Placental syndromes and maternal cardiovascular health.

The placental syndromes gestational hypertension, preeclampsia and intrauterine growth restriction are associated with an increased cardiovascular risk to the mother later in life. In this review, we argue that a woman's pre-conception cardiovascular health drives both the development of placental syndromes and long-term cardiovascular risk but acknowledge that placental syndromes can also contribute to future cardiovascular risk independent of pre-conception health. We describe how preclinical studies in models of preeclampsia inform our understanding of the links with later cardiovascular disease, and how current pre-pregnancy studies may explain relative contributions of both pre-conception factors and the occurrence of placental syndromes to long-term cardiovascular disease.

Central Versus Peripheral Artery Stiffening and Cardiovascular Risk.

The large elastic arteries fulfill an important role in buffering the cyclical changes in blood pressure, which result from intermittent ventricular ejection. With aging and accrual of cardiovascular risk factors, the elastic arteries stiffen, and this process holds a number of deleterious consequences for the cardiovascular system and major organs. Indeed, arterial stiffness is now recognized as an important, independent determinant of cardiovascular disease risk. Additional, important information concerning the mechanisms underlying arterial stiffening has come from longitudinal studies of arterial stiffness. More recently, attention has focused on the role of peripheral, muscular arteries in cardiovascular disease risk prediction and, in particular, the clinical consequences of reversal of the normal gradient of arterial stiffness between central and peripheral arteries, with aging and disease.

Respiratory and Cardiovascular Outcomes in Survivors of Extremely Preterm Birth at 19 Years.

Rationale: Growth and development during adolescence may modify the respiratory and vascular differences seen among extremely preterm (EP) individuals in childhood and early adolescence.Objectives: To assess the trajectory of respiratory and cardiovascular outcomes during transition to adulthood in a national longitudinal cohort study of births before 26 weeks of gestation in the United Kingdom and Ireland.Methods: A total of 129 EP participants and 65 control subjects attended for a center-based evaluation at 19 years of age. Standardized measures of spirometry, hemodynamics, functional capacity, and markers of inflammation were obtained from EP subjects with and without neonatal bronchopulmonary dysplasia and term-born control subjects at 19 years of age and compared with previous assessments.Measurements and Main Results: Compared with the control group, the EP group was significantly impaired on all spirometric parameters (mean FEV1z-score, -1.08 SD [95% confidence interval, -1.40 to -0.77]) and had lower fractional exhaled nitric oxide concentrations (13.9 vs. 24.4 ppb; P < 0.001) despite a higher proportion with bronchodilator reversibility (27% vs. 6%). The EP group had significantly impaired exercise capacity. All respiratory parameters were worse after neonatal bronchopulmonary dysplasia, and respiratory function differences were similar at 11 and 19 years. The augmentation index was 6% higher in the EP group and associated with increased total peripheral resistance (difference in means, 96.4 [95% confidence interval, 26.6-166.2] dyne/s/cm-5) and elevation in central, but not peripheral, blood pressure. Central systolic and diastolic blood pressures increased more quickly during adolescence in the EP group than in the control group.Conclusions: Clinicians should address both cardiovascular and respiratory risks in adult survivors of extremely preterm birth.

Association of aortic stiffness with cognitive decline: Whitehall II longitudinal cohort study.

Aortic stiffness is associated with an increased risk of cardio- and cerebrovascular disease and mortality and may increase risk of dementia. The aim of the present study is to examine the association between arterial stiffness and cognitive decline in a large prospective cohort study with three repeated cognitive assessment over 7 years of follow-up. Aortic pulse wave velocity (PWV) was measured among 4300 participants (mean ± standard deviation age 65.1 ± 5.2 years) in 2007-2009 and categorized based on the tertiles: (lowest third: < 7.41 m/s), (middle third: 7.41-8.91 m/s), and (highest third: > 8.91 m/s). A global cognitive score was calculated in 2007-2009, 2012-2013, and 2015-2016 based on responses to memory, reasoning and fluency tests. Standardized global cognitive score (mean = 0, SD = 1) in highest third versus lowest third of PWV category was lower at baseline (- 0.12, 95% CI - 0.18, - 0.06). Accelerated 7-year cognitive decline was observed among individuals with the highest PWV [difference in 7-year cognitive change for highest third versus lowest third PWV: - 0.06, 95% CI - 0.11, - 0.01, P < 0.01]. Higher aortic stiffness was associated with faster cognitive decline. Clinicians may be able to use arterial stiffness severity as an indicator to administer prompt treatments to prevent or delay the onset of cognitive decline or dementia. Future studies need to determine whether early intervention of vascular stiffness is effective in delaying these outcomes.

Uterine and fetal placental Doppler indices are associated with maternal cardiovascular function.

BACKGROUND: The mechanism underlying fetal-placental Doppler index changes in preeclampsia and/or fetal growth restriction are unknown, although both are associated with maternal cardiovascular dysfunction. OBJECTIVE: We sought to investigate whether there was a relationship between maternal cardiac output and vascular resistance and fetoplacental Doppler findings in healthy and complicated pregnancy. STUDY DESIGN: Women with healthy pregnancies (n=62), preeclamptic pregnancies (n=13), preeclamptic pregnancies with fetal growth restriction (n=15), or fetal growth restricted pregnancies (n=17) from 24-40 weeks gestation were included. All of them underwent measurement of cardiac output with the use of an inert gas rebreathing technique and derivation of peripheral vascular resistance. Uterine and fetal Doppler indices were recorded; the latter were z scored to account for gestation. Associations were determined by polynomial regression analyses. RESULTS: Mean uterine artery pulsatility index was higher in fetal growth restriction (1.37; P=.026) and preeclampsia+fetal growth restriction (1.63; P=.001) but not preeclampsia (0.92; P=1) compared with control subjects (0.8). There was a negative relationship between uterine pulsatility index and cardiac output (r2=0.101; P=.025) and umbilical pulsatility index z score and cardiac output (r2=0.078; P=.0015), and there were positive associations between uterine pulsatility index and peripheral vascular resistance (r2=0.150; P=.003) and umbilical pulsatility index z score and peripheral vascular resistance (r2= 0.145; P=.001). There was no significant relationship between cardiac output and peripheral vascular resistance with cerebral Doppler indices. CONCLUSION: Uterine artery Doppler change is abnormally elevated in fetal growth restriction with and without preeclampsia, but not in preeclampsia, which may explain the limited sensitivity of uterine artery Doppler changes for all these complications when considered in aggregate. Furthermore, impedance within fetoplacental arterial vessels is at least, in part, associated with maternal cardiovascular function. This relationship may have important implications for fetal surveillance and would inform therapeutic options in those pathologic pregnancy conditions currently, and perhaps erroneously, attributed purely to placental maldevelopment. Uterine and fetal placental Doppler indices are associated significantly with maternal cardiovascular function. The classic description of uterine and fetal Doppler changes being initiated by placental maldevelopment is a less plausible explanation for the pathogenesis of the conditions than that relating to maternal cardiovascular changes.

Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study.

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator-fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II-IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.

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 Kingdom's 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.

Vascular inflammation and aortic stiffness: potential mechanisms of increased vascular risk in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha- 1 antitrypsin deficiency (α1ATD) as a comparator lung disease group. METHODS: Participants underwent 18F-Fluorodeoxyglucose (FDG) positron emission tomography imaging to quantify aortic inflammation as the tissue-to-blood-ratio (TBR) of FDG uptake. Aortic stiffness was measured by carotid-femoral aortic pulse wave velocity (aPWV). RESULTS: Eighty-five usual COPD (COPD due to smoking), 12 α1ATD-COPD patients and 12 each smokers and never-smokers were studied. There was no difference in pack years smoked between COPD patients and smokers (45 ± 25 vs 37 ± 19, p = 0.36), but α1ATD patients smoked significantly less (19 ± 11, p < 0.001 for both). By design, spirometry measures were lower in COPD and α1ATD-COPD patients compared to smokers and never-smokers. Aortic inflammation and stiffness were increased in COPD (TBR: 1.90 ± 0.38, aPWV: 9.9 ± 2.6 m/s) and α1ATD patients (TBR: 1.94 ± 0.43, aPWV: 9.5 ± 1.8 m/s) compared with smokers (TBR: 1.74 ± 0.30, aPWV: 7.8 ± 1.8 m/s, p < 0.05 all) and never-smokers (TBR: 1.71 ± 0.34, aPWV: 7.9 ± 1.7 m/s, p ≤ 0.05 all). CONCLUSIONS: In this cross-sectional prospective study, novel findings were that both usual COPD and α1ATD-COPD patients have increased aortic inflammation and stiffness compared to smoking and never-smoking controls, regardless of smoking history. These findings suggest that the presence of COPD lung disease per se may be associated with adverse aortic wall changes, and aortic inflammation and stiffening are potential mechanisms mediating increased vascular risk observed in COPD patients.

Early and late preeclampsia are characterized by high cardiac output, but in the presence of fetal growth restriction, cardiac output is low: insights from a prospective study.

BACKGROUND: Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction. OBJECTIVE: We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction. STUDY DESIGN: We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24-40 weeks. RESULTS: Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 ± 1.35; P = .0001) and lower peripheral vascular resistance Z scores (-0.76 ± 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 ± 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores (-0.80 ± 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 ± 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03). CONCLUSION: Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature.

The age-dependent association between aortic pulse wave velocity and telomere length.

KEY POINTS: Age significantly modifies the relationship between aortic pulse wave velocity and telomere length. The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life-course. ABSTRACT: Ageing is associated with marked large artery stiffening. Telomere shortening, a marker of cellular ageing, is linked with arterial stiffening. However, the results of existing studies are inconsistent, possibly because of the confounding influence of variable exposure to cardiovascular risk factors. Therefore, we investigated the relationship between telomere length (TL) and aortic stiffness in well-characterized, younger and older healthy adults, who were pre-selected on the basis of having either low or high aortic pulse wave velocity (aPWV), a robust measure of aortic stiffness. Demographic, haemodynamic and biochemical data were drawn from participants in the Anglo-Cardiff Collaborative Trial. Two age groups with an equal sex ratio were examined: those aged <30 years (younger) or >50 years (older). Separately for each age group and sex, DNA samples representing the highest (n = 125) and lowest (n = 125) extremes of aPWV (adjusted for blood pressure) were selected for analysis of leukocyte TL. Ultimately, this yielded complete phenotypic data on 904 individuals. In younger subjects, TL was significantly shorter in those with high aPWV vs. those with low aPWV (P = 0.017). By contrast, in older subjects, TL was significantly longer in those with high aPWV (P = 0.001). Age significantly modified the relationship between aPWV and TL (P < 0.001). Differential relationships are observed between aPWV and TL, with an inverse association in younger individuals and a positive association in older individuals. The links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life-course.

Gestational length assignment based on last menstrual period, first trimester crown-rump length, ovulation, and implantation timing.

PURPOSE: Understanding the natural length of human pregnancy is central to clinical care. However, variability in the reference methods to assign gestational age (GA) confound our understanding of pregnancy length. Assignation from ultrasound measurement of fetal crown-rump length (CRL) has superseded that based on last menstrual period (LMP). Our aim was to estimate gestational length based on LMP, ultrasound CRL, and implantation that were known, compared to pregnancy duration assigned by day of ovulation. METHODS: Prospective study in 143 women trying to conceive. In 71 ongoing pregnancies, gestational length was estimated from LMP, CRL at 10-14 weeks, ovulation, and implantation day. For each method of GA assignment, the distribution in observed gestational length was derived and both agreement and correlation between the methods determined. RESULTS: Median ovulation and implantation days were 16 and 27, respectively. The gestational length based on LMP, CRL, implantation, and ovulation was similar: 279, 278, 276.5 and 276.5 days, respectively. The distributions for observed gestational length were widest where GA was assigned from CRL and LMP and narrowest when assigned from implantation and ovulation day. The strongest correlation for gestational length assessment was between ovulation and implantation (r = 0.98) and weakest between CRL and LMP (r = 0.88). CONCLUSIONS: The most accurate method of predicting gestational length is ovulation day, and this agrees closely with implantation day. Prediction of gestational length from CRL and known LMP are both inferior to ovulation and implantation day. This information could have important implications on the routine assignment of gestational age.

Clinical relevance of central blood pressure - a critical review.

Vital organs are exposed to the central rather than the brachial blood pressure. To date, central blood pressure can be assessed noninvasively through the use of several devices. In this review, we critically discuss the clinical relevance of central blood pressure assessment. Considerable evidence suggests that central blood pressure is a better predictor of end-organ damage than brachial blood pressure. However, there is still uncertainty concerning the value of central pressure for predicting cardiovascular outcomes, as the existing studies are underpowered to address this issue. A full synthesis of the available data is needed in this regard. Among the different antihypertensive drug classes, beta-blockers appear to lower central blood pressure less than brachial blood pressure. This difference may, at least in part, explain the reduced efficacy of beta-blockers in the prevention of cardiovascular outcomes compared with the other antihypertensive drug classes, which may lower central and brachial blood pressure to a similar extent. Nevertheless, this differential effect might not be relevant to the newer beta-blockers with vasodilating properties, including nebivolol, celliprolol and carvedilol. However, whether a preferential reduction of central blood pressure results in better outcomes should be further assessed by appropriately powered clinical trials. Other emerging challenges include the assessment of the potential predictive value of central blood pressure variability and the development of new antihypertensive medications based on central blood pressure rather than brachial blood pressure.

Central blood pressure: current evidence and clinical importance.

Pressure measured with a cuff and sphygmomanometer in the brachial artery is accepted as an important predictor of future cardiovascular risk. However, systolic pressure varies throughout the arterial tree, such that aortic (central) systolic pressure is actually lower than corresponding brachial values, although this difference is highly variable between individuals. Emerging evidence now suggests that central pressure is better related to future cardiovascular events than is brachial pressure. Moreover, anti-hypertensive drugs can exert differential effects on brachial and central pressure. Therefore, basing treatment decisions on central, rather than brachial pressure, is likely to have important implications for the future diagnosis and management of hypertension. Such a paradigm shift will, however, require further, direct evidence that selectively targeting central pressure, brings added benefit, over and above that already provided by brachial artery pressure.

Estimation of aortic pulse pressure using Fourier velocity encoded M-mode MR.

PURPOSE: To use a simplified hemodynamic model and Fourier-encoded velocity data to measure pulse pressure (PP) in the descending aorta. MATERIALS AND METHODS: A one-dimensional, cylindrically localized pulse sequence with Fourier velocity encoding (FVE) was used to obtain time-dependent velocity distributions along the descending aorta. Numerical evaluation of a simplified hemodynamic model, based on a cross-sectionally averaged form of the mass conservation equation, allowed estimation of the average pressure waveform and PP along 6-cm-long segments located within the descending aorta. Magnetic resonance (MR)-derived pressures were compared against applanation tonometry (AT) performed in healthy subjects (n = 18) and intravascular pressure measurements (IVPM) obtained in patients (n = 4) undergoing diagnostic cardiac angiography and then found to be either normal or with clinically insignificant coronary artery disease. RESULTS: The root mean square (RMS) error between MR- and AP-derived pressure waveforms was 11.7 ± 5.8%. With respect to IVPM, the RMS error ranged from 4.2% to 14.7%. In terms of pulse pressures, there was good agreement with both AT (bias = 0.99 mmHg; 95% limits of agreement (LOA) = [-5.0 to 7.0 mmHg]; range = 12.0 mmHg) and IVPM (bias = -1.82 mmHg; 95% LOA = [-7.2 to 3.5 mmHg]; range = 10.7 mmHg). CONCLUSION: FVE M-mode and numerical evaluation of a simplified flow model can be used to estimate central pulse pressures noninvasively and accurately with respect to well-established gold standards.

S-Nitrosoglutathione improves haemodynamics in early-onset pre-eclampsia.

AIMS: To determine the effects of in vivo S-nitrosoglutathione (GSNO) infusion on cardiovascular function, platelet function, proteinuria and biomarker parameters in early-onset pre-eclampsia. METHODS: We performed an open-label dose-ranging study of GSNO in early-onset pre-eclampsia. Six women underwent GSNO infusion whilst receiving standard therapy. The dose of GSNO was increased incrementally to 100 µg min(-1) whilst maintaining blood pressure of >140/80 mmHg. Aortic augmentation index, aortic pulse wave velocity, blood pressure and maternal-fetal Doppler parameters were measured at each dose. Platelet P-selectin, protein-to-creatinine ratio and soluble anti-angiogenic factors were measured pre- and postinfusion. RESULTS: Augmentation index fell at 30 µg min(-1) S-nitrosoglutathione (-6%, 95% confidence interval 0.6 to 13%), a dose that did not affect blood pressure. Platelet P-selectin expression was reduced [mean (interquartile range), 6.3 (4.9-7.6) vs. 4.1 (3.1-5.7)% positive, P = 0.03]. Soluble endoglin levels showed borderline reduction (P = 0.06). There was a borderline significant change in pre-to-postinfusion protein-to-creatinine ratio [mean (interquartile range), 0.37 (0.09-0.82) vs. 0.23 (0.07-0.49) g mmol(-1) , P = 0.06]. Maternal uterine and fetal Doppler pulsatility indices were unchanged. CONCLUSIONS: In early-onset pre-eclampsia, GSNO reduces augmentation index, a biomarker of small vessel tone and pulse wave reflection, prior to affecting blood pressure. Proteinuria and platelet activation are improved at doses that affect blood pressure minimally. These effects of GSNO may be of therapeutic potential in pre-eclampsia, a condition for which no specific treatment exists. Clinical studies of GSNO in early-onset pre-eclampsia will determine whether these findings translate to improvement in maternal and/or fetal outcome.

Evaluating the role of inflammation in chronic airways disease: the ERICA study.

Extrapulmonary manifestations are recognized to be of increasing clinical importance in Chronic Obstructive Pulmonary disease. To investigate cardiovascular and skeletal muscle manifestations of COPD, we developed a unique UK consortium funded by the Technology Strategy Board and Medical Research Council comprising industry in partnership with 5 academic centres. ERICA (Evaluating the Role of Inflammation in Chronic Airways disease) is a prospective, longitudinal, observational study investigating the prevalence and significance of cardiovascular and skeletal muscle manifestations of COPD in 800 subjects. Six monthly follow up will assess the predictive value of plasma fibrinogen, cardiovascular abnormalities and skeletal muscle weakness for death or hospitalization. As ERICA is a multicentre study, to ensure data quality we sought to minimise systematic observer error due to variations in investigator skill, or adherence to operating procedures, by staff training followed by assessment of inter- and intra-observer reliability of the four key measurements used in the study: pulse wave velocity (PWV), carotid intima media thickness (CIMT), quadriceps maximal voluntary contraction force (QMVC) and 6-minute walk distance (6MWT). This report describes the objectives and methods of the ERICA trial, as well as the inter- and intra-observer reliability of these measurements.

Cardiovascular responses to experimental weight gain in humans: a feasibility study.

OBJECTIVE: Obesity and hypertension share a well known association. However, the mechanisms underlying their relationship are not well understood. Our goal was to assess the feasibility of a longitudinal, interventional weight gain study with detailed cardiovascular measurements in humans. METHODS: Sixteen healthy, normotensive, young, male volunteers (28 ±â€Š7 years) were enrolled. Body composition, biochemical and cardiovascular data were obtained at baseline, and after an 8-week period of overfeeding (800-1000 kcal/day). Blood pressure (BP), cardiac output (CO) and peripheral vascular resistance (PVR) were determined, as were the minimum forearm vascular resistance (MFVR), forearm blood flow (FBF) response to mental stress and heart rate variability (HRV) parameters. RESULTS: Overfeeding resulted in a median weight gain of 5.6 kg [interquartile range (IQR) 4.6-6.4 kg; P  < 0.001]. Seated systolic and diastolic BP were significantly increased by 10 ±â€Š9 and 4 ±â€Š6 mmHg, respectively, after weight gain ( P  < 0.001 and P  = 0.011, respectively). CO also increased and PVR decreased significantly as a result of weight gain ( P  = 0.032 and P  = 0.044, respectively). MFVR was also significantly decreased after weight gain ( P  = 0.023). The FBF response to mental stress was blunted significantly ( P  = 0.002), and sympathovagal balance and responsiveness to orthostatic challenge altered moderately after weight gain. CONCLUSION: Our overfeeding regimen resulted in moderate weight gain and significant increases in BP. An increase in CO is likely to be the dominant mechanism underlying the observed BP changes, with decreases in PVR partially compensating for these effects. Experimental weight gain, coupled with detailed cardiovascular phenotyping, is a feasible model to examine potential mechanisms underlying obesity-associated hypertension in young adults.

Investigation and management of young-onset hypertension: British and Irish hypertension society position statement.

National and international hypertension guidelines recommend that adults with young-onset hypertension (aged <40 years at diagnosis) are reviewed by a hypertension specialist to exclude secondary causes of hypertension and optimise therapeutic regimens. A recent survey among UK secondary care hypertension specialist physicians highlighted variations in the investigation of such patients. In this position statement, the British and Irish Hypertension Society seek to provide clinicians with a practical approach to the investigation and management of adults with young-onset hypertension. We aim to ensure that individuals receive consistent and high-quality care across the UK and Ireland, to highlight gaps in the current evidence, and to identify important future research questions.