Clin. Cardiol. 15,5-16 (1992)
Regression of Left Ventricular Mass in Systemic Hypertension DEMETRIOS GEORGIOU, M.D., BRUCEH. BRUNDAGE, M.D. Division of Cardiology, Harbor-UCLA Medical Center, and Saint John’s Cardiac Research Center, Torrance, California, USA
Summary: The importance of treatment in systemic hypertension and cardiovascular morbidity and mortality has been established. Although systemic hypertension is the most important factor in the pathogenesis of left ventricular hypertrophy, other factors such as catecholamines and renin-angiotensin system may be involved. Increased left ventricular mass causes reduction in coronary reserve and may lead to acute ischemic events. Equally efficacious antihypertensive agents may have diverse effects on left ventricular hypertrophy and left ventricular function. New tomographic techniques with improved spatial resolution are emerging in the evaluation of left ventricular mass and may therefore provide better assessment of changes in left ventricular mass. With improved measures of left ventricular mass the question as to whether regression of left ventricular mass provides an additional benefit beyond control of blood pressure in hypertensive individuals may be finally answered.
tion and pharmacologic therapy, hypertension remains a major health problem. There is little doubt that controls of systemic hypertension with drug therapy reduces morbidity and At the same time, systemic arterial hypertension is the most common cause of left ventricular hypertrophy (LVH). The prevalence of LVH in hypertension varies among different studies mostly because of differences in the methods of detection. For example, in the Hypertension Detection Follow-Up Program Study (HDFP),’ LVH was found in approximately 5% of patients by electrocardiographywhereas in other studies using echocardiography (echo) LVH ranged from 17 to 42%.394 We review the clinical significance and pathophysiology of LVH, the mechanisms and implications of regression with antihypertensive drug therapy and the currently available techniques for clinical assessment of left ventricular mass (LVM). Finally, new, high-resolution tomographic techniques for the quantitation of LVM will be discussed.
Key words: left ventricular mass, left ventricular hyper-
Significanceof Left Ventricular Hypertrophy
trophy, regression of left ventricular mass, systemic hypertension
Introduction Approximately 60 million people in the United States have systemic arterial hypertension. Despite patient educa-
Address for reprints: Bruce H. Brundage, M.D. Division of Cardiology, F-9 Harbor-UCLA Medical Center lo00 West Carson Street Torrance, California 90509, USA Received: April 9, 1991 Accepted with revision: May 14, 1991
Once clinically recognized, LVH has a poor prognos~s.~-’ In the Framingham Study the 6-year mortality in men over the age of 45 exceeded 40% after the electrocardiographic appearance of LVH.8 Hypertensive LVH has been shown to increase the risk for congestive heart failure9, lo as well as sudden death (Fig. l).I1 Indeed, 75% of patients who develop congestive heart failure have hyperten~ion.~,Patients with LVH by ECG criteria have twice the incidence of sudden death according to the Framingham Study.12,l 3 It appears that congestive heart failure is the result of systolic and diastolic dysfunction and sudden death is the result of ventricular arrhythmia^.'^ In addition, other studies have shown that LVH in patients with hypertension places them at high risk for ischemic events.l52 l6 This is primarily due to decreased coronary reserve produced by hypertrophy and the ability of hypertension to produce atheromatous changes in the coronary arteries.I6 Recently Cooper et al.” have reported a consistent pattern of higher death rates during follow-up among patients with LVH diagnosed by echo and this increased risk is inde-
Clin. Cardiol. Vol. 15, January 1992
6
Left ventricular hypertrophy
r Decreased wall compliance
n
1 Ventricular arrhythmias
/
High blood pressure
Catecholamines
Cardiac failure
Suddideath
FIG.1 Consequences of hypertension-induced left ventricular hypertrophy in humans. Ventricular wall compliance is reduced, leading to inadequate chamber filling and congestive failure. The threshold for ventricular ectopic activity is reduced with the consequence of ventricular fibrillation and sudden death. (Modified from Hachamovitch et al., 1988, Ref. 42, with permission.)
Blood pressure Wall thickness
t f
t 1 I
Ventricular mass Ventricular radius
-
-
End diastolic volume
-t
Systolic wall stress Cardiac index Ejection fraction Myocardial oxvaen consumotion
t
1
Coronary resistance Coronary reserve
t 1
t 1
1
Itl)
t t
t
--
-
--I
t
-
-I
tt
LVMM/EDV
pendent of coronary anatomy and left ventricular (LV) systolic function. Therefore, there is abundant evidence that patients with hypertensive LVH are at increased risk. LVH is not a benign process, but one that deserves serious attention and consideration for therapeutic intervention. Whether regression of LVH by pharmacologic intervention reduces this risk in the hypertensive patient is unknown and still a matter of active research.
t ft
-1
t I 1
t t I1
FIG.2 Ventricular geometry, function, energetics, and coronary reserve in the three types of cardiac hypertrophy in hypertensive heart disease. (From Strauer, 1988, Ref. 18, with permission.)
Pathophysiology of Left Ventricular Hypertrophy Strauer18describes three types of cardiac hypertrophy: concentric (60%),eccentric (25%), and irregular (15%), that is, asymmetric hypertrophy such as seen in hypertrophic cardiomyopathy. Ventricular function, dynamics and energetics are similar in irregular and concentric hypertrophy (Fig. 2). There are two pathophysiologic mechanisms that describe the development of concentric and eccentric hypertrophy: pressure overload and volume overload (Fig. 3). Pressure and volume overload as well as wall thickness are the determinants of wall stress in the left ventricle. As described by Laplace's law, wall stress is directly related to the product of the chamber radius (R) and systolic pressure and is inversely related to the wall thickness. Wall stress = PFUh (P = systolic pressure; R = radius; h = wall thickness). Pressure overload causes increased systolic wall stress and according to Grossman et an addition of sarcomeres in parallel. To normalize systolic wall stress, LV wall thickness increases, thus leading to concentric LVH, seen most commonly in hypertensive hypertrophy and aortic stenosis. Volume overload causes increased diastolic wall stress, and addition of sarcomeres in series,19 causing increased chamber size, thus leading to eccentric hypertrophy. An
Lean Normotensive
& Preload/
%Afterload
r
Volume overload
Pressure overload (Hypertensive hypertrophy)
B-
FIG.3 Structural comparisons of volume and pressure overloadinduced hypertrophy. With volume overload, the ratio of wall thicknessileft ventricular chamber size is preserved; with pressure overload, the ratio of wall thicknessileft ventricular chamber size is increased. (From Hachamovitch et al., 1988,Ref. 42, with per-
mission.)
D. Georgiou and B. H. Brundage: Regression of LV mass in hypertension
7
would present clinically as a diastolic dysfunction with example of this is seen in valvular regurgitant lesions, obesystolic force generation and shortening preserved. Once sity or end-stage hypertensive heart disease. In general, the accumulation of collagen exceeds 20%, replacement volume overloads are associated with an increased diasfibrosis occurs in response to cell loss-that is, a replacetolic cavity volume with minimal thickening of the wall. ment of collagen and muscle fibers occurs beyond the boundIn asymmetric hypertrophy, the cause of irregular hyperaries of the intermuscular space and myocyte force genertrophy is unknown, but it may relate to the more complex ation is impaired. Unfortunately, the pathogenesis is not fiber oxygenation and geometric configuration of the interclear. Regardless of the amount of myocardial cell loss, ventricular septum compared with the LV free wall or the interstitial fibrosis can have a detrimental influence on the fact that the right ventricle is also subjected to a greater diastolic and systolic function of the myocardium and can work load, thus producing a greater degree of thickening of Exresult in pathologic hypertrophy with heart fai1u1-e.~~ the structure that is common in both ventricles. perimental studies in rats have shown that a 4-hour intraPerhaps the most important, yet not well-emphasized, venous infusion of angiotensin I1 leads to coronary artery variable influencing LVM along with arterial pressure is remodeling and interstitial fibrosis.31These observations the concomitant volume load imposed on the heart. In one led to the use of ACE inhibitors as a treatment strategy. At study4 58 essentially hypertensive patients with increased present, it is not clear, however, if the angiotensin-conLVM were found to have higher cardiac output than 257 verting enzyme inhibitors will prove useful in the prevenpatients with similar blood pressures but normal LVM. tion of fibrosis associated with pressure overload hyperFurther support for an important role of volume load in trophy. Based upon the available information, systematic hypertensive cardiac hypertrophy is provided by experiinvestigation is warranted. mental studies2O, in which the lack of LVH regression Myocardial ischemia is another common sequela of proportional to blood pressure reduction during vasodilator long-standing hypertension for a number of reasons: First, treatment appears to be related to LV enlargement resulting an elevated arterial pressure increases LV wall stress and from drug-induced increase in cardiac output. stroke work, thereby augmenting myocardial oxygen deAnother apparent determinant of cardiac status is whole mand. Second, an increase in myocardial mass, as occurs blood viscosity that has long been recognized to be a major in LVH, requires more oxygen for tissue perfusion. The contributor to peripheral resistance. Several studies have coronary vascular bed fails to increase in proportion to the shown that whole blood viscosity or components are eler ~ ~others34,35 have revated in many patients with essential hyperten~ion.~*-~~increase in LV m a s 3 * S t r a ~ e and ported the lumen in intramyocardial arterioles in spontaDevereux et a1.2sfirst suggested the relevance of elevated neously hypertensive rats to be restricted. Evidence from blood viscosity to hypertensive cardiac hypertrophy when human autopsy studies indicates that microvascular damthey documented that echocardiographically measured age is associated with hyperten~ion.~~ Also, long-standing LVM was more closely related to whole blood viscosity systemic hypertension per se promotes atherosclerosis in than to blood pressure and that hypertensive patients the coronary arteries, thereby diminishing myocardial oxywhose LVM fell within the normal range had blood visgen delivery.37.38 Therefore, the combination of hypertencosity levels similar to those of age-sex-matched control sion and coronary artery disease increases oxygen demand subjects. Whether the contribution of whole blood viscosand decreases oxygen supply and thereby contributes to ity reflects an elevation of peripheral resistance or is relatischemia of the myocardium in these patients. Furthered to other mechanisms remains to be clarified. more, coronary reserve is reduced due to an extravascular Congestive heart failure is the end stage of hypertensive andor intravascular increases in flow resistance. heart disease and the result of the inability of the LV to Coronary hemodynamics in hypertensive heart disease 27 If this maintain adaptation to the pressure overload.26$ have been studied in the spontaneous hypertensive rat complication arises earlier in the natural history of hyper(SHR). These s t u d i e demonstrate ~~~~~~ a reduction in corotensive heart disease, then likely there is a second disease nary reserve that is comparable to that seen in humans. The involving the heart such as coronary atherosclerosis, obereduction of coronary reserve in the SHR is reversible if sity or diabetes. In hypertensive patients with obesity the the animal is treated from 5-65 weeks of age (metoprolol coexistence of pressure and volume overload leads to conplus hydralazine) or after the onset of hypertension from centric and eccentric hypertrophy.28This double structural the 20th to the 40th week of age (nifedipine). However, adaptation of the LV predisposes obese hypertensive the influence of reduction in LVM on myocardial perfupatients to premature cardiac failure. sion is poorly documented in humans. Hypothetically, With LVH, reactive interstitial fibrosis may occur. Reacbecause increases in afterload and in LVM can induce tive interstitial fibrosis is seen in the absence of myocyte ischemia, reduction in afterload and LVM should improve necrosis, is progressive in nature and initially is an adapischemia and related symptoms. However, hypertensive tive response that preserves LV function. In studies conpatients with LVH maintain coronary flow reserve by ducted by Jalil et al.29an increase in collagen volume fracmeans of increased perfusion pressure. When perfusion tion secondary to abdominal aorta banding is associated pressure fails to keep up with the hypertrophic process, with significantincrease in both diastolic and systolic stiffcoronary reserve diminishes to values below those seen in ness in the intact hypertrophied rat myocardium. This
8
Clin. Cardiol. Vol. 15, January 1992
patients with nonhypertrophied hearts.41The flow reserve of the endocardia1 layers becomes especially critical at high heart rates. Therefore, tachycardia induced by antihypertensive therapy may acutely expose patients to ischemia, even if reduction in LVM has occurred. Thus, an agent that will decrease heart rate, LVM and therefore oxygen consumption should be ideal as a first-line drug in hypertensive patients with LVH and myocardial ischemia. The reduced coronary blood flow and vascular reserve of the subendocardium in hypertensive cardiac hypertrophy may account for the so-called strain pattern seen on the electrocardiogram of advanced LVH." Furthermore, hypertensive patients with LVH and normal coronary angiograms have been found to have a 70% incidence of angina-like chest pain.15 When LVH is severe, the incidence of chest pain is increased to 80%in these patients.l5 Thus, it appears that LVH affects coronary circulation in several ways. In myocardial hypertrophy coronary blood flow may be reduced as a result of an increase in LVM without a concomitant increase in coronary circulation. When the heart is hypertrophied, coronary vascular resistance increases with a reciprocal diminution in the coronary flow reserve. Although the development of LVH is primarily due to systemic arterial hypertension, other factors have been implicated as participants in the process such as norepinephrine.424 A number of clinical and experimental studies have demonstrated a close relationship between the level of adrenergic activity and the development of LVH.43-46Catecholamines have been shown to promote protein synthesis, collagen deposition, myocardial fibrosis, and LVH.47,48 Recent studies have demonstrated that treatment of hypertension with a-adrenergic-blocking drugs causes a signifi. ~ ~though there is an associacant reduction in L W V ~Even tion between catecholamines and the development of LVH, the precise mechanism by which activation occurs is not completely understood. It has been shown that the addition of norepinephrine to tissue cultured myocytes stimulate DNA-mediatedprotein synthesis within the m y ~ c y t eThis .~~ study suggested that protein synthesis promoted by norepinephrine was mediated through the c-myc protooncogene upon stimulation of the a1-adrenergic receptor on the myocyte wall.50 Other agents have been implicated in the pathogenesis of hypertensive LVH and the initiation of myocardial cell growth (Table I).51Several of these agents are known to be produced in the arteriolar as well as the cardiac myocyte. Therefore, they have been implicated in the hypertrophic and hyperplastic responses to these cells. Furthermore an endogenous renin-angiotensinsystem has been demonstrated in the monocyte.52The presence of renin and its mRNA in the medial layers of blood vessels has been demonstrated using immunohistochemical techniques. Angiotensinogen is also locally synthesized since its messenger RNA has been shown to be present in whole blood vessels and in cultured vascular cells. Thus, coexpression of renin and angiotensinogen in blood vessel cells suggests the possibility of local angiotensinogen production. Studies in cultured
I Autocrine and paracrine influences on blood vessel TABLE growth
Vasoactive agents Angiotensin Serotonin Bradykinin
Prostaglandins Vasopressin Norepinephrine Growth-regulating factors Autocrine Platelet-derived growth factor IGF-I Heparin Paracrine Platelet-derived growth factor Monocyte-derived growth factor Endothelium-derived growth factor Heparin IGF-I TGF-f3 Epidermal growth factor Prostaglandins Oncogenes c-myc c-sis c-fos c-ras Abbreviations: IGF-I = Insulin-like growth factor;TGF-P= p-
transforming growth factor. Source: from Ref. 5 1, reproduced with permission.
cells have shown that angiotensin 11is synthesized intracellularly and subsequently relea~ed.5~ Data from isolated perfused blood vessels provide evidence that this local angiotensin exerts an autocrine or paracrine function or both on 55 Therefore, vascular monocyte vascular ~ontractility.~~, angiotensin 11production can influence vascular tone either by a direct autocrine effect on its own angiotensin I1 receptors or through a paracrine effect by activating angiotensin 11in adjacent smooth muscle cells or indirectly by inducing catecholamine release from adrenergic nerve endings.56 Vascular monocytes have the capacity to synthesize other vasoactive substances such as prostacyclin and many other substances capable of influencing local tone. In summary, multiple potential autocrine-paracrine mechanisms can influence monocyte growth and proliferation. Alterations in this complex and delicate balance of multiple vasoactive substances due to acquired or genetic abnormalities may result in generalized vascular hypertrophy, or hyperplasia, or both and contribute to the pathogenesis of hypertension. With the improved understanding of the role of the autocrine and paracrine influences on myocyte cell growth new antihypertensive agents could be designed. At the present time this is an area of active research.
D. Georgiou and B. H. Brundage: Regression of LV mass in hypertension Recently, Devereux et ~ 1have . suggested ~ ~ that the role of the renin-angiotensin system in the pathogenesis of LVH is not clear. Experimental data support a direct effect of angiotensin on myocardial protein synthesis and suggest that this may be independent of secondary adrenergic effects. Whether these observations are relevant to the pathogenesis of hypertensive cardiac hypertrophy remains uncertain because it has not been established that LVM is systematically greater in high-renin as opposed to low-renin forms of experimental or clinical hypertension. In a more recent study, Schmieder et al? have shown that angiotensin I1 levels correlate significantly with the presence of LVH. The mechanism is most likely direct stimulation of myocardial cell growth in patients with essential hypertension. Since salt intake influences the level of arterial pressure and the activity of the sympathetic adrenergic and reninangiotensin aldosterone sy~tems,5~. 6o it is possible that salt intake may promote myocardial hypertrophy. A study of dietary salt intake of two independent sets of patients found that the higher the 24-hour sodium urinary excretion the greater the LVM.61The authors concluded that in patients with essential hypertension and hypertrophy, dietary sodium intake is a powerful determinant of LVH independent of the hemodynamic load. In another study62 the same investigators found that dietary salt intake seems to be the strongest determinant of cardiac structural adaptation to hypertension. Dietary sodium may influence cardiac adaptation by interacting with the renin-angiotensinaldosterone system, the sympathetic nervous system or fluid volume homeostasis. Whether dietary sodium restriction induces regression of LVH remains unknown although preliminary results indicate that a marked reduction of sodium intake may reduce LVM in essential hypertension if associated with a significant reduction in blood pressure.63
Regression of Left Ventricular Mass The rationale for attempting to reduce LVM derives from the evidence that increased LVM carries an independent risk for congestive heart failure, coronary artery disease and sudden death.9,l o Therefore, regression of LVM is an attractive therapeutic goal. However, experimental and clinical studies suggest that a disproportionately greater reduction in LVM compared with that of blood pressure may lead to an increase in myocardial oxygen consumption, decreased systolic performance and a decrease in coronary reserve.I8 Liebson@recently reviewed more than 60 studies (Table 11) of hypertensive treatment which used echo to assess changes in LVM. The studies enrolled an average of 10 to 15 patients and found that correlation between reduction of LVM and a decrease in blood pressure was weak (r = 0.25; p < 0.02). In monotherapy studies, calcium channel blockers and ACE inhibitors have been shown to be consistently associated with regression of hypertrophy. Nifedipine, verapamil, and diltiazem reduced LVM from 7% (65) to 25% (66),6%
9
(67) to 12% (68),and lo%,respectively. Duration of therapy ranged from one month to one year.69 Dunn70 and Nakashima and co-worker~,~' using ACE inhibitors, showed significant decreases in LVM index and LVM (29.5% and 12%, respectively) within 12 and 28 weeks of treatment. The effect of beta blockers on the regression of LVH is not consistent, whereas the use of diuretics and arterial vasodilators is not usually associated with regression. A number of ~ t u d i e s ~ using ~ - ~beta ~ blockers have shown regression of LVH index and LVM ranging from 10 to 34%after 8 weeks to 12 months of treatment. Drayer et uL76showed no regression in 11 of 20 patients treated with hydrochlorothiazide, but ventricular septa1 thickness decreased in 9 of the 20 patients by an average of l l .7% (+ 2.3%) with 4-6 weeks of therapy. Others report that diuretics 78 or combined with severe salt restrict i ~ can n ~reduce ~ both LVH and blood pressure. One possible explanation for the difference in outcomes of the many studies is the difference in the response of individual patients to the medication. Studies with arterial vasodilators reported a decrease in LVM ranging from 10% to 19%.79, The problem with these studies is that the patients were also treated with diuretics and beta blockers. Therefore, the results79,8o must be interpreted with caution. Regression of LVM has not been associated with clinical LV systolic dysfunction. It is interesting that improvement in LV diastolic filling has been reported to occur with and without decreases in LVM. It is important to note that the participants in most reports had normal LV function. Thus, it is difficult to assess the impact of antihypertensive treatment on LVM regression in the general population. Demonstration of the impact of LVH regression on morbidity and mortality must await the results of larger, long-term studies underway. Schulman et aL8I demonstrated in elderly hypertensive patients with echocardiographically determined LVH that antihypertensive therapy was equally effective with a beta blocker (atenolol) and a calcium channel blocker (verapamil) but had different effects on LVM. After 6 months of blinded therapy, only the patients receiving verapamil had reduction in LVM as determined by echo. In contrast to this study, others have shown atenolol to be effective in decreasing LVM?4 In addition, Schulman et aL8l showed that the LV systolic function and diastolic function were preserved in patients with regression of LVH even after the withdrawal of antihypertensive therapy and return of the blood pressure to pretreatment levels. This partially addresses a concern that discontinuation of therapy in patients after regression of LVH might precipitate cardiac failure, when blood pressure returned to pretreatment levels.82 The observation by Schulman et aL8I that similar reductions of blood pressure by two different classes of antihypertensive agents have different effects on LVM raises several important questions. For example, what degree of LVH regression is desirable? When does regression of LVH become atrophy? Do all drugs provide the same benefits? The concentric hypertrophy associated with hyper-
10
Clin. Cardiol. Vol. 15, January 1992
TABLE I1 Clinical echocardiographic studies of regression of LV mass in hypertension with drug therapy Reduction in LV mass
Duration
51 Year >I Year 210%
Regression of Left Ventricular Mass in Systemic Hypertension DEMETRIOS GEORGIOU, M.D., BRUCEH. BRUNDAGE, M.D. Division of Cardiology, Harbor-UCLA Medical Center, and Saint John’s Cardiac Research Center, Torrance, California, USA
Summary: The importance of treatment in systemic hypertension and cardiovascular morbidity and mortality has been established. Although systemic hypertension is the most important factor in the pathogenesis of left ventricular hypertrophy, other factors such as catecholamines and renin-angiotensin system may be involved. Increased left ventricular mass causes reduction in coronary reserve and may lead to acute ischemic events. Equally efficacious antihypertensive agents may have diverse effects on left ventricular hypertrophy and left ventricular function. New tomographic techniques with improved spatial resolution are emerging in the evaluation of left ventricular mass and may therefore provide better assessment of changes in left ventricular mass. With improved measures of left ventricular mass the question as to whether regression of left ventricular mass provides an additional benefit beyond control of blood pressure in hypertensive individuals may be finally answered.
tion and pharmacologic therapy, hypertension remains a major health problem. There is little doubt that controls of systemic hypertension with drug therapy reduces morbidity and At the same time, systemic arterial hypertension is the most common cause of left ventricular hypertrophy (LVH). The prevalence of LVH in hypertension varies among different studies mostly because of differences in the methods of detection. For example, in the Hypertension Detection Follow-Up Program Study (HDFP),’ LVH was found in approximately 5% of patients by electrocardiographywhereas in other studies using echocardiography (echo) LVH ranged from 17 to 42%.394 We review the clinical significance and pathophysiology of LVH, the mechanisms and implications of regression with antihypertensive drug therapy and the currently available techniques for clinical assessment of left ventricular mass (LVM). Finally, new, high-resolution tomographic techniques for the quantitation of LVM will be discussed.
Key words: left ventricular mass, left ventricular hyper-
Significanceof Left Ventricular Hypertrophy
trophy, regression of left ventricular mass, systemic hypertension
Introduction Approximately 60 million people in the United States have systemic arterial hypertension. Despite patient educa-
Address for reprints: Bruce H. Brundage, M.D. Division of Cardiology, F-9 Harbor-UCLA Medical Center lo00 West Carson Street Torrance, California 90509, USA Received: April 9, 1991 Accepted with revision: May 14, 1991
Once clinically recognized, LVH has a poor prognos~s.~-’ In the Framingham Study the 6-year mortality in men over the age of 45 exceeded 40% after the electrocardiographic appearance of LVH.8 Hypertensive LVH has been shown to increase the risk for congestive heart failure9, lo as well as sudden death (Fig. l).I1 Indeed, 75% of patients who develop congestive heart failure have hyperten~ion.~,Patients with LVH by ECG criteria have twice the incidence of sudden death according to the Framingham Study.12,l 3 It appears that congestive heart failure is the result of systolic and diastolic dysfunction and sudden death is the result of ventricular arrhythmia^.'^ In addition, other studies have shown that LVH in patients with hypertension places them at high risk for ischemic events.l52 l6 This is primarily due to decreased coronary reserve produced by hypertrophy and the ability of hypertension to produce atheromatous changes in the coronary arteries.I6 Recently Cooper et al.” have reported a consistent pattern of higher death rates during follow-up among patients with LVH diagnosed by echo and this increased risk is inde-
Clin. Cardiol. Vol. 15, January 1992
6
Left ventricular hypertrophy
r Decreased wall compliance
n
1 Ventricular arrhythmias
/
High blood pressure
Catecholamines
Cardiac failure
Suddideath
FIG.1 Consequences of hypertension-induced left ventricular hypertrophy in humans. Ventricular wall compliance is reduced, leading to inadequate chamber filling and congestive failure. The threshold for ventricular ectopic activity is reduced with the consequence of ventricular fibrillation and sudden death. (Modified from Hachamovitch et al., 1988, Ref. 42, with permission.)
Blood pressure Wall thickness
t f
t 1 I
Ventricular mass Ventricular radius
-
-
End diastolic volume
-t
Systolic wall stress Cardiac index Ejection fraction Myocardial oxvaen consumotion
t
1
Coronary resistance Coronary reserve
t 1
t 1
1
Itl)
t t
t
--
-
--I
t
-
-I
tt
LVMM/EDV
pendent of coronary anatomy and left ventricular (LV) systolic function. Therefore, there is abundant evidence that patients with hypertensive LVH are at increased risk. LVH is not a benign process, but one that deserves serious attention and consideration for therapeutic intervention. Whether regression of LVH by pharmacologic intervention reduces this risk in the hypertensive patient is unknown and still a matter of active research.
t ft
-1
t I 1
t t I1
FIG.2 Ventricular geometry, function, energetics, and coronary reserve in the three types of cardiac hypertrophy in hypertensive heart disease. (From Strauer, 1988, Ref. 18, with permission.)
Pathophysiology of Left Ventricular Hypertrophy Strauer18describes three types of cardiac hypertrophy: concentric (60%),eccentric (25%), and irregular (15%), that is, asymmetric hypertrophy such as seen in hypertrophic cardiomyopathy. Ventricular function, dynamics and energetics are similar in irregular and concentric hypertrophy (Fig. 2). There are two pathophysiologic mechanisms that describe the development of concentric and eccentric hypertrophy: pressure overload and volume overload (Fig. 3). Pressure and volume overload as well as wall thickness are the determinants of wall stress in the left ventricle. As described by Laplace's law, wall stress is directly related to the product of the chamber radius (R) and systolic pressure and is inversely related to the wall thickness. Wall stress = PFUh (P = systolic pressure; R = radius; h = wall thickness). Pressure overload causes increased systolic wall stress and according to Grossman et an addition of sarcomeres in parallel. To normalize systolic wall stress, LV wall thickness increases, thus leading to concentric LVH, seen most commonly in hypertensive hypertrophy and aortic stenosis. Volume overload causes increased diastolic wall stress, and addition of sarcomeres in series,19 causing increased chamber size, thus leading to eccentric hypertrophy. An
Lean Normotensive
& Preload/
%Afterload
r
Volume overload
Pressure overload (Hypertensive hypertrophy)
B-
FIG.3 Structural comparisons of volume and pressure overloadinduced hypertrophy. With volume overload, the ratio of wall thicknessileft ventricular chamber size is preserved; with pressure overload, the ratio of wall thicknessileft ventricular chamber size is increased. (From Hachamovitch et al., 1988,Ref. 42, with per-
mission.)
D. Georgiou and B. H. Brundage: Regression of LV mass in hypertension
7
would present clinically as a diastolic dysfunction with example of this is seen in valvular regurgitant lesions, obesystolic force generation and shortening preserved. Once sity or end-stage hypertensive heart disease. In general, the accumulation of collagen exceeds 20%, replacement volume overloads are associated with an increased diasfibrosis occurs in response to cell loss-that is, a replacetolic cavity volume with minimal thickening of the wall. ment of collagen and muscle fibers occurs beyond the boundIn asymmetric hypertrophy, the cause of irregular hyperaries of the intermuscular space and myocyte force genertrophy is unknown, but it may relate to the more complex ation is impaired. Unfortunately, the pathogenesis is not fiber oxygenation and geometric configuration of the interclear. Regardless of the amount of myocardial cell loss, ventricular septum compared with the LV free wall or the interstitial fibrosis can have a detrimental influence on the fact that the right ventricle is also subjected to a greater diastolic and systolic function of the myocardium and can work load, thus producing a greater degree of thickening of Exresult in pathologic hypertrophy with heart fai1u1-e.~~ the structure that is common in both ventricles. perimental studies in rats have shown that a 4-hour intraPerhaps the most important, yet not well-emphasized, venous infusion of angiotensin I1 leads to coronary artery variable influencing LVM along with arterial pressure is remodeling and interstitial fibrosis.31These observations the concomitant volume load imposed on the heart. In one led to the use of ACE inhibitors as a treatment strategy. At study4 58 essentially hypertensive patients with increased present, it is not clear, however, if the angiotensin-conLVM were found to have higher cardiac output than 257 verting enzyme inhibitors will prove useful in the prevenpatients with similar blood pressures but normal LVM. tion of fibrosis associated with pressure overload hyperFurther support for an important role of volume load in trophy. Based upon the available information, systematic hypertensive cardiac hypertrophy is provided by experiinvestigation is warranted. mental studies2O, in which the lack of LVH regression Myocardial ischemia is another common sequela of proportional to blood pressure reduction during vasodilator long-standing hypertension for a number of reasons: First, treatment appears to be related to LV enlargement resulting an elevated arterial pressure increases LV wall stress and from drug-induced increase in cardiac output. stroke work, thereby augmenting myocardial oxygen deAnother apparent determinant of cardiac status is whole mand. Second, an increase in myocardial mass, as occurs blood viscosity that has long been recognized to be a major in LVH, requires more oxygen for tissue perfusion. The contributor to peripheral resistance. Several studies have coronary vascular bed fails to increase in proportion to the shown that whole blood viscosity or components are eler ~ ~others34,35 have revated in many patients with essential hyperten~ion.~*-~~increase in LV m a s 3 * S t r a ~ e and ported the lumen in intramyocardial arterioles in spontaDevereux et a1.2sfirst suggested the relevance of elevated neously hypertensive rats to be restricted. Evidence from blood viscosity to hypertensive cardiac hypertrophy when human autopsy studies indicates that microvascular damthey documented that echocardiographically measured age is associated with hyperten~ion.~~ Also, long-standing LVM was more closely related to whole blood viscosity systemic hypertension per se promotes atherosclerosis in than to blood pressure and that hypertensive patients the coronary arteries, thereby diminishing myocardial oxywhose LVM fell within the normal range had blood visgen delivery.37.38 Therefore, the combination of hypertencosity levels similar to those of age-sex-matched control sion and coronary artery disease increases oxygen demand subjects. Whether the contribution of whole blood viscosand decreases oxygen supply and thereby contributes to ity reflects an elevation of peripheral resistance or is relatischemia of the myocardium in these patients. Furthered to other mechanisms remains to be clarified. more, coronary reserve is reduced due to an extravascular Congestive heart failure is the end stage of hypertensive andor intravascular increases in flow resistance. heart disease and the result of the inability of the LV to Coronary hemodynamics in hypertensive heart disease 27 If this maintain adaptation to the pressure overload.26$ have been studied in the spontaneous hypertensive rat complication arises earlier in the natural history of hyper(SHR). These s t u d i e demonstrate ~~~~~~ a reduction in corotensive heart disease, then likely there is a second disease nary reserve that is comparable to that seen in humans. The involving the heart such as coronary atherosclerosis, obereduction of coronary reserve in the SHR is reversible if sity or diabetes. In hypertensive patients with obesity the the animal is treated from 5-65 weeks of age (metoprolol coexistence of pressure and volume overload leads to conplus hydralazine) or after the onset of hypertension from centric and eccentric hypertrophy.28This double structural the 20th to the 40th week of age (nifedipine). However, adaptation of the LV predisposes obese hypertensive the influence of reduction in LVM on myocardial perfupatients to premature cardiac failure. sion is poorly documented in humans. Hypothetically, With LVH, reactive interstitial fibrosis may occur. Reacbecause increases in afterload and in LVM can induce tive interstitial fibrosis is seen in the absence of myocyte ischemia, reduction in afterload and LVM should improve necrosis, is progressive in nature and initially is an adapischemia and related symptoms. However, hypertensive tive response that preserves LV function. In studies conpatients with LVH maintain coronary flow reserve by ducted by Jalil et al.29an increase in collagen volume fracmeans of increased perfusion pressure. When perfusion tion secondary to abdominal aorta banding is associated pressure fails to keep up with the hypertrophic process, with significantincrease in both diastolic and systolic stiffcoronary reserve diminishes to values below those seen in ness in the intact hypertrophied rat myocardium. This
8
Clin. Cardiol. Vol. 15, January 1992
patients with nonhypertrophied hearts.41The flow reserve of the endocardia1 layers becomes especially critical at high heart rates. Therefore, tachycardia induced by antihypertensive therapy may acutely expose patients to ischemia, even if reduction in LVM has occurred. Thus, an agent that will decrease heart rate, LVM and therefore oxygen consumption should be ideal as a first-line drug in hypertensive patients with LVH and myocardial ischemia. The reduced coronary blood flow and vascular reserve of the subendocardium in hypertensive cardiac hypertrophy may account for the so-called strain pattern seen on the electrocardiogram of advanced LVH." Furthermore, hypertensive patients with LVH and normal coronary angiograms have been found to have a 70% incidence of angina-like chest pain.15 When LVH is severe, the incidence of chest pain is increased to 80%in these patients.l5 Thus, it appears that LVH affects coronary circulation in several ways. In myocardial hypertrophy coronary blood flow may be reduced as a result of an increase in LVM without a concomitant increase in coronary circulation. When the heart is hypertrophied, coronary vascular resistance increases with a reciprocal diminution in the coronary flow reserve. Although the development of LVH is primarily due to systemic arterial hypertension, other factors have been implicated as participants in the process such as norepinephrine.424 A number of clinical and experimental studies have demonstrated a close relationship between the level of adrenergic activity and the development of LVH.43-46Catecholamines have been shown to promote protein synthesis, collagen deposition, myocardial fibrosis, and LVH.47,48 Recent studies have demonstrated that treatment of hypertension with a-adrenergic-blocking drugs causes a signifi. ~ ~though there is an associacant reduction in L W V ~Even tion between catecholamines and the development of LVH, the precise mechanism by which activation occurs is not completely understood. It has been shown that the addition of norepinephrine to tissue cultured myocytes stimulate DNA-mediatedprotein synthesis within the m y ~ c y t eThis .~~ study suggested that protein synthesis promoted by norepinephrine was mediated through the c-myc protooncogene upon stimulation of the a1-adrenergic receptor on the myocyte wall.50 Other agents have been implicated in the pathogenesis of hypertensive LVH and the initiation of myocardial cell growth (Table I).51Several of these agents are known to be produced in the arteriolar as well as the cardiac myocyte. Therefore, they have been implicated in the hypertrophic and hyperplastic responses to these cells. Furthermore an endogenous renin-angiotensinsystem has been demonstrated in the monocyte.52The presence of renin and its mRNA in the medial layers of blood vessels has been demonstrated using immunohistochemical techniques. Angiotensinogen is also locally synthesized since its messenger RNA has been shown to be present in whole blood vessels and in cultured vascular cells. Thus, coexpression of renin and angiotensinogen in blood vessel cells suggests the possibility of local angiotensinogen production. Studies in cultured
I Autocrine and paracrine influences on blood vessel TABLE growth
Vasoactive agents Angiotensin Serotonin Bradykinin
Prostaglandins Vasopressin Norepinephrine Growth-regulating factors Autocrine Platelet-derived growth factor IGF-I Heparin Paracrine Platelet-derived growth factor Monocyte-derived growth factor Endothelium-derived growth factor Heparin IGF-I TGF-f3 Epidermal growth factor Prostaglandins Oncogenes c-myc c-sis c-fos c-ras Abbreviations: IGF-I = Insulin-like growth factor;TGF-P= p-
transforming growth factor. Source: from Ref. 5 1, reproduced with permission.
cells have shown that angiotensin 11is synthesized intracellularly and subsequently relea~ed.5~ Data from isolated perfused blood vessels provide evidence that this local angiotensin exerts an autocrine or paracrine function or both on 55 Therefore, vascular monocyte vascular ~ontractility.~~, angiotensin 11production can influence vascular tone either by a direct autocrine effect on its own angiotensin I1 receptors or through a paracrine effect by activating angiotensin 11in adjacent smooth muscle cells or indirectly by inducing catecholamine release from adrenergic nerve endings.56 Vascular monocytes have the capacity to synthesize other vasoactive substances such as prostacyclin and many other substances capable of influencing local tone. In summary, multiple potential autocrine-paracrine mechanisms can influence monocyte growth and proliferation. Alterations in this complex and delicate balance of multiple vasoactive substances due to acquired or genetic abnormalities may result in generalized vascular hypertrophy, or hyperplasia, or both and contribute to the pathogenesis of hypertension. With the improved understanding of the role of the autocrine and paracrine influences on myocyte cell growth new antihypertensive agents could be designed. At the present time this is an area of active research.
D. Georgiou and B. H. Brundage: Regression of LV mass in hypertension Recently, Devereux et ~ 1have . suggested ~ ~ that the role of the renin-angiotensin system in the pathogenesis of LVH is not clear. Experimental data support a direct effect of angiotensin on myocardial protein synthesis and suggest that this may be independent of secondary adrenergic effects. Whether these observations are relevant to the pathogenesis of hypertensive cardiac hypertrophy remains uncertain because it has not been established that LVM is systematically greater in high-renin as opposed to low-renin forms of experimental or clinical hypertension. In a more recent study, Schmieder et al? have shown that angiotensin I1 levels correlate significantly with the presence of LVH. The mechanism is most likely direct stimulation of myocardial cell growth in patients with essential hypertension. Since salt intake influences the level of arterial pressure and the activity of the sympathetic adrenergic and reninangiotensin aldosterone sy~tems,5~. 6o it is possible that salt intake may promote myocardial hypertrophy. A study of dietary salt intake of two independent sets of patients found that the higher the 24-hour sodium urinary excretion the greater the LVM.61The authors concluded that in patients with essential hypertension and hypertrophy, dietary sodium intake is a powerful determinant of LVH independent of the hemodynamic load. In another study62 the same investigators found that dietary salt intake seems to be the strongest determinant of cardiac structural adaptation to hypertension. Dietary sodium may influence cardiac adaptation by interacting with the renin-angiotensinaldosterone system, the sympathetic nervous system or fluid volume homeostasis. Whether dietary sodium restriction induces regression of LVH remains unknown although preliminary results indicate that a marked reduction of sodium intake may reduce LVM in essential hypertension if associated with a significant reduction in blood pressure.63
Regression of Left Ventricular Mass The rationale for attempting to reduce LVM derives from the evidence that increased LVM carries an independent risk for congestive heart failure, coronary artery disease and sudden death.9,l o Therefore, regression of LVM is an attractive therapeutic goal. However, experimental and clinical studies suggest that a disproportionately greater reduction in LVM compared with that of blood pressure may lead to an increase in myocardial oxygen consumption, decreased systolic performance and a decrease in coronary reserve.I8 Liebson@recently reviewed more than 60 studies (Table 11) of hypertensive treatment which used echo to assess changes in LVM. The studies enrolled an average of 10 to 15 patients and found that correlation between reduction of LVM and a decrease in blood pressure was weak (r = 0.25; p < 0.02). In monotherapy studies, calcium channel blockers and ACE inhibitors have been shown to be consistently associated with regression of hypertrophy. Nifedipine, verapamil, and diltiazem reduced LVM from 7% (65) to 25% (66),6%
9
(67) to 12% (68),and lo%,respectively. Duration of therapy ranged from one month to one year.69 Dunn70 and Nakashima and co-worker~,~' using ACE inhibitors, showed significant decreases in LVM index and LVM (29.5% and 12%, respectively) within 12 and 28 weeks of treatment. The effect of beta blockers on the regression of LVH is not consistent, whereas the use of diuretics and arterial vasodilators is not usually associated with regression. A number of ~ t u d i e s ~ using ~ - ~beta ~ blockers have shown regression of LVH index and LVM ranging from 10 to 34%after 8 weeks to 12 months of treatment. Drayer et uL76showed no regression in 11 of 20 patients treated with hydrochlorothiazide, but ventricular septa1 thickness decreased in 9 of the 20 patients by an average of l l .7% (+ 2.3%) with 4-6 weeks of therapy. Others report that diuretics 78 or combined with severe salt restrict i ~ can n ~reduce ~ both LVH and blood pressure. One possible explanation for the difference in outcomes of the many studies is the difference in the response of individual patients to the medication. Studies with arterial vasodilators reported a decrease in LVM ranging from 10% to 19%.79, The problem with these studies is that the patients were also treated with diuretics and beta blockers. Therefore, the results79,8o must be interpreted with caution. Regression of LVM has not been associated with clinical LV systolic dysfunction. It is interesting that improvement in LV diastolic filling has been reported to occur with and without decreases in LVM. It is important to note that the participants in most reports had normal LV function. Thus, it is difficult to assess the impact of antihypertensive treatment on LVM regression in the general population. Demonstration of the impact of LVH regression on morbidity and mortality must await the results of larger, long-term studies underway. Schulman et aL8I demonstrated in elderly hypertensive patients with echocardiographically determined LVH that antihypertensive therapy was equally effective with a beta blocker (atenolol) and a calcium channel blocker (verapamil) but had different effects on LVM. After 6 months of blinded therapy, only the patients receiving verapamil had reduction in LVM as determined by echo. In contrast to this study, others have shown atenolol to be effective in decreasing LVM?4 In addition, Schulman et aL8l showed that the LV systolic function and diastolic function were preserved in patients with regression of LVH even after the withdrawal of antihypertensive therapy and return of the blood pressure to pretreatment levels. This partially addresses a concern that discontinuation of therapy in patients after regression of LVH might precipitate cardiac failure, when blood pressure returned to pretreatment levels.82 The observation by Schulman et aL8I that similar reductions of blood pressure by two different classes of antihypertensive agents have different effects on LVM raises several important questions. For example, what degree of LVH regression is desirable? When does regression of LVH become atrophy? Do all drugs provide the same benefits? The concentric hypertrophy associated with hyper-
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Clin. Cardiol. Vol. 15, January 1992
TABLE I1 Clinical echocardiographic studies of regression of LV mass in hypertension with drug therapy Reduction in LV mass
Duration
51 Year >I Year 210%
