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Older individuals represent a growing population, in industrialized countries, particularly those with cardiovascular diseases, which remain the leading cause of death in western societies. Aging constitutes one of the largest risks for cardiovascular diseases. On the other hand, oxygen consumption is the foundation of cardiorespiratory fitness, which in turn is linearly related to mortality, quality of life and numerous morbidities. Therefore, hypoxia is a stressor that induces beneficial or harmful adaptations, depending on the dose. While severe hypoxia can exert detrimental effects, such as high-altitude illnesses, moderate and controlled oxygen exposure can potentially be used therapeutically. It can improve numerous pathological conditions, including vascular abnormalities, and potentially slows down the progression of various age-related disorders. Hypoxia can exert beneficial effects on inflammation, oxidative stress, mitochondrial functions, and cell survival, which are all increased with age and have been discussed as main promotors of aging. This narrative review discusses specificities of the aging cardiovascular system in hypoxia. It draws upon an extensive literature search on the effects of hypoxia/altitude interventions (acute, prolonged, or intermittent exposure) on the cardiovascular system in older individuals (over 50 years old). Special attention is directed toward the use of hypoxia exposure to improve cardiovascular health in older individuals. [ABSTRACT FROM AUTHOR]

This paper proposes a new estimation formula of the vessel age (VA), an index of the degree of atherosclerosis, based on parameters derived from acceleration plethysmogram (APG), which is the second-order derivative of the photoplethysmogram (PPG). The current estimation formula utilizes the sequence of five extreme values a, b, c, d, e observed in the APG waveform. The multiple regression analysis revealed that the parameters c/a and d/a play a significant role in estimating VA. To improve the estimation accuracy, the slope Sbd between two extreme values b and d is added to parameters c/a and d/a for the estimation. The parameter includes the information which reflects the APG waveform duration known to be an index to probe the large artery stiffness. The new vessel age estimation formula based on the multiple regression of these three parameters is evaluated by the PPG data collected from 347 healthy subjects aged 20-60 years (40.2 ± 12.4). The method will be effectively utilized for the early detection of the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Recent advances in health care have improved the management of cardiometabolic disorders, and prolonged lifespan. However, the ever-rising prevalence of metabolic stress related to obesity (insulin resistance, diabetes, hypertension, and dyslipidemia) has greatly challenged geriatric care. The ubiquitin–proteasome system and autophagy–lysosomal pathways represent two major, yet distinct cellular machineries, for degradation and removal of damaged or long-lived proteins and organelles; the function of which declines with aging. To seek new strategies for cardiovascular aging under various metabolic diseases, it is imperative to understand the precise role for metabolic stress and protein quality control, in particular autophagy, in premature cardiovascular aging. Targeting metabolic stress and autophagy may offer exciting new avenues for the management of cardiovascular aging. Highlights Population-based studies, clinical trials, and experimental data have depicted a close relationship between age-related chronic diseases such as insulin resistance, type 2 diabetes, hypertension, obesity, atherosclerosis, and metabolic dysfunction. Metabolic diseases impose stress on cardiovascular function, fostering premature cardiovascular aging. Proteotoxicity due to poor protein quality control in particular autophagy contributes to the pathogenesis of metabolic dysregulation and aging. Autophagy delays aging, and prolongs lifespan, exhibiting promises for the prevention and therapeutics of metabolic diseases. [ABSTRACT FROM AUTHOR]

The article discusses the most important age-dependent changes in the cardiovascular system. It mentions about the altered cellular function, cardiac shape, plasticity and valvular stiffening which contribute to reduced cardiovascular reserve, the impact of normal ageing on the increase in the late systolic pressure, and concludes that the heart and vessels undergo major changes with advancing age.

Background Pulse pressure amplification (PPA), i.e. the amplification from central arteries to the periphery, is inversely related to arterial stiffness, organ damage and mortality. It is known that arterial stiffness is higher in black than white populations, but it is unclear if this is due to early vascular aging. We therefore investigated whether PPA declines earlier in young normotensive black South Africans, when compared to their white counterparts. Methods We included 875 black and white men and women from the African-PREDICT study (55% black, 41% men), aged 20–30 years, with no prior diagnosis of chronic disease, screened for normotensive clinic blood pressure (BP). We determined supine central PP (cPP), and supine brachial systolic– and diastolic BP, from which brachial PP (bPP) was calculated. PPA was defined as the ratio of the amplitude of the PP between these distal and proximal locations (bPP/cPP). Results We found the mean PPA to be lower in black compared to white participants (1.43 vs. 1.46; P = 0.013). In black adults PPA declined earlier with increasing age (P–trend < 0.001), with a weak trend in whites (P = 0.069) after adjustment for sex, socio-economic status, height, heart rate and mean arterial pressure. In multivariable-adjusted regression, we found an independent inverse association between PPA and age only in the black group (β = − 0.18, P = 0.002). Conclusion PPA declines earlier with age in normotensive black adults younger than 30 years, exemplifying early vascular aging which may predispose black individuals to future cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Objectives To examine the association between midlife cardiovascular health and physical performance 25 years later. Design Cohort study (Atherosclerosis Risk in Communities Study); multinomial logistic and logistic regression adjusted for demographic characteristics and clinical measures. Setting Four U.S. communities: Forsyth County, North Carolina; Washington County, Maryland; Minneapolis, Minnesota; and Jackson, Mississippi. Participants: Individuals aged 54.2 ± 5.8 at baseline (N = 15,744; 55% female, 27% black). Measurements Cardiovascular health was measured at baseline using the American Heart Association's Life's Simple 7 ( LS7) score (0-14) and LS7 component categories (poor, intermediate, ideal) for each risk factor. The Short Physical Performance Battery ( SPPB) was used to quantify physical function as ordinal (0-12) and categorical (low (0-6), fair (7-9), good (10-12) outcomes. Results Mean baseline LS7 score was 7.9 ± 2.4; 6,144 (39%) individuals returned 25 years later for the fifth ARIC examination, at which point the SPPB was administered. Of 5,916 individuals who completed the SPPB, 3,288 (50%) had good physical performance. Each 1-unit increase in LS7 score was associated with a 17% higher SPPB score (rate ratio ( RR) = 1.17, 95% confidence interval ( CI) = 1.15-1.19) and a 29% greater chance of having a late-life SPPB score of 10 or greater compared to SPPB score of less than 10 ( RR = 1.29, 95% CI = 1.25-1.34). Ideal baseline glucose ( RR = 2.53, 95% CI = 2.24-2.87), smoking ( RR = 1.97, 95% CI = 1.81-2.15), blood pressure ( RR = 1.70, 95% CI = 1.54-1.88), body mass index ( RR = 1.51, 95% CI = 1.37-1.66), and physical activity ( RR = 1.31, 95% CI = 1.20-1.43) had the strongest associations with late-life SPPB score, adjusting for other LS7 components. Conclusion Better cardiovascular health during midlife may lead better physical functioning in older age. [ABSTRACT FROM AUTHOR]

Oxidative stress and impaired antioxidant defense are believed to be contributors to the cardiovascular aging process. The transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays a key role in orchestrating cellular antioxidant defenses and maintaining redox homeostasis. Our previous study showed that Exendin-4, a glucagon-like peptide-1 analog, alleviates angiotensin II (ANG II)-induced vascular smooth muscle cell (VSMC) senescence by inhibiting Rac1 activation via cAMP/PKA (Zhao L, Li AQ, Zhou TF, Zhang MQ, Qin XM. Am J Physiol Cell Physiol 307: C1130-C1141, 2014). The objective of this study is to investigate if Nrf2 mediates the antisenescent effect of Exendin-4 in ANG II-induced VSMCs. Here we report that Exendin-4 triggered Nrf2 nuclear translocation, a downstream target of cAMP-responsive element-binding protein (CREB) and expressions of antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1) in a dose- and time-dependent manner. In addition, knockdown of Nrf2 attenuated the inhibitory effects of Exendin-4 on ANG II-induced superoxidant generation and VSMC senescence. PKA/ CREB pathway participated in the upregulations of HO-1 and NQO-1 induced by Exendin-4. Notably, our study revealed that Exendin-4 dose-dependently increased the acetylation of Nrf2 and the recruitment of transcriptional coactivator CREB binding protein (CBP) to Nrf2. The Exendin-4-induced Nrf2 transactivation was diminished in the presence of CBP small interfering RNA. Microscope imaging of Nrf2, as well as immunoblotting for Nrf2, showed that the Exendin- 4-evoked Nrf2 acetylation favored its nuclear retention. Importantly, CBP silencing attenuated the suppressing effects of Exendin-4 on ANG II-induced VSMC senescence and superoxidant production. In conclusion, these results provide a mechanistic insight into how Nrf2 signaling mediates the antisenescent and antioxidative effects induced by Exendin-4 in VSMCs. [ABSTRACT FROM AUTHOR]

Age-associated alterations in cardiovascular structure and function induce cardiovascular disease in elderly subjects. To investigate the effects of normal vascular aging (NVA) and early vascular aging (EVA) on hemodynamic characteristics in the circle of Willis (CoW), a closed-loop one-dimensional computational model was developed based on fluid mechanics in the vascular system. The numerical simulations revealed that higher central pulse pressure and augmentation index (AIx) appear in the EVA subjects due to early arrival of reflected waves, resulted in the increase of cardiac afterload compared with the NVA subjects. Moreover, the hemodynamic characteristics in the CoW show that the EVA subjects in an older age display a higher blood pressure than that of the NVA with a complete CoW. Herein, the increased blood pressure and flow rate coexist in the subjects with an incomplete CoW. In conclusion, the hemodynamic characteristics in the aortic tree and CoW related to aging appear to play an important role in causing cardiovascular and intravascular disease. [ABSTRACT FROM AUTHOR]

Aging has important deleterious effects on the cardiovascular system. We sought to compare intraventricular kinetic energy (KE) in healthy subjects of varying ages with subjects with ventricular dysfunction to understand if changes in energetic momentum may predispose individuals to heart failure. Four-dimensional flow MRI was acquired in 35 healthy subjects (age: 1-67 yr) and 10 patients with left ventricular (LV) dysfunction (age: 28-79 yr). Healthy subjects were divided into age quartiles (1st quartile: <16 yr, 2nd quartile: 17-32 yr, 3rd quartile: 33-48 yr, and 4th quartile: 49-64 yr). KE was measured in the LV throughout the cardiac cycle and indexed to ventricular volume. In healthy subjects, two large peaks corresponding to systole and early diastole occurred during the cardiac cycle. A third smaller peak was seen during late diastole in eight adults. Systolic KE (P = 0.182) and ejection fraction (P = 0.921) were preserved through all age groups. Older adults showed a lower early peak diastolic KE compared with children (P < 0.0001) and young adults (P = 0.025). Subjects with LV dysfunction had reduced ejection fraction (P < 0.001) and compared with older healthy adults exhibited a similar early peak diastolic KE (P = 0.142) but with the addition of an elevated KE in diastasis (P = 0.029). In healthy individuals, peak diastolic KE progressively decreases with age, whereas systolic peaks remain constant. Peak diastolic KE in the oldest subjects is comparable to those with LV dysfunction. Unique age-related changes in ventricular diastolic energetics might be physiological or herald subclinical pathology. [ABSTRACT FROM AUTHOR]

Objectives To evaluate whether fibroblast growth factor 23 ( FGF-23) is related to frailty and to characterize the nature of their joint association with mortality. Design Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality. Setting Cardiovascular Health Study. Participants Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white). Measurements The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality. Results Mean estimated glomerular filtration rate ( eGFR) was 64 ± 17 mL/min per 1.73 m2. Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio ( HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other. Conclusion In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes. [ABSTRACT FROM AUTHOR]

Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1α reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1α increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1α and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1α. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC-1α expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease is a leading cause of morbidity and mortality in the United States. Heart age (the predicted age of a person's vascular system based on their cardiovascular risk factor profile) and its comparison with chronological age represent a new way to express risk for developing cardiovascular disease. This study estimates heart age and differences between heart age and chronological age (excess heart age) and examines racial, sociodemographic, and regional disparities in heart age among U.S. adults aged 30-74 years. Methods: Weighted 2011 and 2013 Behavioral Risk Factor Surveillance System data were applied to the sex-specific non-laboratory-based Framingham risk score models, stratifying the results by age and race/ethnic group, educational and income level, and state. These results were then translated into age-standardized heart age values, mean excess heart age was calculated, and the findings were compared across groups. Results: Overall, average predicted heart age for adult men and women was 7.8 and 5.4 years older than their chronological age, respectively. Statistically significant (p<0.05) racial/ethnic, sociodemographic, and regional differences in heart age were observed: heart age among non-Hispanic black men (58.7 years) and women (58.9 years) was greater than other racial/ethnic groups, including non-Hispanic white men (55.3 years) and women (52.5 years). Excess heart age was lowest for men and women in Utah (5.8 and 2.8 years, respectively) and highest in Mississippi (10.1 and 9.1 years, respectively). Conclusions and Implications for Public Health Practice: The predicted heart age among U.S. adults aged 30-74 years was significantly higher than their chronological age. Use of predicted heart age might 1) simplify risk communication and motivate more persons to live heart-healthy lifestyles and better comply with recommended therapeutic interventions, and 2) motivate communities to implement programs and policies that support cardiovascular health. [ABSTRACT FROM AUTHOR]

Human genetics is a powerful tool for discovering causal mediators of human disease and physiology. Cardiovascular diseases with late onset in the lifecourse have historically not been considered genetic diseases, but in recent years the contribution of a heritable factor has been established. More importantly, over the last decade genome-wide association studies (GWASs) have identified many loci associated with late-onset cardiovascular diseases including coronary artery disease, carotid artery disease, ischemic stroke, aortic aneurysm, peripheral vascular disease, atrial fibrillation, valvular disease and correlates of vascular and myocardial function. Here we review findings from GWASs considered statistically robust with regard to multiple testing (p < 5 × 10 − 8 ) for late-onset cardiovascular diseases and traits. Although for only a handful of the 92 genetic loci described here have the mechanisms underlying disease association been established, new and previously unsuspected pathways have been implicated for several conditions. Examples include a role for NO signaling in myocardial repolarization and sudden cardiac death and a role for the protein sortilin in lipid metabolism and coronary artery disease. Genetic loci with multiple trait associations have also provided novel biological insights. For example, of the 46 genetic loci associated with coronary artery disease, only 16 are also associated with conventional risk factors for cardiovascular disease whereas the remaining two thirds may reflect novel pathways. Much work remains to functionally characterize genetic loci and for clinical utility, but accruing insights into the biological basis of cardiovascular aging in human populations promise to point to novel therapeutic and preventive strategies. This article is part of a Special Issue entitled ‘SI:CV Aging’. [ABSTRACT FROM AUTHOR]

“Inside every old person is a young person wondering what happened.” So, what is aging? Aging is a manifestation of progressive, time-dependent failure of molecular mechanisms that create disorder within a system of DNA and its environment (nuclear, cytosolic, tissue, organ, organism, other organisms, society, terra firma, atmosphere, universe). Continuous signaling, transmitted with different kinetics across each of these environments, confers a “mutual enslavement” that creates ordered functions among the components within the system. Accrual of this molecular disorder over time, i.e. during aging, causes progressive changes in the structure and function of the heart and arteries that are quite similar in humans, non-human primates, rabbits and rats that compromise cardiovascular reserve function, and confer a marked risk for incident cardiovascular disease. Nearly all aspects of signaling within the DNA environment system within the heart and arteries become disordered with advancing age: Signals change, as does sensing of the signals, transmission of signals and responses to signals, impaired cell renewal, changes in the proteome due to alterations in genomic transcription, mRNA translation, and proteostasis. The density of some molecules becomes reduced, and post-translational modifications, e.g. oxidation and nitration phosphorylation, lead to altered misfolding and disordered molecular interactions. The stoichiometry and kinetics of enzymatic and those reactions which underlie crucial cardiac and vascular cell functions and robust reserve mechanisms that remove damaged organelles and proteins deteriorate. The CV cells generate an inflammatory defense in an attempt to limit the molecular disorder. The resultant proinflammatory milieu is not executed by “professional” inflammatory cells (i.e. white blood cells), however, but by activation of renin–angiotensin–aldosterone endothelin signaling cascades that leads to endothelial and vascular smooth muscle and cardiac cells' phenotype shifts, resulting in production of inflammatory cytokines. Progressive molecular disorder within the heart and arteries over time leads to an excessive allostatic load on the CV system, that results in an increase and “overshoot” in the inflammatory defense signaling. This age-associated molecular disorder-induced inflammation that accrues in the heart and arteries does not, itself, cause clinical signs or symptoms of CVD. Clinical signs and symptoms of these CVDs begin to emerge, however, when the age-associated inflammation in the heart and arteries exceeds a threshold. Thus, an emerging school of thought is that accelerated age-associated alterations within the heart and arteries, per se, ought to be considered to be a type of CVD, because the molecular disorder and the inflammatory milieu it creates within the heart and arteries with advancing age are the roots of the pathophysiology of most cardiovascular diseases, e.g. athersclerosis and hypertension. Because many effects of aging on the CV system can be delayed or attenuated by changes in lifestyle, e.g. diet and exercise, or by presently available drugs, e.g. those that suppress Ang II signaling, CV aging is a promising frontier in preventive cardiology that is not only ripe for, but also in dire need of attention! There is an urgency to incorporate the concept of cardiovascular aging as a disease into clinical medicine. But, sadly, the reality of the age-associated molecular disorder within the heart and ateries has, for the most part, been kept outside of mainstream clinical medicine. This article is part of a Special Issue entitled CV Aging. [ABSTRACT FROM AUTHOR]

DNA and histone methylation are well characterized epigenetic marks that are altered during the aging process. In aged cells and tissues, DNA cytosine tagging by methylation undergoes the so-called “epigenetic drift”, in parallel with a change in the methylated histone profile. Despite the large body of knowledge regarding age-dependent epigenetic changes, there are few reports related to this topic in the cardiovascular field. This review summarizes age-dependent changes in DNA and histone methylation with a specific focus on age-related cardiovascular diseases (CVDs). [ABSTRACT FROM AUTHOR]

Objectives To investigate the relationship between telomere length in peripheral blood white cells and cardiovascular function in a healthy, aging Han Chinese population. Methods In 2012, peripheral blood leukocytes were obtained from 139 healthy individuals in Beijing, China, and telomere restriction fragment (TRF) length was assayed using a digoxigenin-labeled hybridization probe in Southern blot assays. Indicators of cardiovascular function were also evaluated, including electrocardiograms (ECG), (RR, P, PR, QRS, ST and T intervals); blood pressure (BP), (SBP, DBP, PP, PPI); cardiovascular ultrasound (left ventricular ejection fraction, LVEF); mitral early and late diastolic peak flow velocity (MVE and MVA); and lipid indices (TC, TG, HDL, LDL, LCI). The relationships of these cardiovascular indictors to telomere length were evaluated. Results No correlations were found between telomere length and ECG, BP or lipid indices even after adjustment for age. Correlations were found between TFR length and some cardiovascular ultrasound indictors (D, MVEA, MVEDT, MVES, MVEL, MVEI, IMT), but these were not seen after adjusting for age. Conclusions We did not find that leukocyte TFR length was associated with cardiovascular ultrasound indictors, ECG, BP, or lipid indices in this population of healthy Han Chinese individuals. Telomere length may serve as a genetic factor in biological aging. [ABSTRACT FROM AUTHOR]

Aging is associated with declines in the neuromuscular and cardiovascular systems, resulting in an impaired capacity to perform daily activities. Frailty is an age-associated biological syndrome characterized by decreases in the biological functional reserve and resistance to stressors due to changes in several physiological systems, which puts older individuals at special risk of disability. To counteract the neuromuscular and cardiovascular declines associated with aging, as well as to prevent and treat the frailty syndrome, the strength and endurance training seems to be an effective strategy to improve muscle hypertrophy, strength and power output, as well as endurance performance. The first purpose of this review was discuss the neuromuscular adaptations to strength training, as well as the cardiovascular adaptations to endurance training in healthy and frail elderly subjects. In addition, the second purpose of this study was investigate the concurrent training adaptations in the elderly. Based on the results found, the combination of strength and endurance training (i.e., concurrent training) performed at moderate volume and moderate to high intensity in elderly populations is the most effective way to improve both neuromuscular and cardiorespiratory functions. Moreover, exercise interventions that include muscle power training should be prescribed to frail elderly in order to improve the overall physical status of this population and prevent disability. [ABSTRACT FROM AUTHOR]

Abstract: Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70±4years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200mg/day); exercise training & placebo; no exercise training & Alagebrium (200mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9±4.5 to 27.2±4.6mLO2/min/kg, p <0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging. [Copyright &y& Elsevier]

Whilst there is a small literature on the cardiovascular toxicity of opiates, there is no detailed antemortem data on non-cardiovascular patient populations. A cross-sectional and longitudinal naturalistic observational study was performed comparing methadone ( N = 71)-, buprenorphine ( N = 593)-, naltrexone ( N = 23)-treated patients with controls ( N = 576) on indices of arterial stiffness and vascular age by Pulse Wave Analysis in primary care, 2006-2011. Controls were younger 29.96 ± 0.45 (mean ± SEM) vs. 34.00 ± 0.34-39.22 ± 1.11 years (all P < 0.005) and had fewer smokers (15.9 % vs. 86.9 %-92.96 %, all P < 0.0001). The sex ratio was similar (69.6 vs. 67.7 % male, P = 0.46). These baseline differences were controlled for by multiple regression. Linear regression of vascular age, central augmentation pressure, central augmentation index and other measures against chronologic age showed significant protective effects by treatment group against the treatment standard of methadone, in both sexes in additive and interactive models (all P < 0.02). Interactive terms in treatment type remained significant including all conventional risk factors accounting for differing opiate exposures. The principal findings from multiple regression were confirmed in the time series analysis up to 5 years by repeated measures nonlinear regression. These studies show that the deleterious impact of chronic opiate pharmacotherapy on vascular age and arterial stiffness varies significantly by treatment type. [ABSTRACT FROM AUTHOR]

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The agerelated accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. [ABSTRACT FROM AUTHOR]

Background. Exercise intolerance is the primary chronic symptom in patients with heart failure and preserved ejection fraction (HFPEF), the most common form of heart failure in older persons, and can result from abnormalities in cardiac, vascular, and skeletal muscle, which can be further worsened by physical deconditioning. However, it is unknown whether skeletal muscle abnormalities contribute to exercise intolerance in HFPEF patients. Methods. This study evaluated lean body mass, peak exercise oxygen consumption (VO2), and the short physical performance battery in 60 older (69±7 years) HFPEF patients and 40 age-matched healthy controls. Results. In HFPEF versus healthy controls, peak percent total lean mass (60.1±0.8% vs. 66.6±1.0%, p < .0001) and leg lean mass (57.9±0.9% vs. 63.7±1.1%, p = .0001) were significantly reduced. Peak VO2 was severely reduced including when indexed to leg lean mass (79.3±18.5 vs. 104.3±20.4ml/kg/min, p < .0001). Peak VO2 was correlated with percent total (r = .51) and leg lean mass (.52, both p < .0001). The slope of the relationship of peak VO2 with percent leg lean mass was markedly reduced in HFPEF (11±5ml/min) versus healthy controls (36±5ml/min; p < .001). Short physical performance battery was reduced (9.9±1.4 vs. 11.3±0.8) and correlated with peak VO2 and total and leg lean mass (all p < .001). Conclusion. Older HFPEF patients have significantly reduced percent total and leg lean mass and physical functional performance compared with healthy controls. The markedly decreased peak VO2 indexed to lean body mass in HFPEF versus healthy controls suggests that abnormalities in skeletal muscle perfusion and/or metabolism contribute to the severe exercise intolerance in older HFPEF patients. [ABSTRACT FROM PUBLISHER]

Abstract: The application of methods drawn from nonlinear and stochastic dynamics to the analysis of cardiovascular time series is reviewed, with particular reference to the identification of changes associated with ageing. The natural variability of the heart rate (HRV) is considered in detail, including the respiratory sinus arrhythmia (RSA) corresponding to modulation of the instantaneous cardiac frequency by the rhythm of respiration. HRV has been intensively studied using traditional spectral analyses, e.g. by Fourier transform or autoregressive methods, and, because of its complexity, has been used as a paradigm for testing several proposed new methods of complexity analysis. These methods are reviewed. The application of time–frequency methods to HRV is considered, including in particular the wavelet transform which can resolve the time-dependent spectral content of HRV. Attention is focused on the cardio-respiratory interaction by introduction of the respiratory frequency variability signal (RFV), which can be acquired simultaneously with HRV by use of a respiratory effort transducer. Current methods for the analysis of interacting oscillators are reviewed and applied to cardio-respiratory data, including those for the quantification of synchronization and direction of coupling. These reveal the effect of ageing on the cardio-respiratory interaction through changes in the mutual modulation of the instantaneous cardiac and respiratory frequencies. Analyses of blood flow signals recorded with laser Doppler flowmetry are reviewed and related to the current understanding of how endothelial-dependent oscillations evolve with age: the inner lining of the vessels (the endothelium) is shown to be of crucial importance to the emerging picture. It is concluded that analyses of the complex and nonlinear dynamics of the cardiovascular system can illuminate the mechanisms of blood circulation, and that the heart, the lungs and the vascular system function as a single entity in dynamical terms. Clear evidence is found for dynamical ageing. [Copyright &y& Elsevier]

Abstract: Aging leads to changes in cardiac structure and function. Evidence suggests that the practice of regular exercise may prevent disturbances in the cardiovascular system during aging. We studied the effects of aging on the morphology and morphometry of cardiac neurons in Wistar rats and investigated whether a lifelong moderate exercise program could exert a protective effect toward some deleterious effects of aging. Aging caused a significant decline (28%) in the number of NADH-diaphorase-stained cardiac neurons. Animals submitted to a daily session of 60min, 5day/week, at 1.1km/h of running in treadmill over the entire life span exhibited a reversion of the observed decline in the number of cardiac neurons. However, most interesting was that the introduction of this lifelong exercise protocol dramatically altered the sizes of cardiac neurons. There was a notable increase in the percentage of small neurons in the rats of the exercise group compared to the sedentary animals. This is the first time that a protective effect of lifelong regular aerobic exercise has been demonstrated on the deleterious effects of aging in cardiac neurons. [Copyright &y& Elsevier]

Abstract: Left ventricular–arterial (VA) coupling has been recognized to be of great significance in understanding both the global and local mechanical performance of the circulatory system. In this study, a closed-loop multi-scale model of the human cardiovascular system is established for the purpose of studying the coupled VA hemodynamic changes during aging. Obtained results show that age-associated changes in arterial properties have some negative but relatively small influences on left ventricular (LV) mechanical performance, whereas they progressively increase LV and aortic systolic pressures, and aortic pulse pressure during aging. Wave analysis reveals that increased aortic characteristic impedance and premature wave reflection induced by arterial stiffening are two coexistent factors responsible for aortic systolic hypertension and increased aortic pulse pressure at old age. In contrast, aortic dilatation can partly counteract the negative influences of arterial stiffening. Coupled LV-systolic and arterial stiffening (a constant VA coupling index) well preserves LV mechanical performance given normal LV diastolic function during aging, but with a concomitant further elevation of LV and aortic systolic pressures. Furthermore, it is found that the states of arterial, LV-systolic and diastolic stiffness can be distinguished by investigating the sensitivity of LV-systolic pressure to various cardiac indices. [Copyright &y& Elsevier]

The cardiovascular and thermoregulatory systems are considered to be susceptible in the aged population, but little is known about baseline cardiac and thermoregulatory homeostasis in rodent models of aging. Radiotransmitters were implanted in male, Brown Norway rats obtained at 4, 12, and 24 months to monitor the electrocardiogram (ECG), interbeat interval (IBI), heart rate (HR), core temperature (Tc), and motor activity (MA). There was no significant effect of age on resting HR and MA. Daytime Tc of the 24-month-old rats was significantly elevated above those of the 4- and 12-month-old groups. Variability of the IBI was highest in the 24-month-old rats. The elevation in daytime Tc beginning around 8 months of age may be a physiological biomarker of aging and may be an important factor to consider in studies using caloric restriction-induced hypothermia to increase longevity. [ABSTRACT FROM AUTHOR]

Over the past decade, numerous studies have shown that increased aortic stiffness is associated with major cardiovascular disease end points, including heart disease, stroke, and kidney disease. Cardiac abnormalities and enhanced atherogenesis in the setting of increased pulsatile load on heart and arteries have been well described. However, recent studies have shown a further association between excessive pressure pulsatility and a number of afflictions of aging that share a predominant microvascular etiology, including many forms of kidney disease and cognitive impairment. In these disorders, microvascular remodeling and impaired regulation of local blood flow, which are related to large artery stiffness and pressure pulsatility, are associated with evidence of diffuse microscopic tissue damage. This brief review will summarize age-related changes in aortic and peripheral vascular function and will discuss potential mechanisms leading from changes in properties of large arteries to excessive pressure pulsatility, abnormal microvascular structure and function, and end-organ dysfunction and damage. [ABSTRACT FROM AUTHOR]

Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (L-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including poly- amine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that age is the chief risk factor for atherosclerotic cardiovascular diseases, but the molecular mechanisms that underlie the increase in risk conferred by aging remain unclear. Evidence suggests that the cardiovascular repair system is impaired with advancing age, thereby inducing age-associated cardiovascular dysfunction. Such impairment could be attributable to senescence of cardiovascular tissues at the cellular level as a result of telomere shortening, DNA damage, and genomic instability. In fact, the replicative ability of cardiovascular cells, particularly stem cells and/or progenitor cells, has been shown to decline with age. Recently, considerable progress has been made in understanding the pathogenesis of human progeroid syndromes that feature cardiovascular aging. Most of the genes responsible have a role in DNA metabolism, and mutated forms of these genes result in alterations of the response to DNA damage and in decreased cell proliferation, which might be common features of a phenotype of aging. Here we review the cardiovascular research on cellular senescence, stem cell aging, and progeroid syndromes and discuss the potential role of cellular senescence in the mechanisms underlying both normal aging and premature aging syndromes. [ABSTRACT FROM AUTHOR]

The article reports on the study conducted to determine the association of on-treatment diastolic blood pressure (BP), mortality rate, and cardiovascular events in the "Systolic Hypertension" in Europe. Elderly patients diagnosed with systolic hypertension received active study drug in the first phase of the study, followed by analysis on the outcome of multivariate Cox regression analysis, during the receipt of placebo and during active treatment. The study shows that intensified antihypertensive treatment, can prevent cardiovascular attacks when systolic BP of older patients with systolic hypertension is not under control.

Background: Although generally assumed to be an adaptive response to increased blood pressure (BP), arterial stiffness is now recognized as an independent predictor of cardiovascular (CV) events [1]. Moreover it precedes hypertension in at least two mouse models [2-3]. Therefore, the present study aims to investigate the temporal development of aortic stiffening and peripheral blood pressure (BP) alterations in spontaneously ageing mice. Methods: A longitudinal cardiovascular characterization of spontaneously ageing C57Bl6 mice (2, 4, 6, 9, 12 and 24- month old) (male, n > 8) was performed. This includes in vivo analysis of peripheral BP (Coda) and aortic pulse wave velocity (aPWV, Vevo2100), combined with ex vivo aortic studies of isometric reactivity (organ baths) and aortic stiffness measurements (Peterson modulus, Ep) in the Rodent Oscillatory Tension set-up for Arterial Compliance (ROTSAC). Results: In vivo and ex vivo characterisation confirms that aortic stiffness precedes peripheral BP alterations in spontaneously ageing C57Bl6 mice, with significantly increased aPWV from 6 month of age (Figure A), whereas peripheral BP measurement only shows elevated pulse pressure in 24 month old mice (30% increase vs. all other ages, Figure B). Ex vivo investigation of the thoracic aorta further reveals that the aortic stiffening is both contraction-independent (Figure C) and dependent (Figure D), since older mice display increased contractions to phenylephrine (PE) (Figure E and F). Conclusion: Spontaneously ageing C57Bl6 mice present with significant aortic stiffness by 6-months of age, which is both contraction-dependent and independent in origin. Aortic stiffness thereby precedes the development of peripheral BP alterations by 18 months. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction and increased arterial stiffness contribute to multiple vascular diseases and are hallmarks of cardiovascular aging. To investigate the effects of aging on shear stress-induced endothelial nitric oxide (NO) signaling and aortic stiffness, we studied young (3-4 mo) and old (22-24 mo) rats in vivo and in vitro. Old rat aorta demonstrated impaired vasorelaxation to acetylcholine and sphingosine 1-phosphate, while responses to sodium nitroprusside were similar to those in young aorta. In a customized flow chamber, aortic sections preincubated with the NO-sensitive dye, 4-amino-5-methyl-amino-2′,7′-difluorofluorescein diacetate, were subjected to steady-state flow with shear stress increase from 0.4 to 6.4 dyn/cm². In young aorta, this shear step amplified 4-amino-5-methylamino-2′,7′-difluorofluorescein fluorescence rate by 70.6 ± 13.9%, while the old aorta response was significantly attenuated (23.6 ± 11.3%, P < 0.05). Endothelial NO synthase (eNOS) inhibition, by ZV°-monomethyl-L-arginine, abolished any fluorescence rate increase. Furthermore, impaired NO production was associated with a significant reduction of the phosphorylated-Akt-to-total-Akt ratio in aged aorta (P < 0.05). Correspondingly, the phosphorylated-to-total-eNOS ratio in aged aortic endothelium was markedly lower than in young endothelium (P < 0.001). Lastly, pulse wave velocity, an in vivo measure of vascular stiffness, in old rats (5.99 ± 0.191 m/s) and in Nω-nitro-L-arginine methyl ester-treated rats (4.96 ± 0.118 m/s) was significantly greater than that in young rats (3.64 ± 0.068 m/s, P < 0.001). Similarly, eNOS-knockout mice demonstrated higher pulse wave velocity than wild-type mice (P < 0.001). Thus impaired Akt-dependent NO synthase activation is a potential mechanism for decreased NO bio-availability and endothelial dysfunction, which likely contributes to age-associated vascular stiffness. [ABSTRACT FROM AUTHOR]

Objective: To characterise the comparative potency of optically pure (R)- and (S)-verapamil as regards negative dromotropic effects on atrioventricular (AV) node conduction and to compare the hemodynamic effects of single doses of the enantiomers in healthy volunteers. Methods: Eight healthy volunteers received a single oral dose of 120 mg (S)-verapamil, 480 mg (R)-verapamil, 240 mg racemic verapamil (rac-verapamil) or placebo on 4 separate occasions. Serum concentrations of (R)- and (S)-verapamil were measured up to 24 h. Cardiovascular effects were assessed by electrocardiography, measurement of blood pressure and transthoracic impedance cardiography (cardiac output and total peripheral resistance). The comparative potency of (R)- and (S)-verapamil with regard to prolongation of the PR interval in the surface ECG was estimated by use of the areas under the effect-time and serum concentration-time curves and linear regression analyses of per cent change in PR interval from baseline versus the logarithm of serum (R)- or (S)-verapamil concentration. Results: The PR interval was significantly prolonged after all verapamil treatments as compared with placebo. (S)-verapamil was 20.6–21.8 times more potent than (R)-verapamil with regard to negative dromotropic effects. (R)-verapamil caused a significantly greater maximum reduction in the mean arterial pressure (MAP) than placebo [15.9±6.8 versus 8.7±3.2 mmHg (mean±SD); 95% CI on the difference, 0.79–13.7 mmHg; p<0.05], whereas MAP was not affected by the other verapamil treatments. No significant changes were observed in heart rate, cardiac output and total peripheral resistance after any verapamil treatment as compared with placebo. Conclusions: (S)-verapamil was about 20 times more potent than (R)-verapamil with regard to negative dromotropic effects on AV node conduction. (R)-verapamil but not (S)-verapamil significantly reduced the MAP as compared with placebo. [ABSTRACT FROM AUTHOR]

The development of myocardial and large vessel stiffness with aging underlies the development of diastolic heart failure and isolated systolic hypertension. Nonenzymatic reaction between glucose and proteins (Maillard reaction) leading to collagen crosslinking in the myocardium and arterial wall has been implicated in age-related increase in cardiovascular stiffness. In the present issue, Chang et al. show that aminoguanidine, an inhibitor of protein crosslinking, retards age-related decline in the elastic properties of the left ventricle and arteries. The significance of these findings is discussed in this commentary. [ABSTRACT FROM AUTHOR]

In light of previous observations that the range of arterial pressures over which cerebral blood flow is autoregulated differs dramatically in neonates and adults, the present experiments explored the hypothesis that pressure-induced intrinsic arterial tone is regulated differently in neonatal and adult cerebral arteries. In cannulated and pressurized endothelium-intact mouse cerebral arteries < 150 μm in diameter, active intrinsic tone was evident at intraluminal pressures as low as 10 mmHg in neonatal arteries, but only at pressures of 60 mmHg or greater in adult arteries. Administration of 10 μM indomethacin produced no significant effect on tone at any pressure in either neonatal or adult arteries, but subsequent addition of 100 μM nitroarginine methyl ester (NAME) significantly vasoconstricted both neonatal and adult arteries at all pressures. Conversely, administration of 100 μM NAME alone significantly vasoconstricted adult arteries only, and subsequent addition of 10 μM indomethacin produced a significant additional vasoconstriction in adult arteries only, indicating an important interaction between the nitric oxide synthase and cyclooxygenase pathways, at least in adult arteries. In the presence of both indomethacin and NAME, intrinsic tone was significantly greater in neonatal than adult arteries, but when the endothelium was removed, tone was similar in neonatal and adult arteries at all pressures. Together, these results suggest that pressure-induced myogenic tone is regulated similarly in neonatal and adult mouse cerebral arteries but that the contribution of endothelial vasoactive factors to intrinsic tone is highly age dependent. [ABSTRACT FROM AUTHOR]

Presents a study which determined whether angiotensin II could reverse age-related, impaired beta-adrenergic receptor-mediated vasorelaxation. Characteristics of an aged cardiovascular system; Methodology; Results and discussion.

Presents information on a stud which examined the use of color kinesis images in the assessment of left ventricular wall motion over a wide range of ages. Methodology of the study; Results and discussion on the study.

SummaryBackground: Previous meta-analysis of outcome trials in hypertension have not specifically focused on isolated systolic hypertension or they have explained treatment benefit mainly in function of the achieved diastolic blood pressure reduction. We therefore undertook a quantitative overview of the trials to further evaluate the risks associated with systolic blood pressure in treated and untreated older patients with isolated systolic hypertensionMethods: Patients were 60 years old or more. Systolic blood pressure was 160 mm Hg or greater and diastolic blood pressure was less than 95 mm Hg. We used non-parametric methods and Cox regression to model the risks associated with blood pressure and to correct for regression dilution bias. We calculated pooled effects of treatment from stratified 2x2 contingency tables after application of Zelen's test of heterogeneity.Findings: In eight trials 15693 patients with isolated systolic hypertension were followed up for 3.8 years (median). After correction for regression dilution bias, sex, age, and diastolic blood pressure, the relative hazard rates associated with a 10 mm Hg higher initial systolic blood pressure were 1.26 (p=0.0001) for total mortality, 1.22 (p=0.02) for stroke, but only 1.07 (p=0.37) for coronary events. Independent of systolic blood pressure, diastolic blood pressure was inversely correlated with total mortality, highlighting the role of pulse pressure as risk factor.Active treatment reduced total mortality by 13% (95% CI 2-22, p=0.02), cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 23%. The number of patients to treat for 5 years to prevent one major cardiovascular event was lower in men (18 vs 38), at or above age 70 (19 vs 39), and in patients with previous cardiovascular complications (16 vs 37).Interpretation: Drug treatment is justified in older patients with isolated systolic hypertension whose systolic blood pressure is 160... [ABSTRACT FROM AUTHOR]

Characterizes the effects of aging on autonomic mediation of heart rate, lung volume and interrelationships between lung volume and heart rate. Demonstration of differences in individual heart rate, lung volume time series content and delay in information transfer between lung volume and heart rate.

Explores the mechanisms of normal aging of the renal and cardiovascular systems and evaluates the effect of hypotensive treatment with angiotensin I-converting enzyme inhibitor on the processes. Increase in perfusion pressure (PP) at onset of perfusion; Disruption of endothelial function and baseline PP; Antagonism of norepinephrine vasoconstriction.

Investigates whether age-related changes in alpha-adrenergic-mediated responses to muscular contraction contribute to age-related changes in cardiovascular responses associated with advanced age. Effect of age on cardiovascular variables at baseline; Effect of adrenergic blockade on age-related hemodynamic responses to muscular contraction.

Discusses existing knowledge on the physiology of cardiovascular aging. Assessment of aging in humans; Value of animal models; General aspects of the longitudinal axis of cardiovascular function; Analysis of the heart; Analysis of the vascular system; Blood pressure; Neurohormonal control mechanisms; Cardiovascular responses to exercise and training; Implications on the methodologies of research.

Discusses age-related changes in cardiovascular responses to catecholamines. Age-related differences in contractile responses to dopamine; Increase atrioventricular-atrioventricular interval and atrioventricular conduction in senescent hearts; Differences in responses to myocardial catecholamine release.

Reports on the prevalence of intermittent claudication (IC) in ambulatory community-resident adults age 65 years or older. Comparison of cardiovascular risk factors and comorbidity of persons with and without IC; Examination of the independent association of IC in predicting all cause and cardiovascular mortality, myocardial infarction, stroke and disability.

Compares the relationship between age and relative and absolute cardiovascular responses for males exposed to the Stroop task or mental challenge. Selection of subjects; Measurement of cardiac performance; Procedure of Stroop task; Discussion of statistical analysis and results; Exhibition of greater absolute cardiovascular response and reduced beta-adrenergic response for the old.

In this issue of Cell, Loffredo et al. demonstrate that exposing an old mouse to the circulatory system of a young mouse reverses age-related cardiac hypertrophy. The authors demonstrate that this effect can be recapitulated by treating old mice with growth and differentiation factor 11 (GDF11). These data suggest that GDF11 therapy may be a useful tool in combating age-related cardiac hypertrophy. [ABSTRACT FROM AUTHOR]