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- ↵⁎Reprint requests and correspondence:
Dr. Michael R. Zile, Division of Cardiology, Medical University of South Carolina, Ashley River Towers, Room 7067, 25 Courtenay Drive, Charleston, South Carolina 29425
The diastolic properties of the left ventricle are determined by factors influencing both its passive distensibility and the active processes of myocardial relaxation (1). At the cellular level, these determinants include changes in the structure and function of intramyofilament proteins such as titin, extramyofilament proteins such as microtubules, interstitial proteins such as fibrillar collagen, as well as the cellular and molecular processes that control calcium homeostasis. All these factors may influence left ventricular (LV) diastolic stiffness, pressure, suction, and filling. In this issue of the Journal, Selby et al. (2) investigated the cellular and molecular mechanisms influencing myocardial calcium homeostasis and their effects on passive and active myocardial properties. These investigators are among the first to use human myocardial tissue samples to examine the mechanisms causing or contributing to LV diastolic dysfunction. The authors made several observations that have important clinical implications, particularly for patients with pressure overload–induced LV remodeling, diastolic dysfunction, and heart failure.
Selby et al. (2) made measurements of myocardial contraction and relaxation in isolated strips of myocardium that were obtained from LV biopsies performed in 14 patients at the time of cardiac surgery. In one-half of the patients, diastolic (resting) tension was increased and, when the stimulation rate was increased from 60 to 180 beats/min, there were further increases in diastolic tension. These myocardial strips had evidence of incomplete relaxation at a baseline stimulation rate of 60 beats/min; in addition, relaxation abnormalities became more marked at an increased stimulation rate of 180 beats/min. Six of these 7 strips with incomplete relaxation were obtained from patients with echocardiographic evidence of LV hypertrophy (LVH). In a second group of myocardial strips obtained from patients without LVH, there was no evidence of relaxation abnormalities (i.e., no change in diastolic tension) at either 60 or 180 beats/min. Selby et al. (2) then evaluated myocardial mechanical properties that reflect calcium homeostasis and the cellular mechanisms that determine cellular calcium transport. In the group with incomplete relaxation and LVH, the authors found a substantial increase in resting tone, abnormal diastolic actin-myosin cross-bridge activation, and an increased cellular calcium load during contraction and relaxation that were “due to a reduced sarcolemmal calcium extrusion reserve” (abnormalities in the sodium-calcium exchanger). These unique observations contribute to a better understanding of the underlying mechanisms that cause LV diastolic dysfunction, to the pathophysiological processes that lead to the development of heart failure, and to a growing base of information that supports the concept of distinct differences in the pathophysiology of systolic heart failure (SHF) and diastolic heart failure (DHF).
Mechanical Measurements and Mechanisms of Calcium Homeostasis
The authors did not directly measure intracellular calcium but used a series of very cleverly devised methods that are thought to reflect changes in intracellular calcium and their control mechanisms. The results from post-rest contraction and rapid cooling contracture experiments reflected sarcoplasmic reticulum (SR) calcium content, retention, release, reuptake, and leak. The results of these experiments indicated that in muscle strips with incomplete relaxation, SR calcium content and release were increased compared with muscle strips with normal relaxation. In addition, systolic tension (total tension at peak contraction) in muscle strips exhibiting incomplete relaxation was increased at both 60 and 180 beats/min. Thus, resting tension was increased in muscle strips exhibiting incomplete relaxation, but developed tension was similar in the 2 groups.
Cross-bridge deactivation produced by treatment with 2,3-butanedione monoxime (BDM) provided the means to quantitate increased resting tone. BDM treatment of myocardial strips with incomplete relaxation decreased diastolic tension to levels comparable to those of muscle strips with normal relaxation. The increased diastolic tension (resting tone) caused by persistent cross-bridge interaction was a result of elevated cytosolic diastolic calcium. Inhibition of SR calcium ATPase using cyclopiazonic acid and of the SR calcium release channels by ryanodine allowed the investigators to assess the contribution of sarcolemmal calcium transport, largely a function of the sodium-calcium exchanger. These studies indicated that the sarcolemmal calcium extrusion could not keep up with the increasing amounts of calcium entering the cell as the stimulation rate is increased (reduced reserve capacity) in muscle strips with incomplete relaxation.
Pathophysiology of Symptom Development in Heart Failure
Data from the study of Selby et al. (2) indicated that an increase in available cytosolic calcium during diastole caused a persistent increase in actin-myosin cross-bridge activation and increased diastolic tone. These cellular and molecular changes would be expected to express themselves hemodynamically as an increase in resting diastolic pressure that might be expected to increase further during exercise or a tachyarrhythmia. These cellular and molecular changes, therefore, provide a mechanism for exercise limitation and intolerance to tachycardia that is so common in patients with DHF.
The authors were cautious not to directly refer to the patients with incomplete relaxation and LVH as having heart failure. However, the balance of their data indicates that these patients had both the LV structural and functional substrate for, if not the actual evidence of, DHF. Indeed, exercise and its accompanying tachycardia would likely have resulted in increased LV diastolic pressures and symptoms of exercise intolerance in the patients with LVH and incomplete myocardial relaxation. These patients, whose filling pressures were mildly increased at rest, would very likely have had an increase in diastolic pressures in an ambulatory setting during activities of daily living. Previous studies using implantable hemodynamic monitors demonstrated that patients similar to those studied by Selby et al. (2) had LV diastolic pressures at the upper limit of normal under resting conditions (night-time minimum pressures); however, under ambulatory conditions (24-h median pressures), diastolic pressures increased significantly (3). Thus, even modest increases in heart rate, those that occur during daily ambulatory activities, may be sufficient to increase diastolic pressures and cause symptoms (New York Heart Association functional classes II to III) in patients with LVH and incomplete relaxation. Such patients would meet most criteria for DHF.
SHF Versus DHF
The clinical presentation of patients with DHF is virtually the same as that seen in patients with SHF; congestion is common to both. However, these 2 syndromes are not components of a continuum, nor do they represent the evolution or progression of a single disorder. Indeed, these 2 heart failure syndromes have substantially different phenotypes and pathophysiology. Several recent studies show differences in epidemiology (frequency distribution and demographic features); organ, cellular, extracellular, and molecular structure; and function as well as responses to pharmacological treatment (4–13).
First, the distribution of LV ejection fraction in populations of patients with heart failure is bimodal (4). This is consonant with 2 clinical syndromes; the patients with a reduced ejection fraction (EF) exhibit features of SHF, whereas those with a preserved EF have DHF. Moreover, epidemiological studies have confirmed distinct differences in the clinical characteristics of these 2 clinical syndromes. For example, coronary atherosclerosis is significantly more common in SHF than DHF. By contrast, older age, female sex, and systemic arterial hypertension are more common in DHF than in SHF. Such epidemiological data indicate that SHF and DHF are “pathophysiologically disparate entities” (5).
Second, the hearts of patients with DHF differ dramatically from those of patients with SHF with regard to both structure and function (6–8). The hearts of those with DHF generally exhibit concentric LV remodeling with normal or near-normal end-diastolic volume, increased wall thickness, and a high ratio of mass to volume. By contrast, the hearts of patients with SHF exhibit eccentric remodeling with an increase in end-diastolic volume, little increase in wall thickness, and a substantial decrease in the ratio of mass to volume. These dramatic differences in organ morphology and geometry are paralleled by anatomic differences at the microscopic level. In DHF, cardiomyocytes exhibit an increased diameter, and there is an increase in the amount of collagen with a corresponding increase in the width and continuity of the fibrillar components of the extracellular matrix. By contrast, in SHF, the cardiomyocytes are elongated, and there are degradation and disruption of the fibrillar collagen. These differences in LV and myocardial structure are associated with differences in LV systolic and diastolic function and indicate distinct differences in the pathophysiology of SHF and DHF.
Third, studies on SHF have demonstrated significant abnormalities in the cellular and molecular mechanisms that control calcium homeostasis. However, the changes in calcium homeostasis in SHF are quite different from those found by Selby et al. (2) in patients with DHF (Fig. 1). Six of 9 characteristics differ in SHF and DHF. In addition, these observations reinforce findings of previous studies that demonstrated that patients with DHF did not exhibit discernable abnormalities in LV systolic pump performance (6–8). In the patients studied by Selby et al. (2), LVEF was normal and myocardial systolic function as measured by developed tension was normal. Thus, there were distinct differences in calcium homeostasis in SHF and DHF.
Fourth, to date, all 5 randomized clinical trials in patients with heart failure with a preserved ejection fraction (DHF) that used pharmacological treatments (all of which had been previously shown to be beneficial in SHF) had a neutral effect on cardiovascular morbidity and mortality (9–13). This difference in response to treatment suggests that patients with DHF are different from patients with SHF. These studies support the need to develop different management strategies for patients with DHF that recognize these differences in pathophysiology.
Implications for the Management of DHF
Why is avoidance of tachycardia so important in patients with diastolic dysfunction and DHF? As heart rate increases, there is an obligatory decrease in the length of diastole, so that the tasks of relaxation, pressure decline, recoil, and filling must occur more rapidly in a shorter diastolic period to maintain low diastolic pressures. Because patients with LVH and incomplete relaxation cannot augment the efficiency of diastolic function, tachycardia leads to increased LV diastolic pressure and symptoms of heart failure. Therefore, the data from Selby et al. suggest that inappropriate tachycardia in patients with DHF should be avoided. However, even with a normal or slow heart rate, diastolic dysfunction persists. Even with a very long diastolic period, increased diastolic tone prevents a decrease in LV diastolic pressure to normal. Therefore, although prevention of excessive tachycardia is a cardinal component of treatment, heart rates less than physiological are not likely to be of therapeutic value. In addition, because agents such as beta-adrenergic blockers and calcium channel blockers have negative effects on diastolic function, careful titration of doses must be made. The tendency for beta-adrenergic blockers to promote chronotropic incompetence should also be considered, especially in older patients. Clearly, future therapeutic trial design should take into account the differences in SHF and DHF discussed here.
The authors have reported that they have no relationships to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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