EDITORIAL COMMENT
The Deconvolution of Diastole*
Thomas H. Marwick, MD, PhD*
School of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia
* Reprint requests and correspondence: Dr. Thomas H. Marwick, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane QLD 4120, Australia (Email: t.marwick{at}uq.edu.au).
Key Words: diastolic • heart failure • rotation • strain • untwist
Heart failure with normal ejection fraction (HFNEF) is a common presentation in elderly persons and seems to have a prognosis almost as bleak as systolic heart failure. Much work on the pathophysiology of this entity has focused on left ventricular (LV) stiffness (1)—indeed, stiffening is often found in these aged, fibrotic hearts. However, disturbances of the end-diastolic pressure-volume relationship are not uniformly identified in these patients, leading to speculation that HFNEF is not really a disorder of diastolic function (2).
In this issue of the Journal, Tan et al. (3) pursue a different mechanistic pathway. Their hypothesis is that the systolic and diastolic abnormalities underlying exercise limitation are partly related to abnormal ventricular twist and deformation, leading to delayed untwisting reduced ventricular suction, and impaired early diastolic filling. A disturbance of early filling due to altered torsion could reasonably be suspected to contribute to exertional dyspnea in patients with HFNEF. In this detailed study of the exercise response in 56 patients with HFNEF, resting velocity, rotation, and deformation were all reduced and failed to increase with exercise. The process of untwisting the apex was reduced and delayed, with reduced suction and increased end-diastolic pressure on exercise. These disturbances correlated with reduced oxygen consumption.
The attractive aspect of this work is that it provides a unifying analysis of untwist and filling, linking systole and diastole. Conceptually, this is an important step, because HFNEF has sometimes been considered as a different entity from systolic heart failure (4). In fact, the apparent preservation of systolic function is more of a reflection of the limitations of ejection fraction (EF), with good evidence of systolic dysfunction from myocardial imaging techniques (5). The "wringing" mechanism of rotatory contraction is important for systole, where it allows magnification of 15% fiber shortening to a 55% EF and equalizes the distribution of wall stress and strain, which is energy efficient (6). The findings of this study are that the reversal of this torsion is also important for LV filling. Animal work showing the association of isovolumic torsion with early LV filling (7) has recently been confirmed in humans (8). The mechanism of this effect is that the twisting energy stored in the heart's elastic tissue during systole is released as the heart snaps back to its existing shape, creating early diastolic suction, filling the LV for the next cardiac cycle. As diastole shortens with the tachycardia associated with exercise, the contribution of untwist might become relatively more important to LV filling, and the reduction of this process in HFNEF might perhaps contribute to the exertional dyspnea of these patients. Finally, the exclusion of respiratory limitation is important but often neglected in studies of HFNEF.
Apart from the linkage of systolic and diastolic LV performance in this study, several other aspects might act as a guide to further work in this field. First, the assessment of cardiac performance at submaximal exercise is an important facet that was driven by technical considerations about the difficulties of speckle tracking at high heart rate. However, these patients are indeed symptomatic with dyspnea during daily living activities and, interestingly, mount an abnormal blood pressure response to low-level exercise (9). As might be expected, differences between HFNEF and control subjects were more marked after exercise. Second, assessment of LV filling pressure with exercise is surely the sine qua non of exercise limitation by heart failure (10). The new American Society of Echocardiography/European Association of Echocardiography guidelines for the diagnosis of diastolic dysfunction attend more to the assessment of LV filling pressure and less to the patterns of mitral filling—perhaps the guidelines will eventually incorporate the assessment of LV filling pressure with exercise. Third, the investigators have particularly addressed apical rotation. Although torsion is also contributed by basal rotation, the latter measurement is difficult because of through-plane motion, and indeed, torsion itself is dependent on LV length, which is hard to measure without 3-dimensional imaging (which itself is limited by prohibitively low frame-rate). The measurement of apical rotation and speed of rotation seems sufficient for this type of study.
The ability to measure rotational parameters with cardiac magnetic resonance and, more recently, 2-dimensional (2D) echocardiography has engendered a renaissance of interest in physiology that was initially recognized 400 years ago. There are, however, some confusing features to our current level of understanding. First, although untwist parameters are reduced by reduced pre-load and afterload (11), afterload was not found to be associated in the process of twist and untwist in this study, perhaps due to its assessment with derived measures rather than separate measurement by sensitive tests of arterial performance. Second, despite the expectation that the rate of untwist would contribute to filling, previous work has been unable to link untwisting rate to filling (8), perhaps reflecting the fact that the measurement of this rate is at the limits of temporal resolution of 2D strain. Third, a recent report provided the surprising information that untwist was augmented in mild diastolic dysfunction—which is a little counter-intuitive to the understanding of delayed relaxation in these patients (12). Finally, strain is a marker of regional EF rather than contractility, which is better reflected by strain rate (9). Again, the measurement of the latter is at the limit of adequate temporal resolution of current iterations of the 2D speckle tracking technique.
What are the clinical implications of these findings? The domination of mechanistic discussions by considerations of relaxation and stiffness has focused our thoughts on means of enhancing LV compliance. Indeed, limited success has been reported with small trials of cross-link breakers (13), although negative results from the third large trial of antagonists to the renin-angiotensin-aldosterone pathway (14) might lead the clinician to believe that a more effective antifibrotic agent would be of value. Recognition of the role of untwisting might lead to greater awareness of the cardiac elastic tissue, although at the moment it is difficult to see a therapeutic response that could be directed toward improving the untwisting process. The control of hypertension is a cornerstone of the treatment of HFNEF in any case. Given the association of untwisting with reduced systolic performance, it seems unlikely an external (perhaps mechanical) means of storing torsional force is likely to provide the missing untwisting effect. After so many negative trials with positive inotropes, it seems unlikely that such as strategy will be trialed in this population, although a subanalysis of the DIG (Digitalis Investigation Group) trial tantalizingly suggested benefit in HFNEF (15). The treatment of ischemia would be a relatively simple way of optimizing systolic function, and perhaps the guidelines should better reflect the importance of excluding coronary artery disease when HFNEF is considered.
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Footnotes
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This work was supported in part by a project grant (546139) from the National Health and Medical Research Council, Canberra, Australia. Research support was also provided by GE Healthcare and Philips Medical Systems.
* 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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References
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1. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle N Engl J Med 2004;350:1953-1959.[CrossRef][Web of Science][Medline]2. Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function? Circulation 2003;107:656-658.[Free Full Text] 3. Tan YT, Wenzelburger F, Lee E, et al. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion J Am Coll Cardiol 2009;53:36-46. 4. Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology Eur Heart J 2007;28:2539-2550.[Abstract/Free Full Text] 5. Yip G, Wang M, Zhang Y, Fung JW, Ho PY, Sanderson JE. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002;87:121-125.[Abstract/Free Full Text] 6. Arts T, Veenstra PC, Reneman RS. Epicardial deformation and left ventricular wall mechanisms during ejection in the dog Am J Physiol 1982;243:H379-H390.[Web of Science][Medline] 7. Notomi Y, Popovic ZB, Yamada H, et al. Ventricular untwisting: a temporal link between left ventricular relaxation and suction Am J Physiol Heart Circ Physiol 2008;294:H505-H513.[Abstract/Free Full Text] 8. Burns A, LaGerche A, Prior D, MacIsaac A. Left ventricular untwisting is an important determinant of early diastolic function in humans J Am Coll Cardiol Img 2009;2:709-716.[Abstract/Free Full Text] 9. Sharman JE. Is there a clinical role of light exercise central blood pressure? Am J Hypertens 2008;21:371.[CrossRef][Web of Science][Medline] 10. Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise J Am Coll Cardiol 2006;47:1891-1900.[Abstract/Free Full Text] 11. Sengupta P, Tajik J, Chandrasekaran K, Khanderia B. Twist mechanics of the left ventricle: principles and application J Am Coll Cardiol Img 2009;1:366-376. 12. Park SJ, Miyazaki C, Bruce CJ, Ommen S, Miller FA, Oh JK. Left ventricular torsion by two-dimensional speckle tracking echocardiography in patients with diastolic dysfunction and normal ejection fraction J Am Soc Echocardiogr 2008;21:1129-1137.[CrossRef][Web of Science][Medline] 13. Hollenberg NK. Advanced glycation end-product cross-link breakers. A novel therapeutic pathway for cardiovascular disease. Am J Hypertens 2004;17:21S-22S.[Web of Science][Medline] 14. Coletta AP, Clark AL, Cleland JG. Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHART-CHF, COMPARE, MOMENTUM, thyroid hormone analogue study, HF-ACTION, I-PRESERVE, {beta}-interferon study, BACH, and ATHENA Eur J Heart Fail 2009;11:214-219.[Abstract/Free Full Text] 15. The Digitalis Investigation Group The effect of digoxin on mortality and morbidity in patients with heart failure N Engl J Med 1997;336:525-533.[CrossRef][Web of Science][Medline]
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