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How Should We Treat Hypertensive Women With Cardiac and Renal Impairment?
AJH
1997;10:242S–246S
How Should We Treat Hypertensive Women With Cardiac and Renal Impairment? Luis M. Ruilope and Carmen Suarez
Arterial hypertension is the most common chronic medical condition requiring office visits to physicians and is a major contributing factor to the development of myocardial infarction and stroke. Its importance as a cardiovascular risk factor is at least as significant in women as in men; however, the ever-growing literature on hypertension shows surprisingly little data concerning sex differences. Large clinical trials of antihypertensive treatment have not clearly demonstrated gender differences in blood pressure response and outcome, but the majority of patients in these trials were men. Even so, some evidence indicates that white women treated for hypertension obtain less benefit than
men. The pathophysiology of hypertension in men and women is similar in many aspects, but important gender differences are now emerging. Studies designed to clarify these differences are required, as a better knowledge of the underlying mechanisms will allow for a more precise stratification of risk and a more accurate approach to both nonpharmacologic and pharmacologic treatment. Am J Hypertens 1997;10:242S–246S © 1997 American Journal of Hypertension, Ltd.
H
argue in favor of comparable thresholds for intervention in men and women. In any case, in women ,65 years particular attention should be paid to glucose intolerance, hyperlipidemia, and left ventricular hypertrophy (LVH) in the presence of hypertension, because these factors increase the risk of coronary disease in middle-aged women.13 LVH is an independent risk factor for myocardial infarction and death in men and women with hypertension,14,15 as well as in asymptomatic subjects with normal blood pressure.16 Given the prognostic importance of LVH, it has been proposed that it is appropriate to look for LVH in all patients at risk.17 On the other hand, the renal consequences of untreated arterial hypertension, defined as a sustained diastolic blood pressure .90 mm Hg, were described for both men and women by Perera.18 Almost half of his hypertensive population developed proteinuria during follow-up and 18% developed chronic renal failure. Since then, the prognosis for renal function has improved dramatically in treated hypertensives.
ypertensive women have increased relative risks for both coronary disease (relative risk 3.5) and stroke (relative risk 2.6) compared with normotensive women.1 Coronary artery disease is the leading cause of death in women,2– 4 although the incidence is lower in women ,65 years than in men.5,6 Because event rates are lower in middle-aged women compared with men of a similar age,3,6 higher treatment thresholds have been recommended for women.7–9 However, the demonstration in the Framingham study that women develop coronary artery disease at the same rate as men (albeit 6 to 10 years later10), the benefits obtained in recently published trials of hypertension in the elderly,11,12 and the similar risk for stroke in both sexes,5
From the Unidad de Hipertensio´n, Hospital 12 de Octubre and Hospital dela Pricesa, Madrid, Spain. Address correspondence and reprint requests to Dr. Luis M Ruilope, Unidad de Hipertensio´n, Hospital 12 de Octubre, 28041 Madrid, Spain.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Essential hypertension, cardiovascular risk, nephrosclerosis, microalbuminuria, left ventricular hypertrophy.
0895-7061/97/$17.00 PII S0895-7061(97)00330-0
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
However, some recent data19 indicate that investigation of renal function in the hypertensive population could be of value for stratifying of cardiovascular risk and for guiding therapeutic behavior. Elevated serum creatinine,20,21 proteinuria,22 and microalbuminuria23,24 in hypertensive patients indicate that their cardiovascular risk is significantly increased. Furthermore, in middle-aged women urinary excretion of high molecular weight b-thromboglobulin and albumin have been shown to be markers of coronary disease risk, indicating that increased platelet activation and endothelial cell disturbance precede coronary heart disease in women.25 DO CARDIOVASCULAR AND RENAL DAMAGE CORRELATE IN ARTERIAL HYPERTENSION? The cardiovascular system is severely affected by the presence of advanced renal failure. In patients on dialysis, cardiovascular mortality is three times that of age- and sex-matched nonuremic controls.26 Increased mortality is associated with a higher frequency of atherosclerotic heart disease, myocardial infarction, LVH, and congestive heart failure. Poor control of intravascular volume, arterial hypertension, and hyperlipidemia are among the most relevant factors leading to cardiovascular death.26 In essential hypertension, there is a correlation between renal damage and an increased rate of cardiovascular death after the early stages of renal damage. In this scenario, elevated serum creatinine and the presence of proteinuria are potent predictors of mortality.20 –22 Hypertensive subjects examined at autopsy are often found to have nephrosclerosis, hardening of the arterioles and arteries of the kidney.27,28 The pathology of this condition is characterized by the presence of hyalinized arterioles and by fibroplastic intimal thickening in small arteries. The presence of hyalinization in the renal arterioles is a marker of the presence of advanced coronary atherosclerosis in otherwise asymptomatic young men and women.29,30 Microalbuminuria (urinary albumin excretion, 30 to 300 mg/day) is a predictor of increased cardiovascular morbidity and mortality in diabetic and nondiabetic populations.31 In essential hypertension, it is associated with factors that increase cardiovascular risk, such as endothelial dysfunction, insulin resistance, LVH, hyperlipidemia, and higher body mass index.31 Recently, it has been shown that microalbuminuria correlates with a high cardiovascular risk in patients with essential hypertension.23,24 Microalbuminuria occurs in 10 to 25% of nondiabetic patients with hypertension and represents the renal expression of a generalized disorder, characterized by increased endothelial cell permeability, underlying the link between elevated urinary albumin excretion and increased car-
HYPERTENSION IN ELDERLY WOMEN
243S
diovascular risk.31 Interestingly, the presence of microalbuminuria has been shown to correlate with LVH32,33 and with increased thickness of the carotid artery wall,34 which correlates with left ventricular mass.35 DO ALL ANTIHYPERTENSIVE DRUGS CONTRIBUTE EQUALLY TO DECREASE CARDIOVASCULAR AND RENAL RISK? The ability of antihypertensive therapy to reduce cardiovascular morbidity and mortality has been well described.36 Furthermore, a recent publication containing data from the Framingham study37 suggests that the long-term benefits of controlling hypertension for reducing cardiovascular disease and total mortality may be much greater than the benefits observed in previous shorter term clinical trials. Benefits among women followed in the Framingham study consisted of a 39% decrease in all-cause mortality and a 53% decrease in cardiovascular mortality. Whether different types of antihypertensive drugs have a similar capacity to reduce cardiovascular morbidity and mortality will become apparent over the next few years with the completion of numerous, large, on-going studies of cardiovascular morbidity and mortality in hypertensive patients. Meanwhile, some data indicate that the capacity of different drugs to facilitate the regression of LVH and microalbuminuria, which may reduce the overall risk of cardiovascular mortality, varies considerably. According to a metaanalysis published by Dahlo¨f et al in 1992,38 regression of LVH was clearly increased after administration of angiotensin converting enzyme (ACE) inhibitors. In a recently published metaanalysis, Schmieder et al39 confirmed that ACE inhibitors are significantly better than diuretics and b-blockers in reducing increased left ventricular mass, whereas the effectiveness of calcium channel blockers lies somewhere between that of standard therapy and the ACE inhibitors (Figure 1). Moreover, the advantages of ACE inhibitors for cardiac and vascular protection seem to go beyond their ability to reduce increased left ventricular mass. Evidence has shown that ACE inhibitors produce cardioprotective and vasculoprotective effects by a number of mechanisms including restoration of the balance between myocardial oxygen supply and demand, reduction of left ventricular preload and afterload, reduction of sympathetic stimulation, antiproliferative and antimigratory effects on smooth mucles cells, improvement of endothelial function, antiplatelet effects, and improvements in arterial compliance and tone.40 In addition, ACE inhibitors may have beneficial effects on reperfusion injury, direct antiatherogenic effects, produce protection from plaque rupture, and enhance endogenous fibrinolysis, al-
244S
RUILOPE ET AL
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
FIGURE 1. Effect of different classes of antihypertensive agents on regression of left ventricular hypertrophy.
though as yet these characteristics have not been demonstrated conclusively in humans. ACE inhibitors facilitate the regression of remodeling41 and improve endothelial function42 in the arterioles of hypertensive patients. Such effects could account for the results of a recent 3-year follow-up study, which found that ACE inhibitors have a greater capacity than b-blockers to reduce deterioration in renal function in essential hypertensives (Figures 2 and 3).43 In this study, patients on standard antihypertensive therapy of diuretics and b-blockers were randomized to continue the same therapy or to switch to nitrendipine or quinapril. Both therapeutic regimens achieved a similar reduction in blood pressure; however, only quinapril reduced the glomerular filtration rate and reduced urinary excretion of albumin.43 A subsequent study of patients with essential hypertension has also demonstrated that ACE inhibitors are more effective than diuretics, b-blockers, and calcium channel blockers in reducing urinary albumin excretion.44 ACE inhibitors have also been shown to reduce the increase in serum creatinine concentrations in patients with nondiabetic nephropathies45 and to decrease the rate of decline in creatinine clearance and reduce the risk of death, renal dialysis, and transplantation in patients with diabetic nephropathies.46 Unfortunately, specific data on the regression of LVH and on decreases in urinary albumin excretion in hypertensive women are lacking. For this reason, any study examining either of these two parameters in women with arterial hypertension would be welcomed. SUMMARY The importance of arterial hypertension as a cardiovascular risk factor seems to be similar for both women and men. However, a higher threshold be-
FIGURE 2. Effect of nitrendipine (NT) and standard therapy (ST) with diuertics and b-blockers on (a) blood pressure, (b) renal plasma flow and glomerular filtration rate, and (c) urinary albumin excretion.
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
HYPERTENSION IN ELDERLY WOMEN
245S
REFERENCES
FIGURE 3. Effect of quinapril (QUIN) and standard therapy (ST) with diuretics and b-blockers on (a) blood pressure, (b) renal plasma flow and glomerular filtration rate, and (c) urinary albumin excretion.
fore initiating antihypertensive therapy may be indicated for women because of the lower prevalence of cardiovascular events in middle-aged women compared with men. Risk stratification has also been considered to lower the threshold for initiation of antihypertensive therapy. In this case, LVH and microalbuminuria are among the risk factors that should prompt earlier administration of pharmacologic therapy to hypertensive women. Studies are needed to investigate the effectiveness of different antihypertensive drugs on facilitating the regression of LVH and microalbuminuria in women presenting with arterial hypertension.
1.
Fiebach NH, Hebert PR, Stampfer MJ, et al: A prospective study of high blood pressure and cardiovascular disease in women. Am J Epidemiol 1989;130:646 – 654.
2.
Kaplan NM: The treatment of hypertension in women. Arch Intern Med 1995;155:563–567.
3.
Anastos K, Charney P, Charon RA, et al: Hypertension in women: what is really known? Ann Intern Med 1991;115:287–293.
4.
Bittner V: Hypertension in women. Curr Opin Nephrol Hypertens 1995;4:204 –207.
5.
Isles C: Blood pressure in males and females. J Hypertens 1995;13:285–290.
6.
Isles CG, Hole DJ, Hawthorne VM, Lever AF: Relation between coronary risk and coronary mortality in women of the Renfrew and Paisley survey: comparison with men. Lancet 1992;339:702–706.
7.
Medical Research Working Party: MRC trial of treatment of mild hypertension. Br Med J 1985;291:97–104.
8.
Sever P, Beevers G, Bulpitt C, et al: Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. Br Med J 1993;306:983–987.
9.
Jackson R, Barham P, Bills J, et al: Management of raised blood pressure in New Zealand: a discussion document. Br Med J 1993;307:107–110.
10.
Castelli WP: Cardiovascular disease in women. Am J Obstet Gynaecol 1988;158:1553–1560.
11.
Dahlo¨f B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet 1991;338: 1281–1285.
12.
MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1993;328:914 –921.
13.
Kannel WB, Wilson PW: Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57– 61.
14.
Casale PN, Devereux RB, Milner M, et al: Value of echocardiographic measurement of left ventricular hypertrophy among employed patients with uncomplicated hypertension. Ann Intern Med 1986;105:173–178.
15.
Koren MJ, Devereux RB, Casale PN, et al: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352.
16.
Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–1566.
17.
Chambers J: Left ventricular hypertrophy. An underappreciated coronary risk factor. Br Med J 1995;311: 273–274.
18.
Perera GA: Hypertensive vascular disease: description and natural history. J Chronic Dis 1955;1:33– 42.
19.
Ruilope LM, Campo C, Rodriguez-Artalejo F, et al: Blood pressure and renal function: therapeutic implications. J Hypertens 1996;14:1259 –1263.
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20.
21.
22.
Shulman NB, Ford CE, Hall WD, et al: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the Hypertension Detection and Follow-up Program. Hypertension 1989;13(suppl I):1-80 –1-93. Aronow WS: Usefulness of serum creatinine as a marker for coronary events in elderly patients with either systemic hypertension or diabetes mellitus. Am J Cardiol 1991;68:678 – 679. Samuelsson O: Hypertension in middle-aged man: management, morbidity and prognostic factors during long-term hypertensive care. Acta Med Scand 1985; 702(suppl):1–79.
23.
Agrawal B, Berger A, Wolf K, Luft FC: Microalbuminuria screening by reagent strip predicts cardiovascular risk in hypertension. J Hypertens 1996;14:223–228.
24.
Ljungman S, Wikstrand J, Hartford M, Berglund G: Urinary albumin excretion—a predictor or risk of cardiovascular disease: a prospective 10-year follow-up of middle-aged normal and hypertensive men. Am J Hypertens 1996;8:770 –778.
25.
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
RUILOPE ET AL
Gorgels WJ, Van der Graaf Y, Hjendahl R, et al: Urinary excretions of high molecular weight beta-thromboglobulin and albumin are independently associated with coronary heart disease in women—a nested case-control study of middle-aged women in the Diagnostich Onderzoek Mammacarcinoom (DOM) cohort, Utrecht, The Netherlands. Am J Epidemiol 1995;192:1157–1164.
26.
Rostand SG, Brunzell JD, Cannon RO, Victor RG: Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053–1058.
27.
Takazakura E, Sawabu N, Handa A, et al: Intrarenal vascular changes with age and disease. Kidney Int 1972;2:224 –230.
28.
Tracy RE, Bhandaru SY, Oalmann MC, et al: Blood pressure and nephrosclerosis in black and white men and women aged 25 to 54. Mod Pathol 1991;4:602– 609.
29.
Tracy RE, Malcom GT, Oalmann MC, et al: Nephrosclerosis in coronary heart disease. Mod Pathol 1994;7:301– 309.
30.
Tracy RE, Strong JP, Newman III WP, et al: Renovasculopathies of nephrosclerosis in relation to atherosclerosis at ages 25–54 years. Kidney Int 1996;49:564 –570.
31.
Ruilope LM, Rodicio JL: Microalbuminuria in clinical practice. Kidney: A Current Survey of World Literature. 1995;4:211–216.
32.
Cerasola G, Cottone S, Mule G, et al: Microalbuminuria, renal dysfunction and cardiovascular complications in essential hypertension. J Hypertens 1996;14: 915–920.
33.
Redon J, Gomez-Sanchez MA, Baldo E, et al: Microalbuminuria is correlated with left ventricular hypertrophy in male hypertensive patients. J Hypertens 1991;9(suppl 6):S148 –S149.
34.
Bigazzi R, Bianchi G, Nanci R, et al: Increased thickness
of the carotid artery in patients with essential hypertension and microalbuminuria. J Hum Hypertens 1995; 9:827– 833. 35.
Roman MJ, Pickering TG, Schwartz JE, et al: Association of carotid atherosclerosis and left ventricular hypertrophy. J Am Coll Cardiol 1995;125:83–90.
36.
Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease, Part 2: Short-term reductions in blood pressure: overview of randomised drug trials in the epidemiological context. Lancet 1990; 335:827– 838.
37.
Sytkowski PA, D’Agostino RB, Belanger AJ, Kannel WB: Secular trends in long-term sustained hypertension, long-term treatment and cardiovascular mortality. Circulation 1996;93:697–703.
38.
Dahlo¨f B, Pennert K, Hansson L: Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens 1992; 5:95–110.
39.
Schmieder RE, Martus P, Klingbell A: Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996;275:1507–1513.
40.
Lonn EM, Yusuf S, Jha P, et al: Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056 –2069.
41.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456 –1462.
42.
Maschio G, Alberti D, Janin G, et al, and the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensinconverting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996;334:939 –945.
43.
Ruilope LM, Alcazar JM, Hernandez E, et al: Long-term influences of antihypertensive therapy on microalbuminuria in essential hypertension. Kidney Int 1994; 45(suppl 45):S171–S173.
44.
Himmelmann A, Hansson L, Hansson BG, et al: ACE inhibition preserves renal function better than betablockade in the treatment of essential hypertension. Blood Pressure 1995;4:85–90.
45.
Schiffrin EL, Deng LY: Comparison of the effects of angiotensin I-converting enzyme inhibition and betablockade for 2 years on function of small arteries from hypertensive patients. Hypertension 1995;25(part 2):699 –703.
46.
Sihn I, Shroeder AP, Aalkjaer C, et al: Regression of media-to-lumen ratio of human subcutaneous arteries and left ventricular hypertrophy during treatment with an angiotensin-converting enzyme inhibitor based regimen in hypertensive patients. Am J Cardiol 1995;76: 38E– 40E.
1997;10:242S–246S
How Should We Treat Hypertensive Women With Cardiac and Renal Impairment? Luis M. Ruilope and Carmen Suarez
Arterial hypertension is the most common chronic medical condition requiring office visits to physicians and is a major contributing factor to the development of myocardial infarction and stroke. Its importance as a cardiovascular risk factor is at least as significant in women as in men; however, the ever-growing literature on hypertension shows surprisingly little data concerning sex differences. Large clinical trials of antihypertensive treatment have not clearly demonstrated gender differences in blood pressure response and outcome, but the majority of patients in these trials were men. Even so, some evidence indicates that white women treated for hypertension obtain less benefit than
men. The pathophysiology of hypertension in men and women is similar in many aspects, but important gender differences are now emerging. Studies designed to clarify these differences are required, as a better knowledge of the underlying mechanisms will allow for a more precise stratification of risk and a more accurate approach to both nonpharmacologic and pharmacologic treatment. Am J Hypertens 1997;10:242S–246S © 1997 American Journal of Hypertension, Ltd.
H
argue in favor of comparable thresholds for intervention in men and women. In any case, in women ,65 years particular attention should be paid to glucose intolerance, hyperlipidemia, and left ventricular hypertrophy (LVH) in the presence of hypertension, because these factors increase the risk of coronary disease in middle-aged women.13 LVH is an independent risk factor for myocardial infarction and death in men and women with hypertension,14,15 as well as in asymptomatic subjects with normal blood pressure.16 Given the prognostic importance of LVH, it has been proposed that it is appropriate to look for LVH in all patients at risk.17 On the other hand, the renal consequences of untreated arterial hypertension, defined as a sustained diastolic blood pressure .90 mm Hg, were described for both men and women by Perera.18 Almost half of his hypertensive population developed proteinuria during follow-up and 18% developed chronic renal failure. Since then, the prognosis for renal function has improved dramatically in treated hypertensives.
ypertensive women have increased relative risks for both coronary disease (relative risk 3.5) and stroke (relative risk 2.6) compared with normotensive women.1 Coronary artery disease is the leading cause of death in women,2– 4 although the incidence is lower in women ,65 years than in men.5,6 Because event rates are lower in middle-aged women compared with men of a similar age,3,6 higher treatment thresholds have been recommended for women.7–9 However, the demonstration in the Framingham study that women develop coronary artery disease at the same rate as men (albeit 6 to 10 years later10), the benefits obtained in recently published trials of hypertension in the elderly,11,12 and the similar risk for stroke in both sexes,5
From the Unidad de Hipertensio´n, Hospital 12 de Octubre and Hospital dela Pricesa, Madrid, Spain. Address correspondence and reprint requests to Dr. Luis M Ruilope, Unidad de Hipertensio´n, Hospital 12 de Octubre, 28041 Madrid, Spain.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Essential hypertension, cardiovascular risk, nephrosclerosis, microalbuminuria, left ventricular hypertrophy.
0895-7061/97/$17.00 PII S0895-7061(97)00330-0
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
However, some recent data19 indicate that investigation of renal function in the hypertensive population could be of value for stratifying of cardiovascular risk and for guiding therapeutic behavior. Elevated serum creatinine,20,21 proteinuria,22 and microalbuminuria23,24 in hypertensive patients indicate that their cardiovascular risk is significantly increased. Furthermore, in middle-aged women urinary excretion of high molecular weight b-thromboglobulin and albumin have been shown to be markers of coronary disease risk, indicating that increased platelet activation and endothelial cell disturbance precede coronary heart disease in women.25 DO CARDIOVASCULAR AND RENAL DAMAGE CORRELATE IN ARTERIAL HYPERTENSION? The cardiovascular system is severely affected by the presence of advanced renal failure. In patients on dialysis, cardiovascular mortality is three times that of age- and sex-matched nonuremic controls.26 Increased mortality is associated with a higher frequency of atherosclerotic heart disease, myocardial infarction, LVH, and congestive heart failure. Poor control of intravascular volume, arterial hypertension, and hyperlipidemia are among the most relevant factors leading to cardiovascular death.26 In essential hypertension, there is a correlation between renal damage and an increased rate of cardiovascular death after the early stages of renal damage. In this scenario, elevated serum creatinine and the presence of proteinuria are potent predictors of mortality.20 –22 Hypertensive subjects examined at autopsy are often found to have nephrosclerosis, hardening of the arterioles and arteries of the kidney.27,28 The pathology of this condition is characterized by the presence of hyalinized arterioles and by fibroplastic intimal thickening in small arteries. The presence of hyalinization in the renal arterioles is a marker of the presence of advanced coronary atherosclerosis in otherwise asymptomatic young men and women.29,30 Microalbuminuria (urinary albumin excretion, 30 to 300 mg/day) is a predictor of increased cardiovascular morbidity and mortality in diabetic and nondiabetic populations.31 In essential hypertension, it is associated with factors that increase cardiovascular risk, such as endothelial dysfunction, insulin resistance, LVH, hyperlipidemia, and higher body mass index.31 Recently, it has been shown that microalbuminuria correlates with a high cardiovascular risk in patients with essential hypertension.23,24 Microalbuminuria occurs in 10 to 25% of nondiabetic patients with hypertension and represents the renal expression of a generalized disorder, characterized by increased endothelial cell permeability, underlying the link between elevated urinary albumin excretion and increased car-
HYPERTENSION IN ELDERLY WOMEN
243S
diovascular risk.31 Interestingly, the presence of microalbuminuria has been shown to correlate with LVH32,33 and with increased thickness of the carotid artery wall,34 which correlates with left ventricular mass.35 DO ALL ANTIHYPERTENSIVE DRUGS CONTRIBUTE EQUALLY TO DECREASE CARDIOVASCULAR AND RENAL RISK? The ability of antihypertensive therapy to reduce cardiovascular morbidity and mortality has been well described.36 Furthermore, a recent publication containing data from the Framingham study37 suggests that the long-term benefits of controlling hypertension for reducing cardiovascular disease and total mortality may be much greater than the benefits observed in previous shorter term clinical trials. Benefits among women followed in the Framingham study consisted of a 39% decrease in all-cause mortality and a 53% decrease in cardiovascular mortality. Whether different types of antihypertensive drugs have a similar capacity to reduce cardiovascular morbidity and mortality will become apparent over the next few years with the completion of numerous, large, on-going studies of cardiovascular morbidity and mortality in hypertensive patients. Meanwhile, some data indicate that the capacity of different drugs to facilitate the regression of LVH and microalbuminuria, which may reduce the overall risk of cardiovascular mortality, varies considerably. According to a metaanalysis published by Dahlo¨f et al in 1992,38 regression of LVH was clearly increased after administration of angiotensin converting enzyme (ACE) inhibitors. In a recently published metaanalysis, Schmieder et al39 confirmed that ACE inhibitors are significantly better than diuretics and b-blockers in reducing increased left ventricular mass, whereas the effectiveness of calcium channel blockers lies somewhere between that of standard therapy and the ACE inhibitors (Figure 1). Moreover, the advantages of ACE inhibitors for cardiac and vascular protection seem to go beyond their ability to reduce increased left ventricular mass. Evidence has shown that ACE inhibitors produce cardioprotective and vasculoprotective effects by a number of mechanisms including restoration of the balance between myocardial oxygen supply and demand, reduction of left ventricular preload and afterload, reduction of sympathetic stimulation, antiproliferative and antimigratory effects on smooth mucles cells, improvement of endothelial function, antiplatelet effects, and improvements in arterial compliance and tone.40 In addition, ACE inhibitors may have beneficial effects on reperfusion injury, direct antiatherogenic effects, produce protection from plaque rupture, and enhance endogenous fibrinolysis, al-
244S
RUILOPE ET AL
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
FIGURE 1. Effect of different classes of antihypertensive agents on regression of left ventricular hypertrophy.
though as yet these characteristics have not been demonstrated conclusively in humans. ACE inhibitors facilitate the regression of remodeling41 and improve endothelial function42 in the arterioles of hypertensive patients. Such effects could account for the results of a recent 3-year follow-up study, which found that ACE inhibitors have a greater capacity than b-blockers to reduce deterioration in renal function in essential hypertensives (Figures 2 and 3).43 In this study, patients on standard antihypertensive therapy of diuretics and b-blockers were randomized to continue the same therapy or to switch to nitrendipine or quinapril. Both therapeutic regimens achieved a similar reduction in blood pressure; however, only quinapril reduced the glomerular filtration rate and reduced urinary excretion of albumin.43 A subsequent study of patients with essential hypertension has also demonstrated that ACE inhibitors are more effective than diuretics, b-blockers, and calcium channel blockers in reducing urinary albumin excretion.44 ACE inhibitors have also been shown to reduce the increase in serum creatinine concentrations in patients with nondiabetic nephropathies45 and to decrease the rate of decline in creatinine clearance and reduce the risk of death, renal dialysis, and transplantation in patients with diabetic nephropathies.46 Unfortunately, specific data on the regression of LVH and on decreases in urinary albumin excretion in hypertensive women are lacking. For this reason, any study examining either of these two parameters in women with arterial hypertension would be welcomed. SUMMARY The importance of arterial hypertension as a cardiovascular risk factor seems to be similar for both women and men. However, a higher threshold be-
FIGURE 2. Effect of nitrendipine (NT) and standard therapy (ST) with diuertics and b-blockers on (a) blood pressure, (b) renal plasma flow and glomerular filtration rate, and (c) urinary albumin excretion.
AJH–OCTOBER 1997–VOL. 10, NO. 10, PART 2
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REFERENCES
FIGURE 3. Effect of quinapril (QUIN) and standard therapy (ST) with diuretics and b-blockers on (a) blood pressure, (b) renal plasma flow and glomerular filtration rate, and (c) urinary albumin excretion.
fore initiating antihypertensive therapy may be indicated for women because of the lower prevalence of cardiovascular events in middle-aged women compared with men. Risk stratification has also been considered to lower the threshold for initiation of antihypertensive therapy. In this case, LVH and microalbuminuria are among the risk factors that should prompt earlier administration of pharmacologic therapy to hypertensive women. Studies are needed to investigate the effectiveness of different antihypertensive drugs on facilitating the regression of LVH and microalbuminuria in women presenting with arterial hypertension.
1.
Fiebach NH, Hebert PR, Stampfer MJ, et al: A prospective study of high blood pressure and cardiovascular disease in women. Am J Epidemiol 1989;130:646 – 654.
2.
Kaplan NM: The treatment of hypertension in women. Arch Intern Med 1995;155:563–567.
3.
Anastos K, Charney P, Charon RA, et al: Hypertension in women: what is really known? Ann Intern Med 1991;115:287–293.
4.
Bittner V: Hypertension in women. Curr Opin Nephrol Hypertens 1995;4:204 –207.
5.
Isles C: Blood pressure in males and females. J Hypertens 1995;13:285–290.
6.
Isles CG, Hole DJ, Hawthorne VM, Lever AF: Relation between coronary risk and coronary mortality in women of the Renfrew and Paisley survey: comparison with men. Lancet 1992;339:702–706.
7.
Medical Research Working Party: MRC trial of treatment of mild hypertension. Br Med J 1985;291:97–104.
8.
Sever P, Beevers G, Bulpitt C, et al: Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. Br Med J 1993;306:983–987.
9.
Jackson R, Barham P, Bills J, et al: Management of raised blood pressure in New Zealand: a discussion document. Br Med J 1993;307:107–110.
10.
Castelli WP: Cardiovascular disease in women. Am J Obstet Gynaecol 1988;158:1553–1560.
11.
Dahlo¨f B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet 1991;338: 1281–1285.
12.
MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1993;328:914 –921.
13.
Kannel WB, Wilson PW: Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57– 61.
14.
Casale PN, Devereux RB, Milner M, et al: Value of echocardiographic measurement of left ventricular hypertrophy among employed patients with uncomplicated hypertension. Ann Intern Med 1986;105:173–178.
15.
Koren MJ, Devereux RB, Casale PN, et al: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352.
16.
Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–1566.
17.
Chambers J: Left ventricular hypertrophy. An underappreciated coronary risk factor. Br Med J 1995;311: 273–274.
18.
Perera GA: Hypertensive vascular disease: description and natural history. J Chronic Dis 1955;1:33– 42.
19.
Ruilope LM, Campo C, Rodriguez-Artalejo F, et al: Blood pressure and renal function: therapeutic implications. J Hypertens 1996;14:1259 –1263.
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20.
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