Luca Faconti

Birth weight and arterial hypertension

Purpose of review To provide an overview of available evidence of the relationship between birth weight and future hypertension development. Recent findings Fetal programming plays a significant role in future hypertension. Both low and high birth weight are able to influence weight gain during childhood, adult weight and blood pressure values during childhood and adulthood. To date, an increasing amount of evidence is available especially for the relationship between low birth weight and hypertension, supported also by pathophysiological studies. Summary In the era of personalized medicine, the possibility to reduce cardiovascular risk before or soon after birth and intervene on risk factors during childhood is appealing and promising for the future.

Ethnic differences in and childhood influences on early adult pulse wave velocity: The determinants of adolescent, now young adult, social wellbeing, and health longitudinal study

Early determinants of aortic stiffness as pulse wave velocity are poorly understood. We tested how factors measured twice previously in childhood in a multiethnic cohort study, particularly body mass, blood pressure, and objectively assessed physical activity affected aortic stiffness in young adults. Of 6643 London children, aged 11 to 13 years, from 51 schools in samples stratified by 6 ethnic groups with different cardiovascular risk, 4785 (72%) were seen again at aged 14 to 16 years. In 2013, 666 (97% of invited) took part in a young adult (21–23 years) pilot follow-up. With psychosocial and anthropometric measures, aortic stiffness and blood pressure were recorded via an upper arm calibrated Arteriograph device. In a subsample (n=334), physical activity was measured >5 days via the ActivPal. Unadjusted pulse wave velocities in black Caribbean and white UK young men were similar (mean±SD 7.9±0.3 versus 7.6±0.4 m/s) and lower in other groups at similar systolic pressures (120 mm Hg) and body mass (24.6 kg/m2). In fully adjusted regression models, independent of pressure effects, black Caribbean (higher body mass/waists), black African, and Indian young women had lower stiffness (by 0.5–0.8; 95% confidence interval, 0.1–1.1 m/s) than did white British women (6.9±0.2 m/s). Values were separately increased by age, pressure, powerful impacts from waist/height, time spent sedentary, and a reported racism effect (+0.3 m/s). Time walking at >100 steps/min was associated with reduced stiffness (P<0.01). Effects of childhood waist/hip were detected. By young adulthood, increased waist/height ratios, lower physical activity, blood pressure, and psychosocial variables (eg, perceived racism) independently increase arterial stiffness, effects likely to increase with age.

Can arterial wave augmentation in young adults help account for variability of cardiovascular risk in different British ethnic groups

Objective: Traditional cardiovascular risk factors do not fully account for ethnic differences in cardiovascular disease. We tested if arterial function indices, particularly augmentation index (AIx), and their determinants from childhood could underlie such ethnic variability among young British adults in the ‘DASH’ longitudinal study. Methods: DASH, at http://dash.sphsu.mrc.ac.uk/, includes representative samples of six main British ethnic groups. Pulse wave velocity (PWV) and AIx were recorded using the Arteriograph device at ages 21–23 years in a subsample (n = 666); psychosocial, anthropometric, and blood pressure (BP) measures were collected then and in two previous surveys at ages 11–13 years and 14–16 years. For n = 334, physical activity was measured over 5 days (ActivPal). Results: Unadjusted values and regression models for PWVs were similar or lower in ethnic minority than in White UK young adults, whereas AIx was higher – Caribbean (14.9, 95% confidence interval 12.3–17.0%), West African (15.3, 12.9–17.7%), Indian (15.1, 13.0–17.2%), and Pakistani/Bangladeshi (15.7, 13.7–17.7%), compared with White UK (11.9, 10.2–13.6%). In multivariate models, adjusted for sex, central SBP, height, and heart rate, Indian and Pakistani/Bangladeshi young adults had higher AIx (&bgr; = 3.35, 4.20, respectively, P < 0.01) than White UK with a similar trend for West Africans and Caribbeans but not statistically significant. Unlike PWV, physical activity, psychosocial or deprivation measures were not associated with AIx, with borderline associations from brachial BP but no other childhood variables. Conclusion: Early adult AIx, but not arterial stiffness, may be a useful tool for testing components of excess cardiovascular risk in some ethnic minority groups.

A randomized controlled crossover trial evaluating differential responses to antihypertensive drugs (used as mono- or dual therapy) on the basis of ethnicity: The comparIsoN oF Optimal Hypertension RegiMens; part of the Ancestry Informative Markers in HYpertension program-AIM-HY INFORM trial.

Background: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a “black versus white” approach; in doing so, they ignore the United Kingdoms largest ethnic minority: Asians from South Asia. Study design: The primary purpose of the AIM‐HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono‐ or dual therapy on the basis of self‐defined ethnicity. A multicenter, prospective, open‐label, randomized study with 2 parallel, independent trial arms (mono‐ and dual therapy), AIM‐HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3‐treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3‐period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4‐treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4‐period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. Conclusion: AIM‐HY INFORM is a prospective, open‐label, randomized trial which aims to evaluate first‐ and second‐line antihypertensive therapies for multiethnic populations.

Arterial-ventricular coupling and parameters of vascular stiffness in hypertensive patients: Role of gender

Objective Non-invasive estimation of arterial–ventricular coupling has been extensively used for the evaluation of cardiovascular performance, however, a relative small amount of data is available regarding arterial–ventricular coupling and its components in hypertension. The present study was designed to investigate the relationship between left ventricular elastance, arterial elastance, parameters of vascular stiffness and the influence of gender in a population of hypertensive individuals. Methods In 102 patients, trans-thoracic cardiac ultrasound, parameters of aortic stiffness (carotid-femoral pulse wave velocity) and wave reflection (augmentation index) were recorded. Ultrasound images of common carotid arteries were acquired for the assessment of intima-media thickness as well as carotid compliance and distensibility coefficient. Results Mean age was 61 years, 32% diabetes, 56% dyslipidemia, 9% previous cardiovascular events; women (n = 32) and men were superimposable for cardiovascular risk factors prevalence. In the population, ventricular elastance was significantly correlated with arterial elastance (r = 0.887), age (r = 0.334), gender (r = −0.494), BMI (r = −0.313), augmentation index (r = 0.479) (all p < 0.001); and with carotid compliance and distensibility coefficient (r = 0.229 and r = − 0.250, respectively, both p < 0.05); however, only arterial elastance and gender were independently associated with ventricular elastance in multiple regression models adjusted for confounding factors. Gender-specific analysis revealed that arterial elastance and augmentation index remained statistically significant associated with ventricular elastance in men (r = 0.275, p = 0.04); instead augmentation index was no longer significant (r = 0.052, p = 0.77) in the female sex. Conclusions In hypertensive patients, main determinants of ventricular elastance are arterial elastance, as an integrated index of arterial vascular load, and gender; however, pressure augmentation might play an additional role in men.

[OP.LB03.05] REDUCING ARTERIAL STIFFNESS INDEPENDENTLY OF BLOOD PRESSURE: PROOF OF CONCEPT? THE RANDOMISED, FACTORIAL 'VASERA' TRIAL.

Objective: Arterial stiffness (AS) as pulse wave velocity (PWV) is a powerful index of prognosis, independent of blood pressure (BP) and could be an important treatment target; increased AS is a common finding in type-2 diabetes (T2D). Our hypothesis was that spironolactone and dietary nitrate in beetroot juice (via the nitrate-nitrite-nitric oxide pathway) would reduce AS independently of any BP change in patients with or at risk of T2D. Design and method: 126 patients were randomised double-blind to daily spironolactone (<50 mg) or doxazosin (control; < 16 mg), and 70 mL ‘Beet-It’ beetroot juice (<∼9 mmol nitrate) or nitrate-depleted beetroot juice (placebo; ∼0.3 mmol nitrate) over 6 months. Vascular measurements were performed at baseline, 3 and 6 months. Cardiac-Ankle Vascular Index (CAVI), a BP-independent measure of AS, by VaSera VS-1500N (Fukuda Denshi), was the primary outcome. Aortic (ao)PWV and BP were measured by Arteriograph as secondary outcomes. Intention-to-treat analysis was performed using SAS by mixed model 2-way ANOVA, adjusted as pre-specified for baseline outcome measure and difference in systolic (S), or mean, BP. Results: SBP reductions on spironolactone and doxazosin were similar (mean[95% CI]: −7.0 [−9.9, −4.2] vs. −6.3 [−9.1, −3.5] mmHg, p = 0.7). Spironolactone did not reduce AS, rather there was some evidence that doxazosin reduced CAVI (−0.11 [−0.30, 0.08] vs. 0.14 [−0.06, 0.34] units, p = 0.080), an effect statistically significant for aoPWV (−0.44 [−0.69, −0.20] vs. −0.07 [−0.32, 0.18] ms-2, p = 0.039). Dietary nitrate did not reduce CAVI, aoPWV or SBP, or increase circulating nitrite despite increasing plasma nitrate compared with placebo juice (165 [89.0, 240] vs. 3.21 [−4.64, 11.1] &mgr;M, p < 0.001). No interaction between treatments was detected. Conclusions: Contrary to our hypothesis and previous estimates, spironolactone did not reduce AS in this fully-controlled trial. Rather, aoPWV was reduced on doxazosin in these T2D and at-risk patients, after adjusting for, so independent of, BP difference between treatments over time. Conversion of nitrate to nitrite was hindered, blunting the beneficial effects of nitrate on BP and aoPWV previously seen in healthy volunteers and hypertensives. The VaSera trial was funded by Fukuda Denshi.

Do arterial stiffness and wave reflection underlie cardiovascular risk in ethnic minorities

Increasing evidence indicates that remarkable differences in cardiovascular risk between ethnic groups cannot be fully explained by traditional risk factors such as hypertension, diabetes or dislipidemia measured in midlife. Therefore, the underlying pathophysiology leading to this “excess risk” in ethnic minority groups is still poorly understood, and one way to address this issue is to shift the focus from “risk” to examine target organs, particularly blood vessels and their arterial properties more directly. In fact, structural and functional changes of the vascular system may be identifiable at very early stages of life when traditional factors are not yet developed. Arterial stiffening, measured as aortic pulse wave velocity, and wave reflection parameters, especially augmentation index, seem to be an important pathophysiological mechanism for the development of cardiovascular disease and predict mortality independent of other risk factors. However, data regarding these arterial indices in ethnic minorities are relatively rare and the heterogeneity between populations, techniques and statistical methods make it difficult to fully understand their role.

5B.03: ARTERIAL-VENTRICULAR COUPLING AND PARAMETERS OF VASCULAR STIFFNESS IN HYPERTENSIVE PATIENTS: ROLE OF GENDER

Objective: The present study was designed to investigate the relationship between left ventricular elastance (ELV), arterial elastance (EA), parameters of vascular stiffness and the influence of gender in a population of hypertensive individuals at high cardiovascular (CV) risk. Design and method: Seventy eight subjects participated in the study. Trans-thoracic cardiac ultrasound exam and parameters of aortic stiffness (carotid-femoral pulse wave velocity, PWV) wave reflection (augmentation index, AIx), aortic and carotid pulse pressure (PP) were obtained. Ultrasound images of the common carotid artery were acquired for the assessment of intima-media thickness (IMT) as well as carotid compliance (CC) and distensibility coefficient (DC). Results: The mean age of subjects was 62,5 years old, 37,2% had diabetes, 48,7% dyslipidemia, 7,7% previous CV events. Women (43%) and men were superimposable for CV risk factors except for older age (63.3 ± 9.2 vs 57.5 ± 10.4 years, p < 0.001) and greater prevalence of dyslipidemia (66% vs 35%, p = 0.04). In the overall population ELV was significantly correlated with EA (r = 0.79,p < 0.001), age, gender and BMI (r = 0.30,p = 0.07,r = -0.64,p < 0.001,r = -0.32,p = 0.004 respectively), AIx (r = 0.53,p < 0.001), aortic PP (r = 0.39,p < 0.001) CC (r = -0.44, p < 0.001) and DC (r = -0.27, p = 0.02), but not with PWV (r = 0.13,p = 0.28). In the multiple regression model including EA, ELV was still significantly correlated with EA, BMI, gender (all p < 0.001) and aortic PP (p = 0.004). Conversely, DC and PWV were not. DC, CC, PWV and IMT were similar in men and women. ELV (p < 0.0001) and EA (p = 0.0002) were higher in women than in men, while EA/ELV was lower (p = 0.0003). While EA and BMI were significantly correlated with ELV both in men (r = 0.74,p < 0.0001) and women (r = 0.77,p < 0.0001), DC was correlated with ELV only in women (women r = 0.04,p = 0.03, men r = -0.21,p = 0.17), and aortic PP (men r = 0.44,p = 0.002, women r = 0.44, p = 0.01) and AIX (men r = 0.37,p = 0.002, women r = 0.33, p = 0.06) only in men. Conclusions: In hypertensive individuals, main determinants of ventricular elastance are arterial elastance as an integrated index of arterial vascular load, central PP, gender and BMI. However, large artery stiffness in women and pressure augmentation in men might play an additional role.

PACED BREATHING REDUCES BLOOD PRESSURE AND ARTERIAL STIFFNESS: IMPACT OF THE AUTONOMIC NERVOUS SYSTEM

Objective: The autonomic nervous system (ANS) plays an important role in regulating blood pressure (BP), but its action on arterial stiffness (AS) is still a subject of debate. Device-guided paced breathing (DGB) has been proposed as a non-pharmacological strategy to control BP –via the effects on ANS – but its effect on AS are unknown. Therefore, we examined if DGB would affect AS in hypertensive (HT) subjects. Design and method: Brachial BP (OMRON-705IT, Omron Corporation, Kyoto, Japan), central BP (pulse-wave analysis of the radial artery, SphygmoCor, AtCor Medical, Sydney, Australia), AS (carotid-femoral pulse wave velocity (cfPWV), Sphygmocor) and ANS activity (high resolution heart rate variability (HRV) as log-ratio of low-frequency/high-frequency range (LF/HF), Schiller Medilog AR12plus, United States) were determined in HT subjects. All measurements were performed in supine position after 15 min of rest and subsequently repeated during supervised DGB therapy which slows breathing < 10 breaths/min. Results: 25 HT patients (11 male), age (mean ± SD) 47 ± 12 years, systolic BP (SBP) 142.8 ± 19.4 mmHg, diastolic BP (DBP) 86.6 ± 8.7 mmHg and heart rate (HR) 72.4 ± 12.5 bpm were recruited. DGB decreased LF/HF by 0.09 ± 0.12 (p < 0.05) and reduced both brachial (−10.19 ± 7.89 mmHg) and central (−8.47 ± 6.80 mmHg) SBP, DBP (−3.6 ± 3.0 mmHg for brachial, p < 0.01) as well as HR (−3.48 ± 6.25 bpm, p < 0.05). cfPWV decreased from 9.81 ± 1.66m/s to 8.66 ± 1.60m/s (p < 0.01) and bivariate correlation showed no associations with changes in SBP, DBP or mean BP (MBP) (ß = 0.117, 0.107, 0.216 respectively; all p > 0.1). Finally, using the regression coefficient from meta-analysis and the observed decrease in MBP, we calculated the predicted reduction of cfPWV attributed to reduction in BP to be = 0.48 m/s, less than 50% of the observed reduction 1.04 (95%CI 0.65,1.28)m/s. Conclusions: DGB decreased central/brachial BP, an effect likely to be mediated by the reduction of sympathetic activity as indicated by HRV. Effects to reduce cfPWV were greater than those predicted from the change in BP suggesting that the ANS may play an independent role in modulating AS in HT subjects.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomised-controlled, VASERA TRIAL: Chronic cardiac effects of dietary nitrate

The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO3−), a potential tolerance‐free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterones potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure).