Stroke May Cause Scar Tissue in the Heart

Cardiac Scar Tissue After Stroke.

The consequences of stroke are long-lasting, not just on the brain but also on other parts of your body, including your heart.  A study published in the journal Cell includes some startling findings.  Dr Alba Simats and colleagues found that stroke triggers persistent inflammation in multiple organs, especially the heart. Through a complex immunological mechanism, the inflammation leads to the development of cardiac fibrosis (scar tissue formation within the heart muscle) in experimental stroke models, with evidence suggesting relevance to human stroke survivors.

They found that stroke triggers the release of a cytokine called interleukin-1β which promotes inflammation. This response is mediated by the innate immune system. Interleukin-1β induces innate immune memory in myeloid immune cells derived from the bone marrow, driving a persistent inflammatory response that leads to cardiac scar tissue formation. In turn, cardiac scar tissue causes diastolic dysfunction after ischemic stroke. One study found that 23% of acute ischaemic stroke patients had diastolic dysfunction. The long-term prevalence of diastolic dysfunction in stroke survivors is unclear.

Diastolic dysfunction can lead to a variety of serious problems, like atrial fibrillation, pulmonary hypertension, and fluid accumulation in the lungs. Symptoms may include fatigue, shortness of breath, and swollen ankles.

While the inflammatory and immunological consequences of acute brain injury are understood, the chronic effects of brain injury on systemic immunity are less certain.  This emerges as a problematic gap in our knowledge because we know that long-term morbidity after stroke is not just due to the brain injury itself but also to secondary comorbidities and complications. After a stroke, 63% of patients experience electrocardiographic (ECG) abnormalities, 25% develop serious arrhythmias, and approximately 19% experience at least one serious cardiac event.

What about Traumatic Brain Injury?

Whether or not the same applies to other types of brain injury, such as traumatic brain injury (TBI), is not certain. The relevant research is still outstanding. However, it is an immune response to damage in the brain that underpins these inflammatory effects. It is biologically plausible that related processes may occur after other forms of acquired brain injury, including TBI, but this has not yet been demonstrated in the same way. This possibility arises because of the common theme of inflammation in most types of brain pathology.

Types of Immunity

So, it is an immune response that causes these changes. Let’s understand that a little better…

The immune system comprises two primary divisions: innate immunity and adaptive immunity.  The innate immune system is the first responder, reacting immediately when foreign pathogens are detected.  The reaction of white blood cells to invasion is a good example of innate immunity.  The reaction is non-specific and irrespective of the identity of the intruder, white blood cells will react.

Adaptive immunity, on the other hand, is the response to specific pathogens.  Adaptive immunity requires that you have to have been previously exposed to the pathogen, whether because of infection or vaccination.  The adaptive immune system therefore remembers features of specific pathogens (antigens) and provides a focused, targeted immunological response to exactly that antigen.

Innate Immune Memory

Now, interestingly, in recent years, we have come to realise that the innate immune system is not quite so dumb and is also capable of learning and remembering.  Dr Simats and colleagues demonstrated that the innate immune response significantly increases inflammation in the heart after stroke.   Research that has examined cardiac structure and function after stroke provides some remarkable insights.  Simats et al. showed that cardiac muscle becomes stiffer after stroke because of increased left ventricular myocardial fibrosis, disrupting normal diastolic functioning.  They found that fibre disorganisation is evident in the myocardium (heart muscle) after stroke. 

Of specific relevance to innate immune memory, there is a higher infiltration of circulating monocytes and enhanced monocyte-to-macrophage differentiation in heart muscle after stroke.  Astonishingly, the Simats team found that within a month of stroke, the immune system replaces 95% of cardiac myeloid cells.  Myeloid cells are immune cells that come from bone marrow. A particular kind of monocyte (those with high levels of Ly6C) infiltrate cardiac muscle, following which the monocytes transform into a macrophage phenotype, triggering inflammation. 

Distinct chronic transcriptomic signatures appear in the brain after stroke.  These changes are indicative of innate immune memory.  Importantly for stroke survivors, these transcriptional changes are persistent and cause an ongoing inflammatory response. There may be ways to support inflammatory resolution, although whether this prevents post-stroke cardiac fibrosis has not yet been demonstrated clinically.

Cardiac Scar Tissue

Fascinating, isn’t it? Experimental stroke models show that stroke can trigger inflammatory processes that promote cardiac fibrosis, and preliminary human findings suggest this may also be relevant in stroke survivors. In other words, stroke may cause scar tissue in the heart. Of course, further research is needed before we can say this with certainty, but that is the direction in which the evidence currently points. Now let’s get a little more technical.

Understand this: cardiac myeloid cells (granulocytes, monocytes, macrophages, and dendritic cells from bone marrow) acquire a highly conserved distinct pro-inflammatory phenotype after stroke that is transmissible by bone marrow transplantation.  (Think about that a little…  If you would like the fine grain detail, have a look here.)  It means that cardiac immune cells undergo a change in how they are genetically expressed after stroke (a change in phenotype) and morph into cells that cause inflammation.

Furthermore, one of the things that Simats and colleagues did was, they took bone marrow from mice that had had strokes (and which had developed cardiac scar tissue) and implanted the bone marrow into healthy mice.  Interestingly, the healthy mice then developed the same cardiac fibrosis as seen in the stroke mice. That scarring arises as a consequence of innate immune memory that drives the inflammatory response after stroke. 

Maladaptation after Stroke

In this situation, the consequences of this immune response are maladaptive and create problems.  For instance, atrial fibrillation is more easily induced after stroke. Cardiac fibrosis is associated with arrhythmias, impaired cardiac function, and worse cardiovascular outcomes. Diastolic dysfunction is serious, as discussed.

In a sense, these are not surprising results.  After all, stroke results in damage to a central physiological control organ of the human body: the brain.  It figures that brain injury should be associated with a ripple effect that causes perturbations in our physiology, affecting not just the heart, but also other organ systems such as the gastrointestinal tract.  Autonomic brain–heart pathways, including vagal and sympathetic pathways, are likely part of the wider brain–heart context, but the Simats mechanism specifically emphasises inflammatory and immune signalling.

In other words, epigenetic reprogramming brings about a brain-heart perturbation. This physiological earthquake is triggered by interleukin-1β. In a nutshell, after a stroke the innate immune response causes a release of interleukin-1β and the resultant immunological cascade leads to cardiac scar tissue formation.

Preventing Cardiac Scar Tissue

Clearly, one would want to prevent these post-stroke cardiac problems. Myocardial fibrosis is not a benign finding. Across multiple cardiovascular conditions, the presence of cardiac fibrosis is associated with worse cardiac function, increased arrhythmia risk, heart failure progression, and increased mortality.  Cardiac abnormalities add to the long-term burden of stroke. Five years post-stroke death or physical dependency occurred in 79% of people who had a haemorrhagic stroke and in 70.6% of those who had ischaemic stroke. It’s serious.

Simats and colleagues tried blocking bone-marrow-to-heart migration of pro-inflammatory monocytes to prevent secondary cardiac comorbidity after stroke. They used a CCR2/CCR5 inhibitor and it worked to prevent cardiac fibrosis in their mice. Bristol-Myers Squibb are currently developing a CCR2/CCR5 inhibitor (BMS-813160). Although the drug has already been studied in human oncology trials, it has not yet been evaluated for preventing post-stroke cardiac fibrosis.

A Helping Hand

Another approach might be to block the effects of interleukin-1β. Fortunately, there have been substantial advances in our understanding of inflammation, especially the mechanisms involved in the resolution of inflammation.  In principle, treatments that promote the resolution of inflammation could potentially reduce the long-term cardiac consequences of stroke.

At Ormond Neuroscience, we have been using some remarkable supplements that change the way macrophages work, shifting macrophages from pro-inflammatory to pro-resolving states. Experimental evidence suggests that specialised pro-resolving mediators can reduce IL-1β and related inflammatory signalling pathways while promoting inflammatory resolution. These are nutritional lipid mediators derived from omega-3 pathways, but they should be discussed in the context of the person’s medical treatment. The mechanistic research underlying these pathways is substantial and continues to expand.

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Get in Touch

If you think that you may be at risk of post-brain injury cardiac abnormalities due to persistent inflammation, please get in touch with Ormond Neuroscience.

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Selected References and Further Reading

Balta, M. G., Loos, B. G., & Nicu, E. A. (2021). Emerging concepts in the resolution of inflammation: Specialized pro-resolving lipid mediators and their roles in inflammatory diseases. Frontiers in Immunology, 12, 632238. Frontiers in Immunology

Bisoendial, R. J., Birjmohun, R. S., Akdim, F., van ’t Veer, C., Spek, C. A., Hartman, D., … Stroes, E. S. G. (2009). C-reactive protein elicits white blood cell activation in humans. American Journal of the Medical Sciences, 337(6), 412–418. American Journal of the Medical Sciences

Doehner, W., Leistner, D. M., Audebert, H. J., Scheitz, J. F., & Endres, M. (2022). The role of cardiologists in stroke medicine: Time to broaden perspectives. Clinical Cardiology, 43(2), 95–103. Clinical Cardiology

Jiang, M., Li, Y., Li, X., & Xie, Y. (2021). Stroke-heart syndrome: Current progress and future outlook. ESC Heart Failure, 8(1), 16–29. ESC Heart Failure

Jin, R., Yang, G., & Li, G. (2010). Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. Journal of Leukocyte Biology, 87(5), 779–789. Journal of Leukocyte Biology

Julliard, W. A., Zaid, Y., & Gros, R. (2023). Specialized pro-resolving mediators: Immunoresolvents at the intersection of inflammation and tissue repair. Frontiers in Immunology, 14, 9962762. Frontiers in Immunology

Kamel, H., Iadecola, C., & Okin, P. M. (2016). Brain-heart interactions after stroke. Stroke, 47(3), 802–808. Stroke

Liesz, A., & Kleinschnitz, C. (2016). Regulatory T cells in post-stroke immune homeostasis. Journal of Neuroinflammation, 13, 248. Journal of Neuroinflammation

Ortega‐Gómez, A., Perretti, M., & Soehnlein, O. (2013). Resolution of inflammation: An integrated view. EMBO Molecular Medicine, 5(5), 661–674. EMBO Molecular Medicine

Scheitz, J. F., Nolte, C. H., Doehner, W., Hachinski, V., & Endres, M. (2018). Stroke-heart syndrome: Clinical presentation and underlying mechanisms. The Lancet Neurology, 17(12), 1109–1120. The Lancet Neurology

Simats, A., Ramiro, L., García-Berrocoso, T., Llovera, G., Torres-Moreno, D., López-Ramírez, M. A., … Chamorro, Á. (2024). Innate immune memory after brain injury drives inflammatory cardiac dysfunction. Cell, 187(8), 1984–2003.e24. Cell

Sposato, L. A., Hilz, M. J., Aspberg, S., Murthy, S. B., Bahit, M. C., Hsieh, C.-Y., … Hachinski, V. (2020). Post-stroke cardiovascular complications and neurogenic cardiac injury: JACC state-of-the-art review. Journal of the American College of Cardiology, 76(23), 2768–2785. Journal of the American College of Cardiology

Sugimoto, M. A., Vago, J. P., Perretti, M., & Teixeira, M. M. (2019). Mediators of the resolution of the inflammatory response. Immunological Reviews, 289(1), 65–79. Immunological Reviews

Takahashi, M. (2023). Innate immune memory and cardiovascular disease. Journal of Atherosclerosis and Thrombosis, 30(6), 741–753. Journal of Atherosclerosis and Thrombosis

Tian, Y., Liu, Y., Wang, T., Zhou, N., Kong, J., Shi, Y., & Wang, H. (2017). Resolution of inflammation: A new therapeutic strategy for ischemic stroke. Current Drug Targets, 18(14), 1716–1724. Current Drug Targets

Tu, W. J., Qiu, H. C., Liu, Q., Zeng, X. W., Zhao, J. Z., & Liu, Q. (2019). Elevated levels of interleukin-1β and stroke outcome. Stroke, 50(9), 2431–2438. Stroke