John R. Cockcroft

The influence of heart rate on augmentation index and central arterial pressure in humans

1 Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. 2 Twenty‐two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non‐invasively, during incremental pacing (from 60 to 110 beats min−1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non‐invasively from the brachial artery. 3 There was a significant, inverse, linear relationship between AIx and heart rate (r=−0.76; P < 0.001). For a 10 beats min−1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r=−0.51; P < 0.001). 4 Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. 5 These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.

Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia

OBJECTIVESnThe goal of this study was to investigate the relation between serum cholesterol, arterial stiffness and central blood pressure.nnnBACKGROUNDnArterial stiffness and pulse pressure are important determinants of cardiovascular risk. However, the effect of hypercholesterolemia on arterial stiffness is controversial, and central pulse pressure has not been previously investigated.nnnMETHODSnPressure waveforms were recorded from the radial artery in 68 subjects with hypercholesterolemia and 68 controls, and corresponding central waveforms were generated using pulse wave analysis. Central pressure, augmentation index (AIx) (a measure of systemic stiffness) and aortic pulse wave velocity were determined.nnnRESULTSnThere was no significant difference in peripheral blood pressure between the two groups, but central pulse pressure was significantly higher in the group with hypercholesterolemia (37 +/- 11 mm Hg vs. 33 +/- 10 mm Hg [means +/- SD]; p = 0.028). Augmentation index was also significantly higher in the patients with hypercholesterolemia group (24.8 +/- 11.3% vs. 15.6 +/- 12.1%; p < 0.001), as was the estimated aortic pulse wave velocity. In a multiple regression model, age, short stature, peripheral mean arterial pressure, smoking and low-density lipoprotein cholesterol correlated positively with AIx, and there was an inverse correlation with heart rate and male gender.nnnCONCLUSIONSnPatients with hypercholesterolemia have a higher central pulse pressure and stiffer blood vessels than matched controls, despite similar peripheral blood pressures. These hemodynamic changes may contribute to the increased risk of cardiovascular disease associated with hypercholesterolemia, and assessment may improve risk stratification.

Heart rate dependency of pulse pressure amplification and arterial stiffness.

BACKGROUNDnPulse pressure and aortic pulse wave velocity, measures of arterial stiffness, are both important determinants of cardiovascular risk. However, assessment of peripheral pulse pressure does not always provide a reliable measure of changes in central pulse pressure or arterial stiffness. The aim of the present study was to assess the effect of acute changes in heart rate on arterial stiffness and on peripheral and central pulse pressure in healthy subjects.nnnMETHODSnTwenty subjects (age range, 20 to 72 years) were studied at cardiac catheterization. Pulse wave analysis was used to determine central pressure, augmentation index (AIx), a measure of systemic arterial stiffness, and aortic pulse wave velocity (PWV) during right atrial pacing (80 to 120 beats/min).nnnRESULTSnPulse pressure amplification increased during pacing due to a reduction in central pressure augmentation. AIx was significantly and inversely related to heart rate (r = -0.70, P < .001) due to an alteration in the relative timing of the reflected pressure wave, rather than a reduction in arterial stiffness, as PWV did not change.nnnCONCLUSIONSnThese data suggest that peripheral pulse pressure does not provide an accurate assessment of changes in central hemodynamics in relation to changes in heart rate, and that aortic stiffness is not affected by acute changes in heart rate.

Changes in the derived central pressure waveform and pulse pressure in response to angiotensin II and noradrenaline in man

1 Peripheral pulse pressure provides a surrogate measure of arterial stiffness. Analysis of the central pressure waveform allows assessment of central pulse pressure and arterial stiffness. The aim of the present study was to assess the effect of vasoconstrictor drugs on pulse pressure amplification and arterial stiffness in vivo. 2 Eight healthy male subjects (mean age 30 years) received an infusion of angiotensin II (1, 3, 6 and 10 ng kg−1 min−1), noradrenaline (10, 30, 60 and 100 ng kg−1 min−1) and matching placebo, in random order, on separate occasions. Peripheral blood pressure and cardiac index were recorded non‐invasively. Pulse wave analysis was used to determine augmentation index (AIx), which provides a measure of systemic arterial stiffness, aortic stiffness and central arterial pressure. 3 Infusion of both active drugs resulted in a significant increase in peripheral mean arterial pressure (PMAP), peripheral vascular resistance, AIx, aortic stiffness and central pulse pressure, but only angiotensin II reduced cardiac index. 4 Peripheral pulse pressure was unaffected by infusion of angiotensin II but increased with noradrenaline, which also produced a greater reduction in pulse pressure amplification than angiotensin II. However, the linear relationship of PMAP with both AIx and aortic stiffness did not differ significantly between drugs. 5 These results demonstrate that intravenous infusion of angiotensin II and noradrenaline increase aortic and systemic arterial stiffness. Despite a similar effect on both parameters, for a given change in PMAP, the two drugs had divergent effects on peripheral pulse pressure and pulse pressure amplification. These data reveal that assessment of peripheral pulse pressure does not always reliably predict changes in central pulse pressure or arterial stiffness.

Endothelium-Derived Nitric Oxide Contributes to the Regulation of Venous Tone in Humans

BACKGROUNDnAlthough nitric oxide (NO) is known to play an important part in the regulation of arterial tone, little is known about its role in veins. The aim of this study was to investigate the role of basal and stimulated NO activity in the regulation of tone of the human venous capacitance bed.nnnMETHODS AND RESULTSnWe measured venous tone using radionuclide forearm venous plethysmography in 24 healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO activity was assessed by measuring the effects on venous tone of an intra-arterial infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA). In the remaining 11 subjects, stimulated NO activity was evaluated by measuring the effects of an intra-arterial infusion of incremental doses of carbachol, followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused dose-dependent venodilation, with a maximal reduction in forearm venous tone of 40.1+/-12.5% (P<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA (48.9+/-6.2% reversal of maximal venodilation, P<0.01). Infusion of L-NMMA alone caused venoconstriction (9.1+/-6.4% increase in venous tone, P=0.002).nnnCONCLUSIONSnHuman forearm capacitance veins exhibit both stimulated and basal NO activity, which indicates that NO contributes not only to the regulation of venous tone but also to resting venous tone in healthy human subjects.

Modulation of the natriuretic peptide system in heart failure: from bench to bedside?

Since the discovery of atrial natriuretic peptide, the unravelling of the natriuretic peptide system has been a story of scientific success. However, bridging the gap between bench and bedside has proved difficult, and as yet has not provided any major clinical progress. In this review we will first give a detailed outline of the key elements constituting the natriuretic peptide system. Secondly, we will briefly explain the underlying rationale, basic concepts and evidence behind currently pursued strategies to potentiate the natriuretic peptide system. Thirdly, we will highlight some of the problems that have so far hindered successful translation of these theoretically viable treatment options into tangible clinical progress.

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy

Backgroundu2002 Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well‐recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS.

Prevalence of traditional and novel markers of cardiovascular disease risk in Scottish adolescents: socioeconomic effects

Information on the health status and physical activity of Scottish adolescents is limited. This study examines the prevalence of cardiovascular disease (CVD) risk in Scottish adolescents by socioeconomic status (SES). Participants were recruited from two high schools that differed in the SES of the students in attendance. The sample included 73 boys and 34 girls (16.4 ± 0.6 years). Variables included anthropometry, physical activity, physical fitness, blood pressure, diet, and 11 metabolic markers of CVD risk. Significant sex differences (P ≤ 0.01) were noted for stature, waist circumference, waist-hip ratio, physical activity, cardiorespiratory fitness, muscular power, sprint speed, and several CVD risk factors: high-density lipoprotein (HDL), low-density lipoprotein (LDL), interleukin-6 (IL-6), and C-reactive protein (CRP) levels. Boys from a lower SES had significantly higher levels of glucose and plasminogen activator inhibitor-1 (PAI-1) but lower levels of adiponectin compared with boys from a higher SES. Girls from a lower SES had significantly (P ≤ 0.01) higher glucose and PAI-1 levels but lower levels of insulin and adiponectin than girls from a higher SES. High fat diets, low physical activity levels, and elevated CRP and total cholesterol levels were the CVD risk factors most commonly identified as being at-risk levels in this cohort, regardless of sex or SES. SES differences were not consistently apparent, but several CVD risk factors were identified as elevated in this sample of adolescents, regardless of sex or SES.

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.

Surrogate markers of cardiovascular risk and chronic obstructive pulmonary disease

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.