Effect of dietary intervention and lipid-lowering treatment on brachial vasoreactivity in patients with ischemic heart disease and hypercholesterolemia☆

Article Outline

• Abstract
• Methods
  • Patients
  • Randomization
  • Dietary advice
  • Ultrasound scanning
  • Statistical analysis
• Results
  • Patients characteristics
  • Lipoproteins, risk factors, and medication
  • Brachial vasoreactivity
  • Dietary intervention
• Discussion
  • Study limitations
  • Conclusion
• Acknowledgements
• References
• Copyright

Abstract 

Background

The “Mediterranean” diet and statin treatment have both independently been shown to improve survival and reduce the risk of cardiovascular events in patients with ischemic heart disease (IHD), but no studies have evaluated the effect of this combination on endothelial function. We therefore sought to evaluate the effect of the combination dietary intervention and lipid-lowering treatment on brachial vasoreactivity.

Methods

A total of 131 consecutive patients with documented IHD and a serum cholesterol level ≥5 mmol/L (193 mg/dL) were randomized to receive Mediterranean dietary advice (n = 68) or no specific dietary advice (n = 63). Endothelial function was assessed at baseline and after 12 months with noninvasive ultrasound scanning vessel-wall tracking of brachial artery flow-mediated vasodilatation (FMD). All patients started statin treatment with Fluvastatin (40 mg once daily) at baseline.

Results

A total of 115 patients completed the study. At baseline, FMD was 4.30% ± 4.89% in the control group versus 4.32% ± 6.15% in the intervention group (P = not significant). After 12 months of follow-up, FMD was significantly higher in the intervention group (control group 5.72% ± 4.87% vs intervention group 8.62% ± 6.60%, P < .01). This was accompanied by a larger intake of fatty fish and a significant decrease in triglyceride levels. In multivariate analysis, randomization status was a significant predictor of FMD after adjustment for classic cardiovascular risk factors and vessel size (P = .02; β = −2.66 [−4.91; −0.41]).

Conclusion

Dietary intervention with the Mediterranean diet and statin treatment improve FMD in the brachial artery in patients with IHD and hypercholesterolemia to a greater degree than statin treatment alone.

Several large randomized trials have shown that low-density lipoprotein (LDL) cholesterol-level lowering with 3-hydroxy 3-methyl glutaryl coenzyme A reductase inhibitors (statins) reduces cardiovascular mortality and morbidity rates in patients with ischemic heart disease (IHD).1, 2 Furthermore, de Lorgeril et al3, 4 have demonstrated that intervention with the “Mediterranean” diet in patients with IHD can dramatically reduce the risk of cardiovascular events, independently of serum lipoprotein levels. These results have also been supported by other dietary intervention studies.5, 6 Endothelial dysfunction may be identified as impaired response to intercoronary acetylcholine infusions or impaired flow-mediated vasodilatation (FMD) of the brachial artery, which have been demonstrated in patients with coronary atherosclerosis7, 8 and hypercholesterolemia.9 The endothelial response of the coronary and peripheral arteries correlate closely.10 Cholesterol-level lowering with statins can improve endothelial function,11, 12 and antioxidant therapy may have additional beneficial effects.13, 14 Recently, diets rich in antioxidants and ω-3 fatty acids postprandially have proven to have a beneficial effect on the endothelium assessed with ultrasound scanning of the brachial artery.15

On the basis of this, we hypothesized that the combination Mediterranean diet and statin treatment improves endothelial function (assessed as brachial vasoreactivity) in patients with IHD and hypercholesterolemia to a greater degree than treatment with statins alone.

Back to Article Outline

Methods 

Patients 

Patients aged 18 to 80 years with a total serum cholesterol level of ≥5.0 mmol/L (193 mg/dL) and documented IHD were prospectively and consecutively enrolled in the study. IHD was considered present when ≥1 of the following conditions were present: 1) recent/remote myocardial infarction (MI), defined as the presence of at least 2 of the following: typical chest discomfort, transient elevation of creatine kinase level >210 IU/L and creatine kinase MB >20 IU/L, or persistent ST elevations or new pathologic Q waves in at least 2 leads; 2) unstable angina (UAP), defined as typical chest discomfort and dynamic ischemic changes in the electrocardiogram; and/or 3) stable angina pectoris (AP), defined as typical chest pain induced by physical exertion and positive exercise test results (horizontal or descending ST depressions >1 mm measured 60 ms after the J-point accompanied by chest pain). Patients with secondary uncontrolled hypercholesterolemia or active liver disease or patients with ongoing lipid-lowering treatment were excluded. The study was approved by the local scientific ethical committee, and all patients gave written informed consent.

Randomization 

After giving written informed consent, the patients were randomized in an unblinded 1-to-1 fashion to receive either dietary advice according to the Mediterranean diet (intervention group) or no specific dietary advice (control group). Treatment with fluvastatin (40 mg every evening) was instituted for all patients. Serum lipids, liver transaminases, blood glucose, and thyroid-stimulating hormone samples were drawn and levels were determined after fasting at randomization and every third month at regular clinical control sessions.

Dietary advice 

The intervention group was given dietary advice by a master of science in clinical nutrition and a specially trained research nurse. In general, the patients were advised to eat at least 600 grams of fruits and vegetables daily, to modify the intake of fat, especially saturated fat from meat and dairy produce, to eat fatty fish at least once a week and preferably several times a week, to eat plenty of bread and cereals, and to replace refined, hard, animal margarine products with vegetable oils, preferably canola oil. The first session was performed as a thorough interview lasting for at least 1 hour and using the 24-hour recall method.16 Every patient had to describe the intake of foods and beverages for the past 24 hours, and the dietary advice was adjusted individually and repeated every third month. The patients were asked at every control session to prepare a written 4-day diary of foods and beverages consumed. They were asked not to weigh the foods but to describe in ordinary words the size of the single ingredients (eg, a small, medium, or large apple) or size of portions of food; furthermore, they were asked to describe in detail fat percentages, especially in dairy produce and minced meat. Also, the patients were asked to note their hot meals. The food diaries were returned to the study nurse, who thoroughly reviewed the contents; in case of doubt, the diary was returned to the patient with appropriate clarifying questions. The finalized food diaries were entered in a food database (Dankost 2000) and subsequently analyzed by a dietitian who was unaware of the randomization status of the patient.

The control group was offered booklets about heart-healthy diets that are usually delivered to patients in the coronary care unit (CCU). They were also offered a single visit to a dietitian who was not participating in the study. The patients were examined every third month at clinical control sessions, but without follow-up on dietary advice. The control group was asked to perform a single diary after 1 year, and the results were entered and analyzed in the same database.

Ultrasound scanning 

Before the institution of statin treatment and dietary intervention, all patients underwent ultrasound scanning of the right upper arm. Patients with recent MI or UAP were examined on the day of discharge from hospital, usually 5 days after admission; patients with remote MI or stable AP were examined immediately after consent. Ultrasound scanning was repeated after 1 year. The scans were performed with a 7.5-MHz linear transducer and a Hewlett Packard Sonos 5500 ultrasound scanning unit. The patients were not required to fast, but the patients were asked not to take their morning medication on the day of the investigation, and every patient had the examination performed at the same time of day at baseline and at 12 months. Patients who smoked were required to refrain from smoking before the investigation. Brachial artery diameter was determined at rest, during reactive hyperemia, again at rest, and after administration of sublingual nitroglycerin. Each subject lay at rest with the arm comfortably immobilized for 5 to 10 minutes before the first scan was obtained. Increased flow was then obtained with the inflation of a pneumatic tourniquet placed around the forearm to a pressure of 300 mm Hg, followed by deflation after 5 minutes. The second scan was taken for 30 seconds before and 90 seconds after cuff deflation. Ten minutes were then allowed for vessel recovery. A second rest scan was recorded, nitroglycerin spray (400 μg) was administered sublingually, and the last scan was obtained. The electrocardiogram was monitored continuously during the scanning. Images were made 20 to 40 mm above the antecubital crease. The image depth was set at 20 mm, and gain settings were adjusted to optimally delineate the lumen arterial wall interface. Images were videotaped for later analysis on a commercial available workstation (Echopac version 6.2, GE Wingmed Ultrasound, Horten, Norway). The tapes were analyzed in random order by an investigator who was blinded to randomization status and all clinical data. Vessel diameters were measured from the anterior to the posterior interface between media and adventitia (“M-lines”) at a fixed distance from an anatomical marker. The mean diameter was calculated from 3 cardiac cycles incident with the R wave on the electrocardiogram. For the hyperemia scan, vessel diameter was obtained approximately 60 seconds after cuff deflation. FMD was calculated for each subject as the percent increase in arterial diameter during the condition of increased flow compared with the rest scan. Similarly, the nitroglycerin-mediated dilatation (NMD) was calculated from the postnitroglycerin scan diameter increase 2.5 minutes after nitroglycerin administration.

Statistical analysis 

Continuous data are expressed as mean values ± SD unless otherwise indicated. Comparisons between groups of discrete variables were performed with the Yates corrected χ² test. Continuous variables between groups were tested with the unpaired Student t test. Comparisons within groups were made with the paired Student t test.

Multivariate analysis of probable associations was performed in a linear regression model, with FMD at 1 year as the dependent variable and randomization status, age, sex, total cholesterol level, medication, baseline vessel size, body mass index, systemic hypertension, and smoking status in the model. Statistical significance was inferred at a P value <.05. Statistical analyses were performed with SPSS for Windows version 10.1 (SPSS Inc, Chicago, Ill).

Back to Article Outline

Results 

Patients characteristics 

A total of 131 patients were enrolled in the study from April 1998 to November 1999. Ninety-three patients (71%) were enrolled during hospitalization for MI or UAP. Thirty-eight patients (29%) with previous MI, previous UAP, or present AP were recruited from the outpatient clinic at the hospital. Sixty-eight patients were randomized to the Mediterranean diet group, and 63 patients were randomized to the usual heart-healthy diet. Five patients were excluded from the study, 3 because of withdrawal of consent, 1 because of diagnosed liver cancer, and 1 because of lack of compliance. Three patients had ultrasound scanning images that could not be analyzed. Another 8 patients died during the study period. Thus, 115 patients completed the study. The demographic and clinical baseline data are given in Table I.

Table I. Baseline clinical patient characteristics

Data are expressed as mean ± SD, or number and (percentage) of patients. NS, Not significant; MI, myocardial infarction.

Lipoproteins, risk factors, and medication 

After 12 months, a significant decrease in total cholesterol and LDL cholesterol levels was seen in both groups (P < .001 for the reduction in both groups). In the 115 patients who completed the study, a significant reduction in triglyceride level was observed only in the intervention group (from 1.77 ± 0.89 mmol/L to 1.42 ± 0.83 mmol/L, P < .05), whereas high-density lipoprotein cholesterol levels remained unchanged in both groups. Table II compares serum lipoproteins and brachial vasoreactivity in the intervention and control groups in the pre- and postintervention periods. In both groups, body weight remained unchanged after 12 months. During the study, 21.7% of the patients stopped smoking, with no difference in tobacco abstinence between groups after 12 months of follow-up. The use of β-blockers was significantly higher in the control group (39.7% vs 63.5%, P = .02), whereas there was no difference in the use of long-acting nitrates, calcium antagonists, vitamins, and angiotensin-converting enzyme inhibitors at 12 months of follow-up. Both groups were >80% compliant with statin treatment.

Table II. Effects of 12 months dietary intervention and statin treatment on brachial vasoreactivity and serum lipids

The 2 groups are compared with respect to pre- and postintervention periods. FMD, Flow-mediated dilatation; NMD, nitroglycerin-mediated dilatation.

Brachial vasoreactivity 

Figure 1 illustrates a normal flow-mediated response. At baseline, no difference in FMD was found in the 2 groups (intervention group, 4.32% ± 6.15 vs control group, 4.30% ± 4.89) (Table II). There was a significant difference in baseline vessel size, with the lowest value in the intervention group (3.86 ± 0.62 mm vs 4.13 ± 0.74 mm, P = .03) (Table II), but when the analysis was stratified for sex, there was no significant difference in vessel diameter in the treatment groups. Also, baseline NMD was significantly higher in the intervention group (15.91% ± 7.49% vs 11.41% ± 5.72%, P = .011) (Table II). After 12 months, a significant (P < .01) improvement in FMD was found in the intervention group compared with the control group (Table II). No differences in the arterial diameter or in the nitroglycerin response were observed. Surprisingly, we observed a reduction in NMD in the intervention group after 12 months; however, this reduction was not significant (P = .08). In multivariate analysis, randomization status was still a significant predictor of FMD after adjustment for sex, age, cardiovascular risk factors, baseline vessel size, and use of antianginal medication (Table III).

• 
  • View Large Image
  • Download to PowerPoint

• Figure 1. 

  A preserved endothelial-dependent response: the brachial artery at rest (left) and during reactive hyperemia (right).

Table III. Multivariate analysis performed as a linear regression model with FMD at 12 months as the dependent variable and randomization status, selected cardiovascular risk factors, vessel size and medication as covariates

Dietary intervention 

All patients showed great interest in participating in the study at first, because the feeling of having responsibility for disease progression was attractive, and they all made an effort to fill out the required food diaries. All patients except 3 were able to complete the food diaries satisfactorily. After 12 months, the intake of fruits and vegetables in the intervention group was larger, although not significantly (Table IV). However, we found a significantly larger intake of fatty fish, a smaller intake of red meat, and significantly higher dietary contents of polyunsaturated fatty acids in the intervention group, and the comprising energy percent from fat was lower (Table IV).

Table IV. Intake of main foods, comprising percent joule in the diet and contents of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in the 2 groups after 12 months of follow-up

Back to Article Outline

Discussion 

In this randomized, dietary and lipid-lowering intervention study, we found that endothelial function assessed with brachial vasoreactivity improved significantly in the group randomized to the Mediterranean diet and statins, which possibly was related to a significant reduction in serum triglyceride levels and a significant larger intake of fatty fish.

Previously, an association between mild-to-moderate hypertriglyceridemia and endothelial dysfunction has also been demonstrated,17 although this has been contradicted by other studies.18 However, it is well established that marine ω-3 fatty acids will reduce serum triglyceride levels, both in healthy individuals and in individuals with hyperlipidemia,19, 20, 21 and it has also previously been reported that marine ω-3 fatty acids improve FMD in subjects with hypercholesterolemia.22 In this study, the intake of fatty fish in the intervention group was high relative to that in the control group. The decrease in triglyceride levels in this study may be the result of an important mechanism related to the diets of the patients in the intervention group. The decrease in triglyceride levels, therefore, provides important information about dietary compliance.

In a recent study, Vogel et al15 investigated the effect of different components of the Mediterranean diet on postprandial FMD. They concluded that a beneficial effect of brachial vasoreactivity appears to be related to antioxidant rich foods, including vegetables, fruits, and their derivatives and ω-3 rich fish and canola oil, but not related to olive oil. These findings are confirmed by this study, and it furthermore adds that the effect is maintained after 12 months of dietary intervention. These findings are new and challenging, but the lack of information about coronary events raises an important question: Is endothelial dysfunction assessed by FMD in the brachial artery suitable as a surrogate end point for cardiovascular events?

Not surprisingly considering that all patients were treated with fluvastatin, we found a highly significant decrease in total and LDL cholesterol values in both groups. It is well established that statin treatment improves the prognosis for patients with IHD, and the effect seems to start after 1 to 2 years. However, conflicting results on the effects of statin treatment on the endothelium of the coronary arteries have been reported. A beneficial effect has been reported after 6 to 12 months of treatment,12, 13 whereas a recently published study reports no effect on the coronary endothelium after 6 months of statin therapy.23

The endothelium is qualitatively the largest endocrine organ in the body24, 25, 26, 27 and plays an important role in vascular homeostasis. The healthy endothelium provides antithrombotic, anti-inflammatory, and vasodilatory properties, which are reduced in the dysfunctional endothelium and which may be modulated via various medications and presumably via dietary changes. Several authors have reported beneficial effects of statins,11 vitamin E,14 estrogen and progesterone therapy,28 L-arginine,29 and angiotensin-converting enzyme inhibitors30 on the arterial endothelium. In the Lyon Diet Heart Study,3, 4 patients received a diet rich in α-linolenic acid, an ω-3 acid precursor for eicosapentanoic acid found in fatty fish. Antioxidant rich diets with more fruits, vegetables, and cereals and diets rich in fatty fish or ω-3 fish oil supplements have also been reported to cause significant decrease in cardiovascular events5, 6, 31; in the Gruppo Italiano por lo Studio della Streptochinasi nell’Infarto miocardico (GISSI)-Prevenzione trial, approximately half the patients were treated with statins, and the mortality rate was reduced beyond statin treatment. No study has evaluated the effect of any preventive treatment both on the peripheral endothelium and on coronary events, which would certainly be interesting.

Study limitations 

We found a significant difference in vessel size at baseline, with the smallest diameter in the intervention group. This may be explained by an unintended prevelance of women who were overweight in the intervention group, because the sex-stratified analysis showed no difference in vessel diameter in the treatment groups. We found that NMD in the 2 groups was different at the baseline examinations and after 12 months, NMD in the intervention group was insignificantly reduced. The larger consumption of long-acting nitrates with a possibility of tolerance-development in the control group could be a possible explanation for the baseline difference; the patients were not required to fast, and some might have taken the morning medication despite being asked not to.

The use of β-blockers was significantly higher in the control group after 12 months. The β-blocker prescribed in this study was solely metoprolol. Although carvedilol previously has been reported to improve FMD in patients with IHD,32 this has not been the case for metoprolol.33 Furthermore, we adjusted FMD for use of β-blocking agents on multivariate analysis without significantly affecting the result, and we find it unlikely that the difference in use of β-blockers had any influence on the results.

The monitoring of patient compliance in this study was done primarily by means of the food diaries, which are open to bias because the patients might write what they think the doctor would like them to eat. We tried to overcome part of this problem by having a dietitian who was not participating in the study and not familiar with the patients analyze the diaries. Furthermore, the investigator responsible for the examinations did not participate in the dietary advice sessions. Objective evidence of compliance was obtained by pill counts and measurement of serum lipoprotein values. We did not measure ω-3 fatty acids in cell membranes, which would certainly have given further strength to these results. Serum lipid levels, however, correlated well with medication intake and intake of fish, and we felt confident that these diaries expressed realistic information about the eating habits in this population.

Previous studies have shown a circadian variation in FMD,34 and the patients in this study were not required to fast. This study was randomized, and the patients were furthermore examined in a relatively narrow time span (from 9:00 am to 1:00 pm), and the time of the ultrasound scanning was completely random for all patients. No patients were examined in the afternoon or in the evening, and each individual was examined at the same time of the day at baseline and at 12 months. Therefore, we find it unlikely that a circadian variation has had any influence on these results.

Conclusion 

The results from this study indicate that statin treatment and dietary intervention improve FMD in patients with IHD and hypercholesterolemia after 12 months of treatment. Larger studies and further observation time are needed to investigate whether this can be correlated to a beneficial effect on coronary events.

Back to Article Outline

Acknowledgements 

We thank research nurse Anni Due for the commitment and thorough work in obtaining food diaries and giving dietary advice.

Back to Article Outline

References 

1. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9
   • View In Article
2. Sacks FM, Pfeffer MA, Moye LA, et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009
   • View In Article
   • MEDLINE
   • CrossRef
3. de Lorgeril M, Renaud S, Mamelle N, et al.  Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454–1459
   • View In Article
   • Abstract
   • CrossRef
4. de Lorgeril M, Salen P, Martin JL, et al.  Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction (final report of the Lyon Diet Heart Study). Circulation. 1999;99:779–785
   • View In Article
   • MEDLINE
5. Burr ML, Fehily AM, Gilbert JF, et al.  Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction (diet and reinfarction trial (DART)). Lancet. 1989;2:757–761
   • View In Article
   • MEDLINE
6. Singh RB, Rastogi SS, Verma R, et al.  An Indian experiment with nutritional modulation in acute myocardial infarction. Am J Cardiol. 1992;69:879–885
   • View In Article
   • MEDLINE
   • CrossRef
7. Cox DA, Vita JA, Treasure CB, et al.  Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. Circulation. 1989;80:458–465
   • View In Article
   • MEDLINE
   • CrossRef
8. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow (an endothelium-dependent mechanism that fails in patients with atherosclerosis). J Am Coll Cardiol. 1990;16:349–356
   • View In Article
   • Abstract
   • Full-Text PDF (436 KB)
   • CrossRef
9. Creager MA, Cooke JP, Mendelsohn ME, et al.  Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234
   • View In Article
   • MEDLINE
   • CrossRef
10. Anderson TJ, Uehata A, Gerhard MD, et al.  Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241
    • View In Article
    • Abstract
    • Full-Text PDF (766 KB)
    • CrossRef
11. Simons LA, Sullivan D, Simons J, et al.  Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia. Atherosclerosis. 1998;137:197–203
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (89 KB)
    • CrossRef
12. Treasure CB, Klein JL, Weintraub WS, et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487
    • View In Article
    • MEDLINE
    • CrossRef
13. Anderson TJ, Meredith IT, Yeung AC, et al.  The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995;332:488–493
    • View In Article
    • MEDLINE
    • CrossRef
14. Neunteufl T, Kostner K, Katzenschlager R, et al.  Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998;32:711–716
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (92 KB)
    • CrossRef
15. Vogel RA, Corretti MC, Plotnick GD. The postprandial effect of components of the Mediterranean diet on endothelial function. J Am Coll Cardiol. 2000;36:1455–1460
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (151 KB)
    • CrossRef
16. Karvetti RL, Knuts LR. Validity of the 24-hour dietary recall. J Am Diet Assoc. 1985;85:1437–1442
    • View In Article
    • MEDLINE
17. Lundman P, Eriksson MJ, Stuhlinger M, et al.  Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol. 2001;38:111–116
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (180 KB)
    • CrossRef
18. Schnell GB, Robertson A, Houston D, et al.  Impaired brachial artery endothelial function is not predicted by elevated triglycerides. J Am Coll Cardiol. 1999;33:2038–2043
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (196 KB)
    • CrossRef
19. Blonk MC, Bilo HJ, Nauta JJ, et al.  Dose-response effects of fish-oil supplementation in healthy volunteers. Am J Clin Nutr. 1990;52:120–127
    • View In Article
    • MEDLINE
20. Fehily AM, Burr ML, Phillips KM, et al.  The effect of fatty fish on plasma lipid and lipoprotein concentrations. Am J Clin Nutr. 1983;38:349–351
    • View In Article
    • MEDLINE
21. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans (a critical review). J Lipid Res. 1989;30:785–807
    • View In Article
    • MEDLINE
22. Goodfellow J, Bellamy MF, Ramsey MW, et al.  Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol. 2000;35:265–270
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (182 KB)
    • CrossRef
23. Vita JA, Yeung AC, Winniford M, et al.  Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation. 2000;102:846–851
    • View In Article
24. Vogel RA. Coronary risk factors, endothelial function, and atherosclerosis (a review). Clin Cardiol. 1997;20:426–432
    • View In Article
    • MEDLINE
    • CrossRef
25. Vogel RA, Corretti MC, Gellman J. Cholesterol, cholesterol lowering, and endothelial function. Prog Cardiovasc Dis. 1998;41:117–136
    • View In Article
    • Abstract
    • Full-Text PDF (1910 KB)
    • CrossRef
26. Celermajer DS. Endothelial dysfunction (does it matter? Is it reversible?). J Am Coll Cardiol. 1997;30:325–333
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (263 KB)
    • CrossRef
27. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med. 1990;323:27–36
    • View In Article
    • MEDLINE
    • CrossRef
28. McCrohon JA, Adams MR, McCredie RJ, et al.  Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. Clin Endocrinol. 1996;45:435–441
    • View In Article
29. Creager MA, Gallagher SJ, Girerd XJ, et al.  L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248–1253
    • View In Article
    • MEDLINE
    • CrossRef
30. Anderson TJ, Elstein E, Haber H, et al.  Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000;35:60–66
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (196 KB)
    • CrossRef
31. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardio. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-55
    • View In Article
32. Matsuda Y, Akita H, Terashima M, et al.  Carvedilol improves endothelium-dependent dilatation in patients with coronary artery disease. Am Heart J. 2000;140:753–759
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (148 KB)
    • CrossRef
33. Muhlen BV, Millgard J, Lind L. Effects of digoxin, furosemide, enalaprilat and metoprolol on endothelial function in young normotensive subjects. Clin Exp Pharmacol Physiol. 2001;28:381–385
    • View In Article
    • MEDLINE
    • CrossRef
34. Etsuda H, Takase B, Uehata A, et al.  Morning attenuation of endothelium-dependent, flow-mediated dilation in healthy young men (possible connection to morning peak of cardiac events?). Clin Cardiol. 1999;22:417–421
    • View In Article
    • MEDLINE
    • CrossRef