Gout Flare and Cardiovascular Events - An Overview

Introduction

Cardiovascular disease (CVD) is one of the leading causes of death globally. The global burden of disease (GBD) reported that about 20 million people died of CVD in 2017. Some of the risk factors in CVD are:

1. Age.

2. Gender.

3. Race.

4. Hypertension (increased blood pressure).

5. Diabetes (a metabolic disease that causes elevated blood sugar levels).

6. Smoking.

7. Increased blood lipids (dyslipidemia).

However, chronic inflammation has recently been implicated as a CVD trigger. Gout is a type of arthritis (a condition where one or more joints become inflamed and result in pain) with chronic inflammation. A gout flare is an intense painful attack of gout. Recently, gout has been reported to be an independent risk factor for CVD.

What Is the Association Between Gout Flares and Cardiovascular Disease?

It is reported that patients with gout flares have higher rates of CVD. Furthermore, it is independent of the conventional cardiovascular risk factors. Gout is characterized by low-grade inflammation with increased proinflammatory cytokine levels and reactive oxygen species (ROS), endothelial dysfunction, and platelet hyperactivity. All these mechanisms are known to precipitate CVD. Gout flares are characterized by inflammation due to the activation of inflammasomes. Inflammasomes are large protein complexes that gather to invoke an inflammatory response in the body. In various trials, blocking inflammasomes prevented recurrent cardiovascular events.

Many inflammatory mediators are released through inflammasomes (protein complexes responsible for immune response, resulting in gout flares. Inflammasomes also cause important events in atherosclerosis, such as oxidative stress and dysfunction of different cell organelles (mitochondria, endoplasmic reticulum, and lysosomes).

What Is the Common Pathophysiology of Gout Flares and Cardiovascular Events?

Gout occurs due to an increased serum uric acid level (hyperuricemia). It leads to the formation of monosodium urate crystals in the joints and swelling sometimes accompanies pain. The pathophysiology depicts the deranged function of tissues and organs. Imaging has shown joint inflammation and synovitis (inflammation of the synovial membrane) in the early stages. Furthermore, inflammation is also a key factor for CVD. CVD in gout patients is divided into three groups:

Atherosclerosis.

Thromboembolism.

Cardiac dysfunction.

The inflammatory process in gout is related to that of CVD.

1. Atherosclerosis: Atherosclerosis is fat and cholesterol buildup on the walls of the artery. The postulated common mechanisms of gout and CVD are systemic inflammation, reactive oxygen species (ROS)-induced oxidative stress, and endothelial dysfunction. All of these can lead to atherosclerosis.

a. Systemic Inflammation: The inflammatory pathways in gout and atherosclerosis share constituents of the immune system. One of the proposed causes of gout is autoimmunity and autoinflammation. Neutrophil (white blood cell involved in acute inflammation) overactivation is linked to the same. Schauer et al. first explained the neutrophil extracellular trap (NET) phenomenon. It involves pushing neutrophilic DNA (deoxyribonucleic acid) out of the cell and eliminating disease-causing organisms. It is hypothesized that gout flares are self-limiting because of this phenomenon. The extracellular DNA exerts a clot-forming effect on the blood vessels leading to atherosclerosis.

b. Reactive Oxygen Species (ROS): ROS are small reactive molecules that play important roles in cellular process regulation in the body. The imbalance between oxidative and antioxidant mechanisms leads to oxidative stress. Oxidative stress is another link between gout and CVD. Xanthine oxidase (XO) catalyzes the oxidation of xanthine to uric acid-producing ROS. XO also leads to endothelial damage via ROS.

c. Endothelial Dysfunction (ED): Endothelium is the inner lining of blood vessels. ED is a disturbed state in which blood vessel stability is lost. ED causes angina (chest pain) and increases the risk of coronary artery disease (CAD). ED is the earliest phenomenon in atherosclerosis development. Low-density lipoproteins (LDL) cholesterol accumulates in the endothelium and is oxidized. The oxidized LDL cholesterol is primarily responsible for atherosclerotic plaque formation. ED has been observed in untreated gout patients. Hyperuricemia and increased C-reactive protein (CRP, a chronic inflammatory protein) concentrations are found in these patients.

2. Venous Thromboembolism (VTE): VTE is the presence of blood clots in a vein. VTE is divided into:

a. Deep vein thrombosis (DVT) - It is the blood clot formation in the deep veins, specifically the legs.

b. Pulmonary embolism (PE) - It is a condition where one or more blood vessels in the lungs are clogged by blood clots.

Gout is considered an independent risk factor for VTE. Thus, increased platelet reactivity has been found in gout patients. The increased platelet reactivity enhances the risk of platelet plug formation and subsequent clotting. This finding suggests the prothrombotic state and connection of VTE and gout.

3. Cardiac Dysfunction: Cardiac dysfunction is linked to chronic systemic inflammation observed in gout. There are two distinct mechanisms.

a. Chronic inflammation, which leads to heart muscle remodeling and diastolic dysfunction (heart ventricles become stiff). It starts with collagen deposition and causes heart cell size to increase. Further, it prevents the heart muscles from contracting and relaxing properly, leading to heart failure.

b. Chronic inflammation and subsequent heart dysfunction lead to atherosclerosis with ischemic heart disease (IHD). IHD occurs due to reduced blood flow to the heart.

The exact pathogenesis of cardiac dysfunction in gout has not been properly investigated. Some studies show an association between serum urate concentration and inflammation. Further data is required to assess the extent of urate concentration and the associated inflammation as independent risk factors for cardiac dysfunction.

How is Cardiovascular Risk Managed in Gout Patients?

Cardiovascular risk management is important in gout patients. Also, gout patients with cardiovascular disease have increased death rates.

1. Medicines: The European League Against Rheumatism (EULAR) task force, in 2019, recommended screening and identification of CVD risk factors and their management in various inflammatory joint disorders. The EULAR recommendations for gout include systematic screening and care in CVD-risk patients. It is important as many drugs targeting CVD can aggravate hyperuricemia and gout flares by decreasing uric acid excretion. Examples include antihypertensive drugs such as beta-blockers, angiotensin-II receptor blockers, thiazides, and loop diuretics.

• Statins are generally safe to use in gout and CVD patients. This is due to their uric acid excretion property. Statins further reduce the mortality rates due to CVD in gout patients.

• Colchicine is used for the treatment of acute gout flares. It is also safe to use in CVD patients. It is because colchicine prevents atherosclerosis by plaque stabilization, decreases cardiovascular damage, and reduces CAD.

• Anakinra (used for rheumatoid arthritis) showed efficacy in a 2019 trial in controlling inflammation during a gout flare without cardiovascular safety issues.

• It has been observed that Allopurinol (a medicine for gout) lowers the risk of myocardial infarction (blockage of the heart muscle’s blood supply).

2. Lifestyle Modification: EULAR recommends a healthy lifestyle for all patients with gout. A healthy lifestyle is defined as a healthy diet, regular exercise, and smoking cessation.

• There is some evidence of exercise and weight loss in patients with gout. Exercise may lower serum uric acid concentration, achieve an optimal uric acid level, and prevent gout flares. EULAR advises avoidance of alcohol and sugar drinks and discourages excessive meat and seafood.

• Smoking cessation has a positive impact. It reduces the risk of CVD. However, smoking cessation has not been associated with gout.

Conclusion

Gout flares are associated with approximately 50% to 70% increased risk of cardiovascular disease. Effective urate-lowering therapy is important to manage gout. The risk factors of CVD should be managed well, namely, hypertension and dyslipidemia. Furthermore, if CVD is present, proper treatment of the condition, along with gout, should be done.