Effect of sacubitril/valsartan or valsartan on ventricular remodeling and myocardial fibrosis in perimenopausal women with hypertension.

OBJECTIVE: To evaluate the impact of sacubitril/valsartan on blood pressure (BP), ventricular structure, and myocardial fibrosis compared with valsartan in perimenopausal hypertensive women. METHODS: This prospective, randomized, actively controlled, open-label study included 292 women with perimenopausal hypertension. They were randomly divided into two groups: sacubitril/valsartan 200 mg once daily and valsartan 160 mg once daily for 24 weeks. The relevant indicators of ambulatory BP, echocardiography, and myocardial fibrosis regulation were assessed at baseline and at 24 weeks. RESULTS: The 24-h mean SBP after 24 weeks of treatment was 120.08 ±â€Š10.47 mmHg in the sacubitril/valsartan group versus 121.00 ±â€Š9.76 mmHg in the valsartan group ( P  = 0.457). After 24 weeks of treatment, there was no difference in central SBP between the sacubitril/valsartan and valsartan groups (117.17 ±â€Š11.63 versus 116.38 ±â€Š11.58, P  = 0.568). LVMI in the sacubitril/valsartan group was lower than that in the valsartan group at week 24 ( P  = 0.009). LVMI decreased by 7.23 g/m 2 from the baseline in the sacubitril/valsartan group and 3.70 g/m 2 in the valsartan group at 24 weeks ( P  = 0.000 versus 0.017). A statistically significant difference in LVMI between the two groups was observed at 24 weeks after adjusting for the baseline LVMI ( P  = 0.001). The levels of α-smooth muscle actin (α-SMA), connective tissue growth factor (CT-GF) and transforming growth factor-ß (TGF-ß) were reduced in the sacubitril/valsartan group compared with the baseline ( P  = 0.000, 0.005, and 0.000). LVMI between the two groups was statistically significant at 24 weeks after correcting for confounding factors 24-h mean SBP and 24-h mean DBP ( P  = 0.005). The LVMI, serum TGF-ß, α-SMA, and CT-GF remained statistically significant between the two groups after further correcting the factors of age, BMI, and sex hormone levels ( P  < 0.05). CONCLUSION: Sacubitril/valsartan could reverse ventricular remodeling more effectively than valsartan. The different effects of these two therapies on ventricular remodeling in perimenopausal hypertensive women might be because of their different effects on the down-regulation of fibrosis-related factors.

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.

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension.

OBJECTIVES: Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated. METHODS: Normotensive female Wistar-Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed. RESULTS: Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes. CONCLUSION: These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team's previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, ß-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

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.

Effects of hormone replacement therapy on left ventricular diastolic function in postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: Postmenopausal women tend to experience significant changes in left ventricular diastolic function (LVDF). However, there are conflicting reports about LVDF between postmenopausal women on hormone replacement therapy (HRT) and those not on HRT. This meta-analysis is to evaluate the effects of HRT on LVDF in postmenopausal women. METHODS: We conducted a systemic review of randomized controlled trials published up to December 31 2019 using Embase, Pubmed, and the Cochrane library database. RESULTS: Eight studies involving 668 postmenopausal women were identified. Our analysis indicated that the ratio of the peak velocity during early filing to late filling from atrial contraction improvement in HRT group was better than that in placebo group (MD 0.20, 95%CI 0.12 to 0.28). There was a significant reduction in deceleration time and left ventricular mass index in HRT group compared with placebo group (MD -21.01, 95%CI -40.11 to -1.91 vs MD -8.26, 95%CI -14.10 to -2.42). No significant difference was observed in left ventricular end systole diameter (MD 0.80, 95%CI -0.72 to 2.31), left ventricular end diastole diameter (MD -0.07, 95%CI -1.25 to 1.10), left atrial size (MD -0.33, 95%CI -1.34 to 0.68)and the isovolumic relaxation time (MD -12.08, 95%CI -27.65 to 3.5). CONCLUSIONS: Our meta-analysis illustrated that postmenopausal women seem to obtain more beneficial effects from HRT on LVDF, though future studies are required to elucidate the specific mechanisms for this phenomenon.

Comparative efficacy of different types of antihypertensive drugs in reversing left ventricular hypertrophy as determined with echocardiography in hypertensive patients: A network meta-analysis of randomized controlled trials.

Reversing left ventricular hypertrophy (LVH) can reduce the incidence of adverse cardiovascular events. However, there is no clear superiority-inferiority differentiation between angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), and diuretics in reversing LVH in hypertensive patients. To provide further evidence for choosing the optimal antihypertensive drug for improving LVH, we performed a network meta-analysis of randomized controlled trials (RCTs) based on the Cochrane library database, Embase, and Pubmed, and identified 49 studies involving 5402 patients that were eligible for inclusion. It was found that ARB could improve LVH in hypertensive patients more effectively than CCB (MD -4.07, 95%CI -8.03 to -0.24) and BB (MD -4.57, 95%CI -8.07 to -1.12). Matched comparison of renin-angiotensin system inhibitors (RASi) showed that the effect of ACEI in reducing left ventricular mass index (LVMi) was not effective as that of ARB (MD -3.72, 95%CI -7.52 to -0.11). The surface under the cumulative ranking for each intervention indicated that the use of ARB was more effective among the different types of antihypertensive drugs (97%). This network meta-analysis revealed that the use of ARB in antihypertensive therapy could achieve better efficacy in reversing LVH in hypertensive patients.

Prognostic value of heart failure echocardiography index in HF patients with preserved, mid-ranged and reduced ejection fraction.

BACKGROUND: To investigate the clinical value of heart failure echocardiography index (HFEI) in evaluating the cardiac function and predicting the prognosis of patients with different types of heart failure (HF). METHODS: Four hundred eighty-nine consecutively admitted HF patients were divided into three groups: HF with reduced ejection (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). The baseline characteristics and ultrasound indexes were compared between the three groups. The correlation between HFEI and one-year risk of adverse events was compared by multivariate logistic regression. The clinical value of HFEI and plasma level of NT-proBNP in assessing the prognosis of patients with chronic heart failure (CHF) was analyzed by the receiver operating characteristic (ROC) curve. RESULTS: HFEI in HFrEF was significantly higher than that in HFmrEF and HFpEF. Multivariate regression analysis indicated that HFEI and plasma level of NT-proBNP were independent risk factors for predicting the short-time prognosis of HF patients. The ROC curve indicated that the HFEI cutoff level of 3.5 and the plasma NT-proBNP level of 3000 pg/ml predicted a poor prognosis of CHF patients with a sensitivity of 64% and a specificity of 75% vs. 68 and 65%. CONCLUSION: HFEI can comprehensively evaluate the overall cardiac function of patients with various types of HF, and may prove to be an important index of assessing the prognosis of HF patients.

Thromboelastography or rotational thromboelastometry for bleeding management in adults undergoing cardiac surgery: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Severe bleeding and massive transfusion of blood products may be associated with increased morbidity and mortality of cardiac surgery. A transfusion algorithm incorporating thromboelastography (TEG) or rotational thromboelastometry (ROTEM) can help to determine the appropriate time and target for the use of hemostatic blood products, which may thus reduce the quantity of blood loss as well as blood products transfused. METHODS: We conducted meta-analysis and trial sequential analysis to evaluate the effects of TEG or ROTEM-guided transfusion algorithms vs. standard treatments for patients undergoing cardiac surgery with cardiac pulmonary bypass. RESULTS: Nineteen studies with a total of 15,320 participants, including 13 randomized controlled trials (RCTs), were included. All-cause mortality was not reduced either in overall studies or in RCTs. Blood loss volume was reduced by 132 mL in overall studies [mean difference (MD): -132.46, 95% CI: -207.49, -57.43; I2 =53%, P<0.01], and by 103 mL in RCTs (MD: -103.50, 95% CI: -156.52, -50.48; I2 =0%, P<0.01). The relative risks (RRs) in RCTs were 0.89 (95% CI: 0.80-0.98; I2 =0%, P=0.02) for red blood cells transfusion, 0.59 (95% CI: 0.42-0.82; I2 =55%, P<0.01) for fresh frozen plasma transfusion, and 0.81 (95% CI: 0.74-0.90; I2 =0%, P<0.01) for platelet transfusion, respectively. Trial sequential analysis of continuous data on blood loss and dichotomous outcomes on transfusion of blood products suggested the benefits of a TEG/ROTEM-guided algorithm. CONCLUSIONS: TEG or ROTEM-guided transfusion strategies may reduce blood loss volume and the transfusion rates in adult patients undergoing cardiac surgery.

Tuberculous pericarditis mimicking multiple tumors in pericardial effusion.

Tuberculosis is still the leading cause of pericardial disease in developing nations. A definite diagnosis of tuberculosis is usually relatively difficult, especially when its manifestations are not typical. We report a 19-year-old man who presented with chest obstruction, shortness of breath, edema of the lower extremities, and mild fever for 14 days. The manifestations of tuberculosis pneumonia were not typical, except for a small high-density shadow in the left upper lung field near the pleura, with a small amount of pleural effusion on chest computed tomography. The tuberculin skin test, acid-fast stain of sputum and pericardial effusion, and bacterial culture showed negative results. Echocardiography showed three free-floating irregular masses in a large amount of pericardial effusion. The masses and exudates were removed by pericardiectomy. The masses were composed of hyperplastic granulation tissue and dead tissue without a normal architecture, mixed with numerous caseous substances, which confirmed the diagnosis of tuberculous pericarditis. This is a unique report of a patient who presented with tuberculous pericarditis with multiple solid masses in a large amount of pericardial effusion, without typical clinical manifestations of tuberculosis.

Oleuropein Protects Cardiomyocyte against Apoptosis via Activating the Reperfusion Injury Salvage Kinase Pathway In Vitro.

Oleuropein, the main glycoside present in olives, has been reported to have cardioprotective effect, but the exact mechanism has not been clearly elucidated. This study attempted to clarify the cardioprotective effect of oleuropein against simulated ischemia/reperfusion- (SI/R-) induced cardiomyocyte injury in vitro and further explore the underlying mechanism. Here we confirmed that oleuropein reduced the cell injury in neonatal rat cardiomyocyte induced by SI/R evidenced by decreasing MTT dye reduction and LDH activity in the culture medium. Meanwhile, the compound also inhibited reactive oxygen species excessive generation and stabilized mitochondrial membrane potential after SI/R. The flow cytometry assessment results indicated the inhibition of cellular apoptosis with oleuropein treatment. Furthermore, western blot analysis showed that oleuropein attenuated the expression of Cyt-C, c-caspase-3, and c-caspase-9, increased the Bcl-2/Bax ratio, and enhanced the phosphorylation of ERK1/2 and Akt after SI/R. However, the phosphorylation enhancement was partially abolished in the presence of LY294002 (PI3K inhibitor) and U0126 (ERK inhibitor). All these findings indicate that oleuropein has the protective potential against SI/R-induced injury and its protective effect may be partly due to the attenuation of apoptosis via the activation of the PI3K/Akt and ERK1/2 signaling pathways.

[Airway remodeling assessed by high-resolution computed tomography in patients with asthma: relationship to biological markers in induced sputum].

OBJECTIVE: To explore the significance of assessing asthma control by high-resolution computed tomography (HRCT) and biological markers in induced sputum. METHODS: Forty-eight patients with asthma (asthma group) and 10 healthy subjects (control group) were retrospectively analyzed. The asthma patients were divided into 4 groups based on severity: 6 with near-fatal attacks, 12 with severe, 14 with moderate and 16 with mild asthma. These patients received step therapy for 6 months based on the guidelines for the prevention and treatment of asthma. After achieving asthma control or partial control, HRCT, lung function and cytokine levels in induced sputum were measured. The ratio of wall area to total airway area (WA%), the ratio of 2 airway wall thickness to outer diameter (2T/D) and lung densities in both the inspiratory and expiratory phases were measured. Matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transformation growth factor-ß(1) (TGF-ß(1)) levels in the sputum were assessed by enzyme-linked immunosorbent assay. RESULTS: There were significant differences in forced vital capacity and forced expiratory volume in 1 second as the percentage of predicted value (FVC% and FEV(1)%, respectively), the ratio of FEV(1)/FVC, and diffusing capacity of the lung for carbon monoxide (D(LCO)) among groups (F = 5.526, 15.064, 16.326, 2.945, respectively, P < 0.05). Sputum levels of MMP-9, TIMP-1 and TGF-ß(1) were significantly increased in the near-fatal asthma, severe asthma, moderate asthma and mild asthma groups [MMP-9: (80 ± 16), (70 ± 9), (59 ± 6), and (52 ± 7) µg/L, respectively; TIMP-1: (212 ± 95), (258 ± 167), (28 ± 51), and 98 ± 60 µg/L, respectively; TGF-ß(1): (586 ± 81), (513 ± 54), (401 ± 45) and (351 ± 57) µg/L, respectively]compared with the control group [MMP9: (46 ± 5) µg/L; TIMP: (19 ± 13) µg/L; and TGF-ß(1): (258 ± 29) µg/L]. These parameters were progressively increased in the asthma groups with the severity of disease (F = 11.179, 49.914, 9.286, respectively, P < 0.05). The ratio of MMP-9/TIMP-1 in sputum was decreased in the near-fatal attack, severe, moderate and mild asthma groups (0.50 ± 0.28, 0.34 ± 0.13, 0.53 ± 0.22, and 0.87 ± 0.75, respectively) compared with the control group (2.93 ± 1.13). The MMP-9/TIMP-1 ratio in the severe asthma group was lowest among the asthma groups (F = 43.335, P < 0.05). 2T/D and WA% were higher in both the near-fatal asthma group (0.51 ± 0.01 and 0.75 ± 0.01, respectively) and the severe asthma group (0.53 ± 0.03 and 0.77 ± 0.03, respectively) as compared to the moderate asthma group (0.43 ± 0.04 and 0.67 ± 0.04, respectively) or the mild group (0.42 ± 0.04 and 0.66 ± 0.04, respectively). 2T/D and WA% were higher in the asthma groups than in the control group (0.35 ± 0.03 and 0.57 ± 0.04, respectively), (F = 40.224, 41.294, respectively, P < 0.05). Lung densities in both the inspiratory and expiratory phases were lower in the near-fatal attack group as compared to those in the other asthma groups or the control group; and the lung density differences between the two phases in the near-fatal attack group were smaller than those in the other asthma groups or the control group (F = 5.048, 13.247, 11.541, respectively, P < 0.05). 2T/D and WA% were correlated positively with MMP-9, TIMP-1 and TGF-ß(1) levels, but negatively with the MMP-9/TIMP-1 ratio, respectively. CONCLUSIONS: HRCT and biological markers in induced sputum could be used to accurately evaluate asthma control. These findings suggest that the severity of asthma, especially, near-fatal attack of asthma, is correlated not only with the degree of airway remodeling, but also with the degree of air trapping.