The research team, led by Lara Benning and Esther Irene Schwarz of the University Hospital Zurich, registered the project on PROSPERO and followed the Meta-analyses Of Observational Studies in Epidemiology checklist. They searched PubMed from 1977 through late 2025, screened titles, abstracts and full texts with two independent reviewers, and applied strict inclusion criteria: studies had to involve individuals with Duchenne muscular dystrophy specifically, report appropriate survival data such as median survival or age at death, and be published in English. Cohorts published more than once contributed only their earliest and most comprehensive dataset. The final pool comprised 44 retrospective and 9 prospective studies, most conducted in Europe, North America and Asia, with a median follow-up of about eight years and a median patient age of just over 14 years.

Statistically, the challenge was considerable, because most studies reported median survival without confidence intervals or interquartile ranges. The authors therefore conducted a meta-analysis of means, first verifying that the underlying distributions showed negligible skewness so that medians could reasonably stand in for means. Standard errors were derived from interquartile ranges using the Wan and colleagues approximation, from 95 percent confidence intervals using the Cochrane Handbook formula, or imputed from sample-size-weighted median standard errors where nothing else was available. For studies that published only Kaplan-Meier survival curves, median survival was reconstructed using a method described by Broomfield and colleagues. Between-study heterogeneity was estimated with restricted maximum likelihood, confidence intervals were adjusted with the Hartung-Knapp method, and random-effects models weighted each study by inverse variance.

The headline numbers are striking. Across all included studies, pooled median survival was 23.9 years. But when the investigators split the evidence by ventilation status, a deep divide appeared. In the 16 studies that included no ventilated patients, pooled median survival was 19.0 years, with a 95 percent confidence interval of 18.2 to 19.7 years and moderate heterogeneity. In the 33 studies that included ventilated patients, pooled median survival reached 28.9 years, with a confidence interval of 27.0 to 30.7 years, though heterogeneity here was extreme, with an I-squared statistic of 98.2 percent. Meta-regression confirmed the pattern quantitatively: each percentage-point increase in the proportion of ventilated patients within a study was associated with a measurable gain in median survival, and ventilation status alone explained roughly 64 percent of the between-study variation.

Equally important is what the cumulative meta-analysis revealed about time itself. When studies were ordered chronologically and the pooled estimate was recalculated with each new addition, median survival rose progressively in both ventilated and non-ventilated cohorts. Stratified by era, median survival moved from 18.8 years in cohorts from around 1980 or earlier, to 22.2 years by around 1990, 25.1 years by around 2000, and 28 years by around 2010, holding at 27.1 years in the most recent period. The trajectory means that a boy diagnosed today, with access to comprehensive care, can reasonably expect to live into his late twenties or thirties, and some patients in well-resourced settings are now reported to survive into their forties and beyond.

The analysis also delivered a nuanced verdict on drug therapy. Glucocorticoids, the anti-inflammatory steroids long used to preserve ambulation and upper limb function in children with Duchenne muscular dystrophy, showed no significant association with survival in the meta-regression, whether or not the analysis was adjusted for study period. In contrast, heart failure medications emerged as powerful predictors of longevity. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was significantly associated with longer median survival, explaining about 70 percent of between-study variation, and beta-blockers showed a similar association, though the authors caution that the beta-blocker finding rested on only six studies. All results remained consistent after adjustment for study period, and sensitivity analyses using alternative period classifications produced the same conclusions.

Perhaps the most consequential shift documented in the analysis concerns why patients die. In the earliest era, respiratory failure accounted for roughly 91.5 percent of deaths, the expected consequence of progressive diaphragm and intercostal muscle weakness. By the period around 1990, cardiac causes had risen to 57.1 percent of deaths, and in the most recent era other causes, including lower respiratory tract infections, gastrointestinal complications and adverse events related to anesthesia and surgery, contributed 45.7 percent. The overall median age at death climbed from 18.6 years in the earliest period to the mid-twenties in recent cohorts. In other words, ventilation has not merely extended life; it has rewritten the disease’s terminal chapter, transferring the burden of mortality from the lungs to the heart and to a widening spectrum of secondary complications.

That shift carries direct clinical implications. Progressive cardiomyopathy is now a major determinant of mortality, and a reduced left ventricular ejection fraction independently predicts earlier death, yet patients with Duchenne muscular dystrophy remain frequently undertreated for heart failure. Part of the problem is diagnostic: the standard New York Heart Association classification of heart failure relies on dyspnea and exercise intolerance, symptoms that skeletal muscle weakness confounds in non-ambulatory patients, so cardiac decline can be under-recognized until late. Current guidelines recommend starting ACE inhibitor or ARB therapy in late childhood, and prophylactic treatment has been linked to a survival benefit. The new meta-regression findings reinforce that recommendation, suggesting that early cardioprotective pharmacotherapy is one of the few modifiable factors clearly tied to longer life in this population.

The authors are candid about the limitations of their work. Assigning birth cohorts to periods was occasionally difficult because patients within single studies were born across wide intervals, and some studies had follow-up too short for death to occur or enrolled predominantly pediatric populations. Only about 38 percent of the pooled patients were deceased at the time of reporting, and mean age at death does not account for censoring. There is also the possibility of immortal-time bias in ventilated cohorts, since patients must survive long enough to receive ventilation. Incomplete reporting precluded detailed analyses of body mass index, glucocorticoid dosing, cough assist devices, scoliosis surgery and geographic variation, all of which may contribute to the pronounced heterogeneity. The team recommends that future studies report restricted mean survival time, the area under the Kaplan-Meier curve, as a more robust measure of average survival.

What emerges from the full picture is a disease transformed by systems of care rather than by any single drug. Non-invasive ventilation delivered through a nasal or facial mask, typically initiated around age twenty based on sleep studies and pulmonary function tests, marked the transformative step, and the analysis found no significant survival difference between non-invasive and invasive ventilation modalities, meaning patients can choose the approach that best preserves their quality of life. Forced vital capacity below one liter remains a strong negative predictor of mortality, and starting home ventilation slows the decline of lung function. But survival now depends equally on proactive cardiac surveillance, early heart failure management, and genuinely multidisciplinary teams spanning respiratory medicine, cardiology, neurology, rehabilitation, gastroenterology, nutrition, palliative care and mental health. Persistent disparities in outcomes across regions and healthcare systems suggest that the next frontier in Duchenne muscular dystrophy is not a molecule but equitable access to the care model that has already proven it can add a decade of life.

Subject of Research: Temporal trends in survival and causes of death in Duchenne muscular dystrophy

Article Title: Improving survival in Duchenne muscular dystrophy across eras: a systematic review and cumulative meta-analysis

Article References: Benning, L., Bousraou, Z., Gruber, B., Ulrich, S., & Schwarz, E. I. (2026). Improving survival in Duchenne muscular dystrophy across eras: a systematic review and cumulative meta-analysis. Journal of Neurology, 273(10), Article 564. https://doi.org/10.1007/s00415-026-14121-4

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14121-4

Keywords: Duchenne muscular dystrophy, survival, home mechanical ventilation, meta-analysis, cardiomyopathy, heart failure therapy, non-invasive ventilation, life expectancy, causes of death, glucocorticoids, dystrophin, multidisciplinary care

Leading the effort, cardiovascular researcher Emily R. Whelan and her colleagues, with radiation oncologist Bradford S. Hoppe and immunologist DeLisa Fairweather as co-senior authors, set out to answer a deceptively simple question that has never been systematically addressed in the laboratory. Mouse models of RIHD exist and are widely used to probe the molecular cascade that connects a dose of radiation to eventual cardiac dysfunction, yet, to the authors’ knowledge, no prior study had examined whether male and female mice respond differently to the same cardiac radiation exposure. Given that sex differences pervade cardiovascular medicine, from the prevalence of autoimmune myocarditis to the presentation of ischemic heart disease, the omission was conspicuous. The new work, the team reports, is the first translational study to demonstrate sex differences in RIHD in mice.

The experimental design was deliberately rigorous. Female and male BALB/cJ mice, an inbred strain frequently used in immunology and cardiology research, received a single 22 Gray dose of radiation delivered precisely to the whole heart through a C5 collimator in an X-ray machine. Twenty-two Gray is a substantial dose, calibrated to model the cardiac exposures accumulated during modern thoracic radiotherapy. Sham-treated control animals underwent identical anesthesia and were placed in the X-ray machine for the same duration but received zero radiation, ensuring that any differences observed could be attributed to the radiation itself rather than to the stress of the procedure. The investigators then tracked the animals across three carefully chosen time points: 24 hours after irradiation, capturing the innate response; day 10, representing the acute phase; and day 35, marking the transition into chronic disease.

At the cellular level, the earliest signature of injury was unmistakable in both sexes. By day 10, cardiomyocytes in the irradiated hearts carried double-stranded DNA breaks, the canonical lesion produced by ionizing radiation as it shreds the double helix. But the damage was not distributed equally. Female mice accumulated significantly more DNA damage than their male counterparts, a difference that reached high statistical significance. On its face, the finding seems paradoxical: the sex that ultimately fared worse clinically was not the one bearing more broken DNA. That dissonance became one of the study’s central puzzles, and its resolution appears to lie in what happened next inside the cells’ power plants.

To understand how the genome responded to the insult, the team performed bulk RNA sequencing of heart tissue at day 10, an approach that captures the activity of thousands of genes simultaneously. The transcriptomic landscape told a story of broad convergence. Both sexes mounted similar pathway-level responses, upregulating cellular repair programs in an attempt to patch the radiation damage, and both exhibited signatures of mitochondrial dysfunction, the progressive impairment of the organelles that generate the energy a beating heart demands. Radiation, in other words, pushed male and female hearts down many of the same molecular roads. But at a critical intersection, the paths diverged: female hearts significantly upregulated Pgc1α, the master transcriptional regulator of mitochondrial biogenesis and function, a change the males did not achieve to the same degree. Pgc1α acts something like a foreman for the cell’s energy infrastructure, coordinating the construction and maintenance of mitochondria, and its induction in females suggests a superior capacity to repair the mitochondrial damage that radiation inflicted on both sexes.

The structural consequences of radiation were visible in the vasculature as well. Radiation increased both vessel area and vessel wall thickness at day 10 and again at day 35, reflecting the vascular remodeling that is a hallmark of RIHD in patients. Here, however, the sexes traded places. By day 35, irradiated males displayed greater vessel area than irradiated females, indicating that the chronic vascular expansion was more pronounced in males. Vascular injury is thought to be a key upstream driver of radiation heart disease, since damaged endothelium promotes inflammation, thrombosis and the fibrotic scarring that stiffens heart tissue, so the male-predominant vascular remodeling foreshadowed the divergent clinical outcomes that followed.

By day 35, the two sexes had arrived at distinctly different destinations. Female mice developed mild cardiomyopathy, measurable but modest, without the hallmarks of aggressive disease. The males told a darker story: their hearts developed myocardial and perivascular fibrosis, the deposition of collagen scar tissue within the muscle itself and around the coronary vessels, along with the features of inflammatory dilated cardiomyopathy, abbreviated iDCM. In iDCM, immune-driven inflammation weakens and enlarges the heart chambers, impairing the pump’s ability to fill and eject blood. Consistent with this inflammatory phenotype, the male hearts showed elevated levels of interleukin-1β, a potent pro-inflammatory cytokine, together with adverse cardiac remodeling. The authors highlight this contrast as one of the study’s key findings: males developed worse cardiomyopathy than females, with elevated IL-1β, cardiac remodeling and inflammatory dilated cardiomyopathy, while females upregulated Pgc1α, which may have improved their heart function.

The implications for human medicine are potentially significant, though the authors are careful to frame them as a starting point rather than a conclusion. Radiation-induced heart disease is a leading cause of non-cancer mortality among long-term survivors of breast cancer and Hodgkin lymphoma, and cardiologists currently manage these patients with the same toolkit used for other forms of heart failure. If the biological mechanisms underlying RIHD differ between men and women, as this mouse study strongly suggests, then prevention strategies, monitoring protocols and even drug choices might eventually need to be tailored by sex. A therapy that bolsters mitochondrial repair, for instance, might conceptually benefit patients whose hearts fail to mount a Pgc1α response, a pattern the data associate with the more severe male phenotype. The elevated IL-1β in males likewise points toward inflammation as a sex-biased therapeutic target, an avenue already being explored in other inflammatory cardiovascular conditions.

The study also carries a methodological message for the research community. Preclinical cardiovascular research has historically leaned heavily on male animals, a practice that regulatory agencies and scientific funders have spent the past decade working to reverse. Had the Mayo Clinic team studied only one sex, they would have produced an incomplete and potentially misleading picture of radiation heart disease: a male-only study would have overstated the severity of RIHD, while a female-only study would have understated it. By running both sexes in parallel with sham controls, identical dosimetry and multi-omics readouts spanning histology, cytokine measurement, echocardiography and transcriptomics, the investigators captured the full divergence of the two phenotypes.

Much remains to be learned. The authors themselves emphasize that further research is needed to better understand the mechanisms driving sex differences in RIHD using translational animal models, and the 35-day window, while sufficient to reveal chronic fibrosis and iDCM in this sensitive strain, is brief compared with the years over which human RIHD unfolds. Hormonal influences, immune cell composition, X-chromosome-linked gene dosage and differences in DNA damage repair capacity are all plausible contributors that the current study raises but does not resolve. What the work delivers, convincingly, is proof of principle: the heart’s response to radiation is not sex-neutral. For the growing population of cancer survivors living with irradiated hearts, that recognition may prove to be the first step toward care that accounts for the biology of the patient as fully as it accounts for the physics of the beam.

Subject of Research: Sex differences in the cardiac response to radiation in a mouse model of radiation-induced heart disease

Article Title: Sex differences in a mouse model of radiation-induced cardiomyopathy

Article References: Whelan, E. R., Perona, E. E., Fliess, J. J., Kocsis, S. C., Weigel, G. J., McCabe, E. J., Hamilton, C., Di Florio, D. N., Balamurugan, V., Beetler, D. J., Macomb, L. P., Strandes, M. W., Wilson, F. C., Murphy, E. F., Darakjian, A. A., Watkins, M. M., Puls, A. M., Hartmoyer, C. J., Bonvie-Hill, N., … Fairweather, D. (2026). Sex differences in a mouse model of radiation-induced cardiomyopathy. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00998-3

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00998-3

Keywords: radiation-induced heart disease, sex differences, cardiomyopathy, mitochondrial dysfunction, Pgc1α, fibrosis, inflammation, DNA damage, vascular remodeling, interleukin-1β, BALB/c mice, radiotherapy

The biology underlying Friedreich ataxia begins with the FXN gene, which encodes frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and cellular energy metabolism. When functional frataxin falls below a critical threshold, patients develop progressive cerebellar ataxia, loss of deep sensory pathways, hypertrophic cardiomyopathy, scoliosis, and an elevated risk of diabetes. Roughly 96 percent of disease-causing alleles involve expansion of a GAA repeat in the first intron of FXN, which silences transcription without altering the protein sequence itself. The remaining 4 percent of pathogenic alleles consist of intragenic variants such as missense changes, nonsense mutations, splice variants, and deletions of varying size. Patients carrying two pure GAA expansions show a reasonably consistent relationship between the length of the shorter repeat, known as GAA1, and clinical severity, which has made genetic testing a powerful prognostic tool.

That predictability breaks down, however, in a subset of patients whose disease course is far more aggressive than their apparent repeat lengths would suggest. A recent investigation into this discrepancy uncovered a surprising mechanism: in roughly half of individuals who seemed by long-range PCR to carry two expanded alleles of the same size, one of the two alleles was not being amplified at all. The test was effectively blind to one allele, producing the false conclusion of homozygosity for identical repeats. Most of these individuals turned out to carry expanded composite repeats, complex rearranged repeat structures that evade standard amplification, but a small number harbored something even more consequential: deletions of the proximal portion of the FXN gene, encompassing the promoter and early exons, which abolish production of frataxin from that allele entirely.

The new report, led by investigators at the Children’s Hospital of Philadelphia using records from the Friedreich Ataxia Clinical Outcome Measures Study, presents the clinical features of patients carrying these covert proximal deletions alongside one expanded GAA allele. The prototypic case is particularly striking. Patient 1 was diagnosed at age six with ataxia superimposed on a pre-existing diagnosis of hypertrophic cardiomyopathy. He lost the ability to walk at age 12, developed diabetes at 13, and suffered severe vision loss at 16. Initial genetic testing had indicated that he inherited two GAA expansion alleles of similar length from his carrier parents. The unraveling of that conclusion came through his younger sister, who developed Friedreich ataxia at age 10 and was found to carry two pure GAA expansions of clearly distinct sizes, 490 and 990 repeats. The genetic mismatch between siblings who shared the same parents prompted deeper analysis.

Long-read whole genome sequencing using Oxford Nanopore Technology, confirmed by a custom PCR assay, resolved the puzzle. Patient 1 had inherited only one GAA-expanded allele; his second allele carried a de novo deletion removing the FXN promoter, exon 1, and part of intron 1. Because the deletion eliminated the sequences targeted by standard diagnostic PCR, the allele appeared simply absent from the analysis, mimicking homozygosity for two similar repeats. The contrast between the siblings is clinically dramatic: Patient 2, carrying two expanded repeats but no deletion, had a much milder course, with no cardiomyopathy and no loss of ambulation at her most recent clinic visit, while her brother with the silent deletion deteriorated rapidly through childhood and adolescence.

The researchers extended the comparison to a broader set of patients with null variants of FXN, alleles that produce no functional frataxin at all. Across sixteen patients with deletions ranging from the proximal promoter region to distal exons, and including frameshift and start codon mutations, a consistent pattern emerged. All affected individuals showed ataxia and at least mild dysarthria early in their course. Those with proximal deletions tended toward early disease onset, with cardiomyopathy and scoliosis appearing in childhood. Poor weight gain and appetite, a recognized endocrine feature of Friedreich ataxia, developed in all patients with deletions, and one patient with a small frameshift variant required placement of a gastric feeding tube for nutrition. Yet the picture was not uniformly grim: a few individuals carrying shorter GAA alleles on their second copy, including one patient with a start codon mutation paired with a repeat of only 68 triplets, remained remarkably mild, with onset as late as age 41 and none of the major complications.

To quantify the impact of null alleles, the team compared the deletion and null variant group with a large cohort of 478 patients homozygous for two expanded GAA alleles. The mean shorter repeat length was statistically indistinguishable between groups, 667 plus or minus 235 repeats in the homozygous cohort versus 734 plus or minus 228 in the deletion group, yet the clinical outcomes diverged sharply. Patients with null variants had a lower average age of onset, 8.3 years versus 12 years, and dramatically higher rates of cardiomyopathy, 93 percent versus 61 percent, a difference that reached statistical significance. Age at death also differed significantly, with 32 percent of the deletion group deceased compared with 9 percent of the homozygous repeat group. Trends toward more frequent diabetes, scoliosis surgery, and vision loss from optic neuropathy were also observed. The conclusion is inescapable: a null allele, which contributes no frataxin whatsoever, produces a more severe phenotype than a second expanded repeat, which still permits a trickle of residual gene expression.

These findings carry a direct message for clinical practice. Patients who appear by commercial testing to carry two identical expanded alleles but who show an unexpectedly severe, even if otherwise typical, Friedreich ataxia phenotype should be evaluated further for an undetected deletion. Conversely, patients with one expanded allele, one apparently normal allele, and a severe phenotype should prompt a search for a null non-GAA variant, while a single expanded allele with a normal second allele and an atypical phenotype more often points toward a missense variant, though exceptions exist. The diagnostic gap exists because standard PCR-based assays target sequences within the proximal gene that are precisely the regions missing in these covert deletions. Long-read whole genome sequencing, which can traverse the entire locus and reveal structural rearrangements, proved essential for detection, and the authors demonstrated that a targeted custom PCR assay can confirm the findings once the deletion is known.

Beyond diagnosis, the study refines the statistical architecture of Friedreich ataxia prognosis. Conventional severity models treat GAA1, the shorter of the two expanded repeats, as the primary determinant of disease course, and for good reason: GAA1 length alone accounts for an R-squared of roughly 0.4 to 0.5 in predicting various clinical parameters, because it best indexes residual FXN transcription. GAA2, the longer repeat, is usually omitted from models because its values are correlated with GAA1 and its independent contribution is difficult to isolate. The new data suggest that in extreme cases, particularly when one allele is a complete null, GAA2 length can further refine severity predictions, explaining some of the variance that GAA1 alone leaves unaccounted for. Patient 11, with a 68-repeat allele paired with a null variant and a remarkably mild course, illustrates how much protective information a short second allele can carry even when its partner produces no protein at all.

The broader significance of this work extends to the growing recognition that Friedreich ataxia is more genetically heterogeneous than standard testing implies. As long-read sequencing becomes more accessible, previously invisible structural variants such as composite repeats and proximal deletions are likely to be uncovered in increasing numbers, reshaping prevalence estimates and improving the accuracy of genetic counseling for families in which recurrence risk depends on knowing exactly what each parent carries. For patients, an accurate molecular diagnosis is the gateway to emerging therapies, including frataxin-enhancing compounds and gene-based approaches currently in development, many of which assume intact target sequences within the FXN gene. Knowing whether a patient’s second allele is a long repeat or a deletion may ultimately influence which therapeutic strategy is appropriate. What began as a puzzling discrepancy between two siblings has exposed a systematic blind spot in Friedreich ataxia genetics, one that the field can now begin to correct.

Subject of Research: Covert proximal FXN gene deletions in compound heterozygote Friedreich ataxia patients

Article Title: Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions

Article References: Lazaropoulos, M. P., Devore, M. C., Lam, C., Park, C., Bidichandani, S., & Lynch, D. R. (2026). Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions. Annals of Clinical and Translational Neurology, 13(10), 2134-2137. https://doi.org/10.1002/acn3.70408

Image Credits: AI Generated

DOI: 10.1002/acn3.70408

Keywords: Friedreich ataxia, FXN gene, frataxin, GAA repeat expansion, genetic testing, long-read sequencing, compound heterozygote, gene deletion, cardiomyopathy, ataxia, null variants, genetic diagnosis

The research team, led by Javier Sanmartin and Roberto Elosua of the University of Vic-Central University of Catalonia, followed PRISMA guidelines and prospectively registered their protocol in PROSPERO. They searched PubMed, Scopus, and Web of Science from database inception through September 2023, with an updated search extending to June 2025. From 5,963 initially identified articles, the investigators retained 115 original studies after removing duplicates and screening titles, abstracts, and full texts. Risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal Tool for Cross-Sectional Studies, and pooled estimates were generated using random-effects models with the Freeman-Tukey double arcsine transformation for proportions.

The headline number is 4 percent. Using the International-Seattle criteria, which define T-wave inversion as a negative T-wave of at least 1 millimeter in two contiguous leads, the pooled prevalence among athletes older than 16 years was 4 percent, with a 95 percent confidence interval of 3 to 6 percent. That figure, however, masks enormous variability: individual studies reported prevalences ranging from 0 to 42 percent, and the between-study heterogeneity, quantified by the I-squared statistic, exceeded 80 percent in most meta-analyses. The authors caution that the pooled estimate should be interpreted with this heterogeneity firmly in mind.

Location on the electrocardiogram matters enormously. Inversions were most common in the anterior leads V2 through V4, at roughly 3 percent, while inferior leads showed about 1 percent and lateral leads essentially 0 percent. This anatomical gradient carries clinical weight because lateral T-wave inversion is the pattern most frequently linked to confirmed structural heart disease. In the studies that evaluated cardiomyopathies among athletes with T-wave inversion, the most commonly identified conditions were hypertrophic cardiomyopathy, arrhythmogenic ventricular cardiomyopathy, and dilated cardiomyopathy, and lateral-lead inversions were disproportionately represented among those diagnosed.

Ethnicity emerged as a major modifier of prevalence. Black athletes showed an overall T-wave inversion rate of 13 percent, compared with 3 percent in Caucasian athletes, a difference consistent with known genetic, endocrine, and hemodynamic factors, including greater myocardial wall thickness and left ventricular mass. Notably, recent work cited in the review found that geographical origin within Africa also matters, with repolarisation abnormalities significantly more common among West African and Middle African athletes than among those from East or North Africa. Sex differences were smaller but present: women showed a slightly higher overall prevalence than men, 7 percent versus 5 percent, driven by anterior and inferior leads.

Perhaps the most striking comparative finding is that T-wave inversion is roughly 49 percent more common in athletes than in non-athletes. Across 14 studies that included control populations, the pooled prevalence ratio was 1.49, with a confidence interval of 1.13 to 1.97. The effect was strongest in the inferior leads, where the ratio reached 1.70. This supports the idea that intense training itself, through ventricular remodeling and autonomic changes, produces repolarisation patterns that would be considered abnormal in a sedentary person but are often physiological in an athlete.

The mechanisms behind these training-related inversions are diverse. The authors describe ventricular remodeling effects, including a high papillary muscle to left ventricular mass ratio and lateral displacement of the cardiac apex, which can explain anterior inversions. Structural variants such as left ventricular false tendons have also been implicated. Enhanced vagal tone in trained athletes activates acetylcholine-controlled potassium channels, reducing the action potential gradient between the epicardium and endocardium and altering the repolarisation vector. Myocardial ischemia, by contrast, can invert the repolarisation gradient in a pathological direction, which is one reason the finding cannot simply be dismissed.

Age adds another layer of nuance. In athletes aged 16 or younger, a juvenile T-wave inversion pattern in leads V1 through V3 is considered a normal variant, reflecting right ventricular dominance in early adolescence, and it generally regresses after age 16. The meta-analysis found this juvenile pattern in about 6 percent of young athletes. Interestingly, meta-regression identified age as the only variable that partially explained the heterogeneity between studies, with older athletes showing higher prevalence, a relationship the authors attribute to cumulative lifetime training volume.

On the critical prognostic question, the picture is murkier. Among 34 studies that assessed structural cardiomyopathies in athletes with T-wave inversion, most reported disease prevalence below 1 percent, though nine studies found rates between 1 and 10 percent and six exceeded 10 percent, likely reflecting deeper inversions, lateral predominance, referral-center recruitment, and more sensitive imaging such as cardiac magnetic resonance. Follow-up data were similarly heterogeneous: annual incidence rates of newly diagnosed cardiomyopathy ranged from 0 to 54.9 cases per 1,000 athletes, and major cardiovascular events ranged from 0 to 83.33 per 1,000 athlete-years. The authors attribute this wide spread to small samples, short follow-up, and selection biases, leaving the true event risk statistically uncertain.

The clinical message is a careful balance. T-wave inversion in athletes is more common than in the general population, most often involves the anterior leads, and frequently reflects benign exercise-induced remodeling, particularly in Black athletes and in younger age groups. Yet because it can also herald hypertrophic, arrhythmogenic, or dilated cardiomyopathy, especially when it appears in lateral leads or is accompanied by ST-segment depression, a thorough evaluation remains essential. The authors call for international, standardized, prospective studies with adequate sample sizes, uniform diagnostic protocols incorporating echocardiography, exercise testing, Holter monitoring, and cardiac magnetic resonance, and long-term follow-up to finally pin down which athletes with inverted T-waves truly need to worry.

Subject of Research: Prevalence and prognostic significance of T-wave inversions on electrocardiograms in athletes

Article Title: Frequency and Prognostic Significance of T-wave Inversions in Athletes: A Systematic Review and Meta-analysis

Article References: Sanmartin, J., Cartanya-Bonvehi, J., Valenzuela, H., Carballeira, L., Montserrat, S., Baranchuk, A., & Elosua, R. (2026). Frequency and Prognostic Significance of T-wave Inversions in Athletes: A Systematic Review and Meta-analysis. Sports Medicine – Open, 12(1), Article 147. https://doi.org/10.1186/s40798-026-01115-9

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01115-9

Keywords: T-wave inversion, athletes, electrocardiogram, sudden cardiac death, cardiomyopathy, sports cardiology, meta-analysis, athlete's heart, ECG screening, ventricular remodeling, hypertrophic cardiomyopathy, prevalence

The research team, led by Yi Zhang and Xiaoyun Feng of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, together with colleagues including corresponding authors Han Wang and Lei Zhang, set out to answer a deceptively simple question: when hyperthyroid patients complain of cardiac symptoms, show abnormal electrocardiograms, or display elevated cardiac biomarkers, is something actually changing inside the heart muscle? Hyperthyroidism has long been associated with increased cardiovascular risk and heart failure, yet a definite, demonstrable link between the hormonal state and cardiomyopathy has remained elusive in the clinical literature. Conventional measures of heart function often look reassuringly normal in these patients, leaving clinicians without an objective marker of early tissue injury.

To probe that question, the investigators conducted a single-center retrospective study comparing 41 hyperthyroid patients who had undergone clinically indicated cardiac magnetic resonance examinations with 31 healthy volunteers serving as controls. Crucially, the patients were not scanned on a whim: each had suspected cardiac involvement, defined by cardiac symptoms, electrocardiographic abnormalities, or elevated cardiac biomarkers such as type B natriuretic peptide or creatine kinase-MB. All participants underwent standardized CMR scanning, allowing the team to compare myocardial tissue characteristics, chamber volumes, mass, and function across the two groups using identical protocols.

The centerpiece of the study was multiparametric CMR, a suite of advanced magnetic resonance techniques that go far beyond the anatomical snapshots of echocardiography. Native T1 mapping measures the intrinsic relaxation time of hydrogen protons in heart tissue without contrast agents; because T1 values shift when the myocardial composition changes — whether through fibrosis, edema, or expansion of the space between cells — the technique acts as a molecular-scale biopsy of the living heart. The researchers also measured T2 values, which are sensitive to water content and inflammation, and calculated the extracellular volume fraction, or ECV, which estimates the proportion of the myocardium occupied by space outside cells, a recognized surrogate for diffuse fibrosis. Feature-tracking analysis of cine images yielded global longitudinal, circumferential, and radial strain, quantifying how much the heart muscle deforms with each beat.

The results were striking in their specificity. Hyperthyroid patients with suspected cardiac involvement had significantly higher myocardial native T1 values than controls — 1301.8 plus or minus 38.5 milliseconds versus 1270.0 plus or minus 19.6 milliseconds, a difference that was highly significant statistically. Because elevated heart rate, age, sex, and body mass index can all influence T1 measurements, the team re-ran the analysis with statistical adjustment for these confounders. The difference persisted: an adjusted difference of 20.89 milliseconds, with a 95 percent confidence interval of 3.08 to 38.71 and a P value of 0.022. In other words, the tissue-level signal was not an artifact of faster hearts or different body compositions — it reflected a genuine alteration in the myocardium itself.

Equally informative was what did not change. The researchers found no intergroup differences in left ventricular T2 values, global myocardial strain, left ventricular mass, or left ventricular ejection fraction. That pattern matters. T2 remained normal, arguing against overt myocardial edema or active inflammation, and strain and ejection fraction remained preserved, meaning the hearts were still pumping effectively and deforming normally by conventional metrics. Yet native T1 — the most sensitive indicator of subtle tissue remodeling — had already shifted. The study thus captures cardiac involvement at a stage where standard functional measures are still silent, a window that could prove decisive for early intervention.

The team also explored how the tissue changes relate to the hormonal storm driving them. In exploratory correlation analyses within the hyperthyroid group, the extracellular volume fraction showed a positive correlation with free triiodothyronine (FT3, r = 0.445, 95 percent CI 0.142 to 0.672, P = 0.006) and with total triiodothyronine (TT3, r = 0.363, 95 percent CI 0.044 to 0.615, P = 0.027). Triiodothyronine, or T3, is the biologically active thyroid hormone that drives cellular metabolism, and its excess is known to promote tachycardia, increased cardiac output, and structural remodeling in animal models. The correlation suggests that the greater the hormone excess, the more the extracellular compartment of the heart muscle expands — a dose-response relationship that strengthens the case for a causal link.

That said, the authors were careful about the robustness of this hormonal association. After adjustment for hematocrit, age, heart rate, and body mass index, the correlation with FT3 remained statistically significant (r = 0.357, 95 percent CI 0.037 to 0.610, P = 0.030), but the association with TT3 was attenuated and no longer reached significance (r = 0.304, 95 percent CI -0.023 to 0.571, P = 0.068). Hematocrit adjustment is particularly important for ECV measurements, since the technique relies on comparing blood-pool and myocardial T1 values before and after contrast administration, and anemia or hemoconcentration can bias the calculation. The partial survival of the FT3 association after these corrections lends cautious support to the idea that active thyroid hormone levels track with myocardial extracellular expansion, though larger prospective cohorts will be needed to confirm it.

Why does any of this matter beyond the imaging physics? Hyperthyroidism affects millions of people worldwide, most commonly women, and its cardiac complications — atrial fibrillation, heart failure, and increased mortality — are among the leading causes of excess risk in these patients. Yet the concept of hyperthyroid cardiomyopathy has hovered in a diagnostic gray zone: patients report palpitations, breathlessness, and fatigue; their ECGs show abnormalities; their biomarkers creep upward; but their echocardiograms and standard CMR assessments often look normal, and the label of a distinct thyroid-driven heart muscle disease has lacked objective tissue-level confirmation. Native T1 mapping now provides exactly that. A rise of roughly 30 milliseconds in unadjusted T1, and over 20 milliseconds after adjustment, may sound numerically modest, but in the world of T1 mapping such shifts are comparable to those seen in early diffuse fibrosis from other systemic diseases, and they occur before ejection fraction falls.

The study’s conclusions are measured but consequential: T1-mapping can detect myocardial tissue alterations among hyperthyroid patients with clinical suspicion of cardiac involvement. For clinicians, the implication is that multiparametric CMR — and native T1 mapping in particular — could become a valuable tool for identifying which hyperthyroid patients have genuine myocardial involvement, stratifying risk, and potentially monitoring whether tissue changes reverse as thyroid hormone levels are brought back under control. For researchers, the ECV-hormone correlations open a mechanistic thread worth pulling: if excess T3 drives extracellular matrix expansion in the myocardium, then early and aggressive hormonal control might prevent the progression from reversible tissue change to established fibrosis and heart failure. The study, approved by the institutional ethics review board of Shanghai General Hospital and supported by the National Natural Science Foundation of China and the Shanghai Municipal Commission of Education, is retrospective and modest in size, and its single-center design means the findings await replication. But as a proof of concept, it demonstrates that the heart of a hyperthyroid patient is not merely beating faster — it is quietly, measurably changing its composition, and for the first time medicine has a noninvasive way to see it.

Subject of Research: Myocardial tissue changes detected by multiparametric cardiac MRI in hyperthyroid patients with suspected cardiac involvement

Article Title: Myocardial tissue characteristics assessed by multiparametric CMR in hyperthyroid patients with suspected cardiac involvement

Article References: Myocardial tissue characteristics assessed by multiparametric CMR in hyperthyroid patients with suspected cardiac involvement. (n.d.). https://doi.org/10.1186/s12880-026-02807-0

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02807-0

Keywords: hyperthyroidism, cardiac magnetic resonance, native T1 mapping, extracellular volume fraction, myocardial strain, thyroid hormone, cardiomyopathy, heart failure, triiodothyronine, BMC Medical Imaging, myocardial fibrosis, CMR imaging

The team began with a strikingly simple question: if you look at the complete inventory of proteins in a failing left ventricle, do hearts that failed for different reasons actually look different from one another? To answer it, they used high-resolution mass spectrometry to quantify 3,788 proteins in cardiac tissue samples collected from patients undergoing advanced care, alongside non-failing control hearts. The patients spanned ischemic cardiomyopathy, dilated and hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, myocarditis, adult congenital heart disease and non-ischemic dilated cardiomyopathy, among other diagnoses. Statistical models adjusted for age, sex and batch effects compared protein abundance in each etiology group against controls.

The first major finding was one of convergence. When patients were grouped by clinical diagnosis, the vast majority of significantly altered proteins were shared across etiologies rather than unique to any single one. Upset plots and enrichment analyses showed that common changes dwarfed diagnosis-specific ones, and functional enrichment mapped all the heart failure groups onto a shared landscape: metabolic reprogramming, altered contractile machinery, extracellular matrix remodeling and inflammatory signaling appeared everywhere. In other words, by the time the heart reaches end-stage failure, the terminal proteomic state looks remarkably similar regardless of what started the decline. This convergence echoes earlier single-nucleus RNA sequencing work, which likewise found common transcriptional signatures across cardiomyopathies, and it helps explain why a one-size-fits-all therapeutic approach has historically achieved only incremental gains.

But convergence at the disease endpoint was only half the story. When the researchers abandoned clinical labels altogether and let an unbiased computational method, non-negative matrix factorization, sort patients purely by proteomic similarity, the cohort split cleanly into two groups. Group 1 and Group 2, comprising 59 and 63 patients with reduced ejection fraction respectively, cut across every clinical etiology: a patient with ischemic disease and a patient with myocarditis could sit in the same molecular camp, while two patients with the same diagnosis could fall into opposing ones. The clustering was robust, reproducible in principal component analyses, and independent of demographic confounders.

What distinguished the two groups was not the cause of disease but the character of the heart’s remodeling response. Group 2 hearts were enriched for proteins derived from activated fibroblasts, smooth muscle cells and pro-inflammatory myeloid cells, signatures consistent with aggressive scar formation and immune infiltration. Overlaying the protein signatures onto a published atlas of 15 cardiac cell types from single-cell transcriptomics revealed that Group 2 mirrored the cellular states observed in dilated cardiomyopathy, including expansions of disease-associated cardiomyocyte populations, activated fibroblast states FB5 through FB9, and pro-inflammatory macrophages, monocytes and dendritic cells. Group 1, by contrast, retained a profile closer to non-failing tissue, relatively enriched for cardiomyocyte contractile and metabolic proteins. The subgrouping was independently validated in bulk RNA sequencing data from 198 heart failure samples in a public cohort, where the same protein signature reproduced the same molecular split at the transcript level.

The researchers then descended one level deeper into biology by profiling the phosphoproteome, the layer of phosphate tags that flip proteins on and off and transmit signals through kinases. From the same tissues they quantified 3,014 phosphosites, and the phosphorylation patterns reproduced the proteomic stratification, confirming that the two subgroups differ not only in which proteins they contain but in which signaling circuits are actually running. Critically, phosphoproteomics is where drug discovery lives: kinases, phosphatases and their downstream effectors are among the most pharmacologically tractable targets in medicine.

By integrating protein abundance, phosphosite regulation and prior knowledge networks of kinases, transcription factors and upstream regulators, the team identified selectively activated, druggable signaling networks confined to one molecular subgroup. Among the circuits implicated were RhoA and ROCK2 signaling, components of the actin cytoskeleton such as the Arp2/3 complex, and mitogen-activated protein kinase pathways including ERK1/2 and p38, alongside regulatory nodes such as glycogen synthase kinase 3 and RAF1. The researchers cross-referenced these targets against the Drug Repurposing Hub, ChEMBL, Open Targets and Mendelian randomization evidence for causal heart failure associations, filtering for known cardiac toxicity, and assembled a shortlist of candidate therapeutic entry points that would apply only to the molecularly defined patients whose networks show that activation. This is precision cardiology at the level of the cell’s control systems rather than its genome.

Perhaps the most clinically consequential result came from the UK Biobank. The remodeling-associated protein signature, originally discovered in end-stage explanted hearts, was tested against plasma proteomic data from an entirely independent cohort of heart failure patients who are, on average, at much earlier stages of disease and treated in the community rather than the transplant center. The signature stratified these patients into subgroups and predicted survival trajectories, with accelerated failure time modeling showing that the molecular group assignments carried prognostic information. This extends the relevance of the tissue-based findings far beyond the operating theater: a blood test grounded in the same biology may eventually help identify which ambulatory patients carry a fibrotic, inflammatory molecular phenotype and which do not.

The implications for drug development are considerable. Heart failure trials have long been plagued by modest average effect sizes, and a plausible explanation is that molecularly heterogeneous populations dilute real benefits among patients whose disease is not driven by the targeted pathway. If a candidate anti-fibrotic or kinase inhibitor benefits only Group 2 biology, enrolling an unstratified population would bury the signal. Stratifying trials by these protein-defined subgroups could sharpen effect estimates, reduce required sample sizes and rescue otherwise promising mechanisms. The prognostic signal in plasma also raises the prospect of patient stratification with routine blood draws rather than myocardial biopsy, something no clinician would contemplate for diagnosis in most heart failure settings.

The study also leaves open questions that will shape the next phase of work. The cohorts are dominated by end-stage disease and reduced ejection fraction, so the behavior of the subgrouping in heart failure with preserved ejection fraction remains untested. The two groups describe biology at a moment in time, and longitudinal studies will need to establish whether patients transition between molecular states as disease evolves, or whether subgroup membership is fixed from the outset. And while the plasma findings demonstrate prognostic value, translating them into a clinically deployable test will require targeted assays and prospective validation. Still, the message of the work is unambiguous: the failing heart’s molecular interior tells a story that diagnosis codes cannot, and listening to that story, in both tissue and blood, may finally make it possible to match heart failure therapies to the biology of the individual patient rather than the label on the chart.

Subject of Research: Molecular subgrouping of human heart failure by proteomic and phosphoproteomic profiling of cardiac tissue

Article Title: Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure

Article References: Hamed, O., Reitz, C. J., Kuzmanov, U., Gramolini, S., Hu, M., Halpern, J., Billia, F., & Gramolini, A. O. (2026). Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure. Nature Cardiovascular Research. https://doi.org/10.1038/s44161-026-00880-w

Image Credits: AI Generated

DOI: 10.1038/s44161-026-00880-w

Keywords: heart failure, proteomics, phosphoproteomics, cardiac remodeling, precision medicine, biomarkers, UK Biobank, fibrosis, kinase signaling, cardiomyopathy, left ventricle, mass spectrometry

Friedreich’s ataxia is a recessive genetic disorder that strikes in childhood or adolescence, progressively robbing patients of coordination, strength, and sensation. In roughly 96 percent of cases, it is caused by biallelic expansions of a GAA repeat sequence within the FXN gene, which silences production of frataxin, a protein essential to mitochondrial function in cells. The deficit cascades across multiple organ systems: the central and peripheral nervous systems degenerate, the heart muscle thickens into hypertrophic cardiomyopathy, the pancreas falters toward diabetes, and scoliosis, spasticity, and optic neuropathy often follow. Most therapeutic strategies now in development aim either to soften the downstream consequences of frataxin loss or to restore frataxin expression directly, through gene therapy delivered by adeno-associated viral vectors, protein replacement, or epigenetic reactivation of the damaged gene.

The idea that transplanted blood-forming cells might help the brain rests on an intriguing biological premise. Cells of the monocyte lineage can, under certain conditions, migrate into the central nervous system and potentially exchange material with resident brain cells, raising the possibility that donor-derived cells could act as delivery vehicles for frataxin to deficient tissue. The concept carries real appeal but also unresolved risks, and the mechanisms that would make it work have never been fully defined. The patient described in the new report, who underwent a complete stem cell replacement for reasons entirely unrelated to her ataxia, offered a natural test of whether such replacement could alter the disease course.

Her medical odyssey began at age ten, when chest pain and a racing heartbeat landed her in the intensive care unit with thyrotoxicosis. During that hospitalization, doctors noted persistent cytopenias, and a bone marrow aspirate revealed acute myeloid leukemia carrying the t(6;9) translocation, a high-risk subtype with a strong tendency to relapse. At the same time, subtle neurological signs emerged: a slightly wide-based gait with externally rotated legs, ataxia, faint tremors confined to her fingers, diminished vibratory sensation, and absent deep tendon reflexes. Genetic testing confirmed biallelic GAA expansions in FXN of 699 and 1066 repeats, establishing the diagnosis of Friedreich’s ataxia, and an echocardiogram revealed moderate left ventricular hypertrophy, the disease’s characteristic cardiac signature.

Treating the leukemia in a child with a fragile heart demanded a delicate balancing act. Induction chemotherapy with a dose-adjusted regimen of cytarabine, daunorubicin, and etoposide failed to achieve remission, forcing a switch to a salvage combination of topotecan, vinorelbine, thiotepa, and clofarabine, which succeeded in driving the leukemia to minimal residual disease negativity after two cycles. She then received an allogeneic hematopoietic stem cell transplant from an 11-of-12 HLA-matched unrelated male donor, using CD34-positive selected peripheral blood stem cells. Her conditioning regimen combined rabbit anti-thymocyte globulin, clofarabine, melphalan, and thiotepa. Remarkably, the procedure proceeded without major unexpected complications, no graft-versus-host disease developed, and she has remained in leukemia remission for the entire decade since.

The neurological story, however, unfolded exactly as it would have without the transplant. Over ten years, her speech became mildly affected, her gait and arm function worsened, and her reflexes and peripheral neuropathic components showed no reversal. Quantitative measures told the same story: her modified Friedreich Ataxia Rating Scale score climbed by 20 points, and her nine-hole peg test times doubled, tracking the trajectory of six comparator patients at the same institution who had similar GAA repeat lengths and ages of onset but received no transplant. She now uses a wheelchair and cannot ambulate independently, and she developed diabetes and sleep apnea along the way. In short, a fully successful bone marrow replacement did nothing to touch the degeneration in her nervous system.

The authors of the report point to several converging reasons why. The blood-brain barrier excludes most donor-derived cells from entering the brain’s parenchyma, and conventional stem cell transplantation does not achieve the deep microglial and monocyte depletion that some researchers believe would be necessary for donor cells to meaningfully repopulate the central nervous system. Frataxin itself is an intracellular mitochondrial protein, which means donor cells cannot perform the kind of cross-correction seen in some other metabolic storage diseases, where secreted enzymes rescue neighboring cells. Friedreich’s ataxia also carries significant developmental components, so replacing frataxin after the developmental window may simply come too late to rescue already-compromised neural circuits. Finally, the chemotherapy required to conquer her leukemia may itself have aggravated her neuropathy, and her secondary diabetes could have blunted any residual benefit.

Yet the case contains one genuinely striking observation. While her neurological scores marched steadily downward, her cardiac hypertrophy stabilized. Ten years after the transplant, her echocardiogram was read as normal, and comparisons of her ejection fraction and intraventricular septal diameter against the six matched comparator patients suggested her heart measures had held steady where others continued to change. The authors urge caution in interpreting this, noting that wall thickness in Friedreich’s ataxia is only modestly predictive of long-term outcome, that reductions in wall thickness can occur without lasting benefit, and that some comparator subjects showed similar stabilization. Ejection fraction changes are typically late phenomena in the disease, so a decade of stability is notable but not definitive proof of cardiac protection.

The clearest confirmation of the transplant’s biological success came from her blood. Genetic testing performed ten years after the procedure showed GAA repeat lengths of 10 and 16, entirely normal values reflecting the donor’s healthy genome, and her blood frataxin levels had returned to the control range, measured at 4.79 nanograms per milliliter for the mature form and 9.25 for the extended form. Her hematopoietic system had been completely rebuilt from genetically unaffected donor cells, demonstrating that full donor chimerism and normalized frataxin production in blood are achievable in a Friedreich’s ataxia patient, even if the nervous system remained beyond reach.

Because Friedreich’s ataxia is not known to elevate cancer risk, the co-occurrence of leukemia in this patient was almost certainly coincidental, but it dramatically complicated her treatment, given the cardiac sensitivity and neurotoxicity risks posed by many chemotherapy agents. The successful outcome nonetheless establishes that Friedreich’s ataxia patients can survive allogeneic stem cell transplantation, just as they have survived heart and liver transplantation in prior reports, opening a door for treating hematologic malignancies in this population. And the hint of cardiac stabilization, combined with the procedure’s relative safety, keeps alive the possibility that stem cell approaches could one day benefit the disease, if deployed in paradigms specifically engineered to deliver frataxin to the central nervous system. The authors are careful to stress that the present observations cannot be taken as evidence of neurological benefit, but the case stands as a rare, decade-long natural experiment that maps both the promise and the hard biological limits of replacing a patient’s blood to heal a brain.

Subject of Research: Allogeneic stem cell transplantation in a patient with Friedreich's ataxia and acute myeloid leukemia

Article Title: Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression

Article References: Gitman, A., Bhandari, N., Castellaro, M., Schadt, K., Cancio, M., & Lynch, D. R. (2026). Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression. Annals of Clinical and Translational Neurology, 13(8), 1733-1735. https://doi.org/10.1002/acn3.70455

Image Credits: AI Generated

DOI: 10.1002/acn3.70455

Keywords: Friedreich's ataxia, stem cell transplantation, frataxin, acute myeloid leukemia, FXN gene, neurodegeneration, cardiomyopathy, blood-brain barrier, gene therapy, GAA repeat expansion, hematopoietic stem cells, case report

NETosis is a relatively recent addition to the immunology lexicon. First recognised as a mechanism for trapping and killing microbes, it involves the formation of neutrophil extracellular traps, or NETs, which are web-like lattices of DNA studded with antimicrobial proteins. The process can unfold in two distinct ways. In vital NETosis, the neutrophil remains alive and functional while deploying its DNA weapon, typically in response to pathogen-associated molecular patterns derived from microbes. In suicidal or lytic NETosis, the cell perishes: its nuclear envelope disintegrates, its plasma membrane ruptures, and DNA chains decorated with citrullinated histones, neutrophil elastase and myeloperoxidase spill into the extracellular space. The molecular choreography is intricate. An enzyme called peptidyl-arginine deiminase 4 citrullinates histones, loosening the grip of chromatin, while granule enzymes translocate to the nucleus to cleave histones further, allowing the genetic material to decondense before its dramatic release.

Although NETosis has been implicated in atherosclerosis and thromboinflammation, its role in chronic heart failure remained underexplored. The research team, led by Sawa Kostin and colleagues, examined left ventricular tissue from 21 patients undergoing orthotopic heart transplantation. The patients fell into three groups matched for age, symptom severity, medication and comorbidities: seven with inflammatory cardiomyopathy following histologically proven myocarditis, seven with idiopathic dilated cardiomyopathy, and seven with ischaemic cardiomyopathy caused by severe coronary artery disease. Crucially, in the ischaemic group the researchers analysed only tissue remote from previous infarcts, ensuring that observed inflammation reflected the failing heart as a whole rather than scarred regions. As controls, they used myocardial samples from five patients with aortic stenosis whose left ventricular function was fully preserved and whose tissue showed no damage, inflammation or fibrosis.

The results were striking. Using immunolabelling for CD66b, a neutrophil marker, the team found that control myocardium contained a median of just 2.48 neutrophils per square millimetre. In the failing hearts, that figure soared to 11.4 cells in dilated cardiomyopathy, 13.9 in ischaemic cardiomyopathy and 15.5 in inflammatory cardiomyopathy, a four- to six-fold increase. To detect NETosis directly, the researchers stained for citrullinated histone 3 and myeloperoxidase, two molecular signatures of NET formation. Confocal microscopy revealed thin, long NET structures, ranging from 5 to 50 micrometres, positive for both DNA and citrullinated histone 3, weaving through the failing myocardium. No such structures appeared in control tissue.

Biochemical and molecular assays corroborated the microscopy. Western blot analysis showed that citrullinated histone 3 protein levels were 4.8-fold higher in inflammatory cardiomyopathy, 4.4-fold higher in ischaemic cardiomyopathy and 2.7-fold higher in dilated cardiomyopathy compared with controls, with all differences statistically significant. Quantitative polymerase chain reaction confirmed that myeloperoxidase messenger RNA was three to four times more abundant in the failing hearts. When the researchers counted neutrophils positive for both CD66b and citrullinated histone 3, they found medians of 7.94 cells per square millimetre in inflammatory cardiomyopathy, 5.51 in dilated cardiomyopathy and 5.79 in ischaemic cardiomyopathy, against just 1.12 in controls. Triple staining for CD66b, citrullinated histone 3 and myeloperoxidase revealed a 4.6- to 6.1-fold increase across all heart failure groups, with no significant differences between aetiologies.

Macrophages told an equally compelling story. These highly plastic cells, which can polarise into classically activated M1-like macrophages that drive inflammation or alternatively activated M2-like macrophages that promote repair and phagocytosis, are among the most active immune participants in cardiac remodelling. Counting CD68-positive cells, the team found a median of 13.3 macrophages per square millimetre in control myocardium, rising to 47.1 in dilated cardiomyopathy, 55.4 in ischaemic cardiomyopathy and 69.4 in inflammatory cardiomyopathy. Remarkably, macrophage numbers correlated very strongly with neutrophil counts, with a Spearman coefficient of 0.918, suggesting the two cell populations accumulate in lockstep within the diseased heart.

Phenotyping revealed a decisive shift. In control tissue, only about 3 percent of macrophages displayed the M1-like profile, identified by co-expression of CD68 with tumour necrosis factor alpha or interleukin-6, while roughly 6.5 percent were M2-like, marked by CD206 or arginase-1. In the failing hearts, M1-like macrophages dominated: 78.5 percent in inflammatory cardiomyopathy, 54.5 percent in ischaemic cardiomyopathy and 53.2 percent in dilated cardiomyopathy. M2-like macrophages also increased, reaching roughly 21 to 23 percent, but never matched the proinflammatory surge. The resulting M1-to-M2 ratio, a measure of inflammatory balance, stood at 3.19 in inflammatory cardiomyopathy and around 2.5 to 2.6 in the other groups, compared with just 0.63 in controls, all differences statistically significant.

The pivotal finding emerged when the researchers correlated NETosis with macrophage polarisation. The percentage of M1-like macrophages correlated positively and significantly with the number of neutrophils undergoing NETosis, with a correlation coefficient of 0.79 for triple-positive citH3/MPO/CD66b cells and 0.68 for citH3/CD66b cells. In contrast, M2-like macrophages showed no meaningful association with NETosis, with coefficients near zero and non-significant p-values. Triple immunolabelling for citrullinated histone 3, tumour necrosis factor alpha and CD206 provided visual confirmation: NET-forming neutrophils were consistently surrounded by far more TNF-alpha-positive M1-like macrophages than CD206-positive M2-like cells.

What might this interplay mean mechanistically? Prior work offers intriguing clues. Co-culture experiments have shown that both M1- and M2-like macrophages can degrade NETs, with M1-like cells dominating the early phagocytic response and M2-like cells completing clearance later. Studies in acute pulmonary ischaemia-reperfusion injury have described a mutual feedback loop in which NETosis drives M1-like polarisation, which in turn promotes further NETosis. The authors suggest that in chronic heart failure this reciprocal interaction may create a positive feedback loop that sustains low-grade myocardial inflammation, a recognised hallmark of the disease. Alternatively, the M1 skewing could represent a compensatory attempt to clear excessive NETs, one that fails to suppress NET formation itself. The concurrent rise in M2-like macrophages, albeit more modest, may reflect involvement in clearing dead cardiomyocytes and contributing to fibrosis, given that the failing heart loses an estimated 20 percent of its cardiomyocytes each year in terminal stages.

The authors are careful to note that correlation does not establish causation, and that the observed associations may be consequences of chronic heart failure rather than drivers of it. The study’s limitations include the small number of patients, the differing aetiologies across groups and considerable interindividual variability. Nevertheless, the consistency of the findings across inflammatory, dilated and ischaemic forms of the disease, and the earlier observation that neutrophil and macrophage accumulation precedes overt heart failure in compensated hypertrophy, lend weight to the idea that this immune axis matters. Recent research also implicates extracellular vesicles released by injured cardiomyocytes in promoting neutrophil-driven inflammation and macrophage polarisation, suggesting multiple routes by which tissue damage could ignite the NETosis-macrophage circuit. If future studies confirm a causal role, inhibiting NETosis or restoring the balance between M1- and M2-like macrophages could become genuine therapeutic strategies for chronic heart failure, a condition that still lacks treatments targeting its inflammatory underpinnings. For now, the study provides a rigorous anatomical and molecular map of that circuit in human tissue, and a clear hypothesis for the next generation of experiments.

Subject of Research: The association between neutrophil extracellular trap formation and proinflammatory macrophage polarisation in human heart failure

Article Title: Increased NETosis in Patients With Heart Failure Is Associated With Macrophage Activation Towards a Proinflammatory Phenotype

Article References: Kostin, S., Cabrera‐Fuentes, H. A., Richter, M., Krizanic, F., Ritter, O., Boisvert, W. A., Preissner, K. T., Kelesidis, T., Siasos, G., & Pagonas, N. (2026). Increased NETosis in Patients With Heart Failure Is Associated With Macrophage Activation Towards a Proinflammatory Phenotype. Journal of Cellular and Molecular Medicine, 30(17), Article e71306. https://doi.org/10.1111/jcmm.71306

Image Credits: AI Generated

DOI: 10.1111/jcmm.71306

Keywords: heart failure, NETosis, neutrophils, macrophages, M1 polarisation, myocardial inflammation, citrullinated histone 3, myeloperoxidase, cardiac remodelling, innate immunity, cardiomyopathy, immunohistochemistry