Plasma levels of the cardiovascular protective endogenous nucleoside adenosine are reduced in patients with primary aldosteronism without affecting ischaemia-reperfusion injury: A prospective case-control study.

BACKGROUND: Patients with primary aldosteronism (PA) experience more cardiovascular events compared to patients with essential hypertension (EHT), independent from blood pressure levels. In animals, mineralocorticoid receptor antagonists limit ischaemia-reperfusion (IR) injury by increasing extracellular adenosine formation and adenosine receptor stimulation. Adenosine is an endogenous compound with profound cardiovascular protective effects. Firstly, we hypothesized that patients with PA have lower circulating adenosine levels which might contribute to the observed increased cardiovascular risk. Secondly, we hypothesized that by this mechanism, patients with PA are more susceptible to IR compared to patients with EHT. DESIGN: In our prospective study in 20 patients with PA and 20 patients with EHT, circulating adenosine was measured using a pharmacological blocker solution that halts adenosine metabolism after blood drawing. Brachial artery flow-mediated dilation (FMD) before and after forearm IR was used as a well-established method to study IR injury. RESULTS: Patients with PA had a 33% lower adenosine level compared to patients with EHT (15.3 [13.3-20.4] vs 22.7 [19.4-36.8] nmol/L, respectively, P < .01). The reduction in FMD after IR, however, did not differ between patients with PA and patients with EHT (-1.0 ± 2.9% vs -1.6 ± 1.6%, respectively, P = .52). CONCLUSIONS: As adenosine receptor stimulation induces various powerful protective cardiovascular effects, its lower concentration in patients with PA might be an important novel mechanism that contributes to their increased cardiovascular risk. We suggest that modulation of the adenosine metabolism is an exciting novel pharmacological opportunity to limit cardiovascular risk in patients with PA that needs further exploration.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Carotid Artery Reactivity Predicts Events in Peripheral Arterial Disease Patients.

OBJECTIVE: Patients with peripheral arterial disease (PAD) have increased risk on future cerebro- and cardiovascular events. Our aim was to examine whether carotid artery reactivity (CAR; a novel, simple procedure to examine endothelial function) predicts cardiovascular events in PAD patients. BACKGROUND: Increased risk for future cardiovascular events in PAD patients is likely related to endothelial dysfunction, highlighting the necessity for simple assessment of endothelial function. METHODS: A total of 172 PAD patients (68 ±â€Š10 years, 67% male) underwent the CAR, which involves ultrasound measurement of carotid artery diameter during sympathetic stimulation produced by 90-second hand immersion in 4°C ice-water (ie, cold pressor test). CAR-responses were dichotomized into carotid constriction or dilation. We recorded cardiac and cerebrovascular events, mortality, and clinical progression to percutaneous transluminal angioplasty or loss of patency during 12-month follow-up. RESULTS: Eighty-two PAD patients demonstrated carotid constriction and 90 patients demonstrated dilation. PAD patients with carotid constriction showed more cardiovascular events compared to patients with dilation (Kaplan-Meier Log rank; P < 0.05). Cox proportional hazard models showed that patients with carotid constriction continued to show higher risk for cardiovascular events [hazard ratio: 4.1; 95% confidence interval (CI), 1.3-12.5] and clinical progression (hazard ratio: 2.0; 95% CI, 1.2-3.3), even after adjustment for other risk factors. Ankle brachial pressure index and carotid intima-medial thickness alone did not predict (cardiovascular) event or improve risk assessment beyond that provided by CAR. CONCLUSION: Carotid vasoconstriction identifies PAD patients with a 4-fold increased risk for future cardiovascular events and 2-fold increased risk for clinical deterioration. CAR provides a simple, novel strategy to predict cardiovascular events and progression in PAD patients. CLINICAL TRIAL REGISTRATION: www.trialregister.nl/trialreg/index.asp, NTR-4117.

Similarity between carotid and coronary artery responses to sympathetic stimulation and the role of α1-receptors in humans.

Carotid artery (CCA) dilation occurs in healthy subjects during cold pressor test (CPT), while the magnitude of dilation relates to cardiovascular risk. To further explore this phenomenon and mechanism, we examined carotid artery responses to different sympathetic tests, with and without α1-receptor blockade and assessed similarity to these responses between carotid and coronary arteries. In randomized order, 10 healthy participants (25 ± 3 yr) underwent sympathetic stimulation using the CPT (3-min left-hand immersion in ice-slush) and lower-body negative pressure (LBNP). Before and during sympathetic tests, CCA diameter and velocity (Doppler ultrasound) and left anterior descending (LAD) coronary artery velocity (echocardiography) were recorded across 3 min. Measures were repeated 90 min following selective α1-receptor blockade via oral prazosin (0.05 mg/kg body wt). CPT significantly increased CCA diameter, LAD maximal velocity, and velocity-time integral area-under-the-curve (all P < 0.05). In contrast, LBNP resulted in a decrease in CCA diameter, LAD maximal velocity, and velocity time integral (VTI; all P < 0.05). Following α1-receptor blockade, CCA and LAD velocity responses to CPT were diminished. In contrast, during LBNP (-30 mmHg), α1-receptor blockade did not alter CCA or LAD responses. Finally, changes in CCA diameter and LAD VTI responses to sympathetic stimulation were positively correlated ( r = 0.66, P < 0.01). We found distinct carotid artery responses to different tests of sympathetic stimulation, where α1 receptors partly contribute to CPT-induced responses. Finally, we found agreement between carotid and coronary artery responses. These data indicate similarity between carotid and coronary responses to sympathetic tests and the role of α1 receptors that is dependent on the nature of the sympathetic challenge. NEW & NOTEWORTHY We showed distinct carotid artery responses to cold pressor test (CPT; i.e., dilation) and lower-body negative pressure (LBNP; i.e., constriction). Blockade of α1-receptors significantly attenuated dilator responses in carotid and coronary arteries during CPT, while no changes were found during LBNP. Our findings indicate strong similarity between carotid and coronary artery responses to distinct sympathetic stimuli, and for the role of α-receptors.

Impact of lifelong exercise training on endothelial ischemia-reperfusion and ischemic preconditioning in humans.

Reperfusion is essential for ischemic tissue survival, but causes additional damage to the endothelium [i.e., ischemia-reperfusion (I/R) injury]. Ischemic preconditioning (IPC) refers to short repetitive episodes of ischemia that can protect against I/R. However, IPC efficacy attenuates with older age. Whether physical inactivity contributes to the attenuated efficacy of IPC to protect against I/R injury in older humans is unclear. We tested the hypotheses that lifelong exercise training relates to 1) attenuated endothelial I/R and 2) maintained IPC efficacy that protects veteran athletes against endothelial I/R. In 18 sedentary male individuals (SED, <1 exercise h/wk for >20 yr, 63 ± 7 yr) and 20 veteran male athletes (ATH, >5 exercise h/wk for >20 yr, 63 ± 6 yr), we measured brachial artery endothelial function with flow-mediated dilation (FMD) before and after I/R. We induced I/R by 20 min of ischemia followed by 20 min of reperfusion. Randomized over 2 days, participants underwent either 35-min rest or IPC (3 cycles of 5-min cuff inflation to 220 mmHg with 5 min of rest) before I/R. In SED, FMD decreased after I/R [median (interquartile range)]: [3.0% (2.0-4.7) to 2.1% (1.5-3.9), P = 0.046] and IPC did not prevent this decline [4.1% (2.6-5.2) to 2.8% (2.2-3.6), P = 0.012]. In ATH, FMD was preserved after I/R [3.0% (1.7-5.4) to 3.0% (1.9-4.1), P = 0.82] and when IPC preceded I/R [3.2% (1.9-4.2) to 2.8% (1.4-4.6), P = 0.18]. These findings indicate that lifelong exercise training is associated with increased tolerance against endothelial I/R. These protective, preconditioning effects of lifelong exercise against endothelial I/R may contribute to the cardioprotective effects of exercise training.

Correlation of carotid artery reactivity with cardiovascular risk factors and coronary artery vasodilator responses in asymptomatic, healthy volunteers.

OBJECTIVES: Carotid artery reactivity (CAR%), involving carotid artery diameter responses to a cold pressor test (CPT), is a noninvasive measure of conduit artery function in humans. This study examined the impact of age and cardiovascular risk factors on the CAR% and the relationship between CAR% and coronary artery vasodilator responses to the CPT. METHODS: Ultrasound was used to measure resting and peak carotid artery diameters during the CPT, with CAR% being calculated as the relative change from baseline (%). We compared CAR% between young (n = 50, 24 ±â€Š3 years) and older participants (n = 44, 61 ±â€Š8 years), and subsequently assessed relationships between CAR% and traditional cardiovascular risk factors in 50 participants (44 ±â€Š21 years). Subsequently, we compared left anterior descending (LAD) artery velocity (using transthoracic Doppler) with carotid artery diameter (i.e. CAR%) during the CPT (n = 33, 37 ±â€Š17 years). RESULTS: A significantly larger CAR% was found in young versus older healthy participants (4.1 ±â€Š3.7 versus 1.8 ±â€Š2.6, P < 0.001). Participants without cardiovascular risk factors demonstrated a higher CAR% than those with at least two risk factors (2.9 ±â€Š2.9 versus 0.5 ±â€Š2.9, P = 0.019). Carotid artery diameter and LAD velocity increased during CPT (P < 0.001). Carotid diameter and change in velocity correlated with LAD velocity (r = 0.486 and 0.402, P < 0.004 and 0.02, respectively). CONCLUSION: Older age and cardiovascular risk factors are related to lower CAR%, while CAR% shows good correlation with coronary artery responses to the CPT. Therefore, CAR% may represent a valuable technique to assess cardiovascular risk, while CAR% seems to reflect coronary artery vasodilator function.

Impact of volunteer-related and methodology-related factors on the reproducibility of brachial artery flow-mediated vasodilation: analysis of 672 individual repeated measurements.

OBJECTIVES: Brachial artery flow-mediated dilation (FMD) is a popular technique to examine endothelial function in humans. Identifying volunteer and methodological factors related to variation in FMD is important to improve measurement accuracy and applicability. METHODS: Volunteer-related and methodology-related parameters were collected in 672 volunteers from eight affiliated centres worldwide who underwent repeated measures of FMD. All centres adopted contemporary expert-consensus guidelines for FMD assessment. After calculating the coefficient of variation (%) of the FMD for each individual, we constructed quartiles (n = 168 per quartile). Based on two regression models (volunteer-related factors and methodology-related factors), statistically significant components of these two models were added to a final regression model (calculated as ß-coefficient and R). This allowed us to identify factors that independently contributed to the variation in FMD%. RESULTS: Median coefficient of variation was 17.5%, with healthy volunteers demonstrating a coefficient of variation 9.3%. Regression models revealed age (ß = 0.248, P < 0.001), hypertension (ß = 0.104, P < 0.001), dyslipidemia (ß = 0.331, P < 0.001), time between measurements (ß = 0.318, P < 0.001), lab experience (ß = -0.133, P < 0.001) and baseline FMD% (ß = 0.082, P < 0.05) as contributors to the coefficient of variation. After including all significant factors in the final model, we found that time between measurements, hypertension, baseline FMD% and lab experience with FMD independently predicted brachial artery variability (total R = 0.202). CONCLUSION: Although FMD% showed good reproducibility, larger variation was observed in conditions with longer time between measurements, hypertension, less experience and lower baseline FMD%. Accounting for these factors may improve FMD% variability.

Assessing the perceived quality of brachial artery Flow Mediated Dilation studies for inclusion in meta-analyses and systematic reviews: Description of data employed in the development of a scoring ;tool based on currently accepted guidelines.

Brachial artery Flow Mediated Dilation (FMD) is widely used as a non-invasive measure of endothelial function. Adherence to expert consensus guidelines on FMD measurement has been found to be of vital importance to obtain reproducible data. This article lists the literature data which was considered in the development of a tool to aid in the objective judgement of the extent to which published studies adhered to expert guidelines for FMD measurement. Application of this tool in a systematic review of FMD studies (http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.011) (Greyling et al., 2016 [1]) indicated that adherence to expert consensus guidelines is strongly correlated to the reproducibility of FMD data.

Adherence to guidelines strongly improves reproducibility of brachial artery flow-mediated dilation.

BACKGROUND: Brachial artery FMD is widely used as a non-invasive measure of endothelial function. Adherence to expert guidelines is believed to be of vital importance to obtain reproducible measurements. We conducted a systematic review of studies reporting on the reproducibility of the FMD in order to determine the relation between adherence to current expert guidelines for FMD measurement and its reproducibility. METHODS: Medline-database was searched through July 2015 and 458 records were screened for FMD reproducibility studies reporting the mean difference and variance of repeated FMD measurements. An adherence score was assigned to each of the included studies based on reported adherence to published guidelines on the assessment of brachial artery FMD. A Typical Error Estimate (TEE) of the FMD was calculated for each included study. The relation between the FMD TEE and the adherence score was investigated by means of Pearson correlation coefficients and multiple linear regression analysis. RESULTS: Twenty-seven studies involving 48 study groups and 1537 subjects were included in the analyses. The adherence score ranged from 2.4 to 9.2 (out of a maximum of 10) and was strongly and inversely correlated with FMD TEE (adjusted R(2) = 0.36, P < 0.01). Use of automated edge-detection software, continuous diameter measurement, true peak diameter for %FMD calculation, a stereostatic probe holder, and higher age emerged as factors associated with a lower FMD TEE. CONCLUSIONS: These data demonstrate that adherence to current expert consensus guidelines and applying contemporary techniques for measuring brachial artery FMD decreases its measurement error.

Interaction between left ventricular twist mechanics and arterial haemodynamics during localised, non-metabolic hyperaemia with and without blood flow restriction.

NEW FINDINGS: What is the central question of this study? Left ventricular (LV) twist is reduced when afterload is increased, but the meaning of this specific heart muscle response and its impact on cardiac output are not well understood. What is the main finding and its importance? This study shows that LV twist responds even when arterial haemodynamics are altered only locally, and without apparent change in metabolic (i.e. heat-induced) demand. The concurrent decline in cardiac output and LV twist during partial arterial occlusion despite the increased peripheral demand caused by heat stress suggests that LV twist may be involved in the protective sensing of heart muscle stress that can override the provision of the required cardiac output. Whether left ventricular (LV) twist and untwisting rate (LV twist mechanics) respond to localised, peripheral, non-metabolic changes in arterial haemodynamics within an individual's normal afterload range is presently unknown. Furthermore, previous studies indicate that LV twist mechanics may override the provision of cardiac output, but this hypothesis has not been examined purposefully. Therefore, we acutely altered local peripheral arterial haemodynamics in 11 healthy humans (women/men n = 3/8; age 26 ± 5 years) by bilateral arm heating (BAH). Ultrasonography was used to examine arterial haemodynamics, LV twist mechanics and the twist-to-shortening ratio (TSR). To determine the arterial function-dependent contribution of LV twist mechanics to cardiac output, partial blood flow restriction to the arms was applied during BAH (BAHBFR ). Bilateral arm heating increased arm skin temperatures [change (Δ) +6.4 ± 0.9°C, P < 0.0001] but not core temperature (Δ -0.0 ± 0.1°C, P > 0.05), concomitant to increases in brachial artery blood flow (Δ 212 ± 77 ml, P < 0.0001), cardiac output (Δ 495 ± 487 l min(-1) , P < 0.05), LV twist (Δ 3.0 ± 3.5 deg, P < 0.05) and TSR (Δ 3.3 ± 1.3, P < 0.05) but maintained carotid artery blood flow (Δ 18 ± 147 ml, P > 0.05). Subsequently, BAHBFR reduced all parameters to preheating levels, except for TSR and heart rate, which remained at BAH levels. In conclusion, LV twist mechanics responded to local peripheral arterial haemodynamics within the normal afterload range, in part independent of TSR and heart rate. The findings suggest that LV twist mechanics may be more closely associated with intrinsic sensing of excessive pressure stress rather than being associated with the delivery of adequate cardiac output.

A survey of substance use for cognitive enhancement by university students in the Netherlands.

BACKGROUND: Pharmacological cognitive enhancement, using chemicals to change cellular processes in the brain in order to enhance one's cognitive capacities, is an often discussed phenomenon. The prevalence among Dutch university students is unknown. METHODS: The study set out to achieve the following goals: (1) give an overview of different methods in order to assess the prevalence of use of prescription, illicit and lifestyle drugs for cognitive enhancement (2) investigate whether polydrug use and stress have a relationship with cognitive enhancement substance use (3) assessing opinions about cognitive enhancement prescription drug use. A nationwide survey was conducted among 1572 student respondents of all government supported Dutch universities. RESULTS: The most detailed level of analysis-use of specific substances without a prescription and with the intention of cognitive enhancement-shows that prescription drugs, illicit drugs and lifestyle drugs are respectively used by 1.7, 1.3, and 45.6% of the sample. The use of prescription drugs and illicit drugs is low compared to other countries. We have found evidence of polydrug use in relation to cognitive enhancement. A relation between stress and the use of lifestyle drugs for cognitive enhancement was observed. We report the findings of several operationalizations of cognitive enhancement drug use to enable comparison with a wider variety of previous and upcoming research. CONCLUSIONS: RESULTS of this first study among university students in the Netherlands revealed a low prevalence of cognitive enhancement drug use compared to other countries. Multiple explanations, such as a difference in awareness of pharmacological cognitive enhancement among students, accessibility of drugs in the student population and inclusion criteria of enhancement substances are discussed. We urge enhancement researchers to take the different operationalizations and their effects on the prevalence numbers into account.