A potential role of autophagy-mediated vascular senescence in the pathophysiology of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is one of the most complex and most prevalent cardiometabolic diseases in aging population. Age, obesity, diabetes, and hypertension are the main comorbidities of HFpEF. Microvascular dysfunction and vascular remodeling play a major role in its development. Among the many mechanisms involved in this process, vascular stiffening has been described as one the most prevalent during HFpEF, leading to ventricular-vascular uncoupling and mismatches in aged HFpEF patients. Aged blood vessels display an increased number of senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). This is consistent with the fact that EC and cardiomyocyte cell senescence has been reported during HFpEF. Autophagy plays a major role in VSMCs physiology, regulating phenotypic switch between contractile and synthetic phenotypes. It has also been described that autophagy can regulate arterial stiffening and EC and VSMC senescence. Many studies now support the notion that targeting autophagy would help with the treatment of many cardiovascular and metabolic diseases. In this review, we discuss the mechanisms involved in autophagy-mediated vascular senescence and whether this could be a driver in the development and progression of HFpEF.

Vascular Aging in Rodent Models: Contrasting Mechanisms Driving the Female and Male Vascular Senescence.

Increasing scientific interest has been directed to sex as a biological and decisive factor on several diseases. Several different mechanisms orchestrate vascular function, as well as vascular dysfunction in cardiovascular and metabolic diseases in males and females. Certain vascular sex differences are present throughout life, while others are more evident before the menopause, suggesting two important and correlated drivers: genetic and hormonal factors. With the increasing life expectancy and aging population, studies on aging-related diseases and aging-related physiological changes have steeply grown and, with them, the use of aging animal models. Mouse and rat models of aging, the most studied laboratory animals in aging research, exhibit sex differences in many systems and physiological functions, as well as sex differences in the aging process and aging-associated cardiovascular changes. In the present review, we introduce the most common aging and senescence-accelerated animal models and emphasize that sex is a biological variable that should be considered in aging studies. Sex differences in the cardiovascular system, with a focus on sex differences in aging-associated vascular alterations (endothelial dysfunction, remodeling and oxidative and inflammatory processes) in these animal models are reviewed and discussed.

Birth Weight and Weight Changes from Infancy to Early Childhood as Predictors of Body Mass Index in Adolescence.

OBJECTIVE: To assess the time point during infancy and early childhood at which greater than expected weight gain is associated with overweight in adolescence. STUDY DESIGN: Current height, weight, and body mass index (BMI) were assessed in 1520 adolescents (mean age of boys, 15.52 ± 0.84 years; mean age of girls, 15.37 ± 0.77 years). Information on weight and height trajectories during infancy and early childhood (birth and 6 other time points) was extracted from mother-child booklets. Conditional relative weights were computed to estimate greater or lower than expected weight gain (ie, soft tissue gain at a specific age independent of linear growth), and their association with BMI in adolescence was investigated using linear regression analysis. RESULTS: The mean BMI in adolescence was 21.77 ± 3.69 in boys and 21.70 ± 3.50 in girls. The proportion of overweight was 14.8% in each group. Overweight adolescents had significantly higher weight z-scores at birth, 1.2 month, 3.3 months, 7.6 months, 1 year, 2 years, and 4 years of age as compared with normal-weight adolescents. There were significant positive associations of weight z-scores and conditional relative weights with adolescent BMI at all ages except birth, which were strongest after the first year of life. In a majority of overweight adolescents, overweight had manifested within the first 4 years of life. CONCLUSIONS: Greater than expected weigh gain at any time in the first years of life is associated with an increased BMI in adolescence. The effect is strongest after the first year.

Premature Vascular Aging in Guinea Pigs Affected by Fetal Growth Restriction.

Cardiovascular risk associated with fetal growth restriction (FGR) could result from an early impaired vascular function. However, whether this effect results in premature vascular aging has not been addressed. We studied the ex vivo reactivity of carotid and femoral arteries in fetal (near term), adults (eight months-old) and aged (16 months-old) guinea pigs in normal (control) and FGR offspring. Additionally, an epigenetic marker of vascular aging (i.e., LINE-1 DNA methylation) was evaluated in human umbilical artery endothelial cells (HUAEC) from control and FGR subjects. Control guinea pig arteries showed an increased contractile response (KCl-induced) and a progressive impairment of NO-mediated relaxing responses as animals get older. FGR was associated with an initial preserved carotid artery reactivity as well as a later significant impairment in NO-mediated responses. Femoral arteries from FGR fetuses showed an increased contractility but a decreased relaxing response compared with control fetuses, and both responses were impaired in FGR-adults. Finally, FGR-HUAEC showed decreased LINE-1 DNA methylation compared with control-HUAEC. These data suggest that the aging of vascular function occurs by changes in NO-mediated responses, with limited alterations in contractile capacity. Further, these effects are accelerated and imposed at early stages of development in subjects exposed to a suboptimal intrauterine environment.

The Impact of Being Born Preterm or Small for Gestational Age on Early Vascular Aging in Adolescents.

OBJECTIVE: To assess the impact of being born preterm or small for gestational age (SGA) on early vascular aging (EVA) in a cohort of healthy Tyrolean adolescents. STUDY DESIGN: This study is part of an ongoing clinical trial, EVA Tyrol, a regional cohort study being conducted in western Austria. EVA was assessed in adolescents (mean age, 16 years) by means of carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (cIMT), and blood pressure measurements. Adolescents were grouped as either term or preterm. Subsequently, being born SGA was taken into consideration in subgroup analysis. Complete data on gestational age and birth weight were available for 930 adolescents. RESULTS: Systolic blood pressure and diastolic blood pressure were significantly higher in the preterm (mean gestational age, 34.8 ± 2.3 weeks) and appropriate for gestational age (AGA) group than in the term and AGA group (P < .05). This finding remained significant in linear regression analysis after adjustment for covariables in all models. PWV was significantly higher in the term-SGA group than in the term-AGA group (6.67 ± 1.73 m/s vs 6.07 ± 1.09 m/s; P < .05). In the linear regression analysis, this finding remained significant in all models. There were no differences in cIMT between study groups. CONCLUSION: Being born preterm or SGA might render persons susceptible to EVA. Long-term follow-up of preterm and SGA individuals is warranted to confirm these results.

Effects of Nutrients and Exercises to Attenuate Oxidative Stress and Prevent Cardiovascular Disease.

BACKGROUND: In recent years, it has become more evident that oxidative stress is involved in the development of cardiovascular disease. Indeed, reactive oxygen species seems to be the common mechanism for endothelial dysfunction, vascular inflammation and arterial stiffness, resulting in a blood pressure increase and early vascular aging. METHODS: This review presents the potential role of antioxidant nutrients and exercise for cardiovascular protection. RESULTS: Flavonoids, vitamins and minerals present in some fruits and foliage are considered natural antioxidants. In fact, fruits and vegetables contain large amounts of antioxidants. Several clinical trials have extensively studied vitamin E, beta-carotene, vitamin C, polyphenols, plus selenium and zinc. In addition, many authors have been carried out clinical trials to evaluate the mechanisms of oxidative stress attenuation after exercise. Exercise responses may vary according to the Frequency, Intensity, Time and Type (FITT) principle, making it difficult to obtain a consensus concerning the exercise properties and redox status. High-intensity interval training (HIIT) has been reported as an efficient option for metabolic adaptations in a short time. Aerobic exercises must be performed at least three times a week, for two months or more, using moderate to vigorous intensity to promote a positive effect on oxidative stress and vascular function. CONCLUSION: The recognition of appropriate nutrients and exercise with antioxidant properties may be an important supportive approach to impair early vascular aging and to prevent cardiovascular disease.

Potential Role of Endothelin in Early Vascular Aging.

Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.

High Blood Pressure States in Children, Adolescents, and Young Adults Associate Accelerated Vascular Aging, with a Higher Impact in Females' Arterial Properties.

The aims of the study were to determine (1) whether the presence of High blood pressure (HBP) states in the youth associate a steeper rate of age-related change in arterial geometrical and wall properties with respect to subjects with no previous cardiovascular risk factor (CRF) exposure, (2) in which parameters and in what magnitude, and (3) the existence of a gender-related difference in the impact of this condition on arterial properties. 300 individuals (mean/range: 15/4-29 years; 133 females) were included. Two groups were assembled: (1) Reference: nonprevious exposure to traditional CRF and (2) HBP: subjects with arterial hypertension and/or elevated blood pressure (BP) levels during the study. Additionally, HBP subjects were separated in BP-related subgroups. Measured parameters were (1) central (aortic) arterial BP and aortic pulse wave analysis parameters, (2) carotid and femoral artery local (pressure-strain elastic modulus) and regional (pulse wave velocity; PWV) stiffness, and (3) arterial diameters and carotid intima-media thickness (CIMT). Age-related changes in these parameters (absolute values and z-scores) were explored by obtaining simple linear regression models for each group. HBP presented a steeper rate of change (accelerated vascular aging; VA) for most of the parameters assessed, mainly in central (aortic) hemodynamics. VA increased as the HBP level got higher. Both males' and females' aging rates were affected by this condition, but females presented a more marked relative age-related increase with HBP exposure. HBP states in the youth gradually associate accelerated VA, with a progressive hemodynamic-structural-functional onset of damage, with females presenting a more marked relative HBP-associated arterial repercussion.