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Vascular aging and target organ damage: is it predictable?

Tadic, Marijanaa; Cuspidi, Cesareb; Grassi, Guidoc,d

doi: 10.1097/HJH.0000000000001705
Editorial Commentaries

aCharité – Universitätsmedizin Berlin, Department of Internal Medicine and Cardiology, Berlin, Germany

bClinical Research Unit, University of Milan-Bicocca and Istituto Auxologico Italiano, Meda

cDepartment of Health Science, University of Milano-Bicocca

dIRCCS Multimedica, Sesto San Giovanni, Milano, Italy

Correspondence to Marijana Tadic, MD, PhD, Department of Internal Medicine and Cardiology, Charité – Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany. E-mail:

The percentage of elderly in the general population is constantly increasing and Osler's statement that ‘we are old as our arteries’ nowadays have completely new meaning and a great importance. The increased arterial stiffness plays a crucial role in arterial remodeling during aging. Vascular stiffness or elasticity correlates inversely with compliance. The structure of the arterial wall significantly changes over the years due to ruptures of the elastic lamina, muscle derangement, interstitial fibrosis, inflammation, decrease in collagen, smooth muscle cell necrosis in tunica media, and ultimately calcification [1]. It has been reported that the intima–media thickness increases three times between the ages 20 and 90 [2]. This is mainly a consequence of elastin disruption and interstitial fibrosis [3], which further results with increase in arterial stiffness leading to elevation in SBP and a widening pulse pressure.

Target organ damage (TOD) represents a step between cardiovascular risk factors and event, and left ventricular hypertrophy (LVH) and albuminuria are widely accepted TOD parameters. Arterial stiffness, LVH and albuminuria are well established risk of cardiovascular morbidity and mortality [4–6]. On the other hand, growing evidence supports the association between arterial stiffness, LVH and albuminuria [7–9].

Vascular aging can be evaluated by several noninvasive measurements: arterial stiffness, central blood pressure, carotid intima–media thickness, and endothelial dysfunction. The assessment of arterial stiffness is usually estimated by carotid-femoral and carotid-ankle pulse wave velocity (PWV).

Vascular aging is part of the normal process of aging and therefore it is not necessarily associated with pathological processes and TOD. Healthy vascular aging (HVA) is a recently introduced term for representing a reduced PWV in the absence of arterial hypertension (SBP < 140 mmHg and/or DBP < 90 mmHg) or antihypertensive therapy [10]. This concept allows a distinction between HVA and non-HVA.

A number of epidemiological studies (The Framingham Heart Study [11] and the Rotterdam study [13] support the predictive role of PWV for adverse cardiovascular events. In the current issue of the Journal Ji et al. [14] show that accelerated vascular aging (non-HVA) is independently associated with left ventricular (LV) diastolic dysfunction, LVH and microalbuminuria. There are several important points of this study that deserve to be commented.

Investigators included 2098 elderly participants (mean age 71.3 ± 6.1 years) from the general Chinese population. However, this study population is somewhat different from those of the Western world, which provided the previously available evidence. Namely, body mass index and waist/hip ratio were significantly lower than in the general population of developed countries [7,11]: a difference in physical activity between Chinese and western population [10] may account for the lean habitus in the current study [14]. Physical activity could be responsible for less pronounced vascular aging in comparison with a Western population [10].

Ji et al. [14] showed that the prevalence of HVA decreased with age and increased number of TOD. This trend in reduction of HVA prevalence is in line with previous investigation performed in a Western population [10]. However, in 60–69-year-old individuals of the Framingham study the occurrence of HVA was only 7.4% [10], while in the Chinese population it was significantly higher: nearly 28% in the same age group and approximately 21% in individuals at least 70 years old [14]. This emphasizes the significance of obesity and lifestyle differences because the prevalence of other cardiovascular risk factors such as arterial hypertension, diabetes, dyslipidemia and smoking was similar as in previous studies conducted in Western populations [7,11–13]. However, in the present study multivariate analysis showed that only age, BMI, previous cardiovascular event and metabolic syndrome were independently associated with non-HVA [14]. Gender, drinking and exercise habits were not independently related with non-HVA. Obviously, this only implies that physical activity was not associated with non-HVA independently of other cardiovascular risk factors, but not that this association did not exist.

Another important finding of the present study is the negative effect of the metabolic syndrome on vascular aging [14]. Recently published results of the Advanced Approach to Arterial Stiffness study showed that carotid-femoral PWV was significantly reduced in the individuals with the metabolic syndrome [15]. Interestingly, the authors of the mentioned investigation showed that the metabolic syndrome had different effect on the cardio-ankle vascular index and carotid-femoral PWV, the former being positively associated with high glycemia and high blood pressure, and negatively with HDL and triglycerides levels, whereas all five components of the metabolic syndrome demonstrated positive associations with carotid-femoral PWV [15]. Considering the fact that all criteria of the metabolic syndrome (abdominal obesity, increased blood pressure, glucose, HDL and triglycerides levels) were increased in the individuals with non-HVA in comparison with the participants with HVA, it is reasonable to suggest that the metabolic syndrome may play a predominant role in the vascular and cardiac remodeling of the present study [14].

Another point deserving to be mentioned is the definition of LV diastolic dysfunction in the present investigation [14]. The authors used three of the four necessary criteria (average E/e′, septal or lateral e′ velocity, left atrial volume index and tricuspid regurgitation velocity) defined by the latest guidelines [16], and also applied somewhat different cut-off values, which could slightly interfere with calculation of the prevalence of LV diastolic dysfunction. The authors reported that the prevalence of LV diastolic dysfunction and LVH gradually increased with aging. Interestingly, the occurrence of LVH was higher than LV diastolic dysfunction in the studied population [14]. Even though the authors did not find a significant influence of sex on non-HVA, it is worth mentioning that women had higher prevalence of both LV diastolic dysfunction and LVH than men [14]. Both variables, as well as microalbuminuria, were associated with non-HVA independently of intima-media thickness, ankle-brachial index and chronic renal failure [14]. The association of LVH and LV diastolic dysfunction with arterial stiffness has been previously shown [17]. However, the mechanisms that could explain this relationship are still not completely explained. Ventricular–vascular coupling is one the most important factors for the development of LVH and LV diastolic dysfunction under the influence of arterial stiffening [18]. Elevated vascular stiffness increases the load imposed on the heart by rising systolic wall stress. The heart responds to this stress by elevation in both systolic and diastolic ventricular stiffness, with or without LVH development. However, after some time LV filling pressure increases and LV wall thickens. Different mechanisms lead to increased arterial stiffness: diabetes, arterial hypertension, obesity, dyslipidemia, metabolic syndrome, oxidative stress. All mentioned risk factors are related with endothelial dysfunction, which could be one of the main causes for vascular aging [19].

An interesting aspect of the present study is the influence of renal function and microalbuminuria on non-HVA. The investigators show that glomerular filtration rate was somewhat lower in non-HVA than in HVA participants [14]. However, the urine albumin to creatinine ratio was almost doubled in non-HVA in comparison with HVA individuals. Additionally, the authors reported that microalbuminuria was independently associated with non-HVA. The prevalence of microalbuminuria gradually increased among non-HVA participants and it was higher among women than men, and among diabetic than nondiabetic individuals. BMI did not interfere with the occurrence of microalbuminuria in the study population [14].

Microalbuminuria was previously shown to be independently related with arterial stiffness and vascular inflammation, but not with intima-media thickness in patients with newly diagnosed arterial hypertension or diabetes [20].

The mechanisms for the association between microalbuminuria and arterial stiffness are not entirely clear, but endothelial dysfunction seems to be one of the most important underlying mechanisms responsible for this relationship. Microalbuminuria has been accepted as an early marker of microvascular damage resulting from vascular endothelial dysfunction. On its turn, endothelial dysfunction contributes to increased arterial stiffness measured by PWV. Therefore, vascular endothelial dysfunction during aging might have a crucial role in the pathogenesis of microalbuminuria and elevated arterial stiffness. Vascular endothelial dysfunction may cause the arterial wall remodeling through structural and functional vascular changes inducing increased arterial stiffness. Furthermore, endothelial dysfunction impacts the glomerular basement membrane, which impairs glomerular barrier permeability and increased albuminuria.

The advantage of the current study is the inclusion of an elderly population. However, one should be aware of the specific characteristics of the Chinese population, which has a significantly lower prevalence of cardiovascular risk factors than Caucasian populations. Additionally, the present study is cross-sectional, which is why its results could not be interpreted as the evidence of a causal relationship between vascular aging and TOD in the general population. The concept of healthy vascular aging is also new and insufficiently investigated. Therefore, the definition of HVA may change in the future, after completion of the large prospective studies.

The potential clinical significance of the present study by Ji et al. is, anyway, relevant, because it shows that arterial stiffness as assessed by PWV can predict TOD in the general and mainly asymptomatic population. Considering the wide availability and low cost of PWV evaluation, which is also a nondemanding technique, PWV could be used in the future as a surrogate marker for overall TOD in the global population. In patients with cardiovascular risk factors such as hypertension, diabetes or metabolic syndrome, other more sophisticated (and expensive) investigations are necessary, but in the global population without risk factors and with low risk of cardiac remodeling, the assessment of arterial stiffness might be a simple solution for detection of subclinical TOD and patients deserving further analysis and attention.

In summary, despite some limitations, the report by Ji and coworkers adds a very important piece in the puzzle of the complex relationship between vascular aging and target organ damage involving LVH, LV diastolic dysfunction and microalbuminuria. However, large prospective studies are necessary in order to establish the predictive importance of vascular aging in different populations.

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Conflicts of interest

There are no conflicts of interest.

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