JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2002; 40:505-510
© 2002 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Modena, M. G.
Right arrow Articles by Rossi, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Modena, M. G.
Right arrow Articles by Rossi, R.

CLINICAL STUDY

Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women

Maria G. Modena, MD, FESC, FACC*,*, Lorenzo Bonetti, MD*, Francesca Coppi, MD*, Francesca Bursi, MD* and Rosario Rossi, MD*

* Institute of Cardiology, Department of Internal Medicine, University of Modena, Modena, Italy

Manuscript received May 23, 2001; revised manuscript received April 10, 2002, accepted April 30, 2002.

* Reprint requests and correspondence: Dr. Maria Grazia Modena, Institute of Cardiology, Department of Internal Medicine, Azienda Ospedaliera-Universitaria, Policlinico, University of Modena, Via del Pozzo, 71. 41100 Modena, Italy.
modena.mariagrazia{at}unimo.it


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The aim of the present study was to assess whether optimized antihypertensive treatment is effective in modifying endothelial function and whether an improvement in flow-mediated vasodilation (FMD) in response to treatment, as an expression of reversible endothelial dysfunction, could predict a more favorable prognosis in a population of postmenopausal women.

BACKGROUND: Hypertensive postmenopausal women have been shown to have abnormal endothelium-dependent vascular function. However, FMD may change over time, according to antihypertensive treatment; the prognostic value of these changes has not been investigated.

METHODS: A total of 400 consecutive postmenopausal women with mild-to-moderate hypertension and impaired FMD underwent ultrasonography of the brachial artery at baseline and after six months, while optimal control of blood pressure was achieved using antihypertensive therapy. They were then followed up for a mean period of 67 months (range 57 to 78). Endothelial function was measured as FMD of the brachial artery, using high-resolution ultrasound.

RESULTS: After six months of treatment, FMD had not changed (≤10% relative to baseline) in 150 (37.5%) of 400 women (group 1), whereas it had significantly improved (>10% relative to baseline) in the remaining 250 women (62.5%) (group 2). During follow-up, we noticed 32 events (3.50 per 100 person-years) in group 1 and 15 events (0.51 per 100 person-years) in group 2 (p < 0.0001).

CONCLUSIONS: This study demonstrates that a significant improvement in endothelial function may be obtained after six months of antihypertensive therapy and clearly identifies patients who possibly have a more favorable prognosis.

Abbreviations and Acronyms
  BAD
  brachial artery diameter
  BP
  blood pressure
  FMD
  flow-mediated dilation, flow-mediated vasodilation
  JNC-V
  Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure
  NO
  nitric oxide
  t-PA
  tissue-type plasminogen activator
  u-PA
  urokinase-type plasminogen activator

It is now well recognized that the endothelium plays a fundamental role in the regulation of vascular tone by releasing a variety of vasodilator substances—first and foremost, nitric oxide (NO)—that modulate the contractile behavior of the underlying vascular smooth muscle cells (1,2). The most important consequence of normal endothelial function in vivo is the ability to release NO in response to physiologic stimuli, such as increases in flow, reflecting flow-dependent endothelium-mediated dilation (flow-mediated dilation [FMD]) (3–5). Recently, it has been demonstrated that high-resolution ultrasound study of endothelium-dependent brachial artery FMD is a useful tool for assessing the change in vasomotor response relating to drug therapy (6–9). Several studies have confirmed that FMD of the brachial artery is impaired in patients with various atherosclerotic risk factors, including advanced age, hyperlipidemia, hypertension, diabetes mellitus, tobacco use, and postmenopausal status (6,8,10–23). In particular, hypertensive postmenopausal women have been shown to have abnormal endothelial function (24). However, endothelial dysfunction may reverse over time, according to antihypertensive treatment (6,8,22–27). In other words, an optimal therapeutic regimen may normalize FMD; but, to date, this phenomenon has not been demonstrated in postmenopausal women, and the prognostic value of these changes has not been investigated. Accordingly, the aim of the present study was to assess whether antihypertensive treatment is effective in modifying endothelial dysfunction in postmenopausal women and whether an improvement of FMD in response to treatment, as an expression of a reversible endothelial dysfunction, could provide a more favorable prognosis in the studied population.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects.   Postmenopausal patients with newly diagnosed mild-to-moderate hypertension (stages 1 and 2, according to the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure [JNC-V]) (28) and impaired FMD were eligible for the study.

Menopause was defined by the absence of menstruation for at least 12 months or by the dosage of hormone serum level (follicle-stimulating hormone >40 IU/l and 17 beta-estradiol <110 pmol/l).

Hypertension was diagnosed on the basis of two consecutive measurements at an interval of one week after an initial high reading. Blood pressure (BP) measurements were performed in accordance with recommendations from the American Society of Hypertension (29).

The patients’ history, physical examination, 12-lead electrocardiogram, and echocardiogram were used to exclude past or present heart disease.

From September 1994 to June 1996, 400 consecutive women were enrolled. All gave written, informed consent to participate in this prospective study, which had been approved by the Science and Ethic Committee of our institution.

Study protocol
The study consisted of two parts: 1) high-resolution ultrasonography of the brachial artery at rest and after six months; and 2) follow-up. Enrolled postmenopausal women underwent a basal study of the brachial artery. A second evaluation was scheduled for six months later. In the interim, patients were to receive optimal antihypertensive treatment. All women were advised to modify their life-style habits according to the recommendations of the JNC-V (28). If these measures were unable to reduce BP, pharmacologic therapy was initiated. Therapies were assigned to maintain systolic BP <140 mm Hg and diastolic BP <90 mm Hg. Patients were visited every four weeks. The choice of the antihypertensive drug used was at the discretion of the study investigators, and was made on the basis of a step-by-step approach when the BP values were unsatisfactory (>140/>90 mm Hg). Women were excluded from the study for the following reasons: hypertension greater than stage 2 (28) at admission; a failure to achieve a BP <140/<90 mm Hg after six months of treatment; an improbability of remaining geographically accessible for study visits for at least four years; or a current participation in other ongoing clinical trials.

Ultrasound studies of the brachial artery
An ultrasound study of the brachial artery was performed in all patients at the entry evaluation and after six months by means of a Acuson 128 XP/10 mainframe (Acuson, Mountain View, California) with a 7.0-MHz linear-array transducer. Images were stored on a super VHS videotape recorder for further analysis.

The technique for assessing brachial artery FMD has been described in detail elsewhere (30–33). Briefly, FMD was assessed in a subject’s right arm in the recumbent position after a 15-min equilibration period in a temperature-controlled room (22 to 25°C). Brachial artery diameter (BAD) was measured by B-mode ultrasound images at end diastole. The artery was longitudinally imaged ~5 cm proximal to the antecubital crease, where the clearest image was obtained and BAD was measured. After the baseline resting scan, a pneumatic tourniquet placed at the level of the mid forearm (proximal to the target artery) was inflated until no blood flow was detected through the brachial artery with the Doppler probe, and this pressure was held for 5 min. Increased flow was then induced with sudden cuff deflation, and a continuous scan was performed for 1 min. For the reactive hyperemia scan, BAD measurements were taken 45 to 60 s after cuff deflation. Flow-mediated dilation was calculated from the diameters as: . According to Vogel (22), we considered FMD to be "normal" when the response of the brachial artery was vasodilation >10% relative to baseline and FMD to be "impaired" when vasodilation was <10% or when there was a vasoconstrictive response.

To evaluate the reproducibility of echographic measurements, 100 echographic studies were re-examined by two different investigators (Drs. Modena and Rossi). The studies were selected at random, without knowledge of the patient’s identity, clinical information, or previous evaluation results. The interobserver variability for FMD resulted in 0.10 ± 1.69%, and the interobserver linear correlation coefficient was 0.90.

Follow-up
After the second echographic examination, patients were seen in our outpatient clinic at regular intervals (on average, every 12 months). Telephone contact was made every three months to reduce the dropout rate. All cardiovascular events were recorded. All cases were validated by a review of hospital records. The last data elaboration was performed in March 2000. The mean follow-up period was, therefore, 67 months (range 57 to 78).

Statistical analysis
Continuous variables were expressed as the mean value ± SD, and categorical variables as percentages. In the first phase of the study, baseline values and those recorded after six months were compared by repeated measures analysis of variance. The two groups were compared, at the beginning of the follow-up period, by the Student t test for unpaired data and the chi-square test with Yate’s correction for continuity, as appropriate.

Because the 400 postmenopausal women had different lengths of follow-up, person-years of exposure were calculated for each participant. For individuals who suffered a cardiovascular event, dropped out, or died, exposure was defined as the time between enrollment and the event, the dropout, or the death. For those who did not suffer a cardiovascular event, drop out, or die, exposure was calculated as the time between enrollment and March 2000. Incidence rates of cardiovascular events among patients with persistent impaired FMD and patients with improved FMD were computed as the number of cardiovascular events divided by the total exposure time for each group. The relative risk of a cardiovascular event was computed as the ratio of the incidence rates among patients with persistent impaired FMD divided by the incidence rate among those with improved FMD. Adjusted estimates of risk were computed by use of the Poisson regression model, which controlled for age, diabetes mellitus, smoking habits, serum cholesterol, body mass index, baseline systolic and diastolic BP, and the BP changes from baseline to six-month visit.

Event-free survival was estimated by the product-limit Kaplan-Meier method. Differences between survival curves were tested with the log-rank chi-square statistic. All probability values are two-tailed. A p value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Patients.   The study included 400 consecutive postmenopausal women with mild-to-moderate hypertension and impaired FMD (FMD ≤10% relative to baseline). At the second evaluation (six months after antihypertensive treatment), FMD had not significantly changed (FMD ≤10% relative to baseline) in 150 (37.5%) of 400 women (group 1; persistent impaired FMD), whereas it had significantly improved (FMD >10% relative to baseline) in the remaining 250 patients (62.5%) (group 2; improved FMD). Baseline demographics, clinical characteristics, and brachial artery characteristics of the two study groups are shown in Table 1. The antihypertensive regimens and proportion of subjects who received a life-style modification only, angiotensin-converting enzyme, calcium channel blockers, beta-blockers and thiazide diuretics, alone or combined, or other drugs are shown in Table 2.


View this table:
[in this window]
[in a new window]
  		Table 1 Main Demographic Clinical and Brachial Artery Characteristics of the Participants: A Comparison Between Groups

 

View this table:
[in this window]
[in a new window]
  		Table 2 Blood Pressure Values at Baseline and After Six Months of Treatment and the Antihypertensive Regimen: A Comparison Between Groups*

 
Outcome
During the study period, there were five deaths, all from noncardiac causes (2 accidental and 3 from a neoplasm). There was no difference in the dropout rate: three patients in group 1 and two patients in group 2 (p = NS). Overall, there were 47 cardiovascular events that required hospitalization. All causes of hospitalization are reported in Table 3. Thirty-two (21.3%) of 150 women experienced a nonfatal cardiovascular event in group 1 (persistent impaired FMD) (3.50 events per 100 patient-years), versus 15 (6.0%) of 250 women in group 2 (improved FMD) (0.51 events per 100 patient-years) (p < 0.0001) (Table 4 and Fig. 1).


View this table:
[in this window]
[in a new window]
  		Table 3 Nonfatal Cardiovascular Events Required Hospitalization Recorded During Follow-Up (Mean 67 Months [Range 57 to 78 Months])

 

View this table:
[in this window]
[in a new window]
  		Table 4 Incidence Rates of Cardiovascular Events Among 400 Postmenopausal Women

 


View larger version (11K):
[in this window]
[in a new window]
  		Figure 1 Cumulative survival rates, free of hospital admission, for cardiovascular events in the two study groups, according to persistent impaired (group 1 = dashed line) or improved (group 2 = dotted line) endothelium-derived FMD.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study demonstrates that in the majority of hypertensive postmenopausal women, a significant improvement in FMD may be obtained after six months of optimized therapy in the majority, and it also clearly identifies patients with a more favorable prognosis. Conversely, a higher risk of nonfatal cardiovascular events can be predicted by a noninvasive variable: a lack of change in FMD.

Comparison with previous studies.   During the last 10 years, we have observed an increasing volume of reports on the role of endothelial dysfunction in different clinical settings (7–9,19–21,34–36). In fact, it has been demonstrated that endothelial dysfunction itself represents the primum movens in the process of atherosclerosis and vascular remodeling, which are the causes of subsequent development of clinically relevant cardiovascular diseases (22,23,37–39). Therefore, several studies have been published on the role of different classes of drugs (6–9,20–24) or particular diets (40,41) that could be related to a modified or reversible endothelial dysfunction, with the possibility that such interventions, if instituted preventively, might modify the subsequent risk of cardiovascular disease. A recent Medline research shows that, in the year 2000 only, more than 500 articles were published on the role of different therapeutic interventions aimed at influencing endothelial function. Those data reveal the enormous interest in the endothelium as the "new target for cardiovascular therapeutics" (42).

Nevertheless, the clinician is nowadays principally interested in the prognostic role of reversible endothelial dysfunction and in the clinical relevance of an improvement in endothelial function. In other words, an important question for the clinician is how much modification of FMD is predictive of subsequent risks of cardiovascular events. The present study represents the only one, to the best of our knowledge, focused on the prognostic role of reversible endothelial dysfunction. The results are evident: there is a significantly lower incidence of events in a hypertensive population in which therapy restores normal FMD, in comparison with hypertensive women in which therapy does not influence an abnormal FMD (i.e., persistence of endothelial dysfunction is predictive of future cardiovascular events).

Mechanisms
It is really difficult, in our opinion, to explain the relationship between persistent endothelial dysfunction and the increased risk of clinical events. Our study does not claim to satisfy the question clearly, because, for instance, it is possible that several (still unknown) molecular processes could be implied. We may only hypothesize about some mechanisms. First of all, we noticed a higher rate of transient ischemic attacks in the group with persistent endothelial dysfunction. It is reasonable that there is a close relationship between the two phenomena. The endothelium has, in fact, an important antithrombotic role. Nitric oxide and prostacyclin act synergistically to prevent platelet adhesion and aggregation (43–45). The regulation of fibrinolysis is another important function of the normal endothelium. The two principal determinants of fibrinolysis are: 1) tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), which promote fibrinolysis; and 2) plasminogen activator inhibitor type 1, which inhibits t-PA and u-PA and enhances formation of thrombi. In normal blood vessels, a basal level of t-PA is secreted, which prevents thrombus formation in the absence of vascular injury (46). In the presence of endothelial dysfunction, enhanced platelet deposition, thrombus formation, and inhibition of vasodilation may explain the high incidence of ischemic episodes in the cerebral vascular territory (47).

A possible interesting mechanism can be hypothesized, taking into account the difference between groups regarding the incidence of acute pulmonary edema, which has a heightened relevance in the group with permanently impaired endothelial dysfunction. It is well known that pulmonary edema in hypertensive patients is characterized by normal systolic function and is accompanied by a sudden increase in peripheral arterial resistance and, therefore, BP values (48,49). Flow-mediated dilation is altered in patients with essential hypertension, and a reduced response to the muscarinic agonist has been demonstrated in humans (13,50). The generalized decrease in this response suggests a dysfunction mediated by a reduced production or effect of NO (51,52). Given the large increase in arterial resistance observed in animals and humans after inhibition of NO synthesis (51,53–55), it is possible that endothelial dysfunction contributes to the increase in BP values observed during acute pulmonary edema.

Study limitations
A limitation of this study consists in the lack of fatal cardiovascular events, which might be explained by the relatively young age of the women (mean age 56.7 years), the short interval between menopause and the time of enrollment into the study (mean 5.2 years), the low prevalence of risk factors other than hypertension, and the absence of previous cardiovascular events. Consequently, our results need further confirmation in large observational studies that should also include male patients.

Clinical implications
An improvement of initially impaired FMD, obtained with optimized antihypertensive therapy, provides a more favorable prognosis in hypertensive postmenopausal women. The present study indicates that no improvement in endothelial function in hypertensive postmenopausal women relates to an increased risk of cardiovascular events when compared with improved endothelial function and, therefore, suggests a clinical usefulness for periodic measurements of FMD. Patients who cannot achieve normalization of FMD should be considered at high risk of subsequent cardiovascular events, and a more aggressive therapeutic approach is justified in these patients.


   Footnotes
 
This study was partially supported by a grant from the Italian Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) and was sponsored by the WOmen’s Cardiovascular Disease Association (WOCDA) and Bene Essere Donna Center (Azienda Policlinico of Modena Authority Project).


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109–142[Medline]
  2. Cooke JP, Stamler S, Andon N, Davies PF, McKinley G, Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am J Phisiol. 1990;25:H804–812
  3. Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension. 1986;8:37–44[Abstract/Free Full Text]
  4. Anderson EA, Mark AL. Flow-mediated and reflex changes in large peripheral artery tone in humans. Circulation. 1989;79:93–100[Abstract/Free Full Text]
  5. Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilation of peripheral conduit arteries in vivo. Circulation. 1995;91:1314–1319[Abstract/Free Full Text]
  6. Iwatsubo H, Nagano M, Sakai T, et al. Converting enzyme inhibitor improves forearm reactive hyperemia in essential hypertension. Hypertension. 1997;29:286–290[Abstract/Free Full Text]
  7. Hornig B, Arakawa N, Haussmann D, Drexler H. Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation. 1998;98:2842–2848[Abstract/Free Full Text]
  8. Giugliano D, Marfella R, Acampora R, Giunta R, Coppola L, D’Onofrio F. Effects of perindopril and carvedilol on endothelium-dependent vascular functions in patients with diabetes and hypertension. Diabetes Care. 1998;21:631–636[Abstract]
  9. Anderson TJ, Elstein E, Haber H, Charbonneau F. 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[Abstract/Free Full Text]
  10. Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24:471–476[Abstract]
  11. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992;340:1430–1432[CrossRef][Medline]
  12. Stroes ESG, Koomans HA, deBruin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet. 1995;346:467–471[CrossRef][Medline]
  13. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27[Abstract]
  14. Iiyama K, Nagano M, Yo Y, et al. Impaired endothelial function with essential hypertension assessed by ultrasonography. Am Heart J. 1996;132:779–782[CrossRef][Medline]
  15. Tsao PS, Niebauer J, Buitrago R, et al. Interaction of diabetes and hypertension on determinants of endothelium adhesiveness. Arterioscler Thromb Vasc Biol. 1998;18:947–953[Abstract/Free Full Text]
  16. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impaired impairs endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–1239[Medline]
  17. Williams SB, Goldfine AB, Timimi FK, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97:1695–1701[Abstract/Free Full Text]
  18. Johnstone M, Creager SJ, Scales K, Cusco JA, Lee B, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510–2516[Abstract/Free Full Text]
  19. Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149–2155[Abstract/Free Full Text]
  20. Lieberman EH, Gerhard MD, Uehata A, et al. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121:936–941[Abstract/Free Full Text]
  21. Gerhard MD, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998;98:1158–1163[Abstract/Free Full Text]
  22. Vogel RA. Coronary risk factors, endothelial function, and atherosclerosis: a review. Clin Cardiol. 1997;20:426–432[Medline]
  23. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol. 1999;34:631–638[Free Full Text]
  24. Rossi R, Molinari R, Aveta P, Muia N, Modena MG. Effects of single drug antihypertensive therapy on endothelium-dependent vasodilation in hypertensive postmenopausal women. (abstr)J Am Coll Cardiol. 2000;35(Suppl A):287A
  25. Shultz PJ, Raij L. Effects of antihypertensive agents of endothelium-dependent and endothelium-independent relaxation. Br J Clin Pharmacol. 1989;28:151S–157S[Medline]
  26. Schiffrin EL, Deng LY. Comparison of effects of angiotensin I–converting enzyme inhibition and beta-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension. 1995;25:699–703[Abstract/Free Full Text]
  27. Taddei S, Virdis A, Ghiadoni L, Mattei P, Salvetti A. Effects of angiotensin converting enzyme inhibition on endothelium-dependent vasodilatation in essential hypertensive patients. J Hypertens. 1998;16:447–456[CrossRef][Medline]
  28. The Fifth Report of the Joint National Commettee on Detection Evaluationand Treatment of High Blood Pressure (JNC-V). Arch Intern Med. 1993;153:154–291[CrossRef][Medline]
  29. American Society of Hypertension. Recommendations for routine blood pressure measurement by indirect cuff sphygmomanometry. Am J Hypertens. 1992;5:207–209[Medline]
  30. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and in adults at risk of artherosclerotis. Lancet. 1992;340:1111–1115[CrossRef][Medline]
  31. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al. Non-invasive measurement of human endothelium dependent responses: accuracy and reproducibility. Br Heart J. 1995;74:247–253[Abstract/Free Full Text]
  32. Anderson TJ, Uehata A, Gerhard MD, et al. Close relationship of endothelial function in the human coronary and peripheral circulation. J Am Coll Cardiol. 1995;26:1235–1241[Abstract]
  33. Mannion TC, Vita JA, Keaney JF Jr, Benjamin EJ, Hunter L, Polak JF. Non-invasive assessment of brachial artery endothelial vasomotor function: the effect of cuff position on level of discomfort and vasomotor responses. Vasc Med. 1998;3:263–267[Abstract/Free Full Text]
  34. Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to achetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491–497[Abstract/Free Full Text]
  35. Nakamura M, Funakoshi T, Yoshida H, Harakawa N, Suzuki T, Hiramori K. Endothelium-dependent vasodilation is augmented by angiotensin converting enzyme inhibitors in healthy volunteers. J Cardivasc Pharmacol. 1992;20:949–954[Medline]
  36. Antony I, Lerebours G, Notenberg A. Angiotensin-converting enzyme inhibitor restores flow-dependent and cold-pressure-test–induced dilations in coronary arteries of hypertensive patients. Circulation. 1996;94:3115–3122[Abstract/Free Full Text]
  37. McLenachan JM, Williams JK, Fish RD, Ganz P, Selwin AP. Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis. Circulation. 1991;84:1273–1278[Abstract/Free Full Text]
  38. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and disease. J Cardiovasc Pharmacol. 1993;22(Suppl 4):S1–14
  39. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinkski T, Luscher T. Reduced endothelial nitric oxide synthase expression and production in humans atherosclerosis. Circulation. 1998;97:2494–2498[Abstract/Free Full Text]
  40. Williams MJA, Sutherland WHF, McCormick MP, deJong SA, Walker RJ, Wilkins GT. Impaired endothelial function following a meal rich in used cooking fat. J Am Coll Cardiol. 1999;33:1050–1055[Abstract/Free Full Text]
  41. 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[Abstract/Free Full Text]
  42. Deedwania PC. Endothelium: a new target for cardiovascular therapeutics. J Am Coll Cardiol. 2000;35:67–70[Free Full Text]
  43. Radomski MW, Palmer RM, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987;92:181–187[Medline]
  44. deGraaf JC, Banga JD, Moncada S, Palmer RM, deGroot PG, Sixma JJ. Nitric oxide functions as an inhibitor of platelets adhesion under flow conditions. Circulation. 1992;82:2284–2290
  45. Mellion BT, Ignarro LJ, Ohlstein EH, et al. Evidence for the inhibitory role of guanosine 3", 5"-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood. 1991;57:946–955
  46. Stiko-Raham A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very-low density lipoprotein. Arteriosclerosis. 1990;10:1067–1073[Abstract/Free Full Text]
  47. Sherman D, Loscalzo J. Endothelial dysfunction and cardiovascular disease. Cardiologia. 1997;42:177–187[Medline]
  48. Zampaglione B, Pascale C, Marchisio M, et al. Hypertensive urgencies and emergencies: prevalence and clinical presentation. Hypertension. 1996;27:144–147[Abstract/Free Full Text]
  49. Dauterman KW, Massie BM, Gheorghiade M. Heart failure associated with preserved systolic function: a common and costly clinical entity. Am Heart J. 1998;135:S310–319[CrossRef][Medline]
  50. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol. 1994;23:1610–1616[Abstract]
  51. Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA. 1989;86:3375–3378[Abstract/Free Full Text]
  52. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993;87:1468–1474[Abstract/Free Full Text]
  53. Luscher TF. Heterogeneity of endothelial dysfunction in hypertension. Eur Heart J. 1992;13(Suppl D):50–55
  54. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl-l-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens. 1992;10:1025–1031[Medline]
  55. Forstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes: characterization, purification, molecular cloning, and function. Hypertension. 1994;23:1121–1131[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
M. Juonala, J. S.A. Viikari, M. Kahonen, T. Solakivi, H. Helenius, A. Jula, J. Marniemi, L. Taittonen, T. Laitinen, T. Nikkari, et al.
Childhood Levels of Serum Apolipoproteins B and A-I Predict Carotid Intima-Media Thickness and Brachial Endothelial Function in Adulthood: The Cardiovascular Risk in Young Finns Study
J. Am. Coll. Cardiol., July 22, 2008; 52(4): 293 - 299.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
R. Matyal
Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review
Anesth. Analg., July 1, 2008; 107(1): 37 - 50.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
J. Balzer, T. Rassaf, C. Heiss, P. Kleinbongard, T. Lauer, M. Merx, N. Heussen, H. B. Gross, C. L. Keen, H. Schroeter, et al.
Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial.
J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2141 - 2149.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
M. Juonala, M. Kahonen, T. Laitinen, N. Hutri-Kahonen, E. Jokinen, L. Taittonen, M. Pietikainen, H. Helenius, J. S.A. Viikari, and O. T. Raitakari
Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: The Cardiovascular Risk in Young Finns Study
Eur. Heart J., May 1, 2008; 29(9): 1198 - 1206.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
M. Coylewright, J. F. Reckelhoff, and P. Ouyang
Menopause and Hypertension: An Age-Old Debate
Hypertension, April 1, 2008; 51(4): 952 - 959.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. Rossi, A. Nuzzo, G. Origliani, and M. G. Modena
Prognostic role of flow-mediated dilation and cardiac risk factors in post-menopausal women.
J. Am. Coll. Cardiol., March 11, 2008; 51(10): 997 - 1002.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
M. R. Vesely and V. Dilsizian
Nuclear Cardiac Stress Testing in the Era of Molecular Medicine
J. Nucl. Med., March 1, 2008; 49(3): 399 - 413.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
S. Brili, D. Tousoulis, C. Antoniades, C. Vasiliadou, M. Karali, N. Papageorgiou, N. Ioakeimidis, K. Marinou, E. Stefanadi, and C. Stefanadis
Effects of Ramipril on Endothelial Function and the Expression of Proinflammatory Cytokines and Adhesion Molecules in Young Normotensive Subjects With Successfully Repaired Coarctation of Aorta A Randomized Cross-Over Study.
J. Am. Coll. Cardiol., February 19, 2008; 51(7): 742 - 749.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. Kooijman, D. H. J. Thijssen, P. C. E. de Groot, M. W. P. Bleeker, H. J. M. van Kuppevelt, D. J. Green, G. A. Rongen, P. Smits, and M. T. E. Hopman
Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans
J. Physiol., February 15, 2008; 586(4): 1137 - 1145.
[Abstract] [Full Text] [PDF]

Home page
 Int J EpidemiolHome page
O. T Raitakari, M. Juonala, T. Ronnemaa, L. Keltikangas-Jarvinen, L. Rasanen, M. Pietikainen, N. Hutri-Kahonen, L. Taittonen, E. Jokinen, J. Marniemi, et al.
Cohort Profile: The Cardiovascular Risk in Young Finns Study
Int. J. Epidemiol., February 8, 2008; (2008) dym225v1.
[Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. L. Huang, A. E. Silver, E. Shvenke, D. W. Schopfer, E. Jahangir, M. A. Titas, A. Shpilman, J. O. Menzoian, M. T. Watkins, J. D. Raffetto, et al.
Predictive Value of Reactive Hyperemia for Cardiovascular Events in Patients With Peripheral Arterial Disease Undergoing Vascular Surgery
Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2113 - 2119.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. Sherwood, J. K. Bower, J. McFetridge-Durdle, J. A. Blumenthal, L. K. Newby, and A. L. Hinderliter
Age Moderates the Short-Term Effects of Transdermal 17{beta}-Estradiol on Endothelium-Dependent Vascular Function in Postmenopausal Women
Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1782 - 1787.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
R. E. Schmieder, C. Delles, A. Mimran, J. P. Fauvel, and L. M. Ruilope
Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes
Diabetes Care, June 1, 2007; 30(6): 1351 - 1356.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. J. Anderson
Prognostic Significance of Brachial Flow-Mediated Vasodilation
Circulation, May 8, 2007; 115(18): 2373 - 2375.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
I. J. Kullo and A. R. Malik
Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification
J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1413 - 1426.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
A. Barac, U. Campia, and J. A. Panza
Methods for Evaluating Endothelial Function in Humans
Hypertension, April 1, 2007; 49(4): 748 - 760.
[Full Text] [PDF]

Home page
 J. Nutr.Home page
J. W. Erdman Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. Hollman, C. L. Keen, G. Mazza, et al.
Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC
J. Nutr., March 1, 2007; 137(3): 718S - 737S.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
J. T. Kuvin, A. Mammen, P. Mooney, A. A. Alsheikh-Ali, and R. H. Karas
Assessment of peripheral vascular endothelial function in the ambulatory setting
Vascular Medicine, February 1, 2007; 12(1): 13 - 16.
[Abstract] [PDF]

Home page
 Vasc MedHome page
A. Suessenbacher, M. Frick, H. F Alber, V. Barbieri, O. Pachinger, and F. Weidinger
Association of improvement of brachial artery flow-mediated vasodilation with cardiovascular events
Vascular Medicine, November 1, 2006; 11(4): 239 - 244.
[Abstract] [PDF]

Home page
 HypertensionHome page
C. M. McEniery, S. Wallace, I. S. Mackenzie, B. McDonnell, Yasmin, D. E. Newby, J. R. Cockcroft, and I. B. Wilkinson
Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans
Hypertension, October 1, 2006; 48(4): 602 - 608.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
J. J. Oliver, V. P. Melville, and D. J. Webb
Effect of Regular Phosphodiesterase Type 5 Inhibition in Hypertension
Hypertension, October 1, 2006; 48(4): 622 - 627.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
S. Taddei and L. Ghiadoni
Phosphodiesterase 5 Inhibition to Treat Essential Hypertension: Is This the Beginning of the Story?
Hypertension, October 1, 2006; 48(4): 546 - 548.
[Full Text] [PDF]

Home page
 HypertensionHome page
M. Juonala, J. S.A. Viikari, T. Ronnemaa, H. Helenius, L. Taittonen, and O. T. Raitakari
Elevated Blood Pressure in Adolescent Boys Predicts Endothelial Dysfunction: The Cardiovascular Risk in Young Finns Study
Hypertension, September 1, 2006; 48(3): 424 - 430.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
M. J Roman, T. Z Naqvi, J. M Gardin, M. Gerhard-Herman, M. Jaff, and E. Mohler
American Society of Echocardiography Report: Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology
Vascular Medicine, August 1, 2006; 11(3): 201 - 211.
[PDF]

Home page
 Arch Intern MedHome page
M. Paul-Labrador, D. Polk, J. H. Dwyer, I. Velasquez, S. Nidich, M. Rainforth, R. Schneider, and C. N. B. Merz
Effects of a randomized controlled trial of transcendental meditation on components of the metabolic syndrome in subjects with coronary heart disease.
Arch Intern Med, June 12, 2006; 166(11): 1218 - 1224.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
R. S. Vasan
Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations
Circulation, May 16, 2006; 113(19): 2335 - 2362.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
H. Sourij, R. Zweiker, and T. C. Wascher
Effects of Pioglitazone on Endothelial Function, Insulin Sensitivity, and Glucose Control in Subjects With Coronary Artery Disease and New-Onset Type 2 Diabetes
Diabetes Care, May 1, 2006; 29(5): 1039 - 1045.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
C. N. Bairey Merz, L. J. Shaw, S. E. Reis, V. Bittner, S. F. Kelsey, M. Olson, B. D. Johnson, C. J. Pepine, S. Mankad, B. L. Sharaf, et al.
Insights From the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part II: Gender Differences in Presentation, Diagnosis, and Outcome With Regard to Gender-Based Pathophysiology of Atherosclerosis and Macrovascular and Microvascular Coronary Disease
J. Am. Coll. Cardiol., February 7, 2006; 47(3_Suppl_S): S21 - S29.
[Abstract] [Full Text] [PDF]

Home page