Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload

Abstract

Left ventricular (LV) volume overload (VO) causes eccentric remodeling with inflammatory cell infiltration and extracellular matrix (ECM) degradation, for which there is currently no proven therapy. To uncover new pathways that connect inflammation and ECM homeostasis with cellular dysfunction, we determined the cardiac transciptome in subacute, compensated, and decompensated stages based on in vivo hemodynamics and echocardiography in the rat with aortocaval fistula (ACF). LV dilatation at 5 wk was associated with a normal LV end-diastolic dimension-to-posterior wall thickness ratio (LVEDD/PWT; compensated), whereas the early 2-wk (subacute) and late 15-wk (decompensated) ACF groups had significant increases in LVEDD/PWT. Subacute and decompensated stages had a significant upregulation of genes related to inflammation, the ECM, the cell cycle, and apoptosis. These changes were accompanied by neutrophil and macrophage infiltration, nonmyocyte apoptosis, and interstitial collagen loss. At 15 wk, there was a 40-fold increase in the matricellular protein periostin, which inhibits connections between collagen and cells, thereby potentially mediating a side-to-side slippage of cardiomyocytes and LV dilatation. The majority of downregulated genes was composed of mitochondrial enzymes whose suppression progressed from 5 to 15 wk concomitant with LV dilatation and systolic heart failure. The profound decrease in gene expression related to fatty acid, amino acid, and glucose metabolism was associated with the downregulation of peroxisome proliferator associated receptor (PPAR)-α-related and bioenergetic-related genes at 15 wk. In VO, an early phase of inflammation subsides at 5 wk but reappears at 15 wk with marked periostin production along with the suppression of genes related to PPAR-α and energy metabolism.

The extracellular matrix in myocardial injury, repair, and remodeling

“…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.…”

“…Volume overload is associated with a distinct profile of changes in the composition of the ECM that ultimately lead to chamber dilation and contribute to systolic dysfunction. In contrast to the marked accentuation in collagen deposition triggered by a pressure load, volume overload is associated with a reduction in interstitial collagen content due to increased MMP expression (113)(114)(115) and augmented autophagic degradation of procollagen in cardiac fibroblasts (116). Pharmacologic inhibition studies suggested that MMP activation is directly implicated in dilative remodeling of the volume-overloaded ventricle (117), but the mechanisms responsible for the distinct cell biological changes and matrix alterations in volume overload remain poorly understood.…”

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

“…Nevertheless, the separation of benefits on systolic and diastolic function with XO inhibition is of great interest in this and other models of heart failure, because the failure to improve symptoms and hospitalizations in the oxypurinol heart failure trial (23) may have been related to an inability of oxypurinol to improve diastolic function and pulmonary congestion. In the volume-overloaded heart, and more so in ischemic cardiomyopathy, this is particularly important because elevated LV diastolic wall stress has a negative impact on LV coronary perfusion pressure and the development of LV endocardial ischemia and fibrosis (12,21,40).…”

“…In summary, the mechanical stimulus of a pure stretch/VO has multiple myocardial events including inflammation and matrix loss, cardiomyocyte and mitochondrial oxidative stress, and increased adrenergic drive (12,17,37). The biological complexity of the pathogenic processes in a pure VO illustrates the challenges of targeting therapies that can prevent progressive cardiac remodeling and failure.…”

Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation

“…Similarly, in the volume overload model of aortocaval fistula, upregulation of genes was related to inflammation, the extracellular matrix, the cell cycle, and apoptosis. 31 There was a 40-fold increase in the matricellular protein periostin, which inhibits connections between collagen and cells, thereby potentially mediating side-to-side slippage of cardiomyocytes and LV dilatation. These findings are consistent with our results that inflammation, the cell cycle, and DNA damage pathways that were upregulated in MR were prevented by sildenafil treatment.…”