Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo-Yap pathway to exacerbate doxorubicin-induced cardiotoxicity.

Doxorubicin-induced cardiotoxicity (DIC), which is a cardiovascular complication, has become the foremost determinant of decreased quality of life and mortality among survivors of malignant tumors, in addition to recurrence and metastasis. The limited ability to accurately predict the occurrence and severity of doxorubicin-induced injury has greatly hindered the prevention of DIC, but reducing the dose to mitigate side effects may compromise the effective treatment of primary malignancies. This has posed a longstanding clinical challenge for oncologists and cardiologists. Ferroptosis in cardiomyocytes has been shown to be a pivotal mechanism underlying cardiac dysfunction in DIC. Ferroptosis is influenced by multiple factors. The innate immune response, as exemplified by neutrophil extracellular traps (NETs), may play a significant role in the regulation of ferroptosis. Therefore, the objective of this study was to investigate the involvement of NETs in doxorubicin-induced cardiomyocyte ferroptosis and elucidate their regulatory role. This study confirmed the presence of NETs in DIC in vivo. Furthermore, we demonstrated that depleting neutrophils effectively reduced the occurrence of doxorubicin-induced ferroptosis and myocardial injury in DIC. Additionally, our findings showed the pivotal role of high mobility group box 1 (HMGB1) as a critical molecule implicated in DIC and emphasized its involvement in the modulation of ferroptosis subsequent to NETs inhibition. Mechanistically, we obtained preliminary evidence suggesting that doxorubicin-induced NETs could modulate yes-associated protein (YAP) activity by releasing HMGB1, which subsequently bound to toll like receptor 4 (TLR4) on the cardiomyocyte membrane, thereby influencing cardiomyocyte ferroptosis in vitro. Our findings suggest that doxorubicin-induced NETs modulate cardiomyocyte ferroptosis via the HMGB1/TLR4/YAP axis, thereby contributing to myocardial injury. This study offers a novel approach for preventing and alleviating DIC by targeting alterations in the immune microenvironment.

Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension.

BACKGROUND: The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. RESULTS: Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P = 0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group. CONCLUSIONS: In older patients with hypertension, intensive treatment with a systolic blood-pressure target of 110 to less than 130 mm Hg resulted in a lower incidence of cardiovascular events than standard treatment with a target of 130 to less than 150 mm Hg. (Funded by the Chinese Academy of Medical Sciences and others; STEP ClinicalTrials.gov number, NCT03015311.).

Protective effect of low-intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. METHODS: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. RESULTS: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. CONCLUSION: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

A tryst of 'blood pressure control- sex- comorbidities': the odyssey of basic public health services in Yunnan in quest for truth.

BACKGROUND: The Basic Public Health Service (BPHS), a recently announced free healthcare program, aims to combat the most prevalent Noncommunicable Disease-"Hypertension" (HTN)-and its risk factors on a nationwide scale. In China, there is a rife that HTN less impacts women during their lifetime. We, therefore, aimed to evaluate the sex disparity in hypertension patients with comorbidities among south-west Chinese and the contribution of BPHS to address that concern. METHODS: We have opted for a multistage stratified random sampling method to enroll hypertensive patients of 35 years and older, divided them into BPHS and non-BPHS groups. We assessed the sex disparity in HTN patients with four major comorbidities- Dyslipidemia, Diabetes Mellitus (DM), Cardiovascular Disease (CVD), and Chronic Kidney Disease (CKD), and descriptive data were compiled. Odds ratios from logistic regression models estimated the effectiveness of BPHS in the management of HTN with comorbidities. RESULTS: Among 1521 hypertensive patients,1011(66.5%) were managed in the BPHS group. The proportion of patients who had at least one comorbidity was 70.7% (95% confidence interval [CI]: 66.3-76.8%), patients aged 65 years and older were more likely to have coexisting comorbidities. Participants who received the BPHS showed significant blood pressure (BP) control with two comorbidities (odds ratio [OR] = 2.414, 95% CI: 1.276-4.570), three or more (OR = 5.500, 95%CI: 1.174-25.756). Patients with dyslipidemia and DM also benefited from BPHS in controlling BP (OR = 2.169, 95% CI: 1.430-3.289) and (OR = 2.785, 95%CI: 1.242-6.246), respectively. In certain high-income urban survey centers, there was sex differences in the HTN management provided by BPHS, with men having better BP control rates than women. CONCLUSIONS: Perhaps this is the first study in China to succinctly show the effectiveness and sex disparity regarding "management of hypertensive comorbidities". This supports that the BPHS program plays a pivotal role in controlling BP, therefore should recommend the national healthcare system to give women a foremost priority in BPHS, especially to those from low-socioeconomic and low-scientific literacy regions.

Two-dimensional speckle tracking echocardiography help identify breast cancer therapeutics-related cardiac dysfunction.

BACKGROUND: Cancer therapeutics-related cardiac dysfunction (CTRCD) from different chemotherapy strategies are underdetermined by echocardiography. As an imaging marker of subclinical cardiac dysfunction, two-dimensional speckle tracking echocardiography (2D-STE) may assist in identifying the impact patterns of different CTRCD. METHODS: A total of 67 consecutive patients with invasive ductal breast carcinoma who will undertake neoadjuvant chemotherapy were enrolled and grouped according to their different chemotherapy regimens based on their biopsy results. Group A included 34 patients who received anthracycline without trastuzumab, whereas Group B had 33 patients who received trastuzumab without anthracycline. Echocardiography was performed at three time-points, i.e., baseline (T0), cycle-2 (T2), and cycle-4 (T4) of chemotherapy. Conventional echocardiographic measurements and 2D-STE strain values, and myocardial work (MW) parameters, were compared between different groups at different time-points. RESULTS: The mean age had no statistical difference between the two groups. E/e' was the only conventional echocardiographic parameter that had variation in group A (P < 0.05). Compared with baseline, GLS in group A decreased at T2, and GCS decreased at T4 (P < 0.05). GLS and GCS in group B both decreased at T4 (P < 0.05). More patients in group A had a more than 15% fall of baseline GLS rather than GCS at T2 (P < 0.05), however, there was no difference of either GLS or GCS decline rate at T4 between the two groups. All the MW parameters in group A had variations overtime, whereas only GCW in group B (P < 0.05). CONCLUSION: Early subclinical myocardial dysfunction can be identified by 2D-STE in breast cancer patients with chemotherapy, and GLS provides profound value in demonstrating the temporal changes in early myocardial damage induced by anthracycline. LV contractility injury in patients with trastuzumab may be mild at first but increases in severity with exposure time as early as cycle-4. Awareness of these differences may help to stratify the prevention of late cardiovascular events caused by different CTRCDs. In addition, GCW may be the most sensitive myocardial work parameter of CTRCD.

Ultrasound characteristics of sclerosing adenosis mimicking breast carcinoma.

BACKGROUND: Sclerosing adenosis (SA) is a benign lesion with complicated pathological components and could mimic breast carcinoma in both clinical palpation and medical imaging findings. The present study was conducted to assess the value of ultrasound (US) characteristics in diagnosing SA and their differentiation from breast carcinoma. METHODS: We retrospectively reviewed the medical records of 305 women (347 lesions) with invasive ductal carcinoma (IDC) and 54 women with single SA lesion, who had breast excision between April 2016 and July 2018. US BI-RADS atlas and elastography were applied and their associated characteristics were compared between SA and IDC. RESULTS: The mean age of SA was younger than that of IDC (43.6 ± 7.4 vs 53.2 ± 10.3, P < 0.001). Compared to IDC, SA had more frequency of parallel orientation (94.44% vs 71.76%, P < 0.001) and circumscribed margin (48.15% vs 4.90%, P < 0.001), less frequency of irregular shape (64.81% vs 95.97%, P < 0.001), hypoechoic echotexture (88.89% vs 98.27%, P = 0.002), calcification (12.96% vs 55.04%, P < 0.001), and posterior acoustic changes (3.70% vs 53.89%, P < 0.001) or associated features (architectural distortion, 3.70% vs 59.65%, P < 0.001; duct changes, 18.52% vs 63.40%, P < 0.001). Vascularity absence was more common in SA compared to IDC (35.19% vs 6.63%, P < 0.001). And the elasticity score was lower in SA (2.38 ± 0.60 vs 3.91 ± 0.81, P < 0.001). After adjusting for age, we found spiculated margin, posterior shadowing, calcification, architectural distortion, and vascularity could independently identify the differences between these two entities. After involving elasticity score, the calcification and vascularity could still be independent indicators for differential diagnosis. CONCLUSION: Understanding SA imaging features will enable radiologists to communicate results to the referring physician consistently, which could benefit a reliable assessment and specific management recommendations. A systematic evaluation of the US BI-RADS atlas together with breast elastography may be a powerful tool to identify SA and differentiate it from breast cancer.

Report on three cases of familial primary aldosteronism type IV.

Primary aldosteronism is the most common cause of secondary hypertension, which is caused by increased aldosterone secretion in the adrenal cortex and contains many subtypes, among which familial hyperaldosteronism is relatively rare. Familial hyperaldosteronism can be divided into four subtypes based on its clinical manifestations and mutated genes: FH-I , FH-II , FH-III , and FH-IV . This article reports on three patients with FH-IV: a mother and her two sons. They were diagnosed with hypertension in other hospitals, and hypokalemia was found during hospitalization in our department. Diltiazem and terazosin were used for elution for 1 month. Renin and aldosterone levels in standing or supine positions improved, and the aldosterone-to-renin ratio was positive. Primary aldosteronism was diagnosed based on improved saline and captopril inhibition tests. As the three patients were blood-related immediate family members, gene screening was performed, diagnosing them with FH-IV . This article reports the clinical characteristics of the three cases in combination with related literature to improve the understanding of FH-IV .

Severe hypertension caused by 17α-hydroxylase deficiency: A case report.

Background: 17α-hydroxylase deficiency (17OHD) is an autosomal recessive genetic disease characterized by low renin hypertension, abnormal sexual development, and reduced androgen levels. The morbidity rate of 17OHD is less than 1/10,000, and a lack of knowledge of this condition may lead to misdiagnosis and delayed treatment. Case presentation: This is a case report of a patient suffering from hypertension who was diagnosed with 17OHD. The patient was misdiagnosed for more than 20 years. The patient presented with hypertension, hypokalemia, sexual infantilism, and delayed bone age. The patient had a 46, XY karyotype and a homozygous mutation of the CYP17A1 gene. The mutation site was c.1319G > A (p.Arg440His). After she took Nifedipine Sustained Release Tablets 30 mg once a day in the morning, her blood pressure dropped and is currently under control at about 145/95 mmHg. Conclusions: With clinicians' increasing awareness of 17OHD, effective treatment based on early diagnosis should correct hypogonadism and avoid the cardiovascular and cerebrovascular complications of hypertension.

Intensive Blood Pressure Lowering Improves Left Ventricular Hypertrophy in Older Patients with Hypertension: The STEP Trial.

BACKGROUND: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, its effect on cardiac remodeling remains not fully understood. This secondary analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial aims to determine the changes in left ventricular hypertrophy (LVH) that occur in the context of intensive SBP lowering. METHODS: A total of 7141 older patients with hypertension were randomly assigned to intensive treatment (SBP target, 110-130 mm Hg) or standard treatment (130-150 mm Hg). LVH was defined according to the Peguero-Lo Presti criteria on a standard 12-lead echocardiogram. RESULTS: At baseline, the prevalence of LVH (16.6% versus 16.5%) and the mean Peguero-Lo Presti value (1811 versus 1808 µV) were comparable between the treatment groups. During a median follow-up of 3.24 years, intensive SBP lowering was associated with a significantly lower risk of new LVH occurrence (hazard ratio, 0.76 [95% CI, 0.66-0.89]; P=0.001) and slower progression of the mean Peguero-Lo Presti index value by -23.47 µV/y (95% CI, -34.93 to -12.01; P=0.000). However, the rates of regression of baseline LVH did not differ significantly. Notably, the beneficial effect of intensive SBP lowering in terms of cardiovascular events (hazard ratio, 0.75 [95% CI, 0.59-0.97]) was not markedly attenuated after adjusting for LVH as a time-varying covariate (hazard ratio, 0.76 [95% CI, 0.59-0.97]). CONCLUSIONS: Intensive SBP lowering protects against LVH development in older hypertensive patients, however, this favorable effect could not explain most of the reduction in cardiovascular events associated with intensive SBP lowering.

Achieved systolic blood pressure and cardiovascular outcomes in 60-80-year-old patients: the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial.

AIMS: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, data is missing on patients who had target-achieved (TA). This study aims to show the cardiovascular effect of maintaining SBP at intensive levels. METHODS: The Strategy of Blood Pressure Intervention in Elderly Hypertensive Patients (STEP) trial was a multicentre, randomized, controlled trial which enrolled 8511 young-older (60-80 years) hypertensive patients without prior stroke to compare the cardiovascular prognosis of the intensive treatment (SBP target, 110 to <130 mmHg) vs. the standard treatment (130 to <150 mmHg). This secondary analysis assessed data in patients who achieved a mean SBP within target values. The association of mean achieved SBP and cardiovascular events was examined using a cubic spline function. RESULTS: In total, 3053 patients (72.0%) in the intensive-treatment group and 3427 (80.3%) in the standard-treatment group had an SBP target achieved, with mean follow-up SBP values of 124.2 mmHg and 137.4 mmHg, respectively. Throughout the median 3.38-year follow-up, the cardiovascular risk was significantly lower in the TA intensive-treatment group than in the TA standard-treatment group [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.46-0.80; P < 0.001]. In the intensive-treatment group, patients failing to achieve SBP targets presented higher cardiovascular risk than those TA patients (HR 2.04, 95% CI 1.44-2.88; P < 0.001). A J-shaped relationship was observed between the mean achieved SBP and risk of cardiovascular events, with the lowest risk at an SBP of 126.9 mmHg. CONCLUSIONS: Maintaining SBP at <130 mmHg offers additional cardiovascular benefits among young-older patients with hypertension. REGISTRATION: ClinicalTrials.gov: NCT03015311.

This present study is a secondary analysis that investigated the association between mean achieved BP in the two treatment groups (SBP target, 110 to <130 vs. 130 to <150 mmHg) and their cardiovascular outcomes in the STEP study (60­80-year-old patients with hypertension).Patients achieving a target in the intensive-treatment group have better cardiovascular outcome than patients achieving a target in the standard treatment arm, supporting the cardiovascular benefits of maintaining SBP <130 mmHg.J-shaped relationships were observed between mean achieved SBP and cardiovascular outcomes (with the nadir around 130 mmHg), but not for stroke.

Accuracy of non-invasive blood pressure measurement in patients with atrial fibrillation.

Although the accuracy of oscillometric blood pressure (BP) measurement is not so satisfied, the BP reading is still associated with cardiovascular events and death in patients with atrial fibrillation (AF). Because the currently used auscultatory or oscillometric methods were developed on sinus rhythm (SR), these BP measurement methods were not reasonable for AF patients. It is suggested that the average of three BP readings in the AF patients is accepted in clinical, even so, high systolic BP (SBP) variability and inaccurate diastolic BP (DBP) value have been reported in AF patients. In sinus rhythm, oscillometric pressure pulses (OPPs) are spindle-like, regardless of the heart rate. However, the shape of OPP is obviously associated with frequency of ventricular rate (VR) in AF patients. When the VR is rapid, the OPP is far from a spindle-like shape. With intro-aortic BP as reference, a study demonstrated that the oscillometric SBP level significantly underestimated the intro-aortic SBP level in the AF patients with increasing VR. In clinical practice, the physician should use the average of three BP readings in the AF patients. When the mean pulse rates (PR) reported by the oscillometric BP devise is less than 90 bpm and the variation of three pulse rate <10 bpm, the oscillometric SBP readings may be clinically accepted in AF patients. It is necessary to develop a new BP measurement method for AF as the current methods in AF are not so accurate as in SR.

Effect of fecal microbiota transplantation on primary hypertension and the underlying mechanism of gut microbiome restoration: protocol of a randomized, blinded, placebo-controlled study.

BACKGROUND: Hypertension is currently the leading modifiable cause of global morbidity and mortality, leading to substantial health and financial burdens. Although multiple studies of management models and innovative therapeutic strategies for hypertension have been conducted, there are still gaps in the field, with a poor control rate reflecting a lack of novel, effective, clinically translated medication or intervention options. Recent animal and human studies repeatedly confirmed a link between the microbiota and hypertension. Of note is our previous study establishing a cause-and-effect relationship between the gut microbiota and blood pressure elevation. A hypothesis of gut microbiota intervention for treating hypertension is thus postulated, and fecal microbiota transplantation (FMT) from healthy donors was performed. METHODS: A multicenter, randomized, placebo-controlled, blinded clinical trial will be performed in 120 grade 1 hypertensive patients for 3 months. All recruited patients will be randomly assigned in a 1:1 ratio to take oral FMT capsules or placebo capsules on day 1, day 7, and day 14 and will be followed up on day 30, day 60, and day 90. The primary outcome is the change in office systolic blood pressure from baseline to day 30. The main secondary outcomes are BP indicators, including changes in systolic and diastolic blood pressure from office and 24-h ambulatory blood pressure monitoring; assessments of ankle-branchial index and pulse wave velocity; profiling of fecal microbial composition and function; profiling of fecal and serum metabolome; changes in levels of blood glucose, blood lipids, and body mass index; and assessment of adverse events as a measure of safety. DISCUSSION: Expanding upon our previous research on the role of the gut microbiota in the pathogenesis of hypertension, this study serves as a clinical translation advancement and explores the potential of fecal microbiota transplantation for treating hypertension. The underlying mechanisms, particularly the roles of specific microorganisms or their postbiotics in blood pressure amelioration, will also be investigated via multiple approaches, such as metagenomic sequencing and metabolomic profiling. TRIAL REGISTRATION: ClinicalTrials.gov NCT04406129 . Registered on May 28, 2020.

Dawning public health services dogma: An indigenous Southwest Chinese perspective in managing hypertension-with or without the "BPHS"?

Background: To alleviate the rising mortality burden due to hypertension and other non-communicable diseases, a new public health policy initiative in 2009 called the Basic Public Health Services (BPHS). Program was introduced by the Chinese government. The goal of the study is to assess the feasibility and impact of a nationwide health care service-the "BPHS". Methods: From January to December 2021, a stratified multistage random sampling method in the survey was conducted to select 6,456 people from 8 cities/districts in Yunnan Province, China, who were above the age of 35 years. 1,521 hypertensive patients were previously aware of their high blood pressure status were matched to the BPHS program database based on ID number and then further divided into BPHS group and non-BPHS (control) group. The results of the current study are based on their responses to a short structured questionnaire, a physical examination, and laboratory tests. The association between BPHS management and its effect on the control of hypertension was estimated using multivariable logistic regression models. We evaluated the accessibility and efficacy of BPHS health care services by analyzing various variables such as blood pressure, BMI, lifestyle modification, anti-hypertensive drugs taken, and cardiovascular risk factors. Results: Among the 1,521 hypertensive patients included in this study, 1,011 (66.5%) were managed by BPHS programme. The multivariable logistic regression model demonstrated that the BPHS facilitated hypertension control (OR = 1.640, 95% CI: 1.237-2.175). A higher proportion of participants receiving lifestyle guidance from the BPHS management showed lowering of total cholesterol. In comparison to the non-BPHS group, those under BPHS management adhered better to antihypertensive medications either single drug (54.3%) or in combination (17.3%) of drugs. Additionally, we also noticed that urban areas with centralized and well-established digital information management system had better hypertension treatment and control. Conclusions: Nearly two-thirds of the hypertensive patients in Yunnan Province were included in BPHS management. The impact of the national BPHS program was evident in lowering risk factors for cardiovascular diseases, promoting healthy lifestyles, lowering blood pressure, increasing medication adherence, and the better control rate of hypertension.

Survey on sodium and potassium intake in patients with hypertension in China.

Sodium and potassium intake in hypertensive patients in China is not clear. The authors aimed to investigate the distribution of sodium and potassium intake in hypertensive patients in China, and to analyze the relationship between sodium and potassium intake and blood pressure. The study was performed in 130 hospitals from 23 provinces across China from 2016 to 2019. Finally, 9501 hypertensive patients average aged 54 years were included. 24 h urinary sodium and potassium excretion were measured. Distribution of urinary electrolytes were described according to age, gender and region. The association between urinary electrolytes and blood pressure was analyzed by multivariate linear regression. Hypertensive patients exhibited an average 24 h urinary sodium and potassium excretion of 156.7 ± 81.5 mmol/d and 39.2 ± 20.2 mmol/d (equivalent to sodium chloride of 9.2 g/d, potassium chloride of 2.9 g/d), sodium/potassium ratio (median) of 4.14 (2.92,5.73). Urinary electrolytes were lower in women than men (sodium: 171.1 vs 138.7, p < .05; potassium: 40.3 vs 37.7, p < .05), in the elderly than in the younger (sodium: 168.7 vs 139.9, p < .05; potassium: 39.5 vs. 37.5, p < .05). For every 1 unit of Na/K ratio increase, blood pressure increased by 0.46/0.24 mmHg. Blood pressure was 2.75/1.27 mmHg higher in quartile 4 than quartile 1 of Na/K. It remains high sodium and low potassium for hypertensive patients in China. Decreased sodium, Na/K ratio and increased potassium may help for blood pressure management.

Pleural effusion and acute right heart failure due to a ruptured right sinus of Valsalva aneurysm and correction by surgical intervention.

In the study, we present the case of a 65-year-old male with rupture of right SVA into the right atrium that caused pleural effusion and acute right-sided heart failure (ARHF), which corrected by surgical intervention.

Strategy of blood pressure intervention in the elderly hypertensive patients (STEP): Rational, design, and baseline characteristics for the main trial.

The optimal systolic blood pressure (SBP) treatment target in elderly people is full of challenge, and non-adherence is one major cause of uncontrolled BP. The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial is a multi-center, randomized controlled trial that aims to examine whether an intensive treatment (110 ≤ SBP < 130 mmHg) will provide more benefits in lowering cardiovascular events than a mild treatment (130 ≤ SBP < 150 mmHg) among people aged 60-80 years. From January 10, 2017 to December 31, 2017, 8511 patients with primary hypertension were recruited at 42 clinical centers throughout China and randomly assigned to the intensive or standard treatment in 1:1 ratio, in which clinical sites are considered as a stratification factor in randomization. Participants will be followed for an average of four years. All participants used the same validated home BP device and all centers used the same validated office BP device which can automatically upload the readings to a data center. The hospitals were randomly classified as the smartphone-based App center or usual care center in 1:1 ratio for the secondary purpose to study the effect of App management on BP control. In this trial, mean age of participants was 66.2 ± 4.8 years, 24.1% were in the range of 70-80 years, and 65% were at high-risk with the 10-year Framingham risk score ≥ 15%. In conclusion, STEP will provide evidence not only to address appropriate target of BP control among hypertensive patients aged 60-80 years, but also to assess an effective model of App management for hypertension. Trial Registration number: ClinicalTrials. gov. Unique identifier: NCT03015311.

A functional radioreceptor assay of alpha-V-beta-3 (alphavbeta3) inhibitors in plasma: application as an ex vivo pharmacodynamic model.

Development of alphavbeta3-integrin inhibitors has been hampered by a lack of pharmacodynamic endpoints to identify doses that inhibit alphavbeta3 in vivo. To address this need, we developed an alphavbeta3 radioreceptor assay (RRA) that could be performed in 100% plasma. The RRA was based on 125I-echistatin binding to plate-immobilized alphavbeta3. Small molecule alphavbeta3 inhibitors efficiently competed echistatin binding to alphavbeta3 when the assay was carried out in buffer. However, when carried out in 100% plasma, the RRA revealed a 45 to >3000-fold loss in compound potencies. The losses in potency reflected, in part, the high plasma protein binding by the compounds examined. The RRA was adapted as an ex vivo pharmacodynamic model. Echistatin binding was measured in the presence of plasma harvested at timed intervals from rats dosed with select compounds. Using this pharmacodynamic model, compound and dose selection was optimized for further testing in models of corneal angiogenesis. Moderate anti-angiogenic activity was achieved when rats were dosed sufficient to achieve sustained (>50%) plasma inhibition through the trough interval. Thus, the RRA provided a simple technique to rank order compound potency in plasma, and could find general use as an ex vivo pharmacodynamic assay to select compounds and doses for preclinical and clinical proof-of-principle studies.

Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5.

A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC(50) = 1.2 µM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC(50) = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.

Non-peptidic alpha(v)beta3 antagonists containing indol-1-yl propionic acids.

We describe the synthesis and structure/activity relationship of RGD mimetics that are potent inhibitors of the integrin alpha(v)beta3. Indol-1-yl propionic acids containing a variety of basic moieties at the 5-position, as well as substitutions alpha and beta to the carboxy terminus were synthesized and evaluated. Novel compounds with improved potency have been identified.