Sonja B. Nikolic

Validity and reliability of central blood pressure estimated by upper arm oscillometric cuff pressure

BACKGROUND Noninvasive central blood pressure (BP) independently predicts mortality, but current methods are operator-dependent, requiring skill to obtain quality recordings. The aims of this study were first, to determine the validity of an automatic, upper arm oscillometric cuff method for estimating central BP (O(CBP)) by comparison with the noninvasive reference standard of radial tonometry (T(CBP)). Second, we determined the intratest and intertest reliability of O(CBP). METHODS To assess validity, central BP was estimated by O(CBP) (Pulsecor R6.5B monitor) and compared with T(CBP) (SphygmoCor) in 47 participants free from cardiovascular disease (aged 57 ± 9 years) in supine, seated, and standing positions. Brachial mean arterial pressure (MAP) and diastolic BP (DBP) from the O(CBP) device were used to calibrate in both devices. Duplicate measures were recorded in each position on the same day to assess intratest reliability, and participants returned within 10 ± 7 days for repeat measurements to assess intertest reliability. RESULTS There was a strong intraclass correlation (ICC = 0.987, P < 0.001) and small mean difference (1.2 ± 2.2 mm Hg) for central systolic BP (SBP) determined by O(CBP) compared with T(CBP). Ninety-six percent of all comparisons (n = 495 acceptable recordings) were within 5 mm Hg. With respect to reliability, there were strong correlations but higher limits of agreement for the intratest (ICC = 0.975, P < 0.001, mean difference 0.6 ± 4.5 mm Hg) and intertest (ICC = 0.895, P < 0.001, mean difference 4.3 ± 8.0 mm Hg) comparisons. CONCLUSIONS Estimation of central SBP using cuff oscillometry is comparable to radial tonometry and has good reproducibility. As a noninvasive, relatively operator-independent method, O(CBP) may be as useful as T(CBP) for estimating central BP in clinical practice.

Metabolomics in hypertension.

Hypertension is the most prevalent chronic medical condition and a major risk factor for cardiovascular morbidity and mortality. In the majority of hypertensive cases, the underlying cause of hypertension cannot be easily identified because of the heterogeneous, polygenic and multi-factorial nature of hypertension. Metabolomics is a relatively new field of research that has been used to evaluate metabolic perturbations associated with disease, identify disease biomarkers and to both assess and predict drug safety and efficacy. Metabolomics has been increasingly used to characterize risk factors for cardiovascular disease, including hypertension, and it appears to have significant potential for uncovering mechanisms of this complex disease. This review details the analytical techniques, pre-analytical steps and study designs used in metabolomics studies, as well as the emerging role for metabolomics in gaining mechanistic insights into the development of hypertension. Suggestions as to the future direction for metabolomics research in the field of hypertension are also proposed.

Metabolomics Data Normalization with EigenMS

Liquid chromatography mass spectrometry has become one of the analytical platforms of choice for metabolomics studies. However, LC-MS metabolomics data can suffer from the effects of various systematic biases. These include batch effects, day-to-day variations in instrument performance, signal intensity loss due to time-dependent effects of the LC column performance, accumulation of contaminants in the MS ion source and MS sensitivity among others. In this study we aimed to test a singular value decomposition-based method, called EigenMS, for normalization of metabolomics data. We analyzed a clinical human dataset where LC-MS serum metabolomics data and physiological measurements were collected from thirty nine healthy subjects and forty with type 2 diabetes and applied EigenMS to detect and correct for any systematic bias. EigenMS works in several stages. First, EigenMS preserves the treatment group differences in the metabolomics data by estimating treatment effects with an ANOVA model (multiple fixed effects can be estimated). Singular value decomposition of the residuals matrix is then used to determine bias trends in the data. The number of bias trends is then estimated via a permutation test and the effects of the bias trends are eliminated. EigenMS removed bias of unknown complexity from the LC-MS metabolomics data, allowing for increased sensitivity in differential analysis. Moreover, normalized samples better correlated with both other normalized samples and corresponding physiological data, such as blood glucose level, glycated haemoglobin, exercise central augmentation pressure normalized to heart rate of 75, and total cholesterol. We were able to report 2578 discriminatory metabolite peaks in the normalized data (p<0.05) as compared to only 1840 metabolite signals in the raw data. Our results support the use of singular value decomposition-based normalization for metabolomics data.

Waiting a few extra minutes before measuring blood pressure has potentially important clinical and research ramifications

Office blood pressure (BP) is recommended to be measured after 5 min of seated rest, but it may decrease for 10 min of seated rest. This study aimed to determine the change (and its clinical relevance) in brachial and central BP from 5 to 10 min of seated rest. Office brachial and central BP (measured after 5 and 10 min), left ventricular (LV) mass index, 7-day home and ambulatory BP were measured in 250 participants with treated hypertension. Office brachial and central BP were significantly lower at 10-min compared with 5-min BP (P<0.001). Seven-day home systolic BP (SBP) was significantly lower than office SBP measured at 5 min (P<0.001), but was similar to office SBP at 10 min (P=0.511). From 5 to 10 min, the percentage of participants with controlled BP increased and the percentage of participants with high central pulse pressure (PP) decreased (P<0.001). Moreover, brachial and central PP were significantly correlated with LV mass index measured at 10 min (r=0.171, P=0.006 and r=0.139, P=0.027, respectively), but not at 5 min (r=0.115, P=0.068 and r=0.084, P=0.185, respectively). BP recorded after 10 min is more representative of true BP control. These findings have relevance to appropriate diagnosis of hypertension and design of clinical trials.

Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion

Intralipid is a fat emulsion that is regularly infused into humans and animals. Despite its routine use, Intralipid infusion can cause serious adverse reactions, including immunosuppression. Intralipid is a complex mix of proteins, lipids, and other small molecules, and the effect of its infusion on the human plasma metabolome is unknown. We hypothesized that untargeted metabolomics of human plasma after an Intralipid infusion would reveal novel insights into its effects. We infused Intralipid and saline into 10 healthy men in a double-blind, placebo-controlled experiment and used GC/MS, LC/MS, and NMR to profile the small-molecule composition of their plasma before and after infusion. Multivariate statistical analysis of the 40 resulting plasma samples revealed that after Intralipid infusion, a less-well-characterized pathway of linoleic acid metabolism had resulted in the appearance of (9Z)-12,13-dihydroxyoctadec-9-enoic acid (12,13-DHOME, P < 10−3), a leukotoxin that has powerful physiological effects and is known to inhibit the neutrophil respiratory burst. Intralipid infusion caused increased plasma 12,13-DHOME. Given that 12,13-DHOME is known to directly affect neutrophil function, we conclude that untargeted metabolomics may have revealed a hitherto-unknown mechanism of intralipid-induced immunosuppression.

Exaggerated blood pressure response to early stages of exercise stress testing and presence of hypertension.

OBJECTIVES Exaggerated exercise blood pressure (EEBP) recorded during exercise testing at moderate-intensity is independently associated with cardiovascular mortality. It is hypothesized that EEBP may be indicative of underlying hypertension unnoticed by standard clinic (resting) BP measures (thus explaining increased mortality risk), but this has never been confirmed by association with hypertension defined using ambulatory BP monitoring, which was the aim of this study. DESIGN Cross-sectional study. METHODS 100 consecutive patients free from coronary artery disease (aged 56±9 years, 72% male) underwent clinically indicated exercise stress testing. Exercise BP was recorded at each stage of the Bruce protocol. Presence of hypertension was defined as 24-hour systolic BP ≥130mmHg or daytime systolic BP ≥135mmHg. RESULTS Exercise systolic BP at stage 1 and 2 of the test was significantly associated with the presence of hypertension (P<0.05), with the strongest association observed between stage 1 exercise systolic BP and 24-h systolic BP >130mmHg (AUC=0.752, 95% CIs 0.649-0.846, P<0.001). 79% of participants achieving systolic BP ≥150mmHg at stage 1 of the test were classified as having hypertension, with systolic BP >150mmHg predicting hypertension independently of age, sex and in-clinic hypertension status (OR=4.83, 95% CIs 1.62-14.39, P=0.005). CONCLUSIONS Irrespective of resting BP, systolic BP ≥150mmHg during early stages of the Bruce exercise stress test is associated with presence of hypertension. EEBP should be a warning signal to health/exercise professionals on the presence of hypertension and the need to provide follow up care to reduce cardiovascular risk.

Persistent elevation of central pulse pressure during postural stress in patients with type 2 diabetes mellitus

An abnormal increase or decrease in blood pressure (BP) in response to postural stress is associated with increased risk of developing hypertension and stroke. However, the haemodynamic responses contributing to changes in central BP with postural stress are not well characterised. We aimed to determine this in controls compared to patients with type 2 diabetes mellitus (T2DM), whom we hypothesised would have an abnormal postural response. 41 participants (20 control, 21 T2DM) underwent measurement of brachial and central BP (by radial tonometry), with simultaneous bioimpedance cardiography (to determine stroke volume (SV) and cardiac output (CO)) and heart rate variability in seated and standing postures. Systemic vascular resistance (SVR; mean arterial pressure/CO), and arterial elastance (EA; end systolic pressure/SV) were calculated. Postural changes were defined as seated minus standing values. Central pulse pressure (PP) was higher in patients with T2DM and did not change from seated-to-standing positions, whereas there was a significant decrease upon standing in controls (P<0.05). The change in central systolic BP (SBP) correlated with change in SVR and EA in controls (r=0.67 and 0.68, P<0.05, respectively), but not in patients with T2DM (r=−0.05 and r=0.03, P>0.05, respectively). SV was the only significant correlate of change in central SBP in T2DM patients (r=0.62, P<0.05) and this was not observed in controls (r=−0.08 P>0.05). We conclude that central haemodynamic responses to postural stress are altered in patients with T2DM and result in persistent elevation of central PP while standing. This may contribute to increased cardiovascular risk associated with T2DM.

645 EFFECTS OF DOWNSTREAM DRUG METABOLITES OF SPIRONOLACTONE ON AORTIC STIFFNESS AND AMBULATORY BLOOD PRESSURE

Background: Spironolactone is an aldosterone antagonist that is thought to have antifibrotic effects (e.g. reduces aortic stiffness), but little is known about the underlying mechanisms. This could occur through direct effects on the endogenous aldosterone pathway or via active metabolites derived from spironolactone. In this study we aimed to determine the physiological actions of downstream metabolites of spironolactone. Methods: Baseline and follow-up serum samples from 115 participants (54 ± 9years) randomized to three months spironolactone (25 mg/d) or placebo were analysed by liquid chromatography/mass spectrometry (LC/MS) using a high resolution LTQ-Orbitrap. Physiological variables recorded at baseline and follow-up included aortic stiffness (pulse wave velocity; PWV) and 24 hour ambulatory BP. Actions of spironolactone metabolites were assessed by correlation with the change in physiological variables after three months spironolactone therapy. Results: Spironolactone significantly reduced aortic PWV and 24 hour systolic BP (P < 0.05 for both). LC/MS detected 43 individual features that were candidate downstream metabolites of spironolactone, although none were correlated with changes in aortic PWV (P > 0.05 for all). However, the spironolactone metabolite canrenoate was associated with the change in daytime systolic BP (r = -0.415, P = 0.007). This remained highly significant on multiple regression (&bgr;=-0.408, P = 0.009) and was independent of age, body mass index and sex (adjusted R2 = 0.268, P < 0.021). Conclusions: Downstream drug metabolites of spironolactone do not appear to have significant antifibrotic effects, as measured by attenuation of aortic stiffness. However, canrenoate appears to be an active metabolite of spironolactone with regard to ambulatory BP lowering effects.