bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardin‐related transcription factor contributes to renal fibrosis through the regulation of extracellular microenvironment surrounding fibroblasts
Authors: Yamamura Yuta , Sakai Norihiko , Iwata Yasunori , Lagares David , Hara Akinori , Kitajima Shinji , Toyama Tadashi , Miyagawa Taro , Ogura Hisayuki , Sato Koichi , Oshima Megumi , Nakagawa Shiori , Tamai Akira , Horikoshi Keisuke , Matsuno Takahiro , Yamamoto Naoki , Hayashi Daiki , Toyota Yoshitada , Kaikoi Daichi , Shimizu Miho , Tager Andrew M. , Wada Takashi
Published: June 2023

Fibroblast accumulation and extracellular matrix (ECM) deposition are common critical steps for the progression of organ fibrosis, but the precise molecular mechanisms remain to be fully investigated. We have previously demonstrated that lysophosphatidic acid contributes to organ fibrosis through the production of connective tissue growth factor (CTGF) via actin cytoskeleton‐dependent signaling, myocardin‐related transcription factor family (MRTF) consisting of MRTF‐A and MRTF‐B‐serum response factor (SRF) pathway. In this study, we investigated the role of the MRTF‐SRF pathway in the development of renal fibrosis, focusing on the regulation of ECM‐focal adhesions (FA) in renal fibroblasts. Here we showed that both MRTF‐A and ‐B were required for the expressions of ECM‐related molecules such as lysyl oxidase family members, type I procollagen and fibronectin in response to transforming growth factor (TGF)‐β1. TGF‐β1‐MRTF‐SRF pathway induced the expressions of various components of FA such as integrin α subunits (αv, α2, α11) and β subunits (β1, β3, β5) as well as integrin‐linked kinase (ILK). On the other hand, the blockade of ILK suppressed TGF‐β1‐induced MRTF‐SRF transcriptional activity, indicating a mutual relationship between MRTF‐SRF and FA. Myofibroblast differentiation along with CTGF expression was also dependent on MRTF‐SRF and FA components. Finally, global MRTF‐A deficient and inducible fibroblast‐specific MRTF‐B deficient mice (MRTF‐AKOBiFBKO mice) are protected from renal fibrosis with adenine administration. Renal expressions of ECM‐FA components and CTGF as well as myofibroblast accumulation were suppressed in MRTF‐AKOBiFBKO mice. These results suggest that the MRTF‐SRF pathway might be a therapeutic target for renal fibrosis through the regulation of components forming ECM‐FA in fibroblasts.
COGNITIVE IMPAIRMENT AND CARDIOVASCULAR RISK FACTORS: FINDINGS FROM THE PURE-COLOMBIA COHORT
Authors: Tiga-Loza Diana Carolina , Calderon-Ardila Ariel , Cohen Daniel , Otero Johanna , Perez Maritza , Rosa Andrea De La , Giraldo Juan Carlos , Vega Karol , Lopez-Lopez Jose , Lopez-Jaramillo Patricio
Published: June 2023

Objective:

To estimate the prevalence of cognitive impairment and its association with cardiovascular risk factors in the cohort population of the Prospective Urban and Rural Epidemiological Study (PURE) for the fifteenth year of follow-up in some departments of Colombia.

Design and method:

Cross-sectional study nested in the PURE cohort in participants with Mini-Cog test for cognitive screening, with a cut-off point of < = 2 points to screen cognitive impairment. We evaluate behavioral cardiovascular factors such as smoking, pathological history such as arterial hypertension, and measurements of blood pressure, weight, height, waist/hip ratio, glucose, triglycerides, cholesterol, hdl, ldl, and creatinine. We stimate The prevalence ratios for cognitive impairment using a generalized linear model with binomial family and link log.

Results:

In 707 participants whose mean age is 64.9 (SD 9.2) years, 66.8% are women, we found that 26.8% with indicators of cognitive impairment, with complete difficulty for the clock sub-test in 24.5% and 3.9% on the memory subtest. A higher prevalence of cognitive impairment was found among hypertensives compared to non-hypertensives (63.7% vs. 41.8%, Prevalence Ratio = 1.51, 95% CI 1.17; 1.93, p = <0.001). In addition, systolic blood pressure was 9 mmHg, higher in participants with cognitive impairment (median 138mmHg vs 129mmHg, p = 0.0001)

Also, the proportion of people with deterioration was higher in those who had a cholesterol greater than 200mg/dL (PR = 1.38 95% CI = 1.11;1.72 p = 0.004) and with an increase in the waist-hip ratio (PR = 3.27 95% CI = 1.21; 8.8 p = 0.019) the above adjusted for age, sex and educational level.

Conclusions:

More than a quarter of the participants in the PURE cohort presented indicators of cognitive impairment, its prevalence was significantly higher in hypertensive patients, in people with high cholesterol and with a significantly higher waist/hip ratio, which indicates the importance of preventing and controlling the Cardiovascular risk factors in older adults with cognitive alterations.
BLOOD PRESSURE, HIGH-SENSITIVITY C-REACTIVE PROTEIN, INTERLEUKIN-6 AND WHITE BLOOD CELLS IN THE COMMUNITY-DWELLING OLDER ADULTS
Authors: Sulicka-Grodzicka Joanna , Wizner Barbara , Zdrojewski Tomasz , Mossakowska Malgorzata , Puzianowska-Kuznicka Monika , Chudek Jerzy , Wiecek Andrzej , Guzik Tomasz
Published: June 2023

Objective:

Increasing evidence indicates an association between blood pressure (BP) and vascular inflammation, although these relationship remains unknown in older adults. Understanding this association in this population is particularly important in the context of increased prevalence of hypertension, as well as role of inflammatory responses in age related comorbidities.

Design and method:

We examined the relationship between BP, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and white blood cells (WBC) among 3571 older (aged > = 65 years) and 587 middle-aged (57 ± 1 years old) adults recruited as a part of the PolSenior health survey .

Results:

BP levels differed in relation to hs-CRP and WBC quartiles in older patients. In particular, systolic BP were 145 ± 22 mmHg and 149 ± 24 mmHg, in the first and fourth quartile of hs-CRP (P = 0.002), and 145 ± 20 mmHg and 150 ± 23 mmHg, respectively for the WBC (P < 0.001). In contrast, systolic BP did not differ between IL-6 quartiles (146 ± 21 mmHg and 145 ± 22 mmHg, P = 0.8). Moreover, the age, gender and body mass index (BMI) adjusted odds ratio (OR) for high BP in subjects with hs-CRP > = 3.7 mg/L was 1.29 (95% CI, 1.05-1.58, P = 0.01) compared with those with hs-CRP < 1 mg/L; in patients with WBC> = 7.1 x 109/L OR was 1.42 (95% CI, 1.16-1.75, P < 0.001) compared with those with WBC < 5.2 x 109/L. Interestingly, in subjects with IL-6 > = 3.4 pg/mL adjusted OR was 0.84 (95% CI, 0.68-1.04, P = 0.11) compared with those with IL-6 < 1.4 pg/mL. In the fully-adjusted model applied in older adults, higher hs-CRP remained associated with high BP, independently of age, gender, BMI, IL-6 and WBC (adjusted OR = 1.12, 95% CI, 1.03 to 1.22, P = 0.008).

Conclusions:

CRP and WBC, but not IL-6, are positively associated with high blood pressure in the population of community-dwelling older adults, independently of age, gender, and BMI. Results of our study may suggest an important role of inflammation in the pathogenesis of increased blood pressure, also in the older population.
REPRODUCIBILITY AND PREDICTIVE VALUE OF WHITE COAT HYPERTENSION IN YOUNG TO MIDDLE AGE SUBJECTS
Authors: Saladini Francesca , Mos Lucio , Vriz Olga , Mazzer Adriano , Zanata Giuseppe , Fania Claudio , Rattazzi Marcello , Palatini Paolo
Published: June 2023

Objective:

The reproducibility and the prognostic value of white-coat hypertension (WCH) is still debated. The aim of the study was to investigate the reproducibility of WCH assessed twice within 3 months and its predictive capacity for development of hypertension needing antihypertensive treatment (HT) in young-to-middle-age subjects screened for stage 1 hypertension.

Design and method:

We investigated 1096, 18-to-45-year old subjects from the HARVEST. Office BP and 24hour BP were measured at baseline and after 3 months. On the basis of BPs measured after 3 months, 132 participants were classified as normotensive, 159 as WCH, 195 as masked hypertensive and 610 as sustained hypertensive. The reproducibility of WCH, office hypertension, and ambulatory hypertension was evaluated with Kappa statistics. The predictive capacity of WCH defined with a single assessment or with double assessment was tested in multivariate Cox models (N = 1054).

Results:

Baseline WCH was confirmed at 3-month assessment in only 33.3% of participants, whereas 31.6% became normotensive, 8.8% masked hypertensive and 26.3% sustained hypertensive. Reproducibility evaluated with weighted Kappa was fair (0.27, 95%CI 0.20 - 0.37) for WCH, poor (0.14, 95%CI 0.09 - 0.19) for office Hypertension (BP> = 140/90 mmHg), and moderate (0.47, 95%CI 0.41 - 0.53) for ambulatory Hypertension (24hBP> = 130/80 mmHg). During 17.4 years of follow-up, 80.5% of participants developed HT. WCH assessed either at baseline (p = 0.86) or after 3 months (p = 0.16) was not a significant predictor of future HT. However, participants who had WCH both at baseline and after 3 months (N = 76) had an increased risk of HT compared to the normotensives (Hazard ratio, 1.50, 95%CI 1.06 - 2.13, p = 0.022). HRs were 1.35 (95%CI 1.02 - 1.80, p = 0.037) in participants with masked hypertension and 1.52 (95%CI 1.19 - 1.95, p < 0.001) in those with sustained hypertension.

Conclusions:

These results show that in young-to-middle-age individuals, WCH was confirmed in only one third of people at repeat assessment. This was mainly due to a poor reproducibility of office hypertension. WCH diagnosed with two but not with one BP assessment showed an increased risk of future HT. Our data indicate that people with WCH at first assessment should undergo a second set of ambulatory and office BP measurements before clinical decisions are made.
ABSENT VASOREACTIVE RESPONSE TO HIGH SODIUM INTAKE COINCIDES WITH SALT SENSITIVITY IN CKD PATIENTS
Authors: Duin Robert van , Oppelaar Jetta , Schijndel Emma Van , Born Bert -Jan van den , Engberink Rik Olde , Vogt Liffert
Published: June 2023

Objective:

Chronic kidney disease (CKD) patients are advised to limit salt intake, because of its detrimental effects on blood pressure (BP) and albuminuria. The salt-sensitive BP response in CKD is classically attributed to impaired renal ability to excrete sodium (Na+) resulting in fluid overload. Yet, BP sensitivity to salt is also linked to vasodysfuction, and may even be fluid independent. We aimed to investigate which factor contributes to BP sensitivity to salt in CKD.

Design and method:

In this randomized crossover study, CKD patients (KDIGO stage G2-3A, proteinuria >0.5 g/d) and healthy controls (HC) followed a 7-day low sodium diet (LSD, <50mmol/d) and high sodium diet (HSD, >200mmol/d), respectively. After each diet, assessment of the hemodynamic profile included daytime BP (Mobil-O-Graph) and cardiac output (CO) measurements (using NexfinTM), by which SVR was calculated accordingly. Extracellular fluid volume (ECV) change was assessed with multi-frequency body impedance spectroscopy (FHCresenius).

Results:

We included 16 HC (median age 36.0 yrs) and 8 CKD patients (median age 49.5 yrs, and median (IQR) proteinuria 0.6 (0.5-1.1) g/d and plasma creatinine 144 (103 - 167) μmol/l. Dietary salt intervention was successful with median difference in urine Na+ excretion of 242.2 vs 224.6 mmol/day in HC and CKD respectively (p = 0.74). After HSD, the median (IQR) change in systolic BP of patients with CKD was 14 mmHg (4 - 18; p = 0.04), while systolic BP change (4 mmHg (-3 - 8)) in HC was not significant (Fig 1A). After HSD, we observed a significant ECV expansion in both CKD and HC subjects (Fig 1B), but no effect on CO. No associations between HSD-induced BP changes and both ECV and CO were found. Systolic BP increase was correlated with SVR decline in HC, but not in CKD patients (Fig 1C).

Conclusions:

In contrast to healthy persons, BP salt sensitivity in CKD does not associate with vasodilation. Regarding the absence of differences with ECV and CO between healthy and CKD persons, our data indicate that the incapacity for vasodilation might explain salt sensitivity in CKD.
ASSOCIATION BETWEEN PEAK EXPIRATORY FLOW AND INCIDENT HEART FAILURE AND MORTALITY IN MIDDLE-AGED AND OLDER CHINESE ADULTS
Authors: Chen Chao -Lei , Feng Ying -Qing
Published: June 2023

Objective:

Previous studies have suggested that pulmonary dysfunction predicts incident cardiovascular disease, posing the question of whether peak expiratory flow, one of the most direct measurements of lung function, could present a modifiable risk factor. In the present study, we aimed to evaluate associations of peak expiratory flow with incident heart failure, cardiovascular death, and all-cause death.

Design and method:

This study included 93,161 participants from the China Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project in Southern China who had lung function measurements at baseline (year 2016-2017) and were annually followed-up to December 2020. The composite endpoints included hospitalization for heart failure, cardiovascular death, and all-cause death. Hospitalization for heart failure were ascertained by linking to the Inpatient Registry and confirmation of death was based on information from local government vital statistics offices. The relationship between peak expiratory flow and all outcomes was assessed using multivariable Cox regression adjusting for age, sex, education, annual income, insurance, residence, occupation, current smoking, current drinking, body mass index, hypertension, diabetes, coronary heart disease, and stroke at baseline.

Results:

The mean age was 54.2 years, and 60.7% were women. At 3.4 ± 0.9 years of follow-up, heart failure occurred in 1361 (1.5%), cardiovascular death in 365 (0.4%), all-cause death in 1346 (1.4%), and the composite in 2490 (2.7%). Compared with the lowest quartile, the HR (95% CI) of the highest quartile in peak expiratory flow was 0.66 (0.55 - 0.78) for incident heart failure, 0.70 (0.51 - 0.95) for cardiovascular death, 0.54 (0.46 - 0.64) for all-cause death, and 0.54 (0.47 - 0.61) for the composite. The restricted cubic spline showed significantly negative relationships of peak expiratory flow with all outcomes. In addition, the association between peak expiratory flow and incident heart failure was not significantly changed after mortality was treated as competing risks in the Fine–Gray proportional sub-distribution hazards models (HR [95% CI]: 0.87 [0.81 - 0.93]).

Conclusions:

Higher peak expiratory flow was significantly associated with decreased risks of incident heart failure, cardiovascular death, and all-cause death in middle aged and elderly Chinese adults, independent of and to a similar extent as major known cardiovascular risk factors.
24 HOURS CHRONOMICS OF AMBULATORY BLOOD PRESSURE/HEART RATE IN TERMS OF ACROPHASE & HYPERBARIC INDEX IN NIGHT SHIFT NURSING PROFESSIONALS: RISK FOR CARDIOVASCULAR DISEASES
Authors: Anjum B. Anjum , Verma Narsingh , Tiwari Sandeep , Naz Qulsoom , Ahmad Kaleem , Singh Ranjana , Mahdi Abbas Ali
Published: June 2023

Objective:

This study was aimed to investigate the effect of Light at night and Rotating night shift as risk factor for cardiovascular diseases. 24 hours chronomics of BP/HR in terms of Double amplitude, Acrophase and Hyperbaric index and its relation with circadian rhythm of salivary cortisol and 6 sulfatoxy melatonin levels in night shift nursing professional.

Design and method:

56 night shift nurses, aged 20 to 40 years, performing day and night shift duties were recruited from the Trauma Center, KGMU, India, and 56 age sex matched actual day workers were also enrolled as controls. During their night and day shift duties, BP/HR were recorded by Ambulatory Blood Pressure Monitoring (ABPM) along with circadian pattern of cortisol in saliva, metalonin in urine also tested.

Results:

Highly significant difference was found in double amplitude (2DA) of among between night (23.10 ± 14.68) and day shift (34.27 ± 16.44) (p < 0.0005). In night shift, hyperbaric index (HBI) of mean SBP was found to be increased at 00 to 03 am (midnight) while during day shift, peak was found at 06 to 09 am. HBI of mean HR was found to be increased at 18 to 21 pm during night shift while in controls, peak was found at 09 to 12 & again 15 to 18 pm of SBP, DBP & HR. Alterations in Acrophase of BP/HR were very common among night shift workers and Ecphasia was found in few nights shift workers. Difference was found in night cortisol levels among night (4.08 ± 3.28) vs day shift (2.62 ± 2.37), while in comparison to night shift or day shift with controls (1.82 ± 1.18) these difference was significant (p < 0.05).

Conclusions:

Alteration in morning melatonin and Night cortisol level were found during night shift. Reverse pattern of Acrophase and HBI of BP/HR along with salivary cortisol during night shift represents desynchronization. It indicates that the circadian rhythm was disrupted during night shift and incomplete recovery occurs during day shift. It may leads to future cardio vascular diseases risk.
THE TRIGLYCERIDE-TO-ADMISSION GLUCOSE RATIO AS AN INDEPENDENT PREDICTOR OF POOR OUTCOME AFTER ISCHEMIC STROKE
Authors: Gasecki Dariusz , Kowalczyk Kamil , Kwarciany Mariusz , Rojek Agnieszka , Narkiewicz Krzysztof , Karaszewski Bartosz
Published: June 2023

Objective:

The serum triglyceride to glucose ratio (TGR) has been shown a reliable surrogate index to screen for risk of insulin resistance, and a marker of high risk in subjects with cardiovascular disease. The gradient of arterial stiffness, as reflected by the pulse wave velocity (PWV) ratio, has been found to be independently related with poor outcome in patients with acute ischemic stroke (AIS).

The aim of the study was to assess the relationship between TGR and stroke severity and to evaluate its potential role as a predictor of functional outcome in patients with AIS.

Design and method:

We enrolled 150 AIS patients (115 males, age 63.1 ± 12.4 years, median NIHSS score 6(3 - 8) points). Carotid-femoral and radial–carotid PWV were measured (SphygmoCor®) within several (6 ± 2) days after stroke onset. TGR was calculated by dividing fasting serum triglycerides by admission glucose. Functional outcome was evaluated 90 days after stroke using the modified Rankin Scale (mRS) with an mRS score of 3 to 6 (dependency or death) considered as a poor outcome.

Results:

TGR was significantly lower, while admission glucose was significantly higher in patients with poor compared to those with good functional outcome (0.87 ± 0.63 vs 1.14 ± 0.68; p = 0.02, and 168.4 ± 71.1 vs 132.5 ± 56.0 mg/dL; p = 0.001, respectively). In a multivariate analysis, TGR was significantly associated with functional outcome after controlling for age, sex, PWV ratio, stroke severity and use of rtPA (adjusted OR = 0.31; 95% CI, 0.11 - 0.91; p = 0.03), while glucose was not (adjusted OR = 1.00; 95% CI, 1.00 - 1.01; p = 0.07).

Conclusions:

Triglyceride-to-glucose ratio might be a useful predictor of functional outcome in patients with acute ischemic stroke, independent of traditional and new vascular factors, including arterial stiffness gradient.
TRANSITION PRACTICES OF HYPERTENSIVE YOUTH FROM PEDIATRIC TO ADULT HEALTH CARE AMONG ESH EXCELLENCE CENTRES
Authors: Stabouli Stella , Persu Alexandre , Aujoulat Isabelle , Weber Thomas , Kreutz Reinhold , Grassi Guido , Lurbe Empar
Published: June 2023

Objective:

Transition refers to the process of changeover from pediatric to adult health care. In the light of the increasing prevalence of arterial hypertension in children and adolescents we aimed to assess transition practices from pediatric to adult health care among Excellence Centres of the European Society of Hypertension (ESH).

Design and method:

A 22-question survey was sent out to ESH Excellence Centres in July 2022. Only one answer per excellence center from the center leader was allowed.

Results:

Forty-nine ESH Excellence centres responded the survey, almost all (98%) affiliated in hospital settings. Specific transition clinics do not exist in 64% of the settings. The median number of young adults diagnosed with childhood hypertension transferred from pediatric clinics to ESH Excellence Centres is 5 per year (interquartile range 2 - 13). In 66% of the centres, the transition process is limited to written medical history (transfer letter). Only 23% centres reported coordinated visits at pediatric and adult clinics. The main criterion for patient transfer to adult clinics is patient age (87% of the centres) with transfer age being at 18 years in 75% of the centres, while 20% reported transfer ages younger than 18 years. In only 9% of the centres patient self-management skills are assessed to decide readiness for transfer to adult clinics. The ESH 2016 guidelines hypertension staging criteria in children and adolescents (Lurbe et al J Hypertens) are applied in 52% of the centres, the ESC/ESH 2018 adult hypertension guidelines (Williams B et al J Hypertens) are used in 21% and national guidelines are used in the remaining centres. Adherence is considered the main challenge during transition process as reported by 68% of the centres, lifestyle by 66%, patients’ lack of understanding of their condition by 50%, and psychosocial issues by 50% of the centres. Fifty-one percent of centres modify treatment after transfer according to adult recommendations, 93% for uncontrolled hypertension and 75% to change in single (combination) pill.

Conclusions:

Coordination and communication between pediatric and adult units should be reinforced as they are major factors for effective transition into adult health care.
THE IMPACT OF COVID-19 PANDEMIC ON BLOOD PRESSURE CONTROL IN PATIENTS WITH TREATED HYPERTENSION. RESULTS OF EUROPEAN SOCIETY OF HYPERTENSION STUDY (ESH ABPM COVID-19 STUDY)
Authors: Wojciechowska Wiktoria , Rajzer Marek , Weber Thomas , Chrostowska Marzena , Doumas Michalis , Fréminville Jean -Baptiste De , Lewandowski Jacek , Wuerzner Gregoire , -Przybylek Maria Gosk , Parati Gianfranco , Niepen Patricia Van Der , Kahan Thomas , Bursztyn Michael , Persu Alexandre , Stergiou George S. , Bilo Grzegorz , Grassi Guido , Mancia Giuseppe , Kreutz Reinhold , Januszewicz Andrzej
Published: June 2023

Objective:

We aimed to assess the impact of the COVID-19 pandemic on blood pressure (BP) control assessed by office and ambulatory blood pressure monitoring (ABPM) in patients with treated hypertension.

Design and method:

Clinical and BP data were collected from 32 centres including Excellence Centres of the European Society of Hypertension. Two groups of patients were compared. Group1 (‘pandemic’) consisting of participants who have undergone two ABPM recordings (visits): visit-2 during the COVID-19 pandemic, and visit-1 performed 9 - 15 months prior to visit-2. Participants in Group2 (‘pre-pandemic’) had two repeated ABPMs, both performed before the pandemic within 9 - 15 months interval between visits.

Results:

Overall, 3384 ABPMs were collected from 1692 patients (50.5% men). 759 patients constituted Group1 and 933 patients Group2. Study groups did not differ regarding sex, age, or body weight. The duration of hypertension and frequency of first-line antihypertensive drug use at visit-1 were also similar in both groups. Beta-blockers were the only class of drugs with a significant decrease between visits (difference between visit-2 and visit-1) in Group1. At visit-1, there were no differences in all BP phenotypes (office and ABPM values) or hypertension control rates (27% vs 26.6%; p = 0.62) between study groups. At visit-2 significantly higher office BP was observed in Group1 compared to Group2, with a mean difference of +2.09 mmHg (p = 0.028) and +1.39 mmHg (p = 0.026) for systolic (SBP) and diastolic (DBP) BP, respectively. Moreover, on visit-2, higher 24-hour daytime and nighttime SBP and DBP were observed in Group1 as compared to Group2. Of note, the prevalence of uncontrolled hypertension (when considering both office and ABPM) was also higher at visit-2 in Goup1 than in Group2 (25.8% vs 20.0%; p = 0.005). Both SBP and DBP, regardless of the measurement method, dropped between visit-1 to visit-2, but to a lesser extent in Group1. Thus, the magnitude of BP decrease between visits was smaller in Group1 (delta24SBP: -1.04 vs -3.2 mmHg; p < 0.001 and delta24DBP: -1.22 vs -1.93 mmHg; p = 0.038).

Conclusions:

The results of the study indicate a negative impact of the COVID-19 pandemic on BP control both in office and during ABPM.
COMBINING RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKADE AND SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITION IN EXPERIMENTAL DIABETES RESULTS IN SYNERGISTIC BENEFICIAL EFFECTS
Authors: Ye Dien , Cruz-Ló Edwyn O. , Veghel Richard Van , Garrelds Ingrid M. , Danser A.H. Jan
Published: June 2023

Objective:

To study the combined effect of RAS blockade and SGLT2i in experimental diabetes.

Design and method:

TGR (mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 12 weeks and treated with either vehicle, the angiotensin receptor blocker valsartan (VAL: 4 mg/kg/day), the SGLT2 inhibitor empagliflozin (EMPA: 10 mg/kg/day) or their combination during the final 3 weeks. Mean arterial blood pressure (MAP) was measured by telemetry.

Results:

MAP before treatment was 120 ± 14 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate (GFR). EMPA did not lower MAP, while VAL did (by 29 ± 7 mm Hg), and when combined the MAP drop was largest (44 ± 6 mm Hg). Only EMPA+VAL reduced the heart weight/tibia length ratio (P = 0.04 vs. vehicle). VAL, but not EMPA, increased plasma renin, and the largest renin rise was observed during EMPA+VAL (P < 0.0001 vs. vehicle) Although both VAL and EMPA alone tended to diminish albuminuria, the reduction was significant (P = 0.01 vs. vehicle) only when both drugs were combined (vehicle, VAL, EMPA and EMPA+VAL 108 ± 18, 89 ± 24, 55 ± 8 and 26 ± 6 ug/mL, respectively). This was accompanied by a reduction in glomerulosclerosis index and no change in GFR. EMPA either alone or in combination with VAL increased water intake and urine production and induced urinary glucose loss, and as a consequence reduced blood glucose and body weight. Renal expression of the fibrosis and inflammatory markers TIMP2, collagen 1alpha 1, fibronectin, Neph1, nephrin was lowest in the dual treatment group.

Conclusions:

RAS blockade and SGLT2i display synergistic beneficial effects on blood pressure, kidney jury and cardiac hypertrophy in a rat with hypertension and diabetes.
EVALUATION OF THE EFFICACY AND SAFETY OF MEDICAL TREATMENT WITH LOWER DOSES OF SPIRONOLACTONE IN A COHORT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Authors: Sconfienza Elisa , Riancho Julien , Gebara Nicole , Ferrão Diana , Freminville Jean -Baptiste De , Lorthioir Aurélien , Azizi Michel , Amar Laurence
Published: June 2023

Objective:

Treatment with mineralocorticoid receptor antagonists is recommended for patients with bilateral forms of primary aldosteronism or with unilateral forms unwilling or unable to undergo surgery, using spironolactone as the primary choice, with a suggested dose of 1 to 2 mg/Kg/day. In clinical practice, however, the dose prescribed has been progressively decreased to achieve a better tolerance of the drug and, consequently, a higher compliance to treatment. Our aim was to evaluate how the lowering of spironolactone dose could have impacted on arterial blood pressure control and on the prevalence of adverse effects.

Design and method:

We retrospectively included 394 patients with primary aldosteronism receiving a medical treatment with spironolactone, with a minimum follow-up of 1 month after the initiation of medical treatment. Patients were divided into two groups, according to the median prescribed dose of spironolactone in our population (50 mg, 25 – 75): subjects treated with >50 mg and patients treated with < = 50 mg of spironolactone daily.

Results:

The median follow-up after the introduction of spironolactone was 6 months, and 135 patients experienced spironolactone-related adverse effects (34.3%), with a higher proportion in men than in women (76.30% vs. 23.70%). The most frequently reported adverse effect was gynecomastia, followed by erectile dysfunction. Subjects receiving a dose >50 mg of spironolactone daily displayed a significantly higher prevalence of side effects (42.2%), while a prevalence of 30.5% was described in the < = 50 mg group. Patients in the lower dose group were treated with a higher number of anti-hypertensive drugs, especially diuretics. No statistically significant differences were seen between the two subgroups in blood pressure measurements at follow-up.

Conclusions:

Treatment with low doses of spironolactone could help achieve a better adherence in patients with primary aldosteronism, with a lower rate of adverse effects compared to patients treated with higher doses, with no differences in blood pressure control at follow-up. This goal could be achieved by prescribing a higher number of anti-hypertensive drugs. These findings could help the clinician in choosing the best therapeutical option for each patient.
UNILATERALLY SELECTIVE ADRENAL VEIN SAMPLING FOR IDENTIFICATION OF SURGICALLY CURABLE PRIMARY ALDOSTERONISM
Authors: Rossi Gian Paolo , Bagordo Domenico , Amar Laurence , Azizi Michel , Riester Anna , Reincke Martin , Degenhart Christoph , Widimsky Jiri , Naruse Mitsuhide , Deinum Jaap , Kocjan Tomaz , Negro Aurelio , Rossi Ermanno , Kline Gregory , Tanabe Akiyo , Satoh Fumitoshi , Rump Lars Christian , Vonend Oliver , Willenberg Holger S. , Fuller Peter J. , Yang Jun , Chee Nicholas Yong Nian , Magill Steven B. , Shafigullina Zulfiya , Quinkler Marcus , Oliveras Anna , Lee Bo -Ching , Chang Chin -Chen , Wu Vin Cent , Kratka Zuzana , Battistel Michele , Rossitto Giacomo , Seccia Teresa Maria
Published: June 2023

Objective:

Adrenal venous sampling (AVS) is recommended for the identification of unilateral surgically curable primary aldosteronism (PA) but, owing to failed bilateral adrenal vein cannulation, is often clinically useless.

Design and method:

We investigated if only unilaterally selective AVS studies can allow identification of the responsible adrenal.

Methods:

Among 1625 patients consecutively submitted to AVS in tertiary referral centers, we selected those with a unilaterally selective AVS result and a final diagnosis of unilateral PA. Using the latter as gold reference, we examined the accuracy of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity.

Results:

The RASI values distribution showed prominent differences between patients with and without unilateral PA. The area under ROC curves (AUROC) was 0.714 and 0.855 for RASI values of the responsible and the contralateral side, respectively. While RASI values >2.55 on the culprit side and less than 0.96 on the contralateral side furnished the highest accuracy for detection of surgically cured unilateral PA, only 20% and 16% had RASI values less than 0.96 and >2.55, respectively, in the patients without unilateral PA.

Conclusions:

With the strength of the gold standard entailing an unambiguous diagnosis of unilateral PA and large real-life dataset, these results indicate the feasibility of identifying unilateral PA using unilaterally selective AVS results.
A NOVEL ELECTRO-HYDRAULIC ACOUSTIC THERAPY REDUCES BLOOD PRESSURE IN HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASE: PRELIMINARY RESULTS
Authors: Wolak Talya , Lerman Amir , Glikson Michael , Sukholutsky Ivetta , Silberman Shuli , Lerman Lilach O.
Published: June 2023

Objective:

Electro-Hydraulic Acoustic Therapy (eHAT), using ∼10% of the energy used in shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. eHAT has been demonstrated to enhance healing in tissues such as bone, muscle, and myocardium, via several mechanisms, particularly by promoting neovascularization. Furthermore, previous animal studies demonstrated that eHAT reduces blood pressure (BP) and preserves renal function after ischemic kidney injury.

The present pilot study explored the clinical safety and efficacy of eHAT and tested the hypothesis that eHAT would reduce BP and preserve renal function in patients with medically-treated hypertension and CKD.

Design and method:

So far, a total of 15 patients with HTN and Stage III a/b CKD were enrolled in this prospective, single-arm study. The patients were treated with six sessions of eHAT during a 3-week period. At each session, 2400 shockwaves were applied to each kidney with 0.09 mJ/mm2 at 2.66Hz (NephrospecTM by Curespec LTD, Yehud, Israel). Follow-up (FU) visits were performed at 1, 3, and 6 months.

Results:

The treatment was well tolerated with no major adverse events or need for analgesic treatment.

Average Automated Office BP (AOBP) showed a strong tendency for a decrease in diastolic BP from baseline to the Primary Efficacy Objective at FU II (3 months post-last treatment), which progressively decreased further at FU III (6 months) (Table 1). Similarly, average Office BP (OBP) detected a strong trend for a progressive decrease in systolic BP from baseline to the Primary Efficacy Objective (Table 1). Levels of eGFR appeared to slightly rise throughout the study, but this change has not reached statistical significance levels (Table 1).

Conclusions:

The current study demonstrates that the eHAT procedure is tolerable and safe in this cohort. Moreover, a 3-week regimen tended to reduce BP and preserve eGFR in patients with controlled HTN and CKD. Therefore, electro-Hydraulic Acoustic Therapy may emerge as a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.
STUDY ON THE MECHANISM OF CARDIAC HYPERTROPHY INDUCED BY TESTOSTERONE THROUGH MTORC2 IN OVARIECTOMIZED FEMALE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Wang Wenting , Yu Jing
Published: June 2023

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:

Twenty-four SHR were randomly divided into three groups: sham operation group (Sham group, n = 8), bilateral ovariectomized group (OVX group, n = 8) and testosterone propionate intervention group (OVX+T group, 2.85mg/kg Weekly, im for4 weeks, n = 8). The systolic blood pressure, diastolic blood pressure and heart rate of SHR were monitored and recorded twice a week. Western Blot was used to detect the protein expression of mTOR, p-mTOR, mTORC2 and its subunits Rictor and p-Rictor. Moreover, the expression of autophagy-related proteins LC3 and P62/SQSTM1 and Mitofusin2 (MFN2) and Dynamin related protein 1 (DRP1) in cardiac myocytes was observed.

Results:

1. Testosterone could activate the expression of mTORC2 in myocardial tissue: testosterone could activate the expression of mTORC2 and the Rictor of mTORC2 in ovariectomized SHR(Figure 1).

2. Testosterone could inhibit cardiomyocyte autophagy: there was no significant difference in the expression of autophagy-related proteins LC3 and P62/SQSTM1 between Sham and OVX groups, while testosterone could decrease the expression of LC3 protein and increase the expression of P62/SQSTM1 protein in OVX+T group (Figure 2).

3. Testosterone could activate the mitochondrial cleavage of cardiomyocytes: the expression of DRP1 was increased in OVX+T group (Figure 3).

Conclusions:

In bilateral ovariectomized SHR, testosterone may inhibit cardiomyocyte autophagy by activating the expression of mTORC2, which leads to cardiac hypertrophy in SHR. And in cardiomyocyte mitochondria, testosterone can promote mitochondrial cleavage.
SALT SENSITIVITY IS MODULATED BY LANOSTEROL SYNTHASE RS2254524 POLYMORPHISM
Authors: Citterio Lorena , Faienza Sipontina , Messaggio Elisabetta , Zagato Laura , Lanzani Chiara , Simonini Marco , Manunta Paolo
Published: June 2023

Objective:

The blood pressure (BP) response to different salt intakes (salt sensitivity-SS), shows variability among individuals, with more frequency in hypertensives compared to the general population. Elevated levels of the Endogenous Ouabain (EO) have been associated with hypertension (HT) and SS.

We characterized the missense variation rs2254524 (Val642Leu; C>A) of the Lanosterol Synthase gene (LSS) coding for an enzyme in steroid biosynthesis, since AA patients on a low-salt diet showed a greater reduction in BP compared to the LSS CC, with only CC having an increase in plasma EO.

We aim at dissecting the functional correlation between LSS polymorphism, EO and SS-HT.

Design and method:

We generated by CRISPR-Cas9 a knock-in mouse model carrying the Lss V643L (LssV643L/V643L), homologous to V642L. Male mice were fed with a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (<0.03% Na) and BP was measured every two days by the tail-cuff system.

Results:

LssV643L/V643L mice were viable, healthy, and undistinguishable phenotypically from WT.

At baseline, the Lss AA affected kidney weight that was significantly enlarged at 3 and 12 months of age, compared to WT.

The Lss V643L mutation did not affect EO and SBP at 3 and 12 months, per se, but affects SBP responsiveness to salt stimulus. We observed a decreased SBP after 10 days of a low-salt diet and increased SBP upon a high-salt diet only in LssV643L/V643L mice compared to the control diet at 3 and 12 months, respectively. Moreover, 12-month-old mice in high-salt diet showed cardiac hypertrophy, and LssV643L/V643L showed a higher incidence of heart fibrosis.

In the adrenal gland of LssV643L/V643L mice, Lss mRNA level was reduced upon high-salt diet.

At 12 months, RNASeq analysis of renal differentially expressed genes revealed a different regulation of multiple Slc genes, both in control and high-salt diet, but also of Cbr2, and Arhgap26.

Conclusions:

The new LssV643L/V643L mouse model resembles the SS-HT phenotype together with EO non-responsiveness observed in HT patients, thus providing a good model of SS-HT. Our results reveal a role of Lss gene in the regulation of BP upon salt stimulus.
ANALYSIS OF THE CONTRIBUTION OF GENES HP, ACE, HPSE1, MTHFR AND HFE TO THE DEVELOPMENT OF HEART FAILURE
Authors: Silva Pedro , Aguiar Laura , Gaspar Marcos , Falcão Luís , Bicho Manuel , Inácio Ângela
Published: June 2023

Objective:

Heart Failure (HF) is a clinical syndrome characterised by typical symptoms, associated with a cardiac incapacity of pumping blood. Although there have been improvements in treating HF, this disease still has a high mortality rate. Genes HP, ACE, HPSE1, MTHFR, and HFE are involved in various events and regulatory mechanisms associated with the disease such as the functionality of Haptoglobin, the activity of ACE and Heparanase enzymes and the metabolisms of Folic Acid and Iron.

The purpose of this study is to investigate the contribution of the variants Hp1/2 (HP), I/D (ACE), rs4693608 (HPSE1), C677T (MTHFR), H63D and C282Y (HFE) to the development of HF individually or in epistasis.

Design and method:

Genotype data previously obtained in 143 HF patients and 246 healthy individuals was used to carry out analysis. The analysis of the data was performed with SPSS software. The association between genotypes and alleles was tested by Chi-Square or Fisher tests. Odds Ratios were calculated as well as the corresponding confidence intervals.

Results:

We have observed a higher risk for developing HF in the presence of: 1) the T allele [OR (IC, 95) = 2,932] and CT genotype [OR (IC, 95) = 3,618] of the C677T polymorphism; 2) epistasis between II and YY genotypes of the I/D and C282Y polymorphisms [OR (IC, 95) = 5,191]; 3) epistasis between II and DD genotypes of the I/D and H63D polymorphisms [OR (IC, 95) = 6,626]; 4) epistasis between the 2 and C alleles of HP gene and C677T polymorphism [OR (IC, 95) = 4,351]; 5) epistasis between the C and A alleles of the C677T and rs4693608 polymorphisms [OR (IC, 95) = 6,804]. A protective effect was observed for the CC genotype of the C677T polymorphism [OR (IC, 95) = 0,341]; between the D allele of the I/D variation and the Y [OR (IC, 95) = 0,233] and D [OR (IC, 95) = 0,279] alleles of the C282Y and H63D polymorphisms, respectively.

Conclusions:

We have concluded that HP, ACE, HPSE1, MTHFR, and HFE genes contribute to the susceptibility of developing HF individually or in epistasis.
CLINICAL AND ECHOCARDIOGRAPHIC DIVERSITY ASSOCIATED WITH PHYSICAL FITNESS: THE PROJECT BASELINE HEALTH STUDY
Authors: Cauwenberghs Nicholas , Daubert Melissa A. , Salerno Michael , Haddad Francois , Kuznetsova Tatiana , Douglas Pamela S.
Published: June 2023

Objective:

Risk factors and subclinical changes in cardiac structure or function may indicate the development of heart failure (HF). However, different HF risk factors and echocardiographic phenotypes may be associated with different risk for HF progression. In community-dwelling individuals, we determined the heterogeneity in risk factor and echocardiographic profiles and assessed its association with physical performance metrics.

Design and method:

2036 participants (50.4 ± 17.0 years, 56.2% women, 37.8% hypertensive) without symptomatic HF underwent echocardiography and physical performance testing including 6-minute walk (6MWT) and treadmill exercise test. Echocardiographic profiles of left and right heart remodeling and dysfunction were defined using sex-specific internal reference values. The cohort was subdivided based on presence (+) or absence (-) of HF risk factors and echocardiographic abnormalities (Echo-/RF-, Echo-/RF+, Echo+/RF-, Echo+/RF+). Participants in Echo+/RF+ were stratified according to the most severe echocardiographic abnormality present (reduced ejection fraction (EF), left ventricular (LV) hypertrophy/diastolic dysfunction or other echo abnormalities). Associations between Echo/RF subgroups and physical performance metrics were assessed.

Results:

Prevalence was: 35.3% for Echo-/RF-, 39.3% for Echo-/RF+, 4.7% for Echo+/RF- and 20.6% for Echo+/RF+. Between the individuals with echocardiographic abnormalities (Echo+), we observed a large diversity in echocardiographic profiles. Yet, participants with echocardiographic abnormalities but no HF risk factors (Echo+/RF-, 18.6% of Echo+) predominantly had echo abnormalities other than LV diastolic dysfunction, hypertrophy and reduced EF, while their physical performance was similar to people with normal echocardiography without HF risk factors (Echo-/RF-). In contrast, Echo+ participants with risk factors (Echo+/RF+) were characterized by LV diastolic dysfunction, hypertrophy or reduced EF, which all related to lower 6MWT distance and lower exercise capacity (Figure panel A). The presence of both HF risk factors and LV dysfunction/hypertrophy was associated with worst physical performance.

Conclusions:

Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the type of echo abnormality and presence of HF risk factors should be considered to distinguish adverse changes from adaptive (benign) remodeling and further stratify HF risk. Concomitant presence of risk factors and LV dysfunction/hypertrophy may identify individuals with poor exercise capacity and thus at high risk for progression towards overt HF (Figure panel B).
CARDIOVASCULAR HAEMODYNAMICS IN TWO GROUPS OF HYPERTENSION: RESISTANT HYPERTENSION AND MALIGNANT HYPERTENSION
Authors: Alsharari Reem , Thomas G. Neil , Lip Gregory , Shantsila Alena
Published: June 2023

Objective:

Patients with malignant and resistant hypertension have poor prognosis and high rate of complications. Understanding the pathophysiological mechanisms underlying the severe forms of hypertension and their relationship to cardiac haemodynamics and vascular function is crucial to the management of blood pressure (BP).

Design and method:

In a cross-sectional comparison, of age and sex matched groups, we assessed left ventricle (LV) strain function using speckle tracking echocardiography (STE), (Figure 1), endothelial function using flow mediated dilation (FMD) and arterial stiffness using pulse wave velocity (PWV) in patients with confirmed RH (n = 23), treated malignant hypertension (MHT) (n = 54) and normotensive control (NC) (n = 23).

Results:

Characteristics pf study population are provided in table 1. Both hypertension groups showed markedly reduced global longitudinal strain (GLS) vs. NC (MHT -15.6% {-17 – -15}, RH -17.7% {-20 – -16} vs. NC -25% {-28 – -22]}, all p < 0.001) with GLS being lower in MHT vs. RH (p < 0.05). Both hypertensive groups also showed preserved but lower global circumferential strain (GCS) vs. NC (MHT -30.7% ± 4.7, RH -30.0% ± 4.3 vs. NC -34.3% ± 4.5, p = 0.004 and p = 0.03, respectively). FMD was markedly attenuated in both hypertensive groups (RH: 5.5 % ±2.6 and MHT: 5.9 %  ± 2.6 vs. NC: 9.9 %  ± 2.5%, p < 0.001). Carotid-femoral pulse wave velocity (cfPWV) was increased in both hypertensives compared to NC (p < 0.05). Subendocardial viability ratio (SEVR) and total peripheral resistance (TPR) were decreased in MHT compared to NC (p = 0.01 and p = 0.002, respectively). After adjustment for potential confounders (presence of hypertension, duration of hypertension, age, BMI, and eGFR), presence of MHT (p < 0.001), presence of RH (p < 0.001) and age (p = 0.01) showed significant negative association with GLS, whereas eGFR showed significant positive association with GLS (p = 0.03), (Table 2).

Conclusions:

This is the first cardio-vascular assessment of two extreme phenotypes of hypertension. Patients with MHT and RH had persistent impaired cardiac remodelling independent of preserved EF, impaired endothelial function and elevated arterial stiffness. Early cardiac remodelling marker, GLS was more impaired in MHT patients.