Inflammation in Cardiac Remodelling

By Nadezhda Glezeva PhD

Inflammation in Cardiac Remodelling

Initial evidence showing a role of inflammation in cardiac remodelling and heart disease came from experimental and clinical observations of immune-inflammatory activation in patients with chronic HF [39]. Since then, multiple studies have shown high levels of pro-inflammatory cytokines such as tumour necrosis factor α (TNFα), interleukin (IL)-1, IL6, IL8, and MCP1 in the circulation and the heart of HF patients [40-46]. Main sources for these cytokines are neutrophil granulocytes, macrophages, monocytes and T cells, as well as platelets, endothelial cells and vascular smooth muscle cells (VSMC).

These cytokines have been repeatedly and consistently shown to bring important prognostic information, which has led to the conclusion that these inflammatory mediators are critically implicated in the mechanisms of progression of HF. Accumulated evidence from these studies supported the existence of a repetitive and progressive state of immune-inflammatory activation which is strongly associated with the progression of ventricular diastolic dysfunction, a state, characterised by an intense release and activation of cytokines, complement, adhesion molecules, autoantibodies and other substances in the circulation [40, 41]. The persistently elevated expression of these immune-inflammatory mediators in the circulation and the myocardium facilitates the development of HF by suppressing myocardial contractility, promoting ventricular remodelling (induction of myocyte apoptosis and cardiac hypertrophy), and inducing imbalance in many extra-cardiac tissue and organ systems including the musculoskeletal, haematopoietic, metabolic, digestive, urinary, and neuropsychological systems. The resulting detrimental imbalance eventually leads to the progression of HF.

Early Vascular Inflammation

In addition to the role of inflammation in late ventricular remodelling and HF stabilization, early vascular inflammation has been shown to be the most common precursor of HTN and atherosclerosis, and asymptomatic individuals with even evidence of low-grade vascular inflammation have an elevated risk for subsequent major cardiovascular (CV) events [47, 48].

It is now well understood that in chronic vascular inflammatory disorders, such as atherosclerosis and HTN, the earliest and most significant inflammatory event to initiate vascular lesion formation is the recruitment of circulating inflammatory cells (neutrophils, monocytes, lymphocytes) that attach to the endothelium, and transmigrate into the vascular lesion. Transmigration is made possible due to the interactions between specific cell surface receptors on the monocytes (E-selectins, P-selectins, complement receptors) and adhesion molecules (ICAM1, vascular cell adhesion molecule-1(VCAM1)), and is directed by chemokine gradients (MCP1, IL8) secreted by injured tissue and the activated vessel wall [49]. Once inside the vessel wall (or inside the myocardium) monocytes differentiate into macrophages which actively release inflammatory cytokines, chemokines, and growth factors, which in turn activate further vascular inflammation and lesion formation.

Inflammation and Hypertension

First evidence from animal studies aimed at investigating the significance of inflammation for the aetiology and progression of HTN have confirmed the significance of this process for hypertensive myocardial remodelling and have also indicated that there exists an intricate cause-effect relationship between inflammatory and fibrotic processes in the hypertensive heart.

Rat Models of Hypertension

In rat models of hypertension (spontaneously-hypertensive (SHR) and renovascular hypertensive rats), distinctive macrophage and fibroblast accumulation has been detected in perivascular regions of the pressure-overloaded heart [50, 51]. In addition, altered ICAM1 expression, observed in the endothelium of SHR suggested that pressure-overload directly regulates the abnormal inflammatory responses associated with this disease [52].

In a rat model of pressure overload caused by suprarenal abdominal aortic constriction (AC), the rapid increase in arterial pressure triggered a series of inflammatory and fibrotic changes in the intramyocardial arterial wall [28]. In this model, the earliest event detected was upregulation of MCP1 and ICAM1 (1 day post insult) in the intramyocardial arteries. This was followed by accumulation of perivascular macrophages, which co-localized to sites of cytokine expression, and also resulted in enhanced transforming growth factor β (TGFβ) expression, fibroblast proliferation, and conversion of fibroblasts to myofibroblasts (day 3). Later in the time-course of events, reactive fibrosis, LVH, and myocyte hypertrophy developed (after day 7), and LVDD was diagnosed at day 28. This model shows a clear evidence of a link between inflammation and fibrosis and establishes inflammation as the initial event, the stimulus which triggers the onset of fibrosis in the perivascular space before the expansion to the inter-muscular interstitium.

MCP-1 and Inflammation

Induction of MCP1 to activate circulating monocytes to invade the vessel wall and thus initiate inflammation is driven not only by stretch, but also by oxidative stress and activation of RAAS [53, 54]. Angiotensin II has been shown to induce MCP1 expression in macrophages and upregulate TGFβ in cardiac myocytes and fibroblasts [55, 56], suggesting that the activation of RAAS may precede the onset of inflammation and fibrosis in pressure overload.

Treatment with an anti-MCP1 monoclonal neutralizing antibody has been shown to abolish macrophage infiltration, attenuate myocardial fibrosis, and improve diastolic function without affecting blood pressure or systolic function [55].

Similarly, defective MCP1 signalling in mouse models of ischemic cardiomyopathy and HTN with LVH was shown to markedly diminish interstitial fibrosis, lower macrophage infiltration and attenuate ventricular dysfunction [57, 58]. Similar beneficial effects were noted also when ICAM1 function was blocked [29]. Thus, these studies suggest that macrophage-mediated perivascular inflammation is a key event triggering early fibrotic changes, reactive myocardial fibrosis and LVDD in HTN and that inhibition of inflammation may be a new strategy to prevent hypertensive myocardial remodelling.

References

39. Levine, B., et al., Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med, 1990. 323(4): p. 236-41.
40. Torre-Amione, G., Immune activation in chronic heart failure. Am J Cardiol, 2005. 95(11A): p. 3C-8C; discussion 38C-40C.
41. Mann, D.L., Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res, 2002. 91(11): p. 988-98.
42. Adamopoulos, S., J.T. Parissis, and D.T. Kremastinos, A glossary of circulating cytokines in chronic heart failure. Eur J Heart Fail, 2001. 3(5): p. 517-26.
43. Torre-Amione, G., et al., Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation, 1996. 93(4): p. 704-11.
44. Hasper, D., et al., Systemic inflammation in patients with heart failure. Eur Heart J, 1998. 19(5): p. 761-5.
45. Aukrust, P., et al., Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol, 1999. 83(3): p. 376-82.
46. Aukrust, P., et al., Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation, 1998. 97(12): p. 1136-43.
47. Ridker, P.M., et al., Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med, 2008. 359(21): p. 2195-207.
48. Savoia, C. and E.L. Schiffrin, Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci (Lond), 2007. 112(7): p. 375-84.
49. Galkina, E. and K. Ley, Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol, 2009. 27: p. 165-97.
50. Hinglais, N., et al., Colocalization of myocardial fibrosis and inflammatory cells in rats. Lab Invest, 1994. 70(2): p. 286-94.
51. Nicoletti, A., et al., Inflammatory cells and myocardial fibrosis: spatial and temporal distribution in renovascular hypertensive rats. Cardiovasc Res, 1996. 32(6): p. 1096-107.
52. Komatsu, S., et al., Effects of chronic arterial hypertension on constitutive and induced intercellular adhesion molecule-1 expression in vivo. Hypertension, 1997. 29(2): p. 683-9.
193
53. Nicoletti, A. and J.B. Michel, Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors. Cardiovasc Res, 1999. 41(3): p. 532-43.
54. Vaziri, N.D., Causal link between oxidative stress, inflammation, and hypertension. Iran J Kidney Dis, 2008. 2(1): p. 1-10.
55. Kai, H., et al., Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res, 2005. 28(6): p. 483-90.
56. Hernandez-Presa, M., et al., Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation, 1997. 95(6): p. 1532-41.
57. Frangogiannis, N.G., et al., Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation, 2007. 115(5): p. 584-92.
58. Ishibashi, M., et al., Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling. Circ Res, 2004. 94(9): p. 1203-10.

Image Designed by Freepik

Leave a Reply

Your email address will not be published. Required fields are marked *