PRECLINICAL STUDY: EDITORIAL COMMENT
Embracing Diversity in Remodeling
A Step in Therapeutic Decision Making in Heart Failure?*
Yellaprada Chandrashekhar, MD*
Division of Cardiology, VA Medical Center and University of Minnesota, Minneapolis, Minnesota.
* Reprint requests and correspondence: Dr. Yellaprada Chandrashekhar, Division of Cardiology 111c, VA Medical Center/University of Minnesota, One Veterans Drive, Minneapolis, Minnesota 55417. (Email: shekh003{at}umn.edu).
The universe is full of magical things waiting for our wits to grow sharper.
Eden Phillpotts (1)
Heart failure (HF) is characterized by adverse cardiac structural changes, including myocellular hypertrophy, interstitial disruption, and a reduction in number of cardiomyocytes (2–4). These changes, collectively called cardiac remodeling, cause chamber enlargement/dysfunction, mediate progression, and predict adverse prognosis in patients with HF. Traditionally, 2 major patterns have been described: concentric remodeling, related to pressure overload (PO), in which increased mass is associated with normal chamber volume, and eccentric remodeling, related to volume overload (VO), in which increased mass is associated with an increased chamber volume. Very often a mixed picture is present, and concentric remodeling might change to an eccentric one with worsening HF.
Despite controversy about these terms (5), they continue to have utility to practicing clinicians for describing morphology, identifying possible etiology, and predicting prognosis. However, clinicians have been less concerned about differences at a cellular level and more importantly, have not seen a need to adopt different treatment strategies based on remodeling patterns. Thus, vasodilator therapy, so effective in ischemic and dilated cardiomyopathy, has been tried in patients with VO remodeling after aortic regurgitation (AR) and mitral regurgitation (MR) with controversial and mostly negative results (6). The report by Ryan et al. (7) in this issue of the Journal helps to place some cellular level background to clinical therapeutic strategies. This group extends their previous work, showing inefficacy of angiotensin-converting enzyme inhibition (ACE-I) in VO remodeling in yet another condition (aortocaval fistula [ACF]). Their study had 2 important findings. First, early left ventricular (LV) dilatation after an ACF is caused by a rapid loss of interstitial collagen (caused by a bradykinin [BK]–matrix metalloproteinase [MMP] mediated degradation), without cardiomyocyte remodeling. A BK2 receptor antagonist (Hoe 140) largely attenuated this early LV dilatation. Second, ACE-I did not attenuate LV dilatation after ACF. This study has implications for therapy in VO heart failure. A brief overview of the pathogenesis of VO versus PO remodeling and some related issues might help to put this study into a clinical perspective.
 |
Components of Remodeling: Myocyte Versus Interstitium
|
|---|
The true mystery of the world is the visible, not the invisible.
Oscar Wilde (8)
Ryan et al. (7) found that LV dilatation in VO was caused by connective tissue dissolution and not myocyte remodeling. Does it matter what components make up the remodeled heart? All forms of remodeling respond with some change in cell volume, number, and collagen. The degree of change in cardiomyocyte versus the interstitium is, however, dynamic and varies with the stimulus (PO vs. VO) as well as its duration. In general, volume overload, with its diastolic wall stress, is initially geared to accommodating a larger volume; it accomplishes this through a lack of increase (or reduction) of interstitial collagen rather than a lengthening of the myocyte. Subsequently, the myocyte starts to hypertrophy. These models often do not show contractile dysfunction even with significant remodeling (9) until very late. This is in agreement with clinical experience in MR and AR. Pressure overload, with high systolic wall stress, is initially geared to accommodate high pressure; it accomplishes that with cellular hypertrophy and a somewhat later increase in interstitial fibrosis. Significant fibrosis often marks the onset of decompensation (transition from hypertrophy to failure) (9). In both VO and PO, length-to-width ratio is initially preserved. Clinical decompensation is often marked by a further increase in length without a proportionate increase in width (3). Many of the clinical heart failure syndromes have a mixed picture of cellular hypertrophy and increased fibrosis.
Is one component more important than the other? Although both of these elements are changed in most heart failure syndromes, one can change without the other (10). There is emerging doubt regarding whether cardiomyocyte remodeling is the most important defect in the remodeling heart. First, all cardiomyocyte remodeling is not bad and we can now differentiate and manipulate pathways to induce good vs. bad cardiomyocyte hypertrophy (11,12). Second, there is growing evidence, albeit controversial, that the remodeled cardiomyocyte does not necessarily contribute to whole-heart dysfunction (13,14). Finally, transgenic studies have shown that florid heart failure can coexist at a time when there is dissociation between cardiomyocyte hypertrophy and interstitial tissue changes; hearts can manifest fibrosis and contractile dysfunction without hypertrophy (10), although some forms of obvious hypertrophy can avoid heart failure (15). Similarly, one can selectively modulate contractility and hypertrophy independent of each other (12,16), and inhibiting hypertrophy is not essential to improving function in the failing heart.
Fibrosis seems to be detrimental in ventricular remodeling of nearly all etiologies, but this conviction may change with further incisive investigations. Myocardial injury generates fibrosis both at the site of and remote from the initial injury (17). A dynamic interaction between extracellular matrix formation, qualitative alterations (e.g., type I/type III), and degradation is an ongoing element of ventricular remodeling. Significant ventricular dilatation can occur even when collagen synthesis exceeds degradation, related to the type of collagen laid down (e.g., the more elastic type III), change in collagen cross-linking, or alterations in interaction with adhesion molecules or cardiomyocytes (9). Not surprisingly, decompensation is associated with increasing fibrosis. Conditions with significant remodeling that have predominant fibrosis (and little cardiomyocyte hypertrophy) respond to modulation of the fibrosis (18). Finally, the benefit seen with MMP inhibition strengthens the role of fibrosis in all forms of heart failure. The data from Ryan et al. (7), from MMP knock out studies, and from inhibiting endothelin 1 suggest that any deviation from normal collagen, either less or more, might have pathogenetic implications. It thus seems that the proportion of changes in cell volume, number, and collagen might also affect strategies to attenuate remodeling.
|
Why Is ACE-I Less Effective in VO Remodeling?
|
|---|
We shall never cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time.
T. S. Eliot (8)
Ryan et al. (7) did not find a benefit of ACE-I in ACF. This raises a question about where ACE inhibitors act and whether there are any predictors that separate VO and PO in terms of therapy. A complete renin–angiotensin system exists in various cells of the heart (15). Locally produced angiotensin II (Ang-II) modulates cardiomyocytes and fibrous tissue at the site of myocardial injury as well as remote from it in both VO and PO. One of the main effects of Ang-II is augmenting fibrosis at the site of injury. These responses are transduced by AT-1 receptors, which are mainly expressed in cardiac fibroblasts. It might even be that the bulk of the Ang-II action is on modulating and sculpting the interstitium, maybe even more than myocyte remodeling. The ACE-I reduces cardiomyocyte remodeling and cardiac fibrosis in a number of cardiac injury models. So why did ACE-I therapy not benefit VO HF? There could be multiple reasons, in addition to the one postulated by Ryan et al. (7). A comparison of the degree of myocyte and chamber remodeling, collagen volume, and known effect of ACE-I is instructive. As seen in Figure 1, beneficial effects of ACE-I seem to be little correlated with myocyte size, myocyte function, and LV chamber size. However, ACE-I has consistently benefited conditions in which fibrosis is a strong component of remodeling, although ACE inhibitors have had little success in conditions in which fibrosis is not prominent. Consistent with the AT-1 receptor distribution data, one could thus postulate that ACE-I benefits are more predicated on there being a strong fibrous tissue response and less so on cardiomyocyte remodeling. Lacking significant fibrosis, ACE-I possibly had no major target to modulate in VO remodeling of ACF or MR. This construct needs further evaluation. This postulate in no way, however, negates the voluminous data about Ang II and ACE-I on myocyte hypertrophy, apoptosis, and other phenomena, but just establishes a preliminary correlation with the best predictor of ACE-I response.
View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Relationship Between Cardiomyocyte and Whole Heart Remodeling, Interstitial Fibrosis, and Effect of ACE-I
Representative myocyte and left ventricular remodeling data are derived from multiple published reports. All studies had age-matched sham-operated controls, and data shown is percent change compared with sham-operated animals. All non-sham animal groups showed significant remodeling and chamber dilatation. There is an expected variability in the available data. Some studies show significantly reduced fibrous tissue volume in MR animals, similar to that seen in aortocaval fistula (A-C Fistula), whereas others show minimal change depending on the time point. A few banding studies, depending on the protocol used, did not find as much benefit with angiotensin-converting enzyme inhibition (ACE-I). Pacing-induced heart failure data are not shown because that syndrome is rather unique and does not fit into the usual classification of volume overload versus pressure overload remodeling. Response to ACE-I is shown as a qualitative depiction of the experience from multiple reports. AR = aortic regurgitation; HT = hypertension; LVEDD = left ventricular end-diastolic dimension; LVESD = left ventricular end-systolic dimension; MI = myocardial infarction; MR = mitral regurgitation.
|
|
|
ACE-I, BK, and MMP in the Remodeling Heart
|
|---|
Two paradoxes are better than one; they may even suggest a solution.
Edward Teller (19)
Finally, Ryan et al. (7) also showed that ventricular remodeling in the VO heart was mediated by the BK–MMP axis, and this was postulated to be the reason that ACE-I was ineffective despite the fact that the renin–angiotensin axis is very active in the VO heart. Once again it is instructive to place BK in the context of all forms of ventricular remodeling.
Bradykinin, because of its potent hypotrophic effects on the myocyte and interstitium via BK2 receptors, can strongly attenuate ventricular remodeling (20,21); ACE has a great proclivity to inactivate bradykinin, and ACE-I increases tissue bradykinin levels. Not surprisingly, a significant amount of the ACE-I effectiveness is contingent on BK increase (20). Ryan et al. (7) suggest that a significant amount of the ACE-I ineffectiveness in VO may also be contingent on BK increase. Unfortunately, they do not have data to show that long-term BK2 inhibition alone, or better yet given with ACE-I, would improve remodeling. This leaves the story incomplete. Second, although ACE-I did not benefit remodeling in ACF, it did not significantly worsen it either (even with the additional possibility that ACE-I concomitantly could also have increased another potent antifibrotic compound N-acetyl-seryl-aspartyl-lysyl-proline [22]). Presumably, if BK is responsible for adverse remodeling (by fibrous tissue dissolution, etc.), more BK after ACE-I theoretically should have made remodeling worse. This did not happen. Either the additional excess of BK is not needed for further remodeling (ceiling effect?) or other mechanisms are also at play.
Alternatively, because BK (either spontaneously or after ACE-I) is antiproliferative and antifibrotic, BK2 benefits (and thus ACE-I benefits) might depend on the degree of underlying fibrosis or myocyte hypertrophy. Although there are few comprehensive data, BK seems to have a somewhat greater effect on fibrous tissue compared with cardiomyocytes (18). It is also interesting that the AT2 receptors (which have potent antigrowth activities) seem to predominantly modulate fibrosis (via a BK2 pathway) and not myocyte hypertrophy after Ang II infusion or after myocardial infarction (23). Thus, one could logically postulate that the BK2 effect (or ACE-I–induced BK effect) might be most prominent and beneficial in conditions in which there is significant fibrous tissue proliferation, such as after myocardial infarction, in aortic banding, in renovascular hypertension, or in diabetic cardiomyopathy, in which attenuation of fibrous tissue might be most important. In VO, with little proliferation or even a net loss of fibrous tissue, BK augmentation might have a lesser effect. This fits with the known difference in the magnitude of benefits of ACE-I in PO versus VO remodeling (Fig. 1). The availability of serum markers for interstitial collagen turnover and newer imaging techniques might help us to clarify whether fibrous tissue quantitation will allow us to identify responders versus nonresponders to ACE-I in various forms of ventricular remodeling.
Are there other explanations for the ACE-I–BK–MMP theory in ACF? There remains the possibility that Hoe 140 increased blood pressure, and this might have reduced the "threatened blood pressure" response with ACF (24). Because vasodilation after ACF has a prominent role in salt and water retention and thus diastolic wall stress, any pressor agent could have reduced the stimulus to remodel and thus falsely show benefit. The investigators rightly used other pressor controls. For a similar degree of pressor response, Ang-II increased collagen volume (less than with Hoe 140), but caused myocyte hypertrophy while reducing remodeling. This lends credence to the collagen dissolution theory, but also suggests that interventions inducing controlled myocyte hypertrophy might also be beneficial (reduced wall stress theory). Second, even subpressor doses of ACE-I can directly reduce MMP generation and influence remodeling (25); effects on MMP generation via BK2 might be attenuated by those directly on MMP itself. Thus, ACE-I did not benefit or worsen the situation in ACF. The MMP level and activity in the chronic ACE-I group might have been instructive. Finally, endothelin is increased in ACF and has a similar effect on interstitial dissolution via mast cells and MMP. An endothelin antagonist might have benefits similar to those of Hoe 140. This would be an interesting area to explore (26).
|
Clinical Perspective
|
|---|
How do these findings apply to everyday practice? All of the major changes in this study by Ryan et al. (7) happened right after the acute insult, and this is far different from when clinicians see patients; thus, timing of intervention might be an issue. If the BK–MMP axis is the culprit, there might be a lively debate regarding inhibiting MMP itself. The MMP inhibitors have had a long and costly development and are likely to get better. On the other hand, mast cell stabilizers (which reduce BK and MMP) are easier to use. This will remain an active area of research. The inhibition of ACE has not been clinically successful in preventing progression in VO caused by AR or MR, and the results of this study are unlikely to affect current practice. Because late-stage VO- or PO-mediated heart failure (the stage at which we see many patients clinically) seems to have many more similarities in cardiac structure, it seems premature to exclude a role for ACE-I in the clearly dilated, late-stage failing heart (e.g., nonsurgical candidates). Finally, we are still not at a point at which all volume overload should be treated similarly, and there are animal data showing that ACE-I is effective in AR (unlike MR and ACF). Interestingly, AR is associated with somewhat more fibrosis than MR or ACF; if the ACE-I fibrosis theory is proven correct, this might explain the benefits of ACE-I in animal studies of AR. Clinical studies have remained controversial. Noninvasive measures of various components of remodeling (27) might refine our ability to modulate therapy in the failing heart.
|
Footnotes
|
|---|
* 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 the JACC or the American College of Cardiology. 
|
References
|
|---|
1. Phillpotts E. A Shadow Passes. 1918.2. Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E. Progressive ventricular remodeling in rat with myocardial infarction Am J Physiol 1991;260:H1406-H1414. 3. Gerdes AM, Capasso JM. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure J Mol Cell Cardiol 1995;27:849-856.[CrossRef][Web of Science][Medline] 4. Chandrashekhar Y, Narula J. Death hath a thousand doors to let out life Circ Res 2003;92:710-714.[Free Full Text] 5. Dorn GWI, Robbins J, Sugden PH. Phenotyping hypertrophyEschew obfuscation. Circ Res 2003;92:1171-1175.[Free Full Text] 6. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Valvular Heart Disease) J Am Coll Cardiol 2006;48:e1-e148.[Free Full Text] 7. Ryan TD, Rothstein EC, Aban I, et al. Left ventricular eccentric remodeling and matrix loss are mediated by bradykinin and precede cardiomyocyte elongation in rats with volume overload J Am Coll Cardiol 2007;49:811-821.[Abstract/Free Full Text] 8. In: Andrews R, Biggs M, Seidel M, editors. The Columbia World of Quotations. New York, NY: Columbia University Press; 1996. 9. Brower GL, Janicki JS. Contribution of ventricular remodeling to pathogenesis of heart failure in rats Am J Physiol 2001;280:H674-H683. 10. O’Connell TD, Swigart PM, Rodrigo MC, et al.  1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload J Clin Invest 2006;116:1005-1015.[CrossRef][Web of Science][Medline] 11. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly Annu Rev Physiol 2003;65:45-79.[CrossRef][Web of Science][Medline] 12. Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways Cell 2002;110:737-749.[CrossRef][Web of Science][Medline] 13. Anand IS, Liu D, Chugh SS, et al. Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction Circulation 1997;96:3974-3984. 14. Sjaastad I, Wasserstrom JA, Sejersted OM. Heart failure—a challenge to our current concepts of excitation-contraction coupling J Physiol 2003;546:33-47.[Abstract/Free Full Text] 15. Oh H, Taffet GE, Youker KA, et al. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival Proc Natl Acad Sci U S A 2001;98:10308-10313.[Abstract/Free Full Text] 16. Perrino C, Naga Prasad SV, Mao L, et al. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction J Clin Invest 2006;116:1547-1560.[CrossRef][Web of Science][Medline] 17. Weber KT. Extracellular matrix remodeling in heart failure Circulation 1997;96:4065-4082. 18. Tschope C, Walther T, Koniger J, et al. Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene Faseb J 2004;18:828-835.[Abstract/Free Full Text] 19. Edward Teller. Wikiquote. Available at: http://en.wikiquote.org/wiki/Edward_Teller. Accessed January 19, 2007. 20. Murphey L, Vaughan D, Brown N. Contribution of bradykinin to the cardioprotective effects of ACE inhibitors Eur Heart J 2003;5(Suppl A):A37-A41.[CrossRef] 21. Yang XP, Liu YH, Mehta D, et al. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B2kinin receptor gene knockout mice Circ Res 2001;88:1072-1079.[Abstract/Free Full Text] 22. Yang F, Yang XP, Liu YH, et al. Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction Hypertension 2004;43:229-236.[Abstract/Free Full Text] 23. Kurisu S, Ozono R, Oshima T, et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis Hypertension 2003;41:99-107.[Abstract/Free Full Text] 24. Harris P. Evolution and the cardiac patient Cardiovasc Res 1983;17:373-378.[Web of Science][Medline] 25. Sakata Y, Yamamoto K, Mano T, et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: its inhibition as a primary effect of angiotensin-converting enzyme inhibitor Circulation 2004;109:2143-2149. 26. Janicki JS, Brower GL, Gardner JD, et al. Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload Cardiovasc Res 2006;69:657-665.[Abstract/Free Full Text] 27. Ciulla MM, Paliotti R, Esposito A, et al. Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial Circulation 2004;110:552-557.
This article has been cited by other articles:
|
|
|
|
 
S. Champetier, A. Bojmehrani, J. Beaudoin, D. Lachance, E. Plante, E. Roussel, J. Couet, and M. Arsenault
Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the {beta}-adrenergic and renin-angiotensin systems
Am J Physiol Heart Circ Physiol,
March 1, 2009;
296(3):
H669 - H677.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Components of Remodeling:...
Why Is ACE-I Less...