Corrigendum: Cardiovascular risk according to body mass index in reproductive-aged women with polycystic ovary syndrome: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fcvm.2022.822079.].

Corrigendum: Research on the mechanism and prevention of hypertension caused by apatinib through the RhoA/ROCK signaling pathway in a mouse model of gastric cancer.

[This corrects the article DOI: 10.3389/fcvm.2022.873829.].

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer.

Hypertension is one of the main adverse effects of antiangiogenic tumor drugs and thus limits their application. The mechanism of hypertension caused by tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors is mainly related to inhibition of the nitric oxide (NO) pathway and activation of the endothelin pathway, as well as vascular rarefaction and increased salt sensitivity; consequently, prevention and treatment differ for this type of hypertension compared with primary hypertension. Apatinib is a highly selective TKI approved in China for the treatment of advanced or metastatic gastric cancer. The RhoA/ROCK pathway is involved in the pathogenesis of hypertension and mediates smooth muscle contraction, eNOS inhibition, endothelial dysfunction and vascular remodeling. In this study, in vivo experiments were performed to explore whether the RhoA/ROCK signaling pathway is part of a possible mechanism of apatinib in the treatment of gastric cancer-induced hypertension and the impairment of vascular remodeling and left ventricular function. Y27632, a selective small inhibitor of both ROCK1 and ROCK2, was combined with apatinib, and its efficacy was evaluated, wherein it can reduce hypertension induced by apatinib treatment in gastric cancer mice and weaken the activation of the RhoA/ROCK pathway by apatinib and a high-salt diet (HSD). Furthermore, Y-27632 improved aortic remodeling, fibrosis, endothelial dysfunction, superior mesenteric artery endothelial injury, left ventricular dysfunction and cardiac fibrosis in mice by weakening the activation of the RhoA/ROCK pathway. The expression of RhoA/ROCK pathway-related proteins and relative mRNA levels in mice after apatinib intervention were analyzed by various methods, and blood pressure and cardiac function indexes were compared. Endothelial and cardiac function and collagen levels in the aorta were also measured to assess vascular and cardiac fibrosis and to provide a basis for the prevention and treatment of this type of hypertension.

Apatinib Through Activating the RhoA/ROCK Signaling Pathway to Cause Dysfunction of Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are associated with differentiated, organized, and contractile phenotype under the effect of various types of physiological conditions those are associated with migratory, proliferative, and synthetic phenotype under the effect of various types of stimuli, which dysfunction drives many cardiovascular diseases. Abnormal cell proliferation and invasion of VSMCs are among the primary causes of hypertension. Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) that highly selectively binds to and strongly inhibits VEGFR-2. Previous studies have confirmed that the TKIs can raise blood pressure through RhoA/ROCK pathway. LARG is a key gene in the RhoA/ROCK pathway and plays a critical role in the continuous vasoconstriction function because it regulates part of signal transduction in VSMCs. In this study, an in vitro experiment was conducted to observe that apatinib caused dysfunction of MOVAS cells through the RhoA/ROCK signalling pathway and Y27632, a nonspecific ROCK inhibitor, and knockout of LARG gene can improve the proliferation, antiapoptosis, oxidative stress, and mitochondrial autophagy of apatinib-induced MOVAS cells. These findings suggest that activation of the RhoA/ROCK signalling pathway could be the underlying mechanism of apatinib-induced dysfunction of MOVAS cells, while ROCK inhibitor and knockout of LARG gene have potential therapeutic value.

PTEN inhibitor attenuates cardiac fibrosis by regulating the M2 macrophage phenotype via the PI3K/AKT/TGF-ß/Smad 2/3 signaling pathway.

Cardiac fibrosis is a key feature of hypertensive cardiac remodeling. In response to microenvironmental stimuli, phenotypic and functional changes in macrophages are considered important determinants of cardiac fibrosis attenuation. VO-OHpic, a phosphatase and tension homolog of chromosome 10 (PTEN) inhibitor, has been demonstrated to be cardioprotective in cardiac remodeling. However, whether VO-OHpic can improve cardiac fibrosis and macrophage polarization remains elusive. The interaction between VO-OHpic and the macrophage phenotype to attenuate cardiac fibrosis was studied in both spontaneously hypertensive rats in vivo and an Ang II-induced hypertension model in vitro. In vitro experiments showed that VO-OHpic promoted M2 macrophage polarization and markedly inhibited proinflammatory M1 macrophages, while VO-OHpic treatment of protein kinase B (AKT)-knockdown/LY294002 (a PI3K inhibitor) macrophages exerted a reduced effect. In a coculture system, culturing cardiac fibroblasts with VO-OHpic-treated macrophages led to significant suppression of proliferation, fibrotic marker expression, and transforming growth factor (TGF)-ß and Smad 2/3 protein expression. Taken together, VO-OHpic mediated a fibro-protective effect and increased M2 macrophage polarization via the phosphatidylinositol 3-kinase (PI3K)/AKT/TGF-ß/Smad2/3 pathway.

Sacubitril/Valsartan Improves Sexual Function and Fibrosis of the Clitoral and Vaginal Tissues in Female Spontaneously Hypertensive Rats.

ABSTRACT: Female sexual dysfunction is common in hypertension. The effects of sacubitril/valsartan (SAC/VAL) as a potential therapy for hypertension and heart failure have not been studied in relation to sexual function and genital fibrosis in female spontaneously hypertensive rats (SHRs). Thirty female SHRs were administered VAL, SAC/VAL, or saline. Ten normotensive female Wistar-Kyoto (WKY) rats were included in the control group. We assessed estrous cyclicity and sexual behavior in the female rats. In addition, the morphology of clitoral and vaginal tissues was evaluated by histological analyses. Western blotting and enzyme-linked immunosorbent assays were used to assess the levels of fibrotic markers in vaginal and clitoral tissues. Furthermore, the protein levels of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), phosphoinositide-3-kinase (PI3K), and AKT expression were measured by Western blotting. SAC/VAL treatment improved hypertension-induced sexual dysfunction, exhibited as a prolonged estrus phase, increased receptivity and proceptive events, and decreased aggressive events, compared with those of VAL treatment and control SHRs without treatments. In addition, SAC/VAL-treated SHRs had lower levels of fibrotic markers, estradiol, and estrogen receptor α/ß than the levels of VAL-treated SHRs or SHRs without treatment. Moreover, SAC/VAL decreased p-PTEN expression and increased p-PI3K and p-AKT expression at the protein level compared with those in VAL treatment alone. VAL and SAC/VAL treatments have significantly increased sexual receptivity and proceptivity, decreased aggressiveness, and improved the fibrosis of vaginal and clitoral tissues in female SHRs. However, SAC/VAL treatment shows more effective results compared with VAL treatment, which may be related to the PTEN/PI3K/AKT pathway.

Cardiovascular Risk According to Body Mass Index in Women of Reproductive Age With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects women of reproductive age. The association between PCOS and cardiovascular risk according to body mass index (BMI) categories is unclear. OBJECTIVE: We evaluated the association between cardiovascular risk according to BMI categories and PCOS in women of reproductive age. METHODS: A literature search was conducted in the EMBASE, MEDLINE, Cochrane Library, and PubMed databases from their inception to 9 September, 2021. Observational cross-sectional, retrospective, and prospective controlled studies were included. The main analyses examined the relationship between cardiovascular risks (i.e., blood pressure and lipid levels) and BMI in women of reproductive age with PCOS. RESULTS: Thirty-eight studies, with a total of 6,078 subjects, were included in this metaanalysis. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in women of reproductive age with PCOS. Lower high-density lipoprotein (HDL)-cholesterol [SMD (95% CI): -0.21 (-0.35, -0.08), p = 0.002], higher triglycerides [SMD (95% CI): 0.38 (0.29, 0.48), p < 0.001], higher low-density lipoprotein (LDL)-cholesterol [SMD (95% CI): 0.29 (0.20, 0.39), p < 0.001], higher nonHDL-cholesterol [SMD (95% CI): 0.42 (0.31, 0.52), p < 0.001] and waist-to-hip ratio (WHR) [MD (95% CI): 0.03 (0.02, 0.04), p < 0.001] were seen in women of reproductive age with PCOS. In addition, the subgroup analysis revealed that systolic BP and HDL-cholesterol increased at BMI < 25 kg/m2 and BMI 25-30 kg/m2. Diastolic BP increased at BMI 25-30 kg/m2. Triglycerides, LDL-cholesterol, nonHDL-cholesterol, and WHR increased in all BMI categories. CONCLUSIONS: PCOS is associated with cardiovascular risk. Lipid levels and BP increased in women of reproductive age with PCOS, regardless of BMI. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (10.17605/OSF.IO/92NBY).

The effect of exercise training and physiotherapy on diastolic function, exercise capacity and quality of life in patients with heart failure with preserved ejection fraction: a systematic review and meta-analysis.

BACKGROUND: Exercise and physiotherapy are accepted as an important contribution to the rehabilitation of patients with heart failure with preserved ejection fraction (HFpEF). But the previous results are unclear partly because of their limited power and small sample sizes. AIMS: We aimed to understand better the effects of two exercise training interventions and two modalities of physiotherapies on exercise capacity, quality of life (QoL), and diastolic dysfunction in HFpEF patients. METHODS: The Cochrane Library, EMBASE, and MEDLINE via PubMed were searched for randomized controlled trials from their inception to May 2021. The effect size was estimated as mean differences (MD) with 95% confidence intervals (CI). RESULTS: A total of 14 articles on 13 trials were included in this meta-analysis with 673 HFpEF patients. The pooling revealed that peak oxygen uptake was improved by endurance training, functional electrical stimulation (FES), and inspiratory muscle training (IMT). Similar results were observed for a 6-minute walk test and QoL. A combination of endurance and resistance training (combined exercise) was beneficial to the ratio of peak early to late diastolic mitral inflow velocities (MD [95% CI]: -2.90 [-4.97, -0.83]; P = 0.006) and the early diastolic mitral annual velocity (MD [95% CI]: 1.40 [0.68, 2.12]; P = 0.006]. IMT improved the ventilation/carbon dioxide ratio slope (MD [95% CI]: -3.36 ml/kg/min [-6.17, -0.54]; P = 0.019]. CONCLUSIONS: FES and IMT improve functional capacity and QoL without a change in diastolic function in HFpEF patients, and the outcomes are similar to endurance training. Notably, combined exercise may improve diastolic function. Key words: diastolic function, exercise training, functional electrical stimulation, heart failure with preserved ejection fraction, inspiratory muscle training.

A narrative review on the interaction between genes and the treatment of hypertension and breast cancer.

OBJECTIVE: The aim to discuss the close relationship between the common biological mechanisms of breast cancer and hypertension, inflammation and oxidative stress, breast cancer gene mutations breast cancer susceptibility gene (BRCA), G protein-coupled receptor kinase (GRK4), etc. and breast cancer treatment includes chemotherapy, Endocrine therapy, Targeted therapy and anti-angiogenesis drugs. In anti-angiogenesis drugs focusing on the mechanism of tyrosine kinase inhibitors (TKI) that may activate the rhoa/rock pathway to cause hypertension, as well as the relationship between breast cancer and antihypertensive drugs includes angiotensin-converting enzyme inhibitors (ACEIs), Calcium channel blockers (CCBs) and ß-blockers (BBs)will be explored. BACKGROUND: Cardiovascular diseases (CVD) and tumors are the two major types of diseases with the highest mortality rates, while hypertension accounts for the largest proportion of CVDs. A large number of the same or similar risk factors are shared between hypertension and tumors, and they influence each other. Many patients, particularly elderly patients, often present with the coexistence of the two diseases. As medical advances have enabled clinicians to cure tumors, many patients with cancer live longer, leading to a gradual increase in the incidence of CVDs, including hypertension. With the second highest incidence among tumors, breast cancer has gradually attracted widespread attention and has been the topic of numerous studies. Studies have confirmed that CVD is one of the causes of death in elderly patients with breast cancer. METHODS: Publications from 1985 to 2020 were retrieved from the Web Of Science, Cochrane Library, PubMed, EMBASE and MEDLINE database. We used a mix of MeSH and keywords. CONCLUSIONS: Hypertension and cancer may share a common mechanism. The screening and risk assessment of breast cancer in patients with hypertension must be strengthened. Breast cancer cardiology is the interdisciplinary study of oncology and cardiology, and in-depth research in this field may result in long-term improvements in the survival and prognosis of patients with both clinical hypertension and breast cancer.

Cerebral infarction as initial presentation in stress cardiomyopathy: Case report and literature review.

RATIONALE: The typical symptoms of stress cardiomyopathy include sudden-onset chest pain and breathlessness or collapse as well as classical symptoms of cardiovascular disease; however, rare reports have described nervous system symptoms as the initial manifestation. Here, we report the case of a young man who presented with a large cerebral infarction as the main clinical symptom of stress cardiomyopathy to increase recognition of the disease. PATIENT CONCERNS: A 28-year-old man was admitted to our hospital for sudden-onset weakness of the right limbs and unconsciousness for 1 day. Ten days prior, he began consuming copious amounts of alcohol (500 mL/day) secondary to reactive depression. DIAGNOSES: Imaging revealed a left internal carotid artery occlusion as assessed by carotid artery ultrasonography. Brain magnetic resonance imaging/magnetic resonance angiography showed new large left cerebral infarction complicated by a reperfusion injury. Moreover, cardiac ultrasonography showed decreased motion of the left ventricular apex, a 3.7 cm mural thrombus in the ventricular apex. The results of coronary and renal artery angiography did not reveal any significant epicardial coronary disease with thrombolysis in the myocardial infarction grade 3 in any of the coronary arteries. INTERVENTIONS: The patient was administered antiplatelet, anticoagulation, antihypertension, antibiotic, and neurotrophic therapies. OUTCOMES: The symptoms of cerebral infarction improved significantly after 12 days of admission. Cardiac ultrasonography showed that the wall movement of the left ventricular apex had recovered fully and the mural thrombus resolved completely. LESSONS: Patients with stress cardiomyopathy exhibit various clinical manifestations and characteristics. On the basis of our in-depth understanding of stress cardiomyopathy, clinicians should diagnose early and develop reasonable and effective therapies to prevent the harmful effects of related complications.