Pre-graduation medical training including virtual reality during COVID-19 pandemic: a report on students' perception.

BACKGROUND: The Coronavirus Disease 19 (COVID-19) pandemic brought significant disruption to in-hospital medical training. Virtual reality simulating the clinical environment has the potential to overcome this issue and can be particularly useful to supplement the traditional in-hospital medical training during the COVID-19 pandemic, when hospital access is banned for medical students. The aim of this study was to assess medical students' perception on fully online training including simulated clinical scenarios during COVID-19 pandemic. METHODS: From May to July 2020 when in-hospital training was not possible, 122 students attending the sixth year of the course of Medicine and Surgery underwent online training sessions including an online platform with simulated clinical scenarios (Body Interact™) of 21 patient-based cases. Each session focused on one case, lasted 2 h and was divided into three different parts: introduction, virtual patient-based training, and debriefing. In the same period, adjunctive online training with formal presentation and discussion of clinical cases was also given. At the completion of training, a survey was performed, and students filled in a 12-item anonymous questionnaire on a voluntary basis to rate the training quality. Results were reported as percentages or with numeric ratings from 1 to 4. Due to the study design, no sample size was calculated. RESULTS: One hundred and fifteen students (94%) completed the questionnaire: 104 (90%) gave positive evaluation to virtual reality training and 107 (93%) appreciated the format in which online training was structured. The majority of participants considered the platform of virtual reality training realistic for the initial clinical assessment (77%), diagnostic activity (94%), and treatment options (81%). Furthermore, 97 (84%) considered the future use of this virtual reality training useful in addition to the apprenticeship at patient's bedside. Finally, 32 (28%) participants found the online access difficult due to technical issues. CONCLUSIONS: During the COVID-19 pandemic, online medical training including simulated clinical scenarios avoided training interruption and the majority of participant students gave a positive response on the perceived quality of this training modality. During this time frame, a non-negligible proportion of students experienced difficulties in online access to this virtual reality platform.

sRAGE and early signs of cardiac target organ damage in mild hypertensives.

BACKGROUND: Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). METHODS: sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). RESULTS: sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = - 0.239, p = 0.034) and LAVi (r = - 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. CONCLUSIONS: In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

Relationship between regulatory T cells subsets and lipid profile in dyslipidemic patients: a longitudinal study during atorvastatin treatment.

BACKGROUND: The CD4+ T-lymphocytes and their subtype CD4 + CD25(high)FoxP3+ regulatory T cells are receiving growing interest as major regulators of atherogenesis. We sought to investigate 1) whether the CD4 + cell subsets were expressed differently in dyslipidemic patients (Pts) and healthy subjects (HS) and 2) whether atorvastatin treatment could be associated in-vivo and in-vitro with cell changes in expression and functional response. METHODS: CD4+ subsets frequency (CD4 + CD25(high)FoxP3+, CD4 + CD25-FoxP3+) and mRNA expression for FoxP3, IL-10 and TGF-ß were evaluated in 30 consecutive Pts at baseline and after a 3-month atorvastatin therapy, and in 17 HS. RESULTS: The % of CD4 + cells did not differ between HS and Pts. The % of CD4 + CD25(high)FoxP3+ was higher in Pts than HS and did not change during treatment. The CD4 + CD25-FoxP3+ cells were similar between the two groups and were lower in Pts at visit 2. Cytokine expression and FoxP3 did not differ in HS and Pts and no substantial change was observed during treatment. At visit 1, CD4 + CD25(high)FoxP3+ cells were significantly correlated with both total-cholesterol (r = 0.570, P = 0.0002), LDL-cholesterol (r = 0.715, P = 0.0001), Apolipoprotein B (r = 0.590, P = 0.0001). In-vitro atorvastatin (up to 5 µM) failed to induce any significant modulation of cell functions. CONCLUSION: CD4 + CD25(high)FoxP3+ regulatory cells seem to be over-stimulated in the early pre-clinical phase of atherosclerosis and a relationship exists between their frequency and circulating lipids. A potential immuno-modulation by statin treatment is not achieved through a normalization in peripheral CD4 + cell subsets.

Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2.

PURPOSE: Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to prevent myopathy, a common and potentially serious dose-dependent adverse effect of these drugs. We have investigated the correlation between elevated CK levels and polymorphisms in the genes encoding transporters involved in statin disposition. METHODS: Patients with and without statin-induced elevated serum CK levels were genotyped for polymorphisms in SLCO1B1 (SLCO1B1 A388G and SLCO1B1 T521C), ABCB1 (ABCB1 C1236T and ABCB1 C3435T) and ABCG2 (ABCG2 C421A). RESULTS: Patients carrying SLCO1B1 T521C or ABCB1 C1236T single nucleotide polymorphisms (SNPs) had an odds ratio (OR) for statin-induced elevated serum CK levels of 8.86 (p<0.01) and 4.67 (p<0.05), respectively, while patients carrying the SLCO1B1 A388G SNP had an OR of 0.24 (p<0.05). An arbitrary score based on genotype combination discriminated patients with and without CK elevation at a specificity of 97 % and a sensitivity of 39 %. CONCLUSION: Genotyping of the SLCO1B1, ABCB1 and ABCG2 genes deserves consideration as a clinical approach to improve statin safety while concomitantly reducing the burden of blood tests for CK measurements.

Simvastatin down-regulates the production of interleukin-8 by neutrophil leukocytes from dyslipidemic patients.

BACKGROUND: Neutrophil (PMN) leukocytes participate to the initial phases of atherosclerosis through the release of Interleukin 8 (CxCL8; IL-8) that contribute to amplification of inflammation. Aim of the study is to investigate the production of IL-8 by PMN leukocytes from dyslipidemic patients treated with simvastatin. METHODS: In 15 dyslipidemic subjects with moderately increased cardiovascular risk, assessed by Framingham Risk Score, blood samples were obtain to investigate PMNs IL-8 production [at baseline and after N-formyl-Met-Leu-Phe (fMLP) stimulation] before and after long-term (1-year) simvastatin treatment. RESULTS: The resting release of IL-8 was higher in dyslipidemic patients at baseline when compared with control subjects (p < 0.05). One year of treatment was significantly associated with reduced IL-8 production (p < 0.01). Moreover, the fMLP-induced IL-8 production in dyslipidemic untreated patients was higher than that of controls (p < 0.05) and was reduced after simvastatin treatment (p < 0.01). IL-8 release after 1 year of treatment was reduced to levels which were lower than those observed in control subjects both for resting and stimulated cytokine production (p < 0.01). CONCLUSIONS: Prolonged treatment with simvastatin is associated with a reduction of IL-8 production, suggesting the possibility of statin to modulate the pro-inflammatory response in PMNs of patients with moderately increased cardiovascular risk.

Hypoalbuminaemia and heart failure: A practical review of current evidence.

Hypoalbuminaemia (serum albumin levels ≤3.5 g/dl) is associated with poor outcomes among patients with heart failure (HF). This narrative review includes original articles and reviews published over the past 20 years and retrieved from PubMed using the following search terms (or their combination): 'heart failure', 'hypoalbuminaemia', 'heart failure with reduced ejection fraction', 'heart failure with preserved ejection fraction', 'all-cause mortality', 'in-hospital mortality', 'hospitalization', 'prognosis'. The aims of this review are to provide an overview on the prevalence of hypoalbuminaemia in HF, its impact on clinical outcomes, and potential mechanisms that may suggest future therapeutic strategies. Hypoalbuminaemia is frequent in HF patients, especially among the elderly. However, data about the exact epidemiology of hypoalbuminaemia are scant due to different definitions, and prevalence is estimated between 5% and 70% across the whole spectrum of ejection fraction. Current evidence points to hypoalbuminaemia as a marker of poor outcomes in HF, irrespective of the ejection fraction, and in other cardiovascular diseases. Among patients who suffered from acute coronary syndrome, those with hypoalbuminaemia had an increased risk of new-onset HF and in-hospital mortality. Albumin, however, might also play a role in the natural history of such diseases due to its antioxidant, anti-inflammatory, and antithrombotic properties. Whether albumin supplementation or nutritional support in general would be beneficial in improving clinical outcomes in HF is not completely clear and should be evaluated in adequately designed studies.

Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment.

BACKGROUND: In diabetes, a variety of pro-inflammatory cellular changes has been found in various cell types, including monocytes which are known to be involved in all the phases of atherogenesis. Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the pro-atherogenic effects of Ang II whereas the type 2 receptor (AT2R) seems associated with atheroprotection. We sought to investigate the potential changes of AT1R-AT2R expression in human monocytes of type 2 diabetic- hypercholesterolemic patients and in hypercholesterolemic subjects, upon clinical treatment with rosuvastatin. METHODS: The AT1R membrane protein and mRNA AT1R and AT2R expression in monocytes were investigated in 10 type 2 diabetic-hypercholesterolemic patients and in 10 hypercholesterolemic subjects, before and after 3-month rosuvastatin treatment. Moreover, the serum cytokine levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected. RESULTS: As expected, rosuvastatin was associated with a change in the lipid profile in the two groups. Both the membrane protein (P = 0.008) and the AT1R mRNA expression (P = 0.038) were significantly reduced during treatment in the absence of AT2R expression change in diabetic-hypercholesterolemic patients whereas no significant difference was observed in hypercholesterolemic subjects. The serum IL-4 levels were increased during treatment whereas no change was observed in IFN-γ in diabetic-hypercholesterolemic patients. No cytokine change was observed in hypercholesterolemic subjects. CONCLUSIONS: Our study on monocytes of diabetic-hypercholesterolemic patients, showing a reduced AT1R but not AT2R expression during rosuvastatin treatment, suggests that statin therapy may modulate favorably the AT1-AT2 receptor balance in subjects with coexistent type 2 diabetes.

Proprotein convertase subtilisin/kexin type 9 inhibitors treatment in dyslipidemic patients: a real world prescription.

AIM: Dyslipidemia is recognized as one of the major risk factors for cardiovascular diseases. This retrospective observational study was aimed to assess the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in dyslipidemic patients with a lipid profile not well controlled by maximally tolerated statin therapy or intolerant to these lipid-lowering drugs. We enrolled 151 patients, of whom, 119 were taking evolocumab and 32 alirocumab. RESULTS: Total cholesterol significantly decreased progressively until the fourth year; after 4 years there was a significant reduction (-125.5 mg/dl, -51.5%, P < 0.0001 vs baseline, and P < 0.05 vs 1 year and P < 0.05 vs 2 years) and -2.8 mg/dl (-2.3%) compared with the third year. Low-density lipoprotein-cholesterol (LDL-C) also decreased significantly until the fourth year. After 3 years, there was a significant reduction (-117.8 mg/dl, -71.5%, P < 0.0001 vs baseline, and P < 0.05 vs 1 year) and -13.9 mg/dl (-22.8%) compared with the second year; after 4 years there was a significant reduction (-121.4 mg/dl, -73.7%, P < 0.0001 vs baseline, and P < 0.05 vs 1 year and P < 0.05 vs 2 years) and -3.6 mg/dl (-7.7%) compared with the third year. High-density lipoprotein-cholesterol increased significantly only during the fourth year of detection. After 3 years, there was a nonsignificant increase (4.9 mg/dl, 10.0%, P = 0.061 vs baseline) and 1.6 mg/dl (3.1%) compared with the second year; after 4 years, there was a significant increase (5.2 mg/dl, 10.6%, P < 0.05 vs baseline) and 0.3 mg/dl (0.6%) compared with the third year. The value of Tg was significantly reduced progressively until the second year and then stabilized in the third and fourth years. After 3 years, the value of Tg stabilized (-48.6 mg/dl, -32.4%, P < 0.01 vs baseline, and P < 0.05 vs 1 year) and -4.8 mg/dl (-4.5%) compared with the second year; after 4 years (-46.4 mg/dl, -31.0%, P < 0.01 vs baseline, and P < 0.05 vs 1 year) there was a slight and nonsignificant increase of 2.2 mg/dl (2.2%) compared with the third year. Regarding adverse events, both drugs were well tolerated. CONCLUSIONS: We showed that PCSK9 inhibitors are well tolerated and provide long-term significant LDL-C lowering in individuals with hyperlipidemia.

Probiotic Therapy With VSL#3® in Patients With NAFLD: A Randomized Clinical Trial.

Aim: To evaluate if VSL#3® [a high-concentration multi-strain probiotic mix containing one strain of Streptococcus thermophilus BT01, three strains of Bifidobacteria (B. breve BB02; B. animalis subspecies [subsp.] lactis BL03, previously identified as B. longum BL03; and B. animalis subsp. lactis BI04, previously identified as B. infantis BI04), and four strains of Lactobacilli (L. acidophilus BA05, L. plantarum BP06, L. paracasei BP07, and L. helveticus BD08, previously identified as L. delbrueckii subsp. bulgaricus BD08)] therapy could improve hepatic parameters. Methods: We enrolled 60 Caucasian patients aged ≥ 18 years of either sex with the diagnosis of non-alcoholic fatty liver disease (NAFLD), according to practice guidance, in a double-blind, placebo-controlled study. Patients were randomized to take placebo or VSL#3®, 2 sachets/day in the morning for 3 months. VSL#3® and placebo were self-administered. Results: We did not observe any change in body mass index (BMI), circumferences, fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and adiponectin (ADN) with neither treatment. A statistically significant triglycerides (Tg) decrease (p < 0.05 vs. baseline, and p < 0.05 vs. placebo, respectively) and high-sensitivity C-reactive protein (Hs-CRP) decrease (p < 0.05 vs. baseline) was observed in the group of patients being treated with VSL#3® compared with placebo. Transaminases and gamma-glutamyltransferase (γ-GT) were significantly reduced in VSL#3® group (p < 0.05 vs. baseline and placebo, respectively) compared with the placebo group. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and hepatic steatosis index (HSI) were significantly lower than the VSL#3® group (p < 0.05 vs. baseline and placebo, respectively) compared with the placebo group. All patients reported an improvement or the disappearance of hepatic steatosis. Conclusion: Probiotic therapy with VSL#3® ameliorates hepatic parameters and echography grading, while reducing Tg and the inflammatory status, without any difference between men and women.

Cytokine production from peripheral blood mononuclear cells and polymorphonuclear leukocytes in patients studied for suspected obstructive sleep apnea.

PURPOSE: The relationship between obstructive sleep apnea (OSA) and atherosclerosis-related inflammation has been poorly investigated, particularly focusing on functional responses of immune cells playing a key role in atherogenesis and in comparison with control groups with similar cardiovascular risk factors which are known to be themselves associated with inflammation. We sought to determine cellular tumor necrosis factor-alpha (TNF-α) production from peripheral blood mononuclear cells (PBMCs) and interleukin (IL)-8 release from neutrophils (PMNs) in patients studied for suspected OSA. METHODS: Thirty-six consecutive patients who underwent a nocturnal complete cardiorespiratory evaluation for suspected OSA were initially evaluated. Serum, PBMCs, and PMNs were isolated (at baseline and after 12 weeks) from patients with apnea-ipopnea index (AHI) >20 (OSA group, n = 16) and from control patients with AHI <5 (nonOSA group, n = 11). All patients continued the same pharmacological therapy for 12 weeks; the OSA group was additionally treated with nocturnal continuous positive-airway-pressure ventilation (cPAP). RESULTS: The two groups had similar clinical characteristics (prevalence of hypertension, dyslipidemia, diabetes, and cardio-metabolic therapies) except for obesity. Resting and stimulated TNF-α production from PBMCs and IL-8 release from PMNs were similar in the two groups. Serum cytokines resulted within the normal range. In the OSA group, cPAP was not associated with changes in cellular responses. CONCLUSIONS: In patients showing similar prevalence of major cardiovascular risk factors and cardio-metabolic therapies, differing for the presence or absence of OSA, cytokine productions from PBMC and PMN were similar and were not modified during cPAP therapy. Studies designed to investigate OSA-associated inflammation should carefully match the control group subjects.

High-dose dexamethasone treatment for COVID-19 severe acute respiratory distress syndrome: a retrospective study.

Low-dose dexamethasone reduces mortality in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). We retrospectively analyzed the efficacy of high-dose dexamethasone in patients with COVID-19-related ARDS and evaluated factors affecting the composite outcome (death or invasive mechanical ventilation). From March 4th to April 1st 2020, 98 patients with COVID-19 pneumonia were included. Those who after at least 7 days from symptom onset presented a worsening of the respiratory function or of inflammatory biomarkers were started on intravenous high-dose dexamethasone (20 mg daily for 5 days, followed by 10 mg daily for 5 days). Most patients were males (62%) with a mean age of 69 years. Hypertension and cardiovascular disease (CVD) were prevalent. Following dexamethasone treatment, a significant improvement in PaO2/FiO2 (277.41 [178.5-374.8] mmHg vs. 146.75 [93.62-231.16] mmHg, p < 0.001), PaO2 (88.15 [76.62-112.0] mmHg vs. 65.65 [57.07-81.22] mmHg, p < 0.001), and SpO2 (96 [95-98]% vs. 94 [90-96]%, p < 0.001) was observed. A concomitant decrease in C-reactive protein and ferritin levels was found (132.25 [82.27-186.5] mg/L vs. 7.3 [3.3-24.2] mg/L and 1169 [665-2056] ng/mL vs. 874.0 [569.5-1434] ng/mL, respectively; p < 0.001 for both vs. baseline). CVD was found to increase the risk of the composite outcome (RR 7.64, 95% CI 1.24-47.06, p = 0.028). In hospitalized patients with COVID-19-related ARDS, high-dose dexamethasone rapidly improves the clinical status and decreases inflammatory biomarkers. CVD was found to increase the risk of the composite outcome. These data support the importance of randomized clinical trials with high-dose dexamethasone in COVID-19 patients.

Optical coherence tomography angiography and arterial hypertension: A role in identifying subclinical microvascular damage?

INTRODUCTION: To evaluate retinal microvasculature modifications by means of optical coherence tomography angiography in human subjects diagnosed with arterial hypertension and to assess potential clinical relevance for early diagnosis. METHODS: A cross-sectional study of 30 subjects affected by arterial hypertension compared to a matched cohort of healthy patients was conducted. Patients were evaluated by the Outpatient Clinic for Hypertension and the Retina Center, University of Insubria, Varese, Italy. Patients were divided into three groups: Group 1-healthy subjects, Group 2-patients first diagnosed with hypertension, and Group 3-patients with treated hypertension. Optical coherence tomography angiography was performed applying different analysis protocols for macula and optic disk, using an AngioVue OCTA System on an Optovue device. Morphological data were compared to and correlated with clinical vascular parameters, to evaluate preclinical microvascular damage. RESULTS: A significant reduction in deep vascular layer density (Group 1: 59.2% ± 1.5% standard deviation; Group 2: 59.2% ± 2.2% standard deviation; Group 3: 57.8% ± 2.6% standard deviation; p < 0.05) as well as an enlargement of the deep foveal avascular zone area (Group 1: 0.34 ± 0.09 mm2; Group 2: 0.36 ± 0.07 mm2; Group 3: 0.39 ± 0.1 mm2; p < 0.05) was measured in patients with first diagnosed hypertension and in treated patients compared to healthy subjects. We also observed a significant decrease in mean foveal choroidal thickness in affected patients compared to controls (Group 1: 319.68 ± 61.72 µm standard deviation; Group 2: 251.04 ± 63.1 µm standard deviation; Group 3: 262.65 ± 51.08 µm standard deviation; p < 0.05). Our preliminary data did not show a significant correlation with microalbuminuria levels. DISCUSSION: Retinal vascular density showed pathological modifications between healthy subjects and hypertensive patients. These preliminary findings suggest that optical coherence tomography angiography may identify pathological markers of an early hypertensive damage and help monitor disease progression with potential therapeutic advantages.

Right ventricular remodelling in mild hypertensive patients: role of left ventricular morpho-functional parameters.

Previous studies suggested that hypertensive patients with left ventricular (LV) hypertrophy display right ventricular (RV) remodelling. Few data are available about RV remodelling in naive hypertensives without severe cardiac organ damage. Our aim was to evaluate the relationship between RV and LV morpho-functional parameters in never-treated patients with grade 1 hypertension and whether central blood pressure (CBP), inflammatory and metabolic parameters are potentially associated with RV remodelling. 150 never-treated subjects without evidence of diabetes or other cardiovascular diseases were enrolled in our study. We recruited 100 patients with mild hypertension (twenty-four hours blood pressure (24 h BP) ≥ 130/80 mmHg) and 50 normotensive subjects matched for gender, age and body mass index. To estimate the LV/RV parameters, we performed echography as well as arterial tonometry to assess pulse wave analysis/velocity (PWA/PWV). We found 24 h BP, CBP and PWV were higher in hypertensive patients than in normotensives. In addition, LV mass index was higher in hypertensives, and greater RV free wall thickness was observed (5.3 ± 1.4 vs 4.6 ± 1.2 mm, P = 0.02). RV thickness correlated with interventricular septum (IVS), systolic CBP and RV E' (r = 0.50, P = 0.0001, r = 0.30, P = 0.003, r = -0.24, P = 0.015); linear regression analysis showed a correlation with only IVS (ß = 0.39, P = 0.001). RV E' was correlated with IVS, LV E' and systolic CBP (r = -0.35, P = 0.0001, r = 0.25, P = 0.012, r = -0.24, P = 0.019); the correlation with IVS and LV E' (ß = -0.310, P = 0.001; ß = 0.27, P = 0.004) was confirmed by linear regression analysis. Our study shows RV remodelling is mostly correlated with IVS thickness, supporting the ventricular interdependence hypothesis.

Effects of dual blockade of Renin-Angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a randomized, controlled pilot study.

BACKGROUND: The renin-angiotensin system (RAS) plays a major role in promoting left ventricular (LV) remodeling in essential hypertension. We designed a controlled, randomized pilot study aimed to test the hypothesis that the dual RAS blockade with angiotensin-converting enzyme (ACE) inhibitor (ACEi) + angiotensin II receptor blocker (ARB) can be more effective in decreasing LV hypertrophy and improving diastolic function than a largely employed association such as ACEi + calcium-antagonist (Ca-A). METHODS: Twenty-four never-treated hypertensive patients with LV concentric hypertrophy were randomized to ramipril + candesartan or ramipril + lercanidipine. Before and after the 6-month treatment they underwent a 24-h blood pressure (BP) monitoring and echocardiographic examination. RESULTS: At baseline, age, body mass index (BMI), 24-h BP, and LV morpho-functional parameters were similar between the two groups. The 6-month treatment induced in both groups a significant decrease of 24-h BP, septal and posterior wall thickness, and LV mass index (LVMi) (ACEi + ARB 155 +/- 19 to 122 +/- 17 g/m(2), P < 0.0001; ACEi + Ca-A 146 +/- 18 to 127 +/- 20 g/m(2), P < 0.0001). Systolic function remained unchanged; LV diastolic parameters increased significantly in both groups. The extent of 24-h BP decrease was similar between the two groups (-13.3/16.3% vs. -12.3/15.8%, P = 0.63/P = 0.71), whereas the decrease of LV mass (-22% vs. -12.8%, P < 0.005) and the improvement of diastolic function were greater in ACEi + ARB group. CONCLUSIONS: In comparison with ACEi + Ca-A, ACEi + ARB treatment showed a greater antiremodeling effect, that can be reasonably ascribed to a BP-independent effect of the dual RAS blockade.

Masked hypertension in type 2 diabetes mellitus. Relationship with left-ventricular structure and function.

BACKGROUND: To evaluate in type 2 diabetes mellitus the relationship between masked hypertension (MH) and left ventricular (LV) morpho-functional characteristics. METHODS: Using 24-hour BP monitoring and echocardiography, we evaluated 71 type 2 diabetic patients, without overt cardiac disease and never treated with antihypertensive drugs: 45 normotensive subjects with clinic BP <130/85 mmHg and 26 sustained hypertensives (SH)(clinic BP > or = 140 and/or 90 mmHg and 24-hour BP > or =125 and/or 80 mmHg), matched for age, gender, BMI and duration of diabetes with clinically normotensive patients. MH was diagnosed with clinic BP <130/85 mmHg and 24-hour BP > or =125 and/or 80 mmHg. RESULTS: Among clinically normotensive patients, 21 (47%) had MH and 24 were true normotensive (NT, 24-hour BP <125/80 mmHg). LV mass increased from NT to MH to SH (p < 0.001); the parameters of LV diastolic function were similar between MH and SH and significantly lower than in NT. CONCLUSION: In type 2 diabetic patients with clinic BP <130/85 mmHg, MH is frequent and is associated with LV remodelling characterized by increased myocardial mass and preclinical impairment of LV diastolic function; the remodelling is qualitatively and for some aspects also quantitatively similar to that found in sustained hypertensive patients. Therefore it would be useful to look for MH in diabetic subjects with clinic BP <130/85 mmHg, who, following the guidelines, are not entitled to antihypertensive treatment: the finding of MH could identify a subgroup of patients at higher cardiovascular risk and therefore needing a prompt antihypertensive treatment.

Family history of hypertension influences left ventricular diastolic function during chronic antihypertensive therapy.

BACKGROUND: Genetic factors play an important role in linking insulin resistance and hypertension, also influencing insulin sensitivity changes during antihypertensive treatment. This study was aimed to evaluate whether genetic predisposition to hypertension can also influence left ventricular (LV) changes during antihypertensive treatment. METHODS: We enrolled 36 never-treated hypertensives: 18 with both parents hypertensive (F+) and 18 with both parents normotensive (F-), matched for age, gender, and body mass index (BMI). The patients were evaluated twice, before and after 2.5 years of treatment with enalapril. At both evaluations the patients underwent: 24-h blood pressure (BP) monitoring, LV echocardiogram, and oral glucose tolerance test, with measurements of glucose and insulin levels. RESULTS: At basal evaluation the two groups were not different with regard to gender, age, BMI, 24-h BP, and fasting glucose; glucose metabolic clearance rate was significantly lower in F+. The LV mass index was similar between the groups, whereas diastolic parameters were significantly lower in F+. At second evaluation, 24-h BP and LV mass were decreased to the same extent in both groups; glucose metabolic clearance rate significantly increased in F- and remained unchanged in F+. The improvement of LV diastolic function, found in both group, was significantly greater in F-. CONCLUSIONS: Genetic predisposition to hypertension, in addition to affecting insulin sensitivity, influences LV functional changes during antihypertensive treatment. Despite a similar extent of 24-h BP and LV mass decrease, F+ patients showed no changes in insulin sensitivity and a smaller improvement in LV diastolic function than F-.

In vitro effects of Apixaban on 5 different cancer cell lines.

BACKGROUND: Cancer is associated with hypercoagulability. However, several data suggest that anticoagulant drugs may have an effect on tumor development and progression mediated by both coagulation dependent processes and non-coagulation dependent processes. Therefore, we investigated the in vitro effects of Apixaban on cell proliferation, mortality, cell migration, gene expression and matrix metalloproteinase in 5 different cancer cell lines. METHODS: The following cancer cell lines, and 2 normal fibroblast cultures (lung and dermal fibroblasts), were studied: OVCAR3 (ovarian cancer), MDA MB 231 (breast cancer), CaCO-2 (colon cancer), LNCaP (prostate cancer) and U937 (histiocytic lymphoma). Proliferation and cell mortality were assessed in control cells and Apixaban treated cultures (dose from 0.1 to 5 µg/ml, 0 to 96-h). Necrosis/Apoptosis (fluorescence microscopy), cell migration (24-h after scratch test), matrix metalloproteinase (MMP) activity and mRNA expression (RT PCR) of p16, p21, p53 and HAS were also assessed. RESULTS: High-dose (5 µg/ml) Apixaban incubation was associated with a significantly reduced proliferation in 3 cancer cell lines (OVCAR3, CaCO-2 and LNCaP) and with increased cancer cell mortality in all, except LNCaP, cancer lines. Apoptosis seems to account for the increased mortality. The migration capacity seems to be impaired after high-dose Apixaban incubation in OVCAR3 and CaCO-2 cells. Data on mRNA expression suggest a consistent increase in tumor suppression gene p16 in all cell lines. CONCLUSIONS: Our data suggest that high-dose Apixaban may be able to interfere with cancer cell in vitro, reducing proliferation and increasing cancer cell mortality through apoptosis in several cancer cell lines.

PCSK9 inhibitors for treating dyslipidemia in patients at different cardiovascular risk: a systematic review and a meta-analysis.

Statin-induced lowering of low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular morbidity and mortality, but many patients do not adequately reduce their LDL-C levels. Monoclonal antibodies targeting PCKS9 are currently in the advanced phase of development. We aimed to investigate the efficacy and safety of PCSK9 inhibitors in patients at different cardiovascular risk in a systematic review. Studies were searched on MEDLINE and EMBASE until January 2016. Differences in the outcomes among groups were expressed as mean differences, or pooled odds ratio (OR) and corresponding 95% confidence interval (CI), which were calculated using a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I 2 statistic. 22 RCTs and 8833 patients were included. Six studies were performed in patients affected by homozygous or heterozygous familial hypercholesterolemia, or with increased cardiovascular risk, two in patients with statin intolerance, three in statin-naïve patients, and 10 in patients unable to achieve LDL-C target with statin therapy. PCSK9 inhibitors were associated with a statistically significant reduction of LDL-C (mean = -48.8%; 95% CI -54.1, -43.4; I 2 = 94%) compared to control groups, and with a statistically significant reduction in death for any cause (OR = 0.34; 95% CI 0.17, 0.69; I 2 = 0) and a favorable trend for cardiovascular events (OR = 0.79; 95% CI 0.61, 1.02; I 2 = 0%). PCSK9 inhibitors reduce LDL-C concentration in every group explored. A significant reduction in death by all cause was observed in the PCSK9 inhibitors groups, compared with control groups, even in the short time frame studied.