Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis.

UNLABELLED: Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE. HYPOTHESIS: Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks. METHODS: Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. RESULTS were compared before/after rifaximin. RESULTS: 20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p = 0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE.

Differential impact of hyponatremia and hepatic encephalopathy on health-related quality of life and brain metabolite abnormalities in cirrhosis.

BACKGROUND & AIMS: Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE. METHODS: Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate+glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. RESULTS: 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE+HN: 7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP (p<0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE, HE+HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores. CONCLUSIONS: Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL.

Asymmetric dimethylarginine is strongly associated with cognitive dysfunction and brain MR spectroscopic abnormalities in cirrhosis.

BACKGROUND & AIMS: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide synthase that accumulates in liver disease and may contribute to hepatic encephalopathy (HE). We aimed at evaluating the association of ADMA with cognition and brain MR spectroscopy (MRS) in cirrhosis. METHODS: Cirrhotic patients with/without prior HE and non-cirrhotic controls underwent cognitive testing and ADMA determination. A subgroup underwent brain MRS [glutamine/glutamate (Glx), myoinositol (mI), N-acetyl-aspartate (NAA) in parietal white, occipital gray, and anterior cingulated (ACC)]. Cognition and ADMA in a cirrhotic subgroup before and one month after transjugular intrahepatic portosystemic shunting (TIPS) were also tested. Cognition and MRS values were correlated with ADMA and compared between groups using multivariable regression. ADMA levels were compared between those who did/did not develop post-TIPS HE. RESULTS: Ninety cirrhotics (MELD 13, 54 prior HE) and 16 controls were included. Controls had better cognition and lower ADMA, Glx, and higher mI compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower mI compared to non-HE cirrhotics. ADMA was positively correlated with MELD (r=0.58, p<0.0001), abnormal cognitive test number (r=0.66, p<0.0001), and Glx and NAAA (white matter, ACC) and negatively with mI. On regression, ADMA predicted number of abnormal tests and mean Z-score independent of prior HE and MELD. Twelve patients underwent TIPS; 7 developed HE post-TIPS. ADMA increased post-TIPS in patients who developed HE (p=0.019) but not in others (p=0.89). CONCLUSIONS: A strong association of ADMA with cognition and prior HE was found independent of the MELD score in cirrhosis.

High aerobic capacity does not attenuate aortic stiffness in hypertensive subjects.

BACKGROUND: It is unknown whether increased physical fitness reduces aortic stiffness in hypertensive individuals. The purpose of this cross-sectional study was to examine, in a cohort of community-dwelling subjects with no history of cardiac events, differences in the impact of aerobic capacity on aortic stiffness between normotensive and hypertensive subjects. METHODS: The study sample included 275 subjects representing a large age range (21-85 years). Of these, 61 subjects (hypertensive cohort) were either hypertensive at enrollment or were taking antihypertensive medication. The remaining 214 subjects (normotensive cohort) had no history of hypertension. The study protocol included maximal cardiopulmonary exercise testing (determination of maximal oxygen consumption, or VO2max) and measurement of aortic wave velocity (AWV) using a novel magnetic resonance-based method. RESULTS: Overall, the hypertensive cohort exhibited significantly elevated AWV in comparison to a subset of normotensives matched for age, sex, and aerobic fitness. Each cohort was then subdivided according to the percentage of predicted VO2max achieved (< 100% = "unfit," > or = 100% = "fit"). Differences between subgroups were assessed by unpaired t test. In the normotensive cohort, AWV was significantly lower in the fit versus the unfit subgroup. However, in the hypertensive cohort, AWV was not significantly different between fit and unfit subgroups nor between treated and untreated subgroups. CONCLUSION: Unlike the situation in healthy normotensive subjects, higher peak aerobic capacity is not associated with lower aortic stiffness in hypertensive individuals.

Relationship between arterial stiffness and heart rate recovery in apparently healthy adults.

INTRODUCTION: Arterial stiffness and heart rate recovery (HRR) following exercise testing have emerged as variables holding significant prognostic value in a number of populations. The purpose of the present study is to examine the relationship between arterial stiffness and HRR in a group of apparently healthy subjects. METHODS: Two hundred and nine apparently healthy subjects underwent maximal exercise testing. Heart rate at one and two minutes post exercise was subtracted from maximal heart rate during the exercise test to produce two measures of heart rate recovery. Aortic wave velocity, in meters per second, was obtained via a new magnetic resonance technique. RESULTS: Pearson Product Moment Correlation analysis revealed a significant correlation between aortic wave velocity and heart rate recovery. Stepwise linear regression analysis revealed that age, maximal aerobic capacity, heart rate recovery at one minute, and diastolic blood pressure were all significant predictors of aortic wave velocity (r = 0.63, r2 = 0.40, p < 0.001). CONCLUSIONS: The results of the present study indicate that heart rate recovery is significantly correlated with a measure of large artery stiffness and adds predictive value to other clinical variables. This analysis provides further evidence that assessment of heart rate recovery should be considered in subjects undergoing exercise testing in clinical practice.

Computer-assisted evaluation of aortic stiffness using data acquired via magnetic resonance.

Aortic stiffness is frequently assessed through pulse wave velocity (PWV) measurements. Based on data acquired by magnetic resonance (MR) using a one-dimensional time-of-flight technique, a new computational tool has been developed to rapidly construct flow velocity images and automatically calculate PWV. Comparison between PWV results obtained from this and a manual analysis demonstrates good agreement (correlation coefficient of 0.9951), while the new method improves the time efficiency by more than 20 times. The new method can also significantly improve flow signal quality and yield more credible results when strong interfering background signals are present.

Internet (WWW) based system of ultrasonic image processing tools for remote image analysis.

Ultrasonic Doppler color imaging can provide anatomic information and simultaneously render flow information within blood vessels for diagnostic purpose. Many researchers are currently developing ultrasound image processing algorithms in order to provide physicians with accurate clinical parameters from the images. Because researchers use a variety of computer languages and work on different computer platforms to implement their algorithms, it is difficult for other researchers and physicians to access those programs. A system has been developed using World Wide Web (WWW) technologies and HTTP communication protocols to publish our ultrasonic Angle Independent Doppler Color Image (AIDCI) processing algorithm and several general measurement tools on the Internet, where authorized researchers and physicians can easily access the program using web browsers to carry out remote analysis of their local ultrasonic images or images provided from the database. In order to overcome potential incompatibility between programs and users' computer platforms, ActiveX technology was used in this project. The technique developed may also be used for other research fields.

Maximal aerobic capacity and the oxygen uptake efficiency slope as predictors of large artery stiffness in apparently healthy subjects.

PURPOSE: Large artery stiffness is now recognized as an important marker of cardiovascular health. The purpose of the present investigation was to assess the relationship between large artery stiffness and the oxygen uptake efficiency slope (OUES) and to determine whether the OUES is a viable surrogate for maximal oxygen uptake (VO(2max)) in a multivariate regression analysis developed to estimate large artery stiffness. METHODS: Two hundred seventy-five apparently healthy subjects (149 men; age = 48.1 +/- 15.8 years/126 women; age = 47.0 +/- 15.3 years) participated in this study. Subjects underwent maximal cardiopulmonary exercise testing to determine VO(2max) and the OUES. The OUES was calculated using 50% and 100% of the exercise data. Measurement of aortic wave velocity (AWV in meters/second) was obtained via magnetic resonance imaging. RESULTS: Pearson product-moment correlation analysis revealed that VO(2max) (r = -0.49, P < .001), the OUES calculation using 50% of exercise data (r = -0.25, P < .001), and the OUES calculation using 100% of exercise data (r = -0.34, P < .001) were all significantly related to AWV. However, only VO(2max) was retained in a linear regression (also including age and resting systolic blood pressure) used to predict AWV. DISCUSSION: Previous research has demonstrated a relationship between VO(2max) and AWV, which was also found in the present study. While the OUES was significantly correlated with AWV, it does not appear to be an adequate replacement for VO(2max) when attempting to gauge large artery compliance.

Association of hypertensive diastolic blood pressure with dyslipidemia during exercise in apparently healthy subjects.

INTRODUCTION: Diastolic blood pressure (DBP), which is influenced by cardiac output and total peripheral resistance, normally remains stable or decreases during the transition from rest to exercise. Dyslipidemia has been shown to attenuate vasodilation, and may therefore impede the normal reduction in peripheral vascular resistance during exercise. This investigation examines differences in lipid levels between apparently healthy individuals with a normal and hypertensive DBP response to exercise. METHODS: From a pool of 275 apparently healthy subjects, 35 individuals (aged 57.8 +/- 15.0 years, 13 men and 22 women) with a normal DBP at rest (<80 mm Hg) that increased to a hypertensive level at maximal exercise (> or = 90 mm Hg) were randomly age and sex matched to 35 subjects (aged 56.5 +/- 13.4 years) with a normal DBP at rest (<80 mm Hg) that remained below a hypertensive level at maximal exercise (<90 mm Hg). RESULTS: A paired t test revealed DBP to be significantly higher in the group with an abnormal response to exercise (97.0 +/- 7.6 mm Hg vs 76.8 +/- 7.4 mm Hg; P < .001). Total cholesterol (204.2 +/- 31.2 mg/dL vs 190.6 +/- 28.9 mg/dL; P < .05) and low-density lipoprotein (126.5 +/- 30.5 mg/dL vs 109.8 +/- 25.5 mg/dL; P < .05) levels were also significantly higher in the group with an abnormal DBP response to exercise. All other variables were similar between groups. DISCUSSION: Results indicate that elevated lipid levels are associated with a hypertensive DBP response during maximal exercise in apparently healthy individuals. The abnormal DBP response to exercise observed in this study may be related to attenuated vasodilation in skeletal muscle induced by higher levels of low-density lipoprotein.

Influence on aerobic fitness on aortic stiffness in apparently healthy Caucasian and African-American subjects.

BACKGROUND: Previous research suggests that arterial stiffness may be significantly higher in African-Americans compared to Caucasians. However, the influence of aerobic fitness on the putative difference in arterial stiffness between these groups has not been previously investigated. METHODS: Two hundred forty-eight subjects (215 Caucasian, 33 African-American) participated in this study. Within one week following enrollment, subjects underwent body mass index (BMI, kg/m2) assessment, cardiopulmonary exercise testing and measurement of aortic wave velocity (AWV, m/s) via magnetic resonance imaging. Initially, 33 Caucasian subjects were randomly age (+/-4 years) and sex-matched (10 male/23 female) to the African-American subjects. 25 Caucasian subjects were then randomly matched for age (+/-4 years), sex (7 male/18 female) and maximal oxygen consumption (VO2Max+/-7 mlO2 kg(-1) min(-1)) to the African-American subjects. Matching based upon VO2Max criteria was not possible for 8 African-American subjects. RESULTS: In the age and sex-matched analysis, Caucasian subjects demonstrated a significantly higher VO2Max (38.3+/-9.6 vs. 27.9+/-8.6 mlO2 kg(-1) min(-1), p<0.001) and lower BMI (24.5+/-3.2 vs. 29.3+/-6.2 kg/m2, p<0.001) and AWV (5.8+/-1.7 vs. 6.7+/-1.5 m/s, p=0.03). However, when subjects were matched for age, sex and VO2Max, the differences in both BMI (26.8+/-5.5 vs. 27.9+/-5.6 kg/m2, p=0.45) and AWV (6.1+/-1.8 vs. 6.5+/-1.6 m/s, p=0.77) were insignificant. CONCLUSIONS: The results of the present study suggest that previously reported differences in arterial stiffness between Caucasians and African-Americans are at least partially a consequence of a lower level of aerobic fitness in the latter group, a phenomenon that has also been previously demonstrated.

Improved aortic stiffness assessment in the elderly using a one-dimensional fluid displacement MR method.

PURPOSE: To assess the in vitro accuracy of two rapid projective MR wave velocity measurement sequences, and their relative performance for assessing aortic stiffness in adults of all ages. MATERIALS AND METHODS: In vitro testing was performed using latex tube phantoms with precisely-known flow wave velocities, both in the presence and absence of simulated static tissue. A total of 104 adults representing a large age range (21-83 years) underwent aortic wave velocity (AWV) measurements using multiple trials of each method in a single MR session. The relative agreement between the two AWV results in each tertile of subject age and the coefficient of variation of the AWV data were assessed. RESULTS: In vitro wave velocities did not differ significantly from the known values for either MR method, with or without simulated static tissue. In vivo, the mean AWVs for the young and middle-aged cohorts did not differ significantly between the two MR methods. However, in the elderly group, the two methods did not agree, and one sequence was found to be superior in this age cohort. CONCLUSION: In elderly individuals, a one-dimensional MR method for evaluating aortic stiffness based on aortic blood displacement yields a smaller coefficient of variation and superior overall performance than a similar method based on aortic blood velocity. The two methods perform equivalently in young and middle-aged subjects.

The relationship between C-reactive protein and other cardiovascular risk factors in men and women.

INTRODUCTION: C-reactive protein (CRP) has emerged as an important indicator of risk for cardiovascular disease. The impact of gender on the relationship between CRP and other cardiovascular risk factors, however, has not been thoroughly investigated. METHODS: Ninety men and 75 women participated in this study. Age, resting systolic and diastolic blood pressure, resting heart rate, body mass index, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and hs-CRP were ascertained. Maximal oxygen consumption was obtained via treadmill testing, and aortic stiffness was measured using magnetic resonance imaging. RESULTS: Log hs-CRP level was significantly higher in the female subjects compared with the males subjects (0.86 +/- 0.67 mg/L vs 0.63 +/- 0.44 mg/L, respectively; P = .003). In the male group, Pearson product moment correlation analysis showed that log hs-CRP was not significantly correlated (P > .10) with any of the other variables of interest. In the female group, however, log hs-CRP was significantly correlated (P < .05) with total cholesterol (r = 0.30), low-density lipoprotein (r = 0.27), tryglycerides (r = 0.51), and body mass index (r = 0.36). Linear regression analysis determined that triglycerides and body mass index explained 30% of the variability in log hs-CRP. CONCLUSIONS: These results indicate that the relationship between CRP and other cardiac risk factors is different between apparently healthy men and women. The prognostic characteristics of CRP and the impact of statin therapy on CRP may therefore differ between men and women. Future research should be directed toward resolving this issue.

Rapid measurement of pulse wave velocity via multisite flow displacement.

A MR method is presented for measuring pulse wave velocity (PWV) and its application to assessing stiffness in the human thoracic aorta. This one-dimensional (1D) flow displacement method applies a single RF comb excitation to the vessel, followed by an oscillating frequency encoding gradient, each oscillation providing a 1D projection of the vessel, enabling one to track fluid motion. The currently implemented sequence excites nine slices within a 20-cm length of vessel and has a temporal resolution of 2.03 msec and a total acquisition time of 140 msec. Offline-reconstructed position-versus-time plots show curvilinear flow displacement trajectories corresponding to fluid motion at each of the excitation positions. The PWV can be reliably calculated by curve-fitting these trajectories to a model. In vitro studies using compliant tubes demonstrate no significant difference between results obtained using this method and those directly obtained using pressure transducers. Compared to another MR method previously developed in our laboratory, the proposed method displays improved temporal resolution and enhanced ability to extract PWV from vessels exhibiting low peak flow velocity. Preliminary data suggest that this method is feasible for in vivo application and may provide a more accurate estimation of aortic wave velocity among subjects exhibiting low peak flow velocity, such as the elderly or those with impaired cardiac function.

MR imaging of normal and matrix-depleted cartilage: correlation with biomechanical function and biochemical composition.

PURPOSE: To correlate articular cartilage function, as reflected in biomechanical properties and biochemical composition, with magnetic resonance (MR) imaging parameters of normal articular cartilage and cartilage partially depleted of matrix components. MATERIALS AND METHODS: Normal articular cartilage from 12 porcine patellae was evaluated biomechanically, biochemically, and with MR imaging (with and without gadolinium enhancement). The patellae were then enzymatically treated to deplete the matrix of either collagen or proteoglycan and then reevaluated biomechanically, biochemically, and with MR imaging. Correlations between cartilaginous tissue function and MR imaging parameters were made. Analysis of variance was performed to assess the effect of enzymatic treatment on measured parameters. Linear correlations among the MR imaging, biochemical, and biomechanical parameters were performed to determine the strengths of the relationships. P <.05 indicated statistically significant differences. RESULTS: Biochemical, biomechanical, and MR analyses enabled detection of changes caused by matrix depletion (P <.05). T2 was the most useful MR imaging parameter for distinguishing proteoglycan loss from collagen loss. T2 correlated significantly with both biomechanical modulus (indicative of cartilage stiffness; P <.001, R2 = 0.51) and biochemical proteoglycan content (P <.001, R2 = 0.44). Differentiation between proteoglycan loss and collagen loss in terms of T1 improved with gadolinium enhancement. With gadolinium enhancement, proteoglycan depletion was associated with a greater decrease in T1 than collagen depletion (P <.05). CONCLUSION: An association between biochemical and biomechanical functional status and MR imaging parameters of articular cartilage was demonstrated. Linear correlations existed between modulus and proteoglycan content in terms of T2. Additionally, proteoglycan loss and collagen loss had differing effects on gadolinium-enhanced T1 when it was expressed as the ratio of T1 after gadolinium enhancement/T1 before gadolinium enhancement.