bluuebunny/crossref_metadata_2025_split huggingface dataset:
TESTOSTERONE COULD INDUCE CARDIAC HYPERTROPHY IN OVARIECTOMIZED SHR THROUGH THE ACTIVATION OF THE MTORC2/ATG9A
Authors: Wang Wenting , Zhu Lulu , Chen Jianshu , Wang Qiongying , Yu Jing 
Published: May 2024

Objective:
The estrogen level of postmenopausal women decreased sharply, while the androgen level did not decrease significantly, which was characterized by the inversion of estrogen / androgen ratio. Therefore, it could be observed that relative excess androgen in the circulation of postmenopausal women, which may be one of the reasons for the increase of cardiovascular disease in postmenopausal women. In this study, the model of postmenopausal hypertension was established by bilateral ovariectomy in spontaneously hypertensive rats (SHR), and the specific mechanism of testosterone-induced myocardial hypertrophy in ovariectomized SHR was explored.

Design and method:
24 SHR were randomly divided into four groups: WKY group (n=6), sham operation group (Sham group, n=6), bilateral ovariectomized group (OVX group, n=6) and testosterone propionate intervention group (OVX+T group, 6mg/kg/Weekly, im for 4 weeks, n=6). Western Blot was used to detect the protein expression of B-MHC, ANP, Androgen receptor, Akt, p-Akt, mTORC2 and its subunits Rictor. Moreover, the expression of autophagy-related proteins LC3 was observed.

Results:
1. Testosterone-induced cardiac hypertrophy in ovariectomized SHR: the expression of B-MHC and ANP was significantly increased in both the OVX and OVX+T groups when compared to the WKY and Sham groups. Additionally, the expression of androgen receptors was markedly upregulated in both the OVX and OVX+T groups. These findings strongly suggest that testosterone primarily induces myocardial hypertrophy in SHR after ovariectomy through androgen receptors.
2. Testosterone activation of mTORC2 expression in myocardial tissue: Testosterone exhibited a notable capacity to activate mTORC2 expression and the p-Rictor subunit in the OVX+T group.
3. Testosterone inhibit cardiomyocyte autophagy: A conspicuous reduction in the expression of LC3II was observed in the OVX+T group when compared to the OVX groups. This reduction indicates that testosterone may effectively inhibit cardiomyocyte autophagy under the experimental conditions.

Conclusions:
In bilateral ovariectomized SHR, testosterone could inhibit cardiac autophagy by activating the expression of mTORC2, which, in turn, leads to cardiac hypertrophy.
BLOOD PRESSURE, RENAL ARTERIAL FUNCTION AND OXIDATIVE-NITRATIVE STRESS IN A RAT MODEL OF POLYCYSTIC OVARY SYNDROME
Authors: Várbíró Szabolcs , Benko Rita , Junhyung Kim , Yoojin Ham , Bányai Bálint , Kiss Stella Tímea , Szekeres Mária , Horvath Eszter Mária 
Published: May 2024

Objective:
Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women, is associated with elevated cardiovascular risk and vitamin D deficiency. This study evaluates blood pressure, renal arterial function and oxidative stress in a rat PCOS model, also exploring the impact of vitamin D supplementation. Assessing mean arterial blood pressure under anesthesia, renal arterial function and oxidative stress in a hyperandrogenic rat model, and the effectiveness of vitamin D substitution.

Design and method:
Thirty-two adolescent female Wistar rats were randomly assigned into four groups. Eight rats received no treatment (controls, C), eight received weekly Vitamin D per os (140 IU/100 g body weight, group D), eight received cutaneous testosterone daily (3.3 mg/100 g, T), and eight received Vitamin D and testosterone together (T+D). In the eighth week of the treatment, rats were anaesthetized with urethane, and blood pressure (MABP) was measured. The isolated renal arterial rings were cut into 3-4 mm long segments for wire myography. Other segments were formaldehyde-fixed and paraffin-embedded for histological evaluations. By immunohistochemical methods, we assessed the oxidative stress marker 4-hydroxynoneal (HNE) and poly(ADP-ribose) polymerase activation shown by nuclear poly(ADP-ribose) polymer (PAR).

Results:
MABP was lower in hyperandrogenic rats, which was not altered by Vitamin D supplementation. Phenylephrine-induced contraction (Phe) in 10-9-10-7 M concentrations was identical in all groups; however, 10-6 M Phe caused a lower contraction in D and T rats (54.4± 21% and 41.9±20% vs. C: 72.78±8% and T+D: 69.68±21%. p<0.05) compared to controls and double treated animals. Endothelium-mediated relaxation did not differ between groups.
PAR staining was also identical, but HNE staining showed a tendency for increment in group T (p=0.12) but not in T+D.

Conclusions:
The decreased mean arterial pressure is likely the result of the compromised sensitivity to alpha1-adrenergic stimulus. The reduced reactivity of the renal artery may influence the activity of the renin-angiotensin-aldosterone system (RAAS). By normalizing the phenylephrine-induced contraction, Vitamin D supplementation might restore RAAS, thus blood pressure regulation.
ACUTE EXERCISE-INDUCED INFLAMMATORY AND THROMBOTIC RESPONSE IN HYPERTENSIVE PATIENTS
Authors: Liakos Charalampos , Aggeli Constantina , Toutouzas Konstantinos , Markou Maria , Vyssoulis Gregory , Tsioufis Constantinos 
Published: May 2024

Objective:
Vigorous physical activity may acutely trigger the onset of an acute coronary syndrome especially in sedentary persons with established cardiovascular risk factors such as arterial hypertension. The rupture of an inflamed coronary plaque and the activation of the coagulation cascade are the main underlying mechanisms. The present study aimed to determine the effect of acute exercise on the inflammatory and thrombotic response in patients with arterial hypertension as compared to normotensive peers.

Design and method:
After excluding patients with any inflammatory or/and coronary artery disease, a total of 60 non-treated hypertensive patients and 65 normotensive individuals underwent a maximal treadmill exercise testing. Blood samples were drawn at rest and immediately after peak exercise. High-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), white blood cell (WBC), interleukin-6 (IL-6), and total fibrinogen (TF) levels, as well as plasminogen activator inhibitor-1 (PAI-1) activity were measured.

Results:
All biomarkers increased with exercise, except PAI-1, which decreased (P<0.05 for the change between resting and peak exercise for all biomarkers). The normotensive group had less marked (P<0.05) exercise-induced changes than the hypertensive group in hsCRP (7.7 vs. 8.6%), SAA (5.6 vs. 11.9%), WBC (45.0 vs. 51.7%), and PAI-1 (-17.3 vs. -20.1%) and a similar (P=NS) change in IL-6 (23.8 vs. 23.0%) and TF (8.5 vs. 8.5%).

Conclusions:
In conclusion, the acute exercise-induced inflammatory and thrombotic response seems to be more pronounced in non-treated hypertensive patients than in normotensive controls. The effect of blood-pressure lowering treatment on the exercise-induced acute phase response remains to be elucidated.
DIURETICS, CCB, RAAS INHIBITORS AND MRAS- WHO IS NEXT IN THE MANAGEMENT OF REFRACTORY HYPERTENSION?
Authors: Leiba Adi , Hadad Orpaz , Lencovsky Ori , Niddam Naomi Nakash , Rappoport Vladimir , Korman Avital Angel , Azran Carmil 
Published: May 2024

Objective:
We analyzed refractory hypertensive (refHTN) patients, i.e. patients whose blood pressure is above goal despite being on 5-7 different antihypertensive drug classes. Our goal was to delineate prescription habits of the 5th-7th antihypertensive medications, adherence rates, and BP control.

Design and method:
In this real-life observational study we utilized the Maccabi Healthcare Services (MHS) database during 2023. MHS is a nationwide Health Maintenance Organization (HMO), providing health services to about one quarter of the Israeli population.
In order to describe adherence rates we compared refractory hypertensive patients who were fully adherent (at least six prescriptions and purchases of each medication during 2023) to partially adherent patients (at least one purchase of each medication).
Blood pressure control was strictly defined as 80% or more BP measurements during 2023 at goal, meaning 130mmHg systolic BP or less and 80mmHg diastolic BP or less.

Results:
Out of 1,821,685 adult members of Maccabi HMO during 2023, 361,721 patients were defined as hypertensive (20%). Only 0.5% (1750) of the hypertensive population were at some stage during 2023 on at least 5 anti-hypertensive medications (i.e., apparent refHTN). Of these only 264 patients (15%) were adherent to their medications during the whole year. There was no significant difference between adherence to the different drug classes: 15% were fully adherent to alpha blockers and central alpha 2 agonists, 16% to beta blockers and 17% to direct vasodilators.
Practically all (99%) prescriptions given to fully adherent patients were of medications acting on the sympathetic nervous system, correlating with our understanding of refHTN (figure 1).
Of the fully adherent patients’ group, only 58 patients (22%) were well controlled during 2023 on a stable 5-7 drug regimen, with 1 patient adherent to 8 drugs. The remaining 78% (205 patients) of the fully adherent group were not optimally controlled and were therefore defined as true refHTN.
There was a non-significant trend towards better control of blood pressure with beta blockers vs. alpha blockers (26% vs. 23% of patients, respectively).

Conclusions:
Novel antihypertensive medications are needed in order to manage this most challenging subgroup of hypertensive patients.
IMPROVEMENT OF COGNITIVE FUNCTION IN HEART FAILURE PATIENTS BY SGLT2 INHIBITORS—CLINICAL ADVANCES, MECHANISMS, AND FUTURE PERSPECTIVES
Authors: Di Xiaofan , Zhang Fangjing , Zhang Yong , Zhang Kefan , Bai Feng , Yu Jing , Wang Qiongying 
Published: May 2024

Objective:
SGLT2 inhibitors belong to a new category of oral antidiabetic medications that decrease blood glucose by obstructing glucose reabsorption in the proximal tubule (PCT), resulting in elevated urinary levels of sodium and glucose. The 2023 ESC guidelines for acute and chronic heart failure encourage the usage of SGLT2 inhibitors in patients with HFmrEF and HFpEF to lower the danger of hospitalization or cardiovascular mortality in heart failure patients. Cognitive decline is a significant issue for heart failure patients. This narrative review's objective is to examine the impact of SGLT2i on cognitive dysfunction associated with heart failure and foster further research, predominantly in the form of large-scale clinical trials.

Design and method:
An exhaustive literature search was executed on PubMed to analyze the fundamental mechanisms of SHLT2 inhibitors on cognitive impairment in heart failure patients, related clinical evaluations, the consequences of cardiac dysfunction on cognitive function, and possible underlying mechanisms.

Results:
The published literature substantiates the argument that cognitive impairment is provoked by cardiac dysfunction. Current research suggests that cognitive dysfunction in patients with heart failure results from inadequate cerebral perfusion, the Locus coeruleus noradrenergic system, chronic inflammation, mitochondrial dysfunction, and microRNA-1. Furthermore, numerous randomized controlled trials have confirmed that SGLT2 inhibitors, with or without diabetes mellitus, enhance cardio-renal outcomes in patients. SGLT2 proteins are present in the central nervous system (CNS). SGLT2 inhibitors reduce oxidative stress, inflammation, and endothelial cell proliferation, as well as improve brain mitochondrial function, synaptic plasticity, acetylcholinesterase activity, amyloid plaques, and modulation of the mTOR pathway. They also attenuate brain injury and cognitive decline. There are additional clinical studies that demonstrate the reduction in the risk of cerebrovascular events and dementia through SGLT2i treatment.

Conclusions:
To summarize, all existing studies establish the direct and indirect neuroprotective effects of SGLT2i. Nevertheless, there is limited clinical research on using SGLT2i for the treatment of cognitive dysfunction related to heart failure. Further clinical experiments are required to determine the effectiveness of SGLT2i treatment in improving cognitive dysfunction associated with heart failure.
EFFECTIVENESS & TOLERABILITY OF METOPROLOL ER, TELMISARTAN & CHLORTHALIDONE IN ESSENTIAL HYPERTENSION PATIENTS WITH STABLE CAD: INDIAN REAL-WORLD STUDY STRATIFIED BY COMORBIDITIES
Authors: Markandeywar Neeraj , M Vijaykumar , Pande Arindam , Kumari Rama , Dutta Soumya , Reddy Susheel , Chile Vijay , Mane Amey , Ahire Prachi , Kudrigikar Vinay , Dharmadhikari Shruti , Khandhedia Chintan , Mehta Suyog , Joglekar Sadhna 
Published: May 2024

Objective:
We conducted a real-world study to assess effectiveness (on blood pressure [BP; mmHg]) and tolerability of fixed dose combination (FDC) of 25/50 mg Metoprolol + 40 mg Telmisartan + 12.5 mg Chlorthalidone in treating hypertension and stable coronary artery disease (CAD). Considering comorbidities as risk factors for hypertension and CAD, this subgroup analysis was conducted in patients with common comorbidities.

Design and method:
A retrospective, multicenter study retrieved data over 15 months from electronic medical records of 1,810 adult patients with essential hypertension [systolic BP (SBP) greater than or equal to 140 and/or diastolic BP (DBP) greater than or equal to 90] and stable CAD. Of 1,784 patients who received this FDC for 24 ± 2 weeks; 1,224 had comorbidities (obesity: 1,062; diabetes mellitus: 494; dyslipidaemia: 270; hypothyroidism: 121).

Results:
Mean change in SBP / DBP (obese: -31.1 / -12.2; diabetes mellitus: -29.8 / -11.4; dyslipidaemia: -28.6 / -10.7; hypothyroidism: -26.4 / -8.5) from baseline to 24 ± 2 weeks was significant (p<0.001, Fig 1). Proportions of patients achieving target BP (SBP < 140 and DBP < 90) was >90% in diabetes mellitus and hypothyroidism and >82% in obese and dyslipidaemia patients. Of 14 patients with adverse events (hypotension being most common), 10 had comorbidities.

Conclusions:
This real-world study demonstrated that the FDC of Metoprolol + Telmisartan + Chlorthalidone was effective in reducing blood pressure and well tolerated in treating patients with hypertension and CAD who had common comorbidities.
EFFECTIVENESS & TOLERABILITY OF METOPROLOL ER, TELMISARTAN & CHLORTHALIDONE IN PATIENTS OF ESSENTIAL HYPERTENSION WITH STABLE CAD: INDIAN REAL-WORLD STUDY STRATIFIED BY BMI
Authors: Ahire Prachi , M Vijaykumar , Pande Arindam , Kumari Rama , Dutta Soumya , Reddy Susheel , Chile Vijay , Mane Amey , Markandeywar Neeraj , Kudrigikar Vinay , Dharmadhikari Shruti , Khandhedia Chintan , Mehta Suyog , Joglekar Sadhna 
Published: May 2024

Objective:
We conducted real world study to assess effectiveness (on blood pressure [BP; mmHg]) and tolerability of fixed dose combination (FDC) of 25/50 mg Metoprolol + 40 mg Telmisartan + 12.5 mg Chlorthalidone in treating hypertension and stable coronary artery disease (CAD). Body mass index (BMI) is one of the factors that affects hypertension and CAD. Hence, we performed this subgroup analysis to assess effectiveness of the FDC based on patients’ BMI.

Design and method:
A retrospective, multicenter study retrieved data over 15 months from electronic medical records of 1,810 adult patients with systolic BP greater or equal to 140 and/or diastolic BP greater or equal to 90 and stable CAD; 1,784 were treated with FDC for 24 ± 2 weeks. Mean change in BP from baseline, proportion of patients achieving target BP (systolic BP < 140 and diastolic BP < 90) and incidence of adverse events were analyzed in patients with BMI < 18.5 kg/m2 (underweight n= 9); 18.5-22.9 kg/m2 (normal n= 249), 23.0-24.9 kg/m2 (overweight n= 464) and greater or equal to 25 kg/m2 (obese n=1,062).

Results:
Mean changes in systolic (underweight, -33.6; normal, -29.9; overweight, -27.7; obese, -31) and diastolic BP (underweight, -12.2; normal, -11.5; overweight, -12; obese, -12.2) from baseline to 24 ± 2 weeks were significant (p<0.001), Fig 1. Proportion of patients achieving target BP at 24 ± 2 weeks in all except underweight category was >84%. Fourteen patients had adverse events; hypotension being most common.

Conclusions:
In a real-world setting, the FDC of Metoprolol + Telmisartan + Chlorthalidone was effective in reducing blood pressure and was well-tolerated in treating hypertension with CAD across all BMI categories. The study demonstrated significant reductions in both systolic and diastolic BP for patients with different BMI levels, highlights the potential benefits of FDC in managing hypertension in various body weight groups.
EFFICACY OF ULTRASOUND RENAL DENERVATION BASED UPON CHANGES IN DETECTED ANTIHYPERTENSIVE MEDICATIONS WITHIN THE RADIANCE HTN-TRIO STUDY
Authors: Zeijen Victor J. M. , Azizi Michel , Kirtane Ajay J. , Kably Benjamin , Daemen Joost 
Published: May 2024

Objective:
The randomized RADIANCE-HTN TRIO trial assessed the safety and efficacy of ultrasound renal denervation (uRDN) among patients with resistant hypertension (HTN), demonstrating a difference in daytime ambulatory systolic BP (DASBP) of -4.5 mmHg in favor of uRDN over a sham procedure at 2 months. Blood pressure results may be confounded by changes in anti-hypertensive medications (AHM). In this analysis, we assessed the BP-lowering efficacy of uRDN adjusted for detected AHM metabolites at baseline and 2 months.

Design and method:
Following standardization on a single triple combination antihypertensive pill, patients with daytime ambulatory blood pressure (DABP) 135/85 mmHg or greater were randomized 1:1 to uRDN or sham. Chemical adherence testing was used to detect AHM or their metabolites in spot urine samples under blinding to treatment assignment at baseline and 2 months. Analysis of covariance (ANCOVA) was utilized to assess the 2-month change in DASBP between groups, adjusting for DASBP at baseline and AHM detected at baseline and 2 months.

Results:
Both DABP and AHM urine metabolite data at baseline and 2 months were available in 100 patients (uRDN n=47; sham n=53). Mean age was 52.6±8.8 years, 23% were female, and 71% were white. At baseline, DASBP was 149±11 mmHg and 2.7±1.2 AHM metabolites were detected. No changes in number of detected drugs between baseline and 2 months were found in 72% of the patients. Between baseline and 2 months, the change in DASBP was -10.9 [95% CI: -15.5, -6.3] mmHg in the uRDN group and -4.0 [-8.0, 0.0] mmHg in the sham group (baseline-adjusted between-group difference: -6.9 [-12.8, -1.1] mmHg; p=0.007). Following additional adjustment for the number of detected AHM at baseline and 2M, the mean between-group difference in DASBP was -9.3 [-14.9, -3.7] mmHg (p=0.0003) in favor of uRDN.

Conclusions:
The blood pressure-lowering efficacy of uRDN in patients with resistant HTN was maintained and numerically more pronounced when adjusting for changes in detected AHM metabolites.
ASSOCIATION OF RESTING HEART RATE AND BLOOD PRESSURE WITH CLINICAL OUTCOMES IN PATIENTS WITH DIABETES MELLITUS: DATA FROM THE KAILUAN COHORT STUDY
Authors: Yin Zifang , Wang Chi , Zheng Mengyi , Tian Lu , Feng Zekun , Li Yanjie , Lan Lihua , Chen Shuohua , Wu Shouling , Xue Hao 
Published: May 2024

Objective:
The present study aimed to evaluate the association of resting heart rate (RHR) and blood pressure (BP) with clinical outcomes in patients with diabetes mellitus in the Kailuan cohort study.

Design and method:
A total of 22,963 diabetes mellitus patients without prior cardiovascular disease were included. RHR and BP were analyzed according to values as high RHR (H-RHR) >=74 bpm versus low RHR (L-RHR) <74 bpm (the cutoff value was determined using the receiver operator characteristics curve analysis), and high BP (H-BP) >=130/80 mmHg versus low BP (L-BP) <130/80 mmHg. The endpoint was a composite of cardiovascular disease (including myocardial infarction, ischemic stroke, and hemorrhagic stroke) and all-cause mortality. We used Cox proportional hazard model to calculate the hazard ratio (HR) and 95% confidence interval (CI) for outcomes according to each of the following four phenotypes: H-RHR/H-BP (reference group), L-RHR/H-BP, H-RHR/L-BP, and L-RHR/L-BP. In addition, given RHR and BP could change over time, we entered RHR/BP groups as a time-dependent explanatory variable in a time-dependent Cox regression analysis. We also investigate the association of RHR/BP groups in the long term, where the long-term RHR/BP groups was determined using updated mean of RHR and BP, with the risk of outcomes.

Results:
After a median 8.19-year follow-up, the endpoint was documented in 4,420 patients (including 2,175 cases of cardiovascular disease and 2,709 cases of all-cause mortality). Compared with the H-RHR/H-BP group, L-RHR and L-BP were individually associated with lower risk of outcomes, whereas L-RHR/L-BP group was associated with the lowest risk of the endpoint (adjusted HR [95% CI] was 0.61 [0.52-0.71] for the composite outcome [P <0.01], 0.49 [0.39-0.63] for cardiovascular disease [P <0.01], and 0.69 [0.58-0.83] for all-cause mortality [P <0.01]) (Table 1). Similar findings were observed in time-dependent Cox regression analysis and time-updated Cox regression analysis (Table 1).

Conclusions:
In patients with diabetes mellitus, lower RHR and lower BP are associated with reduced risk of clinical outcomes. Combined management of RHR and BP may help improve the prognosis of patients with diabetes mellitus.
ANKLE-BRACHIAL INDEX AS SHORT TERM AND LONG-TERM PREDICTOR OF CARDIOVASCULAR EVENTS AFTER MYOCARDIAL INFARCTION: A 3-YEAR FOLLOW-UP STUDY
Authors: Koumelli Areti , Konstantinou Konstantinos , Mantzouranis Emmanouil , Sakalidis Athanasios , Leontsinis Ioannis , Andrikou Ioannis , Manta Eleni , Kakouri Niki , Fragoulis Christos , Kariori Maria , Liatakis Ioannis , Kasiakogias Alexandros , Dimitriadis Kyriakos , Tsioufis Costas 
Published: May 2024

Objective:
The ankle-brachial index (ABI) is a non-invasive index originally proposed for the diagnosis of lower-extremity peripheral artery disease. It is also a marker of atherosclerosis in other vascular sites and may serve as a prognostic marker for cardiovascular events even in the absence of PAD symptoms. However, data on the prognostic value of this index in the setting of acute myocardial infarction (MI) are scarce.

Design and method:
We prospectively evaluated 441 patients [79.4% male; average age 62 years, 67.6% hypertensive, 29.7% diabetes mellitus (DM); 54.9% STEMI] hospitalized for acute MI. Basic demographic, echocardiographic, peri- and postoperative details were recorded and analyzed. The ABI threshold used to define abnormal levels was less than or equal to 0.90 and recorded according to established guidelines using a certified automated device (ABPI MD, MESI®). The primary endpoint was a composite of all-cause and cardiovascular death, as well as major cardiovascular events including decompensated heart failure, new ACS, cerebrovascular event, malignant arrhythmia, PAD event and new onset renal dysfunction. All events were assessed both in-hospital and within 3 years of follow-up.

Results:
The mean ABI of our study population was estimated to be 1.1 (IQR: 1.00 to 1.18). In reduced multivariate regression models ABI was a prognostic indicator for the in-hospital composite endpoint. Particularly, patients with abnormal ABI showed a threefold risk of in-hospital events [HR 2.93, 95% CI: 1.48-5.81, p=0.002]. Regarding all-cause mortality, after multivariate analysis, ABI [HR 2.88, 95% CI: 1.53 – 5.42, p=0.001] maintained its predictive power regardless of hypertension, DM, LDL levels and smoking status of the study population in 3 years follow-up.

Conclusions:
In the setting of an acute MI, lower ABI values expose these patients to a higher risk of in-hospital events and are independently associated with long-term all-cause mortality. Consequently, ABI monitoring in patients with MI may identify patients with a higher risk profile and contribute to early clinical decision making.