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Physiologic considerations in left ventricular hypertrophy
Physiologic Considerations in Left Ventricular Hypertrophy
EDWARD D. FROHLICH, M.D. New Orleans, Louisiana
From the Alton Ochsner Medical Foundation, New Orleans, Louisiana. Requests for reprints should be addressed to, Dr. Edward D. Frohlich, Alton Ochsner Medical Foundation, 15 16 Jefferson Highway, New Orleans, Louisiana 70121.
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Left ventricular hypertrophy is both a target organ response to hypertensive vascular disease as well as a factor that might be responsible for other cardiovascular events. Recent work confirms that the increased cardiac mass associated with hypertension results as a structural adaptation to the increased afterload imposed on the heart. Initially there is a transient period of hyperfunction that is followed by the sustained structural adaptative period of stable hyperfunction. Even before left ventricular failure supervenes, the ventricular mass demonstrates impaired contraction. This article reviews the hemodynamic evidence in favor of this sequence of events but, in addition, points to the pathophysiological and clinical factors that may be responsible for the increased cardiac mass in addition to the pressure overload. These include: the pressor mechanisms per se; the age, sex, and race of the patient; and coexisting diseases. Some of these factors may account in part for the regression of cardiac mass with antihypertensive therapy. However, until we understand more clearly those factors that transduce the physical stimulus for hypertrophy into biochemical events, we shall neither understand completely the development of this structural adaptation of the heart nor its regression with treatment. Prospective data from the Framingham Study demonstrated that hypertension is the most common cause of congestive heart failure in the United States [ 11. When one considers the natural history of hypertensive heart disease and its duration in man [2], its apparent early onset in childhood and adolescence [3], and the magnitude of the prevalence of hypertension [4], these data are not too astonishing. What is perhaps more surprising is the general impression among clinicians that the problem of cardiac failure in hypertension is less frequently encountered. In part, this clinical conclusion is somewhat justified: more patients are being treated for hypertension: therefore, fewer patients should be suffering from the consequences of pressure overload upon the left ventricle. However, the problem of left ventricular failure may be obscured by lack of recognition of the chronically and severely elevated arterial pressures; it may not infrequently develop in patients with a coexistent cardiac disease (most frequently ischemic heart disease); and it may be obscured and attributed to intravascular volume expansion from antihypertensive therapy in the patient with associated preexistent or concomitant cardiac enlargement. This discussion will report on certain physiologic aspects of the heart in hypertension: as an adaptive organ that is forced to perform
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against an increasing and unrelenting pressure overload; as a target organ of other possible coexisting diseases; and as an organ that may be affected by coexisting factors that may also be associated with cardiac enlargement independent of the factor of hypertensive vascular disease. Also considered will be the physiologic roles of the heart: in initiating or responding to reflexive readjustments; in adapting to, or perhaps even
participating in, total body volume homeostasis; as a possible endocrine organ; and as a target organ not only affected by the hypertensive disease process but also by the antihypertensive therapy (Table I). Much of the pertinent information is only presently being accumulated through careful clinical and experimental study. Several of these subjects will be discussed in more extensive detail by others in this sym-
posium issue. Moreover, it is possible that much of what is presently known may only be germane to the normal heart and may not at all be analogous to the circumstances under which ventricular hypertrophy exists [ 21. Therefore, it may not be valid to extend conclusions as to the function of the heart with hypertrophy to the function of the heart hypertrophied from long-standing pressure overload. Moreover, the knowledge already gleaned from the heart with ventricular hypertrophy (produced by one form of pressure- or volume-overload) may not at all be analagous to the left ventricle hypertrophied over an extended time period from an insidiously progressive pressure overload produced by naturally occurring systemic arterial hypertension. Thus, we must remember that information concerning hypertrophy from pressure overload was derived from certain experimental and clinical situations in which the hypertrophy was initiated through a myriad of mechanisms or interventions that were not always similar to the slowly progressing situation found in genetic experimental (for example, spontaneously hypertensive rat) or clinical (for example, essential hypertensive man) hypertension. And even under these situations the pathophysiologic alterations are not homogeneous
Fl. MYOCARDIAL
ADAPTABILITY
Homeometric Autoregulation. One characteristic of both normal and hypertrophied myocardium is its ability to increase its force of contraction in response to in-
creased enddiastolic pressure (or volume) or to certain interventions that serve to augment its external performance [6]. Thus, under a wide variety of controlled experimental situations (as well as in clinical circumstances) the heart is able to adapt to changes in venous return, augmented adrenergic input, and to levels of catecholamines or other circulating substances by shifting from one force-volume relationship to another as a family of parallel curves that relate to one another
TABLE I
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Considerations of Cardiac Function in Left Ventricular Hypertrophy
Myocardial adaptability Homeometric autoregulation Increased myocardial contractility Ventricular hypertrophy Other factors in cardiac enlargement Role of pressor substances Aging Sexual factors Racial factors Collagen deposition Associated diseases (coronary artery disease. diabetes mellitus, obesity, and the like) Other physiologic factors Neural reflexes of cardiac origin Endocrine function of the heart Cardiac role in volume regulation Reversal of ventricular hypertrophy
in proportion to the intervention introduced [7]. Ultimately, the load or the degree of stress imposed on the ventricle may be so great that the myocardium can no longer adapt and the shift of this Frank-Starling relationship to the right achieves a descending limb of the curve [8]. Hypertrophy. The ability of the myocardium to adapt structurally to increased tension by the process of hypertrophy permits the Frank-Starling curve to be shifted more rightward. Eventually, the myocardium can no longer sustain the force necessary to overcome the load imposed on it and a descending limb to the curve can be demonstrated. In a recent study from our laboratory, rats with two kidneys were made hypertensive by placing a clip around only one renal artery [9]. Myocardial hypertrophy soon occurred, but when a volume load was rapidly given intravenously after only four weeks of hypertension, the heart was no longer able to maintain a normal cardiac output at any enddiastolic pressure. In fact, at the maximal volume load (at the end of the one-minute infusion), end-diastolic pressure exceeded that achieved by the normal hearts of sham-operated rats. When the same experiment was performed on rats with hypertension of six weeks duration, a definite descending limb of this Frank-Starling relationship was demonstrated; and this was seen at still higher end-diastolic pressures. Indeed, using a similar volume-loading intervention as a functional test of ventricular pumping ability, spontaneously hypertensive rats (older than one year of age) with marked concentric left ventricular hypertrophy failed to perform as well as two groups of normotensive rats matched according to age and sex [ 10,111. Thus, under rigidly controlled experimental circumstances, a progressive adaptability of the heart is evident in hypertension: first seen as a stage of increased function: this is followed by structural
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:_w x ESSm%Y_ UY?~PTENS!r3'\'-=sO"'_'r,Y
adaptation (that is, hypertrophy) of 1:he myocardium permitting a stable functioning ventricle that is able to cope with the increased wall tension and stress: but ultimately a relationship consistent ‘with a failing left ventricle is demonstrated whic.h, unless reversed therapeutically (with drugs or by unclipping the renal artery), will be followed by frank congestive heart failure and pulmonary edema. This sequence of pathophysiologic events has been lucidly described by Meerson [ 121. Moreover, although in lesser controlled circumstances, a very similar course of pathophysiologic events has been described in the patient with essential hypertension [5,13,14]. Clinical Adaptability. Under the conditions of clinical investigation, it is essential not to compromise the individual patient’s well-being; thus, patient groups with as similar a degree of homogeneity of clinical and demographic criteria as possible are essential. For this reason, patient grouping is necessary. In studies from our laboratory, patients with only essential hypertension were asked to withhold all therapy for at least four weeks while they were followed carefully in our clinic [ 13,141. Patients suspected of having other coexisting diseases such as ischemic heart (that is, coronary arterial atherosclerotic) disease or diabetes mellitus were excluded from study. The following describes our present understanding of the pathophysiologic changes, but these observations are described with some historic perspective. As Freis [ 151 described in 1960, the hemodynamic hallmark of hypertension is an increased total peripheral resistance that results from generalized arteriolar constriction. He also suggested coexisting venoconstriction in essential hypertension. Now, over 20 years later, investigators have confirmed that, in addition to the arteriolar constriction, there is indeed a significant venular constriction that serves to redistribute blood from the peripheral circulations to the cardiopulmonary area [ 16- 181. This serves to increase venous return and adds to the “hyperfunction” of the heart early in hypertension that is provoked by the increased contractility necessary to overcome the ventricular afterload and perhaps the net increased adrenergic activity that is also imposed upon the heart [ 19-211. Julius et al [20] demonstrated this in man with essential hypertension, and we have also shown in the spontaneously hypertensive rat that there is evidence of increased adrenergic activity associated with reduced parasympathetic control [21]. In addition, Tarazi et al [22], reported that not only in milder forms of hypertension, but even in more severe forms of essential hypertension, there is evidence of increased myocardial contractility just as if isoproterenol were administered to normotensive patients. Thus, in these individuals, the Frank-Starling relationship is shifted upward and to the left.
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September 26, 1963
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Adrenergic factors are important in augmenting myocardial contractility, but other naturally occurring humoral agents may also participate in increasing the inotropic and chronotropic function of the heart. These agents include other catecholamines, angiotensin II, increased ionizable calcium, and perhaps vasopressin and other substances [23]. As we learn more about the participation of other pressor mechanisms in hypertension, we shall become more aware of the complexity of the interrelationship of the many agents that participate in myocardial contractility. A number of years ago we compared patients with essential hypertension of increasing severity with normal normotensive persons. These studies demonstrated that as arterial pressure and clinical evidence of vascular disease increased in severity so did the total peripheral resistance [24]. Later, we classified patients according to evidence of cardiac involvement and compared each group with normotensive subjects [ 131. As severity of hypertension progressed from one group to the next (that is, from the normotensive subjects to the patients with essential hypertension without cardiac involvement, to those with left atrial abnormality, and then to those with left ventricular hypertrophy) there was also a progressive rise in arterial pressure following pari passu the increased total peripheral resistance. Normal resting cardiac output was maintained in patients until left ventricular hypertrophy was demonstrated. However, when left atrial abnormality was demonstrated by electrocardiographic findings the left ventricular ejection rate index was impaired even though resting cardiac output was normal. Moreover, there were significant increases in tension time index, left ventricular work, and pressure time per beat with each group of more severe cardiac involvement. There will be considerable discussion in this symposium issue on the echocardiogram in hypertension; but the first study in this area of clinical investigation was reported by Dunn et al [ 141. In that study patients were classified using the same criteria that were used earlier (electrocardiogram and chest roentgenogram), but echocardiographic indices were also measured. The same parallel progression of arterial pressure with elevation of total peripheral resistance and normal cardiac index was maintained until severe hypertrophy occurred. However, using a better index of myocardial contractility than left ventricular ejection rate, significant impairment of left ventricular function was demonstrated in patients with only left atrial abnormality. In these patients the left ventricular ejection fraction and fiber shortening rate were severely reduced in association with a definitely enlarged left atrium. Further, even though the electrocardiogram and chest x-ray film failed to show hypertrophy of the left ventricle in these patients, greater left ventricular mass, septal wall thickness, and posterior wall thickness were demonstrable
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echocardiographically. Increased left atrial mass was also present in the patients with ventricular hypertrophy; its presence before obvious ventricular hypertrophy occurred provided further credibility to the concept that the left atrial abnormality merely reflected the lesser compliance of the left ventricle as it underwent hypertrophy. Thus, the enlarged left atrium provided the first clinical evidence of left ventricular hypertrophy. More recent studies documented still earlier echocardiographic evidence of hypertrophy, even before demonstration of left atrial abnormality. Thus, impaired (diastolic) filling of the left ventricle provides an index of reduced compliance of the stiffer, early-hypertrophying left ventricle [25]. These clinical findings parallel the same sequence of physiologic changes suggested by Meerson [121--a stage of ventricular hyperfunction that preceded a longer stage of stable hyperfunction with hypertrophy, but eventually a stage of depressed myocardial contractility followed by one of overt left ventricular failure. OTHER FACTORS ASSOCIATED WITH INCREASED CARDIAC MASS Notwithstanding the considerable amount of evidence that has been amassed to support the hemodynamic basis for increased cardiac mass in hypertension, a variety of other factors are associated with the cardiomegaly (Table I). Preesor Substances. Over and above the pathogenetic factor of each of the myriad of pressor substances producing myocardial hypertrophy through the hypertensive hemodynamic process that involves elevating pressure and increasing ventricular afterload is the possibility that these agents may have a direct role in the initiation of new myocardial protein synthesis. Several of the known pressor agents have been shown to produce increased myocardial mass, even in the absence of an actual increase in arterial pressure. For examples, the addition of angiotensin II to myocardial cell tissue culture will increase cellular protein synthesis [26], and subpressor infusions of catecholamines will also increase myocardial protein synthesis, initiate development of ventricular hypertrophy, and produce increased collagen deposition and myocardial fibrosis [27,28]. Age, Sex, and Race. In recent years a considerable body of information has accumulated, from large population studies as well as from prospective epidemiologic data, that demonstrates that cardiac enlargement may be directly related to aging, racial, and sexual factors independent of the level of arterial pressure and other hemodynamic alterations [29,30]. Thus, pathologic data have demonstrated that aging, itself, is related to increased cardiac mass and ventricular wall thickness [3 1].Moreover, the prevalence of left ventricular
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hypertrophy is greater in the male patient than in the female patient who may not only tolerate the elevated pressure better but also have less prevalence of cardiac failure [29,30]. These epidemiologic studies are supported by recent controlled experimental studies that indicate that hemodynamic factors may be dissociated from sexual characteristics in response of cardiac mass to pharmacotherapy or hormonal manipulation [32,33]. Other epidemiologic studies have indicated that the black patient with hypertension may have more severe cardiac and vascular disease than the white patient [29,30]. However, a recent hemodynamic study from our laboratory involving black and white patients with hypertension matched with respect to age, sex, height of arterial pressure, body habitus, and (when possible) duration of hypertension showed no differences in systemic hemodynamics [34]. However, black patients seemed to have larger left ventricles that were related in mass to the level of arterial pressure [35] and more severe renal vascular disease [36]. These demographic characteristics point to other physiologic factors that may relate to development of cardiac enlargement and suggest new areas of investigation that should provide rewarding information. Coexisting Diseases. These findings bring to mind the question of whether complicating diseases associated with aging may also participate in the process of cardiac enlargement. Increased collagen deposition may be related to aging, and coexistent ischemic heart disease provides yet another strong possible explanation, In addition to these factors are the findings of a high prevalence of carbohydrate intolerance (if not actual diabetes mellitus) and hyperuricemia (if not gout) [29,30]. With respect to the latter, recent studies from our laboratory have related the finding of elevated serum uric acid levels not to a metabolic disease but to progressively more severe hemodynamic involvement of the kidney by hypertensive vascular disease 1371. Thus, patients with higher uric acid levels had more severely increased total peripheral and renal vascular resistances and lower renal blood flow. Since the functions relate also to the afterload imposed on the left ventricle, it seems reasonable that further investigation into these associations with ventricular hypertrophy will be rewarding. An additional problem frequently associated with hypertension is that of exogenous obesity [38]. Indeed, overweight is a true characteristic of patients with hypertension in addition to sodium sensitivity and more rapid heart rate [29]. In other studies from our laboratory, we have shown that the obesity associated with essential hypertension is related to expanded intravascular (plasma) volume, higher cardiac output in proportion to the degree of volume expansion, and increased total peripheral resistance [39]. Thus, the hearts of patients with obesity and essential hypertenSeptember 26, 1963
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sion are subjected to a dual wo~rkload: increased ventricular preload related to the volume overload and increased ventricuilar after-load related to the elevated arterial pressure and total peripheral resistance. It is, therefore, reasonable to assume that the left ventricle adapts to this twofold load in a more complex structural manner. Further ‘studies in this area are clearly necessary, but these early pathophysiologic characteristics may provide some understanding of the increased risk of cardiovascular morbidity and mortality in these patients. ADDITIONAL PHYSIOLOGIC CONSIDERATIONS Reflex Mechanisms. As arterial pressure increases in the normotensive situation, there is a predictable response on the part of the heart to decrease its rate, reduce its minute output and its vigor of contraction, and for the peripheral arterioles to dilate and reduce total peripheral resistance. One would, therefore, expect that in the hypertensive state there might be a slower heart rate and a lesser cardiac output to compensate for the increased vascular resistance: however, this is not the case. To the contrary, heart rate is frequently faster in most experimental and clinical forms of hypertension and, at least in the earlier stage of hypertension, a hyperdynamic circulation is found [2]. These findings, as well as altered baroreceptor nerve traffic, have led physiologists to conclude that in chronic hypertension a state of “reset” baroreceptors exists [40]. Less information is available as to whether this resetting is corrected with reversal of hypertension. Moreover, there is little to support any thesis that the locus of resetting is within the carotid baroreceptor, the brain stem, or elsewhere. We do know that there is an alteration in the carotid reflex mechanism, but there are no specific studies to indicate that this defect also involves the high pressure left ventricular receptors in hypertension or to indicate that these receptors are altered in the ventricle with hypertrophy. Moreover, if these receptors are altered in hypertension and/or hypertrophy, do they alter blood flow distribution to the peripheral circulations? These foregoing conjectures are related to the effects of hypertension on high-pressure receptors in the great vessels and left ventricle. However, other investigators have been concerned with how cardiogenic reflexes might induce hypertension [41]. How these relate to the clinical forms of hypertension is purely speculative, but there is ample evidence to indicate that hypertension (and presumably left ventricular hyper-, trophy) may follow myocardial infarction [42]. Still another related consideration may concern the physiologic mechanisms that might explain the antihypertensive actions of certain therapeutic agents including the beta-adrenergic receptor blocking drugs [43]. Endocrine and Volume Regulating Mechanisms.
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September26, 1983 The American Journal of Medlclne
What of the role of atrial receptors? Several years ago Braunwald [44] published a provocative editorial referring to the heart as an endocrine organ. In those days he considered primarily the storage capacity of the myocardium for norepinephrine and how this ability was diminished in the failing ventricle. We now know, through the work of James and his associates [45], that serotonin also participates in cardiac pressor reflexes. This report suggested that a pressor response in myocardial infarction could be initiated by the release of serotonin from platelet aggregates, but whether there are differences in responses to serotonin in the normal myocardium and the ventricle with hypertrophy or fibrosis is not known. Recently, physiologists have been concerned about a natriuretic factor that originates in atrial granules [46]. Investigators in our institution have partially purified this substance, isolated from the atria of rats, rabbits, dogs, monkey and man (but not from the ventricle), and have shown that it does produce a very profound natriuresis [47]. These findings suggest that the heart may be a volume-responding or -controlling organ through humoral as well as neural mechanisms. We already know that episodes of paroxysmal atrial tachycardia are followed by significant diuresis. Current thinking explains this phenomenon through a reflex initiated by the distended atrium [48]. However, an additional explanation might be a natriuretic factor that is released. We have already referred to the role of intravascular volume and vascular capacity (that is, peripheral venoconstriction) in hypertension, but question has also been raised as to the role of the heart in response to volume overload, particularly as it might relate to the phenomenon of exaggerated natriuresis in hypertension. Ulrych [49] related this exaggerated sodium excretion in patients with hypertension to the increased cardiac output provoked by the intravascular volume expansion. He suggested that cardiac output increased more in patients with hypertension largely because of a venoconstricted periphery and that greater sodium excretion resulted from some factor over and above an intrarenal factor. Perhaps this is produced by low pressure volume receptors or even the recently postulated atrial natriuretic factor. Reversal of Ventricular Hypertrophy. Later in this symposium issue we will learn about the response of the hypertrophied left ventricle associated with treatment of the hypertensive condition. Some consider this response to therapy as “good”; whether this is good or bad is more of a moral judgment. However, we do know that ventricular hypertrophy is a phenomenon that permits the heart to work more efficiently at higher pressure loads over a long term. This process is subject to therapeutic reversal and especially to the vagaries of man during antihypertensive therapy. Thus, we may
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produce regression of ventricular hypertrophy therapeutically: but if that therapy is discontinued abruptly by the patient, this might not be good. To explain, development of left ventricular hypertrophy is a slow and “normal” response to the progressively increasing pressure and ventricular afterload. Certain antihypertensive drugs (for example, methyldopa, beta-adrenergic receptor blocking drugs, converting enzyme inhibitors, and perhaps the slow-channel calcium antagonists) may regress this process leaving a greater proportion of collagen [9,50-541, whereas other agents (for example, vasodilators) that may have more salutory hemodynamic effects on the myocardium and may even control pressure better may have little effect on the
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hypertrophy [52,54]. This suggests the possibility of a therapeutic dilemma: we may regress hypertrophy but what happens when the arterial pressure abruptly increases if the patient discontinues therapy? Is that heart able to meet the demand of the suddenly increased pressure load without the opportunity to undergo a more long-term, adaptive change? And, is it possible for the myocardium to develop appropriate hypertrophy once the initial hypertrophy has regressed? It is, therefore, apparent that even though much is known about the pathophysiology of the heart in the normal and hypertrophied state, much more remains to be learned. And, is this not the expected result of disciplined inquiry?
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EDWARD D. FROHLICH, M.D. New Orleans, Louisiana
From the Alton Ochsner Medical Foundation, New Orleans, Louisiana. Requests for reprints should be addressed to, Dr. Edward D. Frohlich, Alton Ochsner Medical Foundation, 15 16 Jefferson Highway, New Orleans, Louisiana 70121.
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Left ventricular hypertrophy is both a target organ response to hypertensive vascular disease as well as a factor that might be responsible for other cardiovascular events. Recent work confirms that the increased cardiac mass associated with hypertension results as a structural adaptation to the increased afterload imposed on the heart. Initially there is a transient period of hyperfunction that is followed by the sustained structural adaptative period of stable hyperfunction. Even before left ventricular failure supervenes, the ventricular mass demonstrates impaired contraction. This article reviews the hemodynamic evidence in favor of this sequence of events but, in addition, points to the pathophysiological and clinical factors that may be responsible for the increased cardiac mass in addition to the pressure overload. These include: the pressor mechanisms per se; the age, sex, and race of the patient; and coexisting diseases. Some of these factors may account in part for the regression of cardiac mass with antihypertensive therapy. However, until we understand more clearly those factors that transduce the physical stimulus for hypertrophy into biochemical events, we shall neither understand completely the development of this structural adaptation of the heart nor its regression with treatment. Prospective data from the Framingham Study demonstrated that hypertension is the most common cause of congestive heart failure in the United States [ 11. When one considers the natural history of hypertensive heart disease and its duration in man [2], its apparent early onset in childhood and adolescence [3], and the magnitude of the prevalence of hypertension [4], these data are not too astonishing. What is perhaps more surprising is the general impression among clinicians that the problem of cardiac failure in hypertension is less frequently encountered. In part, this clinical conclusion is somewhat justified: more patients are being treated for hypertension: therefore, fewer patients should be suffering from the consequences of pressure overload upon the left ventricle. However, the problem of left ventricular failure may be obscured by lack of recognition of the chronically and severely elevated arterial pressures; it may not infrequently develop in patients with a coexistent cardiac disease (most frequently ischemic heart disease); and it may be obscured and attributed to intravascular volume expansion from antihypertensive therapy in the patient with associated preexistent or concomitant cardiac enlargement. This discussion will report on certain physiologic aspects of the heart in hypertension: as an adaptive organ that is forced to perform
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against an increasing and unrelenting pressure overload; as a target organ of other possible coexisting diseases; and as an organ that may be affected by coexisting factors that may also be associated with cardiac enlargement independent of the factor of hypertensive vascular disease. Also considered will be the physiologic roles of the heart: in initiating or responding to reflexive readjustments; in adapting to, or perhaps even
participating in, total body volume homeostasis; as a possible endocrine organ; and as a target organ not only affected by the hypertensive disease process but also by the antihypertensive therapy (Table I). Much of the pertinent information is only presently being accumulated through careful clinical and experimental study. Several of these subjects will be discussed in more extensive detail by others in this sym-
posium issue. Moreover, it is possible that much of what is presently known may only be germane to the normal heart and may not at all be analogous to the circumstances under which ventricular hypertrophy exists [ 21. Therefore, it may not be valid to extend conclusions as to the function of the heart with hypertrophy to the function of the heart hypertrophied from long-standing pressure overload. Moreover, the knowledge already gleaned from the heart with ventricular hypertrophy (produced by one form of pressure- or volume-overload) may not at all be analagous to the left ventricle hypertrophied over an extended time period from an insidiously progressive pressure overload produced by naturally occurring systemic arterial hypertension. Thus, we must remember that information concerning hypertrophy from pressure overload was derived from certain experimental and clinical situations in which the hypertrophy was initiated through a myriad of mechanisms or interventions that were not always similar to the slowly progressing situation found in genetic experimental (for example, spontaneously hypertensive rat) or clinical (for example, essential hypertensive man) hypertension. And even under these situations the pathophysiologic alterations are not homogeneous
Fl. MYOCARDIAL
ADAPTABILITY
Homeometric Autoregulation. One characteristic of both normal and hypertrophied myocardium is its ability to increase its force of contraction in response to in-
creased enddiastolic pressure (or volume) or to certain interventions that serve to augment its external performance [6]. Thus, under a wide variety of controlled experimental situations (as well as in clinical circumstances) the heart is able to adapt to changes in venous return, augmented adrenergic input, and to levels of catecholamines or other circulating substances by shifting from one force-volume relationship to another as a family of parallel curves that relate to one another
TABLE I
HYPERTENSION-FROHLICH
Considerations of Cardiac Function in Left Ventricular Hypertrophy
Myocardial adaptability Homeometric autoregulation Increased myocardial contractility Ventricular hypertrophy Other factors in cardiac enlargement Role of pressor substances Aging Sexual factors Racial factors Collagen deposition Associated diseases (coronary artery disease. diabetes mellitus, obesity, and the like) Other physiologic factors Neural reflexes of cardiac origin Endocrine function of the heart Cardiac role in volume regulation Reversal of ventricular hypertrophy
in proportion to the intervention introduced [7]. Ultimately, the load or the degree of stress imposed on the ventricle may be so great that the myocardium can no longer adapt and the shift of this Frank-Starling relationship to the right achieves a descending limb of the curve [8]. Hypertrophy. The ability of the myocardium to adapt structurally to increased tension by the process of hypertrophy permits the Frank-Starling curve to be shifted more rightward. Eventually, the myocardium can no longer sustain the force necessary to overcome the load imposed on it and a descending limb to the curve can be demonstrated. In a recent study from our laboratory, rats with two kidneys were made hypertensive by placing a clip around only one renal artery [9]. Myocardial hypertrophy soon occurred, but when a volume load was rapidly given intravenously after only four weeks of hypertension, the heart was no longer able to maintain a normal cardiac output at any enddiastolic pressure. In fact, at the maximal volume load (at the end of the one-minute infusion), end-diastolic pressure exceeded that achieved by the normal hearts of sham-operated rats. When the same experiment was performed on rats with hypertension of six weeks duration, a definite descending limb of this Frank-Starling relationship was demonstrated; and this was seen at still higher end-diastolic pressures. Indeed, using a similar volume-loading intervention as a functional test of ventricular pumping ability, spontaneously hypertensive rats (older than one year of age) with marked concentric left ventricular hypertrophy failed to perform as well as two groups of normotensive rats matched according to age and sex [ 10,111. Thus, under rigidly controlled experimental circumstances, a progressive adaptability of the heart is evident in hypertension: first seen as a stage of increased function: this is followed by structural
September 26, 1963
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:_w x ESSm%Y_ UY?~PTENS!r3'\'-=sO"'_'r,Y
adaptation (that is, hypertrophy) of 1:he myocardium permitting a stable functioning ventricle that is able to cope with the increased wall tension and stress: but ultimately a relationship consistent ‘with a failing left ventricle is demonstrated whic.h, unless reversed therapeutically (with drugs or by unclipping the renal artery), will be followed by frank congestive heart failure and pulmonary edema. This sequence of pathophysiologic events has been lucidly described by Meerson [ 121. Moreover, although in lesser controlled circumstances, a very similar course of pathophysiologic events has been described in the patient with essential hypertension [5,13,14]. Clinical Adaptability. Under the conditions of clinical investigation, it is essential not to compromise the individual patient’s well-being; thus, patient groups with as similar a degree of homogeneity of clinical and demographic criteria as possible are essential. For this reason, patient grouping is necessary. In studies from our laboratory, patients with only essential hypertension were asked to withhold all therapy for at least four weeks while they were followed carefully in our clinic [ 13,141. Patients suspected of having other coexisting diseases such as ischemic heart (that is, coronary arterial atherosclerotic) disease or diabetes mellitus were excluded from study. The following describes our present understanding of the pathophysiologic changes, but these observations are described with some historic perspective. As Freis [ 151 described in 1960, the hemodynamic hallmark of hypertension is an increased total peripheral resistance that results from generalized arteriolar constriction. He also suggested coexisting venoconstriction in essential hypertension. Now, over 20 years later, investigators have confirmed that, in addition to the arteriolar constriction, there is indeed a significant venular constriction that serves to redistribute blood from the peripheral circulations to the cardiopulmonary area [ 16- 181. This serves to increase venous return and adds to the “hyperfunction” of the heart early in hypertension that is provoked by the increased contractility necessary to overcome the ventricular afterload and perhaps the net increased adrenergic activity that is also imposed upon the heart [ 19-211. Julius et al [20] demonstrated this in man with essential hypertension, and we have also shown in the spontaneously hypertensive rat that there is evidence of increased adrenergic activity associated with reduced parasympathetic control [21]. In addition, Tarazi et al [22], reported that not only in milder forms of hypertension, but even in more severe forms of essential hypertension, there is evidence of increased myocardial contractility just as if isoproterenol were administered to normotensive patients. Thus, in these individuals, the Frank-Starling relationship is shifted upward and to the left.
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September 26, 1963
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Adrenergic factors are important in augmenting myocardial contractility, but other naturally occurring humoral agents may also participate in increasing the inotropic and chronotropic function of the heart. These agents include other catecholamines, angiotensin II, increased ionizable calcium, and perhaps vasopressin and other substances [23]. As we learn more about the participation of other pressor mechanisms in hypertension, we shall become more aware of the complexity of the interrelationship of the many agents that participate in myocardial contractility. A number of years ago we compared patients with essential hypertension of increasing severity with normal normotensive persons. These studies demonstrated that as arterial pressure and clinical evidence of vascular disease increased in severity so did the total peripheral resistance [24]. Later, we classified patients according to evidence of cardiac involvement and compared each group with normotensive subjects [ 131. As severity of hypertension progressed from one group to the next (that is, from the normotensive subjects to the patients with essential hypertension without cardiac involvement, to those with left atrial abnormality, and then to those with left ventricular hypertrophy) there was also a progressive rise in arterial pressure following pari passu the increased total peripheral resistance. Normal resting cardiac output was maintained in patients until left ventricular hypertrophy was demonstrated. However, when left atrial abnormality was demonstrated by electrocardiographic findings the left ventricular ejection rate index was impaired even though resting cardiac output was normal. Moreover, there were significant increases in tension time index, left ventricular work, and pressure time per beat with each group of more severe cardiac involvement. There will be considerable discussion in this symposium issue on the echocardiogram in hypertension; but the first study in this area of clinical investigation was reported by Dunn et al [ 141. In that study patients were classified using the same criteria that were used earlier (electrocardiogram and chest roentgenogram), but echocardiographic indices were also measured. The same parallel progression of arterial pressure with elevation of total peripheral resistance and normal cardiac index was maintained until severe hypertrophy occurred. However, using a better index of myocardial contractility than left ventricular ejection rate, significant impairment of left ventricular function was demonstrated in patients with only left atrial abnormality. In these patients the left ventricular ejection fraction and fiber shortening rate were severely reduced in association with a definitely enlarged left atrium. Further, even though the electrocardiogram and chest x-ray film failed to show hypertrophy of the left ventricle in these patients, greater left ventricular mass, septal wall thickness, and posterior wall thickness were demonstrable
LVH IN ESSENTIAL
echocardiographically. Increased left atrial mass was also present in the patients with ventricular hypertrophy; its presence before obvious ventricular hypertrophy occurred provided further credibility to the concept that the left atrial abnormality merely reflected the lesser compliance of the left ventricle as it underwent hypertrophy. Thus, the enlarged left atrium provided the first clinical evidence of left ventricular hypertrophy. More recent studies documented still earlier echocardiographic evidence of hypertrophy, even before demonstration of left atrial abnormality. Thus, impaired (diastolic) filling of the left ventricle provides an index of reduced compliance of the stiffer, early-hypertrophying left ventricle [25]. These clinical findings parallel the same sequence of physiologic changes suggested by Meerson [121--a stage of ventricular hyperfunction that preceded a longer stage of stable hyperfunction with hypertrophy, but eventually a stage of depressed myocardial contractility followed by one of overt left ventricular failure. OTHER FACTORS ASSOCIATED WITH INCREASED CARDIAC MASS Notwithstanding the considerable amount of evidence that has been amassed to support the hemodynamic basis for increased cardiac mass in hypertension, a variety of other factors are associated with the cardiomegaly (Table I). Preesor Substances. Over and above the pathogenetic factor of each of the myriad of pressor substances producing myocardial hypertrophy through the hypertensive hemodynamic process that involves elevating pressure and increasing ventricular afterload is the possibility that these agents may have a direct role in the initiation of new myocardial protein synthesis. Several of the known pressor agents have been shown to produce increased myocardial mass, even in the absence of an actual increase in arterial pressure. For examples, the addition of angiotensin II to myocardial cell tissue culture will increase cellular protein synthesis [26], and subpressor infusions of catecholamines will also increase myocardial protein synthesis, initiate development of ventricular hypertrophy, and produce increased collagen deposition and myocardial fibrosis [27,28]. Age, Sex, and Race. In recent years a considerable body of information has accumulated, from large population studies as well as from prospective epidemiologic data, that demonstrates that cardiac enlargement may be directly related to aging, racial, and sexual factors independent of the level of arterial pressure and other hemodynamic alterations [29,30]. Thus, pathologic data have demonstrated that aging, itself, is related to increased cardiac mass and ventricular wall thickness [3 1].Moreover, the prevalence of left ventricular
HYPERTENSION-FROHLICH
hypertrophy is greater in the male patient than in the female patient who may not only tolerate the elevated pressure better but also have less prevalence of cardiac failure [29,30]. These epidemiologic studies are supported by recent controlled experimental studies that indicate that hemodynamic factors may be dissociated from sexual characteristics in response of cardiac mass to pharmacotherapy or hormonal manipulation [32,33]. Other epidemiologic studies have indicated that the black patient with hypertension may have more severe cardiac and vascular disease than the white patient [29,30]. However, a recent hemodynamic study from our laboratory involving black and white patients with hypertension matched with respect to age, sex, height of arterial pressure, body habitus, and (when possible) duration of hypertension showed no differences in systemic hemodynamics [34]. However, black patients seemed to have larger left ventricles that were related in mass to the level of arterial pressure [35] and more severe renal vascular disease [36]. These demographic characteristics point to other physiologic factors that may relate to development of cardiac enlargement and suggest new areas of investigation that should provide rewarding information. Coexisting Diseases. These findings bring to mind the question of whether complicating diseases associated with aging may also participate in the process of cardiac enlargement. Increased collagen deposition may be related to aging, and coexistent ischemic heart disease provides yet another strong possible explanation, In addition to these factors are the findings of a high prevalence of carbohydrate intolerance (if not actual diabetes mellitus) and hyperuricemia (if not gout) [29,30]. With respect to the latter, recent studies from our laboratory have related the finding of elevated serum uric acid levels not to a metabolic disease but to progressively more severe hemodynamic involvement of the kidney by hypertensive vascular disease 1371. Thus, patients with higher uric acid levels had more severely increased total peripheral and renal vascular resistances and lower renal blood flow. Since the functions relate also to the afterload imposed on the left ventricle, it seems reasonable that further investigation into these associations with ventricular hypertrophy will be rewarding. An additional problem frequently associated with hypertension is that of exogenous obesity [38]. Indeed, overweight is a true characteristic of patients with hypertension in addition to sodium sensitivity and more rapid heart rate [29]. In other studies from our laboratory, we have shown that the obesity associated with essential hypertension is related to expanded intravascular (plasma) volume, higher cardiac output in proportion to the degree of volume expansion, and increased total peripheral resistance [39]. Thus, the hearts of patients with obesity and essential hypertenSeptember 26, 1963
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LVH IN ESSENT!AI_ UYPEPTENSlnN-=PaY’_!Cu
sion are subjected to a dual wo~rkload: increased ventricular preload related to the volume overload and increased ventricuilar after-load related to the elevated arterial pressure and total peripheral resistance. It is, therefore, reasonable to assume that the left ventricle adapts to this twofold load in a more complex structural manner. Further ‘studies in this area are clearly necessary, but these early pathophysiologic characteristics may provide some understanding of the increased risk of cardiovascular morbidity and mortality in these patients. ADDITIONAL PHYSIOLOGIC CONSIDERATIONS Reflex Mechanisms. As arterial pressure increases in the normotensive situation, there is a predictable response on the part of the heart to decrease its rate, reduce its minute output and its vigor of contraction, and for the peripheral arterioles to dilate and reduce total peripheral resistance. One would, therefore, expect that in the hypertensive state there might be a slower heart rate and a lesser cardiac output to compensate for the increased vascular resistance: however, this is not the case. To the contrary, heart rate is frequently faster in most experimental and clinical forms of hypertension and, at least in the earlier stage of hypertension, a hyperdynamic circulation is found [2]. These findings, as well as altered baroreceptor nerve traffic, have led physiologists to conclude that in chronic hypertension a state of “reset” baroreceptors exists [40]. Less information is available as to whether this resetting is corrected with reversal of hypertension. Moreover, there is little to support any thesis that the locus of resetting is within the carotid baroreceptor, the brain stem, or elsewhere. We do know that there is an alteration in the carotid reflex mechanism, but there are no specific studies to indicate that this defect also involves the high pressure left ventricular receptors in hypertension or to indicate that these receptors are altered in the ventricle with hypertrophy. Moreover, if these receptors are altered in hypertension and/or hypertrophy, do they alter blood flow distribution to the peripheral circulations? These foregoing conjectures are related to the effects of hypertension on high-pressure receptors in the great vessels and left ventricle. However, other investigators have been concerned with how cardiogenic reflexes might induce hypertension [41]. How these relate to the clinical forms of hypertension is purely speculative, but there is ample evidence to indicate that hypertension (and presumably left ventricular hyper-, trophy) may follow myocardial infarction [42]. Still another related consideration may concern the physiologic mechanisms that might explain the antihypertensive actions of certain therapeutic agents including the beta-adrenergic receptor blocking drugs [43]. Endocrine and Volume Regulating Mechanisms.
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September26, 1983 The American Journal of Medlclne
What of the role of atrial receptors? Several years ago Braunwald [44] published a provocative editorial referring to the heart as an endocrine organ. In those days he considered primarily the storage capacity of the myocardium for norepinephrine and how this ability was diminished in the failing ventricle. We now know, through the work of James and his associates [45], that serotonin also participates in cardiac pressor reflexes. This report suggested that a pressor response in myocardial infarction could be initiated by the release of serotonin from platelet aggregates, but whether there are differences in responses to serotonin in the normal myocardium and the ventricle with hypertrophy or fibrosis is not known. Recently, physiologists have been concerned about a natriuretic factor that originates in atrial granules [46]. Investigators in our institution have partially purified this substance, isolated from the atria of rats, rabbits, dogs, monkey and man (but not from the ventricle), and have shown that it does produce a very profound natriuresis [47]. These findings suggest that the heart may be a volume-responding or -controlling organ through humoral as well as neural mechanisms. We already know that episodes of paroxysmal atrial tachycardia are followed by significant diuresis. Current thinking explains this phenomenon through a reflex initiated by the distended atrium [48]. However, an additional explanation might be a natriuretic factor that is released. We have already referred to the role of intravascular volume and vascular capacity (that is, peripheral venoconstriction) in hypertension, but question has also been raised as to the role of the heart in response to volume overload, particularly as it might relate to the phenomenon of exaggerated natriuresis in hypertension. Ulrych [49] related this exaggerated sodium excretion in patients with hypertension to the increased cardiac output provoked by the intravascular volume expansion. He suggested that cardiac output increased more in patients with hypertension largely because of a venoconstricted periphery and that greater sodium excretion resulted from some factor over and above an intrarenal factor. Perhaps this is produced by low pressure volume receptors or even the recently postulated atrial natriuretic factor. Reversal of Ventricular Hypertrophy. Later in this symposium issue we will learn about the response of the hypertrophied left ventricle associated with treatment of the hypertensive condition. Some consider this response to therapy as “good”; whether this is good or bad is more of a moral judgment. However, we do know that ventricular hypertrophy is a phenomenon that permits the heart to work more efficiently at higher pressure loads over a long term. This process is subject to therapeutic reversal and especially to the vagaries of man during antihypertensive therapy. Thus, we may
LVH IN ESSENTIAL
produce regression of ventricular hypertrophy therapeutically: but if that therapy is discontinued abruptly by the patient, this might not be good. To explain, development of left ventricular hypertrophy is a slow and “normal” response to the progressively increasing pressure and ventricular afterload. Certain antihypertensive drugs (for example, methyldopa, beta-adrenergic receptor blocking drugs, converting enzyme inhibitors, and perhaps the slow-channel calcium antagonists) may regress this process leaving a greater proportion of collagen [9,50-541, whereas other agents (for example, vasodilators) that may have more salutory hemodynamic effects on the myocardium and may even control pressure better may have little effect on the
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hypertrophy [52,54]. This suggests the possibility of a therapeutic dilemma: we may regress hypertrophy but what happens when the arterial pressure abruptly increases if the patient discontinues therapy? Is that heart able to meet the demand of the suddenly increased pressure load without the opportunity to undergo a more long-term, adaptive change? And, is it possible for the myocardium to develop appropriate hypertrophy once the initial hypertrophy has regressed? It is, therefore, apparent that even though much is known about the pathophysiology of the heart in the normal and hypertrophied state, much more remains to be learned. And, is this not the expected result of disciplined inquiry?
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