Chronic hypertension natural history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian

Overview

Hypertension is a well-established risk factor for several serious diseases. Chronic uncontrolled hypertension can be complicated by target organ damage. Most common damaged organs include the cardiovascular system, the brain, the kidneys, and the retina. The risk of cardiovascular complications is significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk; it should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.

Prognosis

The overnight blood pressure may be the most predictive[1].

Earlier, an article that was retracted found that the 24-hour blood pressure monitoring better predicts complications that the office blood pressure[2].

Complications

Because patients with hypertension usually have other concomitant cardiovascular risk factors, such as dyslipidemia and diabetes mellitus, the isolated effect of hypertension on cardiovascular outcomes may be difficult to assess. However, the Framingham Heart Study and other trials and observational studies well-established that hypertension has an additive effect, among other risk factors, in its contribution to cardiovascular disease and events.[3][4][5][6] While some risk factors are directly induced by hypertension and its vascular effects, such as renal insufficiency, stroke, and heart failure, the mechanism of other complications, such as dyslipidemia, insulin resistance, and atherogenesis, is not as straightforward.[7] These complications are not only worsened by hypertension, but also may predispose to hypertension and together are risk factors for cardiovascular disease, events, and mortality.[7]

Almost half of all deaths in the USA are attributed to cardiovascular diseases, such as coronary artery disease and stroke. Hypertension is considered a strong risk factor for the development of cardiovascular events in target organs, such as the heart, the brain, the kidneys and within the arterial system.[8] Even more recent data has shown that the 11-year all-cause mortality risk increases with higher SBP and DBP even in the non-hypertensive ranges: compared to men with SBP < 110 mmHg, those with SBP between 120 and 129 had a 1.16 risk of cardiovascular death. The risk increases gradually with increased blood pressure values to reach almost 1.6 times when SBP is only between 140 and 149 mmHg. The risk exceeds two-folds when SBP is > 150 mmHg and exceeds three-folds when SBP > 180 mmHg.[9] The risk of diastolic blood pressures is also significantly associated with cardiovascular disease and death.[9] While higher SBP and DBP have been found to be risk factors for cardiovascular disease, too much lowering of both SBP and DBP is currently under further investigation with the recent introduction of the J-curve phenomenon, defined as increased risk at very high and very low systolic and diastolic blood pressures.[10][11] Whether very low diastolic blood pressures are a cardiovascular risk per se or due to their association with an increased systolic blood pressure and high pulse pressure, the real mechanism remains poorly understood.[12][13][10] When followed for 10 years, patients with hypertension had a 20% risk of fatal and non-fatal cardiovascular events.[14][15]

Newer studies confirm similar findings for non-hypertensive patients who are older than 65 years and fall in the high-normal blood pressure category.[3] In fact, the recent introduction of a pre-hypertension category in clinical practice to non-hypertensive patients was only an emphasis of the association of high blood pressure levels, even among those with high normal blood pressure values, with fatal and non-fatal cardiovascular complications.[16][17] In 2001, Vasan and colleagues[3] compared 2967 men and 3892 women, most of whom were white and whose blood pressures were categorized as optimal (SBP<120 mmHg, DBP<80 mmHg), normal (SBP at 120-129 mmHg, DBP at 80-84 mmHg), or high-normal (SBP at 130-139 mmHg, DBP at 85-89 mmHg). They noted the following associated cardiovascular outcomes during a 12-year follow-up in these patients based on the time-dependent progression of blood pressures: death from a cardiovascular etiology, myocardial infarction, stroke, and congestive heart failure. Using subjects with optimal blood pressure values as controls, the study showed that more cardiovascular end-points were associated with worse categories of blood pressure.[3] High-normal blood pressures had a 1.6- and a 2.5-fold hazard ratio for cardiovascular disease in male and female patients, respectively. Similar but attenuated associations were also concluded even when blood pressure values and co-variants were modeled as time-dependent variables during follow-up.[3] In the study, crude event rates increased remarkably between patient categories and age groups. Among patients older than 65 years with high-normal blood pressures, the crude event rate was 28.1 and 19.5 events per 1000 person-years among male and female patients, respectively; whereas it was only 9.2 and 4.7 events per 1000 person-years in male and female patients younger than 65 years. While the five-year cardiovascular complications are significantly reduced by 25% in elderly patients when blood pressure values are appropriately lowered.[18] it is currently unknown whether patients with high-normal blood pressure values similarly benefit from blood pressure lowering,[3]

Finally, it is important to emphasize that the risks of cardiovascular complications are significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk. It should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.


Cardiac

Hypertensive heart disease is defined as the development of left ventricular hypertrophy, atherogenic coronary artery disease, and/or heart failure due to hypertension.[6] Coronary artery disease is perhaps the most common hazard of long-standing hypertension.[19] It equally affects males and females, all ethnicities, and ages.[9] Hypertensive patients are at two to three-fold increased risk of all clinical forms of atherosclerotic heart disease, including angina, myocardial infarctions, and sudden death.[7] According to the MRFIT trial (Cohort of Men Screened for the Multiple Risk Factor Intervention Trial) that studied more than 300,000 White men between 35 and 57 years for more than 10 years, both high systolic and diastolic blood pressures were significantly associated with coronary artery disease in a continuous and graded fashion.[20][21][22][23][17] Elevated systolic blood pressure levels in patients older than 45 years was particularly notorious.[22] The Framingham Heart Study showed that unrecognized myocardial infarctions were also significantly higher in patients with hypertension vs. those who are not, even when adjusting for use of anti-hypertensive therapy, diabetes, and left ventricular hypertrophy.[18]

Other cardiac complications of hypertension include ventricular hypertrophy, which acts as a consequence and as a predictor of future cardiovascular disease.[24][25][26][27][28][29][30] More than 70% of patients with heart failure have a past history of hypertension.[31][19] According to the first National Health and Nutrition Examination Survey (NHANES I) in 2001, hypertension comprised 10% of the population attributable risk of heart failure.[32] Although the pathophysiology of heart failure in hypertension is complicated, it is believed that it may be caused by both the mechanical chronic pressure that overloads the left ventricle, and causes fibrosis of the myocardium and dysfunctional filling during diastole[33] along with neuro-hormonal alterations that are not usually seen in non-hypertensive subjects.[34] Electrocardiography (ECG) findings consistent with left ventricular hypertrophy (LVH) were independently associated with up to 3.7 times and 1.9 times risk of coronary artery disease among 40-64 year old men and women, respectively.[25][28] Relevant ECG abnormalities, such are premature ventricular beats, increased voltages or repolarizations, were significantly increased as systolic and diastolic blood pressures increased.[7][35][28][36] Finally, ejection fraction may or may not be preserved in heart failure. The frequencies of systolic and diastolic left ventricular dysfunction are approximately the same.[32][37]


Stroke

When adjusting for confounding factors, such as smoking, diabetes, and dyslipidemia, the risk of fatal stroke remained significantly high, reaching up to 3-fold in patients with systolic prehypertension values and progressively worsened to reach approximately 20-fold increase in fatal stroke in patients with SBP > 180 mmHg.[17] Although SBP was more associated with stroke than DBP, both are still considered significant factors in the development of stroke in both genders in patients of all ethnicities above the age of 35.[17] While earlier reports hypothesized that hypertensive patients are at higher risk of hemorrhagic strokes compared to atheroembolic strokes, the Framingham Heart Study showed that paradoxically, both mild and severe hypertension were in fact significantly much more associated with more atheroembolic stroke at a rate of 70% and 56%, respectively.[38]


Renal

A significant relationship between elevated blood pressure values and the 12-year risk of death from renal etiology was made in 1993.[39] Renal disease due hypertension is called nephronagiosclerosis or hypertensive nephropathy. It is attributed to small and medium-size renal arteriolopathy that cause characteristic intimal hyperplasia, hyalinosis, and smooth muscle hypertrophy in the arteriolar media.[40] The mechanism of nephroangiosclerosis and vascular modifications have been poorly identified, but involvement of inflammatory cascades are proposed.[40] Nephroangiosclerosis was shown to be responsible for approximately 25-33% of new cases of end-stage renal disease (ESRD), according to data collected from the End-Stage Renal Disease Program.[40][41] Additionally, the HDFP trial in 1989[42] demonstrated that both higher SBP and DBP were also associated with higher creatinine levels, with a frequency of 8% of elevated creatinine in patients with SBP > 200 mmHg vs. only 2% in patients with SBP between 120 and 139 mmHg. Hypercreatininemia at baseline, defined in the study as serum creatinine levels more than 1.7 mg/dL, was associated with approximately a three-fold increase in mortality. Accordingly, kidney function was considered an independent predictor of mortality.[42] The study enrolled 10940 black and white patients and measured creatinine periodically for 5 years.[42] Creatinine increase was significantly higher in blacks and in older patients.[42] In another trial that assessed renal outcome following anti-hypertensive therapy, DBP < 95 mmHg was associated with stable kidney function.[43]


Ophthalmic

In hypertension, the microvasculature in the retina constricts and undergoes intimal thickening, medial hyperplasia, and subsequent hyaline degeneration.[44] As such, hypertensive retinopathy is a common complication among patients with long-standing hypertension and may be the earliest manifestation.[45] In fact, hypertension has a range of eye manifestations that lead to vision less, especially among adults above the age of 40 years. Ischemic and non-ischemic occlusion of the retinal vein and artery in central and peripheral vessels, retinal emboli, ischemic optic neuropathy, glaucoma, and age-related macular degeneration are also common ophthalmic manifestations significantly associated with hypertension.[45][46] According to Cugati and colleagues, central vein occlusion was seen in 0.4% of the cases, whereas branch retinal vein occlusion was seen in 1.2% among 3654 patients aged 49 and older when followed-up for 10 years.[47] Studies have confirmed that eye involvement in hypertension heralds stroke, heart failure, and other cardiovascular events and mortality.[45][46] Ophthalmic complications of hypertension are significantly reduced with the use of appropriate anti-hypertensive medications and optimal blood pressure control. There are currently 3 grades of retinopathy: mild retinopathy is defined as generalized and focal arteriolar narrowing, arterial wall opacification, and arteriovenous nipping. Moderate retinopathy is defined as flame-shaped or blot-shaped hemorrhages with cotton-wool spots, hard exudates, and/or microaneurysms. Finally, severe retinopathy is defined as signs of mild or moderate retinopathy with optic disc swelling.[45][46]


Peripheral

Blood pressure is also consistently and independently associated with the development of peripheral vascular disease (PVD) in the young and the elderly.[8] High SBP by only 20 mmHg and DBP by only 10 mmHg was associated with more claudication in both men and women at all ages.[8] At the time of diagnosis of hypertension, up to 5% of patients, especially among the elderly, have symptomatic peripheral arterial disease (PAD), such as intermittent claudication.[48] The converse is also true; where approximately half of patients diagnosed with PAD were also found to have hypertension.[48] Patients with PAD are at further increased risk of future cardiovascular events.

References

  1. ↑ Staplin N, de la Sierra A, Ruilope LM, Emberson JR, Vinyoles E, Gorostidi M; et al. (2023). "Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients". Lancet. 401 (10393): 2041–2050. doi:10.1016/S0140-6736(23)00733-X. PMID 37156250 Check |pmid= value (help).
  2. ↑ Banegas JR, Ruilope LM, de la Sierra A, Vinyoles E, Gorostidi M, de la Cruz JJ; et al. (2018). "Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality". N Engl J Med. 378 (16): 1509–1520. doi:10.1056/NEJMoa1712231. PMID 29669232.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Vasan RS, Larson MG, Leip EP, Evans JC, O'Donnell CJ, Kannel WB; et al. (2001). "Impact of high-normal blood pressure on the risk of cardiovascular disease". N Engl J Med. 345 (18): 1291–7. doi:10.1056/NEJMoa003417. PMID 11794147.
  4. ↑ Lowe LP, Greenland P, Ruth KJ, Dyer AR, Stamler R, Stamler J (1998). "Impact of major cardiovascular disease risk factors, particularly in combination, on 22-year mortality in women and men". Arch Intern Med. 158 (18): 2007–14. PMID 9778200.
  5. ↑ Kannel WB (1996). "Blood pressure as a cardiovascular risk factor: prevention and treatment". JAMA. 275 (20): 1571–6. PMID 8622248.
  6. ↑ 6.0 6.1 Frohlich ED (2009). "Hypertensive disease: current challenges, new concepts and management. Preface". Med Clin North Am. 93 (3): xv–xx. doi:10.1016/j.mcna.2009.02.016. PMID 19427488.
  7. ↑ 7.0 7.1 7.2 7.3 Kannel WB (2009). "Hypertension: reflections on risks and prognostication". Med Clin North Am. 93 (3): 541–58, Table of Contents. doi:10.1016/j.mcna.2009.02.006. PMC 3719976. PMID 19427490.
  8. ↑ 8.0 8.1 8.2 Murabito JM, D'Agostino RB, Silbershatz H, Wilson WF (1997). "Intermittent claudication. A risk profile from The Framingham Heart Study". Circulation. 96 (1): 44–9. PMID 9236415.
  9. ↑ 9.0 9.1 9.2 Stamler J, Stamler R, Neaton JD (1993). "Blood pressure, systolic and diastolic, and cardiovascular risks. US population data". Arch Intern Med. 153 (5): 598–615. PMID 8439223.
  10. ↑ 10.0 10.1 Peters R, Beckett N, Fagard R, Thijs L, Wang JG, Forette F; et al. (2013). "Increased pulse pressure linked to dementia: further results from the Hypertension in the Very Elderly Trial - HYVET". J Hypertens. 31 (9): 1868–75. doi:10.1097/HJH.0b013e3283622cc6. PMID 23743809.
  11. ↑ Bangalore S, Messerli FH, Wun CC, Zuckerman AL, DeMicco D, Kostis JB; et al. (2010). "J-curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial". Eur Heart J. 31 (23): 2897–908. doi:10.1093/eurheartj/ehq328. PMID 20846991.
  12. ↑ Kannel WB, Wilson PW, Nam BH, D'Agostino RB, Li J (2004). "A likely explanation for the J-curve of blood pressure cardiovascular risk". Am J Cardiol. 94 (3): 380–4. doi:10.1016/j.amjcard.2004.04.043. PMID 15276113.
  13. ↑ Cruickshank JM, Thorp JM, Zacharias FJ (1987). "Benefits and potential harm of lowering high blood pressure". Lancet. 1 (8533): 581–4. PMID 2881129.
  14. ↑ "1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee". J Hypertens. 17 (2): 151–83. 1999. PMID 10067786.
  15. ↑ Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyörälä K (1998). "Prevention of coronary heart disease in clinical practice. Summary of recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention". J Hypertens. 16 (10): 1407–14. PMID 9814610.
  16. ↑ Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies Collaboration (2002). "Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies". Lancet. 360 (9349): 1903–13. PMID 12493255.
  17. ↑ 17.0 17.1 17.2 17.3 Neaton JD, Wentworth D (1992). "Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group". Arch Intern Med. 152 (1): 56–64. PMID 1728930.
  18. ↑ 18.0 18.1 Kannel WB, Dannenberg AL, Abbott RD (1985). "Unrecognized myocardial infarction and hypertension: the Framingham Study". Am Heart J. 109 (3 Pt 1): 581–5. PMID 3976481.
  19. ↑ 19.0 19.1 Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K; et al. (2009). "Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee". Circulation. 119 (3): e21–181. doi:10.1161/CIRCULATIONAHA.108.191261. PMID 19075105.
  20. ↑ Neaton JD, Kuller LH, Wentworth D, Borhani NO (1984). "Total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration, and diastolic blood pressure among black and white males followed up for five years". Am Heart J. 108 (3 Pt 2): 759–69. PMID 6475745.
  21. ↑ Stamler J, Wentworth D, Neaton JD (1986). "Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT)". JAMA. 256 (20): 2823–8. PMID 3773199.
  22. ↑ 22.0 22.1 Stamler J, Neaton JD, Wentworth DN (1989). "Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease". Hypertension. 13 (5 Suppl): I2–12. PMID 2490825.
  23. ↑ Stamler J (1991). "Blood pressure and high blood pressure. Aspects of risk". Hypertension. 18 (3 Suppl): I95–107. PMID 1889862.
  24. ↑ "Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project. The pooling project research group". J Chronic Dis. 31 (4): 201–306. 1978. PMID 681498.
  25. ↑ 25.0 25.1 Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD (2000). "Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity". JAMA. 284 (3): 311–8. PMID 10891962.
  26. ↑ Perkins P, Forthofer R (1991). "Re: "Predictors of sudden cardiac death among Hawaiian-Japanese men"". Am J Epidemiol. 134 (3): 326–7. PMID 1877591.
  27. ↑ Guzik HJ, Ooi WL, Frishman WH, Greenberg S, Aronson MK (1992). "Hypertension: cardiovascular implications in a cohort of old old". J Am Geriatr Soc. 40 (4): 348–53. PMID 1556362.
  28. ↑ 28.0 28.1 28.2 Liao YL, Liu KA, Dyer A, Schoenberger JA, Shekelle RB, Colette P; et al. (1988). "Major and minor electrocardiographic abnormalities and risk of death from coronary heart disease, cardiovascular diseases and all causes in men and women". J Am Coll Cardiol. 12 (6): 1494–500. PMID 3192848.
  29. ↑ Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1989). "Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study". Ann Intern Med. 110 (2): 101–7. PMID 2521199.
  30. ↑ Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990). "Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study". N Engl J Med. 322 (22): 1561–6. doi:10.1056/NEJM199005313222203. PMID 2139921.
  31. ↑ Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK (1996). "The progression from hypertension to congestive heart failure". JAMA. 275 (20): 1557–62. PMID 8622246.
  32. ↑ 32.0 32.1 He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK (2001). "Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study". Arch Intern Med. 161 (7): 996–1002. PMID 11295963.
  33. ↑ Gradman AH, Wilson JT (2009). "Hypertension and diastolic heart failure". Curr Cardiol Rep. 11 (6): 422–9. PMID 19863866.
  34. ↑ Richards AM, Nicholls MG, Troughton RW, Lainchbury JG, Elliott J, Frampton C; et al. (2002). "Antecedent hypertension and heart failure after myocardial infarction". J Am Coll Cardiol. 39 (7): 1182–8. PMID 11923044.
  35. ↑ Levy D, Salomon M, D'Agostino RB, Belanger AJ, Kannel WB (1994). "Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy". Circulation. 90 (4): 1786–93. PMID 7923663.
  36. ↑ Stamler R, Stamler J, Schoenberger JA, Shekelle RB, Collette P, Shekelle S; et al. (1979). "Relationship of glucose tolerance to prevalence of ECG abnormalities and to 5-year mortality from cardiovascular disease: findings of the Chicago Heart Association Detection Project in Industry". J Chronic Dis. 32 (11–12): 817–28. PMID 315963.
  37. ↑ Zile MR, Brutsaert DL (2002). "New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function". Circulation. 105 (11): 1387–93. PMID 11901053.
  38. ↑ Kannel WB (2000). "Fifty years of Framingham Study contributions to understanding hypertension". J Hum Hypertens. 14 (2): 83–90. PMID 10723112.
  39. ↑ Flack JM, Neaton JD, Daniels B, Esunge P (1993). "Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study". Am J Kidney Dis. 21 (4 Suppl 1): 31–40. PMID 8465834.
  40. ↑ 40.0 40.1 40.2 Zoccali C (2006). "Endothelial dysfunction and the kidney: emerging risk factors for renal insufficiency and cardiovascular outcomes in essential hypertension". J Am Soc Nephrol. 17 (4 Suppl 2): S61–3. doi:10.1681/ASN.2005121344. PMID 16565249.
  41. ↑ "National High Blood Pressure Education Program Working Group report on hypertension and chronic renal failure". Arch Intern Med. 151 (7): 1280–7. 1991. PMID 2064478.
  42. ↑ 42.0 42.1 42.2 42.3 Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG; et al. (1989). "Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group". Hypertension. 13 (5 Suppl): I80–93. PMID 2490833.
  43. ↑ Walker WG, Neaton JD, Cutler JA, Neuwirth R, Cohen JD (1992). "Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group". JAMA. 268 (21): 3085–91. PMID 1433739.
  44. ↑ Tso MO, Jampol LM (1982). "Pathophysiology of hypertensive retinopathy". Ophthalmology. 89 (10): 1132–45. PMID 7155524.
  45. ↑ 45.0 45.1 45.2 45.3 Wong TY, Wong T, Mitchell P (2007). "The eye in hypertension". Lancet. 369 (9559): 425–35. doi:10.1016/S0140-6736(07)60198-6. PMID 17276782.
  46. ↑ 46.0 46.1 46.2 Wong TY, Mitchell P (2004). "Hypertensive retinopathy". N Engl J Med. 351 (22): 2310–7. doi:10.1056/NEJMra032865. PMID 15564546.
  47. ↑ Cugati S, Wang JJ, Rochtchina E, Mitchell P (2006). "Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study". Arch Ophthalmol. 124 (5): 726–32. doi:10.1001/archopht.124.5.726. PMID 16682596.
  48. ↑ 48.0 48.1 Clement DL, De Buyzere ML, Duprez DA (2004). "Hypertension in peripheral arterial disease". Curr Pharm Des. 10 (29): 3615–20. PMID 15579058.

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