Damian Hutter

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.

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.

Coronary collateral flow in response to endurance exercise training.

Background In humans, it is not known whether physical endurance exercise training promotes coronary collateral growth. The following hypotheses were tested: the expected collateral flow reduction after percutaneous coronary intervention of a stenotic lesion is prevented by endurance exercise training; collateral flow supplied to an angiographically normal coronary artery improves in response to exercise training; there is a direct relationship between the change of fitness after training and the coronary collateral flow change. Methods and results Forty patients (age 61 ± 8 years) underwent a 3-month endurance exercise training program with baseline and follow-up assessments of coronary collateral flow. Patients were divided into an exercise training group (n = 24) and a sedentary group (n = 16) according to the fact whether they adhered or not to the prescribed exercise program, and whether or not they showed increased endurance (V o 2max in ml/min per kg) and performance (W/kg) during follow-up versus baseline bicycle spiroergometry. Collateral flow index (no unit) was obtained using pressure sensor guidewires positioned in the coronary artery undergoing percutaneous coronary intervention and in a normal vessel. In the vessel initially undergoing percutaneous coronary intervention, there was an increase in collateral flow index among exercising but not sedentary patients from 0.155 ± 0.081 to 0.204 ± 0.056 (P=0.03) and from 0.189 ± 0.084 to 0.212 ± 0.077 (NS), respectively. In the normal vessel, collateral flow index changes were from 0.176 ± 0.075 to 0.227 ± 0.070 in the exercise group (P=0.0002), and from 0.219 ± 0.103 to 0.238 ± 0.086 in the sedentary group (NS). A direct correlation existed between the change in collateral flow index from baseline to follow-up and the respective alteration of V o 2max (P=0.007) and Watt (P=0.03). Conclusion A 3-month endurance exercise training program augments coronary collateral supply to normal vessels, and even to previously stenotic arteries having undergone percutaneous coronary intervention before initiating the program. There appears to be a dose–response relation between coronary collateral flow augmentation and exercise capacity gained.

Systemic Vascular Dysfunction in Patients With Chronic Mountain Sickness

BACKGROUND Chronic mountain sickness (CMS) is a major public health problem characterized by exaggerated hypoxemia and erythrocytosis. In more advanced stages, patients with CMS often present with functional and structural changes of the pulmonary circulation, but there is little information on the systemic circulation. In patients with diseases associated with chronic hypoxemia at low altitude, systemic vascular function is altered. We hypothesized that patients with CMS have systemic vascular dysfunction that may predispose them to increased systemic cardiovascular morbidity. METHODS To test this hypothesis, we assessed systemic endothelial function (by flow-mediated dilation [FMD]), arterial stiffness, and carotid intima-media thickness and arterial oxygen saturation (Sao(2)) in 23 patients with CMS without additional classic cardiovascular risk factors and 27 age-matched healthy mountain dwellers born and permanently living at 3,600 m. For some analyses, subjects were classified according to baseline Sao(2) quartiles; FMD of the highest quartile subgroup (Sao(2) ≥ 90%) was used as a reference value for post hoc comparisons. RESULTS Patients with CMS had marked systemic vascular dysfunction as evidenced by impaired FMD (CMS, 4.6% ± 1.2%; control subjects, 7.6% ± 1.9%; P < .0001), greater pulse wave velocity (10.6 ± 2.1 m/s vs 8.4 ± 1.0 m/s, P < .001), and greater carotid intima-media thickness (690 ± 120 μm vs 570 ± 110 μm, P = .001). A positive relationship existed between Sao(2) and FMD (r = 0.62, P < .0001). Oxygen inhalation improved (P < .001) but did not normalize FMD in patients with CMS, although it normalized FMD in hypoxemic control subjects (Sao(2) < 90%) and had no detectable effect in normoxemic control subjects (Sao(2) ≥ 90%). CONCLUSIONS Patients with CMS show marked systemic vascular dysfunction. Structural and functional alterations contribute to this problem that may predispose these patients to premature cardiovascular disease. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Exercise induces rapid interstitial lung water accumulation in patients with chronic mountain sickness.

BACKGROUND Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world. In its more advanced stages, exercise intolerance is often found, but the underlying mechanism is not known. Recent evidence indicates that exercise-induced pulmonary hypertension is markedly exaggerated in CMS. We speculated that this problem may cause pulmonary fluid accumulation and aggravate hypoxemia during exercise. METHODS We assessed extravascular lung water (chest ultrasonography), pulmonary artery pressure, and left ventricular function in 15 patients with CMS and 20 control subjects at rest and during exercise at 3,600 m. RESULTS Exercise at high altitude rapidly induced pulmonary interstitial fluid accumulation in all patients but one (14 of 15) with CMS and further aggravated the preexisting hypoxemia. In contrast, in healthy high-altitude dwellers exercise did not induce fluid accumulation in the majority of subjects (16 of 20) (P = .002 vs CMS) and did not alter arterial oxygenation. Exercise-induced pulmonary interstitial fluid accumulation and hypoxemia in patients with CMS was accompanied by a more than two times larger increase of pulmonary artery pressure than in control subjects (P < .001), but no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension (P < .01) and interstitial fluid accumulation (P < .05) in patients with CMS but had no detectable effects in control subjects. CONCLUSIONS To our knowledge, these findings provide the first direct evidence that exercise induces rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS that appear to be related to exaggerated pulmonary hypertension. We suggest that this problem contributes to exercise intolerance in patients with CMS. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Respiratory Nitric Oxide and Pulmonary Artery Pressure in Children of Aymara and European Ancestry at High Altitude

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

Regional left ventricular function during transient coronary occlusion: relation with coronary collateral flow

Objective: To test the hypothesis that regional left ventricular (LV) function during balloon angioplasty is related to the amount of collateral flow to the ischaemic region. Design: Prospective study. Setting: Tertiary referral centre. Methods: In 50 patients with coronary artery disease and without myocardial infarction, regional systolic and diastolic LV function was determined using tissue Doppler ultrasound (TD) before and at the end of a 60 second occlusion of a stenotic lesion undergoing percutaneous transluminal coronary angioplasty (PTCA) through a pressure guidewire. The study population was subdivided into a group with collaterals insufficient (n = 33) and one with collaterals sufficient (n = 17) to prevent ECG ST shifts suggestive of myocardial ischaemia during PTCA. Pulsed TD was performed from an apical window in the myocardial region supplied by the vessel being treated by PTCA. Pressure derived collateral flow index (CFI) was determined by simultaneous measurement of mean aortic (Pao) and distal intracoronary occlusive pressures (Poccl), where CFI = (Poccl − 8)/(Pao − 8). Results: At 60 seconds of occlusion, several parameters of systolic and diastolic TD derived LV long axis function were significantly different between the groups. Also, there was a significant correlation between regional systolic excursion velocity, early diastolic excursion velocity, regional isovolumetric relaxation time, and CFI. Conclusion: During brief coronary artery occlusions, regional systolic and diastolic LV function is directly related to the amount of collateral flow to this territory.

Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

Increased central body fat deposition precedes a significant rise in resting blood pressure in male offspring of essential hypertensive parents: a 5 year follow-up study.

Objectives As long as offspring of essential hypertensive parents (OHyp) are lean, their blood pressure usually remains within normal limits. The mechanism(s) transforming this ‘genetically dysregulated normotension’ into hypertension are unclear. We hypothesized that OHyp are not only genetically prone to develop hypertension, but may also have a particular propensity to accumulate central body fat. Design A 5-year follow-up cohort study. Setting University Hospital in Switzerland. Participants Seventeen young (25 ± 1 years, mean ± SD), lean healthy normotensive male OHyp and 17 age- and sex-matched offspring of normotensive parents (ONorm) paired for baseline blood pressure with the OHyp. Main outcome measures Resting and exercise blood pressure, body weight, body mass index (BMI) and waist-to-hip ratio were assessed at baseline and after 5 years. Results At baseline, body weight, BMI, waist-to-hip ratio and blood pressure did not differ significantly between OHyp and ONorm. At follow-up, body weight was increased in both groups (from 73.9 ± 6.0 to 77.7 ± 8.1 kg in OHyp, P = 0.008, and from 71.5 ± 6.9 to 73.5 ± 6.6 kg in ONorm, P = 0.03). BMI followed a similar pattern. In contrast, waist-to-hip ratio increased in OHyp (from 0.84 ± 0.03 to 0.87 ± 0.03, P = 0.012), but not in ONorm (from 0.84 ± 0.03 to 0.84 ± 0.04, P = 0.79) and was therefore higher in OHyp at follow-up (P = 0.011, OHyp versus ONorm). Peak systolic blood pressure during dynamic exercise also rose at 5 years in the OHyp (from 182 ± 10 to 214 ± 17 mmHg, P = 0.0001) while resting systolic blood pressure only tended to do so (from 121 ± 7 to 128 ± 12 mmHg, P = 0.07). In ONorm, resting and peak dynamic exercise systolic blood pressure remained unchanged (119 ± 11 versus 121 ± 9 mmHg, baseline versus follow-up, P = 0.40, and 186 ± 12 versus 196 ± 22 mmHg, P = 0.10, respectively). Thus, systolic peak exercise blood pressure was significantly (P = 0.014) elevated at follow-up in OHyp compared to ONorm, while resting systolic blood pressure only tended (P = 0.06) to do so. Conclusions Initially lean normotensive OHyp have a disparate long-term course of central body fat as compared to ONorm. Thus, OHyp are not only genetically prone to develop hypertension, but they also have a particular propensity to accumulate central body fat, even before a distinct rise in resting blood pressure occurs. The exaggerated blood pressure response to exercise observed at follow-up in the OHyp represents another marker that confers them a greater risk of developing future hypertension.

Radial artery compliance in response to mental stress in normotensive offspring of hypertensive parents.

Objectives: Compared to normal subjects hypertensive patients have an increased radial artery isobaric distensibility, contrasting with a decrease in elasticity of large arteries and systemic compliance. To address the question whether elasticity is increased in response to long-standing elevated blood pressure or is present at an early stage of the disease, we compared normotensive offspring of hypertensive parents with control subjects. Furthermore, enhanced sympathetic response to mental stress was demonstrated in individuals predisposed to hypertension and might contribute to the elevation of blood pressure via a peripheral mechanism. Thus, anabnormal vasoconstrictive response of the radial artery to psychological stress was sought in these subjects. Design:The geometry and the elastic porperties of the radial artery were assessed in normotensive offspring of hypertensive and normotensiven parents at baseline and during mental stress. Methods:A high-precision echo-tracking ultrasound device was combined with photoplethysmography for continuous measurement of radial artery diameter and isobaric distensibility in 18 normotensive offspring of parents with essential hypertension and 18 control subjects under resting conditions and during a 3-minute mental stress test. Results: Baseline arterial distensibility and compliance were comparable in offspringof hypertensive and normotensive parents. During mental stress, blood pressure and heart rate increased similarly in both groups. Adrenergic activation did not alter the elastic properties of the radial artery in the individuals with a genetic predisposition to essential hypertension. Conclusions:There was no alteration in elastic properties of the radial artery in normotensiven individuals at genetic risk to develop arterial hypertension. Furthermore, mental stress did not abnormally increase the vascular tone of this medium-sized muscular artery in these subjects as compared to controls. This indicates that functional and/or structural vascular alterations do not precede a distinct rise in blood pressure or abnormal blood pressure reactivity in subjects prone to develop essential hypertension.