Role of Monocytes in Heart Failure and Atrial Fibrillation

attaching the interesting parts, I think this is pretty good education material. Everyone can skip to the bold part and read that first

George you going to like what they say here on Fish Oil. By the way, how can I tag people?






What About Atrial Fibrillation?
Atrial fibrosis is a hallmark of the structural cardiac remodeling that takes place in AF, causing an increase in the frequency of AF paroxysms, which, in turn, increase likelihood of progression to permanent AF.169 Atrial fibrosis has been observed in biopsies from patients with AF148 as well as in patients with specific risk factors predisposing to AF, such as valvular heart disease,170 dilated and hypertrophic cardiomyopathy,171 and advanced age.172

Structural heart remodeling in aging and heart disease is associated with fibrosis. With aging, there is a progressive enlargement of the extracellular compartment in the atrial septum attributed to accumulation of connective tissue fibers.173 This process is even more prominent in an HF model,174 where larger areas of fibrosis were observed, similar to the “replacement fibrosis” observed after tissue damage and cell death. Atrial fibrosis may, in itself, be sufficient to increase susceptibility to AF, as shown in mice with atrial fibrosis attributed to overexpression of TGF‐β1.175

Although there are strong indications from animal models that atrial fibrosis can be proarrhythmic,8 some questions regarding the role of atrial fibrosis as a substrate of AF are still unresolved. Experimental data linking inflammation and atrial fibrosis have been conflicting. Most recent data point to the upregulation of profibrotic factors, such as TGF‐β, and accumulation of collagen in the atrial interstitium.176 However, previous studies showed preserved interstitium despite changes in atrial architecture and myocyte characteristics.177 The discrepancy between the data can be partly explained by the findings that profibrotic factors may not accumulate over shorter time periods found in some studies, and that increased gene expression of markers of fibrosis may be the first sign of later fibrosis.178 Another proinflammatory peptide, TNFα, has been shown to be elevated in patients with chronic AF. Released largely by monocytes and macrophages, TNFα has been found at higher levels in patients with nonvalvular AF than those in sinus rhythm.179 This correlates with a more‐significant leuckocyte infiltration and more‐advanced fibrotic changes in the atria.

Some, but not all, human studies have confirmed excessive atrial fibrosis in chronic AF patients compared with those with sinus rhythm.180, 181 The degree of atrial fibrosis and profibrogenic status correlates with the persistence of AF.182 However, from these studies, it is unclear whether the fibrosis is caused by underlying structural disease leading to AF or by AF itself. Given that the degree of the underlying heart disease is not well documented in every study, it is currently difficult to establish the magnitude of effects of particular conditions to the development of atrial fibrosis in AF patients. Some insights into profibrotic effects of background cardiac pathology versus AF come from a comparison of structural heart disease patients with and without AF.170 In this study, AF itself has not been found to be associated with atrial fibrosis, but is instead related to the severity of the structural heart disease. Given the significant differences in AF pathogenesis among patients with or without structural heart disease, studies dedicated to nonvalvular AF would be essential to shed further light to the interactions between AF and connective tissue deposition in the atria.

The question therefore remains of how important atrial fibrosis is as a causative factor for AF in humans. Most animal models show that atrial dilation is accompanied by both atrial fibrosis and conduction disturbances, although conduction disturbances could also be observed in the absence of atrial fibrosis.183, 184 However, frequently used mice models of AF have significant limitations attributed to the fact that this species has a high physiological heart rate and thus AF induced in mice may not accurately reflect pathological processes in humans. In patients undergoing open heart surgery, degree of fibrosis does correlate with the occurrence of postoperative AF185 and with the recurrence of AF.181

Similar to AF, cardiac fibrosis is related to myocardial inflammation and oxidative stress secondary to infiltration of inflammatory cells, thus suggesting further pathophysiological links between the 2.186 The oxidative stress observed in these conditions is further amplified by stimulation of the renin angiotensin‐aldosterone system, which aids NADH oxidase release.187 IL‐1, IL‐6, TNFα, and MCP‐1 are all upregulated in AF predisposing to fibrotic changes and the related electrical and structural remodeling, typical of AF. The role of inflammation in AF development is highlighted by the correlation with C‐reactive protein (CRP) and has been found, in postoperative patients, to be a surrogate marker for predictor of new‐onset AF.188 Also, postablation CRP levels can be used as a marker for risk of recurrence.189

Further evidence on the role of cardiac fibrosis in AF comes from experimental and clinical studies demonstrating that prevention of atrial fibrosis can delay the development of AF. Several treatments (eg, statins, angiotensin‐converting enzyme inhibitors, AT1‐receptor blockers, fish oil, and glucocorticoids) have been proven to effectively delay the structural remodeling process and reduce AF burden in a variety of experimental models.190, 191, 192, 193, 194, 195 Several post‐hoc analyses of clinical trials and small‐scale, proof‐of‐principle studies indicate utility of such approaches in humans, but improvement of the patients' hemodynamics with normalization of atrial pressures might also have contributed to the beneficial effects of these compounds.196

The role of ventricular fibrosis in AF is less established. Patients with AF have more‐marked ventricular fibrosis than those with sinus rhythm.197 Although atrial and ventricular fibrosis are likely to share a common mechanism, there are much more‐limited findings of profibrotic gene expression in ventricular fibrosis in comparison with the atrium.198 TGF‐β seems to play a major role in ventricular fibrosis in AF, but further data are needed to establish the mechanisms that trigger its expression in the myocardium and the role of monocytes and macrophages as a source of TGF‐β in the heart.199



[www.ahajournals.org]



Edited 1 time(s). Last edit at 08/16/2023 11:16PM by Marco.

Thanks for posting this. It's interesting and informative.

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Marco
George you going to like what they say here on Fish Oil. By the way, how can I tag people?

Thanks Marco. It is interesting. No way to tag in our software.

the success of Statin, Glucocorticoids and Fish oil in reducing atrial fibrosis, is likely related in reducing inflammation, especially at myocardium.

If I'm understanding well this paper, IL‐1, IL‐6, TNFα, and MCP‐1 are upregulated during Afib, and are all causing remodeling of the heart by creating new fibrotic tissue. The goal may be to take something during Afib, that can decrease those inflammation markers to prevent atria remodeling or reduce it. I'm looking specifically into two peptides called BPC-157 and TB 500,

My other 2 cents are that normalizing DHEA and Testosterone level both decrease IL-6 and TNFa.

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Marco
My other 2 cents are that normalizing DHEA and Testosterone level both decrease IL-6 and TNFa.

My levels of TNF alpha & IL-6 are very low, but I've never had them tested during afib.

Interesting - thanks for posting Marco!

The left atria enlarges when in AF for extended periods but it also shrinks again when not in AF for several months (year?)
At least that was the case with my atria after being in permanent AF for about 4 months in 2015 (about age 65) and since in paroxysmal with months in sinus in between (subjective and not monitored).
Wonder if the fibrotic tissue stays or also remodels/goes away?

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Joe
Interesting - thanks for posting Marco!

The left atria enlarges when in AF for extended periods but it also shrinks again when not in AF for several months (year?)
At least that was the case with my atria after being in permanent AF for about 4 months in 2015 (about age 65) and since in paroxysmal with months in sinus in between (subjective and not monitored).
Wonder if the fibrotic tissue stays or also remodels/goes away?

I would think it remodels. I'm convicted there are ways to reverse the fibrosis in the heart, as there is in the liver and kidneys for example

It may be another topic, but how did you improve your AFib? if you ever wrote any post about it I would love to read it.