Pathophysiology of Circulating Biomarkers and Relationship With Vascular Aging: A Review of the Literature From VascAgeNet Group on Circulating Biomarkers, European Cooperation in Science and Technology Action 18216.

Impairment of the arteries is a product of sustained exposure to various deleterious factors and progresses with time; a phenomenon inherent to vascular aging. Oxidative stress, inflammation, the accumulation of harmful agents in high cardiovascular risk conditions, changes to the extracellular matrix, and/or alterations of the epigenetic modification of molecules, are all vital pathophysiological processes proven to contribute to vascular aging, and also lead to changes in levels of associated circulating molecules. Many of these molecules are consequently recognized as markers of vascular impairment and accelerated vascular aging in clinical and research settings, however, for these molecules to be classified as biomarkers of vascular aging, further criteria must be met. In this paper, we conducted a scoping literature review identifying thirty of the most important, and eight less important, biomarkers of vascular aging. Herein, we overview a selection of the most important molecules connected with the above-mentioned pathological conditions and study their usefulness as circulating biomarkers of vascular aging.

Silicon photonics-based laser Doppler vibrometer array for carotid-femoral pulse wave velocity (PWV) measurement.

Pulse wave velocity (PWV) is a reference measure for aortic stiffness, itself an important biomarker of cardiovascular risk. To enable low-cost and easy-to-use PWV measurement devices that can be used in routine clinical practice, we have designed several handheld PWV sensors using miniaturized laser Doppler vibrometer (LDV) arrays in a silicon photonics platform. The LDV-based PWV sensor design and the signal processing protocol to obtain pulse transit time (PTT) and carotid-femoral PWV in a feasibility study in humans, are described in this paper. Compared with a commercial reference PWV measurement system, measuring arterial pressure waveforms by applanation tonometry, LDV-based displacement signals resulted in more complex signals. However, we have shown that it is possible to identify reliable fiducial points for PTT calculation using the maximum of the 2nd derivative algorithm in LDV-based signals, comparable to those obtained by the reference technique, applanation tonometry.

Vascular consequences of inflammation: a position statement from the ESH Working Group on Vascular Structure and Function and the ARTERY Society.

: Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue damage and an alteration of arterial structure and function. Increased arterial stiffness is a well recognized cardiovascular risk factor independent of blood pressure levels and an intermediate endpoint for cardiovascular events. In the present review, we discuss immune-mediated mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening. We also show that acute inflammation predisposes the vasculature to arterial dysfunction and stiffening, and alteration of endothelial function and that chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis are accompanied by profound arterial dysfunction which is proportional to the severity of inflammation. Current findings suggest that treatment of inflammation by targeted drugs leads to regression of arterial dysfunction. There is hope that these treatments will improve outcomes for patients.

First international consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD) which was commissioned by the Working Group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

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.

Relationship between wave reflection and renal damage in hypertensive patients: a retrospective analysis.

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.

Renal vasodilating capacity and endothelial function are impaired in patients with obstructive sleep apnea syndrome and no traditional cardiovascular risk factors.

OBJECTIVE: Patients with obstructive sleep apnea syndrome exhibit accelerated vascular aging and renal damage. Aim of the study was to investigate whether vascular dysfunction is a feature of obstructive sleep apnea syndrome per se or instead related to the presence of traditional cardiovascular risk factors. METHODS: Forty patients with moderate-severe obstructive sleep apnea syndrome (20 with, 20 without traditional risk factors) and 20 matched healthy controls were enrolled. Renal vasodilating capacity, endothelium-dependent vasodilation in the brachial artery, carotid-femoral pulse wave velocity and carotid stiffness were measured. Oxidative stress, endothelial biomarkers and leukocyte adhesion molecule levels were also evaluated. RESULTS: Apneic patients without traditional cardiovascular risk factors presented reduced endothelium-dependent vasodilation (3.7±2.1 versus 6.1±3.0%, P<0.05), increased serum E-selectin (49.8±11.5 versus 38.9±17.9 ng/ml, P<0.05), and impaired renal vasodilating capacity (6.0±4.3 versus 10.4±6.1%, P<0.05), as compared to healthy controls. Endothelial NO synthase expression was reduced (0.0133 versus 0.0221×10 copies/µg RNA, P<0.05), whereas oxidative stress parameters and leukocyte adhesion molecules were similar to controls. Patients with obstructive sleep apnea syndrome and traditional risk factors also exhibit increased aortic and carotid stiffness, increased renal resistive index and intima-media thickness, and reduced expression of the endothelial progenitor cell marker CD34: however, these parameters were similar to those of healthy controls in patients with isolated obstructive sleep apnea syndrome. CONCLUSION: Obstructive sleep apnea syndrome is characterized by endothelial dysfunction and activation and impaired renal vasodilating capacity even in the absence of traditional cardiovascular risk factors, possibly due to reduced endothelial NO synthase expression.

The eye and the heart.

The vasculature of the eye and the heart share several common characteristics. The easily accessible vessels of the eye are therefore-to some extent-a window to the heart. There is interplay between cardiovascular functions and risk factors and the occurrence and progression of many eye diseases. In particular, arteriovenous nipping, narrowing of retinal arteries, and the dilatation of retinal veins are important signs of increased cardiovascular risk. The pressure in the dilated veins is often markedly increased due to a dysregulation of venous outflow from the eye. Besides such morphological criteria, functional alterations might be even more relevant and may play an important role in future diagnostics. Via neurovascular coupling, flickering light dilates capillaries and small arterioles, thus inducing endothelium-dependent, flow-mediated dilation of larger retinal vessels. Risk factors for arteriosclerosis, such as dyslipidaemia, diabetes, or systemic hypertension, are also risk factors for eye diseases such as retinal arterial or retinal vein occlusions, cataracts, age-related macular degeneration, and increases in intraocular pressure (IOP). Functional alterations of blood flow are particularly relevant to the eye. The primary vascular dysregulation syndrome (PVD), which often includes systemic hypotension, is associated with disturbed autoregulation of ocular blood flow (OBF). Fluctuation of IOP on a high level or blood pressure on a low level leads to instable OBF and oxygen supply and therefore to oxidative stress, which is particularly involved in the pathogenesis of glaucomatous neuropathy. Vascular dysregulation also leads to a barrier dysfunction and thereby to small retinal haemorrhages.

Sympathetic regulation of vascular function in health and disease.

The sympathetic nervous system (SNS) is known to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular system. In the past decades increasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels. Evidence from experimental studies indicates that the SNS is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, such as nitric oxide (NO), reactive oxygen species (ROS), endothelin (ET), the renin-angiotensin system. Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SNS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute increase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects. However, direct evidence of a cause-effect relationship from human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. On the other hand, large artery stiffness can interfere with autonomic regulation by impairing carotid baroreflex sensitivity.

Effect of acute administration of vitamin C on muscle sympathetic activity, cardiac sympathovagal balance, and baroreflex sensitivity in hypertensive patients.

BACKGROUND: Essential hypertension is characterized by both increased oxidative stress and sympathetic traffic. Experimental studies have shown that reactive oxygen species can modulate autonomic activity. OBJECTIVE: The aim of this study was to determine whether acute administration of the antioxidant vitamin C modifies sympathetic nerve activity in essential hypertension. DESIGN: Thirty-two untreated patients with essential hypertension and 20 normotensive subjects received vitamin C (3 g intravenously in 5 min) or vehicle. Heart rate, noninvasive beat-to-beat blood pressure, and muscle sympathetic nerve activity (microneurography) were monitored at baseline and up to 20 min after the infusion. Spectral analysis of RR interval variability and spontaneous baroreflex sensitivity were also computed. RESULTS: Vitamin C infusion significantly lowered blood pressure in hypertensive patients but not in normotensive subjects (maximal changes in systolic blood pressure: -4.9 ± 10.1 compared with -0.7 ± 4.0 mm Hg, respectively; P < 0.05). Moreover, muscle sympathetic nerve activity was significantly reduced after vitamin C infusion in hypertensive patients (from 53.3 ± 12.2 to 47.4 ± 11.5 bursts/100 heart beats; P < 0.01) but not in healthy subjects (from 42.0 ± 10.1 to 42.7 ± 11.8 bursts/100 heart beats; NS). On the contrary, in 16 hypertensive patients, sodium nitroprusside in equidepressor doses induced a significant increase in muscle sympathetic nerve activity compared with vitamin C (+10.0 ± 6.9 bursts/100 heart beats). Sympathovagal balance and spontaneous baroreflex sensitivity were restored during vitamin C infusion in hypertensive subjects. CONCLUSIONS: These results indicate that acute administration of vitamin C is able to reduce cardiovascular adrenergic drive in hypertensive patients, which suggests that oxidative stress is involved in the regulation of sympathetic activity in essential hypertension.