Search

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

This study analyzed repeated measurement data to clarify the longitudinal associations between hyperuricemia and the risk factors for the development of hypertension (ie, increased arterial stiffness, renal dysfunction, and inflammation), and then examined whether these risk factors show longitudinal associations with the development of hypertension. In 3274 Japanese men without hypertension, the brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum uric acid and CRP (C-reactive protein) levels were measured annually over an 8-year period. Of these, 474 subjects developed hypertension by the end of the study period. Mixed model linear regression analysis revealed a significant longitudinal association of hyperuricemia with increase of the brachial-ankle pulse wave velocity (estimate=5.50, P=0.04), decrease of the estimated glomerular filtration rate (estimate=-2.02, P<0.01), and elevation of the CRP (estimate=0.08×10-1, P=0.02). Hyperuricemia at the study baseline was associated with a significant odds ratio for the development of hypertension by the end of the study period. After adjustments for covariates, the brachial-ankle pulse wave velocity (estimate=0.51×10-2, P<0.01) and CRP (estimate=1.91, P=0.03), but not estimated glomerular filtration rate, were found to show independent longitudinal associations with the new onset of hypertension. In Japanese men without hypertension, hyperuricemia may have a longitudinal association with the development of hypertension, and increased arterials stiffness and inflammation may be involved in the risk of development of hypertension associated with hyperuricemia. [ABSTRACT FROM AUTHOR]

We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index <0.90 and to predict future cardiovascular events. We collected individual participant data on 13 317 Japanese subjects from 10 cohorts (general population-based cohorts, cohorts of patients with past history of cardiovascular events, and those with cardiovascular risk factors). Binary logistic regression analysis with adjustments identified interarm blood pressure difference >5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index <0.90 (odds ratio, 2.19; 95% confidence interval, 1.60-3.03; P<0.01). Among 11 726 subjects without a past history of cardiovascular disease, 249 developed stroke during the average follow-up period of 7.4 years. Interarm blood pressure difference >15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; P<0.01). Therefore, interarm blood pressure differences, measured simultaneously in both arms, may be associated with vascular damage in the systemic arterial tree. These differences may be useful for identifying subjects with an ankle-brachial pressure index of <0.90 in the overall study population, and also a reliable predictor of future stroke in subjects without a past history of cardiovascular disease. These findings support the recommendation to measure blood pressure in both arms at the first visit. [ABSTRACT FROM AUTHOR]

Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular risk. We hypothesized that the number of cardiovascular risk factors determines the progression of vascular aging. One hundred forty-two subjects (mean age 51.9 years, 94 men) without established cardiovascular disease were investigated in 2 examinations over a 2-year period. Subjects were classified at baseline according to their number of risk factors (from 0 to 2 and more). Subjects had determinations of carotid-femoral pulse wave velocity, aortic augmentation index, brachial flow-mediated dilatation, and common carotid intima-media thickness and their annual absolute changes were calculated. Subjects with more risk factors had a gradual higher annual progression of pulse wave velocity (0.092 m/s/y for 0, 0.152 m/s/y for 1, and 0.352 m/s/y for 2 and more; P=0.007). Patients with both hypertension and dyslipidemia have 4× higher annual progression rate compared with subjects without these risk factors (0.398 m/s/y versus 0.102 m/s/y). When only subjects 55 years old and under were considered, the progression rate of augmentation index was higher in subjects with more risk factors (1.15%/y versus 1.50%/y versus 2.99%/y, respectively; P=0.037). No association was found with the annual change of flow-mediated dilatation or carotid intima-media thickness. In the general population, increasing number of risk factors is associated with accelerated deterioration of specific indices of vascular aging, such as pulse wave velocity and augmentation index; in contrast, flow-mediated dilatation and carotid intima-media thickness are insensitive to such changes. Accordingly, the former may be more useful for gauging vascular aging. [ABSTRACT FROM AUTHOR]

An individual participant data meta-analysis was conducted in the data of 14 673 Japanese participants without a history of cardiovascular disease (CVD) to examine the association of the brachial-ankle pulse wave velocity (baPWV) with the risk of development of CVD. During the average 6.4-year follow-up period, 687 participants died and 735 developed cardiovascular events. A higher baPWV was significantly associated with a higher risk of CVD, even after adjustments for conventional risk factors (P for trend <0.001). When the baPWV values were classified into quintiles, the multivariable-adjusted hazard ratio for CVD increased significantly as the baPWV quintile increased. The hazard ratio in the subjects with baPWV values in quintile 5 versus that in those with the values in quintile 1 was 3.50 (2.14-5.74; P<0.001). Every 1 SD increase of the baPWV was associated with a 1.19-fold (1.10-1.29; P<0.001) increase in the risk of CVD. Moreover, addition of baPWV to a model incorporating the Framingham risk score significantly increased the C statistics from 0.8026 to 0.8131 (P<0.001) and also improved the category-free net reclassification (0.247; P<0.001). The present meta-analysis clearly established baPWV as an independent predictor of the risk of development of CVD in Japanese subjects without preexisting CVD. Thus, measurement of the baPWV could enhance the efficacy of prediction of the risk of development of CVD over that of the Framingham risk score, which is based on the traditional cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Erectile dysfunction confers an independent risk for cardiovascular events and total mortality. Aortic pulse wave velocity (PWV) is an important predictor of cardiovascular events and all-cause mortality. We investigated whether PWV predicts major adverse cardiovascular events (MACEs) in patients with erectile dysfunction beyond traditional risk factors. MACEs in relation to PWV were analyzed with proportional hazards models in 344 patients (mean age, 56 years) without established cardiovascular disease. During a mean follow-up of 4.7 years (range, 1-8.5 years), 24 of 344 participants (7.0%) experienced a MACE. Subjects in the highest PWV tertile (>8.8 m/s) had a 4-fold higher risk of MACEs compared with those in the lowest PWV tertile (<7.6 m/s; adjusted hazard ratio, 3.97; P=0.035). A PWV value of 7.81 m/s was associated with a negative predictive value (ability to rule out MACE) of 98.1%. Addition of PWV to standard risk factor model yielded correct patient reclassification to higher or lower risk category by 27.6% (P=0.0332) in the whole cohort. Our results show that higher aortic stiffness is associated with increased risk for a MACE in patients with erectile dysfunction without known cardiovascular disease. Aortic PWV improves risk prediction when added to standard risk factors and may represent a valuable biomarker of prediction of cardiovascular disease risk in these patients. [ABSTRACT FROM AUTHOR]

The article discusses a study aimed at calculating robust quantitative estimates of predictive value of erectile dysfunction (ED) for various outcomes and investigate whether publication bas affected the true predictive ability of ED. Outcomes of interest included total cardiovascular (CV) events, mortality and myocardial infarction (MI). It suggests that the presence of ED increases the risk for future CV events, MI and all-cause mortality and shows a trend to increase risk for CV mortality.

Brachial-ankle elasticity index (baEI; also known as brachial-ankle pulse wave velocity) has been proposed as a surrogate end point for cardiovascular disease. We performed a meta-analysis of longitudinal cohort studies for determining the ability of baEI to predict risk of cardiovascular events and all-cause mortality and dissecting factors influencing this predictive ability. Multiple online databases, reference lists from retrieved articles, and abstracts from international cardiovascular conventions were searched until April 2012. Longitudinal cohort studies that reported associations of baEI with clinical risk were included. Of the 18 studies included (8169 participants; mean follow-up, 3.6 years), 15 reported results on total cardiovascular events (5544 individuals), 7 on cardiovascular mortality (2274 individuals), and 9 on all-cause mortality (5097 individuals). The pooled relative risks for total cardiovascular events, cardiovascular mortality, and all-cause mortality were 2.95 (95% CI, 1.63-5.33), 5.36 (95% CI, 2.17-13.27), and 2.45 (95% CI, 1.56-3.86), respectively, for subjects with high versus low baEI (all P<0.001). An increase in baEI by 1 m/s corresponded with an increase of 12%, 13%, and 6% in total cardiovascular events, cardiovascular mortality, and all-cause mortality, respectively. We conclude that baEI is associated with increased risk of total cardiovascular events and all-cause mortality. Issues such as expansion of data to non-Asian populations, validation of path length estimation, determination of reference values, and prospective comparison with carotid-femoral pulse wave velocity remain to be resolved. [ABSTRACT FROM AUTHOR]

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans. [ABSTRACT FROM AUTHOR]

Increased wave reflection is an independent factor associated with cardiovascular diseases, risk, and mortality. The influence of the menstrual cycle on wave reflections and particularly on the reproducibility of their measurement has never been examined. The aim of the present study was to examine the reproducibility and variability of wave reflection indices in premenopausal healthy women during their menstrual cycle. Thirty-two women were examined at 3 phases of their menstrual cycle: days 1 to 2 (menstrual phase), days 6 to 14 (late follicular), and days 4 to 7 after ovulation (early luteal phase). Applanation tonometry of the radial artery and aortic pulse wave analysis were performed for the calculation of augmentation pressure, augmentation index, and timing of reflected waves. Reproducibility of these measures was evaluated by intraclass correlation coefficient and Bland-Altman analysis, whereas ANOVA was performed to assess their variability during the menstrual cycle. The SD of augmentation index differences between repeated measurements within the menstrual cycle ranged from 7.6% to 9.9%. Bland-Altman analysis indicated no evidence of systemic bias and no trend for the reproducibility of measurements to vary with their underlying mean value. Intraclass correlation coefficient indicated a moderate reproducibility of augmentation index and augmentation pressure (>0.80) and a rather low reproducibility for timing of reflected waves (0.43). Mean augmentation pressure, augmentation index, and timing of reflected waves did not vary significantly during the menstrual cycle (ANOVA). Measurement of wave reflections at the same phase of the menstrual cycle or statistical adjustment could be suggested for optimal study design and data interpretation. [ABSTRACT FROM AUTHOR]

The article provides information on central blood pressure monitoring and antihypertensive therapy as managed by guidelines from the 2003 European Society of Hypertension/European Society of Cardiology. The pathophysiologic relevance of blood vessel pressures are discussed along with its role as markers and predictors of disease. Implementations of the study in the assessment of cardiovascular parameters in normotensive and hemodialysis patients are presented.

Introduction: Hypertension is associated with several circulatory biomarkers and target organ damage. Hypothesis: The present study investigated the relationship between circulatory biomarkers with markers of TOD in never-treated hypertensives. Methods: We enrolled 896 consecutive essential hypertensives (mean age 52.9±12.0 years, 472 males). Markers of TOD [left ventricular mass index (LVMI), pulse wave velocity (PWV), estimated glomerular filtration rate (eGFR), ankle-brachial index (ABI), and microalbuminuria] were evaluated in all patients. LVMI was assessed echocardiographically using the Devereux formula. eGFR was estimated using the MDRD formula. Microalbuminuria was measured with the albumin-creatinine ratio. Organ damage was defined as described in the 2013 European Hypertension Guidelines. Circulatory biomarkers were assessed by measurement of high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), glycated haemoglobin (HbA1c) and thyroid-stimulating hormone (TSH) in blood samples. Results: In multivariable regression analysis, hsCRP exhibited significant association with LVMI (p=0.018), PWV (p<0.001), eGFR (p=0.006) and urine microalbumin (p<0.001), which was independent of relevant confounders. In identical analysis, associations were observed for SAA with PWV (p<0.001), urine microalbumin (p<0.001), LVMI (p<0.001), eGFR (p=0.008) and for HbA1c with LVMI (p=0.001), ABI (p=0.046), PWV (p=0.003). No associations were observed between TSH and TOD. In further analysis, receiver operating characteristic (ROC) curves were generated to evaluate the ability of hsCRP, SAA and HbA1c to discriminate subjects with extended TOD. The area under the curve (AUC) and 95% CIs of the ROC curves for concurrent TOD in 4 or more organs were AUC=0.71 (95% CI: 0.64-0.78, p<0.001) for SAA, AUC=0.68 (95% CI: 0.61-0.75, P<0.001) for HbA1c and AUC=0.65 (95% CI: 0.57-0.74, p<0.001) for hsCRP, respectively. (Figure) Conclusions: Our findings support the close relationship between circulatory biomarkers and TOD in hypertension, as well as, the predictive ability of hsCRP, SAA and HbA1c levels for TOD. However, the exact role of these biomarkers in the development of TOD in hypertension warrants further investigation. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as DSP (desmoplakin) or FLNC (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients., Competing Interests: Disclosures None.

Background and Objectives: There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha ( GLA ) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated., Methods: We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y -positive patients, and (3) the proportion of D313Y -positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation)., Results: Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I 2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I 2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I 2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I 2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I 2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I 2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I 2 = 34%) and 16.2% (95% CI 8%-26.4%; I 2 = 35%) of cases, respectively. D313Y -positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I 2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I 2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I 2 = 61%) of cases, respectively., Discussion: D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y -positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment., (© 2022 American Academy of Neurology.)

Background and Purpose: Blood pressure variables derived by ambulatory monitoring are important prognostic markers in hypertensive patients. Recent studies showed that ambulatory systolic-diastolic pressure regression index (ASDPRI), also known as ambulatory arterial stiffness index, may correlate with cardiovascular (CV) outcomes., Methods: We explored the predictive value of ASDPRI for future CV events, stroke, and all-cause mortality by meta-analyses of 7 longitudinal studies that had evaluated ASDPRI and had followed 20,505 subjects for a mean follow-up of 7.8 years., Results: The pooled relative risk of total CV events (including CV mortality), stroke, and all-cause mortality was 1.51 (95% CI, 1.18-1.93; P=0.001; 5 studies), 2.01 (95% CI, 1.60-2.52; P<0.001; 4 studies), and 1.25 (95% CI, 1.10-1.41; P=0.001; 4 studies), respectively, for high ASDPRI versus low ASDPRI subjects. An increase of ASDPRI by 1 standard deviation was associated with an age-adjusted, sex-adjusted, and risk factor-adjusted relative risk increase of total CV events and stroke by 15% and 30%, respectively. ASDPRI predicted stroke better than total CV events, predicted stroke better in normotensive subjects than in hypertensive patients, and also predicted total CV events better in females than in males. There was not significant publication bias., Conclusions: ASDPRI is an ambulatory blood pressure-derived biomarker that strongly predicts future CV events, stroke, and all-cause mortality. These findings suggest that this index may be useful for risk stratification purposes.

Background: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is essential for maintenance of enzymatic function. We hypothesized that induction of BH4 synthesis might be an endothelial defense mechanism against inflammation in vascular disease states., Methods and Results: In Study 1, 20 healthy individuals were randomized to receive Salmonella typhi vaccine (a model of acute inflammation) or placebo in a double-blind study. Vaccination increased circulating BH4 and interleukin 6 and induced endothelial dysfunction (as evaluated by brachial artery flow-mediated dilation) after 8 hours. In Study 2, a functional haplotype (X haplotype) in the GCH1 gene, encoding GTP-cyclohydrolase I, the rate-limiting enzyme in biopterin biosynthesis, was associated with endothelial dysfunction in the presence of high-sensitivity C-reactive protein in 440 coronary artery disease patients. In Study 3, 10 patients with coronary artery disease homozygotes for the GCH1 X haplotype (XX) and 40 without the haplotype (OO) underwent S Typhi vaccination. XX patients were unable to increase plasma BH4 and had a greater reduction of flow-mediated dilation than OO patients. In Study 4, vessel segments from 19 patients undergoing coronary bypass surgery were incubated with or without cytokines (interleukin-6/tumor necrosis factor-α/lipopolysaccharide) for 24 hours. Cytokine stimulation upregulated GCH1 expression, increased vascular BH4, and improved vasorelaxation in response to acetylcholine, which was inhibited by the GTP-cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine., Conclusions: The ability to increase vascular GCH1 expression and BH4 synthesis in response to inflammation preserves endothelial function in inflammatory states. These novel findings identify BH4 as a vascular defense mechanism against inflammation-induced endothelial dysfunction.

Objective: To investigate the effect of laughter and mental stress on arterial stiffness and central hemodynamics. Arterial stiffness and wave reflections are independent predictors of cardiovascular risk. Chronic psychological stress is an independent risk factor for cardiovascular events, whereas acute stress deteriorates vascular function., Methods: Eighteen healthy individuals were studied on three occasions, according to a randomized, single-blind, crossover, sham procedure-controlled design. The effects of viewing a 30-minute segment of two films inducing laughter or stress were assessed. Carotid-femoral pulse wave velocity was used as an index of arterial stiffness; augmentation index was used as a measure of wave reflections., Results: Laughter decreased pulse wave velocity (by 0.30 m/sec, p = .01), and augmentation index (by 2.72%, p = .05). Conversely, stress increased pulse wave velocity (by 0.29 m/sec, p = .05) and augmentation index (by 5.1%, p = .005). Laughter decreased cortisol levels by 1.67 microg/dl (p = .02), soluble P-selectin by 26 ng/ml (p = .02) and marginally von Willebrand factor (by 2.4%, p = .07) and increased total oxidative status (by 61 micromol/L, p < .001). Stress decreased interleukin-6 (by 0.11 pg/ml, p = .04) and increased total oxidative status (by 44 micromol/L, p = .007). Soluble CD40 ligand and fibrinogen remained unchanged., Conclusions: Positive (laughter) and negative (stress) behavioral interventions have divergent acute effects on arterial stiffness and wave reflections. These findings have important clinical implications extending the spectrum of lifestyle modifications that can ameliorate arterial function.

Objective: Large-artery stiffness and arterial wave reflections have been identified as independent markers and prognosticators of cardiovascular risk. Mental stress is a novel risk factor for coronary artery disease and has been associated with left ventricular dysfunction, myocardial ischemia and infarction, and sudden cardiac death. The purpose of this study was to assess the effect of acute mental stress on aortic stiffness and wave reflections., Methods: The effect of a mental arithmetic test was assessed in 19 healthy individuals using a randomized, sham-procedure-controlled, crossover design. Carotid-femoral pulse wave velocity and augmentation index were measured as indices of aortic stiffness and wave reflections, respectively., Results: Mental stress induced a sustained increase in central systolic and pulse pressure throughout the whole study (systolic: by 7.5 mm Hg, p < .05; pulse: by 5.7 mm Hg, p < .01). The increase in peripheral systolic and pulse pressure was not significant throughout the study, but only when their peak values were compared with baseline (systolic: by 6.2 mm Hg, peak at 0 minutes; pulse: by 6.6 mm Hg, peak at 5 minutes, p < .05 for both). There was a sustained increase in pulse wave velocity (by 0.57 m/s, p < .005) throughout the study denoting a sustained increase in aortic stiffness. Similarly, augmentation index showed a sustained increase with mental stress (by 6.16%, p < .05) denoting increased wave reflections from the periphery., Conclusion: Acute mental stress results in a prolonged increase in aortic stiffness and wave reflections. Given the important pathophysiologic and prognostic role of these parameters, our results provide important mechanistic links between acute mental stress and increased cardiovascular risk.

Background: Aortic stiffness is a marker of cardiovascular disease and an independent predictor of cardiovascular risk. Although an association between inflammatory markers and increased arterial stiffness has been suggested, the causative relationship between inflammation and arterial stiffness has not been investigated., Methods and Results: One hundred healthy individuals were studied according to a randomized, double-blind, sham procedure-controlled design. Each substudy consisted of 2 treatment arms, 1 with Salmonella typhi vaccination and 1 with sham vaccination. Vaccination produced a significant (P<0.01) increase in pulse wave velocity (at 8 hours by 0.43 m/s), denoting an increase in aortic stiffness. Wave reflections were reduced significantly (P<0.01) by vaccination (decrease in augmentation index of 5.0% at 8 hours and 2.5% at 32 hours) as a result of peripheral vasodilatation. These effects were associated with significant increases in inflammatory markers such as high-sensitivity C-reactive protein (P<0.001), high-sensitivity interleukin-6 (P<0.001), and matrix metalloproteinase-9 (P<0.01). With aspirin pretreatment (1200 mg PO), neither pulse wave velocity nor augmentation index changed significantly after vaccination (increase of 0.11 m/s and 0.4%, respectively; P=NS for both)., Conclusions: This is the first study to show through a cause-and-effect relationship that acute systemic inflammation leads to deterioration of large-artery stiffness and to a decrease in wave reflections. These findings have important implications, given the importance of aortic stiffness for cardiovascular function and risk and the potential of therapeutic interventions with antiinflammatory properties.