Myocyte Recovery After Mechanical Circulatory Support in Humans With End-Stage Heart Failure

Δίπλα, Κωνσταντίνα; Mattiello, Julian A.; Jeevanandam, Valluvan; Houser, Steven R.; Margulies, Kenneth B.

doi:10.1161/01.cir.97.23.2316

Cited by 384 publications

(233 citation statements)

References 43 publications

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“…Studies in end-stage heart failure patients treated with left ventricular assist devices have shown that mechanical unloading improves myocyte function and reverses structural remodeling of the failing heart (35,36). This therapy also normalizes Ca 2ϩ transients and increases SERCAmediated Ca 2ϩ uptake.…”

Section: Discussionmentioning

confidence: 99%

A Transgenic Mouse Model of Heart Failure Using Inducible Gαq

Fan

Jiang

Lu³

et al. 2005

Journal of Biological Chemistry

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Receptors coupled to G␣ q play a key role in the development of heart failure. Studies using genetically modified mice suggest that G␣ q mediates a hypertrophic response in cardiac myocytes. G␣ q signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased G␣ q signaling only as adults, we generated transgenic mice that express a silent G␣ q protein (G␣ q Q209L-hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate G␣ q Q209L-hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban (PLB), decreased sarcoplasmic reticulum Ca 2؉ -ATPase activity, and a decrease in L-type Ca 2؉ current density. Changes in Ca 2؉handling and decreased cardiac contractility are apparent 1 week after G␣ q Q209L-hbER activation. In contrast, transgenic mice that express an inducible G␣ q mutant that cannot activate phospholipase C␤ (PLC␤) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca 2؉ current density. These results demonstrate that activation of G␣ q in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLC␤. However, increased PLC␤ signaling is not required for all of the G␣ q -induced cardiac abnormalities.G␣ q is a member of the heterotrimeric G protein superfamily. Heterotrimeric G proteins are composed of three subunits (␣, ␤, and ␥). Receptor activation leads to the exchange of GTP for GDP on the ␣ subunit, which causes G␣ to dissociate from the tightly bound ␤␥ complex. Both G␣ and ␤␥ can then interact with specific effector proteins, resulting in changes in cellular function. Phospholipase C␤ (PLC␤) 3 is the best known effector of the G␣ q subfamily of G proteins (1). Activated G␣ q binds to PLC␤ and increases its enzymatic activity to hydrolyze phosphatidylinositol (4,5)-bisphosphate to form inositol (1,4,5)-trisphosphate and diacylglycerol. Although less well characterized, other signaling effectors of G␣ q include the p110␣/p85␣ phosphatidylinositol 3-kinase (PI3K) complex, which is inhibited by G␣ q ⅐GTP binding 4 (2), and Bruton's tyrosine kinase, which is activated by G␣ q (3). Following cardiac injury, up-regulation of angiotensin II and catecholamines leads to activation of G␣ q and progression to heart failure. The signaling pathway that mediates G␣ q -induced cardiomyopathy is unclear. The presumption has been that activation of PLC␤ by G␣ q is responsible for the cardiac pathology, but this hypothesis has not been directly tested. Activation of PLC␤ leads to the release of Ca 2ϩ from inositol (1,4,5)-trisphosphate-sensitive stores, but the role of this signaling event in cardiac myocytes is unknown. Activation of PLC␤ also leads to the diacylglycerol-dependent activation of so...

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Section: Discussionmentioning

confidence: 99%

A Transgenic Mouse Model of Heart Failure Using Inducible Gαq

Fan

Jiang

Lu³

et al. 2005

Journal of Biological Chemistry

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“…However, recent studies in end-stage heart failure patients treated with left ventricular assist devices have shown that mechanical unloading improves myocyte function and reverses structural remodeling of the failing heart (7,8). This therapy also normalizes Ca 2ϩ transients and increases SERCA-mediated Ca 2ϩ uptake.…”

Section: Table 1 Hemodynamic Measurements In Ql and Wt Micementioning

confidence: 99%

Reversible Heart Failure in Gαq Transgenic Mice

Jiang

Ballou

et al. 2006

Journal of Biological Chemistry

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For many patients with cardiac insufficiency, the disease progresses inexorably to organ dilatation, pump failure, and death. Although there are examples of reversible heart failure in man, our understanding of how the myocardium repairs itself is limited. A well defined animal model of reversible heart failure would allow us to better investigate these restorative processes. Receptors that activate G␣ q , a signal transduction molecule in the heterotrimeric G protein superfamily, are thought to play a key role in the development of heart failure. We demonstrated previously that mice expressing a recombinant G␣ q protein, the activity of which can be turned on or off at will in cardiac myocytes, develop a dilated cardiomyopathy with generalized edema and heart failure following activation of the protein (Fan, G., Jiang, Y. 280, 40337-40346).Here we report that the contractile dysfunction and pathological structural changes in the myocardium improved significantly after termination of the G␣ q signal, even in animals with overt heart failure. Abnormalities in two proteins that regulate Ca 2؉ handling in myocytes, phospholamban and the voltage-dependent L-type Ca 2؉ channel, were also reversed, as was the increased expression of genes that are associated with heart failure. These results indicate that the heart has a substantial reparative capacity if the molecular signals responsible for the myocardial dysfunction can be identified and blocked.Following cardiac injury, activation of G␣ q -coupled receptors in the heart exerts deleterious effects that promote the development of heart failure. To better investigate the role of G␣ q activation in the development of cardiac failure in adult animals, we developed transgenic mice that express a recombinant G␣ q protein, the activity of which can be turned on or off at will. Fusing a mutant hormone-binding domain of the estrogen receptor (hbER) 2 to the carboxyl terminus of constitutively active G␣ q Q209L renders this G␣ q protein inactive (1). However, in the presence of 4-hydroxytamoxifen, the G␣ q Q209L-hbER (QL) protein becomes active. This inducible model allowed us to investigate the consequences of G␣ q activation in myocytes after completion of normal development and growth. We found that tamoxifen activation of the QL protein in adult transgenic mice causes a dilated cardiomyopathy that leads to heart failure (1). Heart failure is often associated with depressed cardiac contractility, which is also exhibited by the QL mice (1). Contractility of cardiac myocytes is regulated by changes in the intracellular Ca 2ϩ concentration. Ca 2ϩ enters the cell through the L-type voltage-dependent Ca 2ϩ channel (LTCC) and induces a large release of Ca 2ϩ from the sarcoplasmic reticulum (SR) through the ryanodine receptor, resulting in myocyte contraction. Relaxation is caused by removal of Ca 2ϩ either by the SR Ca 2ϩ -ATPase (SERCA) or the Na ϩ -Ca 2ϩ exchanger located at the plasma membrane. SERCA is regulated by phospholamban (PLB), which inhibits SERCA when dephospho...

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“…Furthermore, many cellular processes improve, although they do not completely normalise. [5][6][7][8][9][10][11][12][13][14][15] Sufficient recovery of left ventricular function, allowing LVAD explantation, however, is rare and is mainly feasible in patients suffering from acute myocarditis or PPCM. 10,11,13 In these cases, the LVAD will maintain the patient's life, allowing the myocardium to recover from the underlying disease.…”

Section: Discussionmentioning

confidence: 99%

Left ventricular assist device as a bridge to recovery in a young woman admitted with peripartum cardiomyopathy

Oosterom¹,

Jonge²,

Kirkels³

et al. 2008

NHJL

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Left ventricular assist device as a bridge to recovery in a young woman admitted with peripartum cardiomyopathy Left ventricular assist devices (LVAD) are an effective therapeutic option for end-stage heart failure patients as a bridge to cardiac transplantation in those who deteriorate despite maximal therapy and when a donor heart is not ready available. In some patients, cardiac recovery has been reported while supported by an LVAD. In this case report, we describe a 29-year-old female who was admitted to our centre because of peripartum cardiomyopathy (PPCM). Despite intensive treatment with intravenous inotropes and intra-aortic balloon counterpulsation she had a persisting low cardiac index and an LVAD was implanted. In the months following implantation the left ventricular systolic function improved and the left ventricular dimensions normalised. Eventually the LVAD could be explanted nine months after implantation. At this moment, three years after explantation, echocardiography shows a normal-sized left ventricle and almost completely recovered systolic function. (Neth Heart J 2008;16:426-8).

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Myocyte Recovery After Mechanical Circulatory Support in Humans With End-Stage Heart Failure

Cited by 384 publications

References 43 publications

A Transgenic Mouse Model of Heart Failure Using Inducible Gαq

A Transgenic Mouse Model of Heart Failure Using Inducible Gαq

Reversible Heart Failure in Gαq Transgenic Mice

Left ventricular assist device as a bridge to recovery in a young woman admitted with peripartum cardiomyopathy

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