CAN THE HEART REPAIR ITSELF? LATEST RESEARCH ON CARDIAC MUSCLE REGENERATION

The heart is one of the most vital and complex organs in the human body. The blood pumped by the heart delivers oxygen and nutrients to all tissues and removes waste products like carbon dioxide. The heart also plays a key role in regulating blood pressure, body temperature, and hormonal balance.

Various diseases and injuries can damage the heart tissue and impair its function, such as Coronary Artery Disease, Hypertension, Diabetes, and Myocardial Infarction (heart attack). Unlike other organs, heart muscle regeneration is highly limited, which is one reason why heart disease is one of the most fatal conditions and why there are so few treatment options. The World Health Organization cites cardiovascular diseases as the primary cause of mortality globally, accounting for nearly 18 million deaths in 2019. This makes up 32% of the global death rate. Of these mortalities, heart attack and stroke were responsible for 85%. 

Scientists have been researching ways to improve cardiac muscle tissue regeneration. Recent years have seen a few promising breakthroughs that are likely to change future outcomes for patients after heart attack and with heart disease or heart failure.

In this article, we will explore how the heart regenerates, why heart repair mechanisms fail, as well as review the latest research breakthroughs in cardiac muscle regeneration. Learn more about the prospective benefits of stem cell therapy, gene therapy, and tissue engineering for regenerating cardiac muscle below.

Can the Heart Heal itself? How the Heart Keeps Healthy

The simple answer to this question is yes; however, it takes a very long time and depends upon our overall health and well-being.

The heart is mostly composed of muscle tissue that is constantly contracting, making it susceptible to wear and tear. Naturally, the muscle cells of the heart have adapted in ways that allow them to work non-stop, unlike the skeletal muscle cells in our arms and legs, which are not permanently engaged in strenuous activity.

Calcium ions are essential for energy production and maintenance. In heart cells, calcium entering the cell triggers contraction, and calcium exiting the cell triggers relaxation via the calcium-sodium pump. In order to beat continually, cardiac tissue has one of the largest concentrations of mitochondria in the whole body. These help it to produce more energy, handle larger volumes of calcium to sustain the heartbeat 24/7, and minimize the impact of higher oxidation levels.

Oxidation is an ordinary part of energy production, yet when too high, it can lead to excessive inflammation, cell damage and eventual death. Mechanisms to preserve heart muscle integrity and prevent this scenario from occurring are reviewed below:

Cardiac Cell Repair

When oxidation levels are too high in each mitochondria, it can cause them to become damaged, lower energy production, and allow free radicals to leak from the mitochondria, leading to cellular damage as well. This raises inflammation levels and gets the immune system involved in repair.

In order to prevent this from happening, cardiomyocytes (heart muscle cells) have repair mechanisms in place that correct micro damages before they add up. These include:

• Autophagy^[1], which is a process that degrades and recycles damaged or unnecessary cell components, such as proteins, organelles, or pathogens.
• Mitochondrial Biogenesis^[2] or the growth of new, healthy mitochondria to sustain energy output.
• Hypertrophy, where the size and strength of heart muscle cells increase in order to adapt to new demands.

These repair mechanisms can become unbalanced due to too little or too much physical activity over a long period of time, nutritional deficits, a diet high in fat and/or glucose, as well as toxin exposure.

Cell Division and Growth

Cardiomyocyte proliferation is the process by which existing cardiomyocytes divide and produce new cells. In mammals, including humans, cardiomyocyte proliferation is very low and insufficient to compensate for the loss of cells after damage. This is because mammalian cardiomyocytes are mostly terminally differentiated, meaning that they have exited the cell cycle and cannot divide anymore.

Cardiac cell division is stimulated during exercise the most, which releases anti-inflammatory compounds, boosts metabolism, and stretches out the heart muscle tissue. Only a small fraction of cardiomyocytes, estimated at 1-3%, retain the ability to proliferate throughout life.

Moreover, cardiomyocyte cell division takes an exceedingly long time. Studies have shown that, of these cells capable of dividing, some take longer than 8 weeks to do so. The number and rate at which this occurs also lowers substantially through the aging process, which is when people are most vulnerable to contracting heart disease.^[3] At the age of 75, only 0.3% of cardiomyocytes are able to divide on average.

Stem Cells

Like all tissues, the heart has its own pool of stem cells that replace dead cardiomyocytes and contribute towards new blood vessel growth. Unlike other tissues, the number of stem cells available for repair is low and plummets substantially with aging. Cardiac stem cells during youth respond to small amounts of heart damage, actively replacing dead heart tissue. In an aged heart, these stem cells undergo changes that cause them to become faulty and activate prematurely, leading to reductions in their numbers and possible exhaustion.^[4]

Additionally, cardiac stem cell differentiation into cardiomyocytes is still low as opposed to other cell types, often leading to more fibroblast formation (connective tissue cells), which can increase the risk of scarring and heart stiffness.

Why the Heart Can’t Repair Itself After a Heart Attack

One of the main concerns that can limit heart repair would be a heart attack or acute myocardial infarction (AMI).

A heart attack occurs due to an interruption in the blood supply to the heart, which is usually the result of a blockage in a main artery. This deprives the heart tissue of oxygen and nutrients, leading to the death of cardiomyocytes and the formation of lesions and scars. Resultant scar tissue is stiff and non-contractile, reducing the pumping ability of the heart and increasing the risk of heart failure.

In a mild heart attack, the heart stands a chance of regenerating from the damage. However, in most typical heart attacks, up to a billion heart cells can die off at one time, which is roughly 25% of the entire cardiac cell population. In this scenario, heart damage is widespread, and the slow regenerative mechanisms of the heart struggle to keep up. The inflammation that arises as a result tends to impair cellular repair mechanisms and can lead to further cell death following the attack.

Furthermore, repair is slower in a heart after an AMI due to micro blood vessel damage. This compromises the higher need for oxygen and nutrients in aiding the repair process and lends itself towards further cardiac cell death.^[5]

Naturally, those with heart disease are more susceptible to a heart attack than the general population, as well as heart failure. All forms of heart disease often promote chronic inflammation in the heart tissue as well as problematic energy metabolism that can reduce regeneration.

Latest Research and Breakthroughs in Cardiac Muscle Regeneration

Despite the limited regenerative capacity of the human heart, there is hope for the future of cardiac muscle regeneration.

Researchers are developing and testing various strategies and technologies to stimulate and augment the regeneration process, such as stem cell therapy, gene therapy, and tissue engineering. These approaches aim to restore the function and structure of the injured heart by replacing lost cells, enhancing existing cells, lowering inflammation, and promoting better blood vessel growth.

Stem Cell Therapy

Stem cell therapy helps to replace the damaged cells and restore cardiac function by transplanting stem cells into the heart. Stem cells can be derived from various sources, such as the bone marrow, the blood, the adipose tissue, the umbilical cord, or induced pluripotent stem cells (iPSCs). iPSCs are stem cells generated by reprogramming adult cells, such as skin cells or blood cells, into an embryonic-like state, which can then be differentiated into various types of cells, including cardiomyocytes. This is currently at the forefront of cardiac regeneration.

So far, there have been around 60 different clinical trials testing the safety and efficacy of stem cells for heart repair after heart failure and heart attack. In these trials, stem cells from all sources appear to be safe and modestly reduce mortality rates, inflammation, and recurrent heart attacks. Preclinical studies demonstrate better cardiac function, improved autophagy and other repair mechanisms^[6], smaller scar sizes, and improved blood vessel formation. One advantage of stem cell therapy over other types of regenerative therapies is that stem cells don’t necessarily need to be implanted directly into the heart and may still promote heart regeneration when administered intravenously.^[7]

Despite all these promising treatments, results are still mixed and inconclusive, with stem cells not quite delivering the desired effects. Recent breakthroughs have managed to overcome previous challenges with stem cell heart implants, such as stem cell survival, graft rejection avoidance, and tumor formation^[8]. In the next couple of years, we will likely see the results of human clinical trials that are safe and highly effective.

CD34+ Stem Cell Therapy

One specific stem cell therapy currently being developed for treating acute myocardial infarction (AMI or heart attack) pertains to the use of CD34+ hematopoietic (bone marrow-derived) stem cells.

Scientists realized that these cells are released into the bloodstream a few hours after a heart attack to initiate the repair process. They have been shown to fill lesions caused by the AMI, promote cardiomyocyte and blood vessel regrowth, lower scar formation, and prevent further damage. These effects happen through the release of microRNAs, which increase the expression of regenerative genes in the heart.

While offering a fantastic response, it is not sustained for long enough for the heart to be repaired fully and ends after a few days. CD34+ therapy aims to prolong this regenerative response and effectively facilitate full recovery.^[9]

Gene Therapy

Gene therapy is the delivery of genes into the heart to modify the expression or function of the target genes and enhance the regeneration process. It can be achieved by using various vectors, such as viruses, plasmids, or nanoparticles, which can carry and transfer the desired genes into the heart cells.^[10]

Through making subtle genetic changes to cardiac cells, gene therapy can target various aspects of the regeneration process. It has been used with great success in preclinical trials to:

• Increase cardiomyocyte and cardiac stem cell numbers through increasing the expression of genes related to GATA4 and cyclin D2.
• Lower excessive inflammation by inhibiting the expression of genes coding for tumor necrosis factor alpha and other inflammatory compounds.
• Inhibit scar formation by reducing the expression of transforming growth factor beta genes.
• Help to better sync heart cells while beating to avoid arrhythmias, which can be achieved by increasing connexin 43 expression.

Gene therapy is also the backbone of tissue engineering and even some forms of stem cell therapy. It is required to produce specific cell lines that survive implantation into the heart, that can differentiate into cardiomyocytes or perform specialized functions due to being genetically altered.

In a gene therapy trial, a team of scientists managed to create cardiac muscle cells with four altered genes, which were capable of stabilizing the heartbeat of pigs and reducing arrhythmias by 95%^[11]. More therapies like these are expected to improve the accuracy and efficacy of treatment options after more trials take place to confirm their safety.

Tissue Engineering

Tissue engineering^[12] is the creation of artificial tissues or organs that can replace or support the function of damaged ones. Many attempts at transplanting viable heart tissue in order to mend heart damage have resulted in failure, with as many as 98% of the implanted cells dying off in the months following implantation. Tissue engineering aims to improve this process to eventually allow for full regeneration to occur.

Active areas of study include:

• Developing biocompatible implants that create a suitable cellular environment in cardiac tissue, allowing for viable implanted cells to attach and grow.
• Providing viable cells and nutrients for heart tissues and ensuring they land in the right areas. Hydrogels and cardiac patches are being investigated for this purpose.
• Genetic engineering of stem cells and cardiomyocytes for longevity.
• Biologic total or partial heart replacement through the 3D bioprinting of heart tissue and entire hearts.

Tissue engineering has shown promising results in preclinical and clinical studies, demonstrating the improvement of cardiac function, the reduction of the scar size, and the enhancement of the new blood vessel growth in the heart.

Despite the promise, more research and testing remains to be done in order for these techniques to be perfected.

Cardiac Patches

Cardiac patches are biomaterials that can be attached to the surface of the heart to provide viable cells and factors that promote the regeneration of damaged tissue. While cardiac grafts and patches are not new in the surgical treatment of heart deformities and other conditions, cardiac patches that are capable of evoking complete heart regeneration are currently being developed.

The University of Cincinnati is developing one such patch by modifying human stem cells and improving techniques to graft them into living heart tissues. The patch allows for excess fibroblasts to turn back into cardiomyocytes, which can reduce scarring, replenish lost cardiac muscle tissue and drastically improve outcomes. It also contains stem cells derived from blood and marrow that have been reverted to an embryonic state. These are capable of quickly changing into cardiomyocytes, as seen in utero. Further modifications allow for them to mature quickly, effectively replacing damaged heart tissue.

These contributions, coupled with extra cardiomyocytes that would be grafted with the patch into the heart tissue, could allow for complete heart regeneration. In time and more testing, the UC team’s work might end up revolutionizing medical facilities worldwide.^[13] Similar patches are also being developed to reverse congenital heart deformities^[14].

The Future and Potential Benefits of Cardiac Muscle Regeneration Therapy

By restoring the heart’s function and structure, cardiac muscle regeneration therapies can reduce symptoms and complications, improve life quality, and enhance well-being in those with heart failure and heart disease.

Regenerative therapies are expected to reduce healthcare costs in the next decade by reducing the need for medication, hospitalization, surgery, or transplantation and increasing productivity and independence.

Cardiac muscle regeneration techniques are likely to become so advanced in the future that the need for heart surgery and total heart replacement might be avoided entirely.

Conclusion

The heart is a vital and complex organ that has a limited capacity to regenerate after damage. However, there is hope for the future of cardiac muscle regeneration, as researchers are developing and testing various strategies and technologies to stimulate and augment the regeneration process, such as stem cell therapy, gene therapy, and tissue engineering.

These approaches aim to restore the function and structure of the injured heart by replacing the lost cells and enhancing existing cells. The potential for cardiac regeneration implies a future where surgery isn’t required, with many leading longer, better quality lives and saving on healthcare costs..

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