Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension

Article Outline

• Abstract
• Methods
  • Participants and measurements
  • Carotid ultrasonography measurements
  • Blood pressure measurements
  • Body mass index
  • Evaluation of plasma nitrite/nitrate, ADMA, and isoprostane concentrations
  • Interventions
  • Outcomes
  • Statistics
• Results
  • Clinical and laboratory profile
  • Carotid ultrasonography measurements
  • Nitrite/nitrate and Asymmetrical dimethyl-l-arginine concentrations and systemic oxidative stress
• Discussion
• References
• Copyright

Background

Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated.

Objectives

In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostanes).

Methods

In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosis-related diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostane levels were measured.

Results

In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group.

Conclusions

Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure–lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients.

Pharmacological therapies to control blood pressure (BP) have been largely developed and are generally successful. Some drugs were not merely ameliorating the hydrodynamic conditions of the circulation but were actively influencing the biology of the vascular wall. Angiotensin-converting enzyme (ACE) inhibitors have shown a beneficial effect on endothelial function.¹, ², ³, ⁴ The ACE inhibitors and angiotensin II (ANG II) receptor antagonists prevent vascular smooth muscle cell migration and growth, neointima formation, and accumulation of cholesterol in the aorta of experimental models.⁵, ⁶, ⁷, ⁸ These effects are partly mediated by the increased levels of bradykinin, which is degraded by ACE. Bradykinin stimulates nitric oxide (NO) production and has a vasodilating and tissue-protecting effect, even in the presence of ANG II.¹, ², ³ By blocking the formation of ANG II, ACE inhibitors also lower the production of superoxide radicals. These effects reduce the vascular imbalance between NO and superoxide anion as it occurs in the presence of endothelial dysfunction. Therefore, ACE inhibitors may have a pivotal role in the management of atherosclerotic-related diseases independent of their vasodilating and hypotensive effects.¹ Experimental studies show that these drugs can attenuate the development of atherosclerosis in a wide range of species, the most effective being those containing the antioxidant sulfydryl group.⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹ Long-term exposure to high levels of plasma ACE resulted in structural alterations of the carotid.²² However, in the Prevention of Atherosclerosis with Ramipril-2 (PART-2) study,²³ ramipril did not reduce carotid intima-media thickness (IMT) compared to placebo in patients with carotid atherosclerosis.²³, ²⁴ Similar findings were reported in a trial of simvastatin and enalapril administered randomly to normocholesterolemic patients.²⁴ In addition, treatment with fosinopril and pravastatin showed no significant effect on carotid IMT in subjects with an increased urinary albumin excretion.²⁵ Different results were obtained in the Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS) and the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE).²⁶, ²⁷ Thus, the evidence demonstrating that ACE inhibitors have a major effect on lesion progression in humans is limited.

Different ACE inhibitors have quite different chemical functional groups, and these structural variations may account for different in vivo and in vitro effects. The ACE inhibitor captopril has a sulfydryl group to coordinate the zinc ion of the active site, enalaprilat has a carboxylate group, and zofenopril has 2 sulfydryl groups.²⁸, ²⁹ Sulfhydryl ACE inhibition stimulates the NO activity and decreases oxidative stress in human endothelial cells³⁰ and in patients with essential hypertension.³¹ Moreover, sulfhydryl ACE inhibition normalizes nitrate production and potently reduces the asymmetrical dimethyl-l-arginine (ADMA) increase observed in hypertensive patients.³¹ Zofenopril increases NO production in endothelium, decreases atherosclerotic development, and reduces reactive oxygen species,⁹, ¹³, ³², ³³ as well as susceptibility to oxidation of plasma low-density lipoproteins (LDL) and formation of oxidation-specific epitopes in the arterial wall and atherogenesis in apolipoprotein E knockout mice.¹³

To date, long-term effects of ACE inhibitors on atherosclerosis in humans remains still poorly investigated. To address this issue, in 2001, we designed a prospective randomized clinical trial in newly diagnosed hypertensive patients (with no additional risk factors for atherosclerosis) to investigate the efficacy of a non sulfhydryl ACE inhibitor enalapril or the sulfhydryl ACE inhibitor zofenopril for preventing carotid atherosclerosis. High-resolution B-mode ultrasound is extensively used for noninvasive evaluation of atherosclerosis,³⁴ and the IMT of the common carotid artery is a significant predictor of cardiovascular mortality.³⁵

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Methods 

Participants and measurements 

Forty-eight newly diagnosed mildly hypertensive patients were recruited. Exclusion criteria included the presence of other classical risk factors for coronary heart disease (CHD; eg, diabetes/impaired glucose tolerance, hyperlipidemia, smoke habit, family history of atherosclerosis-related diseases); prior or concurrent therapy with ACE inhibitors, antiplatelet drugs, or anticoagulants; history of ischemic events; or refusal to grant informed consent. Patients were classified as hypertensive if they had systolic BP >160 mm Hg or diastolic BP >95 mm Hg. Hyperlipidemia was defined as having total cholesterol >220 mg/dL, or LDL cholesterol >140 mg/dL, or triglyceride >150 mg/dL, and/or taking antihyperlipidemic medications. We used a simple randomization scheme with treatment assignment determined by computerized random number generation in a sequential manner and then provided to the clinical investigators in sealed envelopes. Follow-up measurements were scheduled at 1, 3, and 5 years. Protocol compliance was assessed for each patient, both at the planned annual evaluation periods and at each routine outpatient visit. The trial protocol followed the principles outlined in the Declaration of Helsinki and approved by the Local Ethical Committee.

Carotid ultrasonography measurements 

All carotid ultrasonography measurements were made solely by 2 investigators (G.B. and A.L.) to eliminate interobserver variability. Mean intraday and interday reproducibility values of the investigators were quite acceptable: the intraday coefficients of variation of IMT and vascular lumen diameter of common carotid arteries were 2.7% and 2.5%, respectively, and the mean interday coefficients of variation of IMT and vascular lumen diameter were 5.0% and 5.2%, respectively. Carotid artery IMT was measured by high-resolution B-mode ultrasonography, with a 7.5-MHz high-resolution transducer (Sonos-5500 system; Philips Medical Systems, Andover, MA) as described previously.³⁶, ³⁷ The carotid arteries were carefully examined for wall changes in the longitudinal and transverse views. The common carotid artery, carotid bulb, and internal and external arteries were examined. Presence of carotid atherosclerotic lesions (plaques or shadowing) was determined from scans of all right and left carotid artery segments (common carotid artery, bifurcation, and internal carotid artery). The presence of plaques was defined during ultrasound reading based on wall thickness and arterial wall roughness, loss of alignment, or protrusion into the lumen. Calcification or mineralization, another indicator of atherosclerosis, was based on acoustic shadowing. Right and left common carotid artery wall areas were calculated as the total artery area minus the lumen area assuming a circular lumen and an outer artery structure that was either circular or elliptical. The formula A = πr² − π(r − IMT)², where A is the arterial wall area, r is the artery radius, and IMT is wall thickness, was used to estimate wall area assuming circular configurations. The IMT of the far wall was defined as the distance from the lumen-intima interface (leading edge of the first echogenic line) to the media-adventitia interface (leading edge of the second echogenic line). We measured the IMT of the common carotid arteries bilaterally at 3 points (at 1, 2, and 3 cm proximal to the carotid bifurcation); the averaged value was taken as the carotid IMT. Lesions of apparent plaque,³⁸ appearing either as faint gray echoes (soft plaques) or bright white echoes (calcified plaque) protruding into the lumen, were always excluded from the IMT measurement. Scanning was performed with the patient in the sitting position with the head turned slightly away from the sonographer.

Blood pressure measurements 

Blood pressure was measured at baseline and during the 2 subsequent annual examinations with a mercury sphygmomanometer in a standardized fashion, after 10 minutes of rest with the subject in the supine position.³¹ Systolic and diastolic BPs (mm Hg) were defined according to Korotkoff sounds I and V. All BP measurements were done just before carotid ultrasound measurements and were performed after drug administration by a physician who was blinded as to the patients' profiles and treatment assignments.

Body mass index 

All subjects were weighed without clothing, other than underwear, with the use of the same scale. Height was measured with a special ruler affixed to the wall. Body mass index was routinely calculated as weight (kg) / [height (m)]².

Evaluation of plasma nitrite/nitrate, ADMA, and isoprostane concentrations 

Plasma nitrite/nitrate (NOx) levels were measured with the classical Griess method, as described.³¹ Amounts of plasma nitrite were estimated by a standard curve obtained from enzymatic conversion of NaNO3 to nitrite. The ADMA was measured by reverse-phase high-performance liquid chromatography, as previously described.³¹ Amounts of ADMA in the plasma were estimated from a standard curve of synthetic ADMA (Sigma Chemical Co). In our experimental conditions, the variability of the method was <7%, and the detection limit of the assay was 0.15 mmol/L.³¹ Isoprostanes (8-iso-PGF2α) were measured as previously described.³¹

Interventions 

Subjects were randomized, double blindly, to receive either 20 mg/d of enalapril (n = 24) or 30 mg/d of zofenopril (n = 24). Tablets looked the same.

Outcomes 

The primary efficacy outcome was the change of IMT of the right and left carotid arteries over the course of the study. Secondary outcomes were the change of the vascular lumen diameter of the right and left carotid arteries and the plasma levels of NOx and ADMA.

Statistics 

This is an intent-to-treat analysis, under which we consider IMT values for all patients initially randomized to the enalapril group or the zofenopril group. Our sample size of 48 hypertensive patients (24 enalapril, 24 zofenopril) is sufficient to detect a moderate effect size (that is, difference in means of the 2 groups, divided by the common SD) of 0.5 with a statistical power of 0.7 or a large effect size of 0.85 with a power >0.9 when treatment groups are compared, with a 2-sided t statistic at conventional level 0.05. When we focused the attention to difference in ADMA, however, the study has the power of 90% showing that the mean for zofenopril is at least as high as the mean for enalapril. This represents that the means for the enalapril and zofenopril populations are 0.59 and 0.58, respectively, with a common within-group standard deviation of 0.03, that a difference of 0.04 points or less is unimportant, that the sample size in the 2 groups will be 24 and 24, and that α (2-tailed) is set at .05. Summary statistics are presented as mean ± SD. Differences between the 2 groups at each observation period were assessed with analysis of variance (ANOVA); within- and between-group comparisons across the baseline and follow-up recordings were made with repeated-measures ANOVA.

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Results 

Clinical and laboratory profile 

With regard to baseline characteristics, the enalapril-treated and the zofenopril-treated groups were well matched for age, sex, body mass index, prevalence of smoking, hyperlipidemia, family history of an ischemic event (CHD, peripheral arterial disease, or stroke), or medications received. Summary values are given in Table I. The compliance for both treatments was good. The 2 treatment groups were further characterized for other major risk factors for atherosclerotic diseases and did not differ significantly for any of the parameters analyzed (systolic or diastolic BP, total cholesterol, triglycerides, high-density lipoprotein cholesterol, or LDL cholesterol) at baseline and follow-up measurements (repeated-measures ANOVA with 1 grouping factor, treatment group). Summary statistics are given in Table II.

Table I. Baseline clinical characteristics of the study patients

Values are numbers (percentage) unless indicated otherwise.

Table II. Blood pressure and lipid parameters in study patients

	Enalapril-treated group (n = 24)	Zofenopril-treated group (n = 24)
Systolic BP (mm Hg)
Baseline	163.5 ± 6.4	172.0 ± 6.2⁎
Year 1	138.3 ± 11.8	137.2 ± 8.6
Year 5	136.6 ± 12.5	137.7 ± 12.6
Diastolic BP (mm Hg)
Baseline	100.0 ± 5.4	102.5 ± 6.1
Year 1	75.9 ± 9.8	76.5 ± 6.4
Year 5	75.9 ± 9.8	77.5 ± 10.6
Total cholesterol (mg/dL)
Baseline	195.8 ± 21.5	197.9 ± 23.8
Year 1	192.8 ± 33.1	196.5 ± 31.3
Year 5	199.2 ± 52.6	201.0 ± 34.0
Triglyceride (mg/dL)
Baseline	147.2 ± 72.8	152.9 ± 63.4
Year 1	154.7 ± 73.2	155.6 ± 69.2
Year 5	150.0 ± 69.7	152.1 ± 69.6
HDL cholesterol (mg/dL)
Baseline	52.7 ± 10.9	53.7 ± 11.9
Year 1	58.2 ± 16.2	57.3 ± 13.7
Year 5	57.3 ± 10.8	56.2 ± 10.5
LDL cholesterol (mg/dL)
Baseline	131.5 ± 29.2	129.5 ± 24.8
Year 1	132.7 ± 26.1	127.2 ± 26.3
Year 5	130.9 ± 24.8	130.7 ± 20.7

HDL, High-density lipoprotein.

Carotid ultrasonography measurements 

Common carotid arteries, for both the right and left arteries of each patient, were evaluated in this study. The IMT measurements of the right and left common carotid arteries were determined at baseline and after 1, 3, and 5 years since the beginning of the study. Results, presented in Table III and Figure 1, A, reveal a significantly smaller progression of lesions and vascular remodeling in the zofenopril-treated group compared with the enalapril-treated group. Furthermore, the vascular lumen diameter was increased in patients treated with zofenopril compared with those receiving enalapril (Table III and Figure 1, B).

Table III. Changes of IMT and vascular lumen diameter in carotid arteries

	Enalapril-treated group (n = 24)			Zofenopril-treated group (n = 24)
	Right	Left	Right + Left	Right	Left	Right + Left
IMT, baseline (mm)	0.69 ± 0.09	0.70 ± 0.11	0.70 ± 0.10	0.70 ± 0.11	0.70 ± 0.10	0.70 ± 0.11
Year 1	0.72 ± 0.08	0.72 ± 0.10	0.72 ± 0.10	0.72 ± 0.12	0.72 ± 0.10	0.72 ± 0.11
Year 3	0.74 ± 0.08	0.73 ± 0.11	0.74 ± 0.11	0.72 ± 0.09⁎	0.72 ± 0.08⁎	0.72 ± 0.08⁎
Year 5	0.79 ± 0.09	0.78 ± 0.11	0.78 ± 0.10†	0.74 ± 0.10‡	0.74 ± 0.11‡	0.74 ± 0.11‡,§
Vascular lumen diameter, baseline (mm)	5.96 ± 0.79	5.94 ± 0.73	5.95 ± 0.76	6.00 ± 0.87	6.02 ± 0.78	6.01 ± 0.82
Year 1	5.97 ± 0.66	5.95 ± 0.55	5.96 ± 0.60	5.99 ± 0.79	5.98 ± 0.71⁎	5.99 ± 0.70⁎
Year 3	5.99 ± 0.66	5.96 ± 0.55	5.98 ± 0.60	6.02 ± 0.74‡	5.99 ± 0.70⁎	6.01 ± 0.72‡
Year 5	6.00 ± 0.61	6.00 ± 0.57	6.00 ± 0.59∥	6.03 ± 0.75‡	6.04 ± 0.75‡	6.04 ± 0.75‡,¶
Mean annual proportional change in IMT (%/y)	2.90	2.29	2.29	1.14	1.14	1.14
Mean annual proportional change in vascular lumen diameter (%/y)	0.13	0.20	0.17	0.10	0.07	0.10

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• Figure 1. 

  A, The IMT determinations in zofenopril- and enalapril-treated patients at baseline and after 1, 3, and 5 years since the beginning of the study. B, Vascular lumen diameter determinations in zofenopril- and enalapril-treated patients at baseline and after 1, 3, and 5 years since the beginning of the study. ⁎P < .05 or °P < .01 by ANOVA versus enalapril.

Nitrite/nitrate and Asymmetrical dimethyl-l-arginine concentrations and systemic oxidative stress 

Table IV shows the plasma NOx and ADMA concentrations during the study. After treatment with both ACE inhibitors, plasma NOx concentrations were significantly reduced. However, the magnitude of the reduction achieved with the sulfhydryl ACE inhibitor zofenopril was smaller than that obtained with enalapril. Similarly, the reduction of plasma ADMA concentration was significantly smaller in patients treated with sulfhydryl ACE inhibition. To compare the effects of chronic treatment with zofenopril and enalapril on systemic oxidative stress, the isoprostane 8-iso-PGF2α was measured. As shown in Figure 2, the reduction of 8-iso-PGF2α levels was greater in the zofenopril group, both after 1 and 5 years of treatment.

Table IV. Plasma levels of NOx (μmol/L) and ADMA (μmol/L)

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• Figure 2. 

  Levels of the isoprostane 8-iso-PGF2α at baseline and after 1 and 5 years of treatment with 20 mg/d of enalapril or 30 mg/d of zofenopril. ⁎P < .01 vs respective baseline; °P < .05 vs enalapril.

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Discussion 

We show that long-term treatment with zofenopril may slow the progressive increase of IMT of the carotid artery in newly diagnosed mildly hypertensive patients. This effect was coupled with improved plasma levels of NOx, ADMA, and isoprostanes.

Zofenopril has shown clinical safety and efficacy in patients with hypertension and in those with myocardial infarction.¹ An increase of IMT of the carotid artery is related to higher risk of myocardial infarction, angina, cerebrovascular disease, and peripheral arterial disease.³⁹, ⁴⁰ The Heart Outcomes Prevention Evaluation (HOPE) Study showed that treatment with the ACE inhibitor ramipril reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and congestive heart failure.⁴¹ A recent meta-analysis of randomized controlled trials on carotid IMT and antihypertensive treatment evidenced only a small hindering effect of ACE inhibitors on IMT progression in hypertensive patients.⁴² Therefore, the overall appraisal about the protective effects of ACE inhibitors is relatively weak and based on very limited evidence.²⁷, ⁴³ There is difference between our study (60 months) and previous studies in the observation period (ranged from 6 to 23 months) in some reports from the literature.³⁹, ⁴² This suggests that a too short follow-up enhances the confounding contribution of decreased systolic BP on annual increase of carotid IMT.⁴⁴ However, a dose dependency of the effect of the ACE inhibitor ramipril was reported in the SECURE study where the authors found a reduction of the progression of carotid IMT of 0.004 and 0.008 mm/y with doses of the drug of 2.5 and 10 mg/d, respectively.²⁷ This observation implies that some negative results may be due to inadequate dosage of the drug. Also in our study, we detected a reduction of the progression of carotid IMT of 0.008 mm/y with zofenopril (30 mg/d), but this value is relative to another ACE inhibitor (enalapril, 20 mg/d) and not to placebo, as it is in the SECURE study. Therefore, any direct comparison between the 2 studies is hard to make. Because we used a higher dose of zofenopril in comparison to enalapril (30 vs 20 based on their therapeutic clinical dosage), we cannot exclude a dose dependent effect. It is also noteworthy to recall that in cases where the ACE inhibition has not reduced carotid IMT, as in the PART-2 study, a ramipril-induced reversal of endothelial dysfunction has been claimed.²³ We also suggest a potential protective role of an increased NO availability that can contribute to the reduced progression of the atherosclerotic disease in the zofenopril-treated patients.

The magnitude of change in vascular lumen diameters of common carotid arteries over the course of our study was modest. Glagov et al⁴⁵ showed that, before stenosis is >40%, the actual lumen area seems to remain independent of the plaque area, reflecting the corresponding increase in arterial size. In our study, we measured IMT and vascular lumen diameter in common carotid arteries that showed no plaque (0% stenosis). From our findings, we conclude that zofenopril is effective in slowing progressive IMT and vascular remodeling in hypertensive patients. It is likely that this would be a class effect because previous studies have shown that many other ACE inhibitors (cilazapril, perindopril, captopril, and fosinopril) also prevent neointima formation and inhibit the development of atherosclerosis in hypercholesterolemic patients.², ³ Ramipril also slows progressive carotid IMT in patients with cardiovascular disease and additional risk factors.²⁷ However, in the Quinapril Ischemic Event Trial, quinapril did not reduce progression of coronary atherosclerosis in patients with CHD in the absence of congestive heart failure and/or hyperlipidemia.⁴⁶ When comparing the effects of quinapril (which possesses a high affinity for tissue ACE) and enalapril (which has relatively poor tissue penetrance) on endothelial function in patients with chronic heart failure, only quinapril increased radial artery blood flow at baseline and during reactive hyperemia.⁴⁷ This effect was primarily due to increased NO availability. Interestingly, low-dose zofenopril was more effective than captopril or enalapril in the reduction of atherosclerotic lesions.¹³ In the absence of major contraindications (angioedema, intolerable cough or hypotension, decline in renal function), patients with established atherosclerosis should be treated with ACE inhibitors. Diabetic patients with additional cardiovascular risk factor (dyslipidemia, hypertension, smoking, or microalbuminuria) should also be on ACE inhibitor therapy.⁴⁸, ⁴⁹ Studies have proven that captopril and lisinopril are beneficial after myocardial infarction.⁵⁰, ⁵¹ Ramipril administered at 10 mg/d reduces all-cause mortality and cardiovascular events in a heterogeneous population of patients.⁴¹ As far as the highly lipophilic drug zofenopril, its antioxidant capacity could be related to the higher sulfhydryl group-mediated scavenging activity of free radicals.², ³, ³¹ Sulfhydryl compounds are a major class of protective agents against oxygen radicals generated by radiations.⁵² These considerations are further supported by the fact that in the present study and in a previous one,³⁰, ³¹ the nonsulfhydryl ACE inhibitor enalapril did not exhibit a sustained plasma antioxidant effects. More importantly, this phenomenon is consistent with the lack of protection afforded by enalapril in atherosclerotic mice.¹³ Clinically, zofenopril is effective in reducing cardiac events after myocardial infarction and as an antihypertensive drug in the SMILE study.⁵³, ⁵⁴, ⁵⁵

We also show that the antiatherosclerotic effect of the sulfhydryl ACE inhibitor zofenopril was coupled to an improved NOx/ADMA/oxidative balance. This effect is consistent with that observed in another study.³¹ The NOx measurement is a clinical direct method for measurement of NO production.⁵⁶ The main drawback of the use of the total nitrate as a measure of NO synthesis is that nitrate may arise from sources other than the metabolism of NO. The measurement of total nitrate can be considered a specific indicator of total body NO synthesis. Here, NOx levels were found to be significantly higher in zofenopril-treated compared to enalapril-treated patients. The observation of higher plasma levels of ADMA in the zofenopril group might seem at odds with the reduced carotid IMT of this group. Indeed, it has been reported an association between ADMA plasma levels and IMT of the carotid artery, but it has also been observed a greater effect of ADMA on IMT as the number of risk factors increase.⁵⁷ The patients of this study were free of cardiovascular risk factors other than newly discovered mild hypertension. Because the PART-2 collaborative research group²³ suggested that beneficial effect of ACE inhibitors on major coronary events could be due to reversal of endothelial dysfunction, this needs to be assessed in future investigations. Although, our results may have clinical implications, 1 major problem of establishing an “antiatherosclerotic drug” is the difficulty of assessing “true” antiatherosclerotic activity over many years in human arteries and the clinical relevance of intermediate versus hard end points.

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