Vitamin D Status in Rheumatoid Arthritis: Inflammation,Arterial Stiffness and Circulating Progenitor Cell Number

Background and Aims

Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA.

Methods and Results

CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen.

Conclusions

RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA.     

Determinants of sustained viral suppression in HIV-infected patients with self-reported poor adherence to antiretroviral therapy

Background

Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels.

Methods

Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period.

Results

From January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01–0.99; LPV/r: OR 0.29, 95% CI: 0.09–0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62–18.75; LPV/r: OR 5.65, 95% CI: 1.82–17.56).

Conclusions

The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.     

Paradoxical Association of C-Reactive Protein with Endothelial Function in Rheumatoid Arthritis

Background

Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).

Methodology/Principal Findings

Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01).

Conclusions/Significance

These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.     

Impact of Cardiovascular Risk Factors on Carotid Intima-Media Thickness and Degree of Severity: A Cross-Sectional Study

Objective

Age, hypertension, dyslipidemia and diabetes are common cardiovascular risk factors (CVRFs) that contribute to the development of atherosclerosis in cardiovascular system including carotid artery disease. However, the impact of these risk factors on the increased carotid intima-media thickness (cIMT) and degree of carotid severity remains to be further clarified. This study aims to evaluate the relationship between CVRFs and degree of carotid severity and cIMT in high-risk subjects.

Methods

Four thousand and three hundred ninety-four subjects with one or more risk factors were retrospectively reviewed in this study. Patients were divided into different groups based on age, the type and quantity of CVRFs. cIMT and degree of carotid artery stenosis were measured and analyzed based on carotid ultrasound imaging with findings compared to the CVRFs to determine the correlation between these variables.

Results

Aging was significantly associated with degree of severity (P < 0.05) and cIMT was significantly increased with age (P < 0.05). Individual CVRF analysis shows that hypertension was more related to the degree of severity than dyslipidemia and diabetes with corresponding abnormal cIMT rates being 79.39%, 72.98% and 32.37%, respectively. The prevalence of carotid atherosclerosis were 20.06%, 22.88% and 28.63%, respectively corresponding to patients with zero, one and more than one chronic diseases. The percentage of abnormal cIMT in hypertensive patient group with dyslipidemia is significantly higher than the other groups (P< 0.05).

Conclusions

This study shows a direct correlation between the degree of carotid severity and cIMT and cardiovascular risk factors, especially with age and hypertension. Carotid atherosclerosis is closely related to the number of cardiovascular risk factors.     

Lower Zinc Bioavailability May Be Related to Higher Risk of Subclinical Atherosclerosis in Korean Adults

Background

There is a proposed link between dietary zinc intake and atherosclerosis, but this relationship remains unclear. Phytate may contribute to this relationship by influencing zinc bioavailability.

Objective

The aim of this study is to examine the relationship between zinc bioavailability and subclinical atherosclerosis in healthy Korean adults.

Materials and Methods

The present cross-sectional analysis used baseline data from the Korean multi-Rural Communities Cohort Study (MRCohort), which is a part of The Korean Genome Epidemiology Study (KoGES). A total of 5,532 subjects (2,116 men and 3,416 women) aged 40 years and older were recruited from rural communities in South Korea between 2005 and 2010. Phytate:zinc molar ratio, estimated from a food-based food frequency questionnaire (FFQ) of 106 food items, was used to determine zinc bioavailability, and carotid intima media thickness (cIMT) and pulse wave velocity (PWV) were measured to calculate the subclinical atherosclerotic index.

Results

We found that phytate:zinc molar ratio is positively related to cIMT in men. A higher phytate:zinc molar ratio was significantly related to an increased risk of atherosclerosis in men, defined as the 80^th percentile value of cIMT (5^th vs. 1^st quintile, OR = 2.11, 95% CI 1.42-3.15, P for trend = 0.0009), and especially in elderly men (5^th vs. 1^st quintile, OR = 2.58, 95% CI 1.52-4.37, P for trend = 0.0021). We found a positive relationship between phytate:zinc molar ratio and atherosclerosis risk among women aged 65 years or younger. Phytate:zinc molar ratio was not found to be related to PWV.

Conclusions

Lower zinc bioavailability may be related to higher atherosclerosis risk.     

Association of Insulin Resistance,Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases

Background

Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV).

Methods

The study group included 303 subjects, mean age 51.8 ±13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis.

Results

Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL.

Conclusions

These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.     

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

Objectives

To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA).

Methods

A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US).

Results

RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed.

Conclusions

In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA.     

Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity

Background

Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology.

Objectives

The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls.

Method

Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained.

Results

The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences.

Conclusion

We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.     

Sensory Attenuation Assessed by Sensory Evoked Potentials in Functional Movement Disorders

Background

Functional (psychogenic) movement disorders (FMD) have features associated with voluntary movement (e.g. distractibility) but patients report movements to be out of their control. One explanation for this phenomenon is that sense of agency for movement is impaired. The phenomenon of reduction in the intensity of sensory experience when movement is self-generated and a reduction in sensory evoked potentials (SEPs) amplitude at the onset of self-paced movement (sensory attenuation) have been linked to sense of agency for movement.

Methods

We compared amplitude of SEPs from median nerve stimulation at rest and at the onset of a self-paced movement of the thumb in 17 patients with FMD and 17 healthy controls.

Results

Patients showed lack of attenuation of SEPs at the onset of movement compared to reduction in amplitude of SEPs in controls. FMD patients had significantly different ratios of movement onset to rest SEPs than did healthy controls at each electrode: 0.79 in healthy controls and 1.35 in patients at F3 (t = -4.22, p<0.001), 0.78 in healthy controls and 1.12 at patients C3 (t = -3.15, p = 0.004) and 0.77 in healthy controls and 1.05 at patients P3 (t = -2.88, p = 0.007).

Conclusions

Patients with FMD have reduced sensory attenuation as measured by SEPs at onset of self-paced movement. This finding can be plausibly linked to impairment of sense of agency for movement in these patients.     

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels

Background and Objectives

Obesity and HIV-1/HAART–associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163.

Methods

This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student’s t-test, Mann-Whitney U and χ² test. Pearson and Spearman correlation were used to estimate the strength of association between variables.

Results

Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001–0.521, p = 0.027).

Conclusions

HALS is associated with decreased sTWEAK levels.     

An Investigation of Two-Dimensional Ultrasound Carotid Plaque Presence and Intima Media Thickness in Middle-Aged South Asian and European Men Living in the United Kingdom

Objectives

Ultrasound studies of carotid intima media thickness (cIMT) and plaques are limited in South Asians, a group at elevated cardiovascular disease (CVD) risk. We determined whether South Asians have a difference in these ultrasound markers compared to Europeans living in the United Kingdom and whether measured risk factor(s) could account for any such differences.

Methods

One hundred South Asian men, aged 40 to 70 years and 100 European men of similar age and BMI, without diagnosed CVD or diabetes, underwent carotid ultrasound for measurement of cIMT and carotid plaque presence. Physical activity, cardiorespiratory fitness, anthropometry and blood pressure were assessed, fasted blood taken for measurement of cardiometabolic risk factors and demographic and lifestyle factors recorded.

Results

Age-adjusted mean (SD) cIMT was similar in South Asians and Europeans (0.64 (0.16) mm v 0.65 (0.12) mm, p = 0.64). Plaque was present in 48 South Asians and 37 Europeans and overall, there was no age-adjusted difference between South Asian and Europeans for plaque score(odds ratio 1.49, 95% CI, 0.86-2.80, p = 0.16), however, South Asians appeared to have more plaques at a younger age than Europeans; at age 40-50 years the odds of South Asians having plaques was 2.63 (95% CI, 1.16-5.93) times that for Europeans.

Conclusions

cIMT is similar between healthy South Asian and European men. Whilst there was no overall difference in plaque presence in South Asians, there is an indication of greater plaque prevalence at younger ages - an observation requiring further investigation. Prospective studies linking plaques to CVD outcomes in South Asians are needed to investigate whether these measures help improve CVD risk prediction.     

The relationships of markers of cholesterol homeostasis with carotid intima-media thickness

Background

The relationship of cholesterol homeostasis and carotid intima-media thickness (cIMT) is unknown. To address this, we assessed markers of cholesterol homeostasis (serum plant sterols and cholesterol precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) and cIMT in a middle-aged, statin-naive population.

Methods

In this prospective study of primary prevention cIMT was measured by ultrasound in 583 hospital employees aged 25–60 years without prevalent cardiovascular disease or lipid-modifying medication. The serum concentrations of plant sterols (as markers of cholesterol absorption) were measured by gas-liquid chromatography. Lathosterol serum concentrations were quantitated to assess hepatic cholesterol synthesis.

Results

cIMT correlated positively with serum cholesterol (r = 0.22, P<0.0005) and lathosterol-to-cholesterol (r = 0.18, P<0.001). In contrast, plant sterols, as markers of cholesterol absorption, showed a weak negative correlation to cIMT measurements (r = −0.18; P<0.001 for campesterol-to-cholesterol). Stratifying subjects by serum sterol levels, we found that cIMT increased continuously over quintiles of serum cholesterol (P<0.0005) and was positively associated to serum lathosterol-to-cholesterol levels (P = 0.007), on the other hand, plant sterol levels showed a weak negative association to cIMT (P<0.001 for campesterol-to-cholesterol).

Conclusions

In this population without prevalent cardiovascular diseases or lipid-modifying medication, markers of increased endogenous cholesterol synthesis correlated positively with cIMT, while markers of cholesterol absorption showed a weakly negative correlation. These data suggest that not only total serum cholesterol levels but also differences in cholesterol homeostasis are associated with cIMT.     

Skin Autofluorescence Is Associated with Endothelial Dysfunction in Uremic Subjects on Hemodialysis

Background

Elevated levels of advanced glycation end products (AGEs) within tissues may contribute to endothelial dysfunction, an early indicator of atherosclerosis. We aimed to investigate whether levels of skin AGEs could be a useful marker to predict endothelial dysfunction in uremic subjects on hemodialysis.

Methods and Results

One hundred and nineteen uremic patients on hemodialysis and 57 control subjects with moderate-to-high cardiovascular risk factors and without chronic kidney disease (CKD) were enrolled. We used ultrasound to measure flow-mediated vasodilation (FMD). An AGE reader measured skin autoflurorescence (AF). We then compared differences in FMD and skin AF values between the two groups. The uremic subjects had significantly higher levels of skin AF (3.47±0.76 AU vs. 2.21±0.45 arbitrary units; P<0.01) and significantly lower levels of FMD (4.79%±1.88% vs. 7.19%±2.17%; P<0.01) than the non-CKD subjects. After adjusting for all potential covariates, we found that skin AF level independently predicted FMD in both the hemodialysis and the non-CKD groups. In the hemodialysis group, skin AF ≥ 3.05 arbitrary units predicted abnormal FMD at a sensitivity of 87.9% and a specificity of 78.6% (P<0.01).

Conclusions

Skin AF could be a useful marker to predict endothelial dysfunction in uremic subjects on hemodialysis.     

Gingival Inflammation Associates with Stroke – A Role for Oral Health Personnel in Prevention: A Database Study

Objectives

Gingival inflammation is the physiological response to poor oral hygiene. If gingivitis is not resolved the response will become an established lesion.We studied whether gingivitis associates with elevated risk for stroke. The hypothesis was based on the periodontitis–atherosclerosis paradigm.

Methods

In our prospective cohort study from Sweden 1676 randomly selected subjects were followed up from 1985 to 2012. All subjects underwent clinical oral examination and answered a questionnaire assessing background variables such as socio-economic status and pack-years of smoking. Cases with stroke were recorded from the Center of Epidemiology, Swedish National Board of Health and Welfare, Sweden, and classified according to the WHO International Classification of Diseases. Unpaired t-test, chi-square tests, and multiple logistic regression analyses were used.

Results

Of the 1676 participants, 39 subjects (2.3%) had been diagnosed with stroke. There were significant differences between the patients with stroke and subjects without in pack-years of smoking (p = 0.01), prevalence of gingival inflammation (GI) (p = 0.03), and dental calculus (p = 0.017). In a multiple regression analysis the association between GI, confounders and stroke, GI showed odds ratio 2.20 (95% confidence interval 1.02–4.74) for stroke.

Conclusion

Our present findings showed that gingival inflammation clearly associated with stroke in this 26-year cohort study. The results emphasize the role of oral health personnel in prevention.     

Simultaneous [18F]FDG-PET/MRI: Correlation of Apparent Diffusion Coefficient (ADC) and Standardized Uptake Value (SUV) in Primary and Recurrent Cervical Cancer

Objectives

Previous non–simultaneous PET/MR studies have shown heterogeneous results about the correlation between standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs). The aim of this study was to investigate correlations in patients with primary and recurrent tumors using a simultaneous PET/MRI system which could lead to a better understanding of tumor biology and might play a role in early response assessment.

Methods

We included 31 patients with histologically confirmed primary (n = 14) or recurrent cervical cancer (n = 17) who underwent simultaneous whole-body ¹⁸F-FDG-PET/MRI comprising DWI. Image analysis was performed by a radiologist and a nuclear physician who identified tumor margins and quantified ADC and SUV. Pearson correlations were calculated to investigate the association between ADC and SUV.

Results

92 lesions were detected. We found a significant inverse correlation between SUV_max and ADC_min (r = -0.532, p = 0.05) in primary tumors as well as in primary metastases (r = -0.362, p = 0.05) and between SUV_mean and ADC_min (r = -0.403, p = 0.03). In recurrent local tumors we found correlations for SUV_max and ADC_min (r = -0.747, p = 0.002) and SUV_mean and ADC_min (r = -0.773, p = 0.001). Associations for recurrent metastases were not significant (p>0.05).

Conclusions

Our study demonstrates the feasibility of fast and reliable measurement of SUV and ADC with simultaneous PET/MRI. In patients with cervical cancer we found significant inverse correlations for SUV and ADC which could play a major role for further tumor characterization and therapy decisions.

Key Point 1

This study investigates the correlation of functional parameters in a simultaneous PET/MRI.

Key Point 2

We found significant inverse correlations between ADC and SUV in cervical carcinoma which could increase knowledge about tumor biology.     

Noninvasive Method for Measuring Local Pulse Wave Velocity by Dual Pulse Wave Doppler: In Vitro and In Vivo Studies

Objectives

To evaluate the validity and reproducibility of a noninvasive dual pulse wave Doppler (DPWD) method, which involves simultaneous recording of flow velocity of two independent sample volumes with a measurable distance, for measuring the local arterial pulse wave velocity (PWV) through in vitro and in vivo studies.

Methods

The DPWD mode of Hitachi HI Vision Preirus ultrasound system with a 5–13MHz transducer was used. An in vitro model was designed to compare the PWV of a homogeneous rubber tubing with the local PWV of its middle part measured by DPWD method. In the in vivo study, local PWV of 45 hypertensive patients (25 male, 49.8±3.1 years) and 45 matched healthy subjects (25 male, 49.3±3.0 years) were investigated at the left common carotid artery (LCCA) by DPWD method.

Results

In the in vitro study, the local PWV measured by DPWP method and the PWV of the homogeneous rubber tubing did not show statistical difference (5.16 ± 0.28 m/s vs 5.03 ± 0.15 m/s, p = 0.075). The coefficient of variation (CV) of the intra- and inter- measurements for local PWV were 3.46% and 4.96%, for the PWV of the homogeneous rubber tubing were 0.99% and 1.98%. In the in vivo study, a significantly higher local PWV of LCCA was found in the hypertensive patients as compared to that in healthy subjects (6.29±1.04m/s vs. 5.31±0.72m/s, P = 0.019). The CV of the intra- and inter- measurements in hypertensive patients were 2.22% and 3.94%, in healthy subjects were 2.07% and 4.14%.

Conclusions

This study demonstrated the feasibility of the noninvasive DPWD method to determine the local PWV, which was accurate and reproducible not only in vitro but also in vivo studies. This noninvasive echocardiographic method may be illuminating to clinical use.     

Digital Photoplethysmography for Assessment of Arterial Stiffness: Repeatability and Comparison with Applanation Tonometry

Introduction

Arterial stiffness is an independent risk factor for cardiovascular morbidity and can be assessed by applanation tonometry by measuring pulse wave velocity (PWV) and augmentation index (AIX) by pressure pulse wave analysis (PWA). As an inexpensive and operator independent alternative, photoelectric plethysmography (PPG) has been introduced with analysis of the digital volume pulse wave (DPA) and its second derivatives of wave reflections.

Objective

The objective was to investigate the repeatability of arterial stiffness parameters measured by digital pulse wave analysis (DPA) and the associations to applanation tonometry parameters.

Methods and Results

112 pregnant and non-pregnant individuals of different ages and genders were examined with SphygmoCor arterial wall tonometry and Meridian DPA finger photoplethysmography. Coefficients of repeatability, Bland-Altman plots, intraclass correlation coefficients and correlations to heart rate (HR) and body height were calculated for DPA variables, and the DPA variables were compared to tonometry variables left ventricular ejection time (LVET), PWV and AIX. No DPA variable showed any systematic measurement error or excellent repeatability, but dicrotic index (DI), dicrotic dilatation index (DDI), cardiac ejection elasticity index (EEI), aging index (AI) and second derivatives of the crude pulse wave curve, b/a and e/a, showed good repeatability. Overall, the correlations to AIX were better than to PWV, with correlations coefficients >0.70 for EEI, AI and b/a. Considering the level of repeatability and the correlations to tonometry, the overall best DPA parameters were EEI, AI and b/a. The two pansystolic time parameters, ejection time compensated (ETc) by DPA and LVET by tonometry, showed a significant but weak correlation.

Conclusion

For estimation of the LV function, ETc, EEI and b/a are suitable, for large artery stiffness EEI, and for small arteries DI and DDI. The only global parameter, AI, showed a high repeatability and the overall best correlations with AIX and PWV.     

Iron Stores,Hepcidin, and Aortic Stiffness in Individuals with Hypertension

Background & Aims

Iron accumulation within the arterial wall has been hypothesized to promote atherosclerosis progression. Aim of this study was to evaluate whether the hormone hepcidin and iron stores are associated with arterial stiffness in subjects with essential hypertension.

Methods

Circulating hepcidin, ferritin, and mutations in the hemochromatosis gene were compared between subjects included in the first vs. third tertile (n=284 each) of carotid-femoral pulse wave velocity (PWV) in an unselected cohort of patients with arterial hypertension.

Results

At univariate logistic regression analysis, high PWV was associated with higher ferritin levels (p=0.010), but lower hepcidin (p=0.045), and hepcidin ferritin/ratio (p<0.001). Hemochromatosis mutations predisposing to iron overload were associated with high PWV (p=0.025). At multivariate logistic regression analysis, high aortic stiffness was associated with older age, male sex, lower BMI, higher systolic blood pressure and heart rate, hyperferritinemia (OR 2.05, 95% c.i. 1.11-3.17 per log ng/ml; p=0.022), and lower circulating hepcidin concentration (OR 0.29, 95% c.i. 0.16-0.51 per log ng/ml; p<0.001). In subgroup analyses, high PWV was associated with indices of target organ damage, including micro-albuminuria (n=125, p=0.038), lower ejection fraction (n=175, p=0.031), cardiac diastolic dysfunction (p=0.004), and lower S wave peak systolic velocity (p<0.001). Ferritin was associated with cardiac diastolic dysfunction, independently of confounders (p=0.006).

Conclusions

In conclusion, hyperferritinemia is associated with high aortic stiffness and cardiac diastolic dysfunction, while low circulating hepcidin with high aortic stiffness.     

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Background

Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.

Methods

In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.

Results

The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10^-4).

Conclusion

These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.