European Heart Journal (1992) 13 {Supplement A), 49-52
Cardiovascular risk factors and antihypertensive treatment L.
HANSSON
Department of Medicine, University of Goteborg, Ostra Hospital, S-41685 Goteborg, Sweden
Introduction The dangers of markedly elevated arterial pressure were recognized in the 1950s. In particular, malignant hypertension in the untreated state was known to cause a near 100% 5-year mortality111. With the availability of active and reasonably well tolerated antihypertensive agents, prognosis in this dreaded form of hypertension improved markedly and in 1979 a 75% 5-year survival rate could be reported'21. In non-malignant forms of hypertension the value of antihypertensive therapy has also become firmly established. For a review of the relevant studies in malignant as well as non-malignant hypertension the reader is referred to Hansson and DahlGf 199C3'. Scientific interest in this area has been remarkable in recent years. Two areas have attracted particular attention: firstly, the extent to which elevated arterial pressure can be brought under control with antihypertensive agents and the potential benefits and disadvantages of such treatment, and secondly, the importance of novel risk factors such as echocardiographically determined left ventricular hypertrophy, abdominal obesity, insulin resistance etc. We briefly review these areas here. The value of blood pressure lowering therapy As noted above, this area was reviewed in some detail in 1990131. Today there is little doubt that lowering of elevated arterial pressure conveys a number of benefits, such as improved survival in malignant hypertension12-3' as well as reduced morbidity in non-malignant hypertension'3'. In addition, in 1991 the Systolic Hypertension in the Elderly Program (SHEP) clearly showed that in almost 5000 individuals aged 60 years or above with isolated systolic hypertension that blood pressure lowering therapy reduced the risk of stroke by 36%'4'. Moreover, in 1991 the results of the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) showed, in a double-blind, placebo-controlled trial in hypertensive patients aged 70-84 years, that active antihypertensive therapy reduced stroke morbidity and mortality, cardiovascular morbidity as well as total mortality151. Against this background it is obvious that the benefits of antihypertensive treatment are established beyond doubt. Even so, it would appear that the therapeutic effects of antihypertensive treatment may Correspondence: Dr L. Hansson, Department of Medicine, University of GOteborg, 6stra Hospital, S-41685 Goteborg, Sweden.
0195-668X/92/0A0049 + 04 $03.00/0
be suboptimal in some regards. Thus, in the Dalby study, cardiovascular morbidity was significantly more prevalent in several age groups of treated hypertensive patients as compared to normotensive subjects as exemplified in Table I16'. As can be seen, the blood pressure in the treated patients, although lowered by an average of 24/23 mmHg, was still significantly higher than that in the normotensive control subjects. This could be one explanation for the over-morbidity experienced in this study. In the Glasgow Blood Pressure Clinic Study, which evaluated mortality in treated hypertensive patients over a 6-5-year period, treated patients were found to have two to five times higher mortality than two control populations near Glasgow, with benefits of treatment being most pronounced in those patients in whom blood pressure had been lowered most17'. These two examples illustrate that perhaps the full benefits of antihypertensive treatment are not seen because blood pressure has not been lowered vigorously enough. This aspect is being investigated in the BBB Study (Behandla Blodtryck Battre), in which patients with treated hypertension are randomized to either intensified treatment or unchanged treatment' 8 '. Interim results from the BBB Study show that blood pressure can be reduced further, on average 7 mmHg in diastolic blood pressure, and that this difference can be maintained over several years'9'. Perhaps surprisingly, the further fall in blood pressure, due to an increase in the number of antihypertensive drugs prescribed, was associated with a significant reduction in the number and severity of adverse effects (Table 2"'). The implications of the so called J-shaped curve phenomenon must be considered in this context. However, the two studies published so far, in which a clear warning against a lowering of the diastolic blood pressure to below 85-90 mmHg or against an excessive lowering of diastolic blood pressure (> 17 mmHg) have been criticized'10' and further comments are hardly justified here. The suboptimal lowering of blood pressure in some important intervention trials and hypertension centres are illustrated in Table 3'3). As can be seen, between 20% and 50% of all patients in these series failed to obtain the listed goal blood pressure. The potentially negative effects of antihypertensive compounds on other risk factors, in particular serum lipoproteins, have attracted much interest. As an example, data from the Multiple Risk Factor Intervention Trial (MRFTT) show that administration of various © 1992 The European Society of Cardiology
50 L. Hansson
Table 1 Three-year retrospective analysis of morbidity in treated male hypertensive patients aged 40-59 years in comparison with age- and sex-matched normotensive subjects in Dalby, Sweden * Morbidity
Treated patients (n = 66)
Controls (n = 75)
P value
21% 2% 20% 2% 8%
1% 0% 1% 0% 5%
2000 patients we found that calculated left ventricular mass was positively affected by most antihypertensive agents'13'. However, whereas many agents reduced wall thickness in the heart, diuretics affected left ventricular mass only by reducing the diastolic diameter, i.e. the volume of the left ventricle, which is one of the variables used for the calculation of left ventricular mass'13'. To what extent such differences between classes of compounds may affect prognosis remains to be seen. In fact, it remains to be shown that reversal of left ventricular hypertorphy affects prognosis in a positive way, which at present remains a logical possibility. INSULIN RESISTANCE
Links between insulin, insulin sensitivity, obesity and hypertension have been shown by many investigators, leading to the speculation about a certain syndrome in which these factors are linked'14'. It is particularly interesting to note that some antihypertensive compounds, in particular diuretics, have a negative effect on insulin sensitivity, whereas others, in particular those with a vasodilating effect, appear to reduce insulin resistance'14'. At this time it is not known whether a positive effect on insulin resistance will have positive effects on cardiovascular prognosis, but this is certainly an interesting possibility. ABDOMINAL OBESITY
Abdominal obesity, i.e. the male type of obesity leading to an increased waist/hip ratio, as opposed to the female type of fat distribution, has been claimed to constitute a risk factor for cardiovascular morbidity113'. At present it is not clear if various
classes of antihypertensive compounds have significant effects on the male type of fat distribution or to what extent prognosis may be affected by changes in the pattern of fat distribution. Certainly this constitutes a research area of gTeat actuality. Conclusions A number of risk factors for cardiovascular morbidity have been identified. Some of those, in particular arterial hypertension, can be positively affected by treatment, by which risk is reduced. Some of the problems associated with antihypertensive treatment are that blood pressure has probably not been reduced sufficiently in many instances, thereby leaving a residual risk. Moreover, some antihypertensive agents induce potentially negative changes in other risk factors such as serumlipoproteins, insulin sensitivity and serum uric acid. It is conceivable that such changes may offset some of the benefits derived from the reduction in blood pressure. Other novel risk factors, such as left ventricular hypertrophy, may also be positively affected by antihypertensive drug treatment, i.e. a reversal of cardiac hypertrophy may be obtained. It remains to be shown whether this will result in improved prognosis. Finally, other novel risk factors such as the male type of fat distribution are associated with increased cardiovascular risks. In this area much further research remains until possible differences between antihypertensive drugs are elucidated and to what extent reversal of the male type of fat distribution may affect prognosis. References [1] Pickering GW, Cranston WI, Pears MA. The treatment of hypertension. Springfield: Charles C Thomas, 1961. [2] Gudbrandsson T, Hansson L, Herlitz H, AndriSn L. Malignant hypertension—improving prognosis in a rare disease. Acta Med Scand 1979; 206:495-99. [3] Hansson L, DahlSf B. What are we really achieving with long-term antihypertensive drug therapy? In: Largh JH, Brenner BM, eds Hypertension: pathophysiology, diagnosis and management. New York: Raven Press, 1990: 2131-41. [4] SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255-64. [5] DahlOf B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338: 1281^5^ [6] Lindholm L, Ejlertsson G, Scherste'n B. High risks of cerebro-cardiovascular morbidity in well treated male hypertensives. A retrospective study of 40-59-year-old hypertensives in a Swedish primary care district. Acta Med Scand 1984; 216: 251-9. [7] Isles CG, Walker LM, Beevers DG et al. Mortality in patients of the Glasgow blood pressure clinic. J Hypertension 1986; 4: 141-56. [8] The BBB Study Group. The BBB Study: A prospective randomized study of intensified antihypcrtensive treatment. J Hypertens 1988; 6: 693-7.
52 L. Hansson
[9] Hansson L, Dahldf B, Abelin J. Reduction in blood pressure and adverse effects in the BBB Study. (Abstract). Presented at the European Society of Hypertension Meeting in Milan, June 1991. [10] Hansson L. How far should blood pressure be towered? What is the role of the J-curve? Am J Hypertens 1990; 3: 726-9. [11] Grimm Jr RH. The drug treatment of mild hypertension in the Multiple Risk Factor Intervention Trial: a review. Drugs 1986; 31 (Suppl 1): 13-21. [12] Levy D, Garrison RJ, Sagae DD et al. Prognostic implications of echocardiographically determined left
ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: 1561-6. [13] DahlOf 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. [14] Ferrari P, Weidmann P. Insulin, insulin sensitivity and hypertension. J Hypertens 1990; 8: 491-500. [15] Bjorntorp P. The association between obesity, adipose tissue distribution and disease. Acta Med Scand 1988; 223 (Suppl 723): 121-34.
Cardiovascular risk factors and antihypertensive treatment L.
HANSSON
Department of Medicine, University of Goteborg, Ostra Hospital, S-41685 Goteborg, Sweden
Introduction The dangers of markedly elevated arterial pressure were recognized in the 1950s. In particular, malignant hypertension in the untreated state was known to cause a near 100% 5-year mortality111. With the availability of active and reasonably well tolerated antihypertensive agents, prognosis in this dreaded form of hypertension improved markedly and in 1979 a 75% 5-year survival rate could be reported'21. In non-malignant forms of hypertension the value of antihypertensive therapy has also become firmly established. For a review of the relevant studies in malignant as well as non-malignant hypertension the reader is referred to Hansson and DahlGf 199C3'. Scientific interest in this area has been remarkable in recent years. Two areas have attracted particular attention: firstly, the extent to which elevated arterial pressure can be brought under control with antihypertensive agents and the potential benefits and disadvantages of such treatment, and secondly, the importance of novel risk factors such as echocardiographically determined left ventricular hypertrophy, abdominal obesity, insulin resistance etc. We briefly review these areas here. The value of blood pressure lowering therapy As noted above, this area was reviewed in some detail in 1990131. Today there is little doubt that lowering of elevated arterial pressure conveys a number of benefits, such as improved survival in malignant hypertension12-3' as well as reduced morbidity in non-malignant hypertension'3'. In addition, in 1991 the Systolic Hypertension in the Elderly Program (SHEP) clearly showed that in almost 5000 individuals aged 60 years or above with isolated systolic hypertension that blood pressure lowering therapy reduced the risk of stroke by 36%'4'. Moreover, in 1991 the results of the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) showed, in a double-blind, placebo-controlled trial in hypertensive patients aged 70-84 years, that active antihypertensive therapy reduced stroke morbidity and mortality, cardiovascular morbidity as well as total mortality151. Against this background it is obvious that the benefits of antihypertensive treatment are established beyond doubt. Even so, it would appear that the therapeutic effects of antihypertensive treatment may Correspondence: Dr L. Hansson, Department of Medicine, University of GOteborg, 6stra Hospital, S-41685 Goteborg, Sweden.
0195-668X/92/0A0049 + 04 $03.00/0
be suboptimal in some regards. Thus, in the Dalby study, cardiovascular morbidity was significantly more prevalent in several age groups of treated hypertensive patients as compared to normotensive subjects as exemplified in Table I16'. As can be seen, the blood pressure in the treated patients, although lowered by an average of 24/23 mmHg, was still significantly higher than that in the normotensive control subjects. This could be one explanation for the over-morbidity experienced in this study. In the Glasgow Blood Pressure Clinic Study, which evaluated mortality in treated hypertensive patients over a 6-5-year period, treated patients were found to have two to five times higher mortality than two control populations near Glasgow, with benefits of treatment being most pronounced in those patients in whom blood pressure had been lowered most17'. These two examples illustrate that perhaps the full benefits of antihypertensive treatment are not seen because blood pressure has not been lowered vigorously enough. This aspect is being investigated in the BBB Study (Behandla Blodtryck Battre), in which patients with treated hypertension are randomized to either intensified treatment or unchanged treatment' 8 '. Interim results from the BBB Study show that blood pressure can be reduced further, on average 7 mmHg in diastolic blood pressure, and that this difference can be maintained over several years'9'. Perhaps surprisingly, the further fall in blood pressure, due to an increase in the number of antihypertensive drugs prescribed, was associated with a significant reduction in the number and severity of adverse effects (Table 2"'). The implications of the so called J-shaped curve phenomenon must be considered in this context. However, the two studies published so far, in which a clear warning against a lowering of the diastolic blood pressure to below 85-90 mmHg or against an excessive lowering of diastolic blood pressure (> 17 mmHg) have been criticized'10' and further comments are hardly justified here. The suboptimal lowering of blood pressure in some important intervention trials and hypertension centres are illustrated in Table 3'3). As can be seen, between 20% and 50% of all patients in these series failed to obtain the listed goal blood pressure. The potentially negative effects of antihypertensive compounds on other risk factors, in particular serum lipoproteins, have attracted much interest. As an example, data from the Multiple Risk Factor Intervention Trial (MRFTT) show that administration of various © 1992 The European Society of Cardiology
50 L. Hansson
Table 1 Three-year retrospective analysis of morbidity in treated male hypertensive patients aged 40-59 years in comparison with age- and sex-matched normotensive subjects in Dalby, Sweden * Morbidity
Treated patients (n = 66)
Controls (n = 75)
P value
21% 2% 20% 2% 8%
1% 0% 1% 0% 5%
2000 patients we found that calculated left ventricular mass was positively affected by most antihypertensive agents'13'. However, whereas many agents reduced wall thickness in the heart, diuretics affected left ventricular mass only by reducing the diastolic diameter, i.e. the volume of the left ventricle, which is one of the variables used for the calculation of left ventricular mass'13'. To what extent such differences between classes of compounds may affect prognosis remains to be seen. In fact, it remains to be shown that reversal of left ventricular hypertorphy affects prognosis in a positive way, which at present remains a logical possibility. INSULIN RESISTANCE
Links between insulin, insulin sensitivity, obesity and hypertension have been shown by many investigators, leading to the speculation about a certain syndrome in which these factors are linked'14'. It is particularly interesting to note that some antihypertensive compounds, in particular diuretics, have a negative effect on insulin sensitivity, whereas others, in particular those with a vasodilating effect, appear to reduce insulin resistance'14'. At this time it is not known whether a positive effect on insulin resistance will have positive effects on cardiovascular prognosis, but this is certainly an interesting possibility. ABDOMINAL OBESITY
Abdominal obesity, i.e. the male type of obesity leading to an increased waist/hip ratio, as opposed to the female type of fat distribution, has been claimed to constitute a risk factor for cardiovascular morbidity113'. At present it is not clear if various
classes of antihypertensive compounds have significant effects on the male type of fat distribution or to what extent prognosis may be affected by changes in the pattern of fat distribution. Certainly this constitutes a research area of gTeat actuality. Conclusions A number of risk factors for cardiovascular morbidity have been identified. Some of those, in particular arterial hypertension, can be positively affected by treatment, by which risk is reduced. Some of the problems associated with antihypertensive treatment are that blood pressure has probably not been reduced sufficiently in many instances, thereby leaving a residual risk. Moreover, some antihypertensive agents induce potentially negative changes in other risk factors such as serumlipoproteins, insulin sensitivity and serum uric acid. It is conceivable that such changes may offset some of the benefits derived from the reduction in blood pressure. Other novel risk factors, such as left ventricular hypertrophy, may also be positively affected by antihypertensive drug treatment, i.e. a reversal of cardiac hypertrophy may be obtained. It remains to be shown whether this will result in improved prognosis. Finally, other novel risk factors such as the male type of fat distribution are associated with increased cardiovascular risks. In this area much further research remains until possible differences between antihypertensive drugs are elucidated and to what extent reversal of the male type of fat distribution may affect prognosis. References [1] Pickering GW, Cranston WI, Pears MA. The treatment of hypertension. Springfield: Charles C Thomas, 1961. [2] Gudbrandsson T, Hansson L, Herlitz H, AndriSn L. Malignant hypertension—improving prognosis in a rare disease. Acta Med Scand 1979; 206:495-99. [3] Hansson L, DahlSf B. What are we really achieving with long-term antihypertensive drug therapy? In: Largh JH, Brenner BM, eds Hypertension: pathophysiology, diagnosis and management. New York: Raven Press, 1990: 2131-41. [4] SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255-64. [5] DahlOf B, Lindholm LH, Hansson L et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338: 1281^5^ [6] Lindholm L, Ejlertsson G, Scherste'n B. High risks of cerebro-cardiovascular morbidity in well treated male hypertensives. A retrospective study of 40-59-year-old hypertensives in a Swedish primary care district. Acta Med Scand 1984; 216: 251-9. [7] Isles CG, Walker LM, Beevers DG et al. Mortality in patients of the Glasgow blood pressure clinic. J Hypertension 1986; 4: 141-56. [8] The BBB Study Group. The BBB Study: A prospective randomized study of intensified antihypcrtensive treatment. J Hypertens 1988; 6: 693-7.
52 L. Hansson
[9] Hansson L, Dahldf B, Abelin J. Reduction in blood pressure and adverse effects in the BBB Study. (Abstract). Presented at the European Society of Hypertension Meeting in Milan, June 1991. [10] Hansson L. How far should blood pressure be towered? What is the role of the J-curve? Am J Hypertens 1990; 3: 726-9. [11] Grimm Jr RH. The drug treatment of mild hypertension in the Multiple Risk Factor Intervention Trial: a review. Drugs 1986; 31 (Suppl 1): 13-21. [12] Levy D, Garrison RJ, Sagae DD et al. Prognostic implications of echocardiographically determined left
ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: 1561-6. [13] DahlOf 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. [14] Ferrari P, Weidmann P. Insulin, insulin sensitivity and hypertension. J Hypertens 1990; 8: 491-500. [15] Bjorntorp P. The association between obesity, adipose tissue distribution and disease. Acta Med Scand 1988; 223 (Suppl 723): 121-34.
