Ischemic heart disease (IHD) comprises a spectrum of diseases that are primarily related to the coronary arteries. It is the most common cause of death globally and is associated with significant morbidity ^[1][78]. While traditionally considered synonymous with atherosclerotic disease, we are now beginning to understand the complexities in its pathophysiology beyond just chronic plaque buildup. It is pointed out that inflammation is one branch of the intricate pathway network that has started gathering traction among several investigators.

Atherosclerosis involves the proliferation of smooth muscle cells, cholesterol deposition in the arterial walls, and infiltration of monocytes. These processes result in lesions that narrow blood vessels and restrict distal flow ^[2][79]. Being one of the most common diseases in the world, the link between atherosclerosis and pro-inflammatory cytokines has been quite well-characterized. Vascular smooth muscle cells are known to be a source of IL-6 ^[3][80], which has been shown to play an important role in atherosclerosis. In fact, IL-6 injection has been reported to cause significant increases in other pro-inflammatory cytokines, including IL-1β and TNFα, and early development of atherosclerotic lesions ^[4][81]. IL-6 mRNA transcripts and proteins were observed to be expressed in the atherosclerotic plaques and arterial walls in humans and rodents at higher rates than non-atherosclerotic artery tissue ^[2][5][6][7][79,82,83,84]. Apolipoprotein E (ApoE) and IL-6 double knockout mice were found to have significantly larger and more calcified arterial lesions and no difference in hypercholesterolemia compared to just ApoE knockout animals, and it was suggested that IL-6 expression is important in the formation of fibrous plaque of atheroma ^[8][85]. These findings were replicated by Schieffer et al. ^[9][86], who showed that IL-6/ApoE double knockout mice have significantly increased atherosclerotic lesions and proposed that IL-6 is important in vascular development, lipid homeostasis, and plaque inflammation.

Another study showed that IL-6 expression in plaques increases with age and lesion intensity in the isolated aortic rings of ApoE knockout mice ^[6][83]. While initially seeming contradictory, these studies reinforce the concept that IL-6 plays dual roles, being anti-inflammatory in some circumstances and pro-inflammatory in others. Clinically, higher circulating levels of IL-6 and C-reactive proteins were associated with increased all-cause mortality ^[10][11][87,88], and 6-month mortality was reduced in patients with high IL-6 levels who were given dalteparin therapy ^[11][88]. Patients with type 2 diabetes (T2DM) and macrovascular atherosclerosis showed higher levels of circulating IL-6 compared to patients with atherosclerosis and no diabetes, and in combination with levels of TNFα, were better at predicting atherosclerosis development in T2DM patients ^[12][89]. Patients with atherosclerosis also had higher levels of IL-6 in the blood than patients without atherosclerosis ^[12][13][89,90], and patients with unstable angina showed higher levels of circulating IL-6 than patients with stable angina ^[14][15][91,92]. IL-6 levels were also higher in patients with ischemic heart failure compared to simple coronary artery disease ^[16][93]. Unstable coronary disease patients with complicated hospital courses had higher IL-6 levels than patients with uneventful courses ^[17][94]. Coronary artery disease patients who were given an aerobic exercise program in rehabilitation showed reduced circulating levels of pro-inflammatory cytokines, including IL-6 ^[18][95]. Overall, it appears that while the complete lifetime absence of IL-6 leads to vascular maladaptation and reduced atherosclerosis in animal models, increased circulating IL-6 levels in patients are associated with the development and severity of atherosclerotic disease.

Both IL-1α and β are secreted by different cell types in the vascular wall, including smooth muscle cells and endothelial cells. When cultured with monocyte-derived IL-1 or human recombinant IL-1, smooth muscle cells produced biologically active IL-1 ^[19][105], indicating the presence of this cytokine can stimulate its own expression. Endothelial cells were also shown to produce IL-1 when given inflammatory stimuli such as endotoxin and TNFα ^[20][21][106,107]. IL-1 was observed to be crucial in initiating atherosclerosis in ApoE-deficient mice, as the administration of IL-1Ra significantly reduced fatty streak formation on arterial walls ^[22][23][108,109]. IL-1Ra knockout mice fed an atherogenic diet also had a trend of increased foam cell adhesion area compared to their wildtype littermates, and overexpressing IL-1Ra in LDLR knockout mice was observed to decreased foam cell adhesion area ^[24][110]. Aortic sinus atherosclerotic lesions were significantly reduced in ApoE and IL-1β double knockout mice compared to ApoE deficiency alone ^[25][111]. IL-1β treatment potentiates vasospasm in pig arteries and caused coronary artery lesions ^[26][112]. Clinically, IL-1Ra can be measured as a proxy for IL-1β, and its levels are higher in patients with unstable coronary disease who have a complicated hospital course compared with an uneventful course ^[17][94]. Higher IL-1β levels are found in the pericardial fluid of patients with ischemic heart disease compared to valvular and congenital heart disease groups ^[27][113]. Clinical trials have been performed to try and target IL-1 to reduce atherosclerotic risk. A randomized control trial called CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) with over 10 thousand patients with previous myocardial infarction received different doses of canakinumab, a monoclonal antibody for IL-1β, or placebo ^[28][114]. The highest dose of the drug administered every 3 months resulted in significantly fewer cardiovascular events than placebo, and this result was found to be independent of lipid levels ^[29][115]. Canakinumab also reduced the total amount of serious cardiovascular events long-term, with a median follow-up of ~3.7 years ^[30][116]. These results suggest the potential of anti-inflammatory therapy targeted at IL-1β for reducing cardiovascular risk.

IL-18 is a pro-inflammatory cytokine that is known to induce IFN-γ activity. Some studies have shown links between this pro-inflammatory cytokine and atherogenesis. When ApoE knockout mice were transfected with IL-18 binding protein (which is the endogenous inhibitor of IL-18), fatty steak development was prevented, and atherosclerotic plaques in the aortic sinus advanced more slowly ^[31][127]. In ApoE and IL-18 double knockout mice, the atheromas were significantly smaller and had reduced IFN-γ signaling, although there was increased circulating cholesterol and triglycerides ^[32][128]. In humans, carotid intima-media thickness reflected systemic atherosclerosis and was positively correlated with IL-18 concentrations in the blood ^[33][129]. Clinically, serum IL-18 levels have been shown to be independent risk predictors for death in patients with coronary atherosclerosis and incidence of coronary events in healthy men ^[34][35][130,131].

Thrombosis can occur in the case of atherosclerotic plaque rupture, activating the clotting cascade, and is an important contributor to acute myocardial events. The blood clot can completely obstruct blood flow through the artery, and thus, many pharmacotherapies combating coronary artery disease, such as anticoagulants and anti-platelets, are targeted toward this process. In baboons, TNFα was found to initiate coagulation and fibrinolysis via binding to its p55 receptor (TNFR1) ^[36][139]. TNFα and IL-1 were both found to activate endothelial cells, which shifts them to a pro-thrombotic state ^[37][140]. In patients with atrial fibrillation, IL-6 levels were higher in patients with increased plasma viscosity, and these patients have an increased risk of stroke ^[38][141]. The CANTOS trial also supports the idea that anti-IL-1β therapy could reduce the risk of atherothrombotic disease pathogenesis ^[29][30][115,116].

Acute myocardial infarction (AMI) is, as the name suggests, an acute event in which the heart muscle begins to die from severe ischemia. Multiple pro-inflammatory cytokines were secreted from nonmyocytes post-infarction in rats ^[39][142]. IL-1β increased bone marrow hematopoietic stem cell proliferation and leukocyte production after AMI in ApoE knockout mice, and anti-IL-1β treatment not only reduced this effect but also diminished post-AMI heart failure ^[40][143]. Circulating IL-6 and IL-1β levels were found to be higher in patients with AMI compared to stable angina ^[41][144]. Cardiac mast cells were degranulated and released TNFα following myocardial ischemia, which was considered to play a role in upregulating IL-6 levels in leukocytes, leading to a cytokine cascade that caused tissue injury ^[42][145]. In one study, circulating levels of IL-6 were elevated at admission and 72-h post-AMI compared to controls, and higher levels of IL-6 expression by peripheral blood mononuclear cells at 72-h post-AMI but not at admission were attributed to the activation by macrophage migration inhibitory factor (MIF) ^[43][146]. IL-6 was observed to be a strong predictor of 30-day mortality in patients with AMI complicated by cardiogenic shock ^[44][147] and was even a predictor of the risk of future MI in apparently healthy men ^[45][148]. IL-1β was associated with myocardial dysfunction and non-infarcted left ventricular mass 1-year after ST-elevation myocardial infarction (STEMI) and served as a potential predictor for maladaptive remodeling of the myocardium following AMI and reperfusion ^[46][149].

Although reperfusion of ischemic tissue is the gold standard of treatment in clinical practice, ischemia-reperfusion injury (IRI) has been an increasingly apparent unmet need of the healthcare system. IRI is characterized by many complex cellular processes that happen acutely upon reperfusion, including an increased formation of oxygen free radicals, calcium mishandling, and immune activation. These pathways have been observed to result in complications such as myocardial stunning and microvascular dysfunction, often resulting in necrosis ^[47][158]. In cultured neonatal rat ventricular myocytes, TNFα was found to increase ROS production and induce mitochondrial DNA damage ^[48][159]. This cytokine was released from rat hearts undergoing ischemia-reperfusion (IR) ^[49][50][160,161]. Furthermore, TNFα synthesis was at least partially involved in microvascular transport changes seen in IRI ^[51][162]. TNFα knockout mice had reduced infarct sizes following left coronary artery occlusion and improved cardiac function following reperfusion compared to wildtype mice, suggesting that TNFα aggravated IRI via NF-κB activation, which mediates chemokine and adhesion molecule expression and leukocyte infiltration ^[52][163]. TNFα also upregulated arginase expression in endothelial cells, which contributes to oxidative stress and endothelial dysfunction in IRI ^[53][164]. When given the TNFα inhibitor etanercept before reperfusion, mice had reduced IRI partly via the Notch1 signaling pathway because this agent decreased infarct sizes and improved cardiac function compared to mice with inhibition of the Notch1 pathway ^[54][165]. Inhibition of this pathway reduced inducible nitric oxide synthase and enhanced nitric oxide and superoxide production ^[54][165]. Anti-TNFα administration at the time of reperfusion reduced superoxide formation and improved coronary dilation in mice, and neutropenic mice had more severe oxidative stress when faced with IRI, indicating TNFα’s deleterious role was neutrophil activation-independent and contributed to oxidative stress and endothelial dysfunction ^[55][166].

It may be noted that IL-17A has been shown to induce IRI by activating apoptosis of cardiomyocytes and infiltration of neutrophils. In mice with LAD ligation and reperfusion, IL-17A was elevated, and anti-IL-17A treatment improved infarct size and cardiac function and reduced cardiac troponin-T (cTnT) levels ^[56][182]. Necrostatin-1 (Nec-1) decreased cardiomyocyte necrosis and inflammatory cell recruitment by inhibiting the Hmgb1-IL-23/IL-17 pathway and attenuated ROS production in IR ^[57][183]. IL-1 receptor type 2, which inhibits 1L-1β signaling, was increased in AMI patients following reperfusion, and its overexpression in cardiomyocytes protected from IL-17A-induced apoptosis ^[58][184].

Most of the prominent cardiac diseases are associated with myocardial remodeling, which is considered to cause heart failure. These changes are generally induced by chronic pressure or volume overload and consist of fibrosis, apoptosis/necrosis, and cardiac hypertrophy. This section is intended to discuss the involvement of pro-inflammatory cytokines in some of the clinical causes and manifestations of the adversely remodeled myocardium, as well as the cellular processes involved in these pathologic transformations. It is also planned to describe the occurrence of adverse remodeling of vascular smooth muscle cells in the pathogenesis of hypertension.

Chronic hypertension is one of the most common modifiable cardiovascular risk factors in the world, which is known to cause mechanical stress on the myocardium ^[59][185]. The activation of the renin-angiotensin system (RAS) and elevated sympathetic nervous system activity are classic characteristics of chronic primary hypertension ^[60][186]. Dendritic cells and T-cells are important mediators of hypertension and secrete a multitude of pro-inflammatory cytokines ^[61][187]. In conditions of high blood pressure, the endothelium is subjected to increased stretch, which affects monocyte differentiation. When human monocytes were cultured with stretched aortic endothelial cells, mRNA levels for many pro-inflammatory cytokines were upregulated, including IL-6, IL-1β and TNFα ^[62][188]. The neutralization of IL-6 and hydrogen peroxide production was shown to inhibit intermediate monocyte differentiation in response to endothelial stretch ^[62][188]. Angiotensin II was reported to contribute to the development of hypertension and stimulate IL-6 release from human vascular smooth muscle cells ^[63][64][32,189]. Catecholamines were also found to stimulate IL-6 release from endothelial cells ^[65][190]. IL-6 treatment increased the expression of epithelial sodium channels in murine kidney cortical collecting duct cells ^[66][191], whereas IL-6 knockout mouse studies have shown that IL-6 is an important mediator of angiotensin II and salt-stimulated hypertension ^[67][68][192,193]. Angiotensin II was observed to stimulate IL-6 release via mineralocorticoid receptor activation in humans ^[69][194]. In healthy men, plasma IL-6 levels were reported to exhibit a positive correlation with blood pressure ^[70][195], whereas treatment of the blood pressure-lowering drug Irbesartan was observed to lead to decreased systolic and diastolic blood pressures in parallel to decreased IL-6 levels in young hypertensive males ^[71][196]. Thus, IL-6 has been shown to contribute to hypertension progression, and its levels are depressed by blood pressure-lowering therapies.

The pleiotropic nature of TNFα was highlighted in hypertension. In vitro and in vivo studies have shown that angiotensin II increases the expression of TNFα in renal tissue ^[72][73][197,198]. TNFα knockout mice did not increase the salt and water intake as well as blood pressure in response to angiotensin II infusion, unlike wildtype mice ^[74][199]. Spontaneously hypertensive rats fed high fat and high fructose diets were observed to show increased TNFα concentrations along with overactivity of the RAS ^[75][200]. T-cell production of TNFα was also stimulated in hypertensive mice, which was prevented by TNFα inhibitor etanercept ^[76][201]. Chronic treatment with etanercept prevented hypertension development in fructose-fed rats ^[77][202] and mice with systemic lupus erythematosus ^[78][203]. In Sprague-Dawley rats fed a high salt diet and infused with angiotensin II for 2 weeks, etanercept was observed to attenuate blood pressure rise and protect against renal injury ^[79][204]; however, studies in spontaneously hypertensive rats with high salt intake did not show any effect of etanercept on blood pressure but instead reduced renal inflammation ^[80][81][205,206]. Mice lacking TNFα, specifically in the renal parenchyma, were protected from angiotensin II-induced hypertension and organ damage but increased endothelial nitric oxide synthase expression in kidneys ^[82][207]. In fact, renal expression of TNFα was found to contribute to hypertension in Dahl salt-sensitive rats ^[83][208]. Together, these animal studies have suggested that TNFα mediates hypertension through renal physiology and sodium homeostasis, and the effect of its inhibition is dependent upon the type of experimented model. It is also pointed out that neural inhibition of TNFα may also play a role in hypertensive physiology ^[84][85][209,210]. In Japanese women, TNFα levels were associated with increased systolic and diastolic blood pressures ^[86][211]. Systolic blood pressure was also correlated with TNFα levels in both Canadian men and women with type 2 diabetes ^[87][212]. Hypertensive patients in Mongolia given fish oil supplementation had reductions in TNFα levels compared to control corn oil patients and showed a positive correlation with reduced cardiometabolic risk scores ^[88][213]. However, further clinical studies on the effect of TNFα inhibition on hypertension are needed in order to understand its clinical therapeutic potential.

Cardiac hypertrophy is the compensatory result of a volume and/or pressure-overloaded heart, often associated with hypertension, and leads to heart failure. There are, however, multiple causes for cardiac hypertrophy, all of which are not pathologic in nature, such as exercise. In vitro studies using cardiomyocytes have shown that IL-6 and IL-6R induce cardiac cell hypertrophy ^[89][90][239,240]. Pressure overload-induced cardiac hypertrophy in mice was found to increase myocardial IL-6 and IL-1β levels, although TNFα levels were not affected ^[91][241]. Cardiac fibroblasts induced IL-6 signaling in myocytes to cause cardiac hypertrophy via the p38α pathway ^[92][242]. Pathological cardiac hypertrophy was also reported to be a classic feature of sickle cell disease, where hemolysis increased IL-6 expression in mice ^[93][243]. Mice undergoing excessive exercise training were observed to show signs of pathologic cardiac hypertrophy and increased expression of pro-inflammatory cytokines, including IL-6 ^[94][244]. Inhibition of IL-6 with raloxifene in vitro was shown to reduce the cellular hypertrophy induced by IL-6 treatment ^[95][245]. These observations are consistent with the view that IL-6 may play an important role in the development of adverse cardiac remodeling.

One of the consequences of pro-inflammatory cytokines is tissue repair; however, with limited regenerative capacity, the myocardium has been shown to respond by scar formation ^[96][256]. Several immune cells were found to be recruited to the site of injury during this process and contributed to the development of cardiac fibrosis. In the heart, the transition from fibroblast to myofibroblast has been reported to be a key step in this process, as myofibroblasts are known to produce contractile α-smooth muscle actin (α-SMA) and other extracellular matrix (ECM) proteins ^[97][257]. It has also been demonstrated that the occurrence of fibrosis is associated with excessive ECM deposition, leading to tissue dysfunction ^[98][258]. The expression of multiple pro-inflammatory cytokines post-infarct in cultured rat non-myocyte cardiac cells was also associated with increased collagen production ^[39][142]. In vitro, cardiac fibroblast-conditioned media was shown to increase the expression of multiple pro-inflammatory cytokines in cardiomyocytes compared to standard culture conditions ^[99][259].

TGF-β is perhaps the most notable cytokine involved in fibrosis. In vascular smooth muscle cells and fibroblasts infected with human TGF-β1 adenovirus, collagen type III gene expression was upregulated ^[100][260]. TGF-β stimulated proteoglycan and α-SMA synthesis in cultured myocardial fibroblasts ^{[101][102][103][104]}[261,262,263,264]. Mice with TGF-β deleted in the myocardium were found to have decreased cardiac fibrosis and improved survival probability ^[105][265]. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-16 overexpression caused TGF-β activation in cardiac fibroblasts and thus promoted cardiac fibrosis ^[106][266]. Wnt/β-catenin pathway signaling increased IL-11 production, which activated TGF-β-mediated fibroblast for transition to myofibroblast ^[107][267]. In fact, IL-11 was found to be necessary for the profibrotic action of TGF-β ^[108][268]. TGF-β was also demonstrated to play a critical role in the transition between inflammation and fibrosis, as it suppressed inflammation and promoted extracellular matrix deposition ^[109][269]. In this context, TGF-β is, therefore, often considered an anti-inflammatory cytokine. Inhibition of TGF-β in mice with aortic constriction was found to result in less fibroblast activation and myocardial fibrosis without any change in cardiac hypertrophy ^[110][270]. TGF-β inhibition has been shown to reduce pressure-overload-related cardiac fibrosis in the TAC mouse model of pressure overload ^[111][112][271,272].

Apoptosis is a deliberate programmed cell death response to physical and chemical stress, thereby acting as a protective mechanism in tissues. Apoptosis has been found to be associated with oxidative stress and calcium overload but usually does not cause notable inflammation ^[113][290]. Instead, apoptotic cells express molecules to initiate their phagocytosis, which is a clearance mechanism involving the secretion of anti-inflammatory cytokines such as IL-10 ^[114][291]. However, when apoptotic cells are not cleared appropriately, an inflammatory cascade occurs to eliminate a potential threat, starting with the migration of innate immune cells and, later, the accumulation of macrophages ^[113][290]. Interestingly, TNFα protected adult murine cardiomyocytes against ischemia-induced apoptosis ^[115][292], but mice overexpressing TNFα in cardiac myocytes showed myocardial apoptosis ^[116][293]. During the course of human AMI, TNFα was not associated with apoptosis but rather IL-8-induced myocardial apoptosis via the activation and accumulation of neutrophils ^[117][294]. On the other hand, necrosis is considered a form of accidental cell death that both causes and is caused by inflammation. In necrosis, cells swell, and the plasma membrane becomes disrupted, thus leaking intracellular contents (DAMPs) as well as triggering an inflammatory response. ROS contributes to necrotic cell death by causing mitochondrial damage, and lipoxygenases can also play a role in cell death. Thus far, TNFα has been the primary inflammatory cytokine that is tied to these cell destruction pathways ^[113][290]. These pathways are tightly intertwined with cardiac fibrosis, as they involve the balance between tissue repair and cell death. There are still many unknowns in the relationships between apoptosis, necrosis, and inflammation, as this field is ever-evolving, and more research needs to be carried out to fully understand the mechanisms at play.

The result of several diseases and pathogenic mechanisms discussed so far culminate in heart failure, at which point the heart cannot meet the demands of the body. This section will focus on the role of pro-inflammatory cytokines in affecting cardiac contractility and their role in heart failure in a broader sense to better assess the clinical significance. It should be noted that pro-inflammatory cytokines have been shown to alter contractile protein expression in adult rat cardiomyocytes ^[118][295]. Infusion of IL-6 induced diastolic dysfunction in rats ^[119][285], which is clinically referred to as heart failure with preserved ejection fraction (HFpEF). HFpEF patients were observed to have higher circulating IL-6 and IL-8 levels compared to patients with asymptomatic hypertension ^[120][296], and patients with heart failure had higher IL-6 and TNFα levels compared to healthy individuals ^[121][297]. Patients with HFpEF who have reduced TNFα levels due to low-level vagus nerve stimulation showed global longitudinal strain improvement and better quality of life ^[122][298]. When HFpEF patients were divided into clinical phenogroups, the most functionally impaired group had high levels of TNFα and tissue remodeling and was at the highest risk of cardiovascular death ^[123][299].

Higher IL-6 levels were associated with reduced systolic function in apparently healthy individuals, which perhaps served as a predictive marker for heart failure ^[124][300]. Circulating IL-6 levels were associated with increased severity of congestive heart failure (CHF) ^{[121][125][126]}[297,301,302]. Heart explant specimens from patients with advanced heart failure had higher IL-6 and IL-6R transcript levels than controls, and IL-6 levels were inversely correlated with left ventricular ejection fraction ^[127][303]. IL-6 was also reported to play a role in post-MI heart failure and affect adverse remodeling ^[128][304]. Coronary sinus samples from patients with CHF had high IL-6 and IL-1β levels compared to peripheral venous blood, indicating that these cytokines are secreted into the blood from heart tissue ^[129][305]. The signal transducing receptor subunit glycoprotein 130 (gp130) levels for IL-6 were associated with total and cardiovascular mortality and deaths due to HF ^[130][306]. Higher IL-6 levels at 48–72 h were associated with all-cause mortality in patients with acute heart failure at 30 days ^[131][307]. Physical exercise training in patients with heart failure was reported to reduce IL-6 and TNFα levels and improve functional status ^[132][133][308,309]. It is also noteworthy that in patients with chronic heart failure, there are macrophages that expressed TNFα, which were not present in control patients ^[134][310]. Inhibition of TNFα with adenovirus injection in transgenic mice overexpressing TNFα caused a reversal of the dilated cardiomyopathy seen when given no adenovirus ^[135][311]. The use of left ventricular assist devices (LVAD) reduced cardiac TNFα levels ^[136][312]. Activin A, a member of the TGF-β superfamily, was also implicated in HF ^[137][313], although patients with acute CHF showed lower TGF-β1 than patients without CHF ^[138][314].

The electrical activity of the heart is key to coordinating its muscular activity. The cardiac remodeling involving hypertrophy and fibrosis affects the electrical pathways and can be seen to predispose the development of arrhythmias. The following section is focused on discussing the role of pro-inflammatory cytokines in the pathogenesis of some common types of arrhythmias.

Atrial fibrillation (AFIB) is the most common arrhythmia worldwide, with a lifetime risk of 1/3 to 1/5 in people over the age of 40 ^[139][323]. The lifestyle risk factors of AFIB, such as hypertension and ischemic heart disease, all involve structural remodeling and chronic inflammation ^[139][323]. Several excellent reviews are available in the literature detailing the pathophysiological relationship between inflammation and AFIB ^{[140][141][142]}[77,324,325]. The role of pro-inflammatory cytokines in AFIB is evident from the observation that calcium mishandling was shown to be mediated by IL-6 for contribution to the development of AFIB in sterile pericarditis rats ^[143][326]. The total collagen in left atrial appendage tissue obtained from patients with AFIB was positively correlated with pro-inflammatory cytokines, including IL-6 and TNFα in epicardial adipose tissue ^[144][327]. Both IL-6 and TNFα were associated with increased AFIB risk in the general population, and IL-6 was observed during increased risk of postoperative AFIB ^[145][328]. Although in patients with coronary artery disease, IL-6 levels were associated with AFIB, but not TNFα ^[146][329], IL-6 levels were higher in AFIB patients than non-AFIB controls ^[147][330]. A case-control study showed IL-6, IL-8, and TNFα concentrations were independently seen with AFIB patients compared to controls, and graded TNFα levels were associated with paroxysmal, persistent, and permanent AFIB ^[148][331]. Patients with AFIB had higher IL-6 levels during AFIB than during sinus rhythm, indicating an acute response during arrhythmia ^[149][332].

It has also been reported that cardiac pacing with metoprolol treatment reduced the levels of TNFα and IL-6 in AFIB patients. Furthermore, IL-6 levels were associated with an increased likelihood of AFIB recurrence after ablation ^[145][328] and early recurrence after a short-lasting persistent AFIB with rhythm control ^[150][333]. Lower levels of TNFα were seen with increases in response to catheter ablation in AFIB patients ^[151][334]. In patients with AFIB, baseline IL-6 and TNFα levels were found to be significant predictors for ischemic stroke ^[152][335], and IL-6 levels were higher in AFIB patients at high risk of stroke ^[38][141]. Elevated IL-6 levels were associated with the prognosis of mortality and adverse cardiovascular events in anti-coagulated patients with AFIB, even when adjusted for the clinical CHADS2 risk stratification score ^[153][336]. The pro-fibrotic marker TGF-β was lower in patients with AFIB, declined over increasing AFIB duration, and was negatively correlated with left atrial diameter ^[138][147][314,330]. Together, these data indicate IL-6 may have a role in AFIB by inducing a pro-thrombotic state, whereas both TNFα and IL-6 are involved in the proinflammatory state that potentiates AFIB.

There is a lack of studies published about other arrhythmias and pro-inflammatory markers, as they can often be acute events and can result in sudden cardiac death. In atrial flutter patients, the level of IL-6 was higher in peripheral blood than in blood taken from the coronary sinus, indicating a potentially systemic response, with IL-6 level decreasing over time after ablation ^[154][337]. Left stellectomy in experimental autoimmune myocarditis rats prevented arrhythmias and reduced IL-6 and TNFα levels ^[155][338]. IL-6 has also been shown to be associated with ventricular tachyarrhythmias and an increased risk of sudden cardiac death ^{[156][157][158][159]}[339,340,341,342]. IL-18 gene promoter -137 G/C polymorphism was also associated with an increased risk of sudden cardiac death in the context of hypertension ^[160][343]. It is noteworthy that connexin-43 (Cx-43), a myocardial gap junction protein, has been implicated in ventricular arrhythmogenesis as it was upregulated by TNFα, thus potentially serving a cardioprotective role in preventing arrhythmias ^[161][344]. In young people, TNFα levels were elevated in those with ventricular arrhythmias, and it was suggested that TNFα aggravated arrhythmias ^[162][345]. On the other hand, IL-1β caused the loss of Cx-43, reduced the coupling of myocytes and myofibroblasts, and was indicated to be involved in the arrhythmias seen post-MI ^[163][346]. It is pointed out that TGF-β1 was released by myofibroblasts to induce changes in sodium and potassium ion channels in rats and was suggested to contribute to the electrical remodeling in myocardial injury ^[164][347].

While “cardiomyopathies” is a generic term that refers to a large group of heterogeneous diseases, this section will focus on categories of cardiomyopathies that have not yet been discussed with respect to the role of pro-inflammatory cytokines.

It is not surprising that pro-inflammatory cytokines play a role in cardiomyopathies of infectious or autoimmune origin in rheumatic heart disease (RHD), myocarditis, and pericarditis. It is known that RHD is a major cause of cardiovascular morbidity and mortality in young people, particularly those from developing nations ^[165][348]. Group A streptococcal infections can lead to an aberrant immune response, resulting in valvular damage in the heart. One of the hallmarks of RHD lesions is the infiltration of T-lymphocytes. RHD rats were found to show significantly higher serum and mitral valve IL-17 and IL-6 levels, which are Th17-related cytokines, than controls ^[166][349]. A similar trend was seen in humans, as patients with RHD had higher circulating IL-6, IL-8, IL-2R, and TNFα levels; IL-6 and TNFα levels correlated with valve calcification and functional class severity ^{[167][168][169][170]}[350,351,352,353]. Children with acute rheumatic fever had higher IL-8, IL-2, and IL-1β serum levels compared to those with chronic RHD ^[171][172][354,355]. IL-6 levels were higher, and TNFα levels were lower in patients with acute rheumatic fever ^[173][356]. IL-4, IL-8, and IL-1RA were observed to predict clinical RHD vs. latent RHD, along with polymorphisms in the IL-2, IL-4, and IL-6 genes ^[174][357]. In heart tissue infiltrates from RHD patients, IFN-γ and TNFα expressing Th1 cells were found to be predominant and were considered to contribute to the valvular damage seen in RHD ^[175][358]. In patients with RHD-related mitral stenosis who underwent percutaneous mitral commissurotomy, IL-1β, IL-12, IL-6, and IL-4 were decreased ^[176][359]. Overall, the cytokines related to Th1 and Th17 cells appear to be important in the infiltration of valvular tissue in the heart in RHD.

Myocarditis is characterized by inflammation in the myocardium and usually follows a viral infection, but also from bacteria, fungi, and parasites. Myocarditis can also be a drug- or chemical-induced abnormality. Eventually, myocarditis has been shown to result in dilated cardiomyopathy. In acute viral myocarditis, natural killer cells have been observed to enter the heart followed by activated T-cells to induce myocardial damage ^[177][360]. Mice hearts infected with Coxsackievirus B3 were found to have a primarily Th1-mediated response, with increases in its related cytokines IL-2, IFN-γ, and TNFβ ^[177][360]. In mice infected with encephalomyocarditis-induced dilated cardiomyopathy, IFN-γ, TNFα, and IL1β mRNA levels were increased in the heart tissue 3 days after inoculation, peaked at 7 days post-inoculation, and persisted even 80 days later ^[178][361]. On the other hand, IFN-γ-deficient mice developed severe and even fatal autoimmune myocarditis, suggesting a protective role of this cytokine ^[179][180][362,363]. IL-12 induced autoimmune pathways independent of IFN-γ signaling and caused the proliferation of Th1 cells ^[179][362]. IL-1 and TNF secreted by inflammatory cells in heart infiltrates contributed to postinfectious autoimmune myocarditis ^[181][364]. Non-failing hearts were observed to have IL-1 receptor mRNA expression, while heart tissue from patients with inflammatory myocarditis did not show any IL-1 receptor mRNA expression, suggesting receptor downregulation ^[182][365]. IL-1α, TNFα, and M-CSF levels were higher in patients with acute myocarditis ^[183][366]. Blockade of IL-1 using anakinra prevented myocardial dysfunction in mice ^[184][367]. It should also be mentioned that some studies have examined the role of pro-inflammatory cytokines in pericarditis, which is the inflammation of the pericardium lining the heart. Anakinra, the IL-1 inhibitor, was shown to resolve recurrent pericarditis and its associated symptoms ^{[185][186][187]}[368,369,370]. IL-1 trap rilonacept also rapidly resolved recurrent pericarditis and prevented subsequent episodes ^[188][371]. Although these results suggest a role of IL-1 in the exacerbation of pericarditis episodes, the mechanisms remain unclear.

Hypertrophic cardiomyopathy (HCM) is the most common inherited genetic heart disease and is the top culprit for sudden death in young people ^[189][372]. TGF-β has been implicated in HCM because mutations in sarcomere protein genes and fibrosis are known to contribute to its pathogenesis. In HCM mice, non-myocyte proliferation and fibrosis were observed to be mediated by TGF-β ^[190][373]. Mutations in TGF-β inducible early gene-1 (TIEG) were associated with HCM compared to normal hearts ^[191][374]. TGF-β gene expression and protein levels were elevated in patients with idiopathic HCM myocardium ^{[192][193][194]}[375,376,377]. Patients with HCM had higher levels of circulating TGF-β than controls, and TGF-β levels correlated with clinical adverse events and hospitalizations ^[195][378]. Additionally, high TNFα and IL-2 levels were detected in patients with HCM ^[183][366]. In patients with obstructive HCM undergoing nonsurgical septal reduction, TNFα expression was decreased along with regression of cardiac hypertrophy ^[196][379]. IL-6, IL-1β, IL-18, and IL-1Ra levels were elevated in serum and heart tissue in patients with HCM ^{[197][198][199][200][201]}[380,381,382,383,384]. Given the genetic etiology of HCM, however, it is difficult to suggest if targeting pro-inflammatory cytokines is a viable therapeutic option for these patients.

Diabetic cardiomyopathy is classically considered as a progression to heart failure in diabetic patients in the absence of coronary artery disease, valvular disease, and hypertension, but this definition has not been universally agreed upon by several investigators ^[202][385]. It is thought that myocardial fibrosis is an important contributor to the subsequent diastolic heart failure and arrhythmogenesis that develops and, therefore, must be related to glucose homeostasis and sensing. It is noteworthy that fructose has been observed to increase the expression of TGF-β and collagen markers in vitro, and high fructose feeding in mice was found to induce high expression of multiple pro-inflammatory cytokines, including IL-18, IL-6, IL-1β, and TNFα ^[203][386]. TGF-β was shown to stimulate NLRP3 in cardiac fibroblasts ^[204][387]. In streptozotocin-induced diabetic rats, the NLRP3 inflammasome was activated and resulted in higher circulating IL-1β and IL-18 levels ^[205][388]. Mice with diet-induced diabetes had high IL-1β expression in the left ventricle due to NLRP3 inflammasome activation ^[206][389]. Diabetic rat hearts also showed higher expression of TNFα compared to control hearts, which was inhibited by consumption of deep-sea mineral extracts ^[207][390]. Macrophage migration inhibitory factor (MIF) was also associated with cardiac dysfunction in diabetic patients ^[208][391]. In view of these observations, it is suggested that some pro-inflammatory cytokines may play a critical role in the development of diabetic cardiomyopathy.