Myofibroblasts have characteristics of fibroblasts and smooth muscle cells: they produce extracellular matrix and are able to contract. In so doing, they can contribute to tissue replacement and interstitial fibrosis following cardiac injury. The scar formed after myocardial injury is no longer considered to be passive tissue; it is an active playground where myofibroblasts play a role in collagen turnover and scar contraction. Maintaining the extracellular matrix in the scar is essential and can prevent dilatation of the infarct area leading to heart failure. On the other hand, extracellular matrix deposition at sites remote from the infarct area can lead to cardiac stiffness, an inevitable process of myocardial remodeling that occurs in the aftermath of myocardial infarction and constitutes the basis of the development of heart failure. Defining molecular targets on myofibroblasts in conjunction with establishing the feasibility of molecular imaging of these cells might facilitate the early detection and treatment of patients who are at risk of developing heart failure after myocardial infarction.

http://fulltext.calis.edu.cn/nature/nrcardio/7/1/nrcardio.2009.199.pdf

Myocardial remodeling after infarction: the role of myofibroblasts

Calcium signaling is a central regulator of cardiomyocyte growth and function. Calmodulin is a critical mediator of calcium signals. Because the amount of calmodulin within cardiomyocytes is limiting, the precise control of calmodulin expression is important for the regulation of calcium signaling. In this study, we show for the first time that calmodulin levels are regulated posttranscriptionally in heart failure. The cardiomyocyterestricted microRNA miR-1 inhibited the translation of calmodulin-encoding mRNAs via highly conserved target sites within their 3 untranslated regions. In keeping with its effect on calmodulin expression, miR-1 downregulated calcium-calmodulin signaling through calcineurin to NFAT. miR-1 also negatively regulated the expression of Mef2a and Gata4, key transcription factors that mediate calcium-dependent changes in gene expression. Consistent with the downregulation of these hypertrophy-associated genes, miR-1 attenuated cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes and in the intact adult heart. Our data indicate that miR-1 regulates cardiomyocyte growth responses by negatively regulating the calcium signaling components calmodulin, Mef2a, and Gata4. In the face of biomechanical stress, the heart develops compensatory hypertrophy, the hallmark of which is an increase in the size of cardiomyocytes. Over time, these hypertrophic changes become maladaptive, resulting in decreased contractile performance, cardiomyocyte loss, and, ultimately, heart failure (16). These changes in cardiomyocyte phenotype are linked to pathological changes in cardiomyocyte gene expression (24). Calcium, in conjunction with the calcium-binding protein calmodulin (CaM), is a critical mediator of hypertrophy signaling. Ca/CaM activates the phosphatase calcineurin (CN), leading to nuclear accumulation and the activation of

/pdf/microrna-1-negatively-regulates-expression-of-the-50uhb2c0sh.pdf

MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes.

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.

Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure.

To assess their comparative effects on hemodynamics and myocardial energetics, we administered nitroprusside (1.5 +/- 0.6 microgram/kg-min), dobutamine (10 +/- 3 micrograms/kg-min), and milrinone (67 +/- 13 micrograms/kg-min) sequentially to 10 patients with severe (NYHA class III or IV) congestive heart failure. Each agent led to a significant (p = .001) increase in cardiac index (1.9 +/- 0.5 to 2.7 +/- 0.6 liters/min/m2; 1.7 +/- 0.4 to 2.6 +/- 0.6 liters/min/m2; and 1.8 +/- 0.5 to 2.7 +/- 0.5 liters/min/m2, for nitroprusside, dobutamine, and milrinone, respectively). Dobutamine did not produce a significant change in the pulmonary capillary wedge pressure (27 +/- 5 to 24 +/- 6 mm Hg, NS) nor in mean arterial pressure (83 +/- 9 to 86 +/- 10 mm Hg, NS), but caused a significant rise in heart rate (85 +/- 16 to 99 +/- 17 beats/min, p = .001) and in myocardial oxygen consumption (8.7 +/- 2.1 to 11.1 +/- 3.8 ml O2/min, p = .03). In contrast, nitroprusside and milrinone each caused a significant (p = .001) fall in the pulmonary capillary wedge pressure (27 +/- 6 to 19 +/- 7 mm Hg and 26 +/- 6 to 19 +/- 9 mm Hg, respectively), without significantly increasing either the heart rate (87 +/- 18 to 85 +/- 17 beats/min and 86 +/- 17 to 89 +/- 17 beats/min, respectively) or myocardial oxygen consumption (8.8 +/- 2.3 to 7.6 +/- 2.1 ml O2/min and 8.8 +/- 2.1 to 8.4 +/- 2.1 ml O2/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure.

Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2-dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure.

Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.

The poor prognosis in heart failure, which can be reproduced by overloading the normal heart, may reflect molecular abnormalities associated with cardiac hypertrophy. Because terminally differentiated adult cardiac myocytes have little or no capacity to divide, overload-induced hypertrophy represents an unnatural growth response. The mechanism by which this unnatural growth response shortens survival remains speculative, but may involve apoptosis caused when overload reactivates growth factors to which the adult heart cannot respond with normal cell division. The ability of converting enzyme inhibitors and nitrates, which have growth inhibitory as well as vasodilator effects, to improve prognosis in heart failure may reflect the ability of these drugs to modify this unnatural growth response.

The cardiomyopathy of overload: an unnatural growth response.

Cardiac pumping action is governed by two interdependent systems: those that govern contraction and the emptying of the heart (inotropic) and those that control its relaxation and filling (lusitropic). The signs and symptoms of ‘heart failure’ can be caused by abnormalities of either or both of these systems. Major technological advances in the evaluation of the cardiac patient, especially those that utilize measurements of ventricular volume, coupled with potent new drugs that can modify differently the inotropic and lusitropic properties of the myocardium, make it necessary to understand the role that each plays in the genesis of the clinical syndrome of heart failure.

Inotropic and lusitropic abnormalities in the genesis of heart failure

Impaired pump function in the patient with congestive heart failure can arise from both contraction (inotropic) and relaxation (lusitropic) abnormalities. Because energy is required for both contraction and relaxation, evidence that the failing heart is in an energy-starved state may explain, at least in part, these functional abnormalities. The relative contributions of inotropic and lusitropic abnormalities to clinical disability differ in individual patients with heart failure, so that therapy of heart failure must be tailored to the specific pathophysiology that operates in each patient.

Inotropic and lusitropic abnormalities in heart failure.

The ability of catecholamines to accelerate relaxation in the myocardium appears to be due in part to phosphorylation of the sarcoplasmic reticulum by a cyclic AMP-dependent protein kinase Phospholamban, the substrate for this cyclic AMP-induced phosphorylation, is a 20–22 000 dalton protein that is deeply imbedded in the lipid bilayer of the cardiac sarcoplasmic reticulum

Phosphorylation of phospholamban is accompanied by acceleration of calcium transport into the cardiac sarcoplasmic reticulum This stimulatory effect is due in part to an increase in the Ca2+ sensitivity of the calcium pump and reduction in an apparent positive cooperativity between the two Ca2+-binding sites of the calcium pump ATPase These findings suggest that the dephospho-form of phospholamban inhibits calcium transport by the cardiac sarcoplasmic reticulum through an interaction with the calcium pump ATPase The ability of cyclic AMP-induced phosphorylation to accelerate calcium transport may result from elimination of inhibitory effects of dephospho-phospholamban This hypothesis is supported by similar Ca2+ dependences of calcium transport in phosphorylated cardiac and fast skeletal sarcoplasmic reticulum, the latter lacking phospholamban

Role of phosphorylation of the sarcoplasmic reticulum in the cardiac response to catecholamines

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The cardiomyopathy of overload: an unnatural growth response.

Inotropic and lusitropic abnormalities in the genesis of heart failure

Inotropic and lusitropic abnormalities in heart failure.

Role of phosphorylation of the sarcoplasmic reticulum in the cardiac response to catecholamines