microRNAs combined to radiomic features as a predictor of complete clinical response after neoadjuvant radio-chemotherapy for locally advanced rectal cancer: a preliminary study.

OBJECTIVE: To define a predictive Artificial Intelligence (AI) algorithm based on the integration of a set of biopsy-based microRNAs expression data and radiomic features to understand their potential impact in predicting clinical response (CR) to neoadjuvant radio-chemotherapy (nRCT). The identification of patients who would truly benefit from nRCT for Locally Advanced Rectal Cancer (LARC) could be crucial for an improvement in a tailored therapy. METHODS: Forty patients with LARC were retrospectively analyzed. An MRI of the pelvis before and after nRCT was performed. In the diagnostic biopsy, the expression levels of 7 miRNAs were measured and correlated with the tumor response rate (TRG), assessed on the surgical sample. The accuracy of complete CR (cCR) prediction was compared for i) clinical predictors; ii) radiomic features; iii) miRNAs levels; and iv) combination of radiomics and miRNAs. RESULTS: Clinical predictors showed the lowest accuracy. The best performing model was based on the integration of radiomic features with miR-145 expression level (AUC-ROC = 0.90). AI algorithm, based on radiomics features and the overexpression of miR-145, showed an association with the TRG class and demonstrated a significant impact on the outcome. CONCLUSION: The pre-treatment identification of responders/NON-responders to nRCT could address patients to a personalized strategy, such as total neoadjuvant therapy (TNT) for responders and upfront surgery for non-responders. The combination of radiomic features and miRNAs expression data from images and biopsy obtained through standard of care has the potential to accelerate the discovery of a noninvasive multimodal approach to predict the cCR after nRCT for LARC.

Anastomosis Leak: Is There Still a Place for Indocyanine Green Fluorescence Imaging in Colon-Rectal Surgery? A Retrospective, Propensity Score-Matched Cohort Study.

Anastomotic leakage (AL) represents one of the most relevant complications of colorectal cancer surgery. The aim of this study was to evaluate the utility of intraoperative indocyanine green (ICG) fluorescence imaging in the prevention of AL during laparoscopic colorectal surgery. Methods. We retrospectively analyzed 272 patients who underwent rectal and left colon surgery, consecutively enrolled between 2015 and 2019. Due to the heterogeneity of our groups, a propensity score matching (PSM) was performed with a 1:1 PSM cohort. Results. AL occurred in 36 (13.2%) patients. One hundred seventy-seven (65%) of them underwent an intraoperatory ICG test (ICG-group), whereas 95 patients (35%) did not receive the intraoperatory ICG test (no-ICG group). AL occurred in 10.8% of ICG group patients and in 17.8% of no-ICG group patients (P = 0.07). The ICG group registered significantly less type B and type C fistulas than the no-ICG group (57.9 vs 88.2%; P = .043). After PSM, the overall AL rate was less in the ICG group than the no-ICG group (9.3% vs 16%; P = 0.058), while type B and type C fistulas occurred in 5.48% in the ICG group vs 13.70% in the no-ICG group (P = 0.09). Univariate analysis demonstrated a protective effect of intraoperative ICG imaging against AL occurrence (odds ratio (OR: 0.66)). Conclusions. Hypoperfusion is a well-recognized cause of AL. The ICG assessment of colic vascularization is a simple, inexpensive, and side effects free method, which can sensibly reduce both overall AL and type B and type C fistulas when routinely used.

Near-infrared indocyanine green fluorescent cholangiography in urgent and emergency laparoscopic cholecystectomy: a preliminary study after propensity score-matched study.

INTRODUCTION: Bile duct injury is a major complication of laparoscopic cholecystectomy (LC). Indocyanine green near-infrared fluorescence cholangiography (ICG-NIFC) is a well-recognized technique who provides an intraoperative mapping of the biliary system. METHODS: All patients underwent urgent LC and randomly divided into two groups: in one group, only white light imaging was used and, in the ICG group, ICG was used. Due to the heterogeneity of our groups, a PSM was performed with a 1:1 PSM cohort. RESULTS: The use of ICG clearly decreases the operation time (p value 0.002). The overall rate of intra- and post- operative complications was 4.17% and 15.8% respectively. Post-operative biliary duct injury trend decreases in ICG group and after the homogenization of the 2 cohorts, the intra- and post- operative complications (including vascular and biliary duct injury) results changed with a highest rate of complication in the cohort with no-ICG administration. The use of NIFC demonstrated a protective effect against intra- and post- operative complications and biliary duct injury (HR 0.037, p value 0.337 and HR 0.039, p value 0.647; HR 0.288; p value 0.05 and HR 0.635; p value 0.687, respectively). CONCLUSIONS: The intra-operative use of NIFC showed a trend in the reduction of the rate of intra- and post-operative complications, the duration of surgery, and the length of hospital stay. ICG is a highly safe approach to urgent and emergency LC, as for elective LC, and could lead the surgeon to conduct the procedure more efficiently.

Neoadjuvant systemic treatment in breast cancer surgery: is it always worth it?

BACKGROUND: Surgeons perspective of breast cancer (BC) treatment has deeply changed in recent time. We investigated survival outcomes of BC patients who underwent Neoadjuvant systemic treatment (NAT) before surgery and to assess the role of NAT in determining possible prognosis. METHODS: We retrospectively analyzed a total of 2372 BC patients consecutively enrolled in our prospective institutional database. Seventy-eight patients over 2372 reached the inclusion criteria and underwent surgery after NAT. RESULTS: After NAT, the 50% of luminal-B-HER2+ and the 53% of HER2+ had a pathological complete response (pCR) and only 18.5% of the TNs had a pCR. NAT significantly changed lymph node status (P=0.05). All women with pCR are still alive (No-pCR 0.732 CI: 0.589-0.832; yes-pCR 1.000 CI: 1.00-1.00; P=0.02). The molecular biology of the tumor, after NAT, is strictly related to survival both for 3- and 5-years OS. A triple negative BC have the worst prognosis (HER2+ 0.796 CI: 0.614-1; Luminal-A: 1 CI:1-1; LuminalB-HER2 -: 0.801 CI: 0.659-0975; LuminalB-HER2+: 1 CI:1-1; TN 0.542 CI: 0.372-0789, P=0.002). CONCLUSIONS: We can state that, based on our experience, we can consider safe and effective conservative interventions following neoadjuvant therapy. An adequate selection of patients is crucial. It is also clear how the planning of the therapeutic path plays a key role in an interdisciplinary context. NAT is a source of hope for the future both for the identification of new predictors of prognosis and in the field of research, for the development of new drugs.

High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage.

BACKGROUND: Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). METHODS: Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. RESULTS: A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. CONCLUSION: One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII.

Survival and long-term surgical outcomes after colorectal surgery: are there any gender-related differences?

Colorectal cancer (CRC) incidence and mortality seems to be lower in women than in men. The present study aims to evaluate the impact of gender on CRC diagnosis, treatment, and survival. This is a retrospective cohort study based on a single-center dataset of CRC patients from the University Hospital of Trieste (Italy). Data of 1796 consecutive CRC patients referred to our center from November 11th, 2004, to December 31st, 2017, were analyzed. Right-sided carcinomas are more frequent in women than in men; furthermore, women had a lower surgical complication rate. Men showed a higher 5- and 10-year mortality. This survival benefit for women was observed independently of the tumor localization. The 5-year hazard ratio (HR) for women vs men was 0.776 (p 0.003), and after 10-year 0.816 (p 0.017). Regarding the disease-free survival (DFS), 5 and 10-year HR was 0.759 (p 0.034) and 0.788 (p 0.07), respectively. On multivariable analysis, respecting tumor localization, the odds of female gender were higher than man with right colon disease. Male gender was more independently associated with age at the surgery time. Women survival advantage was higher than men, except for patients older than 80. Surgical outcome and survival after CRC surgical treatment seem to be gender related. For this reason, gender could play an important role in CRC diagnosis and therapy, allowing an earlier diagnosis in women.

The real-word impact of breast and colorectal cancer surgery during the SARS-CoV-2 pandemic.

The postponing of screening and the health care system reorganization, due to the Covid-19 pandemic and lockdown, could led to a concerning decline in breast and colorectal cancer diagnoses. This monocentric retrospective analysis has compared the pre-Covid period (March 2019 to March 2020) to the Covid period (April 2020 to April 2021) in terms of screening programs, clinical, surgical and pathological. A total of 799 patients diagnosed with Breast Cancer (BC) and Colorectal Cancer (CRC) underwent surgery during the two periods. In FVG in 2020 a decrease in mammography screening of 17.1% has been registered compared to 2019; this reduction has been higher for CRC screening, which summed up to 24.5%. As far as BC is concerned, screening-detected tumours rose significantly from 18 to 28%, mastectomies decreased from 40 to 31% and advanced tumours treated surgically decreased from 12 to 6%. Concerning CRC, a significant increase in admissions through the Emergency Department has been registered in spite of a stable percentage of urgent surgery performed, proving that severely symptomatic patients have been treated adequately. Open surgery has significantly decreased, whereas the tumoral stage and complications have remained constant in the two periods. This study has proved that maintaining standards of care and validated protocols during emergency is the most adequate and winning strategy: impact on BC and CRC has been less important than expected. These results support the recommendations for immediate and rapid screening program resumption at operating speed, using prioritization strategies to make up for the diagnostic delays.

Potential Application of Small Interfering RNA in Gastro-Intestinal Tumors.

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the mRNA of pathological genes, have the potential to be of therapeutic value. To be effective in the human body, siRNAs need to be protected against degradation. Additionally, they need to target the tumor, leaving the normal tissue untouched in an effort to preserve organ function. To accomplish these tasks, siRNAs have been formulated with smart delivery systems such has polymers and lipids. While siRNA protection is not particularly difficult to achieve, their targeting of tumor cells remains problematic. Here, after introducing the general features of gastrointestinal cancers, we describe siRNA characteristics together with representative delivery systems developed for gastrointestinal cancers. Afterward, we present a selection of research papers employing siRNAs against upper- and lower- gastrointestinal cancers. For the liver, we also consider papers using siRNAs to combat liver cirrhosis, a relevant risk factor for liver cancer development. Finally, we present a brief description of clinical trials employing siRNAs for gastrointestinal cancers.

Effect of SARS-CoV-2 (COVID-19) Pandemic and Lockdown on Body Weight, Maladaptive Eating Habits, Anxiety, and Depression in a Bariatric Surgery Waiting List Cohort.

PURPOSE: On January 30, 2020, the World Health Organization declared COVID-19 as a "public health emergency of international concern." The primary aim of the study was to evaluate weight and food habit changes during COVID-19 outbreak. The secondary endpoint was to explore the psychological factors, arising during the pandemic, influencing weight and dietary variations. MATERIALS AND METHODS: A survey composed of four different items was conducted by telephone interview: (1) anthropometric data and type of procedure, (2) Hospital Anxiety and Depression Scale (HADS), (3) maladaptive eating behaviors, and (4) personal feelings moved by the COVID-19 spread and lockdown. RESULTS: Fifty-six patients were enrolled. No significant changes in weight, BMI, and maladaptive eating habits were observed. A significant reduction in the anxiety index score was observed. In 17.8% of cases, a change in obesity class was reported, and among these patients, a substantial modification in bariatric procedures was planned (60%). CONCLUSION: This study showed no effect on weight and BMI nor on rates of maladaptive eating habits associated with quarantine/social isolation among severely obese individuals waiting for the bariatric surgery. At the end of lockdown, a considerable proportion of patients modified their initial obesity class, and in selected cases, it could represent a criteria for rearrangement of the planned bariatric procedure. In obese patients, the lockdown and social distancing generated a reduction of fear of confronting and being negatively judged by others. This psychological aspect was assessed with the reduction of the HADS score.

Comparison between male and female breast cancer survival using propensity score matching analysis.

Male breast cancer (MBC) is a rare disease. The few studies on MBC reported conflicting data regarding survival outcomes compared to women. This study has two objectives: to describe the characteristics of a single-cohort of MBC and to compare overall survival (OS) and disease-free survival (DFS) between men and women using the propensity score matching (PSM) analysis. We considered MBC patients (n = 40) diagnosed between January 2004 and May 2019. Clinical, pathological, oncological and follow-up data were analyzed. Univariate analysis was performed to determine the prognostic factors on OS and DFS for MBC. We selected female patients with BC (n = 2678). To minimize the effect of the imbalance of the prognostic factors between the two cohorts, the PSM method (1:3 ratio) was applied and differences in survival between the two groups were assessed. The average age of MBC patients was 73 years. The 5-year OS and DFS rates were 76.7% and 72.2% respectively. The prognostic factors that significantly influenced OS and DFS were tumor size and lymph node status. After the PSM, 5 year-OS was similar between MBC and FBC (72.9% vs 72.3%, p = 0.70) while we found a worse DFS for MBC (72.2% vs 91.4%, p = 0.03). Our data confirmed previous reported MBC characteristics: we found a higher risk of recurrence in MBC compared to FMC but similar OS. MBC and FMC are different entities and studies are needed to understand its epidemiology and guide its management.

Impact of lockdown for SARS-CoV-2 (COVID-19) on surgical site infection rates: a monocentric observational cohort study.

Surgical site infections are the most common in-hospital acquired infections. The aim of this study and the primary endpoint is to evaluate how the measures to reduce the SARS-CoV-2 spreading affected the superficial and deep SSI rate. A total of 541 patients were included. Of those, 198 from March to April 2018, 220 from March till April 2019 and 123 in the COVID-19 era from March to April 2020. The primary endpoint occurred in 39 over 541 patients. In COVID-19 era, we reported a lower rate of global SSIs (3.3% vs. 8.4%; p 0.035), few patients developed a superficial SSIs (0.8% vs. 3.4%; p 0.018) and none experienced deep SSIs (0% vs. 3.4%; p 0.025). Comparing the previous two "COVID-19-free" years, no significative differences were reported. At multivariate analysis, the measures to reduce the SARS-CoV-2 spread (OR 0.368; p 0.05) were independently associated with the reduction for total, superficial and deep SSIs. Moreover, the presence of drains (OR 4.99; p 0.009) and a Type III-IV of SWC (OR 1.8; p 0.001) demonstrated a worse effect regarding the primary endpoint. Furthermore, the presence of the drain was not associated with an increased risk of superficial and deep SSIs. In this study, we provided important insights into the superficial and deep SSIs risk assessment for patients who underwent surgery. Simple and easily viable precautions such as wearing surgical masks and the restriction of visitors emerged as promising tools for the reduction of SSIs risk.

Colorectal cancer-screening program improves both short- and long-term outcomes: a single-center experience in Trieste.

Screening programs (SC) have been proven to reduce both incidence and mortality of CRC. We retrospectively analyzed patients who underwent surgical treatment for CRC between 01/2011 and 01/2017. The current screening program in our region collects patients aged from 50 to 69. For this reason, out of a total of 600 patients, we compared 125 patients with CRC founded during the SC to 162 patients who presented with symptoms and were diagnosed between 50-69 years old (NO-SC). 45% patients in the SC group were diagnosed as AJCC stage I vs 27% patients in the NO-SC group; 14% vs 20% were stage II, 14% vs 26% were stage III, and 3% vs 14% were stage IV (p 0.002). We found a significant difference in surgical approach: 89% SC vs 56% NO-SC patients had laparoscopic surgery (p 0.002). In the NO-SC group, 16% patients underwent resection in an emergency setting. Only 5% patients in the SC group had postoperative complications vs 14% patients in the NO-SC group (p 0.03). We had a 2-year OS of 86%, being 95% in the SC group and 80% in the NO-SC group (p 0.002). Likewise, the whole 2-year DFS was 77%, whereas it was 90% in the SC group and 66% in the NO-SC group (p 0.002). Screening significantly improves early diagnosis and accelerated surgical treatment. We obtained earlier stages at diagnosis, a less invasive surgical approach, and lower rates of complications and emergency surgery, all this leading to an improvement in both OS and DFS.

The Prognostic Impact of the Evolution of RV Function in Idiopathic DCM.

OBJECTIVES: In this study, the authors analyzed the prognostic role of right ventricular systolic function (RVF) longitudinal trends in a large cohort of patients affected by dilated cardiomyopathy (DCM). BACKGROUND: RVF is a known prognostic predictor in DCM; however, whether RVF changes over time to better predict the long-term disease progression has not been investigated. METHODS: From 1993 to 2008, we analyzed 512 patients with DCM (46 years of age [36 to 55 years of age], left ventricular ejection fraction 32% [25% to 41%]) with a potential follow-up of ≥72 months and available data at baseline and at least 1 pre-specified follow-up evaluation (i.e., 6, 24, 48, or 72 months). RV dysfunction was defined as RV fractional area change <35% at 2-dimensional echocardiography. The primary outcome measure was a composite of death or heart transplantation. RESULTS: At enrollment, 103 (20%) patients had RV dysfunction. During follow-up, 89 of them (86%, 17% of the overall cohort) normalized RVF at a median time of 6 months, whereas 38 of the remaining 409 patients with normal baseline RVF (9%; 7% of the overall population) exhibited a new-onset RV dysfunction (median time: 36 months). RVF normalization was significantly associated with subsequent left ventricular reverse remodeling that was observed at a median time of 24 months (odds ratio: 2.49; 95% confidence interval [CI]: 1.17 to 5.3; p = 0.018). At baseline multivariate analysis, RV dysfunction was independently associated with the primary outcome measure (hazard ratio: 1.71; 95% CI: 1.02 to 2.85; p = 0.0413). At time-dependent model, RVF revaluation over time maintained an independent predictive value (hazard ratio: 2.83; 95% CI: 1.57 to 5.11; p = 0.0006). CONCLUSIONS: Patients with DCM frequently present RV dysfunction at first evaluation. However, a complete RVF recovery is largely observed early after optimization of medical therapy and predates subsequent left ventricular reverse remodeling. Systematic revaluation of patients including RVF throughout regular follow-up conferred additive long-term prognostic value to the baseline evaluation.

Early Arrhythmic Events in Idiopathic Dilated Cardiomyopathy.

OBJECTIVES: The study sought to provide an insight into the prevalence, characterization and possible reliable indicators of early sudden cardiac death/malignant ventricular arrhythmias (SCD/MVAs) in a large cohort of dilated cardiomyopathy (DCM). BACKGROUND: DCM generally affects young individuals and is characterized by an unpredictable prognosis with a non-negligible risk of SCD/MVAs, particularly in early stages of disease. METHODS: From 1988 to 2014, 952 patients with DCM were consecutively included in the Heart Muscle Disease Registry of Trieste. RESULTS: Globally, 20 patients (2.1% of the overall population) experienced SCD/MVAs within the first 6 months after enrollment (primary endpoint). At baseline they showed a worse functional class (New York Heart Association functional class III to IV 42% vs. 22%, p = 0.038), a longer QRS complex duration (127 ± 41 ms vs. 108 ± 33 ms; p = 0.013) and a larger indexed left ventricular end-systolic volume (LVESVI) (82 ± 49 ml/m2 vs. 67 ± 34 ml/m2; p = 0.049), as compared to patients without early SCD/MVAs. Beta-blockers were less tolerated (59% vs. 83% in patients with no early SCD/MVAs; p = 0.008), mostly due to hemodynamic intolerance. At multivariate analysis, LVESVI (odds ratio [OR]: 1.012; 95% confidence interval [CI]: 1.000 to 1.024; p = 0.043) and QRS complex duration (OR: 1.017; 95% CI: 1.003 to 1.030; p = 0.015) were independently associated with the primary endpoint, whereas beta-blockers demonstrated a protective effect (OR: 0.169, CI: 0.048 to 0.593; p = 0.006). CONCLUSIONS: Patients with DCM present a significant risk of major arrhythmic events in the first phase of the disease. Baseline LVESVI, QRS duration, and intolerance to beta-blocker therapy might be useful tools in the arrhythmic early risk assessment.

Omega-3 Polyunsaturated Fatty Acids: Structural and Functional Effects on the Vascular Wall.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) consumption is associated with reduced cardiovascular disease risk. Increasing evidence demonstrating a beneficial effect of n-3 PUFA on arterial wall properties is progressively emerging. We reviewed the recent available evidence for the cardiovascular effects of n-3 PUFA focusing on structural and functional properties of the vascular wall. In experimental studies and clinical trials n-3 PUFA have shown the ability to improve arterial hemodynamics by reducing arterial stiffness, thus explaining some of its cardioprotective properties. Recent studies suggest beneficial effects of n-3 PUFA on endothelial activation, which are likely to improve vascular function. Several molecular, cellular, and physiological pathways influenced by n-3 PUFA can affect arterial wall properties and therefore interfere with the atherosclerotic process. Although the relative weight of different physiological and molecular mechanisms and the dose-response on arterial wall properties have yet to be determined, n-3 PUFA have the potential to beneficially impact arterial wall remodeling and cardiovascular outcomes by targeting arterial wall stiffening and endothelial dysfunction.

Baroreflex sensitivity and central hemodynamics after omega-3 polyunsaturated fatty acids supplementation in an animal model of menopause.

OBJECTIVE: Baroreflex sensitivity (BRS) and central arterial function are significantly worsened after menopausal transition. This study tested the hypothesis that administration of n-3 polyunsaturated fatty acids (n-3 PUFA) might contribute to prevent these adverse changes in the vascular function of ovariectomized rats, an animal model of experimental menopause. METHODS: We randomized 30 female Wistar rats, 2months old, into 3 groups: control (CTRL), sham surgery, normal diet; ovariectomized with normal diet (OVX) and ovariectomized with n-3 PUFA supplementation by daily gavage (0.8g/kg/d) (OVX+O3). Two months after surgery, BRS was calculated as the bradycardic response to phenylephrine-induced blood pressure increase, while large artery function was estimated by the graphical analysis of the aortic pressure wave (diastolic to systolic pressure-time integral ratio, DTI/STI). RESULTS: Ovariectomy caused a significant decrease in BRS (CTRL: 6.23±0.68ms/mmHg; OVX: 2.85±0.75; p<0.001). n-3 PUFA supplementation prevented part of the decline of BRS caused by surgical menopause (OVX+O3: 4.75±0.53; p<0.01 vs OVX). In animals treated with n-3 PUFA, the central arterial pressure profile did not show the changes in DTI/STI ratio seen in OVX (OVX: 3.31±1.72; OVX+O3: 3.83±1.52; p<0.01). CONCLUSIONS: In an experimental model of menopause, treatment with n-3 PUFA normalized central hemodynamics and prevented the decrease in BRS, associated with the reduction of compliance of the arterial wall. These findings suggest a therapeutic benefit of n-3 PUFA supplementation in the prevention of postmenopausal vascular disease.

Aldosterone effects on glomerular structure and function.

OBJECTIVE: Experimental evidence suggests that aldosterone directly contributes to organ damage by promoting cell growth, fibrosis, and inflammation. Based on these premises, this work aimed to assess the glomerular effects of aldosterone, alone and in combination with salt. METHODS: After undergoing uninephrectomy, 75 rats were allocated to five groups: control, salt diet, aldosterone, aldosterone + salt diet, aldosterone + salt diet and eplerenone, and they were all studied for four weeks. We focused on glomerular structural, functional, and molecular changes, including slit diaphragm components, local renin-angiotensin system activation, as well as pro-oxidative and profibrotic changes. RESULTS: Aldosterone significantly increased systolic blood pressure, led to glomerular hypertrophy, mesangial expansion, and it significantly increased the glomerular permeability to albumin and the albumin excretion rate, indicating the presence of glomerular damage. These effects were worsened by adding salt to aldosterone, while they were reduced by eplerenone. Aldosterone-induced glomerular damage was associated with glomerular angiotensin-converting enzyme (ACE) 2 downregulation, with ACE/ACE2 ratio increase, ANP decrease, as well as with glomerular pro-oxidative and profibrotic changes. CONCLUSIONS: Aldosterone damages not only the structure but also the function of the glomerulus. ACE/ACE2 upregulation, ACE2 and ANP downregulation, and pro-oxidative and profibrotic changes are possible mechanisms accounting for aldosterone-induced glomerular injury.

Supplementation of omega-3 polyunsaturated fatty acids prevents increase in arterial stiffness after experimental menopause.

BACKGROUND: Menopause is associated with increased arterial stiffness, an independent marker of cardiovascular risk. Omega-3 polyunsaturated fatty acids (N3-PUFAs) are thought to have multiple cardiovascular benefits, including prevention of arterial stiffness. We investigated whether treatment with N3-PUFA prevents increase in arterial stiffness in ovariectomized rats, an animal model of experimental menopause. METHODS: A total of 43 Wistar rats, 2 months old, were divided into 3 groups, control, sham surgery, normal diet (CTRL, n = 15); ovariectomy, normal diet (OVX, n = 14); and ovariectomy with N3-PUFA supplementation (0.8 g/kg/d in daily gavages administration; OVX + O3, n = 14). Two months after surgery, carotid-femoral pulse wave velocity (PWV) and arterial blood pressure (BP) were measured by carotid and femoral cannulation. Aortic morphometric measurements were performed after dissection. RESULTS: Ovariectomy caused a significant increase in BP (P < .05), PWV (P < .0001), and elastic modulus (P = .001) compared to CTRL. After ovariectomy, N3-PUFA supplementation completely prevented increase in arterial stiffness (P < .0001 vs OVX) and BP (P < .05 vs OVX) and resulted in a significant increase in body weight and aortic thickness. CONCLUSIONS: In an experimental model of menopause, N3-PUFA supplementation prevents arterial stiffening and other vascular changes induced by ovariectomy. These results represent a therapeutic benefit of N3-PUFAs in prevention of postmenopausal cardiovascular disease.

Treatment with n-3 polyunsaturated fatty acids reverses endothelial dysfunction and oxidative stress in experimental menopause.

Menopause is associated with endothelial dysfunction and oxidative stress. In this condition, reduced n-3 polyunsaturated fatty acids (n-3 PUFAs) contribute to cardiovascular disease. We investigated whether treatment with n-3 PUFA reverses endothelial dysfunction and oxidative stress in experimental menopause. Thirty female rats underwent either sham-surgery or bilateral ovariectomy or bilateral ovariectomy+oral n-3 PUFA (0.8 g kg(-1) day(-1) for 2 months). Ovariectomy caused endothelial dysfunction to acetylcholine, which was reversed by superoxide scavenger Tiron. Erythrocyte membrane lipid composition was characterized by reduced n-3 PUFA total content and omega-3 index, and by concomitant increase in n-6:n-3 PUFA ratio. Ovariectomy-related oxidative stress, demonstrated by both enhanced superoxide production and 3-nitrotyrosine expression in aorta, was associated with increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX-4 protein expression. Endothelial nitric oxide synthase (eNOS) functional inhibition by l-NG-nitroarginine methyl ester, protein expression and activity did not change. In ovariectomized rats, treatment with n-3 PUFA increased n-3 PUFA total content and omega-3 index and decreased n-6:n-3 PUFA ratio in erythrocyte membrane, reversed vascular oxidative stress, endothelial dysfunction, aortic 3-nitrotyrosine and markedly lowered NOX-4 protein expression; eNOS protein expression also increased, paralleled by reversal of inhibitory binding to Caveolin-1, while ex-vivo functional inhibition and NOS synthesis were unchanged. These findings demonstrate in vivo a therapeutic benefit of n-3 PUFA on menopause-associated endothelial dysfunction by reversal of alterations in membrane lipid composition induced by ovariectomy and by reduction of vascular oxidative stress. In this setting they also identify NOX-4 as a potential target to reduce oxidative stress-mediated vascular complications.