Yves Allemann

Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent

PURPOSE Essential hypertension is, in some patients, complicated by impairment of insulin-mediated glucose disposal and hyperinsulinemia. Whether this metabolic disturbance is a consequence of the hypertensive process or whether it may precede, and thus possibly promote, the development of hypertension has been unknown. SUBJECTS AND METHODS Searching for hereditary or familial defects in hypertension-prone humans, we prospectively investigated insulin sensitivity, plasma insulin and glucose, and serum lipoproteins in normotensive offspring of essential hypertensive as compared with age- and body habitus-matched offspring of normotensive families. RESULTS Compared with 78 control subjects, 70 offspring of essential hypertensive parents had similar age (mean +/- SEM: 24 +/- 1 versus 24 +/- 1 years, respectively) and body mass index (22.3 +/- 0.2 versus 22.4 +/- 0.2 kg/m2), a blood pressure of 127/77 +/- 1/1 versus 123/76 +/- 1/1 mm Hg (p less than 0.05 for systolic), and significantly elevated (p less than 0.01 to 0.001) fasting plasma insulin levels (9.9 +/- 0.3 versus 8.6 +/- 0.3 microU/mL), serum total triglycerides (1.03 +/- 0.06 versus 0.83 +/- 0.03 mmol/L), total cholesterol (4.37 +/- 0.08 versus 3.93 +/- 0.07 mmol/L), low-density lipoprotein cholesterol (2.45 +/- 0.08 versus 2.14 +/- 0.07 mmol/L), and total/high-density lipoprotein cholesterol ratio (4.3 +/- 0.1 versus 3.7 +/- 0.1). Insulin sensitivity was lower (9.4 +/- 0.7 versus 13.2 +/- 1.1 x 10(-4) x minute-1/microU/mL, p less than 0.001), while post-glucose-load plasma insulin levels were higher (p less than 0.05) in the 41 offspring of essential hypertensive parents than in the 38 offspring of normotensive parents so investigated. CONCLUSION These findings demonstrate that young normotensive humans in apparently excellent health but with one essential hypertensive parent tend to have an impairment of insulin-mediated glucose disposal, hyperinsulinemia, and dyslipidemia. It follows that a familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism that can be detected before or at least at a very early stage of the development of high blood pressure as judged by resting blood pressure measurements.

Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia

Background— Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results— We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3±1.2% versus 8.3±1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=−0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid–reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. Conclusions— Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies

Background— Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individuals susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. Methods and Results— We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. Conclusions— Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

Effects of Chronic Baroreceptor Stimulation on the Autonomic Cardiovascular Regulation in Patients With Drug-Resistant Arterial Hypertension

In patients with drug-resistant hypertension, chronic electric stimulation of the carotid baroreflex is an investigational therapy for blood pressure reduction. We hypothesized that changes in cardiac autonomic regulation can be demonstrated in response to chronic baroreceptor stimulation, and we analyzed the correlation with blood pressure changes. Twenty-one patients with drug-resistant hypertension were prospectively included in a substudy of the Device Based Therapy in Hypertension Trial. Heart rate variability and heart rate turbulence were analyzed using 24-hour ECG. Recordings were obtained 1 month after device implantation with the stimulator off and after 3 months of chronic electric stimulation (stimulator on). Chronic baroreceptor stimulation decreased office blood pressure from 185±31/109±24 mm Hg to 154±23/95±16 mm Hg (P<0.0001/P=0.002). Mean heart rate decreased from 81±11 to 76±10 beats per minute−1 (P=0.001). Heart rate variability frequency-domain parameters assessed using fast Fourier transformation (FFT; ratio of low frequency:high frequency: 2.78 versus 2.24 for off versus on; P<0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: −0.002 versus −0.015 for off versus on; P=0.004). In conclusion, chronic baroreceptor stimulation causes sustained changes in heart rate variability and heart rate turbulence that are consistent with inhibition of sympathetic activity and increase of parasympathetic activity in patients with drug-resistant systemic hypertension; these changes correlate with blood pressure reduction. Whether the autonomic modulation has favorable cardiovascular effects beyond blood pressure control should be investigated in further studies.

Diastolic dysfunction precedes myocardial hypertrophy in the development of hypertension

BACKGROUND Left ventricular (LV) hypertrophy and impaired diastolic function may occur early in systemic hypertension, but longitudinal studies are missing. METHODS We performed an echocardiographic follow-up study in young initially normotensive male offspring of hypertensive (OHyp) (n = 25) and normotensive (ONorm) (n = 17) parents. Blood pressure (BP), LV mass, and mitral inflow were determined at baseline and after 5 years. Pulmonary vein flow pattern assessment and septal myocardial Doppler imaging were additionally performed at follow-up. RESULTS At follow-up, BP was not significantly different between the two groups (128 +/- 11/84 +/- 10 v 123 +/- 11/81 +/- 5 mm Hg, OHyp v ONorm) but five OHyp had developed mild hypertension. LV mass index remained unchanged and was not different between the two groups at follow-up (92 +/- 17 v 92 +/- 14 g/m2). Diastolic echocardiographic properties were similar at baseline, but, at follow-up, the following differences were found: mitral E deceleration time (209 +/- 32 v 185 +/- 36 msec, P < .05) and pulmonary vein reverse A wave duration (121 +/- 15 v 107 +/- 12 msec, P < .05) were prolonged in the OHyp as compared to the ONorm. Compared to the normotensive subjects, the five OHyp who developed hypertension had more pronounced alterations of LV diastolic function, that is, significantly higher mitral A (54 +/- 7 v 44 +/- 9 cm/sec, hypertensives v normotensives, P < .05), lower E/A ratio (1.31 +/- 0.14 v 1.82 +/- 0.48, P < .05), increased systolic-to-diastolic pulmonary vein flow ratio (1.11 +/- 0.3 v 0.81 +/- 0.16, P < .005), longer myocardial isovolumic relaxation time (57 +/- 7 v 46 +/- 12 msec, P < .05) as well as smaller myocardial E (10 +/- 1 v 13 +/- 2 cm/sec, P < .05) and E/A ratio (1.29 +/- 0.25 v 1.78 +/- 0.43, P < .05), despite similar LV mass (91 +/- 16 v 93 +/- 18 g/m2). CONCLUSIONS Over a 5-year follow-up, initially lean, normotensive, young men with a moderate genetic risk for hypertension, developed Doppler echocardiographic alterations of LV diastolic function compared to matched offspring of normotensive parents. These alterations were more pronounced in the OHyp who developed mild hypertension and occurred without a distinct rise in LV mass.

Augmented vasoreactivity in adult life associated with perinatal vascular insult.

BACKGROUND Adverse environmental events occurring early in life have received little attention as predictors of disease in the later stages of life. At birth, the transition from gas exchange by the placenta to gas exchange by the lungs requires dramatic changes in the pulmonary circulation, which during this period is particularly vulnerable to noxious stimuli. We measured pulmonary-artery pressure responses to high-altitude exposure, a stimulus that causes pronounced pulmonary vasoconstriction, in young adults who had had transient perinatal hypoxic pulmonary hypertension and in controls of similar age and sex distribution. METHODS Review of neonatal-care records at the Lausanne University Hospital for Children identified 15 individuals who met the eligibility criteria (birth at > or = 34 weeks of gestation, persistence of hypoxaemia during ventilation with oxygen during the first week of life, and persistence of fetal circulation). Ten of these individuals agreed to take part; the control group was ten volunteers without any history of perinatal complications. Systolic pulmonary-artery pressure (by echocardiography) and arterial oxygen saturation were measured at baseline and at high altitude (4559 m). FINDINGS The mean increase in pulmonary-artery pressure at high altitude was significantly greater (p=0.01) in the participants who had had perinatal pulmonary hypertension (from 26.2 mm Hg [SD 2.1] to 62.3 mm Hg [7.3]) than in the controls (from 25.8 mm Hg [2.3] to 49.7 mm Hg [11.3]). The fall in arterial oxygen saturation was similar in the two groups. INTERPRETATION These findings suggest that a transient perinatal insult to the pulmonary circulation leaves a persistent and potentially fatal imprint, which when activated in adult life predisposes to a pathological response. Survivors of perinatal pulmonary hypertension may be at risk of developing this disorder in later life.

Insulin sensitivity and body fat distribution in normotensive offspring of hypertensive parents

Lean, healthy normotensive sons of essential hypertensive parents (OHyp) have lower insulin sensitivity (SI) than sons of normotensive parents (ONorm). We have tried to find out whether this disturbance in insulin metabolism is related to altered body fat distribution, fuel metabolism, or both. 21 OHyp and 21 ONorm of similar age and body-mass index were investigated after fasting overnight. Body composition was assessed by dual-energy X-ray absorptiometry and fuel metabolism by indirect calorimetry and urinary nitrogen excretion. Plasma insulin and glucose concentrations were measured during the frequent sampling intravenous glucose tolerance test, and SI was calculated by the minimum model method. Systolic blood pressure and heart rate were slightly but not significantly higher in OHyp than ONorm but the groups did not differ in fasting plasma insulin or glucose concentrations, carbohydrate or lipid oxidation, lean and fat mass, bone mineral content, or distribution of body fat. By contrast, SI was significantly lower in OHyp than ONorm (8.2 [0.7] vs 13.4 [1.5] 10(-4) L mU-1 min-1, p < 0.01). Within the whole study population upper-body fat mass was positively correlated with fasting plasma insulin (r = 0.33, p < 0.03) and lipid oxidation was positively correlated with SI (r = 0.35, p < 0.04) and negatively correlated with subscapular/triceps skinfold thickness (r = -0.43, p < 0.01). Thus, impairment of SI precedes both the development of overt hypertension and gain or redistribution of body fat. Therefore, the concept that SI is low as a result of altered fat distribution has to be reconsidered, at least in young male offspring of hypertensive parents.

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study

In this randomized, double‐blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6–76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8–78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0±0.7 vs 17.5±0.7 mm Hg; P=.0003 and 11.6±0.4 vs 10.4±0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP‐lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.

High-Altitude Pulmonary Edema: From Exaggerated Pulmonary Hypertension to a Defect in Transepithelial Sodium Transport

High-altitude pulmonary edema (HAPE) is a form of lung edema which occurs in otherwise healthy subjects, thereby allowing the study of underlying mechanisms of pulmonary edema in the absence of confounding factors. Exaggerated pulmonary hypertension is a hallmark of HAPE and is thought to play an important part in its pathogenesis. Pulmonary vascular endothelial dysfunction and augmented hypoxia-induced sympathetic activation may be underlying mechanisms contributing to exaggerated pulmonary vasoconstriction in HAPE. Recent observations by our group suggest, however, that pulmonary hypertension itself may not be sufficient to trigger HAPE. Based on studies in rats, indicating that perinatal exposure to hypoxia predisposes to exaggerated hypoxic pulmonary vasoconstriction in adulthood, we examined effects of high-altitude exposure on pulmonary-artery pressure in a group of young adults who had suffered from transient perinatal pulmonary hypertension. We found that these young adults had exaggerated pulmonary vasoconstriction of similar magnitude to that observed in HAPE-susceptible subjects. Surprisingly, however, none of the subjects developed lung edema. These findings strongly suggest that additional mechanisms are needed to trigger pulmonary edema at high-altitude. Observations in vitro, and in vivo suggest that a defect of the alveolar transepithelial sodium transport could act as a sensitizer to pulmonary edema. The aim of this article is to review very recent experimental evidence consistent with this concept. We will discuss data gathered in mice with targeted disruption of the gene of the alpha subunit of the amiloride-sensitive epithelial sodium channel (alpha ENaC), and present preliminary data on measurements of transepithelial sodium transport in vivo in HAPE-susceptible and HAPE-resistant mountaineers.

Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span

Children conceived by assisted reproductive technologies (ART) display a level of vascular dysfunction similar to that seen in children of mothers with preeclamspia. The long-term consequences of ART-associated vascular disorders are unknown and difficult to investigate in healthy children. Here, we found that vasculature from mice generated by ART display endothelial dysfunction and increased stiffness, which translated into arterial hypertension in vivo. Progeny of male ART mice also exhibited vascular dysfunction, suggesting underlying epigenetic modifications. ART mice had altered methylation at the promoter of the gene encoding eNOS in the aorta, which correlated with decreased vascular eNOS expression and NO synthesis. Administration of a deacetylase inhibitor to ART mice normalized vascular gene methylation and function and resulted in progeny without vascular dysfunction. The induction of ART-associated vascular and epigenetic alterations appeared to be related to the embryo environment; these alterations were possibly facilitated by the hormonally stimulated ovulation accompanying ART. Finally, ART mice challenged with a high-fat diet had roughly a 25% shorter life span compared with control animals. This study highlights the potential of ART to induce vascular dysfunction and shorten life span and suggests that epigenetic alterations contribute to these problems.