Myocardial Fibrosis in Chronic Aortic Regurgitation

Borer, Jeffrey S.; Truter, Sharada L.; Herrold, Edmund M.; Falcone, Domenick J.; Peña, Magda; Carter, John N.; Dumlao, Themy F.; Lee, Jennifer A.; Supino, Phyllis G.

doi:10.1161/01.cir.0000014419.71706.85

Cited by 143 publications

(53 citation statements)

References 39 publications

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“…The limited data on the matricellular protein profile in volume-overloaded hearts are not accompanied by systematic investigations of the potential role of these proteins. Although marked increases in synthesis of fibronectin and periostin have been reported in experimental volume overload (114,119), deposition of these fibrogenic matricellular proteins was not associated with increased secretion of structural matrix proteins.…”

Section: Ecm In Cardiac Pressure and Volume Overloadmentioning

confidence: 74%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

388

318

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Section: Ecm In Cardiac Pressure and Volume Overloadmentioning

confidence: 74%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

388

318

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“…95, 96 Further, a recent investigation in rabbits with experimental AR has highlighted abnormal extracellular matrix (ECM) production featuring a relative abundance of non-collagen ECM, specifically including fibronectin. 97 For the time being, this difference in tissue composition cannot be discriminated by available CMR sequences.…”

Section: Discussionmentioning

confidence: 99%

From Left Ventricular Hypertrophy to Dysfunction and Failure

Lazzeroni

Rimoldi

Camici

2016

Circ J

118

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Left ventricular hypertrophy (LVH) is growth in left ventricular mass caused by increased cardiomyocyte size. LVH can be a physiological adaptation to strenuous physical exercise, as in athletes, or it can be a pathological condition, which is either genetic or secondary to LV overload. Physiological LVH is usually benign and regresses upon reduction/cessation of physical activity. Pathological LVH is a compensatory phenomenon, which eventually may become maladaptive and evolve towards progressive LV dysfunction and heart failure (HF). Both interstitial and replacement fibrosis play a major role in the progressive decompensation of the hypertrophied LV. Coronary microvascular dysfunction (CMD) and myocardial ischemia, which have been demonstrated in most forms of pathological LVH, have an important pathogenetic role in the formation of replacement fibrosis and both contribute to the evolution towards LV dysfunction and HF. Noninvasive imaging allows detection of myocardial fibrosis and CMD, thus providing unique information for the stratification of patients with LVH. DCM is generally caused by viral/bacterial myocarditis, exposure to cardiotoxic substances or is a manifestation of a systemic disease. Before cell death and fibrotic repair occur, multiple factors contribute to contractile dysfunction, including abnormalities in sarcolemmal integrity, energy production, calcium handling and force transmission. 10 Both systolic and diastolic dysfunction worsen with time and EF is progressively reduced, with symptoms and signs of HF. Secondary LVHCardiomyocyte hypertrophy is the primary mechanism by which the heart counteracts a protracted increase in stress (or load) on the ventricular wall. 11 According to Laplace's law, 12 wall stress is directly related to LV cavity size and intracavitary pressure and inversely related to wall thickness. Thus, wall thickening will counteract, at least in part, the increased stress and oxygen demand caused by pressure or volume overload, although, in the long run, this compensatory mechanism may become maladaptive. On the other hand, several other nonhemodynamic factors, including activation of the adrenergic and renin-angiotensin-aldosterone (RAAS) systems, release of growth factors and cytokines, contribute to the development of LVH. 13,14 Pressure Overload In most cases, pressure overload manifests as arterial hypertension (AH) or aortic stenosis (AS).Hypertensive Heart The most common condition associated with an increase in cardiac afterload and wall stress is AH. 15 Approximately 20-60% of patients with uncomplicated AH have evidence of increased LVM on echocardiography. 16 LVM can increase from wall thickening, chamber dilatation or both. Wall thickening occurs more commonly in response to pressure overload whereas chamber dilation occurs more commonly in response to volume overload. Although LV wall thickness is more closely related to systemic diastolic blood pressure (concentric hypertrophy), reflecting pure pressure load caused by increased systemic vascular resistance...

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“…Fibronectin is a major component of the noncollagenous ECM in the heart and functions as a link between the collagen matrix and the sarcolemmal membrane (50). Increased fibronectin expression has been reported in heart failure patients (51) and several animal models of cardiac dysfunction (52)(53)(54). Functionally, increased fibronectin expression would strengthen interactions between the collagen matrix and integrins on the myocyte surface, which has been shown to alter the viscoelastic properties of the myocardium (55).…”

Section: Discussionmentioning

confidence: 99%

Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects

Petrich

Eloff

Lerner

et al. 2004

Journal of Biological Chemistry

105

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The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died ϳ7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor ␤ signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.

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Myocardial Fibrosis in Chronic Aortic Regurgitation

Cited by 143 publications

References 39 publications

The extracellular matrix in myocardial injury, repair, and remodeling

The extracellular matrix in myocardial injury, repair, and remodeling

From Left Ventricular Hypertrophy to Dysfunction and Failure

Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects

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