Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels.

BACKGROUND: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. METHODS: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. RESULTS: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. CONCLUSIONS: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction.

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

Morbid obesity is associated with hypertrophic outward remodeling and increased stiffness of small conduit arteries: An ultra-high frequency ultrasound study.

BACKGROUND AND AIMS: Although many studies have been published on the effect of obesity on large and small arteries, there are no data in the literature regarding the effect of obesity on medium-sized arteries, and in particular of small conduit arteries. The aim of the present study was to investigate whether patients with severe obesity presented structural or functional alterations in different arterial segments. METHODS AND RESULTS: 34 patients with severe obesity (BMI≥35 kg/m2) and 34 age-and sex-matched normal weight patients were recruited as controls. Aortic stiffness (carotid-femoral pulse wave velocity) and wave reflection (augmentation index) were recorded. Ultrasound images of common carotid, radial and interdigital arteries were acquired for the assessment of wall-to-lumen ratio, wall cross-sectional area (WCSA), compliance, distensibility coefficient (DC) and Young's elastic modulus (Einc). Insulin sensitivity was calculated by oral glucose sensitivity index (OGIS). No differences between groups in carotid artery remodeling were found, while WCSA of the radial and interdigital arteries were higher in obese group than in controls. As regard the parameters of vascular elasticity, the DC of radial and interdigital arteries were lower (p = 0.025 and p = 0.001, respectively), as well as the Einc of radial arteries was higher (p = 0.021), in subject with obesity compared to controls. All these correlations were consistent after adjustment for the main covariates. Finally, in a multiple regression analysis OGIS was and independent determinant of interdigital artery DC (R2 = 0.29, p = 0.001). CONCLUSIONS: For the first time, we describe an outward remodeling and increased stiffness in small conduit arteries in severe obesity.

Subclinical cardiac damage in cancer patients before chemotherapy.

Cancer and cardiovascular diseases, including heart failure (HF), are the main causes of death in Western countries. Several anticancer drugs and radiotherapy have adverse effects on the cardiovascular system, promoting left ventricular dysfunction and ultimately HF. Nonetheless, the relationship between cancer and HF is likely not unidirectional. Indeed, cancer and HF share common risk factors, and both have a bidirectional relationship with systemic inflammation, metabolic disturbances, and neurohormonal and immune activation. Few studies have assessed the impact of untreated cancer on the heart. The presence of an active cancer has been associated with elevated cardiac biomarkers, an initial impairment of left ventricular structure and function, autonomic dysfunction, and reduced exercise tolerance. In turn, these conditions might increase the risk of cardiac damage from chemotherapy and radiotherapy. HF drugs such as beta-blockers or inhibitors of the renin-angiotensin-aldosterone system might exert a protective effect on the heart even before the start of cancer therapies. In this review, we recapitulate the evidence of cardiac involvement in cancer patients naïve from chemotherapy and radiotherapy and no history of cardiac disease. We also focus on the perspectives for an early diagnosis and treatment to prevent the progression to cardiac dysfunction and clinical HF, and the potential benefits of cardioactive drugs on cancer progression.

Prognostic value of 24-hour ambulatory blood pressure patterns in diabetes: A 21-year longitudinal study.

AIMS: To establish the long-term prognostic value of abnormal circadian blood pressure (BP) patterns in diabetes. MATERIALS AND METHODS: We retrospectively examined a cohort of 349 outpatients with diabetes who were screened for microvascular complications and followed up for 21 years. Dipping, nondipping and reverse-dipping status were defined based on 24-hour ambulatory BP monitoring (ABPM) as ≥10% reduction, <10% reduction, and any increase in average nighttime versus daytime systolic BP (SBP), respectively. RESULTS: After 6251 person-years of follow-up (median [range] follow-up 21.0 [1.1-22.0] years, 52% women, age 57.1 ± 11.9 years, 81.4% type 2 diabetes and 18.6% type 1 diabetes), a total of 136 deaths (39%) occurred. Compared with dippers, the nondippers and reverse dippers showed progressively higher prevalence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN) and postural hypotension. Reverse dippers showed a 13.4% (2.5-year) reduction in mean overall survival and a twofold increased risk of all-cause mortality after adjustment for traditional risk factors (hazard ratio 2.2 [95% confidence interval 1.3-3.8]). Each 1% decrease in nighttime versus daytime SBP ratio was independently associated with a 4% reduction in 20-year mortality risk. CONCLUSIONS: In patients with diabetes, reverse dipping is associated with a higher prevalence of CKD and CAN and more than doubled the adjusted risk of all-cause mortality over a 21-year observation.

Glomerular hyperfiltration in morbid obesity: Role of the inflammasome signalling.

AIM: Obesity is associated with glomerular hyperfiltration which may precede the development of overt renal damage. Few studies evaluated the link between inflammasome signalling and hyperfiltration. The aim is to evaluate the relationship between IL1-ß/Caspase-1, insulin sensitivity and hyperfiltration in subjects with severe obesity, before and after weight loss. METHODS: Forty-six patients with BMI > 35 kg/m2 , without type-2-diabetes or hypertension, were evaluated at baseline and 6 months after bariatric surgery with oral glucose tollerance test, bioimpedance analysis and blood tests. The eGFR was calculated according to EPIcr-cys formula and insulin sensitivity by Oral Glucose Insulin Sensitivity. IL-1ß/Caspase-1 were measured with the ELISA-kit. HF was defined as eGFR ≥ 140 ml/min (non-indexed for BSA). RESULTS: Sixteen subjects at baseline had hyperfiltration, with a higher insulin resistance, BMI, lean mass and plasma levels of IL-1ß/Caspase-1. After surgery, there was a reduction in BMI and improvement in insulin resistance in all patients. However, in 8 of 16 patients hyperfiltration persisted and IL-1ß/Caspase-1 levels did not decrease (3.22 ± 0.79 vs. 3.13 ± 1.03 and 23.7 ± 12.1 vs. 20.6 ± 9.1, pre vs. post, pg/ml), while cytokines normalized in all the other patients in parallel with the eGFR. In a logistic regression model, correcting for the main covariates, lean mass and IL-1ß before surgery (p = .01 and p = .03, respectively), were the only predictors of hyperfiltration. CONCLUSION: Weight loss is effective in reducing hyperfiltration in most, but not all patients. Hyperfiltration remains unchanged in subjects who do not have a reduction in IL-1ß/Caspase-1, suggesting a pathogenetic role of the inflammasome signalling in the early stages of nephropathy.

Assessment and pathophysiology of microvascular disease: recent progress and clinical implications.

The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

Microvascular Ageing Links Metabolic Disease to Age-Related Disorders: The Role of Oxidative Stress and Inflammation in Promoting Microvascular Dysfunction.

ABSTRACT: Longer life span and increased prevalence of chronic, noncommunicable, inflammatory diseases fuel cardiovascular mortality. The microcirculation is central in the cross talk between ageing, inflammation, cardiovascular, and metabolic diseases. Microvascular dysfunction, characterized by alteration in the microvascular endothelial function and wall structure, is described in an increasing number of chronic age-associated diseases, suggesting that it might be a marker of ageing superior to chronological age. The aim of this review is to thoroughly explore the connections between microvascular dysfunction, ageing, and metabolic disorders by detailing the major role played by inflammation and oxidative stress in their evolution. Older age, hypertension, nutrient abundance, and hyperglycemia concur in the induction of a persistent low-grade inflammatory response, defined as meta-inflammation or inflammageing. This increases the local generation of reactive oxygen species that further impairs endothelial function and amplifies the local inflammatory response. Mitochondrial dysfunction is a hallmark of many age-related diseases. The alterations of mitochondrial function promote irreversible modification in microvascular structure. The interest in the hypothesis of chronic inflammation at the center of the ageing process lies in its therapeutic implications. Inhibition of specific inflammatory pathways has been shown to lower the risk of many age-related diseases, including cardiovascular disease. However, the whole architecture of the inflammatory response underpinning the ageing process and its impact on the burden of age-related diseases remain to be fully elucidated. Additional studies are needed to unravel the connection between these biological pathways and to address their therapeutic power in terms of cardiovascular prevention.

Association between myocardial work and functional capacity in patients with arterial hypertension: an echocardiographic study.

PURPOSE: The aim of this study was to examine myocardial performance using pressure-strain loops in hypertensive patients with different level of blood pressure control. MATERIAL AND METHODS: This cross-sectional study included 204 subjects (45 controls, 70 patients with well-controlled hypertension, 58 patients with uncontrolled hypertension and 31 patients with resistant hypertension) who underwent complete two-dimensional echocardiographic examination including two-dimensional speckle-tracking echocardiography. Pressure-strain curve was used to determine global myocardial work, constructive work, wasted work and work efficiency in all study participants. RESULTS: Left ventricular (LV) longitudinal strain gradually reduced from controls throughout well-controlled hypertensive patients, to patients with uncontrolled and resistant hypertension. Global myocardial work was higher in patients with uncontrolled and resistant hypertension than in controls and well-controlled hypertension. Constructive work was also higher in all hypertensive patients than in controls. Global wasted work and work efficiency were similar between different groups. Global myocardial work index was associated with peak oxygen consumption independently of sex, age, body mass index (BMI), LV structural and functional parameters in all hypertensive participants. CONCLUSIONS: Myocardial work was significantly deteriorated in patients with uncontrolled and resistant arterial hypertension compared to controls and well-controlled hypertensive patients. Global myocardial work was associated with functional capacity independent of clinical and echocardiographic parameters.

The renin-angiotensin-aldosterone system: a crossroad from arterial hypertension to heart failure.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis, promoting critical structural changes in every component of the cardiovascular system, including the heart and blood vessels. Consequently, the RAAS is a crucial therapeutic target for several chronic diseases of the cardiovascular system, spanning from arterial hypertension (AH) to heart failure (HF). AH represents a leading risk factor for the development of symptomatic HF, particularly with left ventricle (LV) preserved ejection fraction (HFpEF). LV diastolic dysfunction and cardiac remodelling are the first discernible manifestations of heart disease in patients with AH. Typically, AH develops many years before the diagnosis of overt HF, providing a therapeutic target for preventive strategies. Treatment of AH is based on different classes of antihypertensive drugs, which show differences in their capacity to prevent the evolution towards HF. The blockers of the RAAS are effective drugs to treat AH and prevent HF with reduced ejection fraction (HFrEF), but the evidence of the potential benefits in patients with HFpEF remains limited. In this review, the authors summarise data from several clinical trials of HFpEF and HFrEF, focusing on the mechanisms leading the transition from AH to HF and late complications.

Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity.

Aims: Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc contributes to obesity-related vascular disease. Methods and results: ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change, -6.9, P < 0.01), demethylase JMJD2C (fold change, 3.2, P < 0.01), and acetyltransferase SRC-1 (fold change, 5.8, P < 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (LepOb/Ob) suppressed p66Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66Shc transcription. Conclusion: These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Association between blood pressure variability, cardiovascular disease and mortality in type 2 diabetes: A systematic review and meta-analysis.

AIM: To investigate the associations of blood pressure variability (BPV), expressed as long-term (visit-to-visit) and short-term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all-cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension-mediated organ damage (HMOD) in adult patients with type 2 diabetes. MATERIALS AND METHODS: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit-to-visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all-cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta-analysis and meta-regression. RESULTS: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all-cause mortality (HR 1.12, 95% CI 1.04-1.21), MACEs (HR 1.01, 95% CI 1.04-1.17), extended MACEs (HR 1.07, 95% CI 1.03-1.11) and MiCs (HR 1. 12, 95% CI 1.01-1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long-term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima-media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. CONCLUSIONS: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes.

Microvascular Endothelial Dysfunction in Patients with Obesity.

PURPOSE OF REVIEW: To examine the state of the art on the pathogenesis of endothelial dysfunction in the microcirculation of patients with obesity, focusing on the complex relationship between the consolidated and the novel mechanisms involved in this alteration. RECENT FINDINGS: Human obesity is associated with vascular endothelial dysfunction, caused by a reduced nitric oxide availability secondary to an enhanced oxidative stress production. Pro-inflammatory cytokine generation, secreted by perivascular adipose tissue, is a major mechanism whereby obesity is associated with a reduced vascular NO availability. Vasculature also represents a source of low-grade inflammation and oxidative stress which contribute to endothelial dysfunction in obese patients. Recently, a direct influence of arginase on endothelial function by reducing nitric oxide availability was demonstrated in small vessels from patients with severe obesity. This effect is modulated by ageing and related to the high levels of vascular oxidative stress. Oxidative stress, inflammation, and enzymatic pathways are important players in the pathophysiology of obesity-related vascular disease. The identification of new therapeutic approaches able to interfere with these mechanisms will result in more effective prevention of the cardiovascular complications associated with obesity.

Aging Modulates the Influence of Arginase on Endothelial Dysfunction in Obesity.

Objective- Arginase can reduce NO availability. In this study, we explored arginase as a determinant of endothelial dysfunction in small arteries from obese patients and its relationship with aging and microvascular remodeling. Approach and Results- Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under L-NAME ( N G-nitro-L-arginine-methyl ester), N(ω)-hydroxy-nor-l-arginine (arginase inhibitor) and gp91ds-tat (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase inhibitor) in vessels from young (age <30 years) control and obese and old (>30 years) control and obese subjects. Media-lumen ratio and amount of vascular wall fibrosis were used as markers of vascular remodeling. Amount of vascular superoxide anions and NO production were determined with immunofluorescence, whereas arginase expression was quantified using Western blot and quantitative polymerase chain reaction. Obese and older age groups had lower vascular NO, as well as higher media-lumen ratio, wall fibrosis, intravascular superoxide, and blunted inhibitory effect of L-NAME on acetylcholine versus controls and younger age groups. N(ω)-hydroxy-nor-l-arginine restored the acetylcholine-induced vasodilation in young and, to a lesser extent, in old obese subjects. This effect was abolished by addition of L-NAME. Gp91ds-tat increased the vasodilatory response to N(ω)-hydroxy-nor-l-arginine in old obese. Superoxide anions and arginase I/II levels were higher in the vascular wall of obese versus controls. Conclusions- Arginase contributes to microvascular endothelial dysfunction in obesity. Its impact is reduced by aging because of higher levels of vascular oxidative stress. Obesity is accompanied by accelerated microvascular remodeling, the extent of which is related to the amount of arginase in the vascular wall.

Olfactory evaluation in Mild Cognitive Impairment: correlation with neurocognitive performance and endothelial function.

Mild Cognitive Impairment (MCI) is an intermediate condition between normal aging and dementia, associated with an increased risk of progression into the latter within months or years. Olfactory impairment, a well-known biomarker for neurodegeneration, might be present in the condition early, possibly representing a signal for future pathological onset. Our study aimed at evaluating olfactory function in MCI and healthy controls in relation to neurocognitive performance and endothelial function. A total of 85 individuals with MCI and 41 healthy controls, matched for age and gender, were recruited. Olfactory function was assessed by Sniffin' Sticks Extended Test (Burghart, Medizintechnik, GmbH, Wedel, Germany). A comprehensive neurocognitive assessment was performed. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery by ultrasound. MCI individuals showed an impaired olfactory function compared to controls. The overall olfactory score is able to predict MCI with a good sensitivity and specificity (70.3 and 77.4% respectively). In MCI, olfactory identification score is correlated with a number of neurocognitive abilities, including overall cognitive status, dementia rating, immediate and delayed memory, visuospatial ability and verbal fluency. FMD was reduced in MCI (2.90 ± 2.15 vs. 3.66 ± 1.96%, P = 0.016) and was positively associated with olfactory identification score (ρs =0.219, P = 0.025). The association remained significant after controlling for age, gender, and smoking. In conclusion, olfactory evaluation is able to discriminate between MCI and healthy individuals. Systemic vascular dysfunction might be involved, at least indirectly, in olfactory dysfunction in MCI.

Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms. METHODS: Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used. RESULTS: Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals. CONCLUSIONS: An acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction.