Peter S. Lacy

Differential Impact of Blood Pressure–Lowering Drugs on Central Aortic Pressure and Clinical Outcomes Principal Results of the Conduit Artery Function Evaluation (CAFE) Study

Background— Different blood pressure (BP)–lowering drugs could have different effects on central aortic pressures and thus cardiovascular outcome despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol±thiazide-based versus amlodipine±perindopril-based therapy) on derived central aortic pressures and hemodynamics. Methods and Results— The CAFE study recruited 2199 patients in 5 ASCOT centers. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Most patients received combination therapy throughout the study. Despite similar brachial systolic BPs between treatment groups (&Dgr;0.7 mm Hg; 95% CI, −0.4 to 1.7; P=0.2), there were substantial reductions in central aortic pressures with the amlodipine regimen (central aortic systolic BP, &Dgr;4.3 mm Hg; 95% CI, 3.3 to 5.4; P<0.0001; central aortic pulse pressure, &Dgr;3.0 mm Hg; 95% CI, 2.1 to 3.9; P<0.0001). Cox proportional-hazards modeling showed that central pulse pressure was significantly associated with a post hoc–defined composite outcome of total cardiovascular events/procedures and development of renal impairment in the CAFE cohort (unadjusted, P<0.0001; adjusted for baseline variables, P<0.05). Conclusions— BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP. Moreover, central aortic pulse pressure may be a determinant of clinical outcomes, and differences in central aortic pressures may be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

Increased pulse wave velocity is not associated with elevated augmentation index in patients with diabetes

Objective Increased arterial stiffness is a risk factor for cardiovascular disease and is a feature associated with diabetes. Pulse wave velocity (PWV) is an accepted index of arterial stiffness and augmentation index (Al) derived from radial applanation tonometry has been advocated as a measurement of arterial stiffness. This study compares the relationship between PWV and Al in people with and without diabetes. Design and methods A total of 66 people with diabetes and 66 age-matched non-diabetic controls were studied. Central aortic pressure waves were generated using applanation tonometry over the radial artery and used to calculate Al. Carotid-femoral PWV (PWV cf ) was measured simultaneously. Results Relative to controls, diabetes was associated with increased pulse pressure (PP) and PWV cf (P<0.01). In contrast, Al did not differ between groups even after adjustment for heart rate. This observation remained consistent irrespective of diabetes type, arterial site, and the presence or absence of antihypertensive therapy. Multiple regression analysis revealed diabetes to be a significant determinant of PWV cf , but not Al. Conclusions PP and PWV cf are increased in people with diabetes, but this is not associated with increased Al. These findings conclusively demonstrate that Al is not a reliable measure of arterial stiffness in people with diabetes.

Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-Heart Rate.

OBJECTIVES The CAFE (Conduit Artery Function Evaluation) study showed less effective central aortic pressure lowering with atenolol-based therapy versus amlodipine-based therapy in people with hypertension. The present study examined the importance of heart rate (HR) as a determinant of this effect. BACKGROUND Recent analyses have suggested that beta-blockers are less effective at reducing cardiovascular events than alternative blood pressure (BP)-lowering therapies. There has been much debate about the mechanism for this shortfall in benefit and specifically the role of HR lowering by beta-blockers. METHODS Central pressures were derived from brachial pressure and radial pulse wave analysis in 2,073 patients, and 7,146 measurements were recorded and analyzed over follow-up for up to 4 years. RESULTS There was no impact of HR on brachial systolic or pulse pressures; however, there was a highly significant inverse relationship between HR and central aortic systolic and pulse pressures (p < 0.001). This was dependent on a strong inverse relationship between HR and augmentation index, indicative of increased wave reflection at lower HRs. Multiple regression, adjusted for brachial BP, showed HR to be the major determinant of central pressures. Moreover, HR and brachial BP accounted for 92% of the variability in central systolic and pulse pressures. Consequently, drug-related differences in central aortic pressures were markedly attenuated after adjustment for HR. CONCLUSIONS When comparing beta-blocker-based treatments with other BP-lowering strategies, HR reduction with beta-blockers is a major mechanism accounting for less effective central aortic pressure reduction per unit change in brachial pressure.

Development and Validation of a Novel Method to Derive Central Aortic Systolic Pressure From the Radial Pressure Waveform Using an N-Point Moving Average Method

OBJECTIVES The purpose of this study was to develop and validate the novel application of a simple n-point moving average (NPMA)--a mathematical low pass filter--to noninvasively derive central aortic systolic pressure (CASP) from the radial artery pressure waveform (RAPWF) in humans. BACKGROUND CASP may be an important independent determinant of clinical outcomes. Development of simple, well-validated methods to noninvasively derive CASP is necessary to facilitate the routine clinical measurement of CASP. METHODS Three studies in different population cohorts were used to develop and validate the NPMA method to derive CASP in humans: 1) a development study (n = 217), describing the optimal application of the NPMA to derive CASP; 2) a validation study comparing NPMA-CASP with CASP derived using a generalized transfer function (GTF-CASP [SphygmoCor system, AtCor, Sydney, Australia]) using 5,349 RAPWFs from the CAFE (Conduit Artery Function Evaluation) study; and 3) an invasive validation study (n = 20) comparing NPMA-CASP with direct aortic root pressure measurements during cardiac catheterization. RESULTS In the development study, when using the NPMA, a denominator of n/4 (where n = tonometer sampling frequency) most accurately defined CASP relative to GTF-CASP. Validation of NPMA-CASP using RAPWFs from the CAFE study revealed excellent correlation and agreement (r(2) = 0.993, mean difference 0.3 ± 1.0 mm Hg). The agreement remained robust after stratification by sex, age, treatment, and diabetes status. There was also excellent correlation and agreement (r(2) = 0.98, p < 0.001) between directly measured aortic root systolic pressures (Millars catheter) at cardiac catheterization versus NPMA-CASP, derived simultaneously from noninvasive RAPWFs. CONCLUSIONS We show that an NPMA with a denominator of one-quarter of the tonometer sampling frequency accurately defines CASP when applied to noninvasively acquired RAPWFs in man. These novel findings have important implications for the simplification of noninvasive CASP measurement and its wider application in clinical trials and clinical practice.

Impact of Statin Therapy on Central Aortic Pressures and Hemodynamics: Principal Results of the Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) Study

Background— Statins reduce the risk of cardiovascular events in people with hypertension. This benefit could arise from a beneficial effect of statins on central aortic pressures and hemodynamics. The Conduit Artery Function Evaluation–Lipid-Lowering Arm (CAFE-LLA) study, an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, investigated this hypothesis in a prospective placebo-controlled study of treated patients with hypertension. Methods and Results— CAFE-LLA recruited 891 patients randomized to atorvastatin 10 mg/d or placebo from 5 centers in the United Kingdom and Ireland. Radial artery applanation tonometry and pulse-wave analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits over 3.5 years of follow-up. Atorvastatin lowered low-density lipoprotein cholesterol by 32.4 mg/dL (95% confidence interval [CI], 28.6 to 36.3) and total cholesterol by 35.1 mg/dL (95% confidence interval, 30.9 to 39.4) relative to placebo. Time-averaged brachial blood pressure was similar in CAFE-LLA patients randomized to atorvastatin or placebo (change in brachial systolic blood pressure, −0.1 mm Hg [95% CI, −1.8 to 1.6], P=0.9; change in brachial pulse pressure, −0.02 mm Hg [95% CI, −1.6 to 1.6], P=0.9). Atorvastatin did not influence central aortic pressures (change in aortic systolic blood pressure, −0.5 mm Hg [95% CI, −2.3 to 1.2], P=0.5; change in aortic pulse pressure, −0.4 mm Hg [95% CI, −1.9 to 1.0], P=0.6) and had no influence on augmentation index (change in augmentation index, −0.4%; 95% CI, −1.7 to 0.8; P=0.5) or heart rate (change in heart rate, 0.25 bpm; 95% CI, −1.3 to 1.8; P=0.7) compared with placebo. The effect of statin or placebo therapy was not modified by the blood pressure–lowering treatment strategy in the factorial design. Conclusions— Statin therapy sufficient to significantly reduce cardiovascular events in treated hypertensive patients in ASCOT did not influence central aortic blood pressure or hemodynamics in a large representative cohort of ASCOT patients in CAFE-LLA.

Evidence against potassium as an endothelium‐derived hyperpolarizing factor in rat mesenteric small arteries

Endothelium‐derived hyperpolarizing factor (EDHF) has recently been identified as potassium released from endothelial cells into the myo‐endothelial space. The present study was designed to test this hypothesis. In rat small mesenteric arteries, mounted in a wire myograph, relaxation to acetylcholine or potassium was not significantly changed following incubation with oxadiazolo‐quinoxalin‐1‐one (ODQ, 4 μM) and indomethacin (10 μM, n=9). Maximal relaxations to acetylcholine occurred in all arteries, were maintained and were significantly greater (P<0.01, n=9) than the transient relaxations to potassium, which only occurred in 30–40% of vessels. Removal of the vascular endothelium abolished relaxant responses both to potassium and acetylcholine (P<0.005, n=9). Compared with responses in 5.5 mM potassium PSS, relaxation responses to added potassium in arteries maintained in 1.5 mM potassium PSS were more marked and were not dependent on the presence of an intact endothelium (n=8). Incubation with BaCl2 (50 μM) significantly inhibited the maximal relaxant response to potassium in the presence of an intact endothelium in 5.5 mM potassium PSS (P<0.05, n=4), but had no effect on relaxation of de‐endothelialized preparations in 1.5 mM potassium PSS (n=5). Treatment with ouabain (0.1 mM) abolished the relaxant response to potassium in 1.5 mM potassium PSS (P<0.001, n=9), but only partly inhibited the maximal relaxant response to acetylcholine in 5.5 mM potassium PSS (P<0.01, n=5). These data show that at physiological concentrations of potassium an intact endothelium is necessary for potassium‐induced relaxation in rat mesenteric arteries. Furthermore, the response to potassium is clearly different to that from acetylcholine, indicating that potassium does not mimic EDHF released by acetylcholine in these arteries.

Excess Pressure Integral Predicts Cardiovascular Events Independent of Other Risk Factors in the Conduit Artery Functional Evaluation Substudy of Anglo-Scandinavian Cardiac Outcomes Trial

Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.

Novel Description of the 24-Hour Circadian Rhythms of Brachial Versus Central Aortic Blood Pressure and the Impact of Blood Pressure Treatment in a Randomized Controlled Clinical Trial: The Ambulatory Central Aortic Pressure (AmCAP) Study

&NA; Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four–hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration– URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Central aortic pressure and clinical outcomes.

Conventional brachial blood pressure (BP) measurement by sphygmomanometry is simple and has remained the gold standard for the measurement of BP for over a century. Moreover, it is well established that brachial BP levels are predictive of cardiovascular morbidity and mortality. When we measure brachial BP, we do so with the assumption that the pressure measured over the brachial artery accurately reflects the pressures at the ‘business end’ of the circulation, notably the larger ‘central arteries’, that is, the aorta. Intuitively, it seems reasonable to assume that if we could routinely and reliably measure pressures in the central arteries, these central aortic pressures should be more predictive of target organ damage and clinical outcomes than brachial BP. On the other hand, if brachial BP measurements always faithfully reflected the pressures in these central arteries, then there would be no need to consider measurement of central aortic pressures and the measurement of brachial BP would suffice. Alas, brachial BP is not the perfect surrogate for central aortic pressure, and brachial BP levels do differ from those recorded contemporaneously for the central circulation, either directly at cardiac catheterization or derived noninvasively by analysis of the radial pressure waveform.

Telomere attrition and accumulation of senescent cells in cultured human endothelial cells

Abstract.  The human umbilical vein endothelial cell (HUVEC) is an important model of the human endothelium that is widely used in vascular research. HUVECs and the adult endothelium share many characteristics including progression into senescence as the cells age. Despite this, the shortening of telomeres and its relationship to the progression into senescence are poorly defined in HUVECs. In this study of several HUVEC lines we show notable consistency in their growth curves. There is a steady decline in the growth rate of HUVECs grown continually in culture and we estimate complete cessation of growth after approximately 70 population doublings. The HUVECs lose telomeric DNA at a consistent rate of 90 base pairs/population doubling and show a progressive accumulation of shortened telomeres (below 5 kilobases). This telomeric loss correlates with the accumulation of senescent HUVECs in culture as assessed by staining for β‐galactosidase activity at pH 6. Although the telomere length of a large population of cells is a relatively crude measure, we suggest that in HUVECs a mean telomere length (as measured by terminal restriction fragment length) of 5 kilobases is associated with entry into senescence. These data demonstrate the strong relationship between telomere attrition and cell senescence in HUVECs. They suggest that DNA damage and subsequent telomere attrition are likely to be key mechanisms driving the development of endothelial senescence in the pathogenesis of vascular disease.