Backward in Coming Forward.

As far back as the ancient Egyptians and Greeks, physicians have observed and interpreted the arterial pulse to help diagnose certain illnesses. However, until William Harvey’s discoveries in the 17th century, some of the basic concepts were misunderstood. Harvey described the circular blood flow in the body and discovered that the arterial pulse is generated by the contraction of the left ventricle. He also came up with the concept that the arterial pulse is a wave, thus paving the way for modern studies in pulse wave analysis. Another pivotal discovery was the introduction of pulse wave velocity (PWV) by Crighton Bramwell in the early 20th century. He recognised that PWV changes in proportion to the arterial wall tension and blood pressure, and thus, is an indirect measure of atrial wall elasticity1. Despite these important historic discoveries, it has only been in the last 20 years, with advances in modern engineering, that the pulse wave analysis has become more widely available, reliable, and reproducible technique to assess arterial pulse waves.Professor Wilkinson is funded by British Heart Foundation (Grant number: FS/12/8/29377)

Effects of oral lycopene supplementation on vascular function in patients with cardiovascular disease and healthy volunteers: a randomised controlled trial.

AIMS: The mechanisms by which a 'Mediterranean diet' reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV). METHODS AND RESULTS: We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: -45% to -10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: -1.6 to -0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: -30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function. CONCLUSIONS: Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01100385

Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.KMMP and IBW were funded by British Heart Foundation. IBW, JC and NS received funding from the Comprehensive Local Research Network and IBW and JC from the National Institute for Health Research: Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley Blackwell via http://dx.doi.org/10.1161/JAHA.115.00276

Surrogate Markers of Cardiovascular Risk and Chronic Obstructive Pulmonary Disease: A Large Case-Controlled Study.

Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid-femoral (aortic) pulse wave velocity, augmentation index, and carotid intima-media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima-media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease

The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial.

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. OBJECTIVES: This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). METHODS: This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). RESULTS: We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. CONCLUSIONS: In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD

Cardiovascular risk prediction using physical performance measures in COPD: results from a multicentre observational study

Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Health Data Research UKFunder: NIHR Cambridge Comprehensive Biomedical Research CentreFunder: NIHR Nottingham BRC respiratory themeObjectives: Although cardiovascular disease (CVD) is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), it is unknown how to improve prediction of cardiovascular (CV) risk in individuals with COPD. Traditional CV risk scores have been tested in different populations but not uniquely in COPD. The potential of alternative markers to improve CV risk prediction in individuals with COPD is unknown. We aimed to determine the predictive value of conventional CVD risk factors in COPD and to determine if additional markers improve prediction beyond conventional factors. Design: Data from the Evaluation of the Role of Inflammation in Chronic Airways disease cohort, which enrolled 729 individuals with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II–IV COPD were used. Linked hospital episode statistics and survival data were prospectively collected for a median 4.6 years of follow-up. Setting: Five UK centres interested in COPD. Participants: Population-based sample including 714 individuals with spirometry-defined COPD, smoked at least 10 pack years and who were clinically stable for >4 weeks. Interventions: Baseline measurements included aortic pulse wave velocity (aPWV), carotid intima–media thickness (CIMT), C reactive protein (CRP), fibrinogen, spirometry and Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) Index, 6 min walk test (6MWT) and 4 m gait speed (4MGS) test. Primary and secondary outcome measures: New occurrence (first event) of fatal or non-fatal hospitalised CVD, and all-cause and cause-specific mortality. Results: Out of 714 participants, 192 (27%) had CV hospitalisation and 6 died due to CVD. The overall CV risk model C-statistic was 0.689 (95% CI 0.688 to 0.691). aPWV and CIMT neither had an association with study outcome nor improved model prediction. CRP, fibrinogen, GOLD stage, BODE Index, 4MGS and 6MWT were associated with the outcome, independently of conventional risk factors (p<0.05 for all). However, only 6MWT improved model discrimination (C=0.727, 95% CI 0.726 to 0.728). Conclusion: Poor physical performance defined by the 6MWT improves prediction of CV hospitalisation in individuals with COPD. Trial registration number: ID 11101

Uses of Arterial Stiffness in Clinical Practice.

As far back as the ancient Egyptians and Greeks, physicians have observed and interpreted the arterial pulse to diagnose disease. In the last 20 years, advances in modern engineering have rendered quantitative pulse wave analysis widely available, reliable, and reproducible. To date, measurement of arterial stiffness has remained almost exclusively a research activity. However, ongoing technological improvements coupled with already strong and growing evidence of clinical value should facilitate integration of arterial stiffness measures into clinical practice in the near future. This brief review will highlight clinical areas where arterial stiffness measures are likely to be the most informative in clinical practice.National Institute for Health Research: Cambridge Biomedical Research Centre

Post-hoc correlation between serum lycopene concentrations and EDV.

<p>Relationship between absolute change in serum lycopene concentrations and absolute change in endothelial dependent vasodilatation (EDV; forearm blood flow response to 15 µg/min acetylcholine measured as %change from preceding saline baseline) for all trial subjects. Absolute change in serum lycopene calculated as final visit serum lycopene minus baseline serum lycopene. Absolute change in EDV calculated as final visit EDV minus baseline EDV. r: correlation coefficient calculated using Pearson correlation analysis.</p

Post-hoc comparisons of baseline values between CVD Patients and HV arms.

<p>Data are presented as mean values (standard deviation - SD). *<i>P</i>-value is for comparison between cardiovascular disease (CVD) patients arm and healthy volunteer (HV) arm at baseline using unpaired, 2-tailed Student <i>t</i>-tests. AIx – augmentation index; DBP – diastolic blood pressure; HDL – high-density lipoprotein; hsCRP – high sensitivity C-reactive protein; LDL – low-density lipoprotein; ox-LDL – oxidised low-density lipoprotein, PWV – pulse wave velocity; SBP – systolic blood pressure.</p