Increase In Pulse Wave Velocity Research Articles

Pulse Wave Velocity in Kawasaki Disease.

Kawasaki disease (KD) is an acute childhood febrile disease of unknown etiology. It exhibits not only coronary artery aneurysms in some cases but also systemic vasculitis. Whether KD is associated with accelerated atherosclerosis remains debatable. The measurement of pulse wave velocity (PWV) is useful as a simple, noninvasive measurement of arterial stiffness, an atherosclerotic manifestation. We herein present a systematic review of clinical studies that focused on PWV in patients with KD. A PubMed-based search identified 8 eligible studies published until June 2015. The PWV of patients with KD, regardless of antecedent coronary artery lesions, was high relative to controls, even though their blood pressure appeared to be similar. Although definitive conclusions cannot be made with the limited information, patients with KD may be at risk of systemic atherosclerosis in association with arterial stiffness. Further research, including longitudinal and outcome studies, is needed to determine the clinical significance of a potential increase in PWV in patients with KD.

Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice.

BackgroundVascular stiffening, a risk factor for cardiovascular disease, is accelerated, particularly in women with obesity and type 2 diabetes. Preclinical evidence suggests that dipeptidylpeptidase-4 (DPP-4) inhibitors may have cardiovascular benefits independent of glycemic lowering effects. Recent studies show that consumption of a western diet (WD) high in fat and simple sugars induces aortic stiffening in female C57BL/6J mice in advance of increasing blood pressure. The aims of this study were to determine whether administration of the DPP-4 inhibitor, linagliptin (LGT), prevents the development of aortic and endothelial stiffness induced by a WD in female mice.MethodsC56Bl6/J female mice were fed a WD for 4 months. Aortic stiffness and ex vivo endothelial stiffness were evaluated by Doppler pulse wave velocity (PWV) and atomic force microscopy (AFM), respectively. In addition, we examined aortic vasomotor responses and remodeling markers via immunohistochemistry. Results were analyzed via 2-way ANOVA, p < 0.05 was considered as statistically significant.ResultsCompared to mice fed a control diet (CD), WD-fed mice exhibited a 24 % increase in aortic PWV, a five-fold increase in aortic endothelial stiffness, and impaired endothelium-dependent vasodilation. In aorta, these findings were accompanied by medial wall thickening, adventitial fibrosis, increased fibroblast growth factor 23 (FGF-23), decreased Klotho, enhanced oxidative stress, and endothelial cell ultrastructural changes, all of which were prevented with administration of LGT.ConclusionsThe present findings support the notion that DPP-4 plays a role in development of WD-induced aortic stiffening, vascular oxidative stress, endothelial dysfunction, and vascular remodeling. Whether, DPP-4 inhibition could be a therapeutic tool used to prevent the development of aortic stiffening and the associated cardiovascular complications in obese and diabetic females remains to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0414-5) contains supplementary material, which is available to authorized users.

Cardiovascular care for older adults: hypertension and stroke in the older adult.

Hypertension and cerebrovascular disease incidence and prevalence rise dramatically with age, owing to longer exposure time to age-associated alterations in vascular function and structure and cardiovascular risk factors. This chapter is aimed at connecting age-related alterations in vascular function and structure to the resultant target organ damage, and to raise awareness of unique presentations and treatment strategies for hypertension and stroke in older adults. Much of this chapter builds on the unique physiology of the older adult, as previously described by Dai, et al.,[1] and applied to the conditions of hypertension and stroke here. Arterial changes with aging include increased calcium deposition, collagen content, and collagen cross-linking, increased intima-media thickness, increased reactive oxygen species and a pro-inflammatory state and increased apoptosis of vascular smooth muscle cells. These changes lead to stiffer vessels that demonstrate less systolic compliance and diastolic elasticity, increased pulse wave velocity, and increased pulse pressure. The early reflected wave and augmented systolic pressure characteristic of arterial stiffness create greater demands on the left ventricle, resulting in left ventricular hypertrophy and impaired relaxation, which ultimately lead to increased left atrial pressure and size. Coupled with changes in endothelial function, neurohormonal regulation and renal function, these hemodynamic processes create the unique physiology of the older adult, manifest by isolated systolic hypertension, target organ damage and cardiovascular disease (CVD).

Chemosensitivity, Cardiovascular Risk, and the Ventilatory Response to Exercise in COPD.

COPD is associated with elevated cardiovascular risk and a potentiated ventilatory response to exercise. Enhanced carotid chemoreceptor (CC) activity/sensitivity is present in other clinical conditions, has been shown to contribute to sympathetic vasoconstrictor outflow, and is predictive of mortality. CC activity/sensitivity, and the resulting functional significance, has not been well examined in COPD. We hypothesized that CC activity/sensitivity would be elevated in COPD, and related to increased pulse wave velocity (a marker of CV risk) and the ventilatory response to exercise. Methods: 30 COPD patients and 10 healthy age-matched controls were examined. Participants performed baseline cardiopulmonary exercise and pulmonary function testing. CC activity was later evaluated by the drop in ventilation with breathing 100% O2, and CC sensitivity was then assessed by the ventilatory response to hypoxia (ΔVE/ΔSpO2). Peripheral arterial stiffness was subsequently evaluated by measurement of pulse wave velocity (PWV) using applanation tonometry while the subjects were breathing room air, and then following chemoreceptor inhibition by breathing 100% O2 for 2 minutes. Results: CC activity, CC sensitivity, PWV and the ventilatory response to exercise were all increased in COPD relative to controls. CC sensitivity was related to PWV; however, neither CC activity nor CC sensitivity was related to the ventilatory response to exercise in COPD. CC inhibition by breathing 100% O2 normalized PWV in COPD, while no effect was observed in controls. Conclusion: CC activity and sensitivity are elevated in COPD, and appear related to cardiovascular risk; however, CC activity/sensitivity does not contribute to the potentiated ventilatory response to exercise.

Clinical predictive factors in diabetic kidney disease progression.

Diabetic kidney disease (DKD) represents a major component of the health burden associated with type 1 and type 2 diabetes. Recent advances have produced an explosion of ‘novel’ assay‐based risk markers for DKD, though clinical use remains restricted. Although many patients with progressive DKD follow a classical albuminuria‐based pathway, non‐albuminuric DKD progression is now well recognized. In general, the following clinical and biochemical characteristics have been associated with progressive DKD in both type 1 and type 2 diabetes: increased hemoglobin A1c, systolic blood pressure, albuminuria grade, early glomerular filtration rate decline, duration of diabetes, age (including pubertal onset) and serum uric acid; the presence of concomitant microvascular complications; and positive family history. The same is true in type 2 diabetes for male sex category, in patients following an albuminuric pathway to DKD, and also true for the presence of increased pulse wave velocity. The following baseline clinical characteristics have been proposed as risk factors for DKD progression, but with further research required to assess the nature of any relationship: dyslipidemia (including low‐density lipoprotein, total and high‐density lipoprotein cholesterol); elevated body mass index; smoking status; hyperfiltration; decreases in vitamin D, hemoglobin and uric acid excretion (all known consequences of advanced DKD); and patient test result visit‐to‐visit variability (hemoglobin A1c, blood pressure and high‐density lipoprotein cholesterol). The development of multifactorial ‘renal risk equations’ for type 2 diabetes has the potential to simplify the task of DKD prognostication; however, there are currently none for type 1 diabetes‐specific populations. Significant progress has been made in the prediction of DKD progression using readily available clinical data, though further work is required to elicit the role of several variables, and to consolidate data to facilitate clinical implementation.

Association of vessel stiffness parameters and subclinical atherosclerosis and mass of bone tissue in postmenopausal women

Aim. To study relation of vessel wall stiffness parameters and subclinical atherosclerosis with mineral density of bone (MDB) in postmenopausal women. Material and methods. Into a simultaneous study were included 107 patients at the age 45-82 y.o., being monitored in outpatient circumstances and signed informed consent. We did not include patients with any clinical sign of atherosclerosis, malignancies, secondary osteoporosis causing diseases, as those who had been taking drugs influencing calcium metabolism or vessel wall stiffness parameters. The intima-media complex (IMC), presence of absence of atherosclerotic lesions (AL) were studied via duplex scanning. Pulse wave velocity (PWV), augmentation index (AI) were measured by application tonometry (SphygmoCor). MDB of the spine and of proximal femur was measured via double energetic x-ray absorptiometry. Statistics done with the software by Statistical Analysis System (USA). Results. With the increase of menopause duration, there was gradual increase of PWV, AI, IMC and decrease of MDB. Maximal values of vessel stiffness and the highest MDB were found in 10 years after menopause. Osteoporosis was diagnosed in 27 (25%) of patients, osteopenia in 38 (36%), normal MDB in 42 (39%). The risk of bone mass decrease and of osteoporosis development increased 3 times in higher values of PWV (≥10 m/s) (р 9 mm (р=0,02) and in 2,45 times if AL in carotid arteries were found (p=0,03). During multifactor regression analysis, negative relation of AI, IMC thickness and MDB remained, though association with PWV and AL was not proven. Conclusion. With the increase of menopause duration there was increase of vessel rigidity parameters PWV, AL, IMC thickness and bone mass loss. Decrease of MDB in postmenopausal women is associated with high values of PWV, IA, IMC thickness and AL amount, but as independent predictors of low bone mass were only AI and IMC.

Ambulatory (24 h) blood pressure and arterial stiffness measurement in Marfan syndrome patients: a case control feasibility and pilot study.

BackgroundThe aim of this work is the investigation of measures of ambulatory brachial and aortic blood pressure and indices of arterial stiffness and aortic wave reflection in Marfan patients.MethodsA case-control study was conducted including patients with diagnosed Marfan syndrome following Ghent2 nosology and healthy controls matched for sex, age and daytime brachial systolic blood pressure. For each subject a 24 h ambulatory blood pressure and 24 h pulse wave analysis measurement was performed.ResultsAll parameters showed a circadian pattern whereby pressure dipping was more pronounced in Marfan patients. During daytime only Marfan patients with aortic root surgery showed increased pulse wave velocity. In contrast, various nighttime measurements, wave reflection determinants and circadian patterns showed a significant difference.ConclusionsThe findings of our study provide evidence that ambulatory measurement of arterial stiffness parameters is feasible and that these determinants are significantly different in Marfan syndrome patients compared to controls in particular at nighttime. Further investigation is therefore indicated.

Clinical Implications

HomeHypertensionVol. 67, No. 5Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 May 2016https://doi.org/10.1161/HYPERTENSIONAHA.116.07596Hypertension. 2016;67:801Protein Aggregation in Aged and Hypertensive Heart (p 1006)Download figureDownload PowerPointDegenerative diseases are largely defined by protein aggregates in affected tissues. We analyzed cardiac aggregates for changes during normal aging and after sustained angiotensin II–induced hypertension. Detergent-insoluble aggregates were isolated from mouse hearts, and constituent proteins were characterized. Gel quantitation indicated pronounced shifts with aging and hypertension, and mass spectrometry identified proteins that altered significantly. Because both aged and hypertensive hearts undergo fibrosis, we examined aggregates from cardiac myofibroblasts. During in vitro senescence, myofibroblasts accrued aggregates containing many proteins that accumulated during normal aging or induced hypertension. There was significant overlap of identified proteins that altered in abundance within cardiac aggregates as mice aged naturally or were made hypertensive by angiotensin II infusion or as cardiac myofibroblasts underwent replicative aging. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual. Many of these proteins relate to inflammation, stress response, and protein homeostasis and have been previously associated with age-progressive neurodegenerative diseases. Cardiac senescence-associated pathology may be considered Alzheimer disease of the heart based on overlap in risk factors (such as ApoE alleles) and protective drugs (eg, aspirin), and the overlap in aggregation components may implicate a common underlying molecular mechanism. Clinicians should be mindful that, as we develop new mechanistic insights and novel therapies for either disease, they might also be applicable to the other.Vascular Function and Cardiovascular Outcomes (p 1045)Nitroglycerine-induced vasodilation may be not only a control test for flow-mediated vasodilation (FMD) measurement but also a useful marker of the grade of atherosclerosis. Although it is well known that FMD is an independent predictor of future cardiovascular events, it has been also shown that FMD is not associated with future cardiovascular events in cases of a relatively low grade of atherosclerosis and in cases of a severe stage of atherosclerosis, after adjusting for various confounders. There is no previous study investigating the association between FMD combined with nitroglycerine-induced vasodilation and cardiovascular events. We evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events in 402 subjects, including healthy subjects and patients with cardiovascular disease. There were significant differences between the Kaplan–Meier curves for first major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, and revascularization) in subgroups of subjects categorized as being above or below the cutoff values for FMD and nitroglycerine-induced vasodilation (Figure). After adjustment for age, sex, body mass index, and cardiovascular risk factors, below cutoff nitroglycerine-induced vasodilation, especially in combination with below cutoff FMD, remained a strong independent indicator of cardiovascular events. FMD combined with nitroglycerine-induced vasodilation may be useful as a surrogate marker of future cardiovascular events.Download figureDownload PowerPointMaladaptive Adventitial Remodeling in Hypertension (p 890)Download figureDownload PowerPointThe primary function of large arteries is to store elastic energy during systole and to use this energy to augment blood flow during diastole. In this way, healthy central arteries decrease the workload on the heart and promote perfusion of critical organs such as the kidney, brain, and heart during diastole. The aorta stiffens in diverse conditions—including aging, hypertension, diabetes mellitus, obesity, and cigarette smoking—which reduces its capacitance, or Windkessel function. Such stiffening is often indicated clinically by an increase in pulse wave velocity and is a harbinger of renal failure, stroke, dementia, and heart failure. Using a mouse model of hypertension, we found that an early, exuberant deposition of collagen thickens the adventitia well beyond that needed to normalize the increased biaxial wall stresses that result from high blood pressure (note striking deposition of collagen in the adventitia in hypertension in the Figure). Moreover, this maladaptive response appears to be driven in large part by inflammation in the adventitia. The most striking consequence of the maladaptive remodeling is a profound loss of energy storage capability, that is, a reduced Windkessel function. This loss occurs because the thickened adventitial collagen limits cyclic outward expansion of the media and thus deformation of the energy storing elastic fibers. These results highlight the need to therapeutically address mechanisms of adventitial inflammation and fibrosis to prevent the untoward long-term effects of central artery stiffening. Previous Back to top Next FiguresReferencesRelatedDetails May 2016Vol 67, Issue 5 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.116.07596 Originally publishedMay 1, 2016 PDF download Advertisement

Chloroquine Attenuates Klotho Gene Deficiency‐induced Arterial Stiffening and Hypertension by Suppression of Autophagy

Background &amp; HypothesisHapodeficiency of the antiaging gene Klotho causes arterial stiffening and hypertension through unknown mechanisms. Our recent study showed that autophagy was upregulated in the aortas of Klotho mutant heterozygous (+/−) mice. We hypothesized that inhibition of autophagy by chloroquine (an anti‐malaria drug) attenuates Klotho deficiency‐induced arterial stiffening and hypertension.Methods &amp; ResultsKlotho mutant heterozygous (+/−) mice and age‐ and sex‐matched wild‐type (WT) mice were used (20–23 months). Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in KL(+/−) mice. Interestingly, inhibition of autophagy by chloroquine reversed Klotho deficiency‐induced increases in PWV and BP within 2 weeks of treatment. The autophagy level, as measured by LC3I/LC3II and autophagy flux, was increased in aortas of KL(+/−) mice. Chloroquine abolished the upregulation of autophagy in Klotho (+/−) mice, indicating effective inhibition of autophagy. Klotho deficiency‐induced arterial stiffness was associated with accumulation of stiffer collagen and degeneration of compliant elastin fibers. In addition, the activity and expression of MMP2, MMP9, and the expression of TGF‐β1, TGF‐β3, RUNX2 and ALP were increased in aortas of KL(+/−) mice, which were attenuated by chloroquine. Scleraxis, a transcription factor in the regulation of collagen synthesis in arterial cells, was increased in aortas of KL(+/−) mice. The upregulation of scleraxis by Klotho deficiency was eliminated by inhibition of autophagy, which was further confirmed by inhibition of autophagy through siRNA knockdown of Beclin‐1 in mouse vascular aortic smooth muscle cells. Therefore, induction of autophagy is essential for Klotho deficiency–induced upregulation of scleraxis.ConclusionKlotho gene deficiency causes arterial stiffening and hypertension through upregulation of scleraxis in an autophagy‐dependent manner.Support or Funding InformationSupported by NIH R01 HL118558, DK093403, HL105302 and HL102074.

0300 : Mechanical and functional vascular impact of a low dose atorvastatin treatment in WHHL rabbits

This study is a new contribution to the analysis of the effects of a low dose of statin used at concentrations below its lipid-lowering effect. an atorvastatin treatment (2.5 mg/kg/day) was tested against controls on 34 male 3 to 12 month-old rabbits. The Arterial stiffness was evaluated on vigil animals by pulse wave velocity (PWV) measurement. In addition, i n vitro measurements were performed to evaluate (1) the endothelial and vascular smooth muscle function, (2) the elasticity of the arterial wall (with a static tensile test) and (3) the composition in collagen and elastin in the aorta (with two-photon and second harmonic generation microscopy). The level of triglycerides, Height Density Lipoprotein and Low Density Lipoprotein remain similar over the time between the control and statin groups. However, an increase in PWV was observed during the time in the group without statin, while it was not in the group with statin (5.17 ±0.50 vs. 2.14 ±0.34 m.s-1; p<0.05; at 12 month, respectively, Figure). In addition, at 12 month, the percentage of elastin was lower in the control group (32.4±1.5) compared to the treated group (33.9±1,4). The observed change in PWV was due to the modification in structural component of the vessel. Chronic low dose of atorvastatin prevents the loss of elasticity in the aorta in the WHHL rabbits. This study shows a beneficial effect of our treatment on the vascular system of the atherosclerotic WHHL rabbit. The author hereby declares no conflict of interest Figure Evolution of pulse wave velocity over the time

SBP, DBP, and pulse blood pressure variability are temporally associated with the increase in pulse wave velocity in a model of aortic stiffness.

Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear. Our objectives were to determine the temporal evolution of both BPV and pulse wave velocity (PWV), a surrogate measure of arterial stiffness, using an animal model of remodeling-dependent aortic stiffening. We thus, developed a new telemetric technique allowing continuous measurement of PWV in conscious, unrestrained rats. Studies were performed in spontaneously hypertensive rats (SHR) treated for 2 weeks with N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (SHR-LN). BPV was evaluated conventionally or with a new device composed of two pressure transducers in two different sets of rats. This allowed a continuous monitoring of telemetered PWV, systolic (SPV), diastolic (DPV), and pulse pressure variability (PPV). Aortic structure was then characterized by immunohistochemical analysis. SPV, DPV, and PPV were increased in SHR-LN, when calculated by 24-h SD or using average real variability a parameter used to assess short-term variability in man. We observed rapid and simultaneous increases in BP, SPV, and PWV. Interestingly, PPV was the most increased parameter resulting mainly from different time course of SPV and DPV. Structural alterations of the aortic wall were observed, with a eutrophic inward remodeling and accumulation of fibronectin and its two main receptors (α5 and αv integrins). This offers unequivocal evidence of a significant relationship between PWV, BPV, and arterial structure.

Immediate post renal transplant period and hypertension: concordance between clinic and ambulatory blood pressure

Background: Markedly increased pulse wave velocity (PWV) with aging has been reported in numerous studies. Arterial wave reflection (WR) timing based on of the Augmentation Index (AI) framework does not change appreciably, despite increased PWV. The cause for this apparent discordance has not been established. Although a distal shift of reflecting sites has been proposed, this proposition has been exclusively based on the timing of the inflection point, which is a very limited approach. We hypothesize that AI is not capable of detecting early-systolic effects of reflection, particularly when PWV is high, leading to an apparent reflection-free period in early ejection. Methods: Simultaneous aortic pressure and flow were measured in anesthetized, open-chest dogs (n1⁄45). Intravenous infusion of methoxamine (MTX) and nitroprusside (NTP) were used to increase and decrease WRs, respectively. A coupled left ventricle-arterial system model was used to alter reflection magnitude and timing. Effects of reflection in early-systole were assessed with a systolic pressure-flow ratio (SPFR). Results: SPFR in the case of NTP remained close to aortic characteristic impedance (Zc) [horizontal dashed line] up until peak flow (Fig.1A). In control and MTX, SPFR grew increasingly divergent from Zc before peak flow (Fig.1B-C). Even when an inflection point is observed on the pressure waveform (Fig.1D, inset), SPFR diverges from Zc before the inflection, indicative of early-systole WRs. Modeling studies confirmed the dog experiments in a noise-free environment; only when wave reflections are substantially delayed and/or minimal does SPFR equal Zc in earlysystole. Divergence from this relation is due to WRs. Conclusion:WRs can alter pressure-flow relations in early-systole, prior to time of peak flow and the inflection point on the pressure waveform. Since AI is blind to early-systolic WRs, it should not be used to assess WR timing, especially when PWV is high. This is a particularly important limitation of AI to recognize when studying older subjects as well as those with hypertension in which PWV is elevated. When an appropriate method is used to gauge WR magnitude and timing in earlysystole, elevated PWV is indeed associated with earlier effects of reflections.

Clustering and combining pattern of metabolic syndrome risk factors and its association with arterial stiffness

IntroductionMetabolic syndrome (MetS) is associated with structural and functional vascular abnormalities that can lead to increased arterial stiffness, which predicts cardiovascular events and increases mortality. However, little is known regarding the implications of risk factor clustering in the arterial stiffness.ObjectiveIn MetS, determine the clustering and the combining pattern of risk factors and its association with arterial stiffness.MethodsWe selected recently diagnosed patients with MetS (n=47, 51 ± 6 y) according to ATP III criteria. A control group (C, n=17, 50 ± 4 years) was also studied. Arterial stiffness was evaluated by pulse wave velocity (PWV) in carotid‐femoral segment. The patients were categorized and analyzed according MetS risk factors clustering (3, 4 and 5 factors). We performed correlation tests and multiple linear regressions to determine predictor variables with PWV and independent variables of sex, age, body mass index, and MetS risk factors.ResultsPatients with MetS had increased PWV compared to C (8.8 ± 0.7, 9.8 ± 1.4 m/s, p=0.01). In multivariate analysis, the variables that remained as predictor of PWV were age (β=0.35, p= 0.01) and triglycerides (β=0.29, p= 0.03). There was a progressive increase of PWV to increase the number of risk factors. Furthermore, the PWV compared to C group was similar for cluster of 3 risk factors, whereas were higher for cluster of 4 and 5 risk factors (8.7 m/s [7.8 to 10.0], 9.4 m/s [7.7to 11.7], 9.8 m/s [7.3 to 13.4] and 10 m/s [9.3 to 13.4]).ConclusionThe number of risk factors amplifies the arterial stiffness. The presence of alteration in the triglycerides worsening the stiffness of large vessels, emphasizing the importance in addressing this risk factor for MetS patients.Support or Funding InformationThis study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP# 2011/17533‐6 ) and, in part, by Fundação Zerbini. Sara Rodrigues was supported by FAPESP# 2013/15323‐0, Edgar Toschi‐Dias was supported by FAPESP# 2013/07651‐7, Felipe X Cepeda was supported by FAPESP# 2015/03274‐0.

Misinterpretation of the Determinants of Elevated Forward Wave Amplitude Inflates the Role of the Proximal Aorta.

BackgroundThe hemodynamic basis for increased pulse pressure (PP) with aging remains controversial. The classic paradigm attributes a predominant role to increased pulse wave velocity (PWV) and premature wave reflections (WRs). A controversial new paradigm proposes increased forward pressure wave amplitude (FWA), attributed to proximal aortic characteristic impedance (Zc), as the predominant factor, with minor contributions from WRs. Based on theoretical considerations, we hypothesized that (rectified) WRs drive the increase in FWA, and that the forward pressure wave does not depend solely on the interaction between flow and Zc (QZc product).Methods and ResultsWe performed 3 substudies: (1) open‐chest anesthetized dog experiments (n=5); (2) asymmetric T‐tube model‐based study; and (3) human study in a diverse clinical population (n=193). Animal experiments demonstrated that FWA corresponds to peak QZc only when WRs are minimal. As WRs increased, FWA was systematically greater than QZc and peaked well after peak flow, analogous to late‐systolic peaking of pressure attributable to WRs. T‐tube modeling confirmed that increased/premature WRs resulted in increased FWA. Magnitude and timing of WRs explained 80.8% and 74.3% of the variability in the difference between FWA and peak QZc in dog and human substudies, respectively.ConclusionsOnly in cases of minimal reflections does FWA primarily reveal the interaction between peak aortic flow and proximal aortic diameter/stiffness. FWA is strongly dependent on rectified reflections. If interpreted out of context with the hemodynamic principles of its derivation, the FWA paradigm inappropriately amplifies the role of the proximal aorta in elevation of FWA and PP.

Tributyltin chloride increases phenylephrine-induced contraction and vascular stiffness in mesenteric resistance arteries from female rats

Tributyltin chloride (TBT) is an organotin compound that reduces estrogen levels in female rats. We aimed to investigate the effects of TBT exposure on vascular tonus and vascular remodelling in the resistance arteries of female rats. Rats were treated daily with TBT (500ng/kg) for 15days. TBT did not change arterial blood pressure but did modify some morpho-physiological parameters of third-order mesenteric resistance arteries in the following ways: (1) decreased lumen and external diameters; (2) increased wall/lm ratio and wall thickness; (3) decreased distensibility and increased stiffness; (4) increased collagen deposition; and (5) increased pulse wave velocity. TBT exposure increased the phenylephrine-induced contractile response in mesenteric resistance arteries. However, vasodilatation responses induced by acetylcholine and sodium nitroprusside were not modified by TBT. It is suggested that TBT exposure reduces vascular nitric oxide (NO) production, because:(1) L-NAME incubation did not cause a leftward shift in the concentration–response curve for phenylephrine; (2) both eNOS protein expression; (3) in situ NO production were reduced. Incubation with L-NAME; and (4) SOD shifted the phenylephrine response curve to the left in TBT rats. Tiron, catalase, ML-171 and VAS2870 decreased vascular reactivity to phenylephrine only in TBT rats. Moreover, increased superoxide anion production was observed in the mesenteric resistance arteries of TBT rats accompanied by an increase in gp91phox, catalase, AT1 receptor and total ERK1/2 protein expression. In conclusion, these findings show that TBT induced alterations are most likely due to a reduction of NO production combined with increased O2− production derived from NADPH oxidase and ERK1/2 activation. These findings offer further evidence that TBT is an environmental risk factor for cardiovascular disease.

EFFECT OF MEASUREMENT POSITION ON CARDIO-ANKLE VASCULAR INDEX (CAVI)

There is a need for new methods to measure the level of arterial stiffness easily at home. A previous report investigating the effect of measurement position on brachial–ankle pulse wave velocity (baPWV) showed that baPWV was higher in the sitting position than in the supine position. This was probably because the increased ankle PWV was associated with increased hydrostatic pressure in the arteries of lower extremities. Therefore, we investigated the effect of measurement position on the cardio-ankle vascular index (CAVI), which is hardly affected by blood pressure. CAVI was measured in 50 healthy males (20–74 years) in five positions: supine, sitting, sitting with the knees flexed at 0[Formula: see text], reclining 50[Formula: see text], and standing. Compared to other positions, CAVI in the supine position was the lowest ([Formula: see text]); [Formula: see text] (the time difference between the second heart sound and the notch of the pulse wave in the upper arm) in the supine position was the highest ([Formula: see text]); and [Formula: see text] (the time difference between the minimum upper arm and ankle pulse wave pattern values) in the supine position was the highest ([Formula: see text]). Thus, our results indicated that changes in measurement position reduced pulse arrival time (increasing pulse wave velocity). We also observed a good correlation between CAVI in the supine position and that in other positions. The present study showed that the measurement position affected CAVI as much as it affected baPWV. Accordingly, correcting for the measurement position would be required when the position differs from supine.

Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase.

Klotho was originally discovered as an aging-suppressor gene. The objective of this study is to investigate whether klotho gene deficiency affects high-fat diet (HFD)-induced arterial stiffening. Heterozygous Klotho-deficient (KL(+/-)) mice and WT littermates were fed on HFD or normal diet. HFD increased pulse wave velocity within 5 weeks in KL(+/-) mice but not in wild-type mice, indicating that klotho deficiency accelerates and exacerbates HFD-induced arterial stiffening. A greater increase in blood pressure was found in KL(+/-) mice fed on HFD. Protein expressions of phosphorylated AMP-activated protein kinase-α (AMPKα), phosphorylated endothelial nitric oxide synthase (eNOS), and manganese-dependent superoxide dismutase (Mn-SOD) were decreased, whereas protein expressions of collagen I, transforming growth factor-β1, and Runx2 were increased in aortas of KL(+/-) mice fed on HFD. Interestingly, daily injections of an AMPKα activator, 5-aminoimidazole-4-carboxamide-3-ribonucleoside, abolished the increases in pulse wave velocity, blood pressure, and blood glucose in KL(+/-) mice fed on HFD. Treatment with 5-aminoimidazole-4-carboxamide-3-ribonucleoside for 2 weeks not only abolished the downregulation of phosphorylated AMPKα, phosphorylated eNOS, and Mn-SOD levels but also attenuated the increased levels of collagen I, transforming growth factor-β1, Runx2, superoxide, elastic lamellae breaks, and calcification in aortas of KL(+/-) mice fed on HFD. In cultured mouse aortic smooth muscle cells, cholesterol plus KL-deficient serum decreased phosphorylation levels of AMPKα and LKB1 (an important upstream regulator of AMPKα activity) but increased collagen I synthesis, which can be eliminated by activation of AMPKα by 5-aminoimidazole-4-carboxamide-3-ribonucleoside. In conclusions, Klotho deficiency promoted HFD-induced arterial stiffening and hypertension via downregulation of AMPKα activity.

Ten-year longitudinal change in aortic stiffness assessed by cardiac MRI in the second half of the human lifespan: the multi-ethnic study of atherosclerosis.

Longitudinal determinants of aortic stiffness (AS) measured by magnetic resonance imaging (MRI) have not been assessed in a large community-based population. Our aim was to examine the determinants of change in thoracic AS over 10 years of follow-up in a multi-ethnic population of individuals 45 years of age and older measured by MRI. We studied 1160 participants (mean age = 60 ± 9 years at baseline, 45% male) with aortic MRI at both the MESA Year 0 and Year 10 examinations. Ascending and descending aorta distensibility (AAD/DAD) and aortic arch pulse-wave velocity (PWV) were measured using MRI. Determinants of the change in AS parameters over 10 years were assessed using linear regression adjusted for baseline values, demographic variables, baseline risk factors and change in risk factors, and chronic risk exposure. AAD and DAD decreased slightly (5% decrease in median for AAD: 1.33-1.26 mmHg(-1) · 10(-3), P = 0.008; 5% decrease in median for DAD: 1.73-1.64 mmHg(-1) · 10(-3), P < 0.001), and PWV increased over 10 years (18% increase in median: 6.8-8.0 m/s P < 0.001). Baseline age was related to a reduction in AAD and DAD and an increase in PWV throughout the follow-up period. Baseline and change in mean blood pressure and continued smoking were associated with a reduction in AAD and an increase in PWV. Furthermore, baseline heart rate was also related to a reduction in AAD and DAD. Blood pressure normalization was related to less aortic stiffening throughout the follow-up period. In our longitudinal, community-based cohort study of adult individuals aged 45 years or greater, greater mean blood pressure and a history of smoking history were associated with increased aortic stiffening over 10 years as assessed by MRI.

Arterial stiffness and ankle brachial index in patients with rheumatoid arthritis and inflammatory bowel disease.

To the Editor; We read the article “Comparison of inflammation, arterial stiffness and traditional cardiovascular risk factors between rheumatoid arthritis and inflammatory bowel disease” by Fan et al. [1] with great interest. In this verywell designed study, authors found that pulse wave velocity (PWV) levels were similar between rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and control groups. In addition, they also showed that ankle brachial index (ABI) levels were higher in controls than IBD, but not RA. They concluded that traditional risk factors, but not inflammatory markers, are major parameters asscociated with arterial stiffness. These findings provide new information about the asscociation between inflammatory diseases and atherosclerosis. In this study, although RA patients have higher Framingham risk score and number of hypertensive patients, there was no significant difference between RA and control groups in PWV and ABI levels. Arterial stiffness has been known as an independent predictor cardiovascular mortality and is increased in rheumathologic diseases despite a low risk for cardiovascular disease according to Framingham score [2]. Moreover, in IBD patients, ABI levels were significantly decreased when compared to control subjects, but PWV levels were not correlated with ABI. Whereas a negative correlation between PWV and ABI was demonstrated in individuals without organic heart disease [3]. We suggest some possible explanations for the lack of increased PWV and decreased ABI in patients with RA and IBD than controls. In present study, authors did not examine renal function tests and hemoglobin levels. We know that patients with chronic renal failure and anemia have increased risk for cardiovascular events and peripheral artery disease [4, 5]. Moreover, they did not examine the association of disease extent and duration with vascular parameters. We think that as disease extent and duration increased, risk of atherosclerosis will be increased due to long-term exposure to inflammation. Before making certain comments on these findings, we think that this study should be reconsidered in light of the above mentioned suggestions. This could provide the readers of the journal clearer information regarding the effects of inflammatory diseases in atherosclerosis. Authors’ Response: Dear Editors of Journal of Inflammation, We are writing in response to the letter concerning our manuscript. We appreciate the interest in our work. As noted, we did not observe a significant increase in mean baPWV in RA patients [1]. Whilst RA has been associated with an increased prevalence of arterial stiffness. there are other other studies that also failed to find an increase in PWV [6, 7] in these patients. Another study reported that only about 30 % of RA patients had increased arterial stiffness [8]. In IBD, PWV has been found to be increased [9] or unchanged [10]. Thus, findings on arterial stiffness in RA and IBD patients have varied between studies, possibly due to the difference in demographics of patients studied. In our study, most patients were well controlled by treatment with disease modifiying drugs. It is known that disease modifying drugs improve endothelial dysfunction and reduce arterial stiffness [11–13]. Disease duration and activity are also likely to influence arterial stiffness [8, 14]. We thus examined the correlations between disease duration and vascular parameters. We did not examine correlations with disease activity since most patients were in remission. PWV was correlated with disease duration in patients with IBD (r = 0.343, p = 0.026) but not with RA. Other investigators also did not find correlations between PWV and disease duration or activity [15]. This study also reported that among the many factors related to arterial stiffness, only old age Correspondence: kadirozturk3041@gmail.com Department of Gastroenterology, Gulhane School of Medicine, Ankara, Turkey

Morphometric changes of the left ventricle and characteristics of peripheral hemodynamics in patients with drug resistant hypertension

Aim. To study morphometric changes of the left ventricle (LV) and characteristics of peripheral hemodynamics in patients with drug resistant hypertension (HT). Material and methods. In total, 120 patients with unmanageable HT of 2-3 degrees, that considered by physicians as drug resistant HT, were included into the study. Patients with HT resistant to full-dose triple antihypertensive therapy (n=43) were included into Group 1. Patients with HT controlled by combination therapy (n=83) were included into Group 2. All the patients underwent echocardiography, volumetric compression oscillometry (to study hemodynamic parameters). Stiffness index (SI, m/s) and reflection index (RI,%) of the pulse wave were also analyzed. Results. The increase in linear and volumetric LV sizes, severe LV hypertrophy were found in Group 1. LV mass index (LVMI) in patients in Group 1 was 134.0±6,5g/m² vs 98.4±3.3 g/m² in Group 2 (p<0.001). LVMI in men in Group 1 was 150.02±10.7 g/m² vs 99.2±4.5 g/m² in Group 2 (p<0.001). LVMI in women in Group 1 was 126±7.8 g/m vs 102.5±3.4 g/m² in Group 2 (p<0.05). The relative left ventricular wall thickness in Group 1 was 0.60, vs 0.50 in Group 2 (p<0.05). In patients of group 1 compared with group 2 there were also found a reduction in arterial compliance (0.84±0.06 vs 1.0±005, respectively; p<0.05), increased pulse wave velocity (820.14±16 vs 741.11±19 cm/sec, respectively; p<0.05), and increase in specific peripheral vascular resistance. Conclusion. Most of patients with drug resistant HT have concentric LV hypertrophy and concentric LV remodeling. The microvasculature remodeling takes place much earlier and is accompanied by possible rarefaction. Increased vascular stiffness is more pronounced in patients with drug resistant HT. It was confirmed by decrease in arterial compliance, and increase in outer diameter of the artery, that led to increase in pulse wave velocity