European Heart Journal (1992) 13 {Supplement G) 53-60
Effect of diuretic therapy on hypertensive left ventricular hypertrophy B. M. MASSIE
University of California, San Fratiscisco, U.S.A. KEY WORDS: Hypertension, left ventricular hypertrophy, diuretics. Left ventricular hypertrophy (LVH) has been indentified as a major independent risk factor for cardiovascular morbidity in patients with essential hypertension. It is also established that antihypertensive drug therapy is associated with regression ofL VH in many patients. However, it is unclear whether all antihypertensive agents are equally effective in regressing L VH and whether this process is drug-specific or primarily related to blood pressure control. There is no universal agreement on the influence of diuretics on LVH in hypertension. Several major trials have shown consistent reversal of electrocardiographic manifestations of LVH during diuretic-based therapy. The results of studies employing echocardiographic measurements have been more variable; however, most echocardiographic studies have been flawed by lack of controls or blinding, short duration of follow-up, small sample size, inclusion of patients without L VH, and lack of consideration ofprevious or concomitant therapy. This review provides a critical examination of the available data on both sides of the question. Introduction SIGNIFICANCE OF LVH IN HYPERTENSION
It has been known for many years that the left ventricular myocardium hypertrophies in response to chronic hypertension1'21, and that hypertrophy serves the important adaptive function of normalizing left ventricular wall stress in the face of a chronic pressure overload. For this reason, LVH has been considered an indicator of the severity and duration of hypertension. However, in recent years, LVH has been viewed more as a mechanism of hypertension-induced cardiac morbidity and mortality, rather than a passive manifestation of this process'3'4'. This re-assessment largely reflects several unexpected observations. First, that quantitative assessments of LVH correlate poorly with measurements of blood pressure1"1. Although measurements of blood pressure, and particularly systolic blood pressure and blood pressure during daily activities or during workplace or exercise stress, correlate better with measurements of left ventricular mass than clinic blood pressure readings'6-8"101, even these explain no more than 25-35% of the variance in left ventricular mass. Thus, additional factors such as genetic predisposition, associated cardiovascular conditions such as coronary artery disease or alcohol abuse, ageing, and activation of neurohormonal systems such as a sympathetic nervous system or the renin-angiotensin system, appear to play a role in the evolution of LVH. A second observation was that LVH is a powerful risk factor for many cardiovascular complications of hypertension. This first became apparent in the Framingham Heart Study, where electrocardiographic indicators of LVH were found to markedly increase the incidence of sudden death, myocardial infarction, and congestive heart failure1"121. With the advent of electrocardiographic measurements of Correspondence: Barry Massie, MD, Veterans Administration Medical Center, Cardiology Section (1I1C), 4150 Clement Street, San Francisco, CA94121, U.S.A. 0195-668X/92/0GO053 + 08 $08.00/0
left ventricular mass, LVH was found to be a risk factor independent of the degree of hypertension'11"161. While this should not be surprising, in view of the previously listed additional determinants of left ventricular mass, it provided the impetus for suggestions that the goal of antihypertensive therapy should be not only blood pressure control, but prevention or reversal of LVH(4l PATHOPHYSIOLOGY OF LVH
As noted previously, LVH probaUy serves initially as an adaptive response. In most animal models of pressure overload LVH and in most human studies, myocardial contractile function remains normal or even increased. While LVH has been recognized as a predecessor of congestive heart failure'171, it is difficult to demonstrate the transition to myocardial dysfunction'2181. In man, it seems likely that the progression to heart failure often involves the presence of concomitant coronary artery disease, diabetes, ageing or other exacerbating factors. In contrast, diastolic dysfunction is very common in patients with hypertensive LVH'3'. While this phenomenon may be difficult to quantify, there is little doubt that diastolic dysfunction may cause heart failure systems in hypertensive patients'""211. It seems likely that this combination of preserved systolic function with abnormal diastolic function reflects changes in the non-myocyte components of the left ventricle120-22-231. It is now recognized that the collagen content of the hypertrophied left ventricle increases, and there is a shift to a greater proportion of Type III collagen fibrils, which are associated with greater myocardial stiffness'241. Another consequence of hypertensive LVH is the development of changes in the coronary circulation. Chronic pressure overload is associated with impaired myocardial blood flow reserve, both due to anatomical and functional changes'23-261. The former includes decreases in capillary density and in the number of small arterioles, while the latter may include vascular smooth muscle hypertrophy © 1992 The European Society of Cardiology
54 B. M. Massie
Table 1 Requirements for optimal echocardiographic assessment endpoints, of the duration of observation should be at least 6 L VH regression months. Ultimately, longer periods of follow-up would be Design features Blinded, randomized treatment groups Placebo or active-treatment control group Duration at least 6 months Patient population Criteria for LVH present Absence of other cardiovascular disease (especially CAD) Previously untreated or treatment withdrawal > 2 months No previous treatment with study drug or related medications Assessments Only high quality echocardiograms included Readers blinded for treatment and sequence Concommitant assessments ofleft ventricular function Relationship to blood pressure response determined
and altered coronary haemodynamics. These changes at least predispose hypertrophied myocardium to ischaemia, and when severe, may themselves lead to ischaemia, particularly in the more vulnerable subendocardium. Finally, LVH is also associated with the increased incidence of ventricular arrhythmias'27"30'. These may reflect increased myocardial fibrosis or ischaemia. In most cases, the arrhythmias are asymptomatic, but the association of LVH with sudden death suggests that they may indicate the presence of a substrate for more lethal arrhythmias.
required to demonstrate an agent did not reduce LVH. Many studies of LVH regression include patients without LVH. While reduction of LV mass in these patients may be of value, a distinction needs to be made between those with and without LVH. It is also important that patients with other forms of cardiovascular disease which may independently lead to LVH, such as coronary artery disease, be excluded. Perhaps the key issue with regard to patient population is the nature of prior treatment. It makes no sense to examine regression of LVH with a specific treatment if the patient has previously received the same or a closely related medication prior to entry. It should be easiest to show LVH regression in previously untreated individuals, or at least in patients who have had prior therapy withdrawn for several months. Since this often is not feasible, patients who have been previously treated with the study drug or related medications must be excluded. The final methodological difficulty with many LVH studies relates to the assessment of LVH. Even under optimal circumstances, with good studies and experienced observers, the variability in LV mass measurements approaches 10%, which is the degree of change observed in most studies. Thus, it is critical to include only patients with high quality echocardiograms, and these should be read blindly with regard to treatment and sequence.
Observations in animal models of hypertension initially suggested that there may be important differences It has been known for some time that antihypertensive between antihypertensive medications with regard to |33 therapy can prevent the development of LVH. More their ability to reverse LVH l These early studies showed recently, numerous studies have demonstrated that treat- that vasodilators may have little effect on left ventricular ment can reverse pre-existing LVH, and even decrease left mass, even though they are effective in controlling blood ventricular mass in individuals who do not meet criteria pressure. In contrast, sympatholytic agents and angiofor LVH'31"34'. However, a number of major questions tensin converting inhibitors consistently reduced left venmust be answered before this knowledge can be integrated tricular mass, sometimes to a degree greater than one into clinical practice. Firstly, are there important differ- might expect from the blood pressure response. Although ences between the ability of various antihypertensive subsequent studies produced conflicting data, these early agents to reverse LVH? Secondly, is reversal of LVH observations led to the hypothesis that factors beyond associated with correction of the pathophysiological blood pressure control, such as inhibition of the adrenergic abnormalities associated with L VH?Thirdly, does reversal nervous system or renin-angiotensin system, were required for optimal regression of LVH. This hypothesis was of LVH improve prognosis? carried forward into human studies, and similar conIn attempting to interpret the available data, one is immediately confronted with the fact that most studies clusions were often reached with inadequate data. Indeed, which examine changes in left ventricular mass during as several recent reviews concluded, there are excellent antihypertensive therapy suffer from serious method- data to indicate that effective treatment with ACE inhibicalcium ological limitations. These make it virtually impossible tors, sympatholytic agents, and at least31 some 34 to address the first and third of these previously stated blockers, can cause regression of LVH' " '. However, questions. Table 1 lists the requirements which need to be there are few data to support the notion that some agents met before the data can be interpreted with confidence. can control blood pressure without reversing LVH, and Several important features deserve particular emphasis. If where these are available, they usually involve obserdrug-specific effects are to be investigated, this can only be vations based on one drug in a multidrug regimen, or done in the context of prospective, randomized, blinded trials that do not meet even the minimum standards outstudies. Most of the published literature in this area rep- lined previously. This is best illustrated with the literature resents uncontrolled studies in which measurements were concerning the effects of diuretic therapy on LVH. made before and after treatment. The duration of treatment is another critical factor. Hypertension and LVH are chronic conditions, yet many of the published studies last Effects of diuretic therapy on LVH only a few months or less. Since it is possible that different Perhaps the greatest controversy concerning the effect agents will regress LVH at different rates, but to similar of specific drug treatment on LVH is with the diuretics'361. Regression of LVH during antihypertensive therapy
Diuretic therapy and L VH 55
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Figure 1 Panel a. This illustrates the cumulative incidence of new electrocardiographic abnormalities indicative of LVH during the 5 year follow-up period of the original Veterans Administration Cooperative Study of patients with entry diastolic blood pressures between 90 and 114mmHg. By all criteria, LVH developed less frequently in the patients treated with a diuretic-based regimen. Panel b. This utilizes the same format to illustrate the incidence of reversion from abnormal to normal in the same cohort. By 5 years, nearly 80% of the patients with LVH by voltage no longer met diagnostic criteria. = control; —=treated group. Reproduced with permission of the American Heart Association from Pobleto el a/.|37).
This reflects, in part, their position as 'conventional' treatment in the period in which very attractive new agents have appeared. Many experts have been disappointed by the lack of greater reductions in mortality and cardiac morbidity in trials employing diuretics, and have suggested that their inability to regress LVH may, in part, be responsible. It is also possible that some of the uncertainties concerning the effects of diuretics reflect lack of adequate studies, since there is less impetus to conduct trials with older, non-proprietary agents. Nonetheless, some data exist concerning the effects of diuretics on LVH, although much of it is often overlooked. In particular, with the recent focus on echocardiographic measurements of left ventricular mass, major studies which have employed electrocardiographic (ECG) criteria are often overlooked. Both the ECG and echocardiographic literature will be reviewed below. EFFECT OF DIURETICS ON ECG INDICATORS OF LVH
Veterans Administration Cooperative Study The Veterans Administration Cooperative Study provided the first conclusive evidence that antihypertensive therapy could reduce cardiovascular morbidity in patients with mild and moderate hypertension. Patients with initial diastolic blood pressures ranging from 90114 mmHg were randomized to treatment with placebo or a combination of hydrochlorothiazide and reserpine, with the addition of hydralazine if needed, and followed from
2-9 to 5 years'371. A subsequent manuscript examined the ECG changes in 143 controls and 137 treated patients. In patients exhibiting voltage criteria for LVH at baseline, 74-4% of treated patients reverted to normal voltage, compared to only 24% in the control group (/*< 0-005). Similar trends were seen with regard to T-waves and ST segment abnormalities. The time course of this improvement can be seen in Fig. l(a). Treatment also prevented the development of ECG changes of LVH (Fig. 1 (b)). This study demonstrates that diuretic based treatment can reverse and prevent LVH, although few patients were receiving diuretic alone.
Hypertension Detection and Follow-up Programme The Hypertension Detection and Follow-up Programme demonstrated a significant reduction in mortality and morbidity over a 5-year period in patients who were more intensively treated with a step care approach, compared to those receiving treatment by their primary physicians. A subsequent manuscript examined the ECG changes in this group1381. The majority of the step-care group was treated with diuretics alone or diuretics plus reserpine. 54-3% of patients who had LVH by voltage criteria or by a combination of voltage and repolarization abnormalities, reverted to normal or improved, as compared to 42-9% in the referred care group. The potential importance of this difference is illustrated by the fact that among
56 B. M. Massie
patients with LVH at baseline, the 5-year mortality was nearly three times as high as those with a normal ECG. Multiple Risk Factor Intervention Trial The Multiple Risk Factor Intervention Trial evaluated the benefit of aggresive modification of coronary artery disease risk factors, including hypertension. The overall trial showed no difference between the Special Intervention group and the Usual Care group, although a post hoc analysis suggested that there may have been an excess of sudden deaths in patients with baseline ECG abnormalities assigned to the Special Intervention group. Since hypertension was aggressively treated with a diuretic as step one and with a diuretic based combination if further therapy was required, this negative result has often been ascribed to an adverse effect of diuretics. Thus, it is potentially surprising to note that the Special Intervention group exhibited 23% fewer new cases of ECG LVH than the Usual Care group (4-2 vs 5-4%, P X « c ra ra
Table 3 includes the negative studies'50"541. All of these studies analysed hydrochlorothiazide as the diuretic, and where stated, the dose was generally high. Only the smallest studies included comparison treatment groups. In three studies, diuretic treatment was only given for 2 months or less. In contrast to the positive studies, in most cases the patients were previously treated; although the specific therapy is not indicated, given the date of publication, it is likely that many patients had previously received diuretics. Of note also is that in several of these studies, blood pressure control was not achieved. Thus, while the echocardiographic data are somewhat variable, the studies which were better designed, longer in duration, included previously untreated or uncontrolled patients, and required blood pressure control, show a strong tendency toward LVH regression with diuretic therapy. One provocative observation is that the majority of positive studies utilized chlorthalidone or the more closely related compound, indapamide, rather than hydrochlorothiazide. It is also noteworthy that the diuretic dosages tended to be lower in the positive studies. Although one might speculate that these alternative diuretics or lower dosages might have a different effect on the heart, this would be premature. In particular, the large VA Cooperative Study did use hydrochlorothiazide, although in lower dosages. Nonetheless, it is known that indapamide has some calcium channel blocking activity, which could be a factor1551.
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Diuretic therapy and L VH 59
conventional wisdom that diuretics, while effective in controlling blood pressure, have no effect upon left ventricular mass. Several reasons for this conclusion merit emphasis. Firstly, heavy weight is given to the studies in which electrocardiographic criteria are employed. These tend to be much larger, better designed, and longer trials, and the conclusion that left ventricular voltage decreases over time is inescapable. Secondly, despite several widely quoted negative studies employing echocardiography, the majority of studies utilizing this measurement technique also show decreases in left ventricular mass. Careful review of these studies suggests several features that tend to distinguish the positive from the negative studies. The most important of these are the relatively longer duration of the positive studies and inclusion of more previously untreated, or at least uncontrolled, subjects. Indeed, the most rigorous and largest of the echocardiographic studies, the recent VA Cooperative Trial, found no significant reduction of left ventricular mass in 3 months, but decreases not only in left ventricular mass, but also in wall thickness, after 1 and 2 years'4'1. It is tempting to speculate that LVH regression may take a longer time with diuretic therapy than with alternative agents, but the finding of a decreased left ventricular mass after 1-5 to 4 months in three small trials suggests that this may not necessarily be the case. Several important questions remain unresolved. In the studies available, it is not clear that there is a significant relationship between the magnitude of blood pressure change and the degree of LVH regression. Since several of the negative studies included patients whose blood pressure was not controlled, however, it is likely that diuretics will not achieve LVH regression without effective reduction in blood pressure. Of note is that the relationship between blood pressure control and LVH regression remains unclear with other classes of antihypertensive drugs as well. It is also unclear whether diuretics other than hydrochlorothiazide are more effective in reducing LVH. It does seem that high doses of diuretics are not advantageous, but these are rarely employed in current practice, in any case. Lastly, the clinical significance of LVH regression remains uncertain. While there is no doubt that LVH is a marker for a worse prognosis in the hypertensive patient, whether LVH regression can reverse this added risk has not been proven. Preliminary data from several groups does suggest that patients who manifest LVH regression have a better prognosis than those who do not, but no information is available to determine whether the nature of the drug treatment effects this benefit156'581. Since left ventricular hypertrophy involves not only the myocytes, but also the interstitium and the coronary vasculature, it is possible that interdrug differences might be present. Finally, while it seems clear that LVH regression is associated with either a preservation or even an improvement in left ventricular systolic function, the changes in diastolic function are much less consistent. Thus, a great deal more research remains to be done, but from the data available at this time, diuretics should be included among the antihypertensive agents which have the potential to reduce or
reverse LVH during long-term, effective blood pressure control. Whether they are comparable to other agents in this regard remains to be determined by further studies, but from the VA Cooperative trial, they appear to be at least as effective as other first line agents.
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[19] Inouye I, Massie B, Loge D et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984; 53: 120-6. [20] Lorell BH, Grossman W. Cardiac hypertrophy: the consequences for diastole. J Am Coll Cardiol 1987; 9: 1189-93. [21] Shepherd RFJ, Zachiariah PK, Shub C. Hypertension and left ventricular diastolic function. Mayo Clin Proc 1989; 64: 1521-32. [22] Douglas PS, Tallant B. Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension. J Am Coll Cardiol 1991; 17:530-6. [23] Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI. Collagen remodelling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 1988; 62: 757-76. [24] Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG, Weber KT. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 1989; 64: 1041-50. [25] Bache RJ. Effects of hypertrophy on the coronary circulation. Prog Cardiovasc Dis 1988; 31: 412-31. [26] Dellsperger KC, Marcus ML. Effects of left ventricular hypertrophy on the coronary circulation. Am J Cardiol 1990; 65: 1504-10. [27] Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984; 77: 18-22. [28] Levy D, Anderson KM, Plehn J, Savage DD, Christiansen JC, Castelli WP. Echocardiographically determined left ventricular structural and functional correlates of complex or frequent ventricular arrhythmias on one-hour ambulatory electrocardiographic monitoring. Am J Cardiol 1987; 159: 836-40. [29] McLenachan JM, Henderson E, Morris KI, Dargic HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med 1987; 317: 787-92. [30] SzlachcicJ, TubauJF, O'Kelly B,Ammon S, Massie BM. What is the role of coronary artery disease in the genesis of ventricular arrhythmias in patients with essential hypertension? J Am Coll Cardiol 1992; 19:803-8. [31] DevereuxRB, Pickering TG, Cody RJ, LaraghJH. Relation of renin-angiotensin system activity to left ventricular hypertrophy and function in experimental and human hypertension. J Clin Hypertens 1987; 3: 87-103. [32] Hachamovitch R, Sonnenblick EH, Strom JA, Frishman WH. Left ventricular hypertrophy in hypertension and the effects of antihypertensive drug therapy. Curr Probl Cardiol 1988; 13: 375-421. [33] Liebson PR. Clinical studies of drug reversal of hypertensive left ventricular hypertrophy. Am J Hypertens 1990; 3: 512-7. [34] Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A meta-analysis of 109 treatment studies. Am J Hypertens 1992; 5: 95-110. [35] Sen S, Tarazi C, Bumpus FM. Cardiac hypertrophy and antihypertensive therapy. Cardiovasc Res 1977; 11:427-33. [36] Moser M, Setaro JF. Antihypertensive drug therapy and regression of left ventricular hypertrophy: a review with a focus on diuretics. Eur Heart J 1991; 12: 1034-9. [37] Pobleto PF, Kyle MC, Pipberger HV et al. Effect of treatment on morbidity in hypertension: Veterans Administration Cooperative Study on Antihypertensive Agents: Effect on the electrocardiogram. Circulation 1973; 48:481-90. [38] Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program. Prevention and reversal of left ventricular hypertrophy with antihypertensive therapy. Hypertension 1985; 7: 105-12. [39] MacMahon S, Collins G, Rautaharju P et al. Electrocardiographic left ventricular hypertrophy and effects of antihypertensive drug therapy in hypertensive participants in the
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Effect of diuretic therapy on hypertensive left ventricular hypertrophy B. M. MASSIE
University of California, San Fratiscisco, U.S.A. KEY WORDS: Hypertension, left ventricular hypertrophy, diuretics. Left ventricular hypertrophy (LVH) has been indentified as a major independent risk factor for cardiovascular morbidity in patients with essential hypertension. It is also established that antihypertensive drug therapy is associated with regression ofL VH in many patients. However, it is unclear whether all antihypertensive agents are equally effective in regressing L VH and whether this process is drug-specific or primarily related to blood pressure control. There is no universal agreement on the influence of diuretics on LVH in hypertension. Several major trials have shown consistent reversal of electrocardiographic manifestations of LVH during diuretic-based therapy. The results of studies employing echocardiographic measurements have been more variable; however, most echocardiographic studies have been flawed by lack of controls or blinding, short duration of follow-up, small sample size, inclusion of patients without L VH, and lack of consideration ofprevious or concomitant therapy. This review provides a critical examination of the available data on both sides of the question. Introduction SIGNIFICANCE OF LVH IN HYPERTENSION
It has been known for many years that the left ventricular myocardium hypertrophies in response to chronic hypertension1'21, and that hypertrophy serves the important adaptive function of normalizing left ventricular wall stress in the face of a chronic pressure overload. For this reason, LVH has been considered an indicator of the severity and duration of hypertension. However, in recent years, LVH has been viewed more as a mechanism of hypertension-induced cardiac morbidity and mortality, rather than a passive manifestation of this process'3'4'. This re-assessment largely reflects several unexpected observations. First, that quantitative assessments of LVH correlate poorly with measurements of blood pressure1"1. Although measurements of blood pressure, and particularly systolic blood pressure and blood pressure during daily activities or during workplace or exercise stress, correlate better with measurements of left ventricular mass than clinic blood pressure readings'6-8"101, even these explain no more than 25-35% of the variance in left ventricular mass. Thus, additional factors such as genetic predisposition, associated cardiovascular conditions such as coronary artery disease or alcohol abuse, ageing, and activation of neurohormonal systems such as a sympathetic nervous system or the renin-angiotensin system, appear to play a role in the evolution of LVH. A second observation was that LVH is a powerful risk factor for many cardiovascular complications of hypertension. This first became apparent in the Framingham Heart Study, where electrocardiographic indicators of LVH were found to markedly increase the incidence of sudden death, myocardial infarction, and congestive heart failure1"121. With the advent of electrocardiographic measurements of Correspondence: Barry Massie, MD, Veterans Administration Medical Center, Cardiology Section (1I1C), 4150 Clement Street, San Francisco, CA94121, U.S.A. 0195-668X/92/0GO053 + 08 $08.00/0
left ventricular mass, LVH was found to be a risk factor independent of the degree of hypertension'11"161. While this should not be surprising, in view of the previously listed additional determinants of left ventricular mass, it provided the impetus for suggestions that the goal of antihypertensive therapy should be not only blood pressure control, but prevention or reversal of LVH(4l PATHOPHYSIOLOGY OF LVH
As noted previously, LVH probaUy serves initially as an adaptive response. In most animal models of pressure overload LVH and in most human studies, myocardial contractile function remains normal or even increased. While LVH has been recognized as a predecessor of congestive heart failure'171, it is difficult to demonstrate the transition to myocardial dysfunction'2181. In man, it seems likely that the progression to heart failure often involves the presence of concomitant coronary artery disease, diabetes, ageing or other exacerbating factors. In contrast, diastolic dysfunction is very common in patients with hypertensive LVH'3'. While this phenomenon may be difficult to quantify, there is little doubt that diastolic dysfunction may cause heart failure systems in hypertensive patients'""211. It seems likely that this combination of preserved systolic function with abnormal diastolic function reflects changes in the non-myocyte components of the left ventricle120-22-231. It is now recognized that the collagen content of the hypertrophied left ventricle increases, and there is a shift to a greater proportion of Type III collagen fibrils, which are associated with greater myocardial stiffness'241. Another consequence of hypertensive LVH is the development of changes in the coronary circulation. Chronic pressure overload is associated with impaired myocardial blood flow reserve, both due to anatomical and functional changes'23-261. The former includes decreases in capillary density and in the number of small arterioles, while the latter may include vascular smooth muscle hypertrophy © 1992 The European Society of Cardiology
54 B. M. Massie
Table 1 Requirements for optimal echocardiographic assessment endpoints, of the duration of observation should be at least 6 L VH regression months. Ultimately, longer periods of follow-up would be Design features Blinded, randomized treatment groups Placebo or active-treatment control group Duration at least 6 months Patient population Criteria for LVH present Absence of other cardiovascular disease (especially CAD) Previously untreated or treatment withdrawal > 2 months No previous treatment with study drug or related medications Assessments Only high quality echocardiograms included Readers blinded for treatment and sequence Concommitant assessments ofleft ventricular function Relationship to blood pressure response determined
and altered coronary haemodynamics. These changes at least predispose hypertrophied myocardium to ischaemia, and when severe, may themselves lead to ischaemia, particularly in the more vulnerable subendocardium. Finally, LVH is also associated with the increased incidence of ventricular arrhythmias'27"30'. These may reflect increased myocardial fibrosis or ischaemia. In most cases, the arrhythmias are asymptomatic, but the association of LVH with sudden death suggests that they may indicate the presence of a substrate for more lethal arrhythmias.
required to demonstrate an agent did not reduce LVH. Many studies of LVH regression include patients without LVH. While reduction of LV mass in these patients may be of value, a distinction needs to be made between those with and without LVH. It is also important that patients with other forms of cardiovascular disease which may independently lead to LVH, such as coronary artery disease, be excluded. Perhaps the key issue with regard to patient population is the nature of prior treatment. It makes no sense to examine regression of LVH with a specific treatment if the patient has previously received the same or a closely related medication prior to entry. It should be easiest to show LVH regression in previously untreated individuals, or at least in patients who have had prior therapy withdrawn for several months. Since this often is not feasible, patients who have been previously treated with the study drug or related medications must be excluded. The final methodological difficulty with many LVH studies relates to the assessment of LVH. Even under optimal circumstances, with good studies and experienced observers, the variability in LV mass measurements approaches 10%, which is the degree of change observed in most studies. Thus, it is critical to include only patients with high quality echocardiograms, and these should be read blindly with regard to treatment and sequence.
Observations in animal models of hypertension initially suggested that there may be important differences It has been known for some time that antihypertensive between antihypertensive medications with regard to |33 therapy can prevent the development of LVH. More their ability to reverse LVH l These early studies showed recently, numerous studies have demonstrated that treat- that vasodilators may have little effect on left ventricular ment can reverse pre-existing LVH, and even decrease left mass, even though they are effective in controlling blood ventricular mass in individuals who do not meet criteria pressure. In contrast, sympatholytic agents and angiofor LVH'31"34'. However, a number of major questions tensin converting inhibitors consistently reduced left venmust be answered before this knowledge can be integrated tricular mass, sometimes to a degree greater than one into clinical practice. Firstly, are there important differ- might expect from the blood pressure response. Although ences between the ability of various antihypertensive subsequent studies produced conflicting data, these early agents to reverse LVH? Secondly, is reversal of LVH observations led to the hypothesis that factors beyond associated with correction of the pathophysiological blood pressure control, such as inhibition of the adrenergic abnormalities associated with L VH?Thirdly, does reversal nervous system or renin-angiotensin system, were required for optimal regression of LVH. This hypothesis was of LVH improve prognosis? carried forward into human studies, and similar conIn attempting to interpret the available data, one is immediately confronted with the fact that most studies clusions were often reached with inadequate data. Indeed, which examine changes in left ventricular mass during as several recent reviews concluded, there are excellent antihypertensive therapy suffer from serious method- data to indicate that effective treatment with ACE inhibicalcium ological limitations. These make it virtually impossible tors, sympatholytic agents, and at least31 some 34 to address the first and third of these previously stated blockers, can cause regression of LVH' " '. However, questions. Table 1 lists the requirements which need to be there are few data to support the notion that some agents met before the data can be interpreted with confidence. can control blood pressure without reversing LVH, and Several important features deserve particular emphasis. If where these are available, they usually involve obserdrug-specific effects are to be investigated, this can only be vations based on one drug in a multidrug regimen, or done in the context of prospective, randomized, blinded trials that do not meet even the minimum standards outstudies. Most of the published literature in this area rep- lined previously. This is best illustrated with the literature resents uncontrolled studies in which measurements were concerning the effects of diuretic therapy on LVH. made before and after treatment. The duration of treatment is another critical factor. Hypertension and LVH are chronic conditions, yet many of the published studies last Effects of diuretic therapy on LVH only a few months or less. Since it is possible that different Perhaps the greatest controversy concerning the effect agents will regress LVH at different rates, but to similar of specific drug treatment on LVH is with the diuretics'361. Regression of LVH during antihypertensive therapy
Diuretic therapy and L VH 55
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Figure 1 Panel a. This illustrates the cumulative incidence of new electrocardiographic abnormalities indicative of LVH during the 5 year follow-up period of the original Veterans Administration Cooperative Study of patients with entry diastolic blood pressures between 90 and 114mmHg. By all criteria, LVH developed less frequently in the patients treated with a diuretic-based regimen. Panel b. This utilizes the same format to illustrate the incidence of reversion from abnormal to normal in the same cohort. By 5 years, nearly 80% of the patients with LVH by voltage no longer met diagnostic criteria. = control; —=treated group. Reproduced with permission of the American Heart Association from Pobleto el a/.|37).
This reflects, in part, their position as 'conventional' treatment in the period in which very attractive new agents have appeared. Many experts have been disappointed by the lack of greater reductions in mortality and cardiac morbidity in trials employing diuretics, and have suggested that their inability to regress LVH may, in part, be responsible. It is also possible that some of the uncertainties concerning the effects of diuretics reflect lack of adequate studies, since there is less impetus to conduct trials with older, non-proprietary agents. Nonetheless, some data exist concerning the effects of diuretics on LVH, although much of it is often overlooked. In particular, with the recent focus on echocardiographic measurements of left ventricular mass, major studies which have employed electrocardiographic (ECG) criteria are often overlooked. Both the ECG and echocardiographic literature will be reviewed below. EFFECT OF DIURETICS ON ECG INDICATORS OF LVH
Veterans Administration Cooperative Study The Veterans Administration Cooperative Study provided the first conclusive evidence that antihypertensive therapy could reduce cardiovascular morbidity in patients with mild and moderate hypertension. Patients with initial diastolic blood pressures ranging from 90114 mmHg were randomized to treatment with placebo or a combination of hydrochlorothiazide and reserpine, with the addition of hydralazine if needed, and followed from
2-9 to 5 years'371. A subsequent manuscript examined the ECG changes in 143 controls and 137 treated patients. In patients exhibiting voltage criteria for LVH at baseline, 74-4% of treated patients reverted to normal voltage, compared to only 24% in the control group (/*< 0-005). Similar trends were seen with regard to T-waves and ST segment abnormalities. The time course of this improvement can be seen in Fig. l(a). Treatment also prevented the development of ECG changes of LVH (Fig. 1 (b)). This study demonstrates that diuretic based treatment can reverse and prevent LVH, although few patients were receiving diuretic alone.
Hypertension Detection and Follow-up Programme The Hypertension Detection and Follow-up Programme demonstrated a significant reduction in mortality and morbidity over a 5-year period in patients who were more intensively treated with a step care approach, compared to those receiving treatment by their primary physicians. A subsequent manuscript examined the ECG changes in this group1381. The majority of the step-care group was treated with diuretics alone or diuretics plus reserpine. 54-3% of patients who had LVH by voltage criteria or by a combination of voltage and repolarization abnormalities, reverted to normal or improved, as compared to 42-9% in the referred care group. The potential importance of this difference is illustrated by the fact that among
56 B. M. Massie
patients with LVH at baseline, the 5-year mortality was nearly three times as high as those with a normal ECG. Multiple Risk Factor Intervention Trial The Multiple Risk Factor Intervention Trial evaluated the benefit of aggresive modification of coronary artery disease risk factors, including hypertension. The overall trial showed no difference between the Special Intervention group and the Usual Care group, although a post hoc analysis suggested that there may have been an excess of sudden deaths in patients with baseline ECG abnormalities assigned to the Special Intervention group. Since hypertension was aggressively treated with a diuretic as step one and with a diuretic based combination if further therapy was required, this negative result has often been ascribed to an adverse effect of diuretics. Thus, it is potentially surprising to note that the Special Intervention group exhibited 23% fewer new cases of ECG LVH than the Usual Care group (4-2 vs 5-4%, P X « c ra ra
Table 3 includes the negative studies'50"541. All of these studies analysed hydrochlorothiazide as the diuretic, and where stated, the dose was generally high. Only the smallest studies included comparison treatment groups. In three studies, diuretic treatment was only given for 2 months or less. In contrast to the positive studies, in most cases the patients were previously treated; although the specific therapy is not indicated, given the date of publication, it is likely that many patients had previously received diuretics. Of note also is that in several of these studies, blood pressure control was not achieved. Thus, while the echocardiographic data are somewhat variable, the studies which were better designed, longer in duration, included previously untreated or uncontrolled patients, and required blood pressure control, show a strong tendency toward LVH regression with diuretic therapy. One provocative observation is that the majority of positive studies utilized chlorthalidone or the more closely related compound, indapamide, rather than hydrochlorothiazide. It is also noteworthy that the diuretic dosages tended to be lower in the positive studies. Although one might speculate that these alternative diuretics or lower dosages might have a different effect on the heart, this would be premature. In particular, the large VA Cooperative Study did use hydrochlorothiazide, although in lower dosages. Nonetheless, it is known that indapamide has some calcium channel blocking activity, which could be a factor1551.
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Diuretic therapy and L VH 59
conventional wisdom that diuretics, while effective in controlling blood pressure, have no effect upon left ventricular mass. Several reasons for this conclusion merit emphasis. Firstly, heavy weight is given to the studies in which electrocardiographic criteria are employed. These tend to be much larger, better designed, and longer trials, and the conclusion that left ventricular voltage decreases over time is inescapable. Secondly, despite several widely quoted negative studies employing echocardiography, the majority of studies utilizing this measurement technique also show decreases in left ventricular mass. Careful review of these studies suggests several features that tend to distinguish the positive from the negative studies. The most important of these are the relatively longer duration of the positive studies and inclusion of more previously untreated, or at least uncontrolled, subjects. Indeed, the most rigorous and largest of the echocardiographic studies, the recent VA Cooperative Trial, found no significant reduction of left ventricular mass in 3 months, but decreases not only in left ventricular mass, but also in wall thickness, after 1 and 2 years'4'1. It is tempting to speculate that LVH regression may take a longer time with diuretic therapy than with alternative agents, but the finding of a decreased left ventricular mass after 1-5 to 4 months in three small trials suggests that this may not necessarily be the case. Several important questions remain unresolved. In the studies available, it is not clear that there is a significant relationship between the magnitude of blood pressure change and the degree of LVH regression. Since several of the negative studies included patients whose blood pressure was not controlled, however, it is likely that diuretics will not achieve LVH regression without effective reduction in blood pressure. Of note is that the relationship between blood pressure control and LVH regression remains unclear with other classes of antihypertensive drugs as well. It is also unclear whether diuretics other than hydrochlorothiazide are more effective in reducing LVH. It does seem that high doses of diuretics are not advantageous, but these are rarely employed in current practice, in any case. Lastly, the clinical significance of LVH regression remains uncertain. While there is no doubt that LVH is a marker for a worse prognosis in the hypertensive patient, whether LVH regression can reverse this added risk has not been proven. Preliminary data from several groups does suggest that patients who manifest LVH regression have a better prognosis than those who do not, but no information is available to determine whether the nature of the drug treatment effects this benefit156'581. Since left ventricular hypertrophy involves not only the myocytes, but also the interstitium and the coronary vasculature, it is possible that interdrug differences might be present. Finally, while it seems clear that LVH regression is associated with either a preservation or even an improvement in left ventricular systolic function, the changes in diastolic function are much less consistent. Thus, a great deal more research remains to be done, but from the data available at this time, diuretics should be included among the antihypertensive agents which have the potential to reduce or
reverse LVH during long-term, effective blood pressure control. Whether they are comparable to other agents in this regard remains to be determined by further studies, but from the VA Cooperative trial, they appear to be at least as effective as other first line agents.
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