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Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF relied on small, hospital referral populations, and knowledge on clinical outcomes remains limited. A study was done to evaluate the prevalence and prognostic implications of cardiomyopathy-associated pathogenic or likely pathogenic (CMP-PLP) genetic variants in patients with AF. In 2 prospective cohort studies, the prevalence of CMP-PLP variants was assessed in the population of patients with AF and early-onset AF. The association between carrying a CMP-PLP variant and the risk of incident cardiomyopathy or heart failure (CMP/HF) after AF diagnosis was evaluated. Finally, the joint contributions of CMP-PLP variants, clinical risk, and polygenic risk were assessed. Included in this study were 2 large longitudinal cohort studies, the UK Biobank (UKB) (data 2006-2023) and the All of Us Research Program (AllofUs) (2018-2022). The UKB and AllofUs cohorts, respectively, contained 393 768 and 193 232 unrelated genotyped participants. Results In the UKB cohort, 32 281 participants (8%) had AF (mean [SD] age, 62 [6] years; 20 459 male [63.4%]). In the AllofUs cohort, 11 901 participants (6%) had AF (mean [SD] age, 67 [12] years; 6576 male [55.3%]). Compared with the biobank populations, CMP-PLP variants were twice as prevalent in patients with AF (UKB, 2.04%; 95% CI, 1.89%-2.20%; AllofUs, 2.52%; 95% CI, 2.25%-2.82%) and 5 times as prevalent in AF with onset before age 45 years (UKB, 4.99%; 95% CI, 3.07%-7.91%; AllofUs, 4.66%; 3.40%-6.32%). Cumulative incidence of CMP/HF was high in patients with AF (18%) compared with patients without AF (3%). Still, among patients with AF without prior CMP/HF (UKB, 20 226; AllofUs, 8330), carrying a CMP-PLP variant was associated with 1.6-fold risk of incident CMP/HF (meta-analysis, 95% CI, 1.32-1.90). Finally, CMP-PLP variants, a polygenic score, and clinical risk factors were independent estimators of CMP/HF. Results of this cohort study suggest that the prevalence of CMP-PLP variants was substantial in patients with early-onset AF. Patients with AF carrying a CMP-PLP variant had an associated increased risk of future CMP/HF, independent of clinical and polygenic risk. These results indicate that genetic testing in patients with AF may identify individuals at higher risk for developing CMP/HF.

Reference:

Wijdeveld LFJM, Ajufo E, Challa SP, et al. Cardiomyopathy-Associated Gene Variants in Atrial Fibrillation. JAMA Cardiol. Published online April 30, 2025. doi:10.1001/jamacardio.2025.0460

Keywords:

Wijdeveld LFJM, Ajufo E, Challa SP,Genetic, Link, Found, Between, Early-Onset AF, Risk, Cardiomyopathy, Heart Failure

The analysis aimed to explore whether type 2 diabetes influences the efficacy and safety of zibotentan when added to dapagliflozin therapy in CKD patients. Data were from a multicenter, double-blind, randomized, active-controlled phase 2b study that enrolled 447 individuals—261 with type 2 diabetes and 186 without.

Participants were assigned to receive either 0.25 mg or 1.5 mg of zibotentan in combination with 10 mg of dapagliflozin or a placebo alongside dapagliflozin. The primary parameter assessed was the change in urinary albumin-to-creatinine ratio (UACR), a marker of kidney function. Researchers also evaluated changes in body weight and B-type natriuretic peptide (BNP), indicators of fluid retention.

The study revealed the following findings:

• Low-dose zibotentan (0.25 mg) combined with dapagliflozin reduced UACR by 37.7% in patients without diabetes.
• The same combination led to a 17.9% reduction in UACR in patients with diabetes.
• The stronger response in non-diabetic patients was not statistically significant.
• High-dose zibotentan (1.5 mg) with dapagliflozin resulted in similar UACR reductions (~34%) in diabetic and non-diabetic patients.
• There was no significant interaction between diabetes status and treatment effect at the higher dose.
• No notable differences were observed in body weight or BNP changes based on diabetes status.
• Fluid retention occurred only in diabetic patients receiving the higher zibotentan dose.
• No cases of fluid retention were seen in non-diabetic patients receiving zibotentan.
• The combination therapy was generally well-tolerated across all patient groups.

Despite these promising findings, the authors emphasized that this was a post hoc analysis of a trial not specifically designed to compare patients based on diabetes status. Therefore, they suggest that the results be interpreted cautiously and viewed as hypothesis-generating. Moreover, the trial’s 12-week duration limits any conclusions about long-term outcomes.

To address these limitations, ongoing trials like ZENITH-HP and ZODIAC are expected to offer further clarity. The ZENITH-HP trial has recruited over 1,500 CKD patients with and without diabetes, while the ZODIAC study is evaluating the individual and combined effects of zibotentan and dapagliflozin in greater detail.

“The analysis supports the potential utility of zibotentan-dapagliflozin combination therapy in CKD management across diverse patient groups, offering a promising approach that appears unaffected by diabetes status,” the researchers concluded.

Reference:

https://doi.org/10.1111/dom.16468

Led by Dr. Pranav Vasu from the Department of Medicine at Creighton University School of Medicine, Phoenix, Arizona, the study analyzed data from the TriNetX US Collaborative Network using electronic health records spanning from January 2004 to October 2024. The retrospective cohort included 5,277 patients with OSA and 5,277 without, all of whom had mild to moderate POAG at baseline.

The investigators examined the risk of progressing to severe POAG over 3-, 5-, and 10-year follow-up periods.

The study led to the following findings:

• Patients with obstructive sleep apnea (OSA) had significantly higher odds of progressing to severe glaucoma after adjusting for baseline characteristics, comorbidities, and medication use.
• The risk of progression to severe glaucoma was nearly 2.8 times higher at 3 years for patients with OSA compared to those without.
• At 5 years, the odds of disease progression were 2.3 times higher for the OSA group.
• After 10 years, the risk remained elevated, with just over 2.1 times higher odds of severe glaucoma among those with OSA.
• There was no significant difference in the rates of minimally invasive glaucoma surgeries (MIGS) or trabeculectomy procedures between patients with and without OSA.
• Laser treatments and tube shunt surgeries were significantly more common in patients with OSA at all follow-up time points.

“These findings suggest that while OSA patients face a markedly greater risk of glaucoma progression, surgical interventions such as MIGS and trabeculectomy are not necessarily used more frequently,” the authors noted. “Instead, there is greater reliance on laser therapies and tube shunt procedures, which may reflect the need to address more advanced or rapidly progressing disease in this group.”

The study highlights the importance of recognizing OSA as a potential accelerator of POAG and suggests that standard management strategies may not be sufficient for this subset of patients. Clinicians are encouraged to consider early screening and timely interventions tailored to individuals with coexisting OSA and glaucoma to help prevent irreversible vision loss.

In light of these findings, the authors advocate for greater clinical vigilance and suggest revisiting current treatment algorithms for POAG patients with OSA. Proactive management, they argue, could help alter the course of disease and preserve visual outcomes over time.

Reference:

Vasu, P., Wagner, I. V., Lentz, P. C., Gumaste, P., Abubaker, Y., Ang, B. C., Ahuja, A. S., Dorairaj, E., Qozat, I., Miller, D. D., & Dorairaj, S. (2025). Obstructive Sleep Apnea as a Potentiator of Primary Open Angle Glaucoma and Necessity for Interventional Therapy. Ophthalmology Glaucoma. https://doi.org/10.1016/j.ogla.2025.05.005

Males are more than four times more likely to receive an autism diagnosis than females. But a new study by researchers at UC San Diego School of Medicine has found no clinical differences in autistic traits between the sexes in toddlers when they are first diagnosed with autism. The study was published in Nature Human Behavior on May 26, 2025. The findings have potential implications for early diagnosis and intervention for autistic children.

Between 2002 and 2022, the researchers assessed more than 2,500 male and female toddlers between 12 and 48 months of age. Of these toddlers, 1,500 were autistic, 600 were typically-developing, and 475 were developmentally delayed. The assessments included 19 different measures of language development, social and motor skills, core autism traits such as repetitive behaviors, cognitive skills, and other developmental characteristics. The study also examined social attention using eye tracking technology. All assessments were conducted at a single site-the UC San Diego Autism Center of Excellence-by licensed clinical psychologists.

The researchers found:

• No clinical differences between male and female autistic toddlers on all but one of the metrics. The sole exception was a measure of daily living skill development based on parent reporting, such as getting dressed and feeding themselves, which females scored just slightly higher on than males.
• When clustered into low, medium and high-ability subtypes across the autism spectrum based on robust state-of-the-art methods, there were also no major clinical differences between males and females within these subtypes.
• No clinical differences between the sexes between 12 and 48 months when the researchers followed the trajectory of development in autistic toddlers over time.
• Few sex differences between developmentally delayed toddlers.

A number of previous studies with fewer than 100 participants each have shown differences between the sexes in autistic toddlers. However, the current study is the largest and most comprehensive of its kind to date, and one of very few studies to assess children with autism at a very early age, according to senior author Karen Pierce, Ph.D., professor of neurosciences and  director of the Autism Center of Excellence at UC San Diego School of Medicine.

“There is no consensus in the field about whether females are more or less impacted than males, and that is probably because there haven’t been really large-scale studies at the earliest ages,” said Pierce. “ Based on previous small studies, we had anticipated there would be some sex differences. So we were a little bit surprised to find nothing at all.”

The researchers did, however, find sex differences between typically developing female and male toddlers, with females performing at significantly higher levels than males on more than half of the tests, especially those measuring social skills, language development, and daily living skills. “This is consistent with the literature; female toddlers seem to develop slightly faster than males in terms of their language ability and their social ability and how well they perform daily living skills — adaptive things for a two-year-old,” said Pierce. “Typically developing females are accelerated in their development relative to males.”

Pierce says the findings for autistic children of no clinical differences between males and females at the time of first onset of autism lead to two possible conclusions.

“One is that previous studies that report sex differences are wrong, perhaps due to small sample size, sampling bias, limited study measures, or other methodological issues,” she said. “An alternative conclusion is that sex differences do not exist at the time of first onset, but instead emerge slowly at later ages, driven by psychosocial factors like socialization or differences in biology that may unfold across development.”

To examine this alternative possibility, a high-quality, large-scale study that tracks autistic children from toddlerhood through school age and beyond would be required, according to Pierce.​

Autism is highly heritable, and Pierce says the findings have implications for understanding the development of the condition, enhancing early detection, and improving early intervention. Because the study found that toddlers with autism clustered into scientifically robust subtypes within the autism spectrum rather than by sex, she thinks it may be preferable to focus on these differences instead when seeking to understand clinical heterogeneity and the most appropriate interventions for each subtype, for example.

“If you can improve a toddler’s language and communication at the youngest ages possible, then they’re going to get their needs met better, and they’re going to be able to contribute to society more effectively, because they can do whatever it is that they love to do,” said Pierce. “It’s really about having every child reach their full potential.”

Reference:

Nazari, S., Ramos Cabo, S., Nalabolu, S. et al. Large-scale examination of early-age sex differences in neurotypical toddlers and those with autism spectrum disorder or other developmental conditions. Nat Hum Behav (2025). https://doi.org/10.1038/s41562-025-02132-6.