Published online before print February 21, 2005, doi: 10.1161/01.HYP.0000153308.91043.97
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(Hypertension. 2005;45:659.)
© 2005 American Heart Association, Inc.
Original Articles |
Effect of Treatment With Candesartan or Enalapril on Subcutaneous Small Artery Structure in Hypertensive Patients With Noninsulin-Dependent Diabetes Mellitus
From the Departments of Medical and Surgical Sciences (D.R., E.P., C.D.C., I.S., S.P., G.E.M.B., M.L.M., M.S., F.Z., M.M., E.A.R.), Biomedical Sciences and Biotechnology (L.R., R.R., R.B.), and Chemistry (G.R.) University of Brescia, Italy.
Correspondence to Damiano Rizzoni, MD, Department of Medical and Surgical Sciences, University of Brescia, Chair of Internal Medicine c/o 2a Medicina, Spedali Civili. 25100 Brescia, Italy. E-mail rizzoni{at}med.unibs.it
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Abstract |
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Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.
Key Words: arteries • diabetes mellitus • hypertrophy • remodeling
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Small-artery remodeling seems to be the earliest form of organ damage in hypertension.1 We have recently demonstrated that in patients with hypertension and/or noninsulin-dependent diabetes mellitus (NIDDM), an elevated media-to-lumen ratio of small resistance arteries dissected from gluteal subcutaneous tissue is an indicator of increased cardiovascular risk and is the most powerful prognostic factor in such high-risk patients.2 The most important mechanism involved is possibly a reduction of the maximal vasodilator capacity in clinically relevant vascular beds.3
Hypertensive patients with NIDDM show the presence of particularly elevated values of media-to-lumen ratio of subcutaneous small arteries, also in comparison with patients with hypertension or with NIDDM alone.4 In addition, the presence of NIDDM is associated with a hypertrophic remodeling of small arteries (vascular smooth muscle cell hypertrophy or hyperplasia), whereas the typical alteration of small arteries in essential hypertension is eutrophic remodeling.5,6 A hypertrophic vascular remodeling has been also observed in patients with renovascular hypertension or acromegaly.6,7 Finally, subcutaneous small resistance arteries of diabetic hypertensive patients show the presence of marked alterations in the extracellular matrix component of the tunica media (an increase in collagen content and a reduction in elastin content).4 It has been previously suggested that changes in extracellular matrix might be crucial for the development, and probably also for the regression, of vascular remodeling.8,9 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers were shown to be able to induce a regression and sometimes a normalization of vascular structural alterations in nondiabetic hypertensive patients10–14 after long-term administration (usually 9 to 12 months). However, in a recently published study, hypertensive patients with NIDDM treated with various antihypertensive drugs maintained a media-to-lumen ratio of subcutaneous arteries significantly greater than normotensive subjects and nondiabetic hypertensive patients,15 thus suggesting that vascular remodeling in hypertensive patients with NIDDM may be particularly difficult to correct. However, no prospective randomized study about the effect of a single antihypertensive drug on small artery remodeling or on extracellular matrix in hypertensive patients with NIDDM has been performed so far.
It has been previously demonstrated that the measurement of the circulating levels of some peptides might give important information about collagen turnover in the cardiovascular system. In particular, N-terminal propeptide of type I collagen (PINP) is a marker of collagen synthesis,16,17 whereas C-terminal telopeptide of type I collagen (ICTP) is a marker of collagen degradation;18 N-terminal propeptide of type III procollagen may reflect both synthesis and degradation. These markers were previously shown to be related to cardiac,16,17,19 and possibly also to vascular, fibrosis. It has been also demonstrated that circulating levels of metalloproteinases (MMPs), which are catabolic enzymes involved in the degradation of extracellular matrix proteins (namely collagen), are decreased in hypertensive patients (especially in those with left ventricular hypertrophy) compared with controls and are increased by drugs that are able to reduce cardiovascular fibrosis.18 Changes in MMP-1 serum levels parallel those of circulating ICTP, whereas changes in circulating PINP move in the opposite direction.18
Given all these considerations, we aimed to investigate the structure of subcutaneous small arteries of hypertensive patients with NIDDM, before and after long-term treatment with the angiotensin II type 1 receptor blockers candesartan and the ACE inhibitor enalapril, using a precise and reliable micromyographic technique. We have also focused our attention on changes in vascular extracellular matrix, as well on circulating indices of extracellular matrix turnover.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Fifteen patients with diagnoses of mild essential hypertension (sitting diastolic blood pressure between 90 and 99 mm Hg and/or sitting systolic blood pressure between 140 and 159 mm Hg at the end of a 2-week placebo run-in period), aged between 30 and 70 years, and with a previous diagnosis of NIDDM, with or without ongoing oral hypoglycemic therapy, were included in the study. Patients were previously untreated for hypertension (n=5) or treated for
1 month in the 3 months preceding the enrollment (n=10). Among the previously treated patients, only those who did not tolerate and/or did not respond to their previous antihypertensive medication were enrolled. Patients previously treated with ACE inhibitors and angiotensin receptor blockers, as well as patients with secondary forms of hypertension or with any disease that could have interfered with the study protocol, were excluded. Characteristics of previous antihypertensive therapy were similar in the 2 groups. The presence of NIDDM was established according to the Guidelines of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.20 Patients were randomized to 1 of the 2 active treatments (candesartan 8 mg once daily or enalapril 10 mg once daily). After 6 weeks of active treatment, if blood pressure was 
130/85 mm Hg, the dose of candesartan and enalapril was doubled (16 mg once daily and 20 mg once daily, respectively). Target blood pressure values were established according to available guidelines.21 If blood pressure was still uncontrolled after 12 weeks of active treatment, a diuretic was added (hydrochlorothiazide 12.5 mg once daily). After 18 weeks of treatment, if blood pressure was still uncontrolled, the dosage of diuretic was doubled (hydrochlorothiazide 25 mg once daily). Patients were then re-evaluated at 6 and 12 months after enrollment. Venous blood samples were taken with the participants in the supine position, after a washout period of at least 2 weeks, for standard hematology and serum biochemistry tests (including triglycerides and total cholesterol), at baseline, 6 months, and 12 months after enrollment. The study was comparative, randomized, and double-blind.
Micromyography
At baseline and at the end of the study (12 months), all participants underwent a biopsy of subcutaneous fat from the gluteal region (3-cm long, 0.5-cm wide, 1.5-cm deep).4,6 Small arteries (
100 to 280 µm of average diameter in relaxed conditions, 2-mm-long) were dissected from the subcutaneous fat of the biopsy samples and mounted as a ring preparation on an isometric myograph (410 A; JP Trading, Aarhus, Denmark) by threading onto 2 stainless steel wires (40-µm diameter). Details about the micromyographic technique of evaluation of small artery morphology were previously reported.6,22–24
The following functional evaluations were performed: a cumulative dose-response curve to acetylcholine at the following concentrations: (10–9, 10–8, 10–7, 10–6, 10–5 mol/L), 3 minutes per concentration, after precontraction with norepinephrine 5 µmol/L; and a concentration-response curve to sodium nitroprusside (10–9, 10–8, 10–7, 10–6, 10–5 mol/L) (endothelium-independent vasodilatation).
The average values obtained from 2 vessels in each experiment were considered. The response to acetylcholine and sodium nitroprusside was expressed as the percent decrease of the wall tension.
The protocol of the study was approved by the ethics committee of our institution (Medical School, University of Brescia), and informed consent was obtained from each participant. The procedures followed were in accordance with institutional guidelines.
Determination of the Composition of Small Artery Walls
Human arteries obtained from subcutaneous biopsy were isolated and fixed in paraformaldehyde 4% for 24 hours. The vessels were washed in phosphate buffer 0.12 mol/L for 24 hours, dehydrated in a series of alcohol, embedded in paraffin, and cut on a microtome at 5-µm-thickness section. After deparaffinization and hydration, the sections were stained for 5 minutes in 1% acid phosphomonolibdic aqueous solution and then stained for 3 minutes in 6% Sirius red in an aqueous solution. After dehydration in alcohol series and clarification with xylene, the slides were mounted in depex. All sections were then analyzed using a light microscope under normal and polarized light. Tissue sections were examined under green filtered light at a magnification of 40x. Five patients from each group were used to study collagen content in the arteries. Measurement of 10 areas per artery was performed. The percentage of total collagen occupying the media layer of vessels was calculated using an image analyzer (ImageproPlus; Immagini e Computer, Milan, Italy). The same sections were examined using polarized light microscopy. Under these conditions, collagen fibers of different thickness are differently colored. The thick and denser type I collagen fibers are detected as orange to red, whereas the thinner type III collagen fibers appear yellow to green.25 The percentage of the different types of collagen occupying the media layer was evaluated with the same automated image analyzer.
Zymographic Analysis
Gelatinase activity in subcutaneous small arteries was assessed by gelatin zymography. Gelatin zymographic analysis of protein extract from the vessels revealed a lytic band, consistent with the presence of proform of MMP-9 at 92 kDa. MMP-9 activity was expressed as absolute units. The method was described in detail previously.26
Echocardiography
In all subjects, a standard echocardiographic evaluation (HP Sonos 5000; Hewlett Packard, Andover, Mass) was performed. Left ventricular internal dimensions, left ventricular posterior wall, and interventricular septum thickness were measured according to the recommendations of the American Society of Echocardiography.27 The diagnosis of left ventricular hypertrophy was considered if left ventricular mass index exceeded 110 g/m2 in females and 131 g/m2 in males.28
Circulating Indices of Extracellular Matrix Collagen Turnover
We have also evaluated some circulating indices of collagen turnover: PINP, ICTP, and N-terminal propeptide of type III procollagen by radio-immuno assay (Orion Diagnostica, Espoo, Finland) at baseline and after 6 months and 12 months of treatment. We also evaluated MMP-1, MMP-2, and MMP-9 serum levels by enzyme-linked immunosorbent assay (Chemicon, Temecula Calif) at baseline and after 6 months and 12 months of treatment.
Statistical Analysis
All data are expressed as mean±SD, unless otherwise stated. One-way analysis of variance (ANOVA) and Bonferroni correction for multiple comparisons were used to evaluate differences among groups. Two-way ANOVA for repeated measures was used for dose-response curves to acetylcholine and sodium nitroprusside (groupxconcentration). All analyses were performed with the BMDP statistical package (BMDP software programs 7D, 8D, 1V, 2V; BMDP Statistical Software Inc, Los Angeles, Calif). The study had 80% power to detect a difference between groups in the media-to-lumen ratio of 0.01 at 5% of significance level.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Demographic Data
Fifteen hypertensive patients with NIDDM were randomized, 8 to treatment based on candesartan, 7 to treatment based on enalapril. In 1 patient in the candesartan group and in 1 in the enalapril group, hydrochlorothiazide was added to further reduce blood pressure. The 2 groups were well-balanced at baseline (Table 1). Average body mass index was in the overweight range. No significant change in fasting glucose was observed during the treatment period. Systolic and diastolic blood pressures were significantly and equally reduced by both treatments (Table 1); 75% of the patients in the candesartan group and 86% in the enalapril group had a final blood pressure
140/90 mm Hg, whereas 38% and 43%, respectively, had a final blood pressure 130/80. No signs of renal impairment were present in any patient (Table 1), and proteinuria, evaluated by 2 consecutive overnight urine sample collections (9 hours, nephelometry), was in the normal or in the microalbuminuric range in all patients (Table 1).
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Echocardiography
Changes in left ventricular mass index were modest, because no patients had left ventricular hypertrophy at baseline (Table 1). Enalapril was slightly more effective than candesartan in reducing left ventricular mass index (enalapril: P<0.05 versus basal values; candesartan: no significant difference).
Morphology of Subcutaneous Small Arteries
Media-to-lumen ratio was significantly reduced and normalized internal diameter was significantly increased by treatment with candesartan (Table 2, Figure 1), whereas enalapril induced a similar reduction in the media-to-lumen ratio but had no significant effect on internal diameter (Table 2). A significant decrease in the total and type I collagen content of the media of small arteries was observed in patients treated with candesartan (Figure 2, Table 2), whereas no change was observed in the enalapril group. Neither candesartan nor enalapril showed any effect on type III collagen (Table 2).
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Zymographic Analysis
MMP-9 activity was significantly increased after treatment with candesartan (Table 2), whereas no statistically significant change was observed with enalapril.
Circulating Indices of Collagen Turnover and MMPs
Circulating indices of collagen turnover pointed toward reduced synthesis of collagen in patients treated with candesartan, as suggested by a reduction in PINP and in PINP/ICTP ratio (Table 3). Again, no change was observed in patients treated with enalapril (Table 3).
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Similarly, serum levels of MMP-2 and MMP-9 were increased during treatment with candesartan, whereas no change was observed during treatment with enalapril (Table 3). MMP-1 showed a similar trend, but differences did not reach statistical significance (Table 3).
Endothelial Function
The vasodilatation to acetylcholine was significantly improved by both treatments (ANOVA P<0.05) (Figure 2). No difference among groups was observed in the responses to sodium nitroprusside (Figure 3).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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For the first time to our knowledge, this study has evaluated small artery structure in hypertensive patients with NIDDM in a prospective study before and after treatment using a direct, reliable, and well-assessed technique. The main result of our study is that enalapril and candesartan proved to be equally effective in correcting small resistance artery remodeling (ie, media-to-lumen ratio), but candesartan seemed to have some advantages in reducing alterations of extracellular matrix. In fact, candesartan decreased total and type I collagen, which is the collagen subtype mostly represented in adult vessels.
It has been shown previously that hypertensive patients with NIDDM have marked structural abnormalities in the resistance arteries, as indicated by an increased media-to-lumen ratio,4 together with an increased collagen content in the media layer.4 It has been also suggested that an impaired myogenic responsiveness of subcutaneous small arteries, with increased wall stress for a given intraluminal pressure, may be the stimulus responsible for vascular hypertrophy in these patients,29 possibly in association with high levels of circulating trophic factors, such as insulin or insulin-like growth factor-1.4
Changes in extracellular matrix components may have a relevant role in the process of vascular remodeling8,9 and may also be triggered by different hemodynamic or humoral factors. Our data suggest that the collagen content of the vascular wall may be modified by angiotensin II type-1 receptor blocker treatment more than by ACE inhibitor treatment. The reasons may be related to a more extensive inhibition of the renin-angiotensin system, particularly of angiotensin II-mediated effects. Angiotensin II and aldosterone are deeply involved in the genesis of extracellular matrix alterations via a profibrotic effects.8,9 The observation of more evident changes in vascular collagen content with candesartan treatment, as evaluated by direct morphological techniques, is strengthened by the detection of more pronounced changes in circulating indices of collagen turnover, particularly of PINP, although they may be a reflection of changes of collagen content in different organs, namely in the heart. In our study, however, changes in left ventricular mass were modest and, in any case, in the opposite direction (ie, enalapril slightly more effective than candesartan). The observation of an increased activity of MMP-9 in subcutaneous small arteries after treatment with candesartan may partially explain differences in the effect on vascular collagen between the 2 drugs. In our study, no change in circulating ICTP levels was observed with candesartan. It was, however, suggested that the ratio between indices of synthesis and degradation of collagens may be more informative that absolute values of the single components of the ratio.17,30 It should also be noted that some differences in baseline values of type 1 collagen content and circulating MMP-2 are present, despite a proper randomization of patients. It cannot be completely ruled out that more evident effects of candesartan on vascular fibrosis may be partly explained by more pronounced alterations in the extracellular matrix in this group.
Hypertensive patients with NIDDM show the presence of an impairment of endothelial function in subcutaneous small arteries, as evaluated by an altered dilatation to acetylcholine and bradykinin.4,29 According to Schofield et al,29 part of the endothelial dysfunction may be related to the presence of an abnormal lipid profile. In our study, a significant improvement of endothelium-dependent vasodilation was observed. No significant change in serum triglycerides and cholesterol was detected (data not shown); however, a statistically significant reduction in blood pressure values was obtained. Therefore, it may be speculated that improvement of endothelial function may be related either to the hemodynamic effect of the 2 drugs or to a possible reduction of oxidative stress, consequent to the inhibition of the renin-angiotensin-aldosterone system activity. Again, pro-oxidative properties of angiotensin II have been well-documented previously.8
Limitations of the Study
The number of patients evaluated in our study is relatively small—albeit it is similar to that of previous studies in essential hypertensive patients10–15—because of the invasiveness of the bioptic procedure and the complexity of the methods used. Patients evaluated in our study were relatively uncomplicated, without any evident cardiac or renal impairment. We do not know, at present, which are the functional or clinical consequences of the reduction of collagen content in the vascular extracellular matrix and, therefore, which clinical significance may be attributed to the different effects of the 2 drugs observed in the present study. Finally, a partially surprising finding of our study was the observation of an increase in the media cross-sectional area and of media thickness of subcutaneous small vessels after treatment with candesartan, whereas no significant change was observed with enalapril. A heterogeneity in vessel diameter may result from sampling vessels at random points in the vasculature; therefore, we have focused our attention to the media to lumen ratio, which is independent from the dimensions of the vessels10 and thus more reliable than the media thickness or the media cross-sectional area when comparisons among groups are concerned. In fact, it has been previously demonstrated that media-to-lumen ratio is the only structural parameter that is independent from the vessel’s dimension, remaining constant for a wide range of diameters (at least in human small resistance arteries of 150 to 300 µm);31 therefore, it is not affected by a possible sampling bias. In addition, it was previously demonstrated in the absence of a time effect in the evaluation of subcutaneous small resistance artery structure, because no difference in the media-to-lumen ratio was observed when biopsies of subcutaneous tissue were repeated in normotensive subjects after 1 year.32
Perspectives
Our data suggest: (1) effective antihypertensive treatment with candesartan or enalapril may partially and equally correct subcutaneous small resistance artery remodeling; (2) candesartan may induce a more pronounced reduction in the vascular collagen content; and (3) endothelial dysfunction may be similarly improved (although not completely normalized) by treatment with candesartan or enalapril. However, a complete normalization of vascular structure in hypertensive patients with NIDDM probably needs additional and different therapeutic strategies, including inhibition of growth factors (insulin, insulin-like growth factors-1), a more pronounced blood pressure reduction, and tighter metabolic control. In particular, combination therapies, including statins, aldosterone antagonists, peroxisome proliferator-activated receptor agonists, and drugs reducing oxidative stress are needed and would be the next step to reduce the risk in these patients. Also, a combination between ACE inhibitors and angiotensin receptor blockers may provide additional benefits.
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Acknowledgments |
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The authors thank Faustini Michela for technical assistance.
Received September 27, 2004; first decision November 2, 2004; accepted December 2, 2004.
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C. Savoia, R. M. Touyz, and E. L. Schiffrin Response to Are the Eutrophic Effects of Angiotensin Receptor Blockers Real? Hypertension, October 1, 2006; 48(4): E19 - E19. [Full Text] [PDF]
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C. Savoia, R. M. Touyz, D. H. Endemann, Q. Pu, E. A. Ko, C. De Ciuceis, and E. L. Schiffrin Angiotensin Receptor Blocker Added to Previous Antihypertensive Agents on Arteries of Diabetic Hypertensive Patients Hypertension, August 1, 2006; 48(2): 271 - 277. [Abstract] [Full Text] [PDF]
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P. Brassard, F. Amiri, and E. L. Schiffrin Combined Angiotensin II Type 1 and Type 2 Receptor Blockade on Vascular Remodeling and Matrix Metalloproteinases in Resistance Arteries Hypertension, September 1, 2005; 46(3): 598 - 606. [Abstract] [Full Text] [PDF]
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