Reversal of peripheral microvascular dysfunction during long-term treatment with the angiotensin converting enzyme inhibitor fosinopril in congestive heart failure

Journal of Cardiac Failure Vol. 5 No. 1 1999

Reversal of Peripheral Microvascular Dysfunction During Long-Term Treatment With the AngiotensinConverting Enzyme Inhibitor Fosinopril in Congestive Heart Failure SOREN GALATIUS, MD,* HENRIK WROBLEWSKI, MD, PhD,* VIBEKE SORENSEN, MD,* STIG HAUNSO, MD, PhD,* TOVE NORGAARD, MD, PhD, * JENS KASTRUP, MD, PhD* Copenhagen and HillerOd, Denmark

ABSTRACT

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF) improves cardiac and peripheral hemodynamic function and exercise performance. However, studies on the effects of long-term treatment with an ACE inhibitor on the neurogenic and nonneurogenic regulation and structural microangiopathy of the peripheral microvasculamre in CHF are lacking. Methods and Results: We investigated the effect of 12 weeks of treatment with the ACE inhibitor fosinopril on peripheral microvascular function in a double-blind, placebo-controlled study of 12 patients treated with fosinopril and 10 patients treated with placebo. All had moderate CHF. Microvascular blood flow and resistance were calculated after application of the local isotope washout method in relaxed and nonrelaxed calf vascular beds in the supine position and during head-up tilt. Skeletal muscle vascular resistance was reduced in the fosinopril group (46 + 6 to 30 _+ 1 mm Hg • rnL -~ • 100 g • rain _+ standard error; P < .05) and differed compared with the effect of placebo (P < .05) where no change was seen (37 _+ 11 to 55 + 13 mm H g . mL ~ • 100 g • rain; not significant [NS]). Also, skin minimal vascular resistance was reduced during fosinopril treatment (13 + 0.6 to 11 -+ 0.7 mm Hg • mL -~ • 100 g" rain; P < .05) and differed compared with the effect of placebo (P < .05) with absence of change (12 + 1.6 to 14 + 1.4 mm Hg • mL -~ • 100 g • rain; NS). Conclusions: These results suggest that long-term ACE inhibitor treatment with fosinopril in patients with CHF improves hemodynamic status to as far as the peripheral microvascular level in both the relaxed and nonrelaxed microcirculation of the lower leg. Key words: microcirculation, vasoconstriction/dilation, renin angiotensin, endothelial function.

From the *Heart Center, The Rigshospital, University of Copenhagen; and the ~Department of Pathology, HillerOd Hospital, HiIlerOd, Denmark. Supported in part by the Danish Heart Foundation; Laurits Peter Christensen and Wife Sigrid Christensen Foundation; Winterthur Borgen Foundation; and Captain Lieutenant Harald Jensen and Wife Foundation, Copenhagen, Denmark; and the Bristol-Myers Squibb Company, Princeton, New Jersey. Manuscript received September 4, 1998; revised manuscript received November 9, 1998; revised manuscript accepted November 16, 1998. Reprint requests: S¢~renGalatius, MD, Department of Medicine B 2014, The Heart Center, The Rigshospital, Blegdamsvej 9, DK 2•00 Copenhagen 0, Denmark. Copyright © 1999 by Churchill Livingstone ® 1071-9164/99/0501-0004510.00/0

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Journal of Cardiac Failure Vol. 5 No. 1 March 1999

Abnormalities of peripheral microvascular function contribute to the pathophysiological characteristics of the syndrome of congestive heart failure (CHF) (1). Such abnormalities include peripheral paradoxical vasodilation during orthostasis (2,3), microangiopathy (4), reduced microvascular distensibility (5), and impaired endothelium-dependent and -independent vasodilation (6,7). Treatment with an angiotensin-converting enzyme (ACE) inhibitor enhances exercise performance, improves central hemodynamics, and reduces mortality in patients with CHF (8-10). ACE inhibitors have sympatholytic effects (11), and we have recently shown that plasma endothelin (ET) is reduced during treatment with the ACE inhibitor fosinopril (12). Augmented baroreceptor control of sympathetic nerve activity has been shown after acute treatment with the ACE inhibitor enalapril (13), and Cody et al. (14) found an improved hemodynamic response to tilt after acute, but not after long-term, treatment with captopril. However, studies on the effects of long-term treatment with an ACE inhibitor on the neurogenic and nonneurogenic regulation and structural microangiopathy of the peripheral microvasculature in CHF are lacking. To investigate if treatment with an ACE inhibitor improves peripheral microvascular function in patients with CHF, we studied the effect of 12 weeks of treatment with fosinopril, a novel phosphinic acid ACE inhibitor, on the neurogenic and nonneurogenic regulation of skeletal muscle and skin blood flow in the lower leg and on structural microangiopathy in the skin in a doubleblinded, placebo-controlled study.

Methods Patients Twenty-two patients (18 men and 4 women) with stable moderate CHF (New York Heart Association class

II or III) with a mean age of 63 years (range, 47 to 75 years) were enrolled. The patients were a subgroup of the 308 patients participating in the Multinational Fosinopril Efficacy and Safety Trial conducted by the Bristol-Myers Squibb Company (Princeton, NJ) investigating the safety and efficacy of 12 weeks of treatment with the ACE inhibitor fosinopril. It was a double-blinded, placebocontrolled, randomized multicenter study (9). The 308 patients enrolled onto the main study came from seven countries. The 22 patients in this substudy came from four Danish centers. Randomization, treatment, and monitoring has been described previously (12). Twelve patients treated with fosinopril and 10 patients treated with placebo were examined at baseline and at weeks 5 and 12. Skin biopsies for histological investigation were performed at baseline and after the 12-week study period. The patients were all treated with diuretics, and 18 patients also received digoxin and had therapeutic serum digoxin levels measured. No patient received direct vasodilator therapy, although five patients received nitrates because of previous symptomatic angina pectoris. No patient had diabetes mellitus, arterial hypertension, or symptoms of neuropathy, peripheral atherosclerosis, or venous insufficiency. There were no signs of edema or skin lesions in the feet. No patient had a myocardial infarction within 6 weeks of the baseline investigation, significant obstructive cardiac valve disease, or restrictive or obstructive cardiomyopathy. Demographic data for the two treatment groups are listed in Table 1. In the case of worsening heart failure requiring supplemental doses of diuretics (frusemide, 40 rag/dose) for more than 2 consecutive days or more than four doses total, the patients were withdrawn from the study and treated with conventional therapy. During the 12-week study period, 3 of the 22 patients were withdrawn (all men) because of worsening heart failure (2 patients) and endocarditis (1 patient). All patients gave written informed consent and the protocol was approved by the local ethical commit-

Table 1. Baseline Characteristics of the Patients

Age (yr) Sex (men/women) Ejection fraction (%) Systolic/diastolic blood pressure (mm Hg) New York Heart Association classification (II/III) Heart failure duration (mon), median (range) Primary cause of CHF Ischemic heart disease Idiopathic dilated cardiomyopathy Valvular Plasma creatinine (mmol/mL) Plasma Na+ (mmol/mL)

Fosinopril (n = 12)

Placebo (n = 10)

63 -+ 8 10/2 27.3 +_ 6.4 127 --- 20/73 ± 11 6/6 36 (2-120)

62 + 10 8/2 25.6 + 7.8 128 ± 20/75 + 8 6/4 30 (7-168)

7 4 1 98.7 ± 18,5 139.5 ± 2.5

7 3 -102.6 ± 32.6 139.3 ± 3.1

Values expressed as mean _+ standard deviation if not otherwise indicated. CHF, congestive heart failure.

Microcirculation and ACE Inhibition

tee. The study conforms with the guidelines of the Declaration of Helsinki.

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initiated after the cuff was released. The cuff was deflated just before and reinflated just after each blood flow measurement.

Hemodynamic Measurements Procedure. The hemodynamic studies were performed in the morning. The subjects were lightly dressed and were placed in the supine position on a tilt table. Room temperature was constant at approximately 23°C. Mean arterial blood pressure was measured in the upper arm with a standard clinical sphygmomanometer placed at heart level; diastolic blood pressure was recorded as Korotkoff phase 5. All investigations in one patient were performed on the same day, and technically unsatisfactory examinations were excluded from data analysis before knowledge of the treatment modality was obtained. Therefore, the number of analyses included in the statistical analysis from the different types of investigations varies. Baroreceptor Regulation of Skeletal Muscle Blood Flow. The neurogenic baroreceptor-mediated regulation of blood flow was investigated in nonrelaxed skeletal muscle tissue by the local isotope washout technique in the proximal anterior tibial muscle during head-up tilt (45°). Technetium 99m (99mTc)-pertechnetate, 0.5 mL, dissolved in isotonic saline (100 MBq/mL) was injected slowly through a 4-cm long, 0.4-mm diameter needle. Blood flow measurements were initiated approximately 10 minutes after injection. Changes in vascular resistance were calculated using mean arterial blood pressure as the perfusion pressure (2). Vascular Distensibility in Skeletal Muscle and Skin. Distensibility (vascular stiffness) was investigated in both skeletal muscle and skin tissues during a 40-ram Hg increase in vascular transmural pressure induced by head-up tilt (5). Skeletal muscle blood flow was measured in the anterior tibial muscle and in skin at the middle of the dorsum of the foot by the local isotope washout technique. To measure the distensibility in relaxed skeletal muscle, a portion (0.5 mL) of a 99mTcpertechnetate-papaverine mixture (12 mg of papaverine and 50.0 MBq of 99mTc-pertechnetate) was used. Skeletal muscle blood flow measurements were initiated approximately 5 minutes after the injection. Distensibility in relaxed skin was measured using 0.1 mL of Xenon 133-histamine mixture (0.05 mg of histamine and 18.5 MBq of ~33Xenon, 370 MBq/mL; Amersham International, Amersham, Bucks, UK) (5) injected intradermally at the dorsum of the foot. A cuff was inflated to 200 mm Hg just above the ankle immediately after the injection to obtain complete cessation of blood flow in the foot. Approximately 2 minutes after the injection, reddening of the skin was seen and blood flow measurements were

Skin Minimal Vascular Resistance. The minimal resistance in the skin was calculated from three to five externally applied counterpressures and the corresponding measured blood flow rates. The skin minimal vascular resistance was measured using approximately 0.1 mL of a mixed histamine (0.05 mg) and 99mTc-pertechnetate (0.1 mCi [3.7 MBq]) solution injected intradermally (4). A 10- × 10-cm, thinwalled, air-filled plastic bag was placed above the cutaneous isotope depot under a sphygmomanometer cuff (4). Cutaneous blood flow rate measurements were initiated when reddening of the skin appeared, and clearance of the isotope was constant. External counterpressure was increased stepwise by inflating the sphygmomanometer cuff and was registered as the pressure in the plastic bag. Blood flow rate was recorded before, during, and after three to five stepwise increases of external counterpressure. Each recording period lasted from 3 to 4 minutes. To calculate cutaneous minimal vascular resistance, isotope washout constants (k) were plotted against the external counterpressures, and the slope of the regression line was calculated by the least squares method (4). Therefore, the slope is the unit flow/pressure, which is equivalent to the reciprocal of minimal vascular resistance. Furthermore, it is possible to measure skin perfusion pressure at rest as the external counterpressure at which blood flow ceases (ie, the X intercept) (4). Skeletal Muscle and Cutaneous Blood Flow Rate Calculations. The gamma emission of the isotopes was registered by a sodium-iodide scintillation detector with a symmetrical 20% window set around the 140-keV photopeak of 99mTc-pertechnetate and the 82-keV photopeak of 133Xenon. The detectors were placed at a distance of approximately 20 cm above the isotope depot, and the accumulated counts were registered every 5 seconds. The slope k of the regression line (the 99mTcpertechnetate and Xenon 133 washout rate constants) was calculated by the least squares method with logaritmically transformed count rates corrected for background activity (2,4,15). Blood flow (f) is proportional to k (min 1) as follows: (1)

f=k

• A • 100mL • min -1 • 100g-1

where A is the tissue-to-blood partition coefficient, (A = 1.0 mL • g-~ in skeletal muscle tissue using 99mTcpertechnetate, A = 0.7 mL • g-1 and 1.0 mL • g - i in cutaneous tissue using Xenon 133 and 99mTc-pertechnetate).

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Journal of Cardiac Failure Vol. 5 No. 1 March 1999

The neurogenic and distensibility investigations consisted of a triad of blood flow measurements, each lasting 1 to 3 minutes, with the labeled areas kept in one of the following positions: (1) supine position, legs at heart level, reference level (ref. 1); (2) 45 ° passive head-up tilt, the labeled areas on the legs lowered approximately 50 cm below heart level (test); and (3) returned to reference level (ref. 2). The entire investigation lasted 5 to 9 minutes. Blood flow at reference level: (2)

(fref, 1 "4- fref. 2) 2

fref =

Blood flow during head-up tilt was expressed relative to the reference flow: ftest/fref, and was then calculated as

ftest (3)

ktest

fre~=

kr~

where ktest is the washout rate constant obtained during the hydrostatic test situation, and kree is the average of the washout rate constants obtained before and just after the test. Blood pressure relations in a vascular system can be described by the Haagen-Poiseuille equation: (4)

F -

(Pa - Pv) R

where F is blood flow (mL/min), Pa - Pv the perfusion pressure (mean arterial pressure minus venous pressure, in m m Hg), and R the resistance (ram Hg- mL -a • 100 grain) in the vascular system. In the present study, relative resistance, R(test)/R(ret), w a s calculated from obtained relative blood flow f(test)/f(ref~,and perfusion pressure, Pa Pv. During head-up tilt, the increase in hydrostatic pressure in the vessels of the lower leg (50 cm below the level of the heart) was approximately 40 m m Hg, so that with a mean arterial blood pressure of 100 m m Hg, the total pressure in the arteries of the lower leg was approximately 140 m m Hg. The pressure within the veins is subject to corresponding hydrostatic effects (40 m m Hg). Therefore, the pressure gradient between arteries and veins, the driving force for the flow of blood (the perfusion pressure), does not vary with height. Accordingly, when perfusion pressure is used to calculate local vascular resistance, the effects of gravity during head-up tilt and passive leg lowering should not be taken into account. However, hydrostatic effects cause considerable increases in transmural pressure that are reflected primarily in the state of stretch and thus of the capacity of the relatively thin-walled veins, arteries, and capillaries. Thus, the effect of a head-up tilt of 45 ° is an increase in the vascular transmural pressure in the lower extremity while maintaining constant perfusion pressure, because tilting increases both arterial and venous hydrostatic pressures by the same amount. The change in blood flow (change in vascular resistance) produced by the increase

in transmural pressure reflects the distensibility of the relaxed vascular bed in skin and skeletal muscle (15) and the effect of arteriolar vasoconstriction in nonrelaxed skeletal muscle.

Histological Examination After the blood flow rate investigations, cutaneous biopsy specimens (3 m m in diameter) were obtained from the skin in the area of investigation. The tissue was fixed in formalin and embedded in paraffin. Four hematoxylin-, eosin-, and periodic acid-Schiff-stained serial sections (2 pm thick) were used for a light microscopic semiquantitative grading of the thickness of the terminal arteriolar basement membranes. The following severity grading was used: grade 1, no conspicuous alteration of the arteriolar wall; grade 2, arteriolar wall hyalinosis comprising less than 50% of arteriolar circumference; grade 3, arteriolar wall hyalinosis comprising greater than 50%, but not the entire arteriolar circumference; and grade 4, hyalinization and thickening of the entire arteriolar wall, with severe narrowing of the arteriolar lumen. At least 30 cross-sections of arterioles were evaluated from each biopsy specimen, and the arterioles with the most pronounced alterations were selected for grading of each tissue sample (4,15). Examinations were performed randomly and blindly by one investigator.

Statistics Comparisons of baseline characteristics between the two treatment groups were performed by the two-tailed, unpaired t-test and by Fisher's exact test when comparing frequencies. The effect of 12 weeks of treatment with fosinopril compared with placebo and the effect of treatment within the two treatment arms was performed by a two-way ANOVA. If significance was obtained, Student's t-test for paired data was used. All values are expressed as mean + standard error (SE) if not otherwise indicated. A P less than .05 was considered significant.

Results Hemodynamic Measurements Blood Pressure. Mean arterial pressure decreased during 12 weeks of treatment with fosinopril (92 + 3 mm Hg at baseline, 87 -+ 3 m m Hg at week 5, and 81 -+ 3 m m Hg at week 12 [mean + SE]; P < .01) compared with absence of effect in the group treated with placebo (90 + 4, 86 + 3, and 90 + 3 mm Hg at weeks 0, 5 and 12, respectively; P < .05 v fosinopril treatment). Neurogenic Regulation. Fosinopril treatment reduced skeletal muscle vascular resistance (46 + 6, 46 + 6, and 30 -+ 1 m m Hg • mL -1 • 100 g • rain at weeks 0,

Microcirculation and ACE Inhibition

5, and 12, respectively; n = 9; P < .05; Fig. 1) versus no change in the placebo-treated group (37 -+ 11, 59 __ 12, and 55_+ 1 3 m m H g . m L - 1 . 1 0 0 g . m i n ; n - 7;P< .05 v fosinopril treatment). The effect of fosinopril on skeletal muscle blood flow did not differ from placebo (2.6 __ 0.4, 2.1 _+ 0.3, and 2.9 _ 0.2 v 2.6 _+ 0.3, 2.1 _+ 0.3, and 2.0 __ 0.4 m L • 100 g 1 . m i n - l , respectively; Fig. 1). No treatment effect was seen in the patients with CHF on an apparently normal neurogenic cardiovascular reflex activation with a decrease in skeletal muscle blood flow ( - 5 5 % _+ 4.0%, - 5 7 % -- 7.0%, - 4 2 % + 6.0% at

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weeks 0, 5 and 12, respectively, in the fosinopril group v - 4 1 % + 9.0%, - 2 4 % _+ 10%, and - 3 2 % _+ 17.0% in the placebo-treated group) and an increase in skeletal muscle vascular resistance (128% _+ 22%, 155% _+ 29%, and 103% _+ 23% v 110% _+ 45%, 65% + 43%, and 116% _+ 61%, respectively).

Nonneurogenic Regulation. During treatment with fosinopril, skin minimal vascular resistance was reduced (13.0 _+ 0.6, 12.5 _+ 0.6, and 11.2 2 0.7 m m Hg" mL -1 • 100 g • rain at weeks 0, 5, and 12, respectively; n = 8; P < .05) compared with the findings in the placebo-

Vascular resistance

100. r, = u

E

80-

03

p<0.05

O O

"" E

60-

i

I

T

T

40-

-rE

E

IN

200

0 5 12 Fosinopril (n=9)

0 5 12 weeks Placebo (n=7)

Blood flow

. i

T

¢3'

=me

E

II

II

02' o m

E

1 0

0

5

12

Fosinopril (n=9)

0

5

12 weeks

Placebo (n=7)

Fig. 1. Resting nonrelaxed vascular resistance and skeletal muscle blood flow in the supine position during 12 weeks of treatment with fosinopril and placebo.

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Journal of Cardiac Failure Vol. 5 No. 1 March 1999

treated group (12.1 _+ 1.3, 11.9 __ 1.6, and 13.8 _+ 1.4 m m H g " m L -1 • 100 g" min; n = 7; not significant [NS], P < .05 v effect of fosinopril; Fig. 2). There was no significant difference between the effect of fosinopril and placebo on vascular stiffness in relaxed skin vessels as measured by vascular distensibility during head-up tilt (13% _+ 4%, 32% _+ 12%, and 35% _+ 8% at weeks 0, 5, and 12, respectively; n = 8 in the fosinopril group v 16% -+ 5%, 30% _+ 8%, and 39% _+ 10%; n = 7 in the placebo group). No treatment effect was seen on relaxed skeletal muscle distensibility (14% _+ 6%, 28% _+ 3%, and 23% _+ 10% at weeks 0, 5 and 12, respectively, in the fosinopril group v 13% -+ 7%, 13% + 10%, and 17% -+ 7% in the placebo-treated group; n = 5; Fig. 3).

Histological Investigation of Skin Biopsy Specimens Semiquanfitative light microscopic examination showed increased thickness of skin arteriolar basement membranes (hyalinosis) in 18 of 22 patients, ie, greater than grade 1 (grade 1, 4 patients; grade 2, 12 patients; and grade 3, 6 patients). There was no significant effect on hyalinosis grade after 12 weeks of treatment with fosinopril or placebo.

Discussion The present study provides evidence that long-term treatment with the ACE inhibitor fosinopril in patients with moderate CHF reduces mean arterial blood pressure, skeletal muscle vascular resistance, and skin min-

r..

imal resistance in the lower leg. There was no significant difference between fosinopril and placebo treatment in relation to the effect on baroreceptor reflex control of calf skeletal muscle blood flow, distensibility in skin and skeletal muscle tissues, and structural microangiopathy. This study supports the finding of Mancini et al. (16), with a decrease in resting calf skeletal muscle vascular resistance during long-term treatment with an ACE inhibitor and shows that this finding was caused by the effect of ACE inhibition, with a contrary effect in the placebo-treated group. This study extends these findings to unstressed relaxed skin, in which minimal vascular resistance was decreased during long-term fosinopril treatment. We further investigated the distensibility of the microcirculation in skin and skeletal muscle with the use of increased transmural pressure during tilt. No difference in the effect of fosinopril and placebo was found despite a 143% increase in skin distensibility and a 65% increase in skeletal muscle distensibility in the fosinopril arm during the 12-week period. Wroblewski et al. (5) found that patients receiving ACE inhibitor treatment had significantly greater skeletal muscle distensibility compared with patients not receiving ACE inhibitor treatment, but no difference in skin distensibility. However, that study was not designed to test for the effect of treatment with an ACE inhibitor. The data from our present and previous studies suggest a positive effect of ACE-inhibitor treatment on microvascular distesibility in patients with CHF. Our study cohort consisted of patients with moderate CHF (New York Heart Association classes II to III) with a mean ejection fraction of 26%. Therefore, it was unexpected to find that the patients showed normal

20p<0.05

= m

E O3

I

O O

-I-

"1"1-

'm

E 10' O')

-r

E E m

m

m

m

m

m

0 5 12 Fosinopril (n=8)

0 5 12 weeks Placebo (n=7)

Fig. 2. Skin minimal vascular resistance decreased during treatment with fosinopril in contrast to the finding in placebo-treated patients.

Microcirculation and ACE Inhibition

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Galatius et al.

23

R e l a x e d skin Blood flow

Vascular resistance IZ] Fosinopril (n=8) BB Placebo (n=7)

40" 20" 03 c.

O

-20" -40-"

0

5

12

0

5

12

0

5

12

0

5

12 weeks

Relaxed skeletal muscle Blood flow

40-]

Vascular resistance D Fosinopril (n=8) BB Placebo (n=5)

A

0 e-

,,c

0

,°1

-20

-30

0

5

12

0

5

12

0

5

12

0

5

12 weeks

Fig. 3. Distensibility in skin (top) and skeletal muscle (bottom) shown as percent change in blood flow (left) and vascular resistance (right) in relaxed vascular beds during head-up tilt.

baroreceptor-mediated vasoconstrictor responses during head-up tilt, with approximately a 50% reduction in calf skeletal muscle blood flow and a doubling in the corresponding resistance. Patients with CHF have a blunted vasoconstrictor response to orthostasis in forearm subcutaneous and skeletal muscle tissues (17,18) and calf subcutaneous tissue (2,3), whereas the response is unexplored in lower leg skeletal muscle. Diverging evidence exists on whether skeletal muscle vasoconstriction is controlled mainly through arterial baroreceptors and subcutaneous vasoconstriction by cardiopulmonary baroreceptors (19,20), and whether baroreceptor-mediated vasoconstriction has the same effect on arm and leg blood flow (21). Also, Creager et al. (22) showed that renal and splanchnic blood flow showed a normal reduction during unloading of cardiopulmonary baroreceptors in patients with CHF. Thus, the vasomotor response to head-up tilt in calf skeletal muscle and subcutaneous tissue in pa-

tients with CHF may be different. In addition, previous studies on baroreceptor reflex regulation of the calf subcutaneous microcirculation was performed on patients with CHF caused by idiopathic dilated cardiomyopathy with a mean ejection fraction of 21% (2). In the present study, the mean ejection fraction was 26%, and two thirds of the patients had ischemic heart disease. These issues may have influenced the findings. We found that treatment with fosinopril had no effect on head-up tiltinduced normal neurogenic vasoconstriction. Cardiac transplantation reverses structural microangiopathy in the skin after 1 year, but not after 3 months (23). Therefore, it may not be surprising that only 12 weeks of treatment with fosinopril did not result in changes that were detectable with the light microscopic semiquantitative method used. However, vascular changes that cannot be shown with this method may still have taken place, which is indicated by the other findings in the present study and

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Journal of Cardiac Failure Vol. 5 No. 1 March 1999

the fact that endothelial-dependent vasodilatation appeared to improve after A C E inhibition (24). Alternatively, an increased number, rather than improved structure of microvessels may be the cause of the decreased regional vascular resistance observed. The present study was not designed to investigate the effect of ACE-inhibitor treatment on microvessel density. In conclusion, 12 weeks of treatment with the A C E inhibitor fosinopril in patients with moderate C H F reduced lower leg skeletal muscle resistance and skin minimal resistance, indicating a beneficial effect of ACEinhibitor treatment in patients with C H F to as far as the peripheral microvascular level.

11.

12.

13.

14.

Acknowledgment The authors thank Lene KlCvgaard for technical assistance.

15.

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