Jaap H. J. Muntinga

Feasibility and impact of the measurement of extracellular fluid volume simultaneous with GFR by 125I-iothalamate.

The feasibility, validity, and possible applications of the assessment of extracellular fluid volume (ECFV) simultaneous with glomerular filtration rate (GFR) were assessed in a series of validation studies using the constant infusion method of (125)I-iothalamate (IOT). In 48 subjects with a broad range of GFR, distribution volume (V(d)) of IOT corresponded well with V(d) bromide (16.71 +/- 3.0 and 16.73 +/- 3.2 l, respectively, not significant), with a strong correlation (r = 0.933, P < 0.01) and without systematic deviations. Reproducibility assessment in 25 healthy male subjects showed coefficients of variation of 8.6% of duplicate measurement of V(d) IOT during strictly standardized (50 mmol Na(+)/d) sodium intake. An increase in dietary sodium intake (200 mmol Na(+)/d) induced a corresponding rise in V(d) IOT of 1.11 +/- 1.5 l (P < 0.01). In 158 healthy prospective kidney donors, the impact of indexing of GFR to ECFV was analyzed. Age, gender, height, and body surface area (BSA) were determinants of GFR. Whereas GFR, GFR/BSA, and GFR/height were gender-dependent, GFR/ECFV was gender-independent and not related to height or BSA. This supports the potential of normalizing GFR by ECFV. Thus, ECFV can be simultaneously assessed with GFR by the constant infusion method using IOT. After appropriate validation, also other GFR tracers could be used for such a simultaneous estimation, providing a valuable resource of data on ECFV in renal studies and, moreover, allowing GFR to be indexed to the body fluid compartment it clears: the ECFV.

Rise in extracellular fluid volume during high sodium depends on BMI in healthy men.

A high sodium (HS) intake is associated to increased cardiovascular and renal risk, especially in overweight subjects. We hypothesized that abnormal sodium and fluid handling is involved, independent of hypertension or insulin resistance. Therefore, we studied the relation between BMI and sodium‐induced changes in extracellular fluid volume (ECFV; distribution volume of 125I‐iothalamate) in 78 healthy men, not selected for BMI. A total of 78 subjects with a median BMI of 22.5 (range: 19.2–33.9 kg/m2) were studied after 1 week on a low sodium (LS) diet (50 mmol Na+/d) and after 1 week on HS (200 mmol Na+/d). The change from LS to HS resulted in an increase in ECFV of 1.2 ± 1.8 l. Individual changes in ECFV were correlated to BMI (r = 0.361, P < 0.01). Furthermore, in response to HS, a higher BMI was associated to a higher rise in filtered load of sodium (FLNa+ = [Na+] × GFR, r = 0.281, P < 0.05). Thus, a shift to HS leads to a larger rise in ECFV in healthy subjects with higher BMI, associated with an elevated FLNa+ during HS. Although no hypertension occurred in these healthy subjects, our data provide a potential explanation for the interaction of sodium intake and BMI on cardiovascular and renal risk. Exaggerated fluid retention may be an early pathogenic factor in the cardiorenal complications of overweight.

Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics

Several studies have demonstrated the beneficial effects of 3 hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on vascular properties, but little is known about treatment intensification. We compared patients in whom statins were started (INITIAL, n=30) for hypercholesterolaemia (>6.5 mmol l(-1)) with a matched patient group of long-time statin users, with similar baseline characteristics for lipids, intima-media thickness (IMT), and pulse wave velocity, in whom treatment with statins was intensified (LONG-TERM, n=54). At baseline and after 1 year, lipid profile, IMT of the carotid and femoral arteries, aortic distensibility using pulse-wave velocity and various properties of the peripheral vascular bed using a recently developed bio-impedance method were measured. After 1 year the relative changes in lipid profile were significantly better in the INITIAL compared with the LONG-TERM-group. The relative changes in IMT of the mean internal carotid and common femoral arteries significantly differed between the INITIAL and LONG-TERM-group (-8 and +11%, -11 and +22%, respectively). After 1 year, in both groups, most other vascular wall characteristics were unaltered compared with baseline. In conclusion, the beneficial structural alterations of the vascular wall were greater after starting than after intensifying already existing lipid-lowering treatment. This suggests that other effects of HMG-CoA reductase inhibitors than lipid-lowering alone must be involved in vascular changes.

Reversal of pathophysiologic changes with long-term lisinopril treatment in isolated systolic hypertension

The purpose of this study was to evaluate in a prospective, double-blind, placebo-controlled study the effect of long-term (2-year) lisinopril treatment on cardiovascular end-organ damage in patients with previously untreated isolated systolic hypertension (ISH). All patients with ISH were derived from a population screening program. End-organ damage measurements, done initially and after 6 and 24 months of treatment, included measurements of aortic distensibility and echocardiographic left ventricular mass index (LVMI) and diastolic function. Blood pressure was measured by office and ambulatory measurements. Of the 97 subjects with ISH selected from the screening, 62 (30 lisinopril) completed the study according to protocol. Office blood pressure decreased in both groups, but ambulatory results significantly decreased with lisinopril-treatment only. Aortic distensibility increased significantly with lisinopril, as opposed to a decrease in placebo-treated subjects. The main effect of increased distensibility occurred between 6 and 24 months, whereas ambulatory blood pressure changed mainly in the first 6 months of treatment. LVMI decreased in both treatment groups, with a significantly higher reduction in lisinopril-treated subjects. Left ventricular diastolic function showed no significant changes in either group. The vascular pathophysiologic alterations of ISH—a decreased aortic distensibility—can be improved with long-term lisinopril treatment, whereas values deteriorate further in placebo-treated subjects. These results, in one of the first studies including subjects with previously untreated ISH only, indicate that lisinopril treatment might favorably influence the cardiovascular risk of ISH.

Redistribution of blood volume in Type I diabetes

Aims/hypothesis. Impaired activity of endothelium-derived nitric oxide in Type I (insulin-dependent) diabetes mellitus will cause an increased vascular tone. Considering the lower production of nitric oxide in veins than in arteries, an impaired activity would have less vasoconstrictive effect in veins. The reported minimally changed total plasma volume in diabetes might, therefore, indicate a redistribution of blood volumes from the arterial to the venous side of the circulation. This could be more pronounced in patients with microalbuminuria. Methods. In 16 normoalbuminuric and 16 microalbuminuric Type I diabetic patients and 16 individually matched healthy control subjects, venous and arterial blood volumes, venous myogenic response and arterial distensibilities were assessed in the upper arm using an electrical bio-impedance method. Results. In diabetic patients, the venous blood volume and venous myogenic response were increased (p < 0.02 and p < 0.05, respectively), whereas the arterial blood volume did not change. Moreover, in diabetic patients the distensibility of the large arteries was decreased (p < 0.05) but increased in the total arterial bed (p < 0.05). Therefore, the distensibility of the small arteries must have been increased. No differences were found between normoalbuminuric and microalbuminuric diabetic patients. Conclusion/interpretation. The increase in venous blood volume and myogenic response and the decrease in distensibility of the large arteries in the upper arm are in agreement with the expected shift towards venous blood volume distribution in Type I diabetes with and without microalbuminuria. Furthermore, they support the haemodynamic hypothesis of the pathogenesis of diabetic microangiopathy. [Diabetologia (2001) 44: 429–432]

Isolated systolic hypertension from a vascular point of view.

Due to the results of antihypertensive intervention studies, isolated systolic hypertension (ISH) has gained new interest lately. Yet, apart from increased aortic stiffness, the specific pathophysiological features of ISH have remained largely undetermined. Therefore, we investigated the elastic properties of the vascular bed of an upper arm segment in uncomplicated ISH patients and matched normotensive controls using an electrical bioimpedance technique. Compared with the controls, the compliance of the arterial bed as a whole at normotensive blood pressure level was on the average 108.0% higher (p < 0.005) in the hypertensive patients. The blood volume of the arterial bed as a whole at operating blood pressure level and that of the larger arteries were significantly higher (40.5%, p < 0.05, and 40.5%, p < 0.01, respectively). The same held true for the venous blood volume (64.4%, p < 0.05), and for the width of the arterial compliance-pressure relation (34.6%, p < 0.01). We concluded that ISH is a separate pathophysiological entity in which all parts of a peripheral vascular bed are changed and the decreased buffering function of the aorta and large arteries is partly compensated for by an increase in small artery compliance.

Age-Related Differences in Elastic Properties of the Upper Arm Vascular Bed in Healthy Adults

The significance of age-related changes in arterial stiffness has remained largely uncertain in healthy subjects. This appears to be partly due to difficulties in the interpretation of methods for measuring arterial stiffness in vivo. Therefore, a recently developed electrical bioimpedance method was used for studying elastic properties of a vascular bed as a function of age. In 66 healthy subjects, aged 22-82 years, we investigated the vascular bed of an upper arm segment. This vascular bed showed an age-related decrease in the venous blood volume (r = -0.31, p < 0.01) and in the distensibility, the inverse of stiffness, of the larger arteries (r = -0.38, p < 0.001). The distensibility of the arterial bed as a whole at normotensive blood pressure, however, appeared to increase with age (r = 0.32, p < 0.005). The arterial and venous blood volumes, arterial compliance and extravascular fluid volume were significantly higher in the males than in the females. Practically all investigated vascular properties appeared to be related with height, body mass or body mass index. We concluded that comparative studies concerning vascular properties should preferably be performed in subjects matched as to age, gender, height and body mass. In healthy subjects the smaller arteries adjust to the age-related decrease in large artery distensibility by means of an age-related increase in distensibility. These age-related changes in arterial distensibility are caused by changes in the females, and seem to be associated with age-related changes in body mass index rather than with aging per se.

Investigation of the arterial and venous upper arm vascular bed

Studies concerning vascular changes in hypertension and exercise have shown an increasing need to investigate the properties of a complete vascular bed in vivo. In this study, the repeatability of a non-invasive method for quantifying properties of the vascular bed of an upper arm segment, was investigated in two groups of volunteers (age 22-55 years). One group of subjects (n = 9) were measured twice at a 15 min interval. The other group (n = 8) were measured 4 times with each subject measured daily at the same time. The estimated quantities included the arterial and venous blood volume, the static arterial compliance, the myogenic response of the arm veins and the extravascular fluid volume of the tissue under an occluding cuff at the upper arm. They not only describe properties of the arterial vascular bed as a whole but also of different sized arteries functioning at different intra-arterial pressure. They were derived from the fluid shifts under the occluding cuff that arise when cuff pressure changes, as determined by electrical impedance and blood pressure measurements. The repeatability of the method was well within the physiologically acceptable range and of the same order of magnitude as that of established methods. Established methods however, provide less information about the properties of a vascular bed and result in controversial estimates of the dynamic arterial compliance. Furthermore, the method eliminates the need to match subjects in comparative studies for arterial blood pressure. These features and the sensitivity of the method for (patho)physiological changes, offer the possibility to investigate in vivo many still unknown aspects of the peripheral circulation.

Blood Pressure Estimation Investigated By Electric Impedance Measurement

The electrical impedance of the left upper arm at changing cuff pressure was measured, together with the finger arterial blood pressure of the other arm at 13 healthy volunteers (66 f 5 yr). Apart from systolic, diastolic and mean arterial pressure, the arterial blood volume per centimetre length (1.4 f 0.3 ml/cm), the venous blood volume as a percentage of the total blood compartment (49.2 f 12.6 %), and the total arterial compliance as a function of mean arterial transmural pressure were estimated, based on a model for the impedance response. The effective physiological arterial compliance amounted to 2.0 2 1.3, the maximum compliance to 33.4 2 12.0 pl.(mmHg)-l.cm-l and the extravascular fluid volume expelled by the cuff to 0.3 2 0.3 ml/cm. These quantities have a close relation with patient-related sources of unreliable blood pressure measurements.

Properties of the upper arm vascular bed investigated by electrical impedance measurements in healthy subjects

The fluid shifts of an upper arm tissue segment under an occluding cuff were estimated from electrical impedance measurements. This was done using parameter estimation with a model. The model included parameters describing the arterial and venous pressure-volume relationship. To gain insight into the precision of the method, repeated measurements were made on healthy volunteers. Most parameters showed a large variation (13–44 %). This variation could only partly be explained by variations in the measured quantities.