Cardiac atrophy and heart remodeling

Remodeling of the heart following hemodynamic unloading

[Please note, this page is no longer updated]

Introduction

The influence of hemodynamic load on the heart

An animal model of unloading-induced cardiac atrophy

Metabolic adaptations

Protein synthesis and degradation

Cell survival and hypertrophic gene transcription pathways

Alterations in myocardial gene expression and calcium regulatory proteins

Hemodynamic unloading of the failing heart

References


1.  Introduction

The life-sustaining, dynamic organ we call the heart is regulated by a balance of hemodynamic and neurohormonal influences which finely maintain optimal structural and functional stability. Changes that trigger any disruption of this balance promote adaptive responses within the heart that are collectively defined as “remodeling”. Remodeling is particularly prominent in the left ventricle (LV) and has been studied extensively in heart failure where LV remodeling can lead to gradual myocardial deterioration. The development of heart failure is often instigated in response to a sustained increase in hemodynamic load. This review will address the role of hemodynamic load in myocardial LV remodeling to spotlight the effects of hemodynamic unloading on normal and failing hearts.

2.  The influence of hemodynamic load on the heart

Hemodynamic load is a critical regulator of myocardial integrity and contractile function. Alterations in hemodynamic load induce immediate responses in cardiomyocytes that elicit rapid adaptation to the changing environment. Adaptations include shifts in substrate metabolism and in rates of protein synthesis and degradation. These shifts are accompanied by modulations in molecular pathways regulating cell survival and myocardial gene expression. Together these adaptations result in extensive LV remodeling as a response to the change in functional demand. The majority of research studies have addressed LV remodeling resulting from hemodynamic overload due to its clinical relevance toward the development of heart failure (Figure 1). Hemodynamic overload induces cardiac hypertrophy leading to an initial increase in muscle mass to compensate for the increase in functional demand. However, under pathological conditions of hemodynamic overload, functional demand overrides the normal physiological compensatory mechanisms leading to impaired contractility and diminished structural integrity of the myocardium. 

Many studies have been performed to characterize the ventricular remodeling that occurs during hypertrophy. As cardiac atrophy is not a major contributing factor to heart failure or other cardiac disease states, far fewer studies have addressed myocardial remodeling that occurs in response to hemodynamic unloading (Figure 1).  Cardiac atrophy is induced during conditions of microgravity, starvation and muscle loss in chronic disease states and represents a secondary consequence resulting from these larger systemic phenomena(1). Studies have shown that reducing hemodynamic load by way of left ventricular assist devices can, in fact, improve cardiac performance in a number of heart failure patients(2,3). Therefore, it is critical to understand the mechanisms regulating cardiac remodeling during unloading-induced myocardial atrophy in addition to those at play during hypertrophy.

Fig. 1 The influence of hemodynamic load on the heart. Download the pathway poster.

3.  Animal model of unloading-induced cardiac atrophy

The rat heterotopic heart transplant model has been reliably used to examine unloading induced atrophic changes in the myocardium(4-11). This model entails the transplantation of an isogenic donor heart from one rat into the abdominal cavity of the recipient rat. This is achieved by end to side anastomization of the donor ascending aorta pulmonary artery to the recipient abdominal aorta and inferior vena cava respectively. The hemodynamic load on the transplanted heart is significantly reduced compared to the native heart. Thus, the transplanted heart exhibits a significantly lower left ventricular pressure and decreased heart rate, mimicking the physiological adaptation to hemodynamic unloading(11). All the findings pertaining to cardiac atrophy discussed in this review are derived from studies employing this model. 

4.  Metabolic adaptations

The metabolic adaptations which occur in response to both cardiac hypertrophy and atrophy are characterized by a decrease in aerobic metabolism in an attempt to increase cardiac efficiency(12). This is indicated by a switch from fatty acid oxidation to glucose metabolism as the main energy source and represents a return to the fetal metabolic state (Figure 1,2)(10,12). Decreased aerobic metabolism is closely linked to reduced contractility and mitochondrial fatty acid oxidation. Evidence of reduced fatty acid oxidation during both pathological hypertrophy and atrophy includes decreased transcript and activity levels of pyruvate dehydrogenase kinase 4 (PDK4), malonyl CoA decarboxylase (MCD) and uncoupling protein-3 (UCP-3)(10).  Additionally, mRNA transcript levels of PPARa, the nuclear transcription factor that regulates PDK4MCD and UCP-3 gene expression, are also decreased (10)

5.  Protein synthesis and degradation

Hemodynamic load regulates cardiomyocyte size by modulating protein synthesis and degradation. Increased protein synthesis during cardiac hypertrophy contributes to increases in cardiomyocyte size and myocardial mass. During cardiac atrophy, rates of protein synthesis are also increased as demonstrated by the upregulation of PI3K/mTOR signaling which regulates protein synthesis via activation of p70S6K. However, during atrophy it has been shown that the rate of protein degradation exceeds the rate of synthesis, resulting in an overall reduction in cell size and myocardial mass (Figure 1)(1,7).  

The ubiquitin proteosome pathway mediates the degradation of many proteins via ATP dependent ligation to ubiquitin (Figure 1). The ubiquitin proteosome pathway plays a prominent role in protein degradation during cardiac atrophy, as characterized by elevated expression levels of ubiquitin B, ubiquitin conjugating enzyme UbcH2, and polyubiquitinated proteins(1,7) . Ubiquitin ligases, specifically Mafbx/Atrogin-1 and MuRF-1, are major regulators of cardiac atrophy. Expression of these ligases is regulated by FOXO transcription factors such as FOXO3a(1,7).  Mafbx/Atrogin-1 targets calcineurin for ubiquitin mediated degradation that in turn inhibits calcineurin mediated hypertrophic signaling(1). Alternately, MuRF-1 promotes ubiquitin mediated degradation of protein kinase C-e another key player in hypertrophic pathways(1). Interestingly, transcript levels of Mafbx/Atrogin-1 and MuRF-1 decline during cardiac atrophy and are elevated during hypertrophy. This is due to increased expression of insulin like growth factor-1 (IGF-1) during cardiac atrophy, which supresses FOXO3aactivity, leading to the downregulation of these ligases. However, during hypertrophy increased transcript levels of Mafbx/Atrogin-1 and MuRF-1 may likely serve as an adaptive mechanism to limit increases in myocardial mass(1,7).

6.  Cell survival and hypertrophic gene transcription pathways

Increased expression of IGF-1 and fibroblast growth factor-2 (FGF-2) is observed during both hypertrophy and atrophy. Typically these growth factors trigger cell survival pathways via downstream activation of Akt(13,14). Increased activation of Akt has been observed in response to pressure overload induced hypertrophy but not unloading induced atrophy. This finding suggested that atrophy, unlike hypertrophy, blunted activation of mTOR, the downstream target of Akt (Figure 1)(9). This was verified using the mTOR inhibitor, rapamycin, where administration of rapamycin further enhanced the atrophic response in chronically unloaded hearts(9). Other signaling pathways such as the MAP kinase and JAK/STAT pathways are enhanced during cardiac hypertrophy(13). Unloading induced atrophy resulted in increased activation of ERK1 but not ERK2JNK or p38 MAP kinases (Figure 2)(9). Janus kinases (JAKs) regulate gene transcripition via activation of STAT protein transcription factors(13). Atrophy also promoted activation of STAT proteins via the JAK/STAT pathway(9)

7.  Alterations in myocardial gene expression and calcium regulatory proteins

Changes in myocardial gene expression have been extensively studied in pressure overload induced hypertrophy. Specific changes in the expression of myosin heavy chain (MHC) isoforms and atrial natriuretic factor (ANF) are observed. Pathological cardiac hypertrophy induces an upregulation of the bMHC isoform and ANF expression(5,12,15) . This expression pattern represents a shift toward the fetal myocardial gene profile and is frequently accompanied by a decrease in sarcoplasmic reticulum Ca2+ ATPase (SERCA2) expression or activity(15,16). Together these alterations contribute to the impaired contractility that is typically observed in pathological hypertrophy and heart failure (Figure 1). Increased expression of bMHC relative to aMHC decreases cardiomyocyte contractility in a calcium independent manner(17). ANF, which is released by atrial cardiomyocytes in response to myocardial stress induced by pressure overload, acts to reduce blood volume and this, in turn, decreases cardiac output and systemic blood pressure. SERCA2 mediates the onset of diastole by orchestrating calcium ion re-uptake into the sarcoplasmic reticulum. Decreased SERCA2 expression and activity disrupts calcium homeostasis, eliciting abnormal calcium transients during systole and prolonging relaxation (Figure 1)(16). Reductions in SERCA2 expression are accompanied by upregulation of the sodium-calcium exchanger (NCX) that attempts to compensate for diminished SERCA2 activity by extruding excess intracellular calcium (Figure 1)(16).  

Cardiac atrophy induced by chronic unloading generates similar shifts toward increased bMHC and ANF expression(5). A decreased rate of intracellular calcium decline and increased relaxation time both resulted from prolonged unloading(4). Unlike pathological hypertrophy, cardiomyocytes from atrophic hearts did not display abnormal calcium transient profiles under basal conditions(4). However, atrophic cardiomyocytes exhibited a depressed contractile reserve while stimulation with increasing extracellular [Ca2+] resulted in diminished fractional shortening compared to control cardiomyocytes(4). Contrary to hypertrophy, there was no decrease in SERCA2 protein expression in atrophic hearts(4). Expression of phospholamban (PLB), the regulator of SERCA2 activity, is increased during prolonged unloading, promoting a decreased SERCA2 to PLB ratio (Figure 1)(4). Expression levels of NCX appear unchanged in atrophic hearts (4)

8.  Hemodynamic unloading of the failing heart

From the aforementioned physiological, metabolic and cellular changes, it is evident that myocardial remodeling during cardiac atrophy shares similarities to pathological hypertrophy. Both conditions induce shifts toward fetal modes of substrate metabolism and myocardial gene expression. Increased protein degradation and a decreased impact on myocardial calcium homeostasis distinguish atrophic remodeling from pathological hypertrophic remodeling (Figure 1). Regardless, the effects of hemodynamic unloading on the normal heart are detrimental to overall cardiac performance. In contrast, hemodynamic unloading does appear to have a positive impact on failing hearts where a phenomenon of “reverse remodeling” is induced (Figure 1)(2,3).  

Left ventricular assist devices (LVAD) function by unloading the left ventricle. Specifically, an LVAD is used to bridge end-stage heart failure patients to heart transplant and have been shown to improve cardiac performance in a number of heart failure patients(2,3). Improved contraction and relaxation rates as well as enhanced b-adrenergic responsiveness are evident in cardiomyocytes isolated from LVAD supported versus non-supported failing hearts 2,3). Normalization of expression of SERCA2, NCX and other calcium regulatory proteins in LVAD supported hearts indicate some restoration of calcium homeostasis (Figure 2)(3). Although there is a reduction in cardiomyocyte hypertrophy and apoptosis with LVAD support, the Akt/Gsk-3b pro-survival signaling pathway is not activated(2,3). LVAD supported hearts demonstrate normalized UCP-3 expression but not normalized expression of other metabolic enzymes suggesting that the shift back to fatty acid oxidation is incomplete (Figure 1)(2). Extracellular matrix remodeling via collagen degradation contributes to increased wall stiffness in failing hearts.  Despite decreased rates of collagen degradation, wall stiffness does not necessarily decline with LVAD support(2,3).

In conclusion, hemodynamic unloading is detrimental to the normal heart but beneficial to the failing heart by improving cardiac performance through reverse remodeling. While further investigation is required to fully comprehend the multiple complex mechanisms regulating reverse remodeling, it is evident that many parallel phenomena exist between cardiac atrophy and hypertrophy. The rat heterotopic heart transplant model has provided important insight into cardiac atrophic remodeling that can be studied in the relative absence of other systemic influences. A possible adaptation of the heterotopic transplant model to incorporate transplantation of overloaded donor hearts may provide an effective experimental setup to further examine the role of reverse remodeling in the clinical management of human heart failure. 

9.  References

    1. Razeghi P. and Taegtmeyer H.  Ann.  NY. Acad. Sci. Vol 1080: p110-119, 2006
    2. Burkhoff D., Klotz S., Mancini D.M.  J. Cardiac Fail.  Vol 12:  p227-239, 2006
    3. Klotz S., Danser J.A.H, Burkhoff D.  Prog. Biophys. Mol. Biol. Vol 97: p479-496, 2008 
    4. Ito K., Nakayama M., Hasan F., Yan X., Schneider M.D., Lorell B.H. Circulation Vol 107: p 1176-1182, 2003
    5. Depre C., Shipley G.L., Chen W., Han Q., Doenst  T., Moore M.L., Stepkowski S., Davies P.J. A, Taegtmeyer H.  Nature Med. Vol 11: p1269-1275, 1998
    6. Welsh D.C., Dipla K., McNulty P.H., Mu A., Ojamaa K.M., Klein I., Houser S.R., Margulies K.B.  Am. J. Physiol. Heart Circ. Physiol. Vol 281:  p1131- 1136, 2001
    7. Razeghi P., Baskin K.K., Sharma S., Young M.E., Stepkowski S., Essop M.F., Taegtmeyer H.  Biochem. Biophys. Res. Comm. Vol 342: p361-364, 2006
    8. Razeghi P., Sharma S., Ying J., Li Y., Stepkowski S., Reid M.B., Taegtmeyer H. Circulation Vol 108: p2536-2541, 2003
    9. Sharma S., Ying J., Razeghi P., Stepkowski S., Taegtmeyer H. Cardiology Vol 105:p128-136, 2006
    10. Taegtmeyer H., Razeghi P., Young M.E. Clin. Exp. Pharm. Physiol. Vol 29: p346-350, 2002
    11. Geenen D.L., Malhotra A., Buttrick P.M., Scheuer J. Am. J. Physiol. Vol 267: pH2149-H2154, 1994
    12. Rajabi M., Kassiotis C., Razeghi P., Taegtmeyer H.  Heart Fail. Rev. Vol 12: p331-343, 2007
    13. Hefti M.A., Harder B.A., Eppenberger H.M., Schaub M.C. J. Mol. Cell Cardiol.  Vol 29: p2873-2892, 1997
    14. Ren J., Samson W. K., Sowers J.R. J. Mol Cell Cardiol.  Vol 31:  2049-2061, 1999
    15. McMullen J.R. and Jennings G.L. Clin. Exp. Pharm. Physiol. Vol 34: 255-262, 2007
    16. Houser S.R., Placiento V.,  Weisser J.  J. Mol. Cell Cardiol. Vol 32: p1595-1607, 2000
    17. Herron T.J., Vandenboom R., Formicheva E., Mundada L., Edwards T., Metzger J.M. Circulation Res. Vol 100: p1182- 1190, 2007



    Sign up