according to the US Surgeon General it is highly conceivable that by 2025 approximately 165,000 Americans will die from an opioid overdose. Alcohol abuse, according to data from the World Health Organization (WHO), results in 3 million deaths worldwide every year, which represents 5.3% of all deaths globally [4].
Amosy E. M’Koma
Departments of Biochemistry, Cancer Biology, Neuroscience and Pharmacology
Jamie N. Ware
Departments of Obstetrics and Gynecology
Rosemary K. Nabaweesi
Center for Health Policy, Meharry Medical College, Nashville, TN 37208, USA.
Sanika S. Chirwa
Departments of Biochemistry, Cancer Biology, Neuroscience and Pharmacology
Abstract
Inflammatory bowel disease (IBD) is a term for two autoimmune diseases encompassing Crohn’s disease (CD) and ulcerative colitis (UC) which are lifelong diseases affecting more than 3 million adults (1.3%) in the United States. IBD is characterized by chronic inflammation of the whole digestive system which results in damage to the gastrointestinal (GI) tract. IBD often emerges during adolescence and young adulthood. Maternal morbidity includes physical and psychological conditions that result from or are aggravated by pregnancy and have an adverse effect on a woman’s health, the baby’s health or both. Some women have health challenges that arise before or during pregnancy that could lead to complications. It is recommended for women to receive health care counseling before and during pregnancy. Compared to other developed countries, the United States has the highest rate of women dying of pregnancy related complications. During the past 25 years maternal mortality has been getting worse. African American women (AAW) with and/or without IBD are dying at significantly higher rates than other groups. This is linked to several factors, i.e., systemic, institutionalized, and structural racism in health-care delivery and subsequent toxic stress from people’s lived experiences of racism, limited knowledge about healthcare system function, lack of access to healthcare, (inclusiveness and insurance policies) all of which negatively impact these patients. African Americans (AAs) are also up to three times as likely to experience severe maternal morbidity: unexpected outcomes of labor and delivery, deficient or lacking prenatal care and social determinants of health like lack of transportation, adequate employment, limited literacy, and limited healthcare access contribute to poor health outcomes. Studies on IBD patients indicate Medicaid expansion is associated with reduced rates of maternal morbidity, particularly for African American Women (AAW) and increased access to preconception and prenatal services that make pregnancy and childbirth safer for parent and baby. Herein we examine the physiological changes of pregnancy in patients diagnosed with inflammatory bowel disease and their relationship perinatal outcomes and parenthood.
