The Role of Inflammation in the Cardiovascular Continuum and the Aging Process
Inflammation plays a role at various stages of the cardiovascular (CV) continuum, in both atherosclerotic and non-atherosclerotic CV diseases. Where to look for inflammation in the pathophysiology of CV diseases, why inflammation is related to aging, and how to utilize these findings in clinical practice was explained in a lecture by MUDr. Peter Wohlfahrt, Ph.D., from the Center of Preventive Cardiology IKEM in Prague, at the XXXII Annual Meeting of the Czech Cardiology Society.
Inflammation in Atherosclerotic CV Diseases
The core of the CV continuum is atherosclerosis. It is a chronic inflammatory disease of the vascular wall, involving both innate and acquired immunity. Risk factors are at the beginning. All major CV risk factors – hypertension, diabetes, dyslipidemia, smoking, obesity, and age – promote inflammation.
At the beginning of the CV continuum, endothelial dysfunction occurs, facilitating the penetration of lipid particles into the subendothelial space of the vascular wall. This triggers inflammation and oxidative stress, modifying lipid particles, which then attract cells of the monocyte-macrophage system. These cells phagocytose lipid particles and transform into foam cells. These cells produce pro-inflammatory cytokines (interleukin IL-1β and tumor necrosis factor alpha /TNF-α/), which attract more cells of both the innate and acquired immunity. Pro-inflammatory TH1 lymphocytes produce interferon gamma (IFN-γ). This activates the inflammasome, which activates IL-1, thereby triggering a systemic inflammatory response including the activation of IL-6, which induces the liver to produce C-reactive protein (CRP).
Continuing inflammation in the vascular wall leads to destabilization of the atheromatous plaque, the lipid core enlarges, a necrotic core forms, the fibrous cap thins, and plaques become prone to ulceration and rupture.
Several findings demonstrate the role of inflammation in the development of CV diseases:
- The first is the increased CV risk in patients with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, or psoriasis, which are all characterized by systemic inflammation.
- Even local inflammation leading to a systemic inflammatory response is sufficient to increase CV risk. For example, individuals with periodontitis have a 1.5× higher risk of myocardial infarction (MI) and a 2× higher risk of stroke.
- Another proof of the role of inflammation in the pathogenesis of CV diseases is the evaluation of genetic determinants of CV diseases. More than a quarter of the 400 known gene variants affecting CV risk are related to the immune system and inflammation.
- The relationship between inflammation and atherosclerotic diseases is also evidenced by the fact that increased inflammatory parameters predict CV risk. For example, elevated levels of high-sensitivity CRP (hsCRP) correlate with the risk of future coronary heart disease (CHD), and IL-6 levels correlate with the extent of atherosclerosis in coronary CT.
- A compelling proof of the role of inflammation in the development of CV diseases is the fact that reducing systemic inflammation decreases CV risk. In the JUPITER study, statin treatment reduced LDL cholesterol (LDL-c) levels by 50% and hsCRP levels by 37%, which was accompanied by a reduction in the risk of MI, stroke, and a 20% decrease in overall mortality.
The Role of Inflammation in Non-Atherosclerotic Heart Diseases
In aortic stenosis, inflammation plays a role. The mechanism is similar to the atherosclerotic process. Endothelial damage allows LDL-c and lipoprotein (a) to penetrate the valve interstitium, leading to inflammation. IL-6 and TNF-α activate smooth muscle cells, transforming them into osteoblast-like cells, causing micro and macrocalcifications, and the development of aortic stenosis. While statins effectively reduce LDL-c levels, angiotensin-converting enzyme inhibitors (ACEi) also suppress systemic inflammation. Clinical studies have shown that ACEi administration may slow the process of aortic stenosis.
Inflammation also contributes to the development of atrial fibrillation (AF). Activation of the inflammasome in the cardiomyocytes of the left atrium leads to an inflammatory response, and the subsequent apoptosis of cardiomyocytes and fibrosis is the basis for AF development.
Inflammation also affects the development of heart failure through the desensitization of beta-receptors and changes in calcium circulation in the sarcoplasmic reticulum. This supports the development of both systolic and diastolic dysfunction.
Inflammation and the Aging Process – the Concept of Inflammaging
It has been shown that signs of aging in the face can indicate an increased risk of CHD. The number of signs of facial aging correlates with the risk of coronary artery stenosis. The relationship between inflammation and aging is bidirectional. Inflammation accelerates atherosclerosis, increases the risk of CHD, heart failure, aortic stenosis, and AF, and decreases functional capacity. Conversely, with increasing age, systemic chronic inflammation intensifies, with increased levels of CRP and IL-6, deposition of abnormal proteins, and amyloid and transthyretin deposits activating the inflammasome and triggering a systemic inflammatory response. The microbiome also changes, with a higher prevalence of facultative anaerobic bacteria that potentiate systemic inflammation.
How to Use These Findings Therapeutically
The effect of canakinumab, a monoclonal antibody against IL-1β, was evaluated in patients after MI with elevated hsCRP levels. Canakinumab reduced hsCRP by 37%. Without clinically significant reductions in LDL-c levels, a statistically significant 15% reduction in the risk of major CV events was observed. However, canakinumab administration was associated with a significant increase in the incidence of sepsis and sepsis-related mortality, and therefore the drug was not approved.
Colchicine, which inhibits the inflammasome and reduces systemic inflammation, reduced the risk of major CV events (including MI, stroke, CV mortality, and coronary revascularization) by 31% in patients with chronic CHD compared to placebo. However, colchicine administration increased non-cardiovascular mortality and the risk of pneumonia. Therefore, colchicine is recommended only for patients after repeated CV events or when control of standard CV risk factors is not achieved.
Currently, we do not have an effective and safe therapy that targets only inflammation. Therefore, in patients with subclinical systemic inflammation, it is important to compensate for all standard CV risk factors – hypertension, dyslipidemia, obesity, diabetes, smoking, and intestinal microbiome composition. All these interventions lead to safe suppression of inflammation.
According to the 2023 guidelines of the European Society of Hypertension (ESH), it is recommended to achieve target blood pressure (BP) values of 120−129/70−79 mmHg. Early and appropriately indicated hypertension therapy with ACEi, due to their anti-inflammatory effect, offers an opportunity to simultaneously suppress systemic inflammation and reduce CV risks – in addition to BP reduction, it can also slow the process of aortic stenosis.
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Source: Wohlfahrt P. Inflammation and the CV Continuum. XXXII Annual Meeting of the Czech Cardiology Society, April 30, 2024.
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