With over half a billion people affected worldwide and approximately 60 million new cases reported annually, cardiovascular diseases remain the leading global cause of mortality [source: World Heart Report 2024 – World Heart Federation, Ginevra].
Among these conditions, the loss of myocardial contractility due to the death of cardiac muscle cells (cardiomyocytes) – often resulting from a heart attack or cardiomyopathy – represents one of the most pressing healthcare challenges. The impact of this issue is further exacerbated by an ageing global population. This condition, known as heart failure, occurs when the heart is unable to pump sufficient blood to meet the body’s needs, failing to effectively supply oxygen to vital organs.
Data from Europe and North America highlight a shifting epidemiological trend, with a decline in the average age of heart failure patients. In the United States alone, nearly 7 million adults suffer from this condition, which accounts for 14% of all annual deaths. Significantly, mortality rates among younger patients are rising: between 1999 and 2019, heart failure-related deaths among individuals aged 15 to 44 increased from 2.36% to 3.16%, marking a steeper rise compared to patients over 75 [source: Global Epidemiology of Heart Failure – Nature Reviews Cardiology, June 2024].
TAKEAWAYS
Natural regeneration of healthy cardiac muscle
In a healthy human heart, cardiomyocytes retain the ability to renew themselves throughout life, albeit at a slow rate. This renewal occurs at approximately 0.5% per year in adulthood, meaning that over a lifetime, around 40% of ventricular cardiomyocytes are replaced. However, the extent to which this regeneration occurs in patients with heart failure remains unclear.
«The musculoskeletal system has a remarkable capacity for regeneration after injury. For example, if you tear a muscle while playing sports, resting is usually enough for it to heal», explains Hesham Sadek, researcher and director of the Sarver Heart Center at the University of Arizona. «By contrast, when the heart muscle is damaged, it does not grow back».
Previous studies have suggested that cardiac muscle cells might undergo significant regeneration following injury, such as a heart attack. However, proving this hypothesis has been particularly challenging. «Identifying and monitoring cardiomyocyte proliferation after myocardial injury is highly complex due to inflammation, scar formation, and the infiltration of other cell populations into the damaged area» [source: “A latent cardiomyocyte regeneration potential in human heart disease” – National Library of Medicine, 2023].
Cardiac muscle regeneration in heart failure patients
There is no cure for heart failure, though medications can slow its progression. In cases of advanced heart failure, the only alternative to transplantation is the surgical implantation of a Left Ventricular Assist Device (LVAD). This device helps the heart pump blood, reducing the workload on the cardiac muscle and prolonging the patient’s life [source: Centers for Disease Control and Prevention, May 2024].
A recent study, “A Latent Cardiomyocyte Regeneration Potential in Human Heart Disease” (published in Circulation, January 2025), led by an international team at the Sarver Heart Center, University of Arizona, has provided compelling evidence of cardiomyocyte renewal in patients with LVADs. The researchers observed that the heart tissue of patients with cardiomyopathy who were supported by these devices exhibited a higher rate of cardiomyocyte regeneration than what is typically seen in healthy hearts. As a result, these patients experienced a significant recovery of myocardial function.
Rest and cardiac muscle regeneration
This study was inspired by earlier research conducted at the University of Texas Southwestern Medical Center on the relationship between rest and cardiac muscle regeneration. That research highlighted that cardiomyocytes multiply actively during fetal development but that «their ability to proliferate ceases immediately after birth, as they must dedicate all their energy to continuously pumping blood, leaving no time for rest» [source: “Transient Regenerative Potential of the Neonatal Mouse Heart” – Science, 2011].
This finding led the international research team to question whether an LVAD might provide the cardiac muscle with a physiological equivalent of bed rest, similar to how rest aids muscle recovery following an injury.
The LVAD functions by pumping blood directly into the aorta, effectively bypassing the heart. This means that in patients with an LVAD, the myocardium remains in a state of relative rest, potentially creating an environment conducive to cardiomyocyte regeneration.
With this hypothesis in mind, the University of Arizona research team set out to investigate further. Let’s examine their findings.
Examining cardiac tissue
The study focused on laboratory analysis of human cardiac tissues. Healthy heart tissue was sourced from KI Donatum, a programme within the Karolinska Institute Stockholm, Sweden, which provides researchers with post-mortem samples donated with informed consent, either from the donor during their lifetime or from their next of kin after death.
Meanwhile, heart tissue samples from patients with advanced heart failure – collected from the left ventricle at the time of LVAD implantation, then sectioned and preserved at -80°C – were obtained from the Medical University of Graz (Austria), the Karolinska Institute Stockholm, Lund University (Sweden), and institutions affiliated with the Utah Transplantation Center in the United States.
The objective was clear: to investigate cardiomyocyte regeneration in patients with advanced heart failure, both with and without an LVAD, and to compare these findings with samples from individuals without cardiovascular disease.
A key initial finding from the research team was that in «patients without LVAD support, cardiomyocyte generation was significantly reduced compared to healthy individuals».
In contrast, patients with an LVAD displayed a marked increase in cardiac muscle cell renewal, supporting the hypothesis that the failing myocardium retains significant regenerative potential, provided it is mechanically unloaded with ventricular assist support. Let’s delve deeper into these findings.
Focus on DNA repair and reverse remodelling
To validate their hypothesis, the researchers concentrated on the DNA repair process following cardiac injury. They emphasised that, in laboratory settings, this process can sometimes «create a misleading impression of active cardiomyocyte renewal», even when this is not the case.
To clarify this, the team analysed single-cell RNA sequencing data from cardiomyocytes in both injured hearts without an LVAD and hearts from patients with an LVAD. Their findings revealed that «in both cases, most DNA repair genes were not differentially regulated, indicating that their expression remained similar».
The critical distinction lay in functional improvement of the cardiac muscle, a process the authors termed “reverse remodelling”.
Up until now, most studies on heart regeneration in rodents – both neonatal and adult – have observed increased cardiomyocyte proliferation following myocardial injury. However, even if new cardiomyocytes were generated, they would have a limited lifespan and a negligible effect on regeneration, due to the hostile microenvironment in failing hearts.
While these hearts can activate the cell cycle, they «fail to support complete and successful cell division».
Given this context, the Sarver Heart Center at the University of Arizona has now demonstrated that mechanical unloading and circulatory support via an LVAD can induce structural, cellular, and molecular changes in the compromised myocardium of patients with advanced heart failure. This leads to reverse remodelling, with «a cardiomyocyte renewal rate of 3.1% per year, approximately six times higher than the physiological renewal rate in healthy individuals».
Glimpses of Futures
This study marks the beginning of a new era in human cardiac muscle regeneration research, providing direct evidence supported by observations and data on DNA repair activity and the reverse remodelling process.
But what might the future hold? Using the STEPS framework, we can anticipate potential future scenarios by analysing the social, technological, economic, political, and sustainability impacts of these findings.
S – SOCIAL
The discovery of the regenerative potential of cardiomyocytes in the damaged adult human heart could, in the future, lay the foundation for new targeted therapies for patients with advanced heart failure. In particular, the findings from the Sarver Heart Center at the University of Arizona pave the way for further research into the molecular mechanisms involved in myocardial recovery and the development of new pharmaceutical strategies to enhance this process. One hypothesis to be tested in future laboratory studies is whether mechanical unloading and circulatory support via LVADs could reverse the production of free radicals, which are responsible for oxidative DNA damage. This damage, in turn, halts the cardiomyocyte cell cycle, preventing regeneration. If this hypothesis is confirmed, it could open up revolutionary new avenues for therapeutic intervention.
T – TECHNOLOGICAL
The next step, the authors explain, is to define the exact causal relationship between reverse remodelling, myocardial functional improvement, and cardiomyocyte renewal in the studied patients. The goal is to determine why some individuals exhibit a more pronounced cardiac muscle regeneration capacity than others. It is likely that phenotypic traits and genetic characteristics play a crucial role in this variability. For this reason, the findings published in Circulation could, in the future, be further explored using advanced genetic engineering techniques, beyond the already employed RNA sequencing. For example, genome editing could be used to identify and correct genetic errors within the genome itself that might be responsible for the failure of cardiac muscle cell regeneration following injury.
E – ECONOMIC
According to American Heart Association estimates, total healthcare costs associated with heart failure in the U.S. are projected to reach $53.1 billion by 2030, with hospitalisations accounting for 80% of this expenditure. A similar trend is seen in the European Union, where cardiovascular diseases currently impose an economic burden of €282 billion per year, equivalent to €630 per European citizen. In a future where cardiomyocyte regeneration in the damaged human heart becomes an established and exploitable biological process, researchers and clinicians will be able to develop targeted therapeutic strategies to activate and enhance this regeneration. As a result, global healthcare costs – both direct and indirect – associated with heart failure are expected to decline, easing the financial strain on healthcare systems worldwide.
P – POLITICAL
From a political perspective, initiatives such as the European Council’s resolution on cardiovascular health, adopted on 3 December 2024, and welcomed by the European Alliance for Cardiovascular Health (EACH), represent a significant step forward. Beyond strengthening prevention, early diagnosis, and screening efforts for all cardiovascular diseases – including heart failure – such policies also aim to secure adequate funding for innovative research projects. Furthermore, they help drive progress in therapeutic treatments by supporting digital health technologies and, as in this case, cutting-edge genetic engineering techniques. By fostering political commitment to cardiovascular research, these measures ensure that breakthroughs like cardiomyocyte regeneration receive the financial and regulatory backing necessary for clinical translation.
S – SUSTAINABILITY
The impact of this research must not be restricted by barriers to healthcare access, particularly for heart failure patients from ethnically diverse backgrounds or low-income regions. A key initiative in this regard is the JACARDI project (Joint Action on CARdiovascular diseases and DIabetes), a four-year EU programme launched in November 2023 with €53 million in funding from the European Commission. JACARDI aims to tackle the healthcare challenges posed by cardiovascular disease and diabetes in an inclusive manner, «with a specific focus on cultural and ethnic diversity among patients». It also prioritises gender equity, addressing the social dimensions of healthcare inequality in these two major disease areas.
