Endothelial dysfunction in hypertension: pathophysiological mechanism or marker of cardiovascular risk?

Introduction Vascular endothelial production of nitric oxide (NO) plays an important role in the modulation of vessel tone and structure, protecting the vascular wall from atherosclerosis. In pathological conditions, however, the endothelium also produces pro-atherogenic substances (mainly reactive oxygen species), which inactivate NO. The Endothelial dysfunction, induced by reduced NO availability, is known to contribute to the development and progression of vascular damage. For this reason, endothelial function has been a major focus of cardiovascular research in the last few decades. Because NO has a very short half-life and its in vivo measurement is difficult, many researchers prefer to measure its biological activity, particularly the NO-dependent vasodilation, at the level of the coronary and peripheral circulation by endothelial stimuli. The most widely used technique involves measurement of brachial artery flow-mediated dilation. This test allows non-invasive evaluation of endothelium-dependent vasodilation in the peripheral macrocirculation induced by a mechanical stimulus (increase in shear stress caused by 5 minutes of forearm ischemia). The vasodilatatory response is reduced in the presence of major cardiovascular risk factors, particularly essential hypertension. Conclusions Studies conducted mainly in high-risk patients have demonstrated that endothelial dysfunction within the coronary or peripheral circulation is predictive of cardiovascular events (independently of classical risk factors). Drug therapy can improve endothelial function by increasing the availability of NO (a possible adjunctive benefit in terms of preventing vascular damage and improving the prognosis). Future studies will establish whether the evaluation of endothelial function by non-invasive, standardized, reproducible, low-cost techniques is an important test for cardiovascular risk stratification in clinical practice

Adipocytokine levels mark endothelial function in normotensive individuals

BACKGROUND: Endothelial dysfunction is an independent risk factor for cardiovascular events. Inflammatory mediators released by the adipose tissue can lead to local insulin resistance and endothelial dysfunction. This study addressed the relationship of adipocytokines with endothelial function and blood pressure. METHODS: In 92 newly diagnosed, drug-naïve essential hypertensive patients (HT, mean age 49 yrs) without organ damage and 66 normotensive subjects (NT, mean age 47 yrs), by an automated system, we measured endothelium-dependent and -independent vasodilation as brachial artery flow-mediated dilation before and after administration of glyceryl-trinitrate. Retinol binding protein-4 (RBP4) and resistin levels were determined by ELISA and RIA, respectively. Oxidative stress was evaluated by measuring serum malondyaldehyde (MDA). RESULTS: Flow-mediated dilation was significantly (p = 0.03) lower in HT (5.3 ± 2.6%) than NT (6.1 ± 3.1%), while response to glyceryl-trinitrate (7.5 ± 3.7% vs 7.9 ± 3.4%) was similar. RBP4 (60.6 ± 25.1 vs 61.3 ± 25.9 μg/ml), resistin (18.8 ± 5.3 vs 19.9 ± 6.1 ng/ml) and MDA levels (2.39 ± 1.26 vs 2.08 ± 1.17 nmol/ml) were not different in HT and NT. RBP4 (r = −0.25; p = 0.04) and resistin levels (r = −0.29; p = 0.03) were related to flow-mediated dilation in NT, but not in HT (r = −0.03 and r = −0.10, respectively). In NT, multivariate analysis including RBP4 and confounders showed that only BMI or waist circumference remained related to flow- mediated dilation. In the multivariate model including resistin and confounders, BMI, age and resistin were significantly related to flow-mediated dilation, while only age significant correlated with this parameter when BMI was replaced by waist circumference. CONCLUSIONS: Adipocytokine levels may be independent predictors of endothelial dysfunction in the peripheral circulation of healthy subjects, providing a pathophysiological link between inflammation from adipose tissue and early vascular alterations

la disfunzione endoteliale nell ipertensione arteriosa meccanismo fisiopatologico o marcatore di rischio cardiovascolare

Summary Introduction Vascular endothelial production of nitric oxide (NO) plays an important role in the modulation of vessel tone and structure, protecting the vascular wall from atherosclerosis. In pathological conditions, however, the endothelium also produces pro-atherogenic substances (mainly reactive oxygen species), which inactivate NO. The Endothelial dysfunction, induced by reduced NO availability, is known to contribute to the development and progression of vascular damage. For this reason, endothelial function has been a major focus of cardiovascular research in the last few decades. Because NO has a very short half-life and its in vivo measurement is difficult, many researchers prefer to measure its biological activity, particularly the NO-dependent vasodilation, at the level of the coronary and peripheral circulation by endothelial stimuli. The most widely used technique involves measurement of brachial artery flow-mediated dilation. This test allows non-invasive evaluation of endothelium-dependent vasodilation in the peripheral macrocirculation induced by a mechanical stimulus (increase in shear stress caused by 5 minutes of forearm ischemia). The vasodilatatory response is reduced in the presence of major cardiovascular risk factors, particularly essential hypertension. Conclusions Studies conducted mainly in high-risk patients have demonstrated that endothelial dysfunction within the coronary or peripheral circulation is predictive of cardiovascular events (independently of classical risk factors). Drug therapy can improve endothelial function by increasing the availability of NO (a possible adjunctive benefit in terms of preventing vascular damage and improving the prognosis). Future studies will establish whether the evaluation of endothelial function by non-invasive, standardized, reproducible, low-cost techniques is an important test for cardiovascular risk stratification in clinical practice

Case report: Novel FHR2 variants in atypical Hemolytic Uremic Syndrome: A case study of a translational medicine approach in renal transplantation

Atypical hemolytic–uremic syndrome (aHUS) is a severe thrombotic microangiopathy in which kidney involvement is common. aHUS can be due to either genetic or acquired abnormalities, with most abnormalities affecting the alternative complement pathway. Several genetic factors/alterations can drive the clinical presentation, therapeutic response, and risk of recurrence, especially recurrence following kidney transplantation. We report here the case of a 22-year-old man who developed a severe form of aHUS. Renal biopsy revealed thrombotic microangiopathy and features of chronic renal damage. Despite two eculizumab infusions, the patient remained dialysis dependent. Two novel rare variants, c.109G>A (p.E37K) and c.159 C>A (p.Y53*), were identified in the factor H-related 2 ( FHR2 ) gene, and western blot analysis revealed a significant reduction in the level of FHR2 protein in the patient’s serum. Although FHR2 involvement in complement 3 glomerulopathy has been reported previously, a role for FRH2 as a complement modulator has not yet been definitively shown. In addition, no cases of aHUS in individuals with FHR2 variants have been reported. Given the role of FHRs in the complement system and the fact that this patient was a candidate for a kidney transplant, we studied the relevance of low FHR2 plasma levels through a set of functional in vitro assays. The aim of our work was to determine if low FHR2 plasma levels could influence complement control at the endothelial surface with a view to identifying a therapeutic approach tailored to this specific patient. Interestingly, we observed that low FHR2 levels in the patient’s serum could induce complement activation, as well as C5b–9 deposition on human endothelial cells, and affected cell morphology. As C5b–9 deposition is a prerequisite for endothelial cell damage, these results suggest that extremely low FHR2 plasma levels increase the risk of aHUS. Given their ability to reduce C5b–9 deposition, recombinant FHR2 and eculizumab were tested in vitro and found to inhibit hemolysis and endothelial cell surface damage. Both molecules showed effective and comparable profiles. Based on these results, the patient underwent a kidney transplant, and received eculizumab as induction and maintenance therapy. Five years after transplantation, the patient remains in good general health, with stable graft function and no evidence of disease recurrence. To our knowledge, this is first reported case of an aHUS patient carrying FHR2 mutations and provides an example of a translational therapeutic approach in kidney transplantation

Performances in cerebellar and neuromuscular transmission tests are correlated in migraine with aura

In previous studies, we described subclinical abnormalities of neuromuscular transmission and cerebellar functions in migraineurs. The aim of this study was to search if these two functions are correlated in the same patient. Thirteen migraineurs [five without aura (MO) and eight with aura (MA)] underwent both stimulation-SFEMG and 3D-movement analysis. Single fiber EMG (SFEMG) results were expressed as the “mean value of consecutive differences” (mean MCD). Precision of arm-reaching movements (measured with an infrared optoelectronic tracking system) was expressed as the average deviation in the horizontal plane. Median values of mean MCD and mean horizontal deviation were not different between MO and MA. However, in MA, but not in MO, both variables were positively correlated. Thus, we conclude that neuromuscular transmission and cerebellar functions are correlated in the same patient when affected by migraine with aura. We suggest that this correlation might be due to a common molecular abnormality

Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65-89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects

Relazione fra rigidita arteriosa, riflessioni dell'onda sfigmica e danno vascolare renale nei pazienti ipertesi

La rigidità arteriosa espone la microcircolazione a pulsatilità aumentata. La riflessione dell’onda sfigmica potrebbe avere effetto protettivo, riducendo la pulsatilità trasmessa a distretti vascolari a bassa resistenza come quello cerebrale o quello renale. Nel presente studio si è indagata l’ipotesi nel rene, esaminando la relazione fra riflessioni dell’onda e indici di resistenza. Abbiamo ricercato nei nostri database gli ipertesi sottoposti a misurazioni tonometriche e doppler renale nella stessa sessione. L’Augmentation Index (AIx) e la Pulse Wave Velocity (PWV), indici rispettivamente di riflessione d’onda e rigidità arteriosa, sono stati misurati con l’apparecchio SphygmoCor; dalla forma d’onda, tramite un modello di approssimazione del flusso aortico, è possibile calcolare il coefficiente di riflessione (Reflection Magnitude, RM), come rapporto fra onda retrograda e anterograda. L’indice di resistenza renale (RI), una misura di danno vascolare, è stato misurato nelle arterie interlobari mediante Doppler. Sono stati analizzati 216 pazienti, prevalentemente maschi (63%), età 53,3 ± 11,5 anni, RI 0,632 ± 0,066; AIx, 27,5 ± 11,1%; PWV, 8,52 ± 1,81 m/s; RM, 64,2 ± 12,7 %. RI è risultato associato positivamente con AIx (r=0,32, p<0,0001), RM (r=0,29, p<0,001) e PWV (r=0,44, p<0,0001). Né AIx, né RM hanno correlazione negativa con RI in modelli che includono fattori di confondimento e covariate. Quando i pazienti sono stati divisi in terzili di AIx e PWV, non sono risultate differenze di RI fra quelli con basso AIx e alta PWV e quelli con alto AIx e bassa PWV (n=17 vs. 25; 0,645 ± 0,053 vs. 0,632 ± 0,064; p=ns), nonostante una differenza di RM (74,9 ± 6,7 vs. 51,2 ± 7,3 %; p<0,001). La riflessione d’onda, stimata tramite AIx o misurata come RM, è correlata positivamente con RI in una popolazione di ipertesi. Non si evidenzia una correlazione negativa neanche correggendo per fattori confondenti, o quando è esaminata separatamente dall’influenza della rigidità arteriosa. Nel complesso, questi risultati suggeriscono che la riflessione d’onda non ha un effetto benefico significativo sul danno vascolare renale negli ipertesi

Cardiovascular effects of arsenic: clinical and epidemiological findings

Several population studies relate exposure to high levels of arsenic with an increased incidence of ischemic heart disease and cardiovascular mortality. An association has been shown between exposure to high levels of arsenic and cardiovascular risk factors such as hypertension and diabetes mellitus, and vascular damage such as subclinical carotid atherosclerosis. The mechanisms underlying these phenomena are currently being studied and appear to indicate an alteration of vascular function. However, the effects of low levels of exposure to arsenic and their potential detrimental cardiovascular effect are less explored. The article provides an overview of the pathophysiologic mechanisms linking low-level arsenic exposure to the occurrence of cardiovascular disease and its complications, and some potential preventive strategies to implement

Relationship between wave reflection and renal damage in hypertensive patients

OBJECTIVE: Arterial stiffening has harmful effects; peripheral pulse wave reflections deleteriously increase central pressure, but on the contrary they could also possibly be protective, as the pulse is transmitted to the microcirculation to a lesser extent. The aim of this study was, therefore, to explore the relationship between wave reflection and small vessel damage in the kidney. METHODS: In 216 hypertensive patients, data on renal resistive index, obtained by Doppler ultrasound sampling of the interlobar arteries, as well as augmentation index (AIx) and carotid-to-femoral pulse wave velocity (PWV), were retrospectively analyzed. Reflection magnitude was computed through a triangular flow estimate. RESULTS: AIx and reflection magnitude were positively correlated with resistive index; age, BMI, central pulse pressure, and cholesterol, but not AIx or reflection magnitude, were predictors of resistive index in multivariate analyses. Crossing tertiles of PWV and AIx, resistive index did not differ between patients with high AIx and low PWV (n=25; 0.632 (0.064)) and those with low AIx and high PWV (n=17; 0.645 (0.053)), despite a difference in reflection magnitude (74.9 (6.7) vs. 51.2 (7.3)%; P<0.001). CONCLUSION: Pressure wave reflection is positively correlated with resistive index in a hypertensive population. No negative relationship was found even adjusting for confounders or when it was examined separately from the influence of arterial stiffness. These findings do not support the hypothesis of peripheral wave reflections having a significant protective role for the microcirculation of a low resistance vascular bed such as the kidney