50TH ANNIVERSARY HISTORICAL ARTICLE
Heart failure1
Gary S. Francis, MD, FACCa
a George M. and Linda H. Kaufman Center for Heart Failure, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Reprint requests and correspondence: Gary S. Francis, M.D., Department of Cardiology F-25, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
The following review summarizes two important articles on heart failure and cardiomyopathy that were published in the American Journal of Cardiology two decades apart. Both articles are extraordinary in their link to the more modern era of cardiology, and specifically to the area of heart failure.
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Heart failure from the point of view of quantitative anatomy
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By A. J. Linzbach (1).
Summary
1. All normal human hearts have essentially the same number of myocardial fibers and myocardial nuclei. During physiologic growth the number of myocardial fibers remains constant; the fibers enlarge, but their length-to-width ratio remains constant (harmonic growth). The number of capillaries increases with growth, with one capillary per four fibers in the infant and one capillary per fiber in the adult. However, the width of the spaces of the capillary net is essentially the same for all age groups. The number of fibers and nuclei is roughly the same for the right ventricle as the left; the left ventricle is heavier than the right because its fibers are thicker. There are fewer layers of fibers in the right ventricle than in the left. It follows from this that the inner surface area of the right ventricle must be greater than for the left.
2. The average weight of the normal heart in man is about 300 gm. Through athletic exertion it can attain a weight of 500 gm. This increase is due to an extension of physiologic growth, with the fibers increasing in length and width but not increasing in number. The growth results in a larger than normal mobilizable blood volume.
3. As a result of pathologic demands for increased heart work as, for example, in hypertension, the "critical" heart weight of 500 gm. is exceeded. Increases in heart weight above the "critical" level are due to increase in the number of fibers with little further thickening. There is also an increase in capillaries, with the ratio of one capillary per fiber maintained. The coronary insufficiency than occurs with advanced hypertrophy is not principally due to a failure of capillary supply but to the fact that with hypertrophy the growth of the coronary arteries and coronary ostia is retarded and atherosclerotic lesions of the coronary system become more frequent.
4. As a result of the coronary insufficiency a dilatation takes place. However, the Z-band to Z-band distance (i.e., the length of sarcomeres) of myocardial fibers in dilated hearts is the same as for normal hearts. In addition to longitudinal growth of the muscle fibers in dilatation there are also structural alterations in the myocardium with rearrangements of the architectural relationship among the muscle fibers. Therefore, dilatation as encountered in man is not characterized by overstretched fibers. This is true of dilatation whether due to coronary sclerosis, myocarditis or excessive hypertrophy. It is called "structural dilatation" as opposed to the "functional dilatation" of the acutely overloaded heart. There is an increased residual ventricular volume in the dilated heart, but it is not mobilizable.
5. Structural dilatation is the morphologic substrate of the decompensated heart. The cross section area of muscle capable of contracting is too small for the increased volume of the ventricle. Cardiac insufficiency results, not from overstretching of the fibers or inadequate oxygen consumption per fiber length in the Starling sense, but for strictly mechanical reasons. The unit muscle weight may produce a normal amount of energy liberated on contraction but it is no longer adequate to expel a normal stroke volume from a ventricle of these dimensions. In other words, the essence of myocardial failure is the discrepancy between the amount of energy necessary to expel a stroke volume and the amount of energy available. In these studies it has been shown that in most clinical cardiac disorders with heart failure the discrepancy can be adduced from changes in the quantitative morphology of the heart. Originally published in The American Journal of Cardiology, March 1960
Review.
It is remarkable that for more than 100 years dispute has persisted and continues to occupy the editorial pages of scholarly journals regarding the fundamental mechanism of heart failure. Linzbach points out in his classic 1960 article "Heart failure from the point of view of quantitative anatomy" that at the turn of the century clinicians championed a morphologic point of view regarding hypertrophy and heart failure, whereas pathologists defended a primary functional abnormality (1). Although a functional basis for heart failure has gradually won the hearts and minds of investigators in recent times, there is now a growing recognition that left ventricular remodeling and structural problems related to remodeling may be the core lesion of chronic heart failure, with functional abnormalities being perhaps more of a secondary phenomenon (2).
It was Linzbach’s belief that the pathophysiologic abnormalities of the heart, including heart failure, could only be understood when quantitative structural relations of this organ were known. Measurable changes in the size and shape of the diseased heart were an essential requirement. In Linzbach’s 1960 paper he points out that in both normal and abnormal hearts, the average distance between Z bands, which is the length of the sarcomeres, was in all cases 1.4 µ. This important finding, that the length of the sarcomeres is not altered by hypertrophy or pathologic dilatation, was a landmark observation. He also pointed out that the sarcomere length was virtually the same for a wide variety of mammals, suggesting that this feature was highly conserved throughout evolution. Experiments conducted by Linzbach and his group led them to estimate that normal ventricular filling involved a change of sarcomere length from 1.4–1.5 µ to 2 µ. He pointed out that the maximum sarcomere lengthening still compatible with normal heart function is a little beyond 2 µ. This extraordinarily important observation meant that stretching of the muscle fibers to adapt to heart function is highly limited.
Linzbach’s laboratory had previously demonstrated that all normal human hearts have essentially the same number of myocytes and nuclei (3). Even though the right ventricle is about half as heavy as the left ventricle, it has essentially the same number of cells or myocytes. The cells of the right ventricle were demonstrated by him and others to be smaller than those of the left ventricle, and were arranged somewhat differently. The paper goes on to demonstrate that during normal postnatal growth of the heart, the cardiac myocytes become wider and longer but maintain a fixed length to width ratio. This concept is most important in the context of today’s understanding regarding morphometric changes that occur in heart failure. Gerdes and colleagues have demonstrated that an alteration of the length-width ratio is one of the most consistent changes that occurs during left ventricular remodeling (4). The largest myocytes observed by Linzbach and colleagues were in patients with heart failure, and this has been confirmed by Gerdes and colleagues using more modern techniques of cell isolation (5).
Most importantly, Linzbach points out that as physiologic or pathologic hypertrophy occurs, the increase in the weight of the heart is not due to an increase in the number of cardiac myocytes, but is rather due to the cardiac myocytes becoming thicker and longer. There is basically an extension of the physiologic growth process of each cell. Linzbach made the distinction between physiologic hypertrophy and pathologic hypertrophy based on the weight of the heart. He considered 500 grams to be the critical heart weight beyond which pathologic hypertrophy was occurring. In the paper he points out that a left ventricular weight of 200 grams or more is also consistent with pathologic hypertrophy. Without the advantage of modern cell isolation techniques, Linzbach conceded that there may be an increase in the number of cardiac myocytes and cardiac myocyte nuclei in concentric pressure hypertrophy. Today we recognize that indeed there may be some post-neonatal myocardial cell hyperplasia, and it may be increased in the failing heart (6). In general, most experts continue to believe that cardiac myocytes, being highly differentiated cells, uncommonly enter into cell cycle. However, they clearly do increase in size, although this is normally not accompanied by ploidy or an increase in the number of nuclei. Despite nearly 40 years since the publication of the Linzbach paper, this field remains an area of disputatious but intense study.
In the 1960 paper Linzbach goes on to describe the anatomic basis of left ventricular dilatation. He observes that cardiac myocytes may become stretched in diastole, but again finds that the Z band to Z band distance appears fixed at 1.4 µ, which is the same as in the normal and undilated hypertrophied heart. He goes on to state that the dilation of these hearts must then involve plastic structural changes within the myocardium, probably due to elongation of individual cardiac cells. He speculates that focal hypoxic necrosis commonly occurs during dilation, causing over stretching during isometric contraction. He recognizes that cardiac dilation can occur without hypertrophy, and is seen in various types of cardiomyopathy including diphtheritic myocarditis and chronic coronary atherosclerosis. Importantly, Linzbach points out that structural dilatation of the heart is a hallmark of decompensated heart failure. This principle still holds today, and is the basis for the development of innovative anti-remodeling drugs, such as matrix metalloproteinase inhibitors. He makes the interesting point that heart failure results not from inadequate oxygen consumption per cardiac myocyte, but is a consequence strictly of mechanical inefficiency. He hypothesizes that each "unit muscle weight" in heart failure likely produces a normal amount of energy during contraction, but that this amount of energy is no longer adequate to expel a normal stroke volume from a ventricle with markedly enlarged dimensions. The large, dilated heart structurally obligates a low ejection fraction. This concept was revisited in a recent editorial (7).
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The natural history of idiopathic dilated cardiomyopathy
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By Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye RL (8).
Abstract
Between 1960 and 1973, a total of 104 patients at the Mayo Clinic had a diagnosis of idiopathic dilated cardiomyopathy on the basis of clinical and angiographic criteria; these patients were followed up for 6 to 20 years. Twenty-one percent of the patients had a history of excessive consumption of alcohol, 20 percent had had a severe influenza-like syndrome within 60 days before the appearance of cardiac manifestations and 8 percent had had rheumatic fever without involvement of cardiac valves several years before; thus, possible etiologic risk factors of infectious-immunologic type may be important. Eighty patients (77 percent) had an acccelerated course to death, with two thirds of the deaths occurring within the first 2 years. Twenty-four patients (23 percent) survived, and 18 of them had clinical improvement and a normal or reduced heart size. Univariate analysis at the time of diagnosis revealed three factors that were highly predictive (p less than 0.01) of the clinical course: age, cardiothoracic ratio on chest roentgenography and cardiac index. Systemic emboli occurred in 18 percent of the patients who did not receive anticoagulant therapy and in none of those who did; thus, anticoagulant agents should probably be prescribed unless their use is contraindicated.
Originally published in The American Journal of Cardiology, March 1981
Review.
The paper by Fuster and colleagues on the natural history of idiopathic dilated cardiomyopathy remains a time-honored classic (8). The study was basically a carefully performed retrospective analysis of 104 patients studied at the Mayo Clinic between 1960 and 1973 with a diagnosis of idiopathic dilated cardiomyopathy. The diagnosis was established on the basis of rigorous clinical and angiographic criteria. Follow-up varied from six to twenty years. Although it is a retrospective study with inherent selection bias, it provides some of the most accurate information derived from a systematic set of observations at a single institution on this important diagnosis. In essence, the authors believed it was the study of the natural history of idiopathic dilated cardiomyopathy and therefore unique. All of the patients underwent cardiac catheterization at baseline, and the duration of follow-up was the longest reported to date. It is a classic example of how a carefully done descriptive study (i.e., non-hypothesis driven) can still have an enormous impact on a field of study.
The authors were clearly ahead of their time in suggesting that early identification of the syndrome prior to the development of ventricular dilation, presumably by echocardiography, could enable earlier and possibly more successful therapeutic intervention. This speculation was later realized during the organization and implementation of the SOLVD (Studies Of Left Ventricular Dysfunction) prevention trial. We now know that early introduction of angiotensin converting enzyme inhibitors forestalls the onset of heart failure and markedly reduces the need for hospitalization (9).
The important issue of systemic embolism in dilated cardiomyopathy was addressed by Fuster et al. (8). They noted that over half of the emboli occurred within the first year of diagnosis, and suggested that such patients might benefit from administration of oral anticoagulant agents. They firmly state in the paper that their current policy is to prescribe long term anticoagulant therapy in all patients with idiopathic dilated cardiomyopathy unless there is a specific contraindication. The issue of whether or not to anticoagulate such patients still has not been completely resolved, with strong feelings both for (10) and against (11). Uncontrolled data would suggest that some anticoagulation may be useful for selected patients with heart failure (12). A large randomized controlled trial has recently been planned and will likely be launched in the near future to better resolve this important clinical question.
The Fuster paper points out that about two-thirds of the patients die in the first two years after diagnosis, demonstrating an accelerated course to death. On the other hand, the remaining patients demonstrated subjective improvement, and many went on to stabilize with even some diminishment in heart size. The authors recognized that the more severe the clinical and hemodynamic manifestations at the time of diagnosis, the worse the long term prognosis. Since then many investigators have demonstrated that high filling pressures and a low cardiac index are associated with a very poor prognosis. The Mayo group recognized that 21% of the patients with idiopathic dilated cardiomyopathy were identified as having excessive alcohol consumption according to standard criteria. They went on to reiterate that alcohol may be deleterious in any patient with cardiomyopathy, and recommend complete abstinence from alcohol. Only three of the patients had peri-partum cardiomyopathy, and the authors believed that a family history of idiopathic dilated cardiomyopathy was rare, occurring in only 2 of 104 patients. More current information would suggest that familial cardiomyopathy may be more common (13,14), but this is clearly an area that needs additional study.
The Fuster paper ends by making suggestions for future investigators, including the need to make prospective and systematic observations in various populations at risk, the need for sequential biopsies to assess the histological and ultra-structural changes, and the necessity to develop serologic identification markers for possible infectious and immunologic processes. In fact, myocardial biopsy of patients with dilated cardiomyopathy is perhaps done less frequently today, in part because it has seemingly little impact on the management of the syndrome. Specific histologic and ultra-structural changes as well as serological identification of infectious and immunologic processes have generally been lacking, although myocardial biopsy is still required for the diagnosis of inflammatory myocarditis and infiltrative cardiomyopathies. The paper remains a classic in that it accurately portrays the natural history of idiopathic dilated cardiomyopathy as viewed in 1981 in a manner that very much mirrors today’s view of this common disorder. Although treatment has improved over the years, an understanding of the biologic underpinnings of the syndrome remain for future investigation.
These two papers are extraordinary in their link to the more modern era of cardiology, and specifically to the area of heart failure. Both of them are well worth re-reading. What is striking is how the key observations were made, even though the techniques are somewhat dated by today’s standards. Nevertheless, these two papers further emphasize that careful studies done in relatively small numbers of patients can lead to profound and lasting mechanistic enlightenment, a feature usually missing from today’s mega trials.
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Footnotes
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1 50th Anniversary Historical Article
Introduction
In this edition of the Journal, we release the second in a series of reviews of influential articles that have been previously published in ACC journals, including the American Journal of Cardiology (from 1958 to 1982), and JACC (from 1983 to the present). The publication of these articles is only one aspect of the ACC’s 50th anniversary commemoration, which highlights 50 years of leadership in cardiovascular care and education. The articles are intended to encourage reflection on the remarkable progress made in cardiovascular medicine over time, as well as to acknowledge the amazing prescience of some early investigators in anticipating and, in many cases, later guiding developments in their field.
The working group responsible for selecting these articles and asking reviewers to write editorials solicited suggestions from the ACC’s clinical committees and individual members.
The group achieved consensus fairly easily, including whom the group should ask to prepare the accompanying editorials. We initially drew up a list of 14 general areas to cover in this series, but later found that there are several major areas of modern cardiology, prominently molecular cardiology in which the truly landmark articles have, alas, not yet been published in JACC. Therefore, the working group decided not to categorize by subject, but instead, to concentrate on the most important articles.
The working group, a task force of the Subcommittee for the Commemoration of the ACC 50th Anniversary, owes a great deal to Ms. May A. Roustom and the efficient and tireless staff at Heart House for facilitating this project. We also wish to thank all who suggested articles and, most important, the authors who prepared reviews for their willingness to contribute their time and wisdom.
Influential Articles in JACC Working Group
Sharon A. Hunt, M.D., F.A.C.C.
Rick A. Nishimura, M.D., F.A.C.C.
H.J.C. Swan, M.D., Ph.D., M.A.C.C.
Michael J. Wolk, M.D., F.A.C.C. 
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References
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1. Linzbach AJ. Heart failure from the point of view of quantitative anatomy. Am J Cardiol. 1960;:370–382
2. Cohn JN. Structural basis for heart failure: ventricular remodeling and its pharmacological inhibition. Circulation. 1995;91:2504–2507[Free Full Text]
3. Linzbach AJ. Fifth Freiburger Symposium. Springer Verlag. Berlin, 1958. p. 94.
4. Gerdes AM, Kellerman SE, and Schocken DD. Implications of cardiomyocyte remodeling in heart dysfunction. In: The Failing Heart. Eds. Dhalla NS, Beamish RE, Takeda N, Nagano M. Lippincott-Raven. Philadelphia, New York, pp. 197–205.
5. Gerdes AM, Kellerman SE, Moore JA, et al. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation. 1992;86:426–430[Abstract/Free Full Text]
6. Katjstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci. 1998;95:8801–8805[Abstract/Free Full Text]
7. Cohn JN, Francis GS. Cardiac failure: a revised paradigm. J Card Failure. 1995;1:261–266[CrossRef][Medline]
8. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Bradenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol. 1981;47:525–531[CrossRef][Medline]
9. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691[Abstract]
10. Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol. 1998;31:749–753[Abstract/Free Full Text]
11. Baker DW, Wright RF. Management of heart failure: IV anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA. 1994;272:1614–1618[Abstract/Free Full Text]
12. Koniaris LS, Goldhaber SZ. Anticoagulation in dilated cardiomyopathy. J Am Coll Cardiol. 1998;31:745–748[Abstract/Free Full Text]
13. Grünig E, Tasman JA, Kücherer H, Franz W, Kübler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998;31:186–194[Abstract/Free Full Text]
14. Baig MK, Goldman JH, Caforio ALP, Coonar AS, Keeling PJ, McKenna WJ. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol. 1998;31:195–201[Abstract/Free Full Text]
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