The Longitudinal Decline in Peak VO2 with Aging in Healthy Individuals is Associated with a Reduction in Peripheral Oxygen Utilization but not in Cardiac Output.

Aging is associated with a significant decline in exercise fitness assessed by maximal exercise oxygen consumption (VO2-max). The specific VO2-max components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A-V) O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age 21-96 years; average follow-up 12.6 years) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. VO2-peak, a surrogate of VO2-max, was used to assess aerobic capacity during upright cycle exercise. Peak exercise left ventricular (LV) volumes, heart rate, and cardiac output were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A-V) O2-peak from CO-peak and VO2-peak. In unadjusted models, VO2-peak, (A-V) O2-peak, and CO-peakdeclined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in VO2-peak and (A-V) O2 peak were observed with advanced entry age but not in CO-peak. The association between the declines in VO2-peak and (A-V) O2-peakwas stronger among those >=50 years compared to their younger counterparts but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak VO2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A-V) O2 are warranted.

Glucose-6-phosphate dehydrogenase deficiency accelerates arterial aging in diabetes.

AIMS: High glucose levels and Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) have both tissue inflammatory effects. Here we determined whether G6PDd accelerates arterial aging (information linked stiffening) in diabetes. METHODS: Plasma glucose, interleukin 6 (IL6), and arterial stiffness (indexed as carotid-femoral Pulse Wave Velocity, PWV) and red blood cell G6PD activity were assessed in a large (4448) Sardinian population. RESULTS: Although high plasma glucose in diabetics, did not differ by G6DP status (178.2 ± 55.1 vs 169.0 ± 50.1 mg/dl) in G6DPd versus non-G6PDd subjects, respectively, IL6, and PWV (adjusted for age and glucose) were significantly increased in G6PDd vs non-G6PDd subjects (PWV, 8.0 ± 0.4 vs 7.2 ± 0.2 m/sec) and (IL6, 6.9 ± 5.0 vs 4.2 ± 3.0 pg/ml). In non-diabetics, neither fasting plasma glucose, nor IL6, nor PWV were impacted by G6PDd. CONCLUSION: G6PDd in diabetics is associated with increased inflammatory markers and accelerated arterial aging.

Dilated hypertrophic phenotype of the carotid artery is associated with accelerated age-associated central arterial stiffening.

Hypertrophic carotid geometric phenotypes (h-CGP) are predictors of incident cardiovascular disease (CVD). While arterial aging is hypothesized as a contributor to this associated risk, the association of CGPs with chronological age is not clear. In this manuscript we examine whether hypertrophic CGPs represent accelerated biological, rather than chronological, aging by examining their association with carotid-femoral pulse wave velocity (PWV), the hallmark of arterial aging. We analyzed data from 5516 participants of the SardiNIA study with a wide range of age at baseline (20-101 years), and a median follow-up time of 13 years (mean 11.5 years; maximum 17.9 years). Baseline CGPs were defined based on the common carotid lumen diameter, wall thickness, and their ratio. Subject-specific rates of change of PWV, blood pressure parameters, body mass index, glucose, and lipids were estimated using linear mixed effects models. Compared to those with typical(t-) CGP, those with dilated hypertrophy (dh-) CGP had a greater longitudinal increase in PWV; this increase was significantly greater among older individuals and men. The greater PWV longitudinal increase in dh-CGP remained significant after adjusting for baseline values and rates of change of covariates. Dilated hypertrophic CGP is independently associated with accelerated increase in age-associated arterial stiffening over time, with a strong association in men than in women. Future studies are needed to examine if this association mediates the increased risk for CVD observed in individuals with hypertrophic cardiac remodelling and the role of retarding it to reduce this risk. HIGHLIGHTS: • Individuals with dilated hypertrophic geometric phenotypes of the common carotid artery (increased age- and sex-specific wall thickness and lumen diameter) have greater future central arterial stiffening, independently of other determinants of arterial stiffening. • The dilated hypertrophic phenotype group has a greater age-specific arterial dilation, wall thickening, and stiffness (the arterial aging triad). This suggests that this phenotype is a form of accelerated aging that might explain the worse clinic outcomes observed in this group. • Understanding the natural history of the carotid geometric phenotype across the lifespan and the determinants of the deleterious progression towards the dilated hypertrophic phenotype are needed to develop interventions that reduce the adverse clinical outcomes associated with it.

Power dynamics and health initiative design as determinants of peacebuilding: a case study of the Syrian conflict.

Peace-through-health has emerged as a promising concept but with variable evidence of success. Cooptation of health initiatives in conflict is believed to be a major challenge undermining peacebuilding potential. We examine the role that existing power structures and health initiative characteristics play at various levels of a conflict in peacebuilding outcomes. Using the Syrian conflict as a case study, we assess healthcare initiatives' characteristics and their peacebuilding tendencies accounting for power dynamics at the (1) state citizen, (2) interbelligerents and (3) intercommunity conflict levels, drawing on the WHO's framework for health and peace initiatives. Healthcare interventions at state citizen and interbelligerent levels generally addressed combat-related and material-dependent health needs, relied on large-scale international funding and centralised governance structures, and bestowed credit to specific agencies with political implications. These characteristics made such initiatives prone to cooptation in conflict with limited peacebuilding capacity. Healthcare initiatives at the community level addressed more basic, service-dependent needs, had smaller budgets, relied on local organisations and distributed credit across stakeholders, making them less amenable to cooptation in the conflict with more propeace potential. A pilot peacebuilding health initiative designed to leverage these propeace attributes navigated the political environment, minimised cooptation and fostered community collaboration, resulting in peacebuilding potential. In summary, peacebuilding health initiatives are more likely to materialise at the community as compared with higher political levels. Further studies, accounting for conflict power structures, are needed to examine the effectiveness of such initiatives and identify methods that maximise their peacebuilding outcomes.

Ankle-Brachial Index and Energy Production in People Without Peripheral Artery Disease: The BLSA.

Background Lower ankle-brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross-sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown. Method and Results We analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow-up (mean follow-up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant (kPCr) from phosphorus-31 magnetic resonance spectroscopy. Greater kPCr indicated higher mitochondrial oxidative capacity. Although kPCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change (Change) of left and right ABI and kPCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline kPCr, both left and right baseline ABI, and ABI change in both legs, (kPCr)Change was directly associated with ipsilateral (left) (ABI)Change (standardized [STD]-ß=0.14; P=0.0168) but not with contralateral (right) (ABI)Change (P=0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD-ß=0.18; P=0.0051). (kPCr)Change was steeper in White race participants (STD-ß=0.16; P=0.0122) and body mass index (STD-ß=0.13; P=0.0479). There was no significant association with current smoking status (P=0.63), fasting glucose (P=0.28), heart rate (P=0.67), mean blood pressure (P=0.78), and low-density lipoprotein (P=0.75), high-density lipoprotein (P=0.82), or triglycerides (P=0.15). Conclusions In people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.

Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging.

To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.

Physicians' Attitudes Toward Telemedicine Consultations During the COVID-19 Pandemic: Cross-sectional Study.

BACKGROUND: To mitigate the effect of the COVID-19 pandemic, health care systems worldwide have implemented telemedicine technologies to respond to the growing need for health care services during these unprecedented times. In the United Arab Emirates, video and audio consultations have been implemented to deliver health services during the pandemic. OBJECTIVE: This study aimed to evaluate whether differences exist in physicians' attitudes and perceptions of video and audio consultations when delivering telemedicine services during the COVID-19 pandemic. METHODS: This survey was conducted on a cohort of 880 physicians from outpatient facilities in Abu Dhabi, which delivered telemedicine services during the COVID-19 pandemic between November and December 2020. In total, 623 physicians responded (response rate=70.8%). The survey included a 5-point Likert scale to measure physician's attitudes and perceptions of video and audio consultations with reference to the quality of the clinical consultation and the professional productivity. Descriptive statistics were used to describe physicians' sociodemographic characteristics (age, sex, designation, clinical specialty, duration of practice, and previous experience with telemedicine) and telemedicine modality (video vs audio consultations). Regression models were used to assess the association between telemedicine modality and physicians' characteristics with the perceived outcomes of the web-based consultation. RESULTS: Compared to audio consultations, video consultations were significantly associated with physicians' confidence toward managing acute consultations (odds ratio [OR] 1.62, 95% CI 1.2-2.21; P=.002) and an increased ability to provide patient education during the web-based consultation (OR 2.21, 95% CI 1.04-4.33; P=.04). There was no significant difference in physicians' confidence toward managing long-term and follow-up consultations through video or audio consultations (OR 1.35, 95% CI 0.88-2.08; P=.17). Video consultations were less likely to be associated with a reduced overall consultation time (OR 0.69, 95% CI 0.51-0.93; P=.02) and reduced time for patient note-taking compared to face-to-face visits (OR 0.48, 95% CI 0.36-0.65; P<.001). Previous experience with telemedicine was significantly associated with a lower perceived risk of misdiagnosis (OR 0.46, 95% CI 0.3-0.71; P<.001) and an enhanced physician-patient rapport (OR 2.49, 95% CI 1.26-4.9; P=.008). CONCLUSIONS: These results indicate that video consultations should be adopted frequently in the new remote clinical consultations. Previous experience with telemedicine was associated with a 2-fold confidence in treating acute conditions, less than a half of the perceived risk of misdiagnosis, and an increased ability to provide patients with health education and enhance the physician-patient rapport. Additionally, these results show that audio consultations are equivalent to video consultations in providing remote follow-up care to patients with chronic conditions. These findings may be beneficial to policymakers of e-health programs in low- and middle-income countries, where audio consultations may significantly increase access to geographically remote health services.

Aging- and gender-related modulation of RAAS: potential implications in COVID-19 disease.

Coronavirus disease 2019 (COVID-19) is a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is frequently characterized by a marked inflammatory response with severe pneumonia and respiratory failure associated with multiorgan involvement. Some risk factors predispose patients to develop a more severe infection and to an increased mortality; among them, advanced age and male gender have been identified as major and independent risk factors for COVID-19 poor outcome. The renin-angiotensin-aldosterone system (RAAS) is strictly involved in COVID-19 because angiotensin converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 and also converts pro-inflammatory angiotensin (Ang) II into anti-inflammatory Ang(1-7). In this review, we have addressed the effect of aging and gender on RAAS with emphasis on ACE2, pro-inflammatory Ang II/Ang II receptor 1 axis and anti-inflammatory Ang(1-7)/Mas receptor axis.

Longitudinal uncoupling of the heart and arteries with aging in a community-dwelling population.

Although mechanical energy transfer between the heart and arterial system, referred to as arterial-ventricular (AV) coupling, is an important determinant of cardiovascular performance, how AV coupling changes over time within and among individuals as they age has not been fully explored. We studied 129 participants (baseline age 21-96) of the Baltimore Longitudinal Study of Aging, free of clinical CVD. Participants underwent repeated multigated cardiac blood pool scans to estimate left ventricular (LV) volumes (SV, EDV, and ESV). Total systemic vascular resistance (TSVR), total arterial compliance (TAC), effective arterial elastance (Ea), and end-systolic LV elastance (Elv) were calculated using LV volumes and brachial BP measurements; calculated Ea/Elv was the measure of AV coupling. Linear mixed-effects models were used to estimate person-specific rates of change (Change) for each variable. The rate at which Ea increased over time was faster than the rate at which Elv increased, resulting in AV uncoupling (increased Ea/Elv) over time that was significantly greater in women than in men. Loss of arterial compliance was the main determinant of (Ea/Elv)Change, which was negatively associated with changes in SV and EDV but positively with changes in ESV. Progressive AV uncoupling occurred with aging and was more pronounced in women than men. While Ea change did not differ by sex, Elv increased at a slower rate in women than in men. AV uncoupling was inversely associated with EDV and SV rates of change and a directly associated with an increase in ESV rate of change. Additional studies are needed to explore the functional consequences of AV uncoupling in healthy individuals with respect to the emergence of age-associated clinical cardiovascular diseases, such as heart failure with preserved ejection fraction.

Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study.

Levels of angiotensin-converting enzyme 2 (ACE2), the gateway for COVID-19 virus into the cells, have been implicated in worse COVID-19 outcomes associated with aging and cardiovascular disease (CVD). Data on age-associated differences in circulating ACE2 levels in humans and the role of CVD and medications is limited. We analyzed data from 967 participants of the InCHIANTI study, a community-dwelling cohort in the Chianti region, Italy. Relative abundance of ACE2 in plasma was assessed using a proteomics platform. CVD diagnoses, use of renin-angiotensin-aldosterone system (RAAS) antagonists: ACEi, ARBs, and aldosterone antagonists, were ascertained. Multiple linear analyses were performed to examine the independent association of ACE2 with age, CVD, and RAAS antagonist use. Age was independently associated with lower log (ACE2) in persons aged ≥ 55 years (STD ß = - 0.12, p = 0.0002). ACEi treatment was also independently associated with significantly lower ACE2 levels, and ACE2 was inversely associated with weight, and positively associated with peripheral artery disease (PAD) status. There was a trend toward higher circulating ACE2 levels in hypertensive individuals, but it did not reach statistical significance. In a stratified analysis, the association between log (ACE2) and log (IL-6) was more evidenced in participants with PAD. Circulating ACE2 levels demonstrate curvilinear association with age, with older individuals beyond the sixth decade age having lower levels. ACEi was associated with greater circulating ACE2 levels. Interestingly, ACE2 was elevated in PAD and positively associated with inflammatory markers, suggesting compensatory upregulation in the setting of chronic inflammation. Further studies are needed to comprehensively characterize RAAS components with aging and disease, and assess its prognostic role in predicting COVID-19 outcomes.

Sex Differences in Longitudinal Determinants of Carotid Intima Medial Thickening With Aging in a Community-Dwelling Population: The Baltimore Longitudinal Study on Aging.

Background Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age-associated hemodynamic alterations in men and in women are not fully explored. Methods and Results We analyzed repeated measures of IMT, blood pressure, and carotid-femoral pulse wave velocity over a 20-year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease. Linear mixed-effects models were used to calculate the individual rates of change (Change) of IMT, pulse pressure, mean arterial pressure, and pulse wave velocity, among other covariates. Multivariate regression analysis was used to examine the association of IMTChange with baseline and rates of change of hemodynamic parameters and cardiovascular risk factors. IMT increased at accelerating rates from 0.02 mm/decade at age 50 years to 0.05 mm/decade at age 80 years greater rates in men than in women. IMTChange was positively associated with baseline low-density lipoprotein, low-density lipoproteinChange, and baseline systolic blood pressure and systolic blood pressureChange, but inversely with baseline diastolic blood pressure and diastolic blood pressureChange. When blood pressure was expressed as pulse pressure and MAP, IMTChange was positively associated with baseline pulse pressure and pulse pressureChange and inversely with baseline mean arterial pressure and mean arterial pressureChange. In sex-specific analysis, these associations were observed in women, but not in men. Conclusions In summary, our analyses showed that IMT increases at accelerating rates with aging. Age-associated changes in IMT were modulated by concurrent changes of low-density lipoprotein in both sexes, and of pulsatile and mean blood pressure in women but not men.

Longitudinal Changes in Resting Metabolic Rates with Aging Are Accelerated by Diseases.

Resting metabolic rate (RMR) declines with aging and is related to changes in health status, but how specific health impairments impact basal metabolism over time has been largely unexplored. We analyzed the association of RMR with 15 common age-related chronic diseases for up to 13 years of follow-up in a population of 997 participants to the Baltimore Longitudinal Study of Aging. At each visit, participants underwent measurements of RMR by indirect calorimetry and body composition by DEXA. Linear regression models and linear mixed effect models were used to test cross-sectional and longitudinal associations of RMR and changes in disease status. Several diseases were associated with higher RMR at baseline. Independent of covariates, prevalent COPD and cancer, as well as incident diabetes, heart failure, and CKD were associated with a steeper decline in RMR over time. Chronic diseases seem to have a two-phase association with RMR. Initially, RMR may increase because of the high cost of resiliency homeostatic mechanisms. However, as the reserve capacity becomes exhausted, a catabolic cascade becomes unavoidable, resulting in loss of total and metabolically active mass and consequent RMR decline.

Subclinical Longitudinal Change in Ankle-Brachial Index With Aging in a Community-Dwelling Population Is Associated With Central Arterial Stiffening.

Background Aging is associated with a modest decline in ankle-brachial index (ABI); however, the underpinnings of this decline are not fully understood. The greater systolic ankle than brachial blood pressure, a normal ABI implies, is partially attributed to lower central than peripheral arterial stiffness. Hence, we examined the hypothesis that the age-associated decline in ABI is associated with central arterial stiffening with aging, assessed by pulse wave velocity. Methods and Results We analyzed longitudinal data from 974 participants aged 27 to 95 years from the Baltimore Longitudinal Study of Aging who were free of clinically significant cardiovascular disease. Participants had an average of 4 visits with a 6.8-year average follow-up time. Linear mixed-effects models showed that the average ABI decline beyond the age of 70 years was 0.03 per decade. In multiple regression analysis, the ABI rate of change was inversely associated with initial age (standardized ß=-0.0711, P=0.0282), independent of peripheral disease factors and baseline ABI. After adjustment, the pulse wave velocity rate of change was inversely associated with ABI rate of change (standardized ß=-0.0993, P=0.0040), rendering the association of the latter with initial age nonsignificant (standardized ß=-0.0265, P=0.5418). Conclusions A modest longitudinal decline in ABI beyond the age of 70 years was shown to be independent of traditional risk factors for peripheral arterial disease but was accounted for by an increase in pulse wave velocity. A modest decline in ABI with aging might be a manifestation of changes in central hemodynamics and not necessarily attributable to peripheral flow-limiting factors.

Age-related changes of the retinal microvasculature.

PURPOSE: Blood vessels of the retina provide an easily-accessible, representative window into the condition of microvasculature. We investigated how retinal vessel structure captured in fundus photographs changes with age, and how this may reflect features related to patient health, including blood pressure. RESULTS: We used two approaches. In the first approach, we segmented the retinal vasculature from fundus photographs and then we correlated 25 parameterized aspects ("traits")-comprising 15 measures of tortuosity, 7 fractal ranges of self-similarity, and 3 measures of junction numbers-with participant age and blood pressure. In the second approach, we examined entire fundus photographs with a set of algorithmic CHARM features. We studied 2,280 Sardinians, ages 20-28, and an U.S. based population from the AREDS study in 1,178 participants, ages 59-84. Three traits (relating to tortuosity, vessel bifurcation number, and vessel endpoint number) showed significant changes with age in both cohorts, and one additional trait (relating to fractal number) showed a correlation in the Sardinian cohort only. When using second approach, we found significant correlations of particular CHARM features with age and blood pressure, which were stronger than those detected when using parameterized traits, reflecting a greater signal from the entire photographs than was captured in the segmented microvasculature. CONCLUSIONS: These findings demonstrate that automated quantitative image analysis of fundus images can reveal general measures of patient health status.

Lower Mitochondrial Energy Production of the Thigh Muscles in Patients With Low-Normal Ankle-Brachial Index.

BACKGROUND: Lower muscle mitochondrial energy production may contribute to impaired walking endurance in patients with peripheral arterial disease. A borderline ankle-brachial index (ABI) of 0.91 to 1.10 is associated with poorer walking endurance compared with higher ABI. We hypothesized that in the absence of peripheral arterial disease, lower ABI is associated with lower mitochondrial energy production. METHODS AND RESULTS: We examined 363 men and women participating in the Baltimore Longitudinal Study of Aging with an ABI between 0.90 and 1.40. Muscle mitochondrial energy production was assessed by post-exercise phosphocreatine recovery rate constant (kPCr) measured by phosphorus magnetic resonance spectroscopy of the left thigh. A lower post-exercise phosphocreatine recovery rate constant reflects decreased mitochondria energy production.The mean age of the participants was 71±12 years. A total of 18.4% had diabetes mellitus and 4% were current and 40% were former smokers. Compared with participants with an ABI of 1.11 to 1.40, those with an ABI of 0.90 to 1.10 had significantly lower post-exercise phosphocreatine recovery rate constant (19.3 versus 20.8 ms-1, P=0.015). This difference remained significant after adjusting for age, sex, race, smoking status, diabetes mellitus, body mass index, and cholesterol levels (P=0.028). Similarly, post-exercise phosphocreatine recovery rate constant was linearly associated with ABI as a continuous variable, both in the ABI ranges of 0.90 to 1.40 (standardized coefficient=0.15, P=0.003) and 1.1 to 1.4 (standardized coefficient=0.12, P=0.0405). CONCLUSIONS: An ABI of 0.90 to 1.10 is associated with lower mitochondrial energy production compared with an ABI of 1.11 to 1.40. These data demonstrate adverse associations of lower ABI values with impaired mitochondrial activity even within the range of a clinically accepted definition of a normal ABI. Further study is needed to determine whether interventions in persons with ABIs of 0.90 to 1.10 can prevent subsequent functional decline.

Longitudinal Association Between Serum Uric Acid and Arterial Stiffness: Results From the Baltimore Longitudinal Study of Aging.

Serum uric acid (SUA) has long been associated with increased cardiovascular risk, with arterial stiffness proposed as a mediator. However, evidence on the association between SUA and arterial stiffness is limited to contradicting cross-sectional studies. In this analysis, we examined the longitudinal relationship between SUA and pulse wave velocity, a measure of arterial stiffness, in a community-dwelling population. We studied 446 women and 427 men participating in the BLSA (Baltimore Longitudinal Study of Aging), with 1409 and 1434 observations, respectively, over an average period of 6 years. At baseline, mean ages of women and men were 65±13 and 68±13 years; mean SUA, 4.6±1.1 and 5.7±1.3 mg/dL; mean pulse wave velocity, 8.1±1.7 and 8.6±1.9 m/s, respectively (P<0.0001). In gender-stratified models accounting for age, blood pressure, renal function, metabolic measures, and medications, there was a significant interaction between SUA and follow-up time in men (ß=0.69; P=0.0002) but not in women. Men, but not women, in the highest gender-specific SUA tertile at baseline (SUA≥6.2 mg/dL in men and SUA≥4.9 mg/dL in women) had a greater rate of pulse wave velocity increase over time than those in the lowest tertiles (ß=0.997; P=0.012). This gender difference was lost when the distribution of SUA in men and women was made comparable by excluding hyperuricemic men (SUA≥6.2 mg/dL). In conclusion, higher SUA was associated with greater increase in pulse wave velocity in men but not women; this association was lost when men with SUA≥6.2 mg/dL were not included, suggesting a threshold for SUA association with arterial stiffness, which is more frequently reached in men.

The Pressure of Aging.

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and an increase of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and an increase in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age. There is an increased prevalence of salt-sensitive hypertension with advancing age that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand.

The conundrum of arterial stiffness, elevated blood pressure, and aging.

Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naïve. The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short- and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level. Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits-all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves.