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Effects of Thyroid Hormone on Cardiac Function - The Relative Importance of Heart Rate, Loading Conditions, and Myocardial Contractility in the Regulation of Cardiac Performance in Human Hyperthyroidism

Departments of Clinical and Molecular Endocrinology and Oncology (B.B., G.L.) and Clinical Medicine, Cardiovascular and Immunological Sciences (E.A.P., S.F.), University Federico II School of Medicine, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Bernadette Biondi, M.D., Department of Clinical and Molecular Endocrinology and Oncology, Division of Endocrinology, via S. Pansini 5, 80131 Naples, Italy. E-mail: . bebiondi{at}libero.it

Abstract

The cardiovascular manifestations of thyroid hormone excess, including tachycardia, a widened pulse pressure, a brisk carotid and peripheral arterial pulsation, a hyperkinetic cardiac apex, and loud first heart sound have long been recognized and are a cornerstone for clinical diagnosis (1, 2, 3, 4, 5, 6, 7, 8, 9). A number of studies in the past decades have provided critical insights into the mechanisms that are responsible for the hyperdynamic cardiocirculatory state in overt hyperthyroid patients, suggesting that it probably results from the combined effects of thyroid hormone on certain molecular pathways on the heart and vasculature, at both the genomic and nongenomic level (10).

Despite these advances, it is not yet clear whether, in spontaneous human hyperthyroidism, the high cardiac output state (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) is sustained prevalently by changes in peripheral hemodynamics (vascular hypothesis), or by changes in myocardial contractility (myocardial hypothesis) (19, 21). This issue has major clinical and pathophysiological implications. In fact, although peripheral and myocardial mechanisms are not mutually exclusive, the major contribution of one of the two mechanisms may have important consequences with regard to the "economy" of the cardiovascular system, given the notion that increased cardiac performance due to inotropic stimulation is less efficient than that due to modulation of the loading status. Accordingly, here we review research on the effects of spontaneous human hyperthyroidism on heart rate, preload, afterload, and myocardial contractility in an attempt to establish how these factors interact with each other and to what extent they contribute to increasing cardiac performance at rest.

Thyroid hormone and heart rate

Heart rate is an important mechanism for the regulation of cardiac output. Apart from determining the rate of cardiac ejection, it affects both systolic and diastolic function. An accelerated heart rate increases the minute stroke work at any given level of cardiac preload—a finding consistent with improved myocardial contractility (force-frequency relation) (25). A high heart rate also increases the rate of myocardial relaxation, thus improving early cardiac filling (lusitropic effect) (25). However, acceleration of the frequency of cardiac contraction does not increase cardiac performance if preload is not augmented or, at least, maintained constant. Pacing-induced increase in contraction frequency generally reduces preload and stroke volume, so that cardiac output remains constant (26, 27). On the other hand, an increased heart rate reduces diastolic filling time and, thus, leads to greater dependence on atrial systole. This explains the important pathophysiologic impact of atrial fibrillation on cardiac performance. Interestingly, heart rate may also affect peripheral hemodynamics. Studies of atrially paced normal subjects have demonstrated that an increase in the frequency of cardiac contraction reduces the "dynamic" compliance of the arterial tree and augments arterial pressure (28, 29, 30). This effect probably results from altered timing of the reflected pressure wave from the peripheral arterial tree consequent to the reduction in absolute duration of systole. That is, as systolic time lessens because of increased heart rate, the reflected pressure wave returning from the peripheral arterial tree would be added to and so enhance the forward pressure wave, thereby increasing blood pressure (Fig. 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. Potential effect of the increase in heart rate on arterial pressure in hyperthyroid patients.

Thyroid hormone and preload

Preload is the hemodynamic force exerted on the ventricular wall during filling and, thus, corresponds to ventricular end-diastolic wall stress or tension sensu strictu. It contributes greatly to the determination of ventricular end-diastolic volume and modulates myocardial performance significantly (i.e. it governs the extent and velocity of wall shortening). Thus, preload plays a major role in regulation of the stroke volume of the heart (Frank-Starling mechanism). Indeed, it is the most efficient mechanism by which cardiac output is adjusted to the peripheral metabolic demand. In the intact organism, preload is largely regulated by venous return, which, in turn, depends on systemic vascular resistance and venous tone. Total blood volume and atrial contraction may also significantly contribute to regulating cardiac preload (25). To measure ventricular preload in the intact heart, one should simultaneously record internal dimension, wall thickness, and pressure at end-diastole, the latter being measured by means of invasive methodology (cardiac catheterization). Alternatively, given normal ventricular size, chamber geometry (radius/wall thickness), and distensibility, and given the curvilinear shape of the ventricular diastolic pressure-volume relationship, end-diastolic internal dimension or volume are considered reliable indices of ventricular preload (25).

It has yet to be established whether the impact of hyperthyroidism on cardiac preload in humans contributes to the increased left ventricular (LV) performance in humans (13, 18, 19, 20, 21, 23, 24, 43, 44, 45, 46, 47, 48, 49, 50). Gibson and Harris (43) and Anthonisen et al. (13) demonstrated that blood volume is increased in hyperthyroid patients, which supports the hypothesis that preload has a mandatory role in determining the high output state. Similarly, Resnick and Laragh (44) demonstrated that the renin-angiotensin-aldosterone system is activated in hyperthyroid patients. Thyroid hormone has been shown to up-regulate erythropoietin secretion and, in turn, red blood cell mass, which may also contribute to the increase in total blood volume and cardiac preload (12, 43, 45). Despite this evidence, the finding of unchanged or only marginally increased LV end-diastolic dimension or volume in hyperthyroidism has been invoked in support of the view that the Frank-Starling mechanism is not implicated in augmenting cardiac performance (18, 19, 20, 21, 23, 24, 46, 47, 48, 49, 50). However, the augmented heart rate, as occurs in hyperthyroidism, would be expected to reduce ventricular end-diastolic dimension or volume if preload was not increased, given the inverse relationship between the two variables (26, 27). Thus, the normal or marginally increased end-diastolic dimension or volume reported in the above-cited studies should be considered indicative of an effective increase in preload. This is supported by the finding that end-diastolic volume was higher in hyperthyroid patients than in normal subjects atrially paced at the same heart rate (19). Moreover, practically none of those studies corrected LV end-diastolic dimension or volume for body size (18, 19, 20, 21, 24, 46, 47, 48, 49, 50). Because weight loss is almost invariably associated with thyrotoxicosis, it cannot be excluded that these indices of LV preload, although normal in absolute terms, were inappropriately high for the patients’ body size.

Further evidence for increased preload in hyperthyroidism is provided by the consistent increase in indices of early LV filling, and by the faster LV relaxation independent of the effect of heart rate and catecholamines (50). In fact, increased indices of early transmitral peak flow velocity (18, 23, 48, 51) and shortened LV isovolumic relaxation time in hyperthyroid patients (18, 23, 48, 50) may reflect greater venous return, which leads to an increased proto-diastolic transmitral pressure gradient (due to increased atrial pressure) and earlier mitral valve opening. Alternatively, the shorter isovolumic relaxation time may be due to improved diastolic function per se, which, in turn, would allow the increased venous return to be accommodated without relevant changes in filling pressure. By accentuating the isovolumic intracavity pressure decay, the increased rate of ventricular relaxation enhances ventricular suction (52, 53, 54, 55). Accordingly, the greater early atrioventricular pressure gradient in hyperthyroid patients could be sustained by enhanced ventricular suction rather than by a relevant increase in atrial pressure (Fig. 2). This interpretation is supported by the observation of comparable values of LV end-diastolic volume and pressure in hyperthyroid patients and normal subjects (19).

View larger version (22K): [in this window] [in a new window]   Figure 2. Effect of ventricular suction on the atrio (dotted line)-ventricular (solid line) pressure gradient and transmitral Doppler flow velocimetry.

Afterload is the hemodynamic force exerted on the ventricular wall during ejection, corresponding, therefore, to end-systolic wall stress or tension sensu strictu. It contributes to the determination of ventricular end-systolic volume and modulates myocardial performance significantly (i.e. it governs the extent and velocity of wall shortening). Thus, afterload is a determinant of the stroke volume of the heart (force-velocity relation) in that it provides a crucial servomechanism for the functional coupling of the cardiac pump to the arterial system. In the intact organism, afterload is largely regulated by arterial pressure (vascular afterload), which, in turn, depends on interaction between the steady (systemic vascular resistance) and pulsatile (global arterial compliance, aortic characteristic impedance, and indices of wave propagation and reflection) components of arterial load. Changes in ventricular size and chamber geometry may also affect ventricular afterload (cardiac afterload) (25). Afterload in the intact heart can be measured by simultaneous recording of internal dimension, wall thickness, and pressure at end-systole, which requires cardiac catheterization. Alternatively, given the correlation between systolic arterial pressure and end-systolic ventricular pressure, end-systolic wall stress estimated from cuff sphygmomanometer measurements is a reliable measure of ventricular afterload (25).

In many review articles on the effects of thyroid hormone on the cardiovascular system, ventricular afterload has long been reported to be reduced in hyperthyroid patients (56, 57, 58). This notion gained credence thanks to the finding that thyroid hormone directly promotes arterial smooth muscle relaxation (59, 60, 61), so leading to a reduction in systemic vascular resistance both acutely and chronically (11, 12, 13, 15, 16, 19, 21, 22, 23, 24, 44, 62). However, the reduction in the steady component of arterial load is not accompanied by a reduction in LV end-systolic wall stress in hyperthyroid patients (21), largely because of a consistent trend toward higher systolic arterial pressure (12, 13, 19, 21, 24, 63, 64). This observation strongly supports the hypothesis that in hyperthyroidism, despite a marked reduction in systemic vascular resistance, the pulsatile arterial load undergoes a compensatory change. As a result, by maintaining or even increasing the aortic input impedance, the pulsatile arterial load would sustain the systolic arterial pressure and prevent reduction of ventricular afterload. The mechanism underlying increasing pulsatile components of vascular afterload in hyperthyroidism is unclear. Albeit speculative, the increase in heart rate in hyperthyroidism could play a major role in this mechanism because it reduces the dynamic compliance of the arterial tree, thus increasing the aortic input impedance and, in turn, increasing systolic arterial pressure (28, 29, 30).

Thyroid hormone and myocardial contractility

The term "myocardial contractility" refers to the intrinsic property of the cardiac muscle to do work, that is "the potential to do work" (25). Thus, it corresponds to the performance of the heart independent of the effect of heart rate and/or loading status sensu strictu. By contrast, the term "LV systolic function" represents the aggregate effect of all the mechanisms that control cardiac performance (heart rate, preload, afterload, and myocardial contractility).

In hyperthyroid patients there is a consistent improvement in LV systolic function at rest (17, 18, 19, 21, 23, 46, 47, 48, 49, 63, 65, 66, 67, 68, 69, 70). There are two schools of thought as to how this finding should be interpreted in terms of myocardial contractility. Controversy is fueled by the different importance given to changes in heart rate and cardiac loading conditions. In studies in which preload and/or afterload were considered to be substantially unaffected by thyroid hormone excess, the enhancement of LV systolic function, independent of the effect of heart rate, was viewed as the result of a mandatory increase in the level of myocardial contractility (18, 21, 23, 46, 47, 48, 49, 63, 65, 66, 67). By contrast, in studies in which thyroid hormone was thought to have a pronounced effect on heart rate and peripheral circulation, the presence of an effective increase in myocardial contractility was considered too simplistic (19, 49). The studies by Merillon et al. (19) and by Feldman et al. (21) are emblematic of the two contradictory interpretations. Merillon et al. (19) assessed LV function in seven thyrotoxic patients by cardiac catheterization in comparison with 11 normal controls atrially paced at a near identical heart rate. They found no differences between the two groups in such parameters of contractile performance as LV ejection fraction, rate of rise of LV pressure as a proportion of the total pressure, velocity of circumferential fiber shortening, and ratio of LV end-systolic pressure to end-systolic volume. Conversely, it was noted that atrial pacing, but not hyperthyroidism, was accompanied by a marked reduction in both end-diastolic volume and pressure and by a significant increase in systemic vascular resistance and mean aortic pressure. As expected, cardiac performance was not increased in atrially paced subjects. Although from a pathophysiological perspective atrial pacing and hyperthyroidism are not strictly comparable (acute vs. chronic condition), the authors concluded that there was no realistic increase in the true level of myocardial contractility independent of changes in heart rate and preload in human hyperthyroidism. This suggested that the high output state was probably due to the synergistic interaction between the increase in heart rate and ventricular preload. In contrast, Feldman et al. (21) studied LV function in 11 hyperthyroid patients by means of echocardiography and in 11 age-matched normal subjects. They found no differences between the two groups in LV end-diastolic diameter or in end-systolic meridional wall stress. Differently, the rate-corrected mean velocity of circumferential fiber shortening (a measure of LV function claimed to be independent of preload and heart rate) was much higher in hyperthyroid patients. As a result, when LV end-systolic wall stress was related to the rate-corrected velocity of fiber shortening, the values of hyperthyroid patients were above the mean regression line for normal subjects, thereby reflecting the presence of an increased contractile state. The authors, however, did not consider that the normal end-diastolic dimension despite the augmented heart rate in their patients corresponded to an effective increase in preload, given the inverse relationship between the two variables (26, 27). The noninvasive method of assessing myocardial contractility by relating the rate-corrected circumferential fiber shortening velocity to meridional LV end-systolic wall stress may overestimate myocardial performance in pathophysiological states characterized by simultaneous increases in preload and heart rate (71).

Thyroid hormone and cardiac performance: integrated responses

The concept that emerges from this review is that the increase in heart rate and preload could play a major role in augmenting LV performance in human hyperthyroidism, thus reinforcing the notion that the hyperkinetic cardiovascular state in human hyperthyroidism is an adaptive response to the increase in the peripheral metabolic demand promoted by thyroid hormone (72, 73). Therefore, it seems that the effects of thyroid hormone on peripheral circulation play a central role in regulating cardiac performance (Fig. 3). By reducing systemic vascular resistance, thyroid hormone would shift blood from the arterial to the venous compartment of the vascular system, thus unloading the arterial tree. This effect, coupled with activation of the renin-angiotensin-aldosterone system and with increased red blood cell mass, would increase blood volume and, in turn, the venous return to the heart. At the same time, by increasing heart rate and improving ventricular diastolic function, thyroid hormone would enhance ventricular suction, thus allowing the heart to accommodate the greater venous return without major changes in ventricular end-diastolic pressure and dimension. This mechanism would mask the increase in cardiac preload, leading to an underestimation of the extent to which the Frank-Starling mechanism contributes to improving cardiac performance. On the other hand, by reducing the dynamic compliance of the arterial tree, the increase in heart rate would help to increase systolic arterial pressure. As a result, by counteracting the marked reduction in diastolic arterial pressure due to the fall in systemic vascular resistance, the slight but significant increase in systolic blood pressure would, in turn, maintain mean arterial pressure and increase pulse pressure. Consequently, the increased LV performance would be converted into the typical hyperdynamic cardiocirculatory state. Therefore, although the augmented LV performance is important in determining the high output state in human hyperthyroidism, the alterations in the peripheral circulation seem to be of at least equal significance. That is, if the increase in LV pump function is necessary to sustain the high output state, changes in peripheral circulation must act in concert to develop and maintain the hyperkinetic cardiovascular state.

View larger version (22K): [in this window] [in a new window]   Figure 3. Pathophysiological paradigm of the mechanisms by which at-rest cardiac output is increased in human hyperthyroidism (dotted line, inhibitory action). SVR, Systemic vascular resistance; RAAS, renin-angiotensin-aldosterone system; DAP, diastolic arterial pressure; SAP, systolic arterial pressure; AP, arterial pressure; LVEDV, LV end-diastolic volume; LVESV, LV end-systolic volume.

The importance of loading conditions in augmenting cardiac performance in human hyperthyroidism is supported by evidence of a higher LV mechanical work efficiency (i.e. the ratio between minute external work and the energy cost required to do it). In fact, although the hypermetabolic state in hyperthyroidism is accompanied by an increased cardiac minute work index and myocardial oxygen consumption (11, 16), Feldman et al. (21) and Bengel et al. (24) found (using different methodology) that estimates of LV work were higher than those of myocardial oxidative metabolism in hyperthyroid subjects. These observations are in line with the notion that the increase in cardiac performance due to adjustments in the loading status of the heart is more energetically efficient than that secondary to changes in myocardial contractility. In fact, changes in preload and/or afterload may "passively" regulate myocardial performance, without a major increase in myocardial oxygen demand. Conversely, the regulation of myocardial contractile state is almost invariably accompanied by remarkable changes in absolute myocardial oxygen consumption.

Conclusion

The augmented cardiac performance accompanying human hyperthyroidism seems to be mostly an adaptive response to changes in peripheral hemodynamics rather than the result of a mandatory enhancement of myocardial contractility. This view is in line with the notion that, at steady state, cardiac output can neither exceed nor fall below the venous return (i.e. cardiac output is normally determined by the needs of the body, and not by the heart). This view is supported by evidence of increased efficiency of the functional coupling of the heart to the arterial system and of improved mechanical work efficiency in hyperthyroidism. In this context, it is clear that the hyperthyroid cardiovascular system is highly "stressed" at rest and that its functional reserve is reduced. Therefore, it is conceivable that any adverse event that might impair the overall efficiency of the cardiovascular system (loading derangement, lost of sinus rhythm, or depression of intrinsic myocardial contractility) may precipitate congested circulation or a true congestive heart failure. It is noteworthy that the persistent increase in heart rate may per se cause cardiac performance to deteriorate with time (reversible tachycardia-induced cardiomyopathy) and, therefore, precipitate congested circulation (high output congestive heart failure) (75). On the other hand, because the cardiac output reserve directly correlates with exercise capacity, and given the direct relationship between the absolute metabolic cost of workload and fatigue perception, it is not surprising that hyperthyroid patients often complain of low exercise capacity and tolerance.

Acknowledgments

We are grateful to Jean Ann Gilder for editing the text.

Footnotes

This study was supported in part by MURST (co-financed project, year 2000) Grant MM06263471-005.

Abbreviation: LV, Left ventricular.

Received June 4, 2001.

Accepted November 19, 2001.

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