Barry J. McDonnell

Central Pressure: Variability and Impact of Cardiovascular Risk Factors: The Anglo-Cardiff Collaborative Trial II

Pulse pressure varies throughout the arterial tree, resulting in a gradient between central and peripheral pressure. Factors such as age, heart rate, and height influence this gradient. However, the relative impact of cardiovascular risk factors and atheromatous disease on central pressure and the normal variation in central pressure in healthy individuals are unclear. Seated peripheral (brachial) and central (aortic) blood pressures were assessed, and the ratio between aortic and brachial pulse pressure (pulse pressure ratio, ie, 1/amplification) was calculated in healthy individuals, diabetic subjects, patients with cardiovascular disease, and in individuals with only 1 of the following: hypertension, hypercholesterolemia, or smoking. The age range was 18 to 101 years, and data from 10 613 individuals were analyzed. Compared with healthy individuals, pulse pressure ratio was significantly increased (ie, central systolic pressure was relatively higher) in individuals with risk factors or disease (P<0.01 for all of the comparisons). Although aging was associated with an increased pulse pressure ratio, there was still an average±SD difference between brachial and aortic systolic pressure of 11±4 and 8±3 mm Hg for men and women aged >80 years, respectively. Finally, stratifying individuals by brachial pressure revealed considerable overlap in aortic pressure, such that >70% of individuals with high-normal brachial pressure had similar aortic pressures as those with stage 1 hypertension. These data demonstrate that cardiovascular risk factors affect the pulse pressure ratio, and that central pressure cannot be reliably inferred from peripheral pressure. However, assessment of central pressure may improve the identification and management of patients with elevated cardiovascular risk.

Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans

Arterial stiffness is an independent predictor of mortality and is regulated by a number of factors, including vascular smooth muscle tone. However, the relationship between endothelial function and definitive measures of arterial stiffness and wave reflections has not been described in healthy individuals. Therefore, we tested the hypothesis that endothelial function is inversely correlated with aortic pulse wave velocity (PWV), central pulse pressure, and augmentation index in healthy individuals. Peripheral and central pulse pressure and augmentation index were determined at rest, and global endothelial function was measured using pulse wave analysis and administration of sublingual nitroglycerin and inhaled albuterol. Aortic PWV was also determined at baseline in a subset of 89 subjects. In a separate group of subjects (n=89), aortic PWV was measured and brachial artery flow-mediated dilatation assessed as a measure of conduit artery endothelial function. Global endothelial function was significantly and inversely correlated with aortic PWV (r=−0.69; P<0.001), augmentation index (r=−0.59; P<0.001), and central (r=−0.34; P<0.001) and peripheral pulse pressure (r=−0.15; P=0.03). Moreover, there was a stronger correlation between central rather than peripheral pulse pressure. After adjusting for potential confounders, global endothelial function remained independently and inversely associated with aortic PWV and augmentation index. There was also a significant, inverse relationship between conduit artery endothelial function and aortic PWV (r=0.39, P<0.001), which remained independent after adjusting for confounding factors. In healthy individuals, a decline in endothelial function is associated with increased large artery stiffness, wave reflections, and central pulse pressure.

Aortic Calcification Is Associated With Aortic Stiffness and Isolated Systolic Hypertension in Healthy Individuals

Arterial stiffening is an independent predictor of mortality and underlies the development of isolated systolic hypertension (ISH). A number of factors regulate stiffness, but arterial calcification is also likely to be important. We tested the hypotheses that aortic calcification is associated with aortic stiffness in healthy individuals and that patients with ISH exhibit exaggerated aortic calcification compared with controls. A total of 193 healthy, medication-free subjects (mean age±SD: 66±8 years) were recruited from the community, together with 15 patients with resistant ISH. Aortic pulse wave velocity (PWV) was measured noninvasively, and aortic calcium content was quantified from high-resolution, thoraco-lumbar computed tomography images using a volume scoring method. In healthy volunteers, calcification was positively and significantly associated with aortic PWV (r=0.6; P<0.0001) but was not related to augmentation index or brachial PWV. Calcification was significantly higher in treatment-resistant and healthy subjects with ISH compared with controls (mean [interquartile range]: 1.92 [1.14 to 3.66], 0.84 [0.35 to 1.75], and 0.19 [0.1 to 0.78] cm3, respectively; P<0.0001 for both). In a multiple regression model, aortic calcium was independently associated with aortic PWV along with age, mean arterial pressure, heart rate, and estimated glomerular filtration rate (R2=0.51; P<0.0001). Only age, calcium phosphate product, and aortic PWV were independently associated with calcification. These data suggest that calcification may be important in the process of aortic stiffening and the development of ISH. Calcification may underlie treatment resistance in ISH, and anticalcification strategies may present a novel therapy.

Increased Stroke Volume and Aortic Stiffness Contribute to Isolated Systolic Hypertension in Young Adults

Isolated systolic hypertension is a common condition in individuals aged older than 60 years. However, isolated systolic hypertension has also been described in young individuals, although the mechanisms are poorly understood. We hypothesized that in young adults, isolated systolic hypertension and essential hypertension have different hemodynamic mechanisms and the aim of this study was to test this hypothesis in a cohort of subjects from The ENIGMA Study. Peripheral and central blood pressure, aortic pulse wave velocity, cardiac output, stroke volume, and peripheral vascular resistance were determined in 1008 subjects, aged 17 to 27 years. Compared with normotensive subjects, those with isolated systolic hypertension had significantly higher peripheral, central, and mean blood pressure, aortic pulse wave velocity, cardiac output, and stroke volume (P<0.001 for all comparisons). However, there were no differences in pulse pressure amplification, heart rate, or peripheral vascular resistance between the two groups. Compared with subjects with essential hypertension, mean pressure, heart rate, and peripheral vascular resistance were all significantly lower in isolated systolic hypertensive subjects, but pulse pressure amplification, aortic pulse wave velocity, cardiac output, and stroke volume were higher (P<0.001 for all comparisons). We have demonstrated that in young adults, isolated systolic hypertension and essential hypertension arise from different hemodynamic mechanisms. Isolated systolic hypertension appears to result from an increased stroke volume and/or aortic stiffness, whereas the major hemodynamic abnormality underlying essential hypertension is an increased peripheral vascular resistance. Long-term follow-up of these individuals is now required to determine whether they are at increased risk compared with age-matched normotensive individuals.

Variation in the Human Matrix Metalloproteinase-9 Gene Is Associated With Arterial Stiffness in Healthy Individuals

Background—Arterial stiffness is an important determinant of cardiovascular risk. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes including serine proteases and matrix metalloproteinases (MMPs). Serum MMP-9 levels correlate with arterial stiffness and predict cardiovascular risk. Polymorphisms in the MMP-9 gene are also associated with large artery function in subjects with coronary artery disease. Therefore, we investigated the influence of known MMP-9 (−1562C>T, R279Q) polymorphisms on arterial stiffness in a large cohort of healthy individuals (n=865). Methods and Results—Aortic pulse wave velocity (PWV) and augmentation index were assessed. Supine blood pressure, biochemical markers, MMP-9 levels, and serum elastase activity (SEA) were also determined. Genomic DNA was extracted and genotyping performed. Aortic PWV, serum MMP-9, and SEA were higher in carriers of the rare alleles for the −1562C>T and R279Q polymorphisms. These polymorphisms were also associated with aortic PWV after correction for other confounding factors. Stepwise regression models with known or likely determinants of arterial stiffness revealed that ≈60% of the variability in aortic PWV was attributable to age, mean arterial pressure, and genetic variants (P<0.001). Conclusions—We have demonstrated for the first time that aortic stiffness and elastase activity are influenced by MMP-9 gene polymorphisms. This suggests that the genetic variation in this protein may be involved in the process of large artery stiffening.

The Impact of Cardiovascular Risk Factors on Aortic Stiffness and Wave Reflections Depends on Age. The Anglo-Cardiff Collaborative Trial (ACCT III)

Ageing exerts differential effects on arterial stiffness and wave reflections. However, the impact of cardiovascular risk factors on arterial stiffness and wave reflections and, particularly, how such effects are influenced by ageing has not been assessed within a single large population, covering a sufficiently wide age range. Therefore, we determined the extent to which age alters the impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections. Aortic stiffness and wave reflections were assessed in 4421 individuals (age range 18 to 92 years). When treated as continuous variables, clinic systolic, diastolic, and pulse pressures and glucose levels were independently associated with stiffness, and, with the exception of diastolic pressure, these associations were more marked in older individuals. In contrast, clinic systolic and diastolic pressures and smoking were independently associated with wave reflections, with stronger associations observed in younger individuals. The impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections is strongly dependent on age and is largely driven by blood pressure. Additional studies are required to assess the impact of these arterial measures on cardiovascular outcome within a single population.

Does Wave Reflection Dominate Age-Related Change in Aortic Blood Pressure Across the Human Life Span?

Abstract—Aortic systolic and pulse pressure rise with age because of aortic stiffening. Two factors are responsible: a larger incident wave because of increased aortic characteristic impedance and premature return of wave reflection from peripheral sites. This study aimed to determine the relative contribution of each factor before and after age 60 years. Aortic pressure waveforms were generated for 3682 healthy subjects using a generalized transfer function applied to radial pressure waveforms recorded by applanation tonometry. Linear regression and product of coefficient mediation analysis were performed in the cross-sectional cohort to determine the yearly contribution of the incident and reflected waves (waves measured as first systolic peak and augmented pressure, respectively) to aortic systolic and pulse pressure elevation with age. This was done separately for subjects ≤60 and >60 years of age, with both sexes initially pooled and subsequently separated. Analyses were repeated with correction for height, weight, heart rate, and mean arterial pressure. Before age 60 years, the reflected wave was a greater (P<0.05) contributor to age-related aortic systolic and pulse pressure elevations, with no significant contribution of the incident wave in this age group in sex-pooled analysis. After age 60 years, both incident and reflected waves were significant (P<0.05) and comparable contributors (P difference >0.05) to age-related aortic systolic and pulse pressure elevations. This general pattern was observed in both sexes and persisted after correction for confounders. Wave reflection is important across the life span, whereas aortic characteristic impedance contributes significantly only beyond age 60 years.

Left ventricular mechanics in humans with high aerobic fitness: adaptation independent of structural remodelling, arterial haemodynamics and heart rate

Key points  •  During cardiac contraction, left ventricular (LV) mechanics play an important role in equalising transmural fibre stress and ensuring efficient ejection of blood. •  The factors responsible for altered LV mechanics in humans with high aerobic exercise capacity are unknown but are believed to be related to changes in LV structure or heart rate. •  We performed a comprehensive assessment of LV mechanics and cardiovascular function at rest and during dynamic exercise in individuals with moderate and high aerobic exercise capacity. •  Our novel data indicate that there is no direct association between altered LV mechanics in humans with high aerobic fitness and classic indicators of cardiovascular adaptation. •  The findings provide evidence of a previously unknown type of physiological LV adaptation that may have important implications for exercise training in various healthy and diseased populations.

Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans.

An exaggerated blood pressure (BP) response to exercise predicts future cardiovascular risk. The mechanisms underlying exercise-induced hypertension remain unclear, although endothelial dysfunction and elevated arterial stiffness may contribute. Given the association between reductions in nitric oxide (NO) and vascular dysfunction, we sought to determine whether acute inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA) would lead to exaggerated BP responses to maximal exercise and attenuate exercise-induced reductions in arterial stiffness. In 10 healthy subjects (31±5 years), BP and heart rate (HR) were measured before, during and after an incremental cycling exercise test to determine maximal oxygen consumption (VO2max). Trials were performed with placebo (saline) or intravenous infusion of L-NMMA on separate days in a randomized, double-blind, crossover design. Central (aortic) and peripheral (femoral) arterial stiffness were assessed using pulse wave velocity (PWV). BP was increased with L-NMMA at rest and during sub-maximal exercise, but not at maximal exercise (mean BP 117±5 vs 118±8 mm Hg, saline vs L-NMMA, P>0.05). Furthermore, L-NMMA had no influence on exercising HR or VO2max (P<0.05). Notably, aortic PWV was similarly increased after exercise with either saline or L-NMMA (P<0.05), whereas postexercise decreases in femoral PWV were attenuated with L-NMMA (P<0.05). Our findings suggest that NO is an important contributor to reductions in femoral artery stiffness after maximal exercise in healthy individuals. Furthermore, acute pharmacological inhibition of NO synthase causes augmented BP responses to sub-maximal exercise, but does not lead to exaggerated BP responses to maximal exercise or reduce maximal oxygen consumption.

Use of the oral contraceptive pill is associated with increased large artery stiffness in young women: the ENIGMA study.

Background The oral contraceptive pill (OCP) is widely prescribed throughout the world. Although it is associated with a small but significant increase in blood pressure, the influence of the OCP on large artery stiffness and wave reflection is unclear. The aim of this study was to determine the relationship between use of the OCP and aortic stiffness and wave reflections in a young, healthy cohort of women. Methods Participants were drawn from the ENIGMA study, which examines the natural history of blood pressure in young adults. A detailed medical history and lifestyle questionnaire, including OCP details were taken. Blood pressure was measured according to the British Hypertension Society guidelines. Aortic pulse wave velocity (aPWV) was measured together with augmentation index (AIx). Stroke volume (SV) and cardiac output (CO) were also assessed. Results Women taking the OCP (n = 225) had a higher SBP and pulse pressure compared with nonusers (n = 660; 112 ± 12 vs. 110 ± 11 and 43 ± 8 vs. 42 ± 8 mmHg, respectively, P < 0.05 for both). CO and SV were also higher (6.6 ± 1.5 vs. 6.3 ± 1.5 l/min, P < 0.01 and 81 ± 16 vs. 78 ± 19 ml, P < 0.05) as was aPWV (5.5 ± 0.7 vs. 5.4 ± 0.7 m/s, P < 0.05). However, there was no difference in DBP (68 ± 9 vs. 69 ± 9 mmHg), mean arterial pressure (81 ± 10 vs. 81 ± 10 mmHg) or AIx (2 ± 12 vs. 3 ± 13%) between the groups. Conclusion Use of the OCP is associated with elevated pulse pressure and SV and a small increase in aPWV in young women. The longer term implications of these effects require further investigation.