Over the past 20 years, preclinical studies and early stage clinical trials at VCU Health have generated meaningful data advancing the understanding of inflammation and the heart. This research has earned international recognition for Pauley, Abbate and his colleagues.

Mediating the cardiotoxicity of cancer drugs. Sterile inflammation, or inflammation in the absence of a pathogen, has been linked to aggravating numerous disease processes, including the aftermath of injury to the heart.

This injury may be a result of a heart attack or exposure to cardiotoxic agents including FDA-approved treatments for certain types of cancer. Persistent inflammation in the heart can cause damage or failure. and John R.

Congdon Sr. Endowed Chair at Pauley. The goal of the research is to better understand the basis of cardiotoxicity — damage to the heart caused by chemotherapy drugs — and inform the discovery of new methods of prevention for chemotherapy-induced heart failure.

From left: Jordana Kron, M. Blocking inflammation with anakinra. Inflammation is an inevitable response to injury, but too much inflammation leads to more injury.

Abbate and his team have been working on how to modulate the inflammatory response in heart disease so that patients can heal faster and have better cardiac health.

In particular, they have started with patients with heart attacks for whom there is a major injury to the heart muscle. The focus of their studies has been anakinra, a drug that blocks a specific mediator of inflammation called interleukin-1 IL-1 , a small protein in the blood that mediates fever and other inflammatory responses.

IL-1 also promotes heart failure following a heart attack. In heart attacks, there is a clear insult to the heart — a blockage that causes lack of oxygen and cell death and injury. By resetting the inflammation, some can help improve cardiac function and help heart failure patients do better, feel better and possibly keep them out of the hospital.

Recently, the team has looked at inflammation of the pericardium, the sack around the heart. In some instances, the pericardium becomes inflamed, a condition called pericarditis.

For many years, studies of targeted anti-inflammatory drugs in heart attacks and heart failure were unique to VCU, Abbate said.

Notably, VCU has become internationally renowned for its VCUART and REDHART studies focusing on inflammation and centered around blocking IL-1 in heart disease. Abbate and colleague Benjamin Van Tassell, Pharm.

With active NIH funding for the past 10 years building on research from earlier clinical trials, and with another multimillion dollar grant awarded in February, the upcoming IL-1 blockade in STEMI trial 4 study will enroll patients with heart attacks and integrate cardiac magnetic resonance imaging and exercise testing to learn if these combined measures prevent patients from developing heart failure.

Why, then, does pharmacological therapy improve HFrEF with relatively little impact on HFpEF? Increased sympathetic nerve activity occurs in all phenotypes of heart failure Parati and Esler, Initially, the increase in sympathetic nerve activity is compensatory but the sustained increase eventually is detrimental and worsens the prognosis Kaye et al.

The mechanisms mediating the increased sympathetic activity are not completely understood but the work in preclinical models of heart failure indicate that the central nervous system plays a major role, particularly nuclei such as the hypothalamic paraventricular nucleus PVN , the nuclei of the lamina terminalis that lack a blood—brain barrier [e.

Figure 1. Schematic highlighting, on the left side, the compensatory increases in inflammation, activation of the renin—angiotensin system RAS and activation of sympathetic nerve system SNS induced by heart failure.

On the right is shown the potential actions on the compensatory mechanisms of drugs aimed at reducing the actions of inflammatory mediators in the central nervous system CNS. The PVN projects to the intermediolateral cell column were sympathetic preganglionic motor neurons reside, and the PVN also sends collaterals to the RVLM neurons which send direct projections to the sympathetic preganglionic motor neurons as well Shafton et al.

Thus, the PVN has the anatomical connections that directly and indirectly influence sympathetic nerve activity. The PVN also receives inputs from the SFO and RVLM. An imbalance of excitatory and inhibitory inputs within the PVN has been suggested to contribute to the excessive sympathetic nerve activity in heart failure in rats Zheng et al.

Peripheral afferent inputs that appear to contribute to the activation of the central pathways mediating the increased sympathetic outflow in heart failure include overactivity of the afferent renal nerves, overactivity of the carotid sinus afferents and angiotensin II Schultz et al.

In heart failure, there is activation of the renin—angiotensin system which plays an active role in the remodelling of the heart and in fluid and electrolyte imbalance which are compensatory initially but eventually leads to worsening of the condition Figure 1. Given the wide distribution of the renin—angiotensin system in the cardiovascular system and in the heart, it is not surprising that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have become key first line therapeutic interventions in heart failure.

The renin—angiotensin system is complex and consists of different receptor subtypes and, upon activation, they may initiate similar or even antagonistic responses, as is seen with the activation of type 1 AT1R and type 2 AT2R angiotensin receptors in various tissues Kurdi et al.

In addition to the classical ten amino acid peptide, angiotensin II, there are several angiotensin peptides e. These peptides may have their own actions through binding to the classical or their own specific receptors such as in the case with Ang that can bind AT1R, AT2R and the mas receptor Iusuf et al.

The latter may be particularly important for cardiac hypertrophy and fibrosis Wang et al. Adding to the complexity is the fact that components of the renin—angiotensin system are widely distributed and can induce local production of angiotensin for example in the heart as well as systemic production of angiotensin.

Further, the presence of a central renin—angiotensin system means that locally produced angiotensin in the brain can also play a key role in cardiovascular disease and autonomic dysfunction.

Additionally, centrally mediated actions can be elicited by peripherally produced angiotensin II acting on nuclei that lack a blood brain barrier, like the SFO Wright and Harding, Angiotensin II can elicit an increase in sympathetic nerve activity and this involves both central as well as peripheral sites of action.

Several nuclei within the central nervous system, like the PVN, SFO and RVLM, have dense concentrations of angiotensin receptors and contribute to the increase in sympathetic nerve activity induced by angiotensin II and observed in heart failure Zheng et al.

Thus, there exists an inter-relationship between the renin—angiotensin system and sympathetic nerve activation in heart failure. This inter-relationship may also exist with inflammation since angiotensin II can mediate inflammatory responses and could contribute to the increase in inflammation that is seen in heart failure.

Markers of inflammation in the heart and in the circulation are observed in patients diagnosed with heart failure Figure 1. Indeed, the levels of circulating cytokines are correlated with the severity of heart failure and prognosis Rauchhaus et al.

It has been known for some time that pro-inflammatory cytokines, for example tumour necrosis factor alpha TNF-α , interleukin-1β, interleukin-2 and interleukin-4, can induce pulmonary oedema, ventricular contractility abnormalities and dysfunctional cardiac metabolism which can result in reduced cardiac function Hegewisch et al.

Circulating pro-inflammatory cytokines can also influence cardiac function further afield than just locally in the heart. More recent work has suggested that circulating pro-inflammatory cytokines can activate the sympathetic nervous system via activation of cells within the SFO.

The effects of circulating pro-inflammatory cytokines on sympathetic nerve activity can be reproduced by direct microinjection of those pro-inflammatory cytokines into the SFO Wei et al.

The mechanisms involved are not clear but activation of the local renin—angiotensin system in the SFO and subsequent increases in prostaglandins and reactive oxygen species in the PVN and further cytokine production in the PVN appear to be involved Wei et al.

A critical role of the pro-inflammatory cytokine, TNF-α, in the SFO is further reinforced by the finding that the knockdown of the TNF-α receptor 1 in the SFO reduced the increase in sympathetic nerve activity normally observed in the myocardial infarction-induced model of heart failure Yu et al.

Despite the improved cardiac haemodynamics in the treated rats, cardiac function did not improve over the short observation period. Thus, although abundant preclinical evidence would suggest that targeting the pro-inflammatory cytokines would be a useful therapy to treat heart failure, functional improvement in heart failure still appears elusive.

To date, it has been very disappointing to see the results of clinical trials that have attempted to inhibit the actions of pro-inflammatory cytokines.

Clinical trials targeting TNF-α using etanercept or infliximab in heart failure e. Although such trials have not provided the outcomes expected based on preclinical studies, there may still be some positive and encouraging signs emerging from more recent studies targeting other pro-inflammatory cytokines CANTOS trial.

In particular, the finding using Canakinumab to inhibit interleukin-1β function, showed a reduction in hospitalisations and mortality due to heart failure Everett et al.

It would appear perplexing that studies in animals strongly suggest a role of pro-inflammatory cytokines in the aetiology of heart failure, yet the outcomes of clinical trials using anti-inflammatory therapeutics have been decidedly unimpressive and have not provided support for such a view.

What could explain this paradox? There are several possibilities that could be considered, and I would like to focus on two in this mini-review; Firstly, the target needs to be more specifically identified. Second, the inflammatory mediators in the CNS play a greater role, thus targeting these more specifically may be required.

The evidence to date indicates that pro-inflammatory mediators like TNF-α, interleukins, reactive oxygen species and angiotensin II are increased in heart failure. These increases occur locally within the myocardium, systemically i. Therapeutic agents like angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are front line therapy for heart failure, both in HFrEF and HFpEF.

However, the evidence suggests they ameliorate the symptoms of HFrEF and have positive outcomes, but they have little or no positive influence on HFpEF. Anti-TNF-α treatments investigated in animal models of heart failure showed great promise; unfortunately, these hopes have not been fulfilled in clinical studies.

But as noted earlier, there is a glimmer of hope from the recent findings in the CANTOS trial raising the possibility that specific targeting of interleukin-1β may be beneficial.

This does raise the possibility that targeting specific pro-inflammatory mediators may be the way forward and clearly needs more work. Another issue that needs to be addressed is the role of inflammatory mediators within the CNS, which may be playing a larger role than hitherto appreciated.

Circumstantial evidence for this view arises from many studies. For example, TNF-α is increased in specific brain nuclei known to influence sympathetic nerve function Kang et al. Direct microinjections of TNF-α into specific brain nuclei increases sympathetic nerve activity Korim et al.

and anti-TNF-α treatment reduces the abnormally elevated sympathetic nerve activity in an ischaemia-induced model of heart failure in rats Guggilam et al.

These studies suggest a key role for TNF-α within the brain in heart failure aetiology. This view is further supported by studies in which reducing the synthesis of TNF-α by decreasing the function of TNF-α-converting enzyme resulted in improved systemic haemodynamic variables while increased levels of the enzyme resulted in worse symptoms of heart failure in rats Yu et al.

Interleukins in the brain are also important. The gene transfer of human interleukin a potent anti-inflammatory using intraventricular administration in a rat model of heart failure resulted in amelioration of heart failure symptoms Yu et al. Similarly, inhibition of pro-inflammatory cytokines in the brain using pentoxifylline reduced the neurohumoral excitation, that normally accompanies heart failure, in the coronary ligation model of heart failure in rats Kang et al.

It should not be forgotten that there may exist a complex relationship between central and peripheral pro-inflammatory mediators. For example, elevated levels of circulating pro-inflammatory cytokines and angiotensin II can activate neurons in the SFO and result.

in an increased production of pro-inflammatory mediators within the brain. Pro-inflammatory processes in the brain may contribute to the sympathetic nerve dysregulation observed in heart failure; for example, increased levels of reactive oxygen species Gao et al.

Inhibition of the production of reactive oxygen species in the brain ameliorated the autonomic dysfunction normally observed in ischaemia-induced heart failure in mice Lindley et al. It is also noteworthy that increased production of reactive oxygen species can also be induced by angiotensin II Gao et al.

Thus, pro-inflammatory mediators could maintain the increased sympathetic nerve activity and contribute to the detrimental outcomes in heart failure. In this regard, it is interesting to note the findings of a recent Cochrane review on the impact of six different angiotensin-converting enzyme inhibitors on outcomes in patients with HFpEF.

This review found little or no effect on all-cause and cardiovascular mortality and quality of life measures of angiotensin-converting enzyme inhibitors on this phenotype of heart failure Martin et al.

However, only one of the inhibitors used is known to cross the blood brain barrier leaving the question of whether targeting of pro-inflammatory mediators, like angiotensin within the CNS is beneficial in heart failure unanswered.

Since attenuating the increase in pro-inflammatory cytokines in the CNS can ameliorate the increase in sympathetic nerve activity observed in heart failure, perhaps further studies which target specific peripheral and CNS pro-inflammatory mediators is needed Figure 1.

From the preceding arguments, targeting specific pro-inflammatory mediators in the CNS may be a novel therapeutic approach to deal with the detrimental outcomes in heart failure and needs to be addressed.

However, there is perhaps, a more critical issue, and that is related to the access of effective doses of the drugs to the site of action in the CNS. It is not possible to answer this easily because targeting the CNS for therapeutic intervention presents unique challenges due to the presence of the blood brain barrier and the ability to get drugs effectively to their site of action.

Recent advances in delivery technology, however, are exciting Vashist et al. Among the possibilities are i transient disruption of the blood brain barrier, ii direct microinjections into the cerebrospinal fluid, a rather invasive methodology which is unlikely to be welcomed by patients for regular ongoing treatment, iii extracellular vesicles and iv nanotechnology transporting techniques.

The latter is particularly attractive and is advancing at a rapid rate Saeedi et al. Nanotechnology involving nanoparticles that contain two chemicals, one used as a diagnostic marker to allow for visualisation and tracking of the particle, and the second a therapeutic agent, have been described.

An example is the recent targeting of microglia with such nanoparticles containing the anti-inflammatory drug, rolipram Cahalane et al.

In this in vitro study, microglia preferentially took up the nanoparticles compared to astrocytes. A promising result for future in vivo studies, given the role of microglia in inflammatory mediated processes within the brain. For example, the use of liposomes containing anti-vesicular cell adhesion molecule-1, to target vascular endothelial cells in vivo , increased penetration into the CNS dramatically.

This technique has been useful in reducing inflammation in the brain and restoring integrity of the blood brain barrier in a model of brain inflammation Marcos-Contreras et al. A similar targeting technique has been used in vivo to alter the behaviour of mice in studies of depression.

Using negatively charged liposomes containing trefoil factor 3, because of its anti-depressant functions, resulted in improved mobility and reduced immobility in behavioural tests in mice Qin et al. A similar positive outcome has been observed using a more targeted approach in which the liposomes were modified so that their affinity for monocytes was markedly increased Qin et al.

Other strategies utilised include stimuli sensitive nanoparticles. These exciting methodologies utilise environmentally sensitive nanoparticles that can change their shape according to the micro-environment, for example pH. redox capability, presence of enzymes Lee and Thompson, ; Mohamed et al.

In contrast, low-dose methotrexate did not show a reduction in plasma markers of inflammation in the Cardiovascular Inflammation Reduction Trial CIRT.

Nevertheless, new evidence supports the role of inflammation in atherosclerosis development as seen in the Colchicine Cardiovascular Outcomes Trial COLCOT [ 12 ].

The study showed that colchicine could significantly reduce the CV events in patients after myocardial infarction [ 13 ]. The underlying mechanism behind the reduction of CV events is likely to include direct inhibition of the NLRP3 inflammasome, TNF-α, IL, and IL-6, in addition to IL-1β [ 14 ].

Based on the clinical and experimental data, future therapies might be directed toward a combination of lipid-lowering and inflammation-inhibiting agents in patients with CVDs [ 15 ].

However, the risks and implications of inhibiting inflammation in the treatment of CVD in the host response to infection is yet another aspect to be studied.

Understanding cell-mediated immunology and molecular pathways behind CVDs is paramount in the development and implementation of effective anti-inflammatory and immune-modulating therapies for patients with CVD.

Currently, we have state-of-the-art techniques at our disposal, including advanced in vivo imaging, genome-wide association studies, transgenic lineage tracing mice, mendelian randomization studies, and clinical trials to acquire a deep understanding of the immune landscape involving CVDs.

In summary, we expect this article collection to gather evidences in both basic and clinical research in the CVD field to reinforce existing knowledge and open new therapeutic opportunities for treating these disorders. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction.

Cardiovasc Res. Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, Gherardi RK, Chazaud B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med.

Tonkin J, Temmerman L, Sampson RD, Gallego-Colon E, Barberi L, Bilbao D, Schneider MD, Musarò A, Rosenthal N. Mol Ther. Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease.

Wolf D, Ley K. Immunity and Inflammation in Atherosclerosis. Circ Res. Humphrey LL, Fu R, Buckley DI, Freeman M, Helfand M. Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis.

J Gen Intern Med. Bigeh A, Sanchez A, Maestas C, Gulati M. Inflammatory bowel disease and the risk for cardiovascular disease: does all inflammation lead to heart disease? Trends Cardiovasc Med.

Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol. Lazzerini PE, Capecchi PL, El-Sherif N, Laghi-Pasini F, Boutjdir M. Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies. J Am Heart Assoc.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med.

Now imagine a coronary artery that has been injured — by tobacco smoke, high blood pressure, or other factors. The injury again triggers the inflammatory process, and the area gets flooded with cells and other responding substances.

In this case, however, some of those responders can do more harm than good. They can trigger a cascade of events — including disrupted plaque deposits and blood clots that cut off blood flow to the heart — that lead to a heart attack. Many of those people were diligently taking their cholesterol medications, but still doing things that can contribute to inflammation, including eating the wrong foods, overstressing, sitting too much, and accumulating ever more belly fat.

What can you do? Sinha says. Substances known as free radicals can damage your blood vessels. Free radicals can result from a diet heavy with processed foods and lacking in natural antioxidants. A better choice is the Mediterranean diet: eat plenty of vegetables, fruits, and nuts, and choose the healthy fats found in avocados, fish and olive oil.

If you drink alcohol, choose red wine. Have a couple squares of dark chocolate best with 70 percent or more cacao. Avoid foods with high-fructose corn syrup and trans fats. Exercise causes the release of chemicals like nitric oxide, which keeps your arteries relaxed.

Gym workouts are good, but also be sure to get plenty of exercise throughout your day. Aim for 8,, steps daily, keeping track with a pedometer, fitness tracker band or phone app. Virtually all of the ingredients needed for a heart attack can be found right inside those belly fat cells, including inflammatory chemicals and chemicals that cause increased blood clotting.

A diet that is high in carbohydrates is a major cause of belly fat, due to the increase in insulin they can trigger. So keep an eye on the sweets, sodas, breads, and all those so-called low-fat foods that may be making you fatter.

Excessive and persistent stress, anger, depression, hostility, and worry can cause low-grade inflammation. Sinha advises. We use cookies to give you the best possible user experience.

In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable.

However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines.

Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections.

Keywords: atherosclerosis; cerebral artery aneurysm; coronary artery disease; coronary atherosclerotic plaque; inflammation; stroke. Postdoctoral position in cancer biology is available to carry out projects focused on studying the effects of small molecules in cancer. edu a edu at The Ohio State University OSU currently has opportunities for tenure-track Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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