Hugues Milon

Heart Rate: An Important Confounder of Pulse Wave Velocity Assessment

Arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) is an index of arterial stiffness, and its prognostic value has been repeatedly emphasized. The purpose of the present study was to assess the effect of heart rate (HR) on PWV. Twenty-two subjects with a mean age of 77.8±8.4 (SD) years and permanent cardiac pacing were studied. In each subject, PWV was measured at 5 different pacing frequencies in the same session (60, 70, 80, 90, 100 bpm), the order of the various frequencies being randomly determined. Furthermore, to test the reproducibility, a repeat measurement of PWV was obtained in one randomly selected frequency. Blood pressure (BP) was measured by conventional means at each pacing frequency. PWV appeared fairly reproducible because no significant difference was disclosed between the 2 measurements obtained at the same HR level (P =0.5) and both measurements were strongly correlated (r =0.87, P <0.001). No significant BP variation was observed during pacing. There was a highly significant effect of HR on PWV estimated by a one-way, within-subjects analysis of variance (P =0.01). This study demonstrates that HR is an important factor in the intraindividual variation of PWV in elderly subjects. This raises methodological concern about the measurement of this parameter. Standardizing PWV for HR level seems mandatory if one wants to interpret PWV changes in clinical trials or in the follow-up of patients.

Spontaneous baroreflex sensitivity: toward an ideal index of cardiovascular risk in hypertension?

Objective Estimating the risk entailed by classical risk factors like blood pressure (BP) or serum cholesterol may be difficult because of their variability and the often unknown duration of exposure. Having variables integrating the impact of those classical risk factors on the cardiovascular system would probably aid the prediction of cardiovascular events. The present study aimed at determining whether cardiac baroreflex sensitivity (BRS), correlates with several risk factors and thus is a good candidate for being such an integrative variable. As a comparison, left ventricular mass (LVM), pulse wave velocity (PWV), and creatinine were also tested for association with risk factors. Design A total of 302 subjects referred for hypertension, were considered. They had a 24-h BP recording and a determination of BRS by two different methods (sequence and alpha coefficient), in two different positions (lying and standing). They were also tested for the presence of left ventricular hypertrophy (LVH) (by echocardiography and electrocardiogram) and had a PWV measurement. Biological testing included serum lipids, blood glucose, creatinine, proteinuria and urinary excretion of microalbumin. Results There was a strong correlation between the two methods of BRS measurement in each position (P < 0.001). BRS determined by the sequence method in the lying position was correlated significantly and independently with age, 24-h systolic BP, heart rate, and serum cholesterol with P values < 0.001, < 0.001, < 0.01, and < 0.05, respectively. In an univariate analysis, BRS was also correlated with echocardiographic LVM index (r =− 0.21, P < 0.05) and PWV (r =− 0.27, P < 0.001), which possibly reflects its dependence on both vascular and cardiac damages. Conclusion The present study supports the hypothesis that BRS could encompass the impact over time of several risk factors on the cardiovascular system . Thus, it may constitute a valuable parameter in assessing more precisely the risk of cardiovascular events.

N-Terminal Pro-Brain Natriuretic Peptide: A Powerful Predictor of Mortality in Hypertension

See Editorial Commentary, pp 670–671Natriuretic peptides are controregulatory hormones associated with cardiac remodeling, namely, left ventricular hypertrophy and systolic/diastolic dysfunction. We intended to address the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in hypertension. We prospectively studied the relationship between plasma NT-proBNP and all-cause mortality in 684 hypertensive patients with no history or symptoms of heart failure referred for hypertension workup in our institution from 1998 to 2008. After a mean duration of 5.7 years, we observed 40 deaths (1.04 deaths per 100 patients per year). After adjustment for traditional cardiovascular risk factors, including ambulatory blood pressure and serum creatinine, the risk for all-cause mortality more than doubled with each increment of 1 log NT-proBNP (hazard ratio: 2.33 [95% CI: 1.36 to 3.96]). The risk of death of patients with plasma NT-proBNP ≥133 pg/mL (third tertile of the distribution) was 3.3 times that of patients with values <50.8 pg/mL (first tertile; hazard ratio: 3.30 [95% CI: 0.90 to 12.29]). This predictive value was independent of, and superior to, that of 2 ECG indexes of left ventricular hypertrophy, the Sokolov-Lyon index and the amplitude of the R wave in lead aVL. In addition, it persisted in patients without ECG left ventricular hypertrophy, which allowed refining risk stratification in this relatively low-risk patient category. In this large sample of hypertensive patients, plasma NT-proBNP appeared as a strong prognostic marker. This performance, together with the ease of measurement, low cost, and widespread availability of NT-proBNP test kits, should prompt a wide use of this marker for risk stratification in hypertension.

Effect of abdominal aortic grafts on aortic stiffness and central hemodynamics

Graft-prosthesis and stentgraft placements are effective modalities for treating abdominal aortic aneurysm, but related changes in arterial stiffness are not well established. The present study sought to assess aortic stiffness after aneurism repair by measuring pulse wave velocity (PWV). The graft-related variation of carotid–femoral PWV was compared with that of carotid–radial PWV, the latter being unaffected by vascular treatment. The secondary objective was to evaluate potential differences between graft-prosthesis and stentgraft in terms of aortic stiffness and augmentation index, a composite indicator integrating wave reflexion. Fifty patients were included (39 had a graft-prosthesis and 11 had a stentgraft). In the whole group and after a median postoperative follow-up of 47 days, carotid–femoral PWV increased by +1.0 m/s [−12.3, +10.3], while carotid–radial PWV slightly decreased by −0.3 m/s [−4.4; +3.5] (P = 0.001). The effect of the type of prosthesis on the PWV was not significant. Nevertheless, the augmentation index increased after stentgraft implantation (+4% [−10; +17]) and decreased after graft-prosthesis placement (−8.5% [−47; +17]) (P < 0.01). This difference was not explained by a heart rate or a treatment effect and was likely attributable to the prosthesis per se. This study demonstrates the impact of aortic grafts on aortic stiffness. Besides, it suggests that stentgraft increases reflected waves more than graft-prostheses. These changes of vascular properties may influence the outcomes after surgery.

Arterial stiffness is associated with left atrial size in hypertensive patients

BACKGROUND Arterial stiffness is a strong predictor of cardiovascular events and particularly of stroke. A likely explanation is the development of atherosclerotic lesions at the carotid level, favored by increased local stiffness. Another possibility involves cardiac consequences of aortic stiffness and particularly left atrial dilatation with its subsequent risk of atrial fibrillation (AF) and cerebral embolism. AIMS The present study investigated the link between arterial stiffness, pulse pressure and left atrial size, a determinant of AF risk. METHODS Arterial stiffness was determined from pulse wave velocity (PWV) and pulse pressure (PP). Left atrial size was also measured. Several potential confounders were taken into account including indices of ventricular remodeling and diastolic function (estimated by NT-Pro brain natriuretic peptide (NT-proBNP) levels). RESULTS Three-hundred and ten hypertensive patients, aged 53 +/- 13 years, were included. Mean 24-h blood pressure (BP) was 154 +/- 20 over 93 +/- 13 mmHg. Significant relationships were found between left atrial diameter (LAD) and PWV (r=0.27, P<0.001) and between LAD and 24-h PP (r=0.32, P<0.001). LAD was also correlated significantly, although not always tightly, with left ventricular dimensions, geometry and NT-proBNP. In two different multivariate models, LAD remained significantly correlated with PWV or with 24-h PP, independently of classical determinants like age, gender, body mass index, ventricular remodeling (i.e. dimensions and geometry) and filling pressure. CONCLUSION These results led us to propose AF as a new possible pathophysiological link between arterial stiffness and stroke. These results also emphasize the cardiac consequences of arterial stiffness which can fuel a new approach to AF prevention.

Difference between office and ambulatory blood pressure or real white coat effect: does it matter in terms of prognosis?

Objective The blood pressure (BP) response to the doctors visit, generally referred as the white coat (WC) response, is usually estimated by the difference between office BP (OBP) and ambulatory BP (ABP). The purpose of this study was to determine the validity of this estimation. To that end, we compared the real WC effect and the estimated WC effect (OBP–ABP) in terms of magnitude and consequences on target organs. Design The study comprised 88 patients referred for hypertension. The real WC effect was measured using a Finapres device and expressed as the maximal WC effect (Max WC) or the average WC effect (Aver WC). For the estimation of target organ damages, the whole hypertensive group was separated into two groups according to the medians of the Aver WC, the Max WC, and the estimated WC effects, successively. Left ventricular mass index, E to A mitral wave ratio and pulse wave velocity were compared between groups as were serum creatinine, cholesterol and glucose levels. Results The estimated WC effect proved to be a bad index of the real response to the doctors visit as assessed by their difference of magnitude between the two (20 ± 17, 12 ± 12 and 30 ± 14 mmHg as estimated WC, Aver WC and Max WC effects, respectively), their loose correlations (r = 0.31, P = 0.004 between estimated WC and Aver WC effects; r = 0.27, P = 0.01 between estimated WC and Max WC effects), and finally by the fact that they were in agreement in less than two-thirds of the patients for the categorization of the WC response. Concerning target organ damages, no difference in terms of cardiac mass, diastolic function, arterial distensibility, renal function and cardiovascular risk profile could be discerned between the groups with a high and a low WC effect, either real or estimated, when age and ABP were taken into account. Conclusion The present work supports the view that the true WC effect and its estimation are not equivalent. However, the way in which the WC response is defined does not alter its effect on target organs or cardiovascular risk profile.

A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension

Objective To study the association of the A1166C polymorphism of angiotensin II type 1 receptor gene (AGTR1) with blood pressure and central arterial stiffness in a population of hypertensive patients referred to hospital for further work-up. Methods One hundred and eighty-five patients, referred to our department from April 1998 to February 2002, were included. Blood pressure was measured by conventional and 24-h ambulatory methods, and arterial stiffness by carotid–femoral pulse wave velocity (PWV) determination. Genotyping for the AGTR1 A1166C polymorphism was performed by polymerase chain reaction. Results AGTR1 A1166C polymorphism was not associated with systolic or diastolic blood pressure, measured either by conventional (P = 0.89 and P = 0.67, respectively) or by 24-h ambulatory (P = 0.57 and P = 0.56, respectively) methods. Conversely, this polymorphism was significantly associated with PWV (P = 0.006) and had a dose–allele effect, PWV increasing with the number of A alleles (10.6 ± 2.4 m/s in CC, 11.9 ± 2.5 m/s in AC and 12.7 ± 2.7 m/s in AA patients, P = 0.002). Multiple regression analysis showed that A1166C polymorphism was still independently associated with PWV (P = 0.01) and was the third most important determinant of PWV after age (P < 0.0001) and 24-h mean blood pressure (P < 0.0001). Conclusion In our study population, central arterial stiffness assessed by PWV was significantly and independently associated with the A1166C polymorphism, increased PWV being associated with the presence of the A allele. Further investigations are required for identification of the underlying mechanisms.

Outcome Associations of Carotid-Femoral Pulse Wave Velocity Vary With Different Measurement Methods

BACKGROUND The impact of various methods of travel distance estimation on the prognostic value of pulse wave velocity (PWV) and on the adequacy of cut-offs has never been addressed within a single population of hypertensive patients. METHODS Four carotid-femoral PWVs were calculated from four different travel distances (Direct, Real, Subtracted, and Estimated) divided by the same travel time in 426 hypertensives (mean age 51.2 ± 13.8 years, mean systolic blood pressure 155.6 ± 21.1 mm Hg). The incidence of death from any cause and major cardiovascular events was studied. PWV predictive accuracies were determined using C-index analysis. Hazard ratios (HRs) associated with specific values of PWV were determined with Cox model analyses using cubic splines. RESULTS Mean PWV ranged from 8.3 ± 2.3 m/s for the Subtracted one to 11.6 ± 3.0 m/s for the Direct one (P < 0.001). When included as continuous variables in a Cox model, the four PWVs were significantly associated with outcome (all P < 0.001), and had similar C-index (0.608-0.617). In multivariable analysis, the HR calculated for a Direct PWV of 12 m/s was neutral (HR = 1.02). In contrast, the same analysis provided HR ranging from 1.79 to 2.90 with the other PWVs. CONCLUSIONS Different travel distances markedly impact PWV values and prognostic cut-offs. PWV cut-offs should consequently be ascertained jointly with the method of measurement used. There is an urgent need for standardization of PWV assessment before implementing this parameter in the routine management of hypertensives.

Significance of urinary angiotensinogen in essential hypertension as a function of plasma renin and aldosterone status.

Objective This study was performed to test the significance of urinary angiotensinogen (UAGT) in essential hypertensive patients stratified as a function of plasma renin and aldosterone. Methods and results A sample of 248 essential hypertensives, investigated under their usual sodium diet and either off-medication or under a standardized treatment, was separated into two groups on the basis of upright plasma active renin and aldosterone medians. Patients with plasma active renin and aldosterone below medians are referred to as the low renin–aldosterone essential hypertensive group (LRA-EH). Others subjects are defined as other essential hypertensives (O-EH). Blood pressure (BP) was recorded by 24-h ambulatory monitoring. UAGT was measured by a specific enzyme-linked immunosorbent assay for total angiotensinogen. Because UAGT was markedly increased in the presence of overt proteinuria (≥ 300 mg/24 h), proteinuric patients (n = 29) were excluded from subsequent analyses. UAGT was a significant predictor of systolic and diastolic BP in LRA-EH females (P < 0.01 and P = 0.05, respectively) but not in males. By contrast, urinary sodium excretion (P < 0.001) and maintenance of treatment (P = 0.002) were significant predictors of systolic BP in males. These correlations were not observed in O-EH, whether males or females. Conclusions In the present study, UAGT stands as a strong predictor of BP in women with low plasma renin/aldosterone, suggesting an involvement of the tubular renin–angiotensin system in these subjects. Higher sodium intake or the need to maintain treatment may account in part for the lack of a similar relationship in males.

Effect modification of aortic atheroma on the prognostic value of heart rate in hypertension.

Background: Although some epidemiological studies have advocated a prognostic value of heart rate (HR) in hypertensive patients, the influence of vascular damages on this prognostic value has not been tested yet. Methods: HRs were collected by pulse palpation in 1204 primary hypertensive patients in sinus rhythm without cardiac-slowing drugs. Aortic damages were assessed by aortography, whereas cardiac disease was assessed by medical history, symptoms and electrocardiogram. Results: In a multivariable Cox model adjusted for major confounders, HR was of prognostic significance for all-cause [hazard ratio 1.12 (1.06–1.19) for 10 bpm increment and 1.39 (1.18–1.64) for HR ≥82 vs. <82 bpm] and cardiovascular death [hazard ratio 1.10 (1.02–1.20) for 10 bpm increment and 1.37 (1.09–1.72) for HR ≥82 vs. <82 bpm] after 35 years of follow-up. This association was particularly manifested at 15 years of follow-up. At that time, with the same multivariable survival model, the association between HR and cardiovascular death was stronger in patients with aortic atheroma [2.76 (1.47–5.18) for an HR ≥82 vs. <82 bpm] than in patients without [hazard ratio 1.36 (0.76–2.43) for an HR ≥82 vs. <82 bpm, P for interaction = 0.054]. Similarly, the association between HR and cardiovascular death was stronger in patients with an overt cardiac disease than those without (P for interaction = 0.044). Conclusion: In hypertensive patients, the prognostic significance of HR for cardiovascular outcome is modulated by the presence of aortic atherosclerosis or cardiac disease. This should prompt us to a thorough examination of cardiovascular damages in hypertensive patients when HR is elevated.