Is Myocardial Fibrosis Impairing Right Heart Function?

Bogaard, Harm Jan; Voelkel, Norbert F.

doi:10.1164/rccm.201812-2307ed

Cited by 16 publications

(12 citation statements)

References 20 publications

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“…Unlike the more robust and pressure-resistant left ventricle (75), pressure overload of the right ventricle induced by PAB resulted in stronger reactive remolding, including marked free wall fibrosis, which is an important pathophysiological factor correlating with disease severity (76)(77)(78) and promotes diastolic dysfunction by reducing myocardial compliance (7,79,80). Perhaps preserving RV compliance and diastolic function by reducing collagen accumulation induced by PAB, SLIT3 deficiency attenuated its dilation (Figure 5, C and D), prevented the transition from adaptive concentric remodeling to maladaptive hypertrophy and fibrosis associated with decompensated failure (Supplemental Figure 5, B and C), and, importantly, exhibited an excellent long-term cardioprotective effect in the setting of persistent afterload ( Figure 5, H and I; and refs.…”

Section: Discussionmentioning

confidence: 99%

SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling

Gong¹,

Wang²,

Shen³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 99%

SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling

Gong¹,

Wang²,

Shen³

et al. 2020

JCI Insight

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“…46,66 The lack of improvement in RV function in PAB mice treated with pirfenidone may indicate that reducing fibrosis alone, without simultaneously addressing other RV maladaptations (metabolic remodeling with impaired inotropy, reduced capillary and inflammation), is insufficient. 67 The precision of the pirfenidone approach contrasts with multipronged benefits of PDK inhibition we employed.…”

Section: Limitationsmentioning

confidence: 99%

Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension

Tian

Dasgupta

et al. 2020

Circulation Research

112

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Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension contributes to RV failure. While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental pulmonary arterial hypertension. Methods and Results: Male Sprague-Dawley rats received monocrotaline (MCT; 60 mg/kg) or saline. Drinking water containing no supplement or the PDK (pyruvate dehydrogenase kinase) inhibitor dichloroacetate was started 7 days post-MCT. At week 4, treadmill testing, echocardiography, and right heart catheterization were performed. The effects of PDK activation on mitochondrial dynamics and metabolism, RVfib proliferation, and collagen production were studied in RVfib in cell culture. Epigenetic mechanisms for persistence of the profibrotic RVfib phenotype in culture were evaluated. PDK expression was also studied in the RVfib of patients with decompensated RV failure (n=11) versus control (n=7). MCT rats developed pulmonary arterial hypertension, RV fibrosis, and RV failure. MCT-RVfib (but not left ventricular fibroblasts) displayed excess mitochondrial fission and had increased expression of PDK isoforms 1 and 3 that persisted for >5 passages in culture. PDK-mediated decreases in pyruvate dehydrogenase activity and oxygen consumption rate were reversed by dichloroacetate (in RVfib and in vivo) or siRNA targeting PDK 1 and 3 (in RVfib). These interventions restored mitochondrial superoxide and hydrogen peroxide production and inactivated HIF (hypoxia-inducible factor)-1α, which was pathologically activated in normoxic MCT-RVfib. Redox-mediated HIF-1α inactivation also decreased the expression of TGF-β1 (transforming growth factor-beta-1) and CTGF (connective tissue growth factor), reduced fibroblast proliferation, and decreased collagen production. HIF-1α activation in MCT-RVfib reflected increased DNMT (DNA methyltransferase) 1 expression, which was associated with a decrease in its regulatory microRNA, miR-148b-3p. In MCT rats, dichloroacetate, at therapeutic levels in the RV, reduced phospho-pyruvate dehydrogenase expression, RV fibrosis, and hypertrophy and improved RV function. In patients with pulmonary arterial hypertension and RV failure, RVfib had increased PDK1 expression. Conclusions: MCT-RVfib manifest a DNMT1-HIF-1α-PDK–mediated, chamber-specific, metabolic memory that promotes collagen production and RV fibrosis. This epigenetic mitochondrial-metabolic pathway is a potential antifibrotic therapeutic target.

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“…Far less is known about the mechanisms driving RV fibrosis (5)(6)(7). This is notable since we and others have demonstrated that some established therapies targeting LV fibrosis, such as angiotensin receptor antagonism, do not attenuate RV fibrosis (8,9).…”

Section: Introductionmentioning

confidence: 99%

α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension

Vang¹,

Bós²,

Fernández-Nicolas³

et al. 2021

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Right ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibroblast α7 nicotinic acetylcholine receptor (α7 nAChR) drives smoking induced RV fibrosis. Here we sought to define the role of α7 nAChR in RV dysfunction and fibrosis in the settings of RV pressure overload as seen in PH. We show that RV tissue from PH patients has increased collagen content and ACh expression. Using experimental rat model of PH, we demonstrate that RV fibrosis and dysfunction are associated with increases in ACh and α7 nAChR expression in the RV but not in the LV. In vitro studies show that α7 nAChR activation leads to an increase in adult ventricular fibroblast proliferation and collagen content mediated by a Ca 2+ / epidermal growth factor receptor (EGFR) signaling mechanism. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model. Further, mice lacking α7 nAChR exhibit improved RV diastolic function and have lower RV collagen content in response to persistently increased RV afterload, compared to wild-type controls. These finding indicate that enhanced α7 nAChR signaling is an important mechanism underlying RV fibrosis and dysfunction, and targeted inhibition of α7 nAChR is a novel therapeutic strategy in the setting of increased RV afterload.

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Is Myocardial Fibrosis Impairing Right Heart Function?

Cited by 16 publications

References 20 publications

SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling

SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling

Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension

α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension

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