Chronic inflammatory diseases, myocardial function and cardioprotection

Abstract

The association between chronic inflammatory diseases (CIDs) and increased cardiovascular (CV) risk is well documented and can be a most threatening complication in these patients. However, the pathogenetic mechanisms underlying increased CV risk remain elusive, especially in their cellular and biochemical pathways. Using animal models to understand mechanisms underlying cardiac involvement are limited. Additionally, treatments may influence cardiovascular events through different outcomes. Some drugs used to treat CIDs can negatively affect cardiac function by a direct toxicity, whereas others may protect the myocardium. In the present article, we focus on the cardiac manifestations and risk factors, the pathogenetic mechanisms, and the effect of treatments on myocardial function and cardioprotection for five common worldwide CIDs (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, psoriasis and inflammatory bowel disease). We also give recommendations in order to evaluate common targets between CID and CV disease (CVD) and to design therapies to alleviate CID‐related CVD.

LINKED ARTICLES

This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc

Abbreviations

CAD

coronary artery disease

CCTA

coronary CT angiography

CD

Crohn's disease

CIDs

chronic inflammatory diseases

CV

cardiovascular

CVD

cardiovascular disease

CXCR

chemokine C‐X‐C motif receptor

DMARD

disease‐modifying antirheumatic drugs

ECs

endothelial cells

IBD

inflammatory bowel disease

IHD

ischaemic heart disease

MVD

microvascular dysfunction

PTP‐PEST

tyrosine‐protein phosphatase non‐receptor type 12

RA

rheumatoid arthritis

SLE

systemic lupus erythematosus

SSc

systemic sclerosis

TC

total cholesterol

Th1

T helper cell type 1

Th17

T helper cell type 17

UC

ulcerative colitis

1. INTRODUCTION

Chronic inflammatory systemic diseases like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic multiple sclerosis are a heterogeneous group of disorders characterized by an excessive immune response due to the interaction between predisposing genetic factors, dysregulation of the immune system and environmental factors. The association of increased cardiovascular (CV) risk with chronic inflammatory conditions is well recognized and can be one of the most threatening complications in these patients (Mason & Libby, 2015). The manifestations vary by disease and all structures in the heart can be affected resulting in significant morbidity and mortality (Hollan et al., 2013; Roifman, Beck, Anderson, Eisenberg, & Genest, 2011). Traditional CV risk factors such as hypertension, dyslipidaemia, aging and smoking do not fully account for the increased CV risk in these patients and the disease is likely an independent risk factor.

Although the role of systemic inflammation in the development of premature atherosclerosis, ischaemic heart disease (IHD) and heart failure in these patients has been demonstrated, and immune mechanisms shared by CV and systemic inflammatory diseases have been identified, the pathogenetic mechanisms underlying increased CV risk in patients with chronic inflammatory disorders still remain elusive, especially in their cellular and biochemical pathways. The heart can be damaged either directly by a localized autoimmune process involving deposition of immune complexes and activation of the complement system leading to functional impairment of various cardiac structures or indirectly by the general chronic inflammation induced by other injured organs. In this respect, chronic inflammation has been suggested as an important contributing factor to the development of atherosclerotic disease, ultimately leading to myocardial infarction in patients with chronic inflammatory diseases (CIDs; Mason & Libby, 2015). In addition, disease treatments may precipitate CV events, although this is rather complex. Some drugs used to treat chronic inflammatory diseases can, sometimes, negatively affect cardiac function by a direct toxicity (such as antimalarials, glucocorticoids and non‐steroidal anti‐inflammatory drugs) or by worsening a pre‐existing cardiac disease. On the other hand, other drugs (such as methotrexate) may represent paradigms of potential treatments for CV disease (CVD) co‐morbidities (Mangoni, Zinellu, Sotgia, Carru, & Erre, 2017).

In this review, we aim to describe the cardiac manifestations and the pathophysiology of CV involvement in the most frequent chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). In addition, we discuss the contribution of inflammatory disorders as potential CV risk factors and the role of treatment in chronic inflammatory disease patients.

Published articles for inclusion in this narrative review were sourced from the authors' record of papers on atherosclerosis and chronic inflammatory diseases, collected from January 2000 to August 2019, as well as from PubMed searches with the terms “rheumatoid arthritis,” “systemic lupus erythematosus,” “systemic sclerosis,” “psoriasis,” “inflammatory bowel disease,” “myocardial,” cardiovascular,” and “cardioprotection” in particular those papers presenting comprehensive reviews or meta‐analyses, plus in vivo studies and clinical trials on the aforementioned chronic inflammatory diseases that associate with CVD and cardioprotection.

2. RHEUMATOID ARTHRITIS

2.1. Cardiac manifestations and risk factors

Rheumatoid arthritis is a common autoimmune disease characterized by synovial inflammation, autoantibody production (rheumatoid factor and anti‐citrullinated protein antibody), joint deformity, and systemic features and affects 1% of the general population (McInnes & Schett, 2011). Patients with rheumatoid arthritis have increased risk of developing heart disease from both ischaemic and non‐ischaemic causes in comparison with the general population (Meune, Touze, Trinquart, & Allanore, 2009). Common CV manifestations include pericarditis (Voskuyl, 2006), myocardial dysfunction (Hurd, 1979), valvular heart disease (Roldan, DeLong, Qualls, & Crawford, 2007), atherosclerosis (Aubry et al., 2007; Chung et al., 2005; Ikonomidis, Makavos, et al., 2019; Maradit‐Kremers et al., 2005) and increased aortic stiffness and dysfunction of the coronary microcirculation (Roldan, 2008; Table 1).

TABLE 1.

Main manifestations of cardiac involvement in chronic inflammatory diseases

Cardiovascular manifestations	Chronic inflammatory disease
	Rheumatoid arthritis	Systemic lupus erythematosus	Systemic sclerosis	Psoriasis	Inflammatory bowel disease
Acute myocardial infarction		✓	✓		✓
Aortic root dilation/regurgitation	✓
Aortic stiffness	✓			✓
Arterial stiffness					✓
Atherosclerosis	✓	✓	✓	✓	✓
Coronary artery disease		✓	✓
Coronary microcirculation dysfunction	✓			✓
Fibrosis			✓
Heart failure	✓				✓
Ischaemic heart disease					✓
LV hypertrophy			✓
Microvascular dysfunction			✓
Myocarditis					✓
Pericarditis	✓				✓
Peripheral arterial disease		✓
Pulmonary arterial hypertension			✓
Stroke		✓	✓
Systolic/diastolic dysfunction	✓		✓	✓
Valvular heart disease	✓

Although co‐morbidities affecting CV and respiratory system occur twice as often in rheumatoid arthritis patients (Batko et al., 2019), these patients display an increased risk of heart failure independent of traditional CV risk factors (del Rincon, Williams, Stern, Freeman, & Escalante, 2001; Maradit‐Kremers et al., 2005). Systemic inflammation plays a pivotal role in the atherosclerotic process in rheumatoid arthritis (Chung et al., 2005) and the amount of systemic inflammation and immune dysregulation are major risk factors at least partly responsible for CVD burden in rheumatoid arthritis patients.

There is a “paradoxical” relation between serum lipid levels and CV risk in rheumatoid arthritis. Patients with high disease activity have lower total cholesterol (TC) and LDL values compared with the general population, while the CV risk is increased (Myasoedova et al., 2011). Moreover, HDL levels are also reduced, whereas triglycerides levels are elevated compared to healthy controls. Therefore, TC/HDL ratio is a better CV risk predictor in rheumatoid arthritis than individual lipid levels (Toms et al., 2011).

2.2. Pathogenetic mechanisms

The pathophysiology of rheumatoid arthritis involves inflammatory mediators, including cytokines such as TNF‐α and IL‐1, IL‐6, IL‐12, IL‐15, IL‐17, IL‐18 and IL‐23. These are released by type 1 helper (Th1) and type 17 helper (Th17) T cells and dendritic cells (McInnes & Schett, 2011) and may induce endothelial dysfunction, accelerated atherosclerosis and atheromatous plaque instability or even have a negative inotropic action (Choy, 2012; Ikonomidis et al., 2008; Liang et al., 2009; Sattar & McInnes, 2005). Furthermore, cytokines such as IL‐1 may cause myocardial dysfunction through impairment of mitochondrial function, generation of nitro‐oxidative stress with increased production of intracellular ROS, inducible NO synthase, peroxynitrite and induction of cytokines with negative inotropic action such as IL‐6 (Ikonomidis et al., 2008, 2014). Apoptosis has a crucial role in the development of myocardial dysfunction in the setting of high inflammatory activity in rheumatoid arthritis.

In an animal model of inflammatory arthritis, designated as SKG mice, changes in the number and phenotype of cardiac immune cells were observed both before and after myocardial infarction which likely influences cardiac repair and ventricular remodelling post‐myocardial infarction, contributing to detrimental cardiac outcomes with inflammatory arthritis (Hsieh et al., 2017). Furthermore, an acquired form of cardiomyopathy was shown in collagen antibody‐induced arthritis mouse model, which mimics human rheumatoid arthritis. The heart displayed molecular and functional maladaptation including hypertrophy and increased fibrotic deposition, impaired cardiomyocyte Ca²⁺ signalling, mildly reduced cardiac contractility and oxidation‐dependent modification of important Ca²⁺ handling proteins, which resulted in long‐lasting cardiac remodelling and impaired contractile function (Pironti et al., 2018).

The main molecular pathogenetic mechanisms involved in cardiac manifestations in rheumatoid arthritis are shown in Figure 1.

FIGURE 1.

Main pathogenetic mechanisms of cardiovascular involvement by different chronic inflammatory diseases. ACPA, anti‐citrullinated protein antibody; ADMA, asymmetric dimethylarginine; ICAM‐1, intercellular adhesion molecule 1; MVD, microvascular dysfunction; RF, rheumatic factor; VCAM‐1, vascular cell adhesion molecule

2.3. Effect of rheumatoid arthritis treatment on myocardial function and cardioprotection

Treatment of rheumatoid arthritis aims towards the suppression of disease activity and reduction of CV risk by decrease of systemic inflammation. Mainstays of rheumatoid arthritis treatment are corticosteroids, disease‐modifying antirheumatic drugs (DMARDs; e.g. methotrexate) and cytokine inhibitors (e.g. anti‐TNF‐α, anti‐IL‐1 and anti‐IL‐6 agents). The effects of these agents on cardiac disease observed in rheumatoid arthritis are summarized in Table 2. Both methotrexate and TNF‐α antagonists have been associated with a cardioprotective effect due to suppression of systemic inflammation (Barnabe et al., 2011; Lee et al., 2018; Micha et al., 2011; Roubile et al., 2015). These studies have shown prospectively that biological agents reduce the number of adverse cardiac events while this response was not observed in those patients that ceased biological agents during follow‐up (Lee et al., 2018). A beneficial effect on myocardial and vascular function has been also indicated after treatment with cytokine inhibitors (Ikonomidis et al., 2008, 2014, 2009). Anti‐IL‐1 regimens seem to have a more favourable profile on myocardial function when compared to anti‐IL‐6 regimens, whereas anti‐IL‐6 regimens mostly benefit vascular function (Ikonomidis, Pavlidis, et al., 2019). In addition, two recent meta‐analyses indicated that tocilizumab (an anti‐IL‐6 agent) is safe in terms of CV outcomes compared to disease‐modifying antirheumatic drugs (Castagné et al., 2019) and may also be associated with decreased risk of major adverse cardiovascular events in comparison to TNF‐α inhibitors (Singh et al., 2019).

TABLE 2.

Effects of currently used medication for chronic inflammatory diseases on cardiac manifestations

Inflammatory disease	Drug	Effect on CV outcome
		Clinical studies	Experimental studies and underlying mechanisms
Rheumatoid arthritis (RA)	Anti‐IL‐1 (Anakinra)	Improvement of vascular and left ventricular function in RA patients (Ikonomidis et al., 2008) Improvement of myocardial deformation in RA patients (Ikonomidis et al., 2009) Improvement of vascular function, myocardial deformation, and twisting in CAD patients with RA (Ikonomidis et al., 2014)
	Anti‐IL‐6 (Tocilizumab)	Improvement of vascular function in RA patients (Ikonomidis, Pavlidis, et al., 2019) Decreased risk of major adverse CV events (non‐fatal MI, need for coronary revascularization, cardiovascular death with or without angina, CHF, peripheral artery disease, or abdominal aortic aneurysm) in RA patients (Singh et al., 2019)
	Anti‐TNF‐α	Reduced risk of CV events including MI in RA patients (Barnabe, Martin, & Ghali, 2011) Reduced risk of major CV events (defined as angina, MI, coronary artery bypass graft, PCI, other heart disease, stroke/transient ischaemic attack, or death from cardiovascular causes) in patients with inflammatory arthritis including RA (Lee et al., 2018)
	Auranofin		Reduction of infarct size and improved cardiac function after I/R likely via PTP‐PEST‐ErbB‐2 signalling axis in an in vivo model of AMI in mice (Yang et al., 2019)
	Methotrexate	Reduction of CV events in RA patients (Micha et al., 2011; Roubile et al., 2015)
Systemic Lupus Erythematosus (SLE)	Antimalarials (chloroquine and hydroxychloroquine)	Antimalarial‐induced cardiomyopathy in SLE patients (Tselios et al., 2016; Tselios et al., 2019)	Conferred atheroprotection through a p53‐dependent mechanism in atherosclerosis‐prone ApoE‐null mice (Razani, Feng, & Semenkovich, 2010) Improved NO‐mediated vasorelaxation of mesenteric arteries in a murine model of SLE (Virdis et al., 2015) Reduced heart rate and LV pressure in Langendorff perfused rat hearts and exerted cardiotoxic effects in isolated cardiomyocytes (Blignaut, Espach, van Vuuren, Dhanabalan, & Huisamen, 2019) Reduce pressure overload‐induced cardiac hypertrophy but impaired cardiac relaxation and contractility in rats (Chaanine et al., 2015)
	Glucocorticoids	Deleterious effects in heart and vessels in patients with SLE (Wu et al., 2016)
	Immunosuppressants (mycophenolate mofetil)		Attenuation of atherosclerosis in lupus‐prone mice (van Leuven et al., 2012)
	Methotrexate		Reduction of cardiac vasculopathy via activation of AMPK‐CREB in murine model of inflammatory vasculopathy (Thornton et al., 2016)
Systemic sclerosis (SS; lacks a specific therapy)	Nintedanib (inhibitor of GF‐RTKs)		Antifibrotic effects and amelioration of histological features of pulmonary arterial hypertension, microangiopathy and pulmonary fibrosis in Fra2 mouse model of SS (Huang et al., 2017)
Psoriasis	Anti‐IL‐12/23 (ustekinumab)	Improvement of coronary microcirculatoy function, arterial stiffness, and myocardial function in psoriasis patients—greater improvement than Anti‐TNF‐α or cyclosporine treatment (Ikonomidis et al., 2017) Reduction of aortic vascular inflammation with reduction in inflammatory cytokines associated with CV disease in psoriasis patients (Gelfand et al., 2019)
	Anti‐IL‐17A (secukinumab)	Improvement of vascular and myocardial function in psoriasis patients—greater improvement than methotrexate or cyclosporine treatment (Makavos et al., 2019) Improvement of arterial flow‐mediated dilation in psoriasis patients suggesting beneficial effects on CV risk by improving endothelial function (von Stebut et al., 2019)
	Anti‐TNF‐α (etanercept),	Improvement of cardiac function in psoriasis patients (Ikonomidis et al., 2017)
	Anti‐TNF‐α	Reduced risk of major CV events (angina, MI, coronary artery bypass graft, PCI, other heart disease, stroke/transient ischaemic attack, or death from cardiovascular causes) in patients with inflammatory arthritis including psoriasis (Lee et al., 2018)
	Cyclosporine	Improvement of cardiac function in psoriasis patients (Ikonomidis et al., 2017)
	Diverse biological therapies (anti‐TNF‐α, anti‐IL‐12/23, or anti‐IL‐17)	Reduction of coronary inflammation (indicated by reduction of perivascular fat attenuation index) in psoriasis patients (Elnabawi, Oikonomou, et al., 2019) Reduction of non‐calcified plaque burden in psoriasis patients suggesting beneficial modulation of coronary plaque composition (Elnabawi, Dey, et al., 2019)
	Methotrexate	Improvement of vascular and myocardial function in psoriasis patients (Makavos et al., 2019)
	NF‐κB inhibitor (dimethyl fumarate)		Reduction of myocardial infarct size after I/R in rats in vivo likely through inhibition of NF‐κB in cardiac endothelial cells (Meili‐Butz et al., 2008)
Inflammatory bowel disease (IBD)	5‐Aminosalicylic acids	Decreased risk of IHD in IBD patients (Rungoe et al., 2013)
	6‐Mercaptopurine		Induction of calcium deposition in in vitro cultured vascular smooth muscle cells and in ex vivo media layer of rat aorta rings which might accelerate the evolution of arteriosclerosis and CVD (Prüfer et al., 2014)
	Anti‐TNF‐α	Non‐significant decrease of IHD in IBD patients (Rungoe et al., 2013)
	Azathioprine + aminosalicylates	Lower risk of CVD (calculated by Framingham Risk Score, a gender‐specific algorithm for estimating the 10‐year CV risk) in comparison to aminosalicilates only, and increased anti‐inflammatory cytokines in women with ulcerative colitis (UC; dos Santos et al., 2015)

Abbreviations: AMI, acute myocardial infarction; AMPK, AMP‐activated protein kinase; ApoE, apolipoprotein E; CREB, cAMP response element‐binding protein; CHF, congestive heart failure; CV, cardiovascular; Fra2, fos‐related antigen‐2; GF, growth factor; IHD, ischaemic heart disease; PTP‐PEST, tyrosine‐protein phosphatase non‐receptor type 12; RTK, receptor tyrosine‐kinases.

As far as the lipid control is concerned, management of disease activity (mainly by methotrexate or anti‐TNF‐α agents) results in an overall increase of serum lipids, mainly of HDL, with a neutral effect (Daïen et al., 2012) or even improvement of the TC/HDLc ratio (Navarro‐Millán et al., 2013). Early aggressive treatment of inflammation in rheumatoid arthritis with methotrexate monotherapy or combination therapies including anti‐TNF‐α improves the atheroprotective composition of HDL (Charles‐Schoeman et al., 2017). Statins have been proved effective in the reduction of cholesterol, atherosclerotic burden, CV events and cumulative mortality in rheumatoid arthritis patients (Schoenfeld et al., 2016), whereas combination of their anti‐inflammatory properties when co‐administered with non‐steroidal anti‐inflammatory drugs and disease‐modifying antirheumatic drugs may improve inflammation and serum lipid profile (McCarey et al., 2004) and may result in an incremental CV risk reduction (Lv et al., 2015).

Data on the effect of treatment for rheumatoid arthritis on cardioprotection are scarce. Very recently, it has been demonstrated that Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis reduces infarct size and results in better cardiac function when it is administered in mice before reperfusion. The potential underlying mechanism may involve the protein tyrosine phosphatases (PTP)‐PEST‐ErbB‐2 signalling axis (Yang et al., 2019). In a mouse model of adjuvant‐induced arthritis, which mimics RA in humans, ischaemic preconditioning did not result in a significant reduction of myocardial necrosis area induced by 30 min of ischaemia and 60 min of reperfusion (Wojciechowska et al., 2013). This effect might be associated with the presence of chronic systemic inflammation in these animals. The reduced benefits of ischaemic preconditioning may be one reason for the increased CV risk in patients with rheumatoid arthritis. However, to the best of our knowledge, there are no other studies that have investigated the effects of rheumatoid arthritisin conditioning cardioprotective mechanisms of the myocardium.

In summary, there is a clear correlation between rheumatoid arthritis and myocardial function mainly through increased inflammation, oxidative stress and apoptosis. However, since the majority of anti‐inflammatory cardioprotective strategies have failed in the clinical setting mainly because these drugs are directed to a particular cytokine (reviewed in detail in Andreadou et al., 2019), studies in clinically relevant animal rheumatoid arthritis models need to be performed, in order to investigate if rheumatoid arthritis interferes with the conditioning cardioprotective mechanisms.

3. SYSTEMIC LUPUS ERYTHEMATOSUS

3.1. Cardiac manifestations and risk factors

Systemic lupus erythematosus is a chronic autoimmune disease characterized by high levels of antinuclear antibodies in the serum and the most specific clinical features are skin rash and glomerulonephritis (Larosa, Iaccarino, Gatto, Punzi, & Doria, 2016). According to a recent review of epidemiological data, systemic lupus erythematosus prevalence displays an increasing trend over the last decades (Rees, Doherty, Grainge, Lanyon, & Zhang, 2017) with the female population being affected much more frequently compared with males. However, regardless of the sex, there is a strong correlation between systemic lupus erythematosus and CVD development, which represents one of the main reasons of morbidity and mortality among systemic lupus erythematosus patients (O'Sullivan, Bruce, & Symmons, 2016). Coronary heart disease, acute myocardial infarction, ischaemic stroke and peripheral arterial disease (Arkema, Svenungsson, Von Euler, Sjöwall, & Simard, 2017; Chuang et al., 2015; Hak, Karlson, Feskanich, Stampfer, & Costenbader, 2009) are among the main CV complications in systemic lupus erythematosus (Table 1).

Traditional along with disease‐specific risk factors might be considered for understanding the increased CVD risk in SLE. Hypertension, dyslipidaemia and diabetes are more common in systemic lupus erythematosus patients than controls (Bruce, Urowitz, Gladman, Ibañez, & Steiner, 2003). Related to this, metabolic syndrome and an exacerbated inflammatory state, measured as C‐reactive protein plasma levels, are also more prevalent in systemic lupus erythematosus compared with the general population (Chung et al., 2007). But traditional factors alone do not explain the higher CVD incidence. All these factors converge into atherosclerosis, which appears to be more frequent among systemic lupus erythematosus patients, similar to other autoimmune disorders, but with a more accelerated progression (Tektonidou et al., 2017).

3.2. Pathogenetic mechanisms

Although the pathogenic mechanisms of accelerated atherosclerosis remain unclear, possible explanations have been proposed. Such putative mechanisms have been recently reviewed elsewhere (Liu & Kaplan, 2019). Certainly, high BP, dyslipidaemia and other traditional risk factors contribute to the primary lesion of the intima layer, endothelium activation and plaque formation. However, specific disease factors seem to be responsible for the remarkable endothelial damage‐repair imbalance manifested in systemic lupus erythematosus. Reflecting this profound imbalance, circulating endothelial progenitor cells able to repair endothelial damage are decreased in systemic lupus erythematosus patients (Moonen et al., 2007). In contrast, circulating apoptotic endothelial cells (ECs) are increased, probably linked to the impairment of NO vasorelaxation pathway (Rajagopalan et al., 2004). Evidence suggests that IFN‐α, secreted by plasmacytoid dendritic cells located in plaques, plays a central role in this disequilibrium, contributing to endothelium and platelet activation, diminished EC differentiation (Thacker et al., 2012), impaired endothelium‐dependent vasorelaxation (Buie, Renaud, Muise‐Helmericks, & Oates, 2017), foam cell maturation, and plaque destabilization (Li et al., 2011). Likewise, a systemic lupus erythematosus special kind of neutrophil encountered in plaques, the low‐density granulocyte, could provoke EC death through enhanced metalloproteinase externalization (Carmona‐Rivera, Zhao, Yalavarthi, & Kaplan, 2015). In addition, chemokine receptor (CXCR) 3 expressed in CD4⁺T cells as well as CXCR ligands are increased in both SLE patients and animal models, and such levels correlate with the thickness of the internal carotid wall and plaque formation (Clement et al., 2015). Autoantigenic antibodies, which are the hallmark of systemic lupus erythematosus, are implied in the first term in plasmacytoid dendritic cell activation leading to an unspecific amplification of the humoral immune response, thus establishing a feedforward loop (Döring et al., 2012). Together, endothelial dysfunction and chronic inflammation may ultimately lead to the observed accelerated progression of atherosclerosis in systemic lupus erythematosus. Finally, an example of the synergistic effect of traditional and disease‐specific CVD risk factors is the case of systemic lupus erythematosus patients with metabolic syndrome. These patients have reduced circulating endothelial progenitor cells, higher plasmatic pro‐inflammatory cytokines levels and more pronounced arterial stiffness, when compared to systemic lupus erythematosus patients without metabolic syndrome (Castejon et al., 2016). The main pathogenetic molecular mechanisms that are involved in CVD manifestations in systemic lupus erythematosus are illustrated in Figure 1.

Various mouse models have been developed to dissect the cellular and genetic mechanisms of systemic lupus erythematosus, to identify therapeutic targets and to screen treatments (Li, Titov, & Morel, 2017). However, apart from an early study demonstrating multiple small infarcts in mice with systemic lupus erythematosus and small coronary artery disease (CAD; Yoshida, Fujiwara, Fujiwara, Ikehara, & Hamashima, 1987), there are no studies focusing on cardiac manifestations in these animal models.

3.3. Effect of systemic lupus erythematosus treatment on myocardial function and cardioprotection

Medication in systemic lupus erythematosus may contribute to the observed CVD in these patients (Table 2). Current treatment for systemic lupus erythematosus encompasses antimalarials, glucocorticoids, immunosuppressive and biological agents (Fanouriakis et al., 2019). Widely used antimalarials exhibit contradictory effects regarding CVD. In mice, chloroquine confers atheroprotection through a p53‐dependent process (Razani et al., 2010), while in humans it does not reduce the carotid intima‐media layer thickness (McGill et al., 2019). More specifically, in a murine model of systemic lupus erythematosus, hydroxychloroquine safeguards endothelial integrity, thus restoring vasorelaxation mediated by NO in mesenteric arteries (Virdis et al., 2015). Furthermore, although hydroxychloroquine‐induced cardiomyopathy is considered to be extremely rare (Yogasundaram et al., 2014), there are recent claims that antimalarial cardiotoxicity may be underdiagnosed and suggest a causal link between antimalarials and cardiomyopathy in systemic lupus erythematosus (Tselios et al., 2016; Tselios et al., 2019). Even a single high dose of chloroquine significantly reduces heart rate and left ventricular pressure in an ex vivo rat model, in the absence of mitochondrial damage (Blignaut et al., 2019). Hydroxychloroquine and chloroquine toxicity is understood in terms of lysosomal accumulation, hydrolase inhibition, enhanced lysosomal storage and impaired autophagy that culminates in degenerated mitochondria, left ventricle hypertrophy and fibrosis (Chaanine et al., 2015).

Concerning glucocorticoids in systemic lupus erythematosus, evidence is more straightforward showing deleterious side effects in heart and vessels (Wu et al., 2016) and clinicians agree in minimizing or withdrawing glucocorticoid dosage whenever it is possible (Fanouriakis et al., 2019). Cumulative doses of steroids, consumed as systemic lupus erythematosus treatment, strongly correlate with carotid plaque formation and carotid intima‐media thickness increase (Wu et al., 2016). Other immunosuppressive agents such as mycophenolate mofetil and methotrexate have been shown to reduce atheromatous plaque formation (van Leuven et al., 2012) and cardiac vasculopathy (Thornton et al., 2016) in systemic lupus erythematosus‐prone and inflammatory vasculopathy mice models respectively.

In summary, CVD is a major cause of morbidity and mortality in systemic lupus erythematosus. Together, traditional and disease‐related factors synergistically act to produce arterial intima layer damage, inflammation, atherosclerosis and subsequent CVD. Pro‐inflammatory factors play a key role in accelerated atherosclerosis progression of systemic lupus erythematosus, although the precise mechanisms are not fully understood. Current treatment of systemic lupus erythematosus could either exacerbate or counteract CVD. Further research is necessary in order to identify common targets of systemic lupus erythematosus and CVD that may lead to novel therapeutic strategies.

4. SYSTEMIC SCLEROSIS

4.1. Cardiac manifestations and risk factors

Systemic sclerosis is a multi‐systemic immune‐mediated disorder characterized by excessive fibrosis of the skin and internal organs (Spethman et al., 2014). As shown in Table 1, patients with systemic sclerosis present various types of CV complications, ranging from subclinical atherosclerosis, LV hypertrophy and diastolic dysfunction to acute coronary syndromes even in the absence of significant coronary artery stenosis (Au et al., 2011; Chu et al., 2013; Derk & Jimenez, 2007; Spethman et al., 2014; Ungprasert et al., 2014). In parallel, they exhibit significant microvascular dysfunction (MVD) which is responsible for multiple manifestations of this disease, such as Raynaud phenomenon, pulmonary artery hypertension or renal sclerosis (Faccini, Kaski, & Camici, 2016).

Contribution of traditional CV risk factors to CAD is small in systemic sclerosis, whereas there is independent involvement of chronic inflammatory disease contributing to endothelial dysfunction and atherosclerosis (Kakuta et al., 2015).

4.2. Pathogenetic mechanisms

Chronic systemic inflammation, a critical component of atherosclerosis, is present in systemic sclerosis and has been demonstrated to be associated with a significant degree of endothelial dysfunction (Ungprasert et al., 2014). Therefore, it is very likely that systemic sclerosis patients, who exhibit increased inflammation and endothelial dysfunction, are predisposed to development of atherosclerotic lesions. High concentrations of TNF‐α or IL‐6 contribute to the development of accelerated atherosclerosis and promote endothelial dysfunction, which is proved by elevated serum levels of endothelial injury biomarkers, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1 or VEGF (Faccini et al., 2016). At the same time, patients with systemic sclerosis exhibit an underlying coronary microvascular dysfunction, which may precede coronary atherosclerosis after many years, being correlated with a systemic inflammatory response (Faccini et al., 2016). Inflammation‐related microvascular dysfunction at the level of coronary arteries may be responsible for myocardial ischaemia in the absence of obstructive CAD, a frequent observation in systemic sclerosis patients. At the level of coronary circulation, microvascular dysfunction can lead to an increased rate of major CV events via complex mechanisms that involve endothelial dysfunction and increased platelet aggregation.

Contraction band myocardial necrosis resulting from ischaemia and myocardial fibrosis are the most common pathological findings at necropsy in patients with systemic sclerosis who suffered a cardiac death. Myocardial inflammation was also documented in systemic sclerosis patients by histological and MRI studies, who found a significantly higher amount of scar in systemic sclerosis patients as compared to controls (P < .0001), which followed a diffuse distribution pattern (Mavrogeni et al., 2015).

In summary, all these observations prove that chronic systemic inflammation and fibrosis play a pivotal role in initiation and progression of cardiac manifestations in systemic sclerosis (Figure 1).

4.3. Effect of systemic sclerosis treatment on myocardial function and cardioprotection

As systemic sclerosis is a clinically heterogeneous disease affecting multiple organ systems, the optimal treatment of this disease remains a challenge. In present, there is no recommendation for any specific drug that would stop progression of the disease. However, consensus recommendations clearly address the major clinical conditions associated with systemic sclerosis. The European League Against Rheumatism Scleroderma Trials and Research group released an updated consensus recommendation for the treatment of systemic sclerosis, which is structured in six distinct recommendations, one for each organ specific involvement: dihydropyridine‐type calcium antagonists and i.v. prostanoids for severe systemic sclerosis‐related digital vasculopathy, PDE type 5 inhibitors for systemic sclerosis‐related Raynaud phenomenon or digital ulcers, endothelin receptor antagonists, prostacyclin analogues and PDE type 5 inhibitors for systemic sclerosis‐related pulmonary arterial hypertension, methotrexate for systemic sclerosis‐related skin involvement, cyclophosphamide for interstitial lung disease, angiotensin‐converting enzyme inhibitors for scleroderma renal crisis and proton pump inhibitors for gastrointestinal manifestations (Kowal‐Bielecka et al., 2017). While the consensus recommendations clearly address these clinical conditions associated with systemic sclerosis, there is no recommendation for any specific drug that would stop progression of this systemic disease.

There are very few studies using animal models to investigate the potential of some new drugs to treat systemic sclerosis‐related cardiac fibrosis (Table 2). For instance, Fra‐2 transgenic mice were demonstrated to represent a suitable preclinical model for the study of systemic sclerosis‐related cardiomyopathy, resembling the clinical manifestations of systemic sclerosis and developing systemic fibrotic disease, systemic sclerosis‐like microvascular disease and pulmonary arterial hypertension (Huang et al., 2017; Venalis et al., 2015). Using this animal model, it has been demonstrated that Nintedanib, an inhibitor targeting growth factor receptor TK, exerts antifibrotic effects and ameliorates histological features of pulmonary arterial hypertension, microangiopathy and pulmonary fibrosis (Huang et al., 2017). However, human studies with Nintedanib have been reported only for lung diseases, while CV effects of this drug have not been tested yet in clinical applications.

In conclusion, systemic sclerosis is a highly heterogenous inflammatory disease which lacks a specific therapy that would stop its progression. The treatment of systemic sclerosis is currently focused on organ specific complication. Preclinical studies using murine models show promising results of several recent therapies on systemic sclerosis‐related cardiomyopathy, mainly based on their anti‐fibrotic effect and should be further tested in clinical trials.

5. PSORIASIS

5.1. Cardiac manifestations and risk factors

Psoriasis is an immune‐mediated disease affecting up to 3% of the adult general population characterized by skin lesions, arthritis in 10% of patients, and systemic manifestations (Gelfand et al., 2005). Main CV complications are summarized in Table 1 and include increased prevalence of atherosclerosis, increased aortic stiffness, coronary microcirculatory dysfunction and impaired myocardial function (Ikonomidis et al., 2015; Kimball et al., 2008; Ogdie et al., 2015).

Increased rates of risk factors such as hypertension, diabetes, dyslipidaemia and obesity in patients with psoriasis have been reported (Tam et al., 2008). Patients with psoriatic arthritis are at higher CV risk compared to plaque‐type psoriasis alone; thus, CVD risk assessment is recommended for all patients with psoriatic arthritis at least once every 5 years and should be reassessed following major changes in antirheumatic therapy (Agca et al., 2017).

5.2. Pathogenetic mechanisms

Psoriasis and CVD share common pathophysiological mechanisms, including inflammation, oxidative stress and common genetic susceptibility (Ogdie et al., 2015). Figure 1 summarizes the main pathophysiological molecules that link psoriasis with CVD.

Chronic inflammation is important in the development of both psoriasis and atherosclerosis with the involvement of inflammatory mediators such as TNF‐α, IL‐1β, IL‐6, IL‐12, IL‐17, IL‐22 and IL‐23, released primarily by activated dendritic cells and Th1 and Th17 lymphocytes (Prinz, 2010; Reich, 2012; Figure 2). Activated lymphocytes and high levels of circulating cytokines observed in psoriasis are responsible for endothelial inflammation and atheromatous plaque formation and rupture (Pryshchep, Sato, Goronzy, & Weyand, 2006). Several of these cytokines have been associated with myocardial and vascular dysfunction including arterial stiffness (Pryshchep et al., 2006; Yong et al., 2013), coronary atherosclerosis (Zhang et al., 2006), left ventricular hypertrophy and cardiac remodelling (Madhur et al., 2010; Sheu et al., 2013) and myocardial ischaemia (Ikonomidis et al., 2005, 2017). IL‐17A, one of the main inflammatory mediators in psoriasis (Lockshin, Balagula, & Merola, 2018), has pro‐atherogenic action (Karbach et al., 2014) and has been detected in patients with acute coronary syndromes (Cheng et al., 2008). IL‐17 induces the expression of pro‐inflammatory cytokines (TNF‐α, IL‐1, and IL‐6) in keratinocytes and fibroblasts (Eid et al., 2009) and consequently promotes the differentiation of T helper 17 (Th17) cells responsible for IL‐17A release (Figure 2).

FIGURE 2.

Immune cells and cytokines implicated in the pathogenesis of psoriasis. Deregulation of innate immunity by genetic and/or environmental triggers results in the production of cytokines that activate myeloid dendritic cells. Activated dendritic cells present antigens and secrete mediators such as IL‐23 and IL‐12, leading to the differentiation of type 1 and type 17 helper T cells (Th17 and Th1). T cells, in turn, secrete mediators (e.g. TNF‐α, IL‐17 and IL‐22) that activate keratinocytes and induce the production of proinflammatory cytokines (TNF‐α, IL‐1 and IL‐6) which feed back into the proinflammatory disease cycle. At the same time, secreted proinflammatory cytokines and chemokines (TNF‐α and INF‐α) contribute to the formation of atheromatic plaque

Oxidative stress biomarkers such as malondialdehyde and protein carbonyls are increased in psoriasis and are associated with vascular and impaired coronary microcirculatory function (Ikonomidis et al., 2015). It has been indicated that the above‐mentioned biomarkers of oxidative stress are also implicated in atherosclerosis (Stocker & Keaney, 2004) and in autoimmune rheumatic diseases (Kaiser, Abdulla, Henningsen, Skov, & Hansen, 2019).

Additionally, compositional alterations of psoriatic HDL have been reported which lead to impairment of cholesterol efflux capacity of HDL. The functional impairment of HDL may contribute to the excess CV mortality of psoriatic patients and may provide a link between psoriasis and CVD (Holzer et al., 2012).

5.3. Effect of psoriasis treatment on myocardial function and cardioprotection

Mainstays of psoriasis treatment are corticosteroids, disease‐modifying antirheumatic drugs (e.g. methotrexate), cyclosporine and cytokine inhibitors (e.g. anti‐TNF‐α, anti‐IL‐12/23, and anti‐IL‐17 agents). Treatment with cytokine inhibitors seems to have a favourable profile on CV function in psoriasis patients (see Table 2 for details). Treatment with anti‐IL‐12/23 resulted in reduction of aortic vascular inflammation and a greater improvement of coronary microcirculatory function, arterial stiffness, and myocardial function compared to TNF‐α inhibition or cyclosporine treatment in psoriasis patients (Gelfand et al., 2019; Ikonomidis et al., 2017). Additionally, inhibition of IL‐17A resulted in a greater improvement of vascular and myocardial function compared with cyclosporine or methotrexate treatment, suggestive of a stronger beneficial effect on overall CV function in psoriasis (Makavos et al., 2019; von Stebut et al., 2019). Treatment with biological agents was associated with reduction of coronary inflammation indicated by significant reduction of perivascular fat attenuation index measured by coronary CT angiography (CCTA; Elnabawi, Oikonomou, et al., 2019). Moreover, in psoriasis patients, treatment with biological agents resulted in 6% reduction of non‐calcified plaque burden assessed by CCTA, suggestive of a beneficial modulation of coronary plaque composition (Elnabawi, Dey, et al., 2019). Thus, CCTA may be a useful tool to assess the burden of CAD and monitor response to anti‐inflammatory treatment.

Over the past decades, murine models of psoriasis have been developed as tools for understanding the pathogenesis of this disease. These models include transgenic mice, knockout mice, and reconstituted models of psoriasis (reviewed in Nakajima & Sano, 2018). As far as cardioprotection studies are concerned, dimethyl fumarate, a small molecule drug for psoriasis, has been shown to reduce myocardial infarct size in rats undergoing 45‐min ischaemia followed by 120 min of reperfusion probably through inhibition of nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) in cardiac endothelial cells (Meili‐Butz et al., 2008). Studies using the K5.Stat3C mouse, an animal model of psoriasis, demonstrated the clinical relevance of STAT3 targeting as a novel therapy for psoriasis (Nakajima & Sano, 2018). Taking into account that STAT3 activation is an important signalling cascade for cardioprotection (Andreadou et al., 2017), we may conclude that psoriasis may interfere with the cardioprotective conditioning mechanisms. However, to the best of our knowledge, cardioprotection studies in animal models of psoriasis have not been performed.

6. INFLAMMATORY BOWEL DISEASE

6.1. Cardiac manifestations and risk factors

Inflammatory bowel disease is a chronic inflammatory, immunological mediated disorder that comprises ulcerative colitis (UC) and Crohn's disease (CD). Crohn's disease is characterized by transmural inflammation of any part of the gastrointestinal tract, mainly at ileum and/or colon (Gajendran, Loganathan, Catinella, & Hashash, 2018), whereas in ulcerative colitis, mucosal inflammation occurs from rectum to colon (Gajendran et al., 2019). Aetiology is defined by a complex interplay of genetic and environmental factors, as well as gut microbiota and lifestyle (Ananthakrishnan, 2015).

Besides gastrointestinal symptoms, there has been recorded a wide plethora of extra‐intestinal manifestations of inflammatory bowel disease, including CVD (Harbord et al., 2016), which represents the main cause of death in both ulcerative colitis and Crohn's disease (Fumery et al., 2014). As shown in Table 1, inflammatory bowel disease patients present premature signs of subclinical atherosclerosis (Cappello et al., 2017) and increased risk of ischaemic heart disease (IHD), acute myocardial infarction and heart failure (Aniwan, Pardi, Tremaine, & Loftus, 2018; Feng et al., 2017; Fumery et al., 2014). Additional cardiac manifestations are arrhythmias and pericarditis and myocarditis (Mitchell, Harrison, Junga, & Singla, 2018).

Systemic chronic inflammation has been pointed out as responsible for the larger CVD incidence among inflammatory bowel disease patients. Related to this last statement, inflammatory bowel disease clinical activity correlates in a considerable manner with CVD and systemic inflammation, measured as plasmatic C‐reactive protein levels (Le Gall et al., 2018). Consequent to inflammation, a hypercoagulable state has been reported in inflammatory bowel disease, which associates to thrombosis and to a dramatically exacerbated mortality risk (Andrade et al., 2018).

6.2. Pathogenetic mechanisms

Presumed pathogenic mechanisms that lead to CVD in inflammatory bowel disease are here briefly reviewed. Damage to intestinal mucosa permits exposure of bacterial hyper‐acylated LPS to the circulation, thus enabling the system to mount a generalized inflammatory response (McDonnell et al., 2011). TNF‐α along with other released cytokines then targets endothelium, producing an impairment of vasorelaxation pathways and an increase in adhesion molecules that trigger leukocyte infiltration, both phenomena implicated in atherosclerosis initiation and progression (Steyers & Miller, 2014). Accordingly, the levels of the endothelium NO synthase inhibitor asymmetric dimethylarginine are higher in inflammatory bowel disease patients than in controls, and such increase correlates with platelet count and other inflammation parameters (Owczarek, Cibor, & Mach, 2010). Moreover, inflammatory bowel disease endothelium exhibits abnormally high levels of CD40 whereas soluble CD40 levels, produced by platelets, are also high in inflammatory bowel disease patients, reflecting an enhanced platelet activation state (Danese et al., 2003). This enhanced platelet activation state may conduce to the reported procoagulant state and thromboembolism (Andrade et al., 2018). Also, CD40–CD40L interaction produces the release of multiple inflammation mediators, some of them implied in the Th17 subset differentiation that characterizes Crohn's disease and ulcerative colitis inflammation (Iezzi et al., 2009; Ueno et al., 2018). Finally, as CD40 activation by its ligand promotes secretion of TNF‐α and that TNF‐α induces endothelial CD40 and adhesion molecules expression, a feedforward loop establishes with the aforementioned deleterious consequences to endothelial integrity seen in inflammatory bowel disease (Cibor et al., 2016; Danese et al., 2006). The major signalling molecules involved in CVD complications in inflammatory bowel disease are illustrated in Figure 1.

6.3. Effect of inflammatory bowel disease treatment on myocardial function and cardioprotection

First line therapy of ulcerative colitis patients consists in 5‐aminosalicylates for both maintaining remission and treating active disease. Corticosteroids are also effective inducing remission in ulcerative colitis mesalamine‐resistant patients as well as in Crohn's disease. Other inflammatory bowel disease therapies comprise immunosuppressive agents, namely, azathioprine, 6‐mercaptopurine, methotrexate, tacrolimus, cyclosporine A and more recently, antibodies, fusion proteins and small molecules (Su et al., 2019). 5‐Aminosalicylic acid improves lipid profile in mice fed with a high‐fat and high‐cholesterol diet, possibly due to PPARα and PPARγ up‐regulation (Wang & Bao, 2017). In addition, 5‐aminosalicylic acid also ameliorates the insulin resistance state of mice subjected to a high‐fat diet (Luck et al., 2015). In line with this, the risk of CVD is suggested to be lower among ulcerative colitis patients receiving azathioprine and salicylate‐based therapy compared with those treated only with salicylates (dos Santos et al., 2015). In contrast, 6‐mercaptopurine, a by‐product of azathioprine metabolism, induces calcium deposition in in vitro cultured vascular smooth muscle cells and in ex vivo media layer of rat aorta rings. These findings point out that 6‐mercaptopurine might accelerate the evolution of atherosclerosis and CVD (Prüfer et al., 2014). With respect to anti‐TNF‐α agents, a slight non‐significant decrease of ischaemic heart disease is observed in users when compared to non‐users in an inflammatory bowel disease patient's cohort study (Rungoe et al., 2013). More recently, anti‐TNF‐α agents, infliximab and adalimumab, were shown to lower plasma insulin levels and the homeostatic model assessment of insulin resistance index in inflammatory bowel disease patients. Hence, such drugs could reduce the risk of CVD (Paschou et al., 2018).

Different effects have been reported concerning the use of steroids as inflammatory bowel disease therapy. Corticosteroids have been associated with an increased risk of CV events in a Danish cohort of patients with inflammatory bowel disease (Rungoe et al., 2013). On the other hand, another study could not demonstrate differences in vascular parameters (carotid intima‐media thickness, carotid plaque, and aortic stiffness) among patients treated with steroids (Cappello et al., 2017). The association of steroid therapy and CVD may be related to the unfavourable long‐term side effects (diabetes, hypertension, and obesity) which represent well‐known CV risk factors (Welsh, Grassia, Botha, Sattar, & Maffia, 2017). The effects of drugs currently used for inflammatory bowel disease treatment on cardiac manifestations are summarized in Table 2.

In conclusion, CVD risk is significant in inflammatory bowel disease evolution, accounting as the main cause of death among ulcerative colitis and Crohn's disease patients. This fact cannot be explained by traditional risk factors for CVD, since inflammatory bowel disease patients display less frequency of such factors. In addition, most of the immunosuppressive agents currently used as inflammatory bowel disease treatment are associated with a reduced risk of CVD. However, systemic chronic inflammation in inflammatory bowel disease seems to lead to endothelial dysfunction, more inflammation, and a hypercoagulable state that might evolve into CVD, posing a life‐threatening situation to inflammatory bowel disease patients.

7. CONCLUSION

CV manifestations present a considerable burden for patients with chronic inflammatory diseases. Although atherosclerosis is a common chronic inflammatory disease manifestation among the different diseases, ultimately leading to myocardial infarction in patients with chronic inflammatory diseases (Mason & Libby, 2015), different and specific CVD manifestations also exist among the different types of chronic inflammatory diseases (Table 1). Additionally, the different chronic inflammatory diseases share common but also different signalling molecules responsible for the chronic inflammatory disease complications that are apparent in these patients (Figure 1). Therefore, there is still considerable need to expand understanding of the underlying pathogenesis of cardiac complications in patients with chronic inflammatory diseases in order to identify potential novel targets to treat these patients. Appropriate animal models mimicking the different diseases should be indispensable tool in the search of pathogenetic mechanisms, although it is conceivable that no single animal model perfectly mimics a human disease. A range of inducible and spontaneous mouse models of systemic autoimmune diseases is available for mechanistic and therapeutic studies (reviewed in Sanghera et al., 2019; McNamee, Williams, & Seed, 2015). However, despite the significant clinical relevance of cardiac manifestations in chronic inflammatory diseases, experimental studies using these animal models to understand mechanisms underlying cardiac involvement are limited. Additionally, and importantly, it should be noted that despite the relevance and translatability of animal models of chronic inflammatory diseases (reviewed in McNamee et al., 2015), studies on myocardial infarction in these animals are scarce. Therefore, translational studies in animal models should be conducted in order to identify common molecular targets between chronic inflammatory diseases and myocardial infarction.

Treatment for chronic inflammatory diseases also results in divergent results in the myocardium. Hence, appropriate management strategies that consider the increased risk of CV complications in patients with chronic inflammatory diseases are important. Such strategies should focus on the prediction of CVD risk and its management through targeting the molecular pathogenetic mechanisms of each disease and traditional CVD risk factors.

7.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019).

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Lazou A, Ikonomidis I, Bartekova M, et al. Chronic inflammatory diseases, myocardial function and cardioprotection. Br J Pharmacol. 2020;177:5357–5374. 10.1111/bph.14975