(Circulation. 2000;102:319.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Plasma Disappearance of Albumin and Impact of Capillary Thickness in Idiopathic Dilated Cardiomyopathy and After Heart Transplantation
From the Heart Center, the Rigshospital, Copenhagen (S.G., H.W.,V.B.S., J.K.); the Department of Cardiology, Hvidovre Hospital, Copenhagen (L.-B.H.); and the Department of Pathology, Hillerød Hospital, Hillerød (T.N.), Denmark.
Correspondence to S. Galatius, MD, The Heart Center B2014, The Rigshospital, DK 2100 Copenhagen Ø, Denmark. Galatius@dadlnet.dk
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Abstract |
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Background—The increased plasma disappearance of albumin has previously been described in decompensated congestive heart failure (CHF); this disappearance normalized after diuretic treatment. Cardiac transplantation (HTX) and current medical treatment affect microvascular structure and function. We investigated the plasma disappearance of albumin and the impact of microvascular thickness and electrostatic properties in patients with compensated CHF and after HTX.
Methods and Results—The fraction of intravascular albumin that passes to the extravascular space per unit time, as determined from the plasma disappearance of intravenously injected 131I-labeled albumin, was increased to 7.8±1.7% in 16 patients with CHF compared with 18 controls (6.5±1.9%, P<0.05); these levels normalized after HTX (5.8±2.6%, P<0.01, n=17). The change in ratio between 131I-albumin and simultaneously injected negatively charged glycosylated 125I-albumin (selectivity index, >1/hour in controls) was lower in patients with HTX (0.993±0.022/hour) than in controls (1.008±0.019/hour; P<0.05), which indicated a relatively increased plasma disappearance of negatively charged albumin in HTX patients. Capillary basement membrane thickness was evaluated semiquantitatively from skin biopsies and showed no difference in the 3 groups (control, CHF, and HTX patients). However, in all 3 study groups, subjects with thicker capillary basement membranes had lower albumin escape rates (6.1±1.8%, n=32, versus 7.6±2.6% in subjects without thickening of capillary basement membranes, n=19; P<0.05).
Conclusions—The plasma disappearance of albumin increased in patients with compensated CHF and it normalized after HTX. The present normalized capillary basement thicknesses in patients with CHF and the direct association between this parameter and plasma albumin disappearance indicate that previous compensatory microvascular basement membrane growth results in restricted permeability. Microvascular electrostatic properties did not relate to plasma albumin disappearance.
Key Words: heart failure • microcirculation • serum albumin • permeability
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Introduction |
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Both regulatory and structural abnormalities of peripheral microcirculation are present in patients with congestive heart failure (CHF).1 Cardiac transplantation (HTX) and long-term treatment with angiotensin-converting enzyme (ACE) inhibitors seem to reverse some of these abnormalities.1 2 3 However, edema may still be present both before and after HTX.1 One of several factors in the pathogenesis of peripheral edema may be the increased loss of intravascular albumin, which may be influenced by the degree of microvascular abnormalities. More than 2 decades ago, Hesse et al4 demonstrated that the plasma disappearance of albumin was increased in patients with decompensated CHF and peripheral edema; however, these levels normalized after 1 to 2 weeks of diuretic treatment. In accordance with this observation, short-term volume expansion increased the transcapillary escape rate of albumin (TERalb) in healthy controls.5 TERalb was directly related to right atrial pressure in these studies,4 5 but it was normal in patients who had elevated right atrial pressure due to chronic obstructive lung disease with pulmonary hypertension.6 TERalb is also related to mean arterial pressure in both type 1 diabetes and essential hypertension.7 However, treatment with ACE inhibitors, which is a cornerstone of the modern treatment of CHF, reduced TERalb in normotensive patients with type 1 diabetes.8 Thus, factors other than those which are directly pressure- and volume-dependent seem to be of importance to the degree of plasma albumin disappearance. The degree of plasma albumin disappearance is unknown in CHF patients who are treated with modern treatment modalities, and it has never been investigated after HTX.
The electrostatic properties of the microvascular wall may have a barrier function; the disappearance of albumin and the disturbance of the electrostatic properties of the vascular wall were most pronounced in diabetic patients with nephropathy.9 Such patients also had the highest degree of thickening in the basement membranes of terminal arterioles and capillaries.10 This resembles the structural microangiopathy found in CHF.11 However, the pathogenesis of this thickening may be different because it may be more metabolically dependent in diabetes and more pressure dependent in CHF.1 11 12 The roles played by the thickening of capillary basement membranes and the electrostatic properties of the vessel wall on the loss of intravascular albumin are unknown in patients with CHF and after HTX.
The aims of the present study were (1) to determine the plasma disappearance of albumin in patients with compensated CHF caused by idiopathic dilated cardiomyopathy (IDCM) who are treated with long-term ACE inhibition and/or HTX and (2) to test the impact of capillary thickness and the electrostatic properties of the vessel wall on plasma albumin disappearance.
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Methods |
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Subjects
Demographic data are given in Table 1
. The study population consisted of 18
healthy control subjects, 16 patients with CHF due to IDCM, and 17
patients who had HTX because of end-stage CHF due to IDCM. Four
patients were studied both before and after HTX. All subjects were
male, and the groups were age-matched. The diagnosis of IDCM was based
on clinical and hemodynamic findings. No patient had a
history of diabetes, hypertension, chronic obstructive lung
disease, angina, or myocardial infarction.
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All heart transplant recipients were clinically stable and free from
clinical or biopsy-verified rejection, infection, or other major
illness. All patients with CHF were treated with diuretics
(mean furosemide-equivalent dose, 100 mg; range, 20 to 300 mg) and an
ACE inhibitor (mean captopril-equivalent dose, 100 mg;
range, 37.5 to 150 mg). In addition, 13 patients with CHF were also
treated with digoxin (mean dose, 312.5 µg; range, 125 to 500 µg),
11 were treated with anticoagulants, 3 with aspirin, and 1 with a
calcium antagonist from the
dihydropyridine class. Because all the patients in
the present study had CHF due to IDCM, the disease was diagnosed at
the time of first symptoms of CHF. Treatment with ACE
inhibitors and diuretics began at the time of
diagnosis for all patients who had their first symptoms <3 years
before this study took place; treatment had lasted 
3 years in
patients who were diagnosed earlier. After HTX, all patients were
treated with triple immunosuppression, including
cyclosporine, azathioprine, and low-dose glucocorticoid. In
addition, 12 HTX patients were treated with diuretics, 14 were
on aspirin, and 10 were treated with a calcium antagonist
from the dihydropyridine class.
Because the aim of the study was to investigate patients in the
clinical setting, all medication was continued, and patients’ diets
were not modified. The patients had been stable without any change in
medication for 4 weeks before the study. All patients were in a
compensated state, ie, no jugular venous stasis, no basal
pulmonary rales, no signs of congestion at x-ray, no clinical
signs of ascites, and no peripheral edema. All subjects
gave written informed consent, and the protocol was approved by the
local ethics committee. The study conforms with the guidelines of the
Declaration of Helsinki.
Procedure
The investigations were performed in the morning after an
overnight fast. The subjects were lightly dressed and placed in the
supine position. Room temperature was kept constant during the
investigations at 
23°C. A canula was inserted into the antecubital
vein of both forearms. The right arm was placed on a heating cushion to
ensure abundant blood flow and the immediate mixing of injected
albumin. Investigations began after a minimum of 30 minutes in
the supine position. Arterial blood pressure was measured
at the upper arm with a standard clinical sphygmomanometer at heart
level; diastolic blood pressure was recorded at
Korotkoff phase 5.
TERalb
The procedure and theoretical basis for the calculation of
TERalb have been described in detail
previously.13 14 Briefly, 4 to 8 µCi of nonglycosylated
131I-albumin and glycosylated
125I-albumin (both tracers from
Kjeller) produced from human serum albumin by
electrolytic labeling were injected simultaneously. Both
tracer preparations were approved for use in humans and contained <1%
free radioactive iodide. The radiolabeled nonglycosylated
albumin was demonstrated by metabolic studies to
behave like endogenous albumin,13 and
glycosylation did not seem to alter
metabolism.15 The tracer preparations were
injected into the vein of one arm, and 5-mL blood samples were drawn
from the opposite arm at 2, 10, 15, 20, 30, 40, 50, and 60 minutes to
determine TERalb. Plasma radioactivity was
counted in duplicate in each sample, and the counts were corrected for
radio decay. To correct for changes in plasma water during the
TERalb measurements, counts were expressed as
cpm/µmol albumin. After logarithmic transformation of this
ratio, TERalb was determined from the slope of
the regression line.13
Plasma volume was calculated from the radioactivity at time zero by retropolation of the plasma disappearance curve and the injected amount of radioiodinated albumin, as measured by weighing the syringes before and after injection. The intravascular mass of albumin equals the plasma volumexplasma concentration of albumin. The serum albumin concentration was determined with a coefficient of variation of <3% on a Hitachi 917 by immunoturbidimetry with reagents from Dakopatts A/S using the procedure recommended by the manufacturer. The outflux of albumin (µmol/hour) was calculated by multiplying the intravascular mass of albumin (mmol) by the TERalb measurement. Finally, the volume of plasma water cleared for albumin (mL · kg-1 · min-1) was calculated by multiplying plasma volume and TERalb.13 15
Selectivity Index
The theoretical basis for the comparison of the plasma
disappearance of nonglycosylated/glycosylated labeled albumin
by calculating the selectivity index was described in detail by
Bent-Hansen et al.15 16 The glycosylation of
125I-albumin was performed in sterile,
closed vials. The incubation mixture consisted of 4 µCi of
125I-albumin 0.03 mg/µCi,
550 mmol/L glucose, and 0.9% benzylic alcohol in 25 mmol/L
phosphate buffer (pH 7.8) to a final volume of 2.0 mL. Before use, the
vials were kept incubated at 37°C for 48 hours. At all other times,
they were kept at a temperature <4°C. This procedure results in a
degree of glycosylation of 5.5 mol of glucose per mol albumin.
Glycosylation increases the net anionic charge of the
compound17 without significantly altering its
size.18 The selectivity index is the
131I-albumin/125I-albumin
clearance ratio per hour, and it expresses the relative disappearance
of nonglycosylated versus glycosylated albumin. It will be >1
in controls,16 and it is calculated from the slope of the
correlation line (method of least squares) of the zero ratio (the
sample at 2 minutes was drawn to determine the zero ratio) divided
by the ratio at 10, 15, 20, 30, 40, 50, and 60 minutes. The comparison
of the simultaneously determined plasma activities, instead
of comparing the calculated TER of nonglycated
albumin and that of glycated albumin, yields a much
more sensitive analysis, which cancels some of the considerable
variation in the calculation of TER.16
Histological Examination
The histological examination was performed as
previously described.11 In brief, sections from cutaneous
biopsies of the lower leg were used for a blinded, light microscopic,
semiquantitative grading of the thickness of basement membranes in
terminal arterioles and capillaries (Figure 1). Grading was as follows: grade 1, no
thickening (Figure 1A); grade 2, thickening comprising <50% of
the vascular wall; grade 3, thickening comprising >50% but not the
entire circumference of the vessel (Figure 1B); and grade 4,
thickening and severe narrowing of the entire vessel.
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Statistics
Normally distributed data according to Shapiro Wilk’s W test
were compared between groups by 1-way ANOVA and, if significant, by
Student’s t test for unpaired data. When data were not
normally distributed, the corresponding nonparametric test
was used. Fischer’s exact test was used to test for differences in
vascular structure between the groups. Simple regression
analysis was performed between relevant parameters
and albumin permeability parameters and
histological grading of biopsies. In all
analysis, P<0.05 was considered significant. Values
are presented as mean±SD in the text and as mean±SE in
figures, if not otherwise indicated.
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Results |
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Systolic and diastolic blood pressures and serum creatinine levels were significantly higher in cardiac transplant recipients than in controls and CHF patients; the latter 2 groups did not differ from each other. CHF patients and cardiac transplant recipients had significantly higher heart rates than controls. The cardiac transplant recipients had the highest heart rates (Table 1
).
Albumin Permeability Parameters
The albumin permeability parameters are listed
in Table 2. Plasma volume did not differ
significantly between the 3 groups, although patients with HTX tended
to have the lowest plasma volume (borderline significance compared with
CHF patients, P=0.08; not significant compared with
controls). An inverse correlation existed between time since HTX and
plasma volume (r=-0.47, P<0.05).
TERalb was highest in CHF patients and lowest in
patients after HTX. The plasma volume clearance of albumin was
significantly higher in CHF patients compared with controls and HTX
patients. The serum albumin concentration was lower in HTX
patients compared with controls and CHF patients, as was the total
plasma content of albumin (intravascular mass of
albumin). Thus, the resulting total flux of albumin
across the capillary membrane was significantly higher in CHF patients
than in controls or HTX patients; the latter 2 groups differed little
(borderline significance of P=0.06). The
TERalb, plasma volume, intravascular mass of
albumin, and albumin flux in the 4 patients
investigated before and after HTX generally showed a pattern similar to
that found in the entire population (Figure 2).
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The plasma disappearance of the nonglycosylated albumin
versus negatively charged glycosylated albumin expressed as the
selectivity index (change in simultaneous transport ratio
per hour) showed a significant difference between cardiac transplant
recipients and the control group; the plasma disappearance of
nonglycosylated albumin was favored in controls (Table 2).
Microvascular Histology and Albumin Transport
The semiquantitative light microscopic examination showed a
thickening of basement membranes in terminal arterioles and in
capillaries in a number of subjects in all 3 study groups; none of the
groups differed from each other (Table 2). However, subjects
from all 3 groups with thickening of the capillary basement membranes
(grade 2 to 3) showed significantly lower TERalb
levels than subjects without thickening of the capillary basement
membrane (6.1±1.8%, n=32, versus 7.6±2.6%, n=19;
P<0.05; Figure 3). The
pattern was similar in the 3 individual study groups as well, although
it was only significant in controls (P<0.05; Figure 3). The subjects with basement membrane thickening of the
capillaries also had higher serum albumin levels than subjects
without thickening (641±78 versus 580±63 mmol/L;
P<0.01).
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Discussion |
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The major finding of this study is that compensated patients with CHF caused by IDCM have an increased plasma albumin disappearance that normalizes after HTX. In addition, the thickening of capillary basement membranes is associated with a reduced plasma albumin disappearance and a higher plasma albumin level in patients with CHF before and after HTX, as well as in healthy control subjects; neither patient group differed from controls in capillary morphology. Finally, after HTX, patients seem to have a reduced selectivity index, which suggests reduced microcirculatory negative charge sites. This apparently has no association with the degree of plasma albumin disappearance.
The plasma disappearance of albumin has been thoroughly characterized in patients with type 1 diabetes of differing severities.9 13 In contrast, the most recent study of this parameter in CHF patients is >2 decades old,4 and no studies exist describing the whole-body microvascular disappearance of albumin after HTX. Present studies in these 2 patient populations seem warranted because (1) peripheral edema possibly affected by capillary permeability is still a clinical problem before and after HTX and (2) previous studies concerned patients with CHF of various causes who were treated in a manner far different from today.
Plasma Disappearance of Albumin in CHF
In the study by Hesse et al,4 patients with
peripheral edema and elevated right atrial pressure had
increased TERalb. This normalized, despite
slightly elevated right atrial pressures, after 1 to 2 weeks of sodium
depletion and volume reduction. In contrast, the patients in the
present study all had no visible peripheral edema and
had plasma volumes similar to those of controls. Therefore, it is
interesting that these patients had increased
TERalb. However, a rate constant may not be an
exact measure of permeability. Thus, both a volume and a concentration
factor were included; these factors illustrated that CHF patients also
had increased albumin clearance and whole-body albumin
flux. This may mirror the present use of ACE inhibitors
and aspirin or warfarin, because both treatment modalities may increase
capillary area through either reduced procoagulant state and
microvascular clotting or through reduced vasoconstriction. ACE
inhibition may also reduce basement membrane hyalinosis,11
which may influence microvascular permeability.19 In the
present study, all but one patient with CHF were on aspirin or
other anticoagulant therapy, and all were on long-term treatment with
an ACE inhibitor.
Structural Microangiopathy and TERalb
The association between increased capillary basement membrane
thickness and reduced TERalb indicates that a
thicker microvascular wall may act as a more solid and less permeable
barrier. Our findings support the view that the structural
microvascular alterations previously demonstrated in CHF were
compensatory and secondary to increased microvascular hydrostatic
pressure.11 In addition, the present data suggest that
this compensatory structural alteration may have restricted colloid
permeability and thus acted as an edema-protective factor. These
results agree with the finding of reduced pulmonary
microvascular permeability in CHF19 and a thickened
capillary-to-alveolar space-layer ratio in pulmonary
hypertension.20 However, these results are in direct
contrast to findings in type 1 diabetes, in which increasing
microvascular basement membrane thickness10 occurs with
increased TERalb and increased severity of
diabetic complications.7 15 Thus, our data support the
view that the microvascular alterations seen in diabetes may be primary
(metabolically and genetically determined according to the
Steno hypothesis12 ) rather than secondary (early
alterations in capillary pressure).13 The relationship
between TERalb and cutaneous capillary basement
membrane alterations is based on the assumption that the observed
alterations in skin capillaries are a general microvascular phenomenon,
because much of TERalb comes from
albumin clearance from visceral organs and skeletal muscle. The
assumption seems relevant because differences in organ albumin
clearance seem to be caused by differences in capillary density and
perfusion rather than differences in the permeability of the individual
vessels.9 In addition, cutaneous arteriolar basement
membrane alterations and the distensibility of skin and skeletal muscle
were interrelated.11
The 3 study groups did not differ with respect to capillary and arteriolar basement membrane thickness. In previous studies from our laboratory, patients with CHF had increased arteriolar basement membrane thicknesses, and no or very few controls had alterations >grade 1.1 11 Angiotensin II has vascular mitogenic properties,21 and ACE inhibitors may reverse vascular structural alterations.3 Thus, the fact that all CHF patients in the present study were on long-term treatment with an ACE inhibitor may explain the similar distribution of basement membrane thickness of capillaries. In contrast, at the time when the previous investigations were performed, fewer patients had been treated for a shorter period with ACE inhibitors.11 The evaluation of biopsies was performed blindly and semiquantitatively by one person in the present study, which is in accordance with previous studies.11 Therefore, the semiquantitative grading of biopsies, all apparently within a normal range, may have resulted in a differentiated grading within a more narrow spectrum of basement membrane thickness.
HTX and TERalb
TERalb and the clearance of albumin
were reduced after HTX compared with levels in CHF patients. The
whole-body albumin flux was lower in HTX patients than in
controls and CHF patients as a result of (1) the low
TERalb, (2) the relatively low plasma volume, and
(3) the low serum albumin found in HTX patients. The low
TERalb, despite high arterial
pressure, may be a result of reduced capillary permeability (diffusion
coefficient), perhaps through a reduction in inflammatory mediators;
for example, cyclosporin reduced proteinuria in
glomerulonephritis.9 22 The low levels of serum
albumin do not seem to be caused by an increased extracorporal
loss of albumin because none of the patients had proteinuria.
More likely, reduced albumin synthesis may explain the low
serum albumin levels after chronic illness. Alternatively, the
overall albumin mass was not reduced, but rather distributed in
a larger extracellular fluid volume in HTX patients.23
However, we did not demonstrate increased plasma volume in HTX
patients.
Selectivity Index
The glycation of albumin takes place at free lysine amino
terminals, thereby increasing the net anionic charge of the
molecule.24 The size increases to a lesser degree, making
the simultaneous transport index (ie, the selectivity index
of the 2 albumins) a sensitive tool for a charge-dependent
permeability analysis. In the kidney, the
glomerular basement membrane functions not only as a simple
molecular sieve, but also as an electrostatic barrier. The degeneration
of this barrier in the kidney of patients with type 1 diabetes is
probably a factor in the degree of urinary albumin
excretion.25 The single earlier investigation comparing
human whole-body disappearance of glycosylated and nonglycosylated
albumin suggested a similar role of charge-dependency in
relation to TERalb in progressive type 1
diabetes.16
In the present study, controls had a significantly higher selectivity index (a more electronegative barrier) than HTX patients, which suggests that a reduction in negative charge sites occurs in HTX patients. The anionic properties of the microvascular wall are likely caused by the high content of negatively charged glucosaminoglycans,16 thus indicating a defect synthesis of glucosaminoglycans in HTX patients. However, neither HTX patients who had an entirely normal plasma disappearance of albumin nor CHF patients, who had a selectivity index that did not differ from those of controls, had any association with TERalb. Nevertheless, the permeability to albumin and lipoproteins was highly correlated.26 Therefore, an increased transfer of negatively charged lipoproteins and of glycosylated products across the endothelium may cause vascular injury and be a factor in the characteristic vasculopathy seen after HTX.27 However, the role of whole-body microcirculation as an electric barrier is relatively vague and unclear and based only on data from the present and one previous study.15 Therefore, further studies are warranted. The glycosylation procedure of the present and previous investigation were identical, differing only in patient population. Nevertheless, the selectivity index was numerically lower in the controls of the present study.15
Existing data have established the dependence of TERalb on body fluid volume and pressure in subjects without diabetes.4 5 7 We extend this knowledge on factors that impact TERalb by illustrating its dependence on microvascular morphology and its apparent independence of charge in subjects without diabetes. However, in addition to the mentioned factors, numerous other factors, such as endothelial function, general vascular function, exterior pressure, and air composition,28 may also have an important, independent impact on TERalb. Furthermore, although all patients investigated were selected among subjects who previously had no disease, we cannot entirely exclude the possibility that the results generated reflect a late stage of a disease of systemic origin.
In conclusion, compensated CHF due to IDCM is associated with an increased plasma disappearance of albumin, which normalizes after HTX. These patients have a microvascular basement morphology similar to that of healthy controls. However, in all 3 groups, an increasing basement membrane thickness was directly associated with a reduced plasma disappearance of albumin. Thus, increasing basement membrane thickness may act as one edema-protective mechanism in certain pathophysiological states. In HTX patients, a possible reduction in microvascular charge-negative sites was found; this apparently did not influence overall plasma albumin disappearance.
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Acknowledgments |
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This study was supported by the Danish Heart Foundation, the Laurits Peter Christensen and wife Sigrid Christensen Foundation, the Captain Lieutenant and Mrs Harald Jensen Foundation, and the Gerhard Brøndsted Foundation (Copenhagen, Denmark). The authors thank Lene Kløvgaard for technical assistance.
Received August 30, 1999; revision received February 1, 2000; accepted February 14, 2000.
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