Mark Butlin

Arterial blood pressure measurement and pulse wave analysis—their role in enhancing cardiovascular assessment

The most common method of clinical measurement of arterial blood pressure is by means of the cuff sphygmomanometer. This instrument has provided fundamental quantitative information on arterial pressure in individual subjects and in populations and facilitated estimation of cardiovascular risk related to levels of blood pressure obtained from the brachial cuff. Although the measurement is taken in a peripheral limb, the values are generally assumed to reflect the pressure throughout the arterial tree in large conduit arteries. Since the arterial pressure pulse becomes modified as it travels away from the heart towards the periphery, this is generally true for mean and diastolic pressure, but not for systolic pressure, and so pulse pressure. The relationship between central and peripheral pulse pressure depends on propagation characteristics of arteries. Hence, while the sphygmomanometer gives values of two single points on the pressure wave (systolic and diastolic pressure), there is additional information that can be obtained from the time-varying pulse waveform that enables an improved quantification of the systolic load on the heart and other central organs. This topical review will assess techniques of pressure measurement that relate to the use of the cuff sphygmomanometer and to the non-invasive registration and analysis of the peripheral and central arterial pressure waveform. Improved assessment of cardiovascular function in relation to treatment and management of high blood pressure will result from future developments in the indirect measurement of arterial blood pressure that involve the conventional cuff sphygmomanometer with the addition of information derived from the peripheral arterial pulse.

The Relationship of Age With Regional Aortic Stiffness and Diameter

OBJECTIVES The purpose of this study was to determine the impact of age on regional aortic pulse wave velocity (aPWV). BACKGROUND aPWV is an independent predictor of cardiovascular risk and increases exponentially with age. However, it is unclear whether such changes occur uniformly along the length of the aorta or vary by region. METHODS A total of 162 subjects, aged 18 to 77 years and free of cardiovascular disease and medication, were recruited from the Anglo-Cardiff Collaborative Trial. Cine phase contrast magnetic resonance imaging was performed at 5 aortic levels. Systolic diameter and average blood flow were measured at each level and regional aPWV (regional aPWV measured by cine phase contrast magnetic resonance imaging) determined in 4 aortic segments: the arch (R1), the thoracic-descending aorta (R2), mid-descending aorta (R3), and the abdominal aorta (R4) and across the entire aorta. RESULTS Regional PWV measured by cine phase contrast magnetic resonance imaging values increased from the valve to the bifurcation in the 4 segments (PWV-R1- PWV-R4: 4.6 ± 1.5 m/s, 5.5 ± 2.0 m/s, 5.7 ± 2.3 m/s, 6.1 ± 2.9 m/s, respectively) and did not differ between genders. The greatest age-related difference in stiffness occurred in the abdominal aorta (+0.9 m/s per decade, p < 0.001) followed by the thoracic-descending region (+0.7 m/s, p < 0.001), the mid-descending region (+0.6 m/s, p < 0.001) and aortic arch (+0.4 m/s, p < 0.001). The average systolic diameters decreased moving distally (L1-5: 3.1 ± 0.4 cm, 2.3 ± 0.3 cm, 2.1 ± 0.3 cm, 1.9 ± 0.2 cm, and 1.7 ± 0.2 cm, respectively). The greatest variation in systolic diameter as a function of age occurred in the ascending region (+0.96 mm/decade, p < 0.001). Values of aPWV measured across the entire aorta were strongly correlated with PWV-tonometry (R = 0.71, p < 0.001), although they were significantly lower (mean difference 1.7 ± 1.6 m/s, p < 0.001). CONCLUSIONS The greatest difference in aortic stiffness occurs in the abdominal region, whereas the greatest difference in diameter occurs in the ascending aorta, which may help offset an increase in wall stiffness.

Basal NO Locally Modulates Human Iliac Artery Function In Vivo

We demonstrated previously that endogenous NO influences large-artery distensibility in the ovine hindlimb. However, the role of basal NO in larger human conduit arteries is controversial. The aim of this study was to investigate whether basal production of NO, acting locally, influences iliac artery distensibility in humans. Distensibility was assessed by intra-arterial measurement of the pulse wave velocity. Eighteen subjects, free of significant coronary or iliac artery disease, were studied after diagnostic cardiac catheterization. Simultaneous pressure waveforms were recorded with a high-fidelity dual-pressure sensing catheter, placed in the common iliac artery during intra-arterial infusion of saline (baseline), glyceryl trinitrate (4 nmol/min), or NG-monomethyl-l-arginine (8 and 16 &mgr;mol/min). Drugs were infused proximally, via the catheter to perfuse the segment of artery under study, or distally, via the sheath, to control for any reflex changes in flow or sympathetic activation. Velocity was calculated using the foot-to-foot methodology. Six subjects received glyceryl trinitrate and 12 NG-monomethyl-l-arginine. There was no change in velocity after infusion of glyceryl trinitrate or NG-monomethyl-l-arginine via the sheath. However, infusion of glyceryl trinitrate via the catheter significantly reduced velocity by 31.43±5.80% (mean±SEM; P<0.01; P=0.02 for comparison). Likewise, infusion of the highest dose of NG-monomethyl-l-arginine via the catheter significantly increased velocity by 27.25±8.20% (P=0.001; P=0.02 for comparison). Importantly, there was no change in mean arterial blood pressure throughout the studies. These data indicate that under resting conditions, local NO production modulates human iliac artery distensibility and that exogenous NO increases arterial distensibility.

The accuracy of central SBP determined from the second systolic peak of the peripheral pressure waveform.

Background Recent evidence suggests that central aortic blood pressure may be a better predictor of cardiovascular risk than peripheral blood pressure. The central SBP (cSBP) can be estimated from the late systolic shoulder of the radial pulse waveform. We compared the second systolic peak of the radial waveform (pSBP2) with the central systolic pressure derived by a generalized transfer function in a large cohort, across a wide age range, of patients from the Anglo-Cardiff Collaborative Trial. We also compared pSBP2 with the true cSBP measured by cardiac catheterization [invasively measured cSBP (cSBPi)]. Methods Noninvasive measurements were made by applanation tonometry using the SphygmoCor device. The aortic pressure waveform was derived from the radial waveform using a validated transfer function. Invasive measures of cSBPi were carried out in a group of 38 patients undergoing diagnostic cardiac angiography, and radial artery pressure waveforms were simultaneously recorded using the SphygmoCor device. Results Overall, there was a strong correlation (r = 0.99, P < 0.001) and good agreement between pSBP2 and the derived cSBP (mean difference ± SD 1 ± 4 mmHg). However, there was a systematic bias with a greater difference between these measures at lower average pressures. There was also a strong correlation and good agreement between the invasively measured cSBPi and pSBP2 (r = 0.92, P < 0.001, mean difference 2 ± 6 mmHg). Conclusion The second systolic shoulder of the peripheral pressure waveform approximates the cSBP in a large cohort of patients across a wide age range, but this may be inaccurate at low SBP values.

Is obstructive sleep apnoea causally related to arterial stiffness? A critical review of the experimental evidence.

Large elastic arteries and smaller muscular conduit arteries become stiffer with ageing, a process that is accelerated in the presence of cardiovascular disease (CVD). In recent years, numerous techniques have been developed to measure arterial stiffness, either in single vessels or in entire muscular arterial trees. These techniques have increasingly been shown to improve stratification of cardiovascular risk and risk reduction beyond that provided by conventional risk factors. Obstructive sleep apnoea (OSA) has been increasingly linked with excess cardiovascular morbidity and mortality however the mechanisms are still not well understood. Robustly designed studies have shown that treatment of OSA with nasal continuous positive airway pressure improves important intermediate risk factors for CVD including hypertension and endothelial function. More recently, there has been increased exploration of arterial stiffness in both cross-sectional and interventional studies in OSA patients. This review aims to give the reader a better understanding of the measurement and pathophysiology of arterial stiffness as well as providing an indication of how well a prognostic indicator are the various measures of arterial stiffness for hard cardiovascular endpoints. A critical appraisal is then provided of cross-sectional and interventional studies that have explored these same techniques in OSA populations.

Heart Rate Dependence of Aortic Pulse Wave Velocity at Different Arterial Pressures in Rats

Arterial stiffness, as measured by aortic pulse wave velocity (PWV), is an independent marker of cardiovascular disease and events in both healthy and diseased populations. Although some cardiovascular risk factors, such as age and blood pressure, show a strong association with PWV, the association between heart rate (HR) and PWV is not firmly established. Furthermore, this association has not been investigated at different arterial blood pressures. To study effects of HR on aortic PWV at different mean arterial pressures (MAPs), adult (12 weeks; n=7), male, anesthetized Sprague-Dawley rats were randomly paced at HRs of between 300 and 450 bpm, at 50-bpm steps. At each pacing step, aortic PWV was measured across a physiological MAP range of 60 to 150 mmHg by infusing sodium nitroprusside and phenylephrine. When compared at the same MAP, increases in HR resulted in significant increases in PWV at all of the MAPs >80 mmHg (ANOVA, P<0.05), with the greatest significant change of 6.03±0.93% observed in the range 110 to 130 mmHg. The positive significant association between HR and PWV remained when PWV was adjusted for MAP (ANOVA, P<0.001). These results indicate that HR dependency of PWV is different at higher pressures than at lower pressures and that HR may be a confounding factor that should be taken into consideration when performing analysis based on PWV measurements.

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes

BackgroundDiabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation.MethodsMale Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenous infusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using a radioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis.ResultsPWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 ± 125 nmol/L vs 108 ± 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated and untreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation.ConclusionPWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.

Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice

Nitric oxide (NO) can modulate arterial stiffness by regulating both functional and structural changes in the arterial wall. Tissue transglutaminase (TG2) has been shown to contribute to increased central aortic stiffness by catalyzing the cross-linking of matrix proteins. NO S-nitrosylates and constrains TG2 to the cytosolic compartment and thereby holds its cross-linking function latent. In the present study, the role of endothelial NO synthase (eNOS)-derived NO in regulating TG2 function was studied using eNOS knockout mice. Matrix-associated TG2 and TG2 cross-linking function were higher, whereas TG2 S-nitrosylation was lower in the eNOS(-/-) compared with wild-type (WT) mice. Pulse-wave velocity (PWV) and blood pressure measured noninvasively were elevated in the eNOS(-/-) compared with WT mice. Intact aortas and decellularized aortic tissue scaffolds of eNOS(-/-) mice were significantly stiffer, as determined by tensile testing. The carotid arteries of the eNOS(-/-) mice were also stiffer, as determined by pressure-dimension analysis. Invasive methods to determine the PWV-mean arterial pressure relationship showed that PWV in eNOS(-/-) and WT diverge at higher mean arterial pressure. Thus eNOS-derived NO regulates TG2 localization and function and contributes to vascular stiffness.

Exercise, vascular stiffness, and tissue transglutaminase.

Background Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (NO)‐induced S‐nitrosylation of tissue transglutaminase (TG2) contributes to age‐related vascular stiffness. In the current study, we tested the hypothesis that exercise restores NO signaling and attenuates vascular stiffness by decreasing TG2 activity and cross‐linking in an aging rat model. Methods and Results Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator‐stimulated phosphoprotein abundance, suggesting reduced NO signaling. TG2 cross‐linking activity was significantly increased in old animals, whereas TG2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (PWV) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (MAP). The PWV‐MAP correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise. Conclusions Increased vascular stiffness during aging is associated with decreased TG2 S‐nitrosylation, increased TG2 cross‐linking activity, and increased vascular stiffness likely the result of decreased NO bioavailability. In this study, a brief period of moderate aerobic exercise enhanced NO signaling, attenuated TG cross‐linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by PWV.

Carotid-femoral pulse wave velocity assessment using novel cuff-based techniques: comparison with tonometric measurement.

Background: Carotid-femoral pulse wave velocity, a predictor of cardiovascular outcome, is conventionally measured using a tonometer sequentially placed upon the carotid and femoral arteries, gated using an electrocardiogram. Leg cuff detection of the femoral pulse removes the need for signal gating, reduces the time required for a single measurement, but gives different pulse wave velocity values to tonometric analysis. A novel algorithm to correct for the transit time and distance related to the additional femoral segment was applied to the cuff-based approach in this study. Method: Eighty-eight individuals were recruited across four centres and carotid-femoral pulse wave velocity measured in triplicate using two operators with both a tonometer-based device and a device using an inflated thigh cuff with and without the use of the novel algorithm. Comparison was made by Bland–Altman and regression analysis. Results: The unadjusted cuff-based approach gave lower pulse wave velocity values than the tonometer-based approach (6.11 ± 1.27 and 7.02 ± 1.88 m/s, P < 0.001). With application of the algorithm, the cuff-based device gave similar pulse wave velocity values (7.04 ± 1.72 m/s) as the tonometer-based approach (P = 0.86). Analysis of covariance with age showed a difference between the tonometer and cuff-based methods (P < 0.001), with a dependence upon age (P = 0.004). The adjusted cuff-based method gave similar results to the tonometer-based method (P = 0.94), with no dependence upon age (P = 0.46). Conclusion: This study provided validation of a cuff-based assessment of carotid-femoral pulse wave velocity against the universally accepted tonometric method. Adjusting the cuff-based method for the additional femoral segment measured gives results comparable to the tonometer-based method, for which the majority of population data exist to date.