Indications and Treatment Outcomes of Below-the-Knee Peripheral Artery Interventions in the XLPAD Registry
Endovascular treatment for BTK PAD is more often performed in patients with CLTI compared with IC, where it is often combined with an inflow artery intervention or complex lesion crossings. Despite similar procedural success, 1-year MALE is significantly higher in CLTI, driven mainly by over a 2-fold increase in all-cause mortality and major amputations.
KEY FINDINGS: Endovascular treatment for BTK PAD is more often performed in patients with CLTI compared with IC, where it is often combined with an inflow artery intervention or complex lesion crossings. Despite similar procedural success, 1-year MALE is significantly higher in CLTI, driven mainly by over a 2-fold increase in all-cause mortality and major amputations.
BACKGROUND: There are unresolved questions regarding indications and outcomes of endovascular below-the-knee (BTK) interventions in patients with symptomatic peripheral artery disease (PAD) in real-world clinical practice. We analyzed 884 patients from the multicenter XLPAD registry between 2006 and 2023 with nonstent BTK PAD interventions. Primary outcome: freedom from major adverse limb events (MALE) at 1 year, a composite of all-cause death, major amputation, or clinically driven revascularization.
DETAILS: Majority (62.8%) of the BTK interventions were performed for chronic limb threatening ischemia (CLTI), while remaining (37.2%) in patients with intermittent claudication (IC), performed together with an inflow femoropopliteal artery intervention in 58% or involving complex lesion crossings (11.8%). Nearly, 74% were men, mean age 68.0 ± 10.7 years. Mean Rutherford class was 4.65 in CLTI and 2.71 in IC groups. Moderate to severe calcification was present in 25% of cases. Significantly greater number of lesions were treated in the CLTI group (1.84 ± 1.52 vs 2.08 ± 1.61; p = 0.029). Lesion lengths (CLTI: 129.3 ± 85.1 mm vs IC: 115.5 ± 82.5; p = 0.075) were comparable. Nearly, 92% of lesions were treated with balloon angioplasty. Drug-coated balloon use was higher in IC (5% vs 15%, p <0.001), whereas atherectomy use was high in both groups (CLTI: 45.4% vs IC: 49.9%; p = 0.201). Procedural success was similar (CLTI: 92% vs IC: 88.8%; p = 0.098), however 1-year MALE was significantly higher in CLTI patients (30.5% vs 15.8% vs; p <0.0.001), driven by higher all-cause mortality (5.6% vs 2.1% vs; p = 0.014) and major amputations (14% vs 3.7%; p 0.001).
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Source: Rozol, Z. P., Sayfo, S., Fernandez-Vazquez, D., et al. (2025). Indications and Treatment Outcomes of Below-the-Knee Peripheral Artery Interventions in the XLPAD Registry. American Journal of Cardiology. 2025; 251: 38-45. Published: September 15, 2025. DOI: 10.1016/j.amjcard.2025.05.011 .
Formononetin May Protect Against Anthracycline Cardiotoxicity Through Cardiac Metabolic Improvement
A preclinical study identified ERRa as an early metabolic regulator of anthracycline-induced cardiotoxicity, with its reduction occurring before overt cardiac dysfunction. Formononetin, an ERRa activator, improved cardiac metabolism and function in mouse and pig models while also enhancing doxorubicin's anticancer activity in breast cancer organoids. The findings suggest a potential dual-action strategy for protecting the heart during anthracycline therapy, but clinical studies are still needed.
KEY FINDINGS: The findings identify ERRα downregulation as an early and potentially causal component of anthracycline-induced cardiac injury. Formononetin improved cardiac energy metabolism and function in experimental models while retaining, and potentially enhancing, doxorubicin's anticancer activity in breast cancer organoids. The study therefore suggests that pharmacologic activation of ERRα could represent a future strategy for simultaneously addressing anthracycline cardiotoxicity and cancer treatment. However, the evidence remains preclinical, and clinical studies are required to determine whether these findings translate into cardioprotection in patients receiving anthracycline chemotherapy.
BACKGROUND: Anthracyclines such as doxorubicin are effective anticancer agents, but their use can be limited by anthracycline-induced cardiotoxicity (AIC). Early metabolic disturbances in cardiac muscle may contribute to the development of cardiac dysfunction. This study investigated the role of estrogen-related receptor α (ERRα), a regulator of cardiac energy metabolism, in AIC and evaluated whether pharmacologic activation of ERRα with formononetin could provide cardiac protection while maintaining anticancer activity.
DETAILS: The investigators used a porcine model of anthracycline cardiotoxicity to examine changes in ERRα over time and cardiomyocyte-specific gain- and loss-of-function mouse models to assess its functional role. Mechanistic experiments, including ChIP-qPCR, reporter assays, and microscale thermophoresis, were used to investigate how formononetin interacts with the ERRα pathway. Cardiac tissue from patients who had received chemotherapy was also examined, while human breast cancer patient-derived organoids were used to evaluate potential effects on tumor activity. ERRα expression was reduced in hearts from the porcine AIC model and in cardiac tissue from patients treated with chemotherapy. In pigs, the reduction occurred at the 6-week subclinical stage, before overt cardiac dysfunction developed. Increasing ERRα expression specifically in cardiomyocytes enhanced mitochondrial metabolic programs and fatty-acid oxidation and preserved systolic function after doxorubicin exposure, whereas ERRα reduction worsened metabolic dysfunction and cardiac impairment.
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Drug screening identified formononetin as a selective ERRα activator. In mouse and pig models, formononetin increased ERRα activity, improved cardiac mitochondrial metabolism, and reduced anthracycline-associated cardiac injury. Mechanistic experiments indicated that formononetin interacts with the ERRα/PGC-1α complex and promotes its stability, supporting activation of downstream metabolic pathways.
Importantly, formononetin also demonstrated anticancer activity in human breast cancer patient-derived organoids. Treatment with formononetin alone reduced organoid viability and proliferation, while combining formononetin with doxorubicin produced greater antitumor effects.
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Source: Wang, X., Ling, G., Wei, Y., et al. Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement. Circulation Research. 2026; 139(7): e329042. Published: September 11, 2026. DOI: 10.1161/CIRCRESAHA.126.329042.
Somatic Diseases May Affect the Brain Primarily Through Vascular Injury and Neuronal Loss
A narrative review found that common age-related somatic diseases were consistently associated with brain atrophy, neuronal loss, and cerebrovascular lesions. Evidence linking these diseases to amyloid and tau pathology was limited and inconsistent. The findings suggest that systemic diseases may contribute to dementia primarily through non-Alzheimer's mechanisms, particularly vascular injury and neuronal loss. The review underscores the importance of recognizing mixed dementia and considering systemic health in the assessment of cognitive decline.
KEY FINDINGS: Common age-related somatic diseases appear to be more consistently associated with cerebrovascular injury, brain atrophy, and neuronal loss than with amyloid or tau pathology. These findings suggest that the relationship between systemic disease and dementia may involve multiple non-AD pathways rather than a direct effect on classical AD pathology. The review highlights the importance of recognizing mixed dementia and considering systemic health when evaluating brain aging and cognitive decline.
BACKGROUND: Several common age-related somatic diseases are associated with an increased risk of dementia, but the neuropathological pathways underlying these associations remain incompletely understood. This narrative review examined evidence linking heart disease, type 2 diabetes, kidney disease, liver disease, lung disease, and anemia with brain pathology, including Alzheimer's disease (AD)-related amyloid and tau pathology and non-AD changes such as neuronal loss, brain atrophy, cerebrovascular lesions, neuroinflammation, and non-AD proteinopathies.
DETAILS: The authors conducted a PubMed search for human studies investigating associations between somatic diseases and brain pathology using postmortem examinations, brain imaging, or cerebrospinal fluid biomarkers. The available evidence was qualitatively synthesized and graded according to its strength. The review specifically evaluated whether common systemic diseases were associated with AD-related pathology or with other forms of brain injury that may contribute to cognitive impairment and dementia.
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Across the conditions examined, the strongest and most consistent associations were between somatic diseases and global neuronal loss or brain atrophy, as well as cerebrovascular lesions. In contrast, associations between somatic diseases and amyloid or tau deposition were limited and inconsistent. The review found no systematic studies examining neuroinflammation or non-AD proteinopathies in relation to somatic diseases.
Overall, the available evidence suggests that systemic diseases may contribute to brain damage predominantly through non-AD mechanisms, particularly cerebrovascular injury and diffuse neuronal loss, rather than by directly driving the characteristic amyloid and tau pathology of AD. The authors emphasize that these processes may contribute to the complex combination of pathologies frequently underlying dementia in older adults.
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Source: Grande, G., Valletta, M., Gasparini, F., et al. Brain pathology in relation to somatic diseases: Exploring the body–brain crosstalk. Journal of Internal Medicine. 2026; 300(3): 223–237. Published: June 2, 2026. DOI: 10.1111/joim.70119.
Hypertension at 5 Months Postpartum in Women With Gestational Diabetes
Among 678 women with recent gestational diabetes mellitus, 26.4% developed hypertension by 5 months postpartum. Higher early-pregnancy weight and blood pressure, Black or mixed ethnicity, and gestational hypertension or pre-eclampsia were associated with increased risk. Postpartum hypertension was also associated with greater adiposity and dyslipidemia. The findings support structured postpartum screening for blood pressure and broader cardiometabolic risk after GDM.
KEY FINDINGS: Approximately one in four women with recent GDM developed hypertension by 5 months postpartum. Higher maternal weight and blood pressure early in pregnancy, as well as Black or mixed ethnicity, were associated with increased risk, while gestational hypertension or pre-eclampsia was also associated with postpartum hypertension. Women with postpartum hypertension had greater adiposity and more frequent dyslipidemia, highlighting the broader cardiometabolic abnormalities present after GDM. Because early-pregnancy characteristics provided only modest prediction, the findings support structured postpartum assessment that includes blood pressure and broader cardiometabolic risk evaluation rather than focusing solely on dysglycemia.
BACKGROUND: Gestational diabetes mellitus (GDM) is associated with an increased risk of later cardiometabolic disease, including hypertension. However, the occurrence and determinants of hypertension soon after pregnancy complicated by GDM have not been well defined. This prospective study evaluated the incidence and predictors of hypertension at 5 months postpartum and examined its relationship with other cardiometabolic abnormalities in women with recent GDM.
DETAILS: This single-center observational prospective cohort study was conducted at King's College Hospital, London, between September 2023 and January 2025. Women with GDM who received routine prenatal care at 12 weeks' gestation were invited for a postpartum assessment at approximately 5 months after delivery; women with chronic hypertension were excluded. The assessment included blood pressure, BMI, waist circumference, glucose status, lipid profile, and renal function. Hypertension was defined as systolic BP ≥ 130 mmHg, diastolic BP ≥ 80 mmHg, or receipt of antihypertensive treatment. Of 912 women with GDM invited for postpartum review, 696 (76.3%) attended. After excluding 18 women with chronic hypertension, 678 women constituted the study cohort. Follow-up occurred at a median of 5.1 (IQR, 4.4-6.7) months after birth.
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Among the 678 women with previous GDM, 179 (26.4%) developed hypertension at a median of 5.1 (IQR, 4.4-6.7) months postpartum. Women who subsequently developed hypertension had higher early-pregnancy weight and blood pressure. At 12 weeks' gestation, median weight was 79.3 kg versus 69.3 kg among women who remained normotensive, while median systolic BP was 121.8 versus 115.5 mmHg and median diastolic BP was 74.5 versus 70.3 mmHg, respectively. Obesity at this stage was also more frequent among women who later developed hypertension (50.3% vs 28.5%). Pregnancy hypertensive disorders were more common among women who developed postpartum hypertension. Gestational hypertension occurred in 8.4% versus 3.8%, and pre-eclampsia in 9.5% versus 1.8%, among women who developed postpartum hypertension compared with those who remained normotensive.
Multivariable analysis identified higher maternal age, Black or mixed ethnicity, higher weight, and higher systolic and diastolic BP at 12 weeks as predictors of postpartum hypertension. Black ethnicity was associated with an adjusted OR of 1.88 (95% CI, 1.19-3.00), mixed ethnicity with an adjusted OR of 2.75 (95% CI, 1.21-6.24), and weight ≥ 73 kg with an adjusted OR of 1.57 (95% CI, 1.04-2.38). Each 1-mmHg increase in systolic BP was associated with an adjusted OR of 1.04 (95% CI, 1.02-1.07), and each 1-mmHg increase in diastolic BP with an adjusted OR of 1.04 (95% CI, 1.00-1.07). Development of gestational hypertension or pre-eclampsia was associated with an adjusted OR of 3.00 (95% CI, 1.69-5.34).
At the postpartum assessment, women with hypertension had a median BMI of 30.1 (IQR, 26.7-36.8) kg/m² compared with 27.0 (IQR, 23.5-30.6) kg/m² among normotensive women. A waist-to-height ratio > 0.5 was present in 87.7% versus 69.1%, and dyslipidemia in 35.8% versus 24.4%, respectively. Dysglycemia and renal dysfunction did not differ significantly between the groups.
The prenatal prediction model had only modest discriminatory ability. The AUC was 0.723 (95% CI, 0.680-0.766) using characteristics available at 12 weeks and 0.739 (95% CI, 0.697-0.782) after adding gestational hypertension or pre-eclampsia. At a 20% false-positive rate, detection rates were 49.5% and 53.7%, respectively.
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Source: Gomez Fernández, C., Charakida, M., Moser, M., et al. Hypertension at 5 months postpartum in women with gestational diabetes. Ultrasound in Obstetrics & Gynecology. 2026; 68(2): 202-210. Published: July 17, 2026. DOI: 10.1002/uog.70291.
Potassium Binders May Support Continued RAAS Inhibitor Therapy in Chronic Kidney Disease and Heart Failure
Second-generation potassium binders were associated with greater persistence of RASi and MRA therapy than first-generation binders. Continued RASi use was associated with lower observed mortality and hospitalization, but not with a clear difference in 3P-MACE. These findings suggest potassium binders may facilitate sustained RAASi therapy in CKD and HF.
KEY FINDINGS: In this Swedish nationwide observational cohort, second-generation potassium binders were associated with greater persistence of RASi and MRA therapy at 6 months than first-generation binders. RASi persistence was also associated with lower observed all-cause mortality and hospitalization, although no clear difference in 3P-MACE was identified. The findings support the potential role of potassium binders in maintaining guideline-directed RAASi therapy in patients with CKD and/or HF.
BACKGROUND: Renin–angiotensin–aldosterone system inhibitors (RAASi) provide important cardiorenal benefits in chronic kidney disease (CKD) and heart failure (HF), but their use can increase the risk of hyperkalemia. Hyperkalemia frequently leads to RAASi discontinuation despite the benefits of continued therapy. This study evaluated whether potassium binders, particularly second-generation agents, were associated with greater persistence of RAASi and mineralocorticoid receptor antagonist (MRA) therapy.
DETAILS:
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Source: Furuland, H., Larsson, A. O., Uhde, M., et al. Potassium Binders and Continuation of Renin–Angiotensin System Inhibitors/Mineralocorticoid Receptor Antagonist in Chronic Kidney Disease and Heart Failure (the DEMONSTRATE Database. Journal of Internal Medicine. 2026; 300(2): 179-192. Published: Augusts, 2026. DOI: 10.1111/joim.70087.
2026 Dyslipidemia Guideline Expands Eligibility for Primary Prevention Statin Therapy in US Adults
The 2026 dyslipidemia guideline substantially expands primary prevention statin eligibility in US adults, with an estimated 87.5 million adults (56.6% of the target population) eligible for therapy, including 21.5 million newly eligible individuals. The expansion primarily affects younger, lower-risk adults compared with prior recommendations.
KEY FINDINGS: The 2026 dyslipidemia guideline substantially increases the number of US adults recommended for primary prevention statin therapy. This expansion includes a large group of individuals who were not previously considered candidates for statins and who generally have lower estimated 10-year ASCVD risk. The findings highlight the potential impact of updated risk assessment strategies on preventive cardiovascular care and clinical decision-making regarding statin initiation.
BACKGROUND: The 2026 American Heart Association/American College of Cardiology/multisociety guideline on dyslipidemia introduced updated recommendations for estimating atherosclerotic cardiovascular disease (ASCVD) risk and determining eligibility for primary prevention statin therapy. This study evaluated the projected population-level impact of these updated recommendations compared with the 2018 lipid guidelines.
DETAILS: This nationally representative cross-sectional study analyzed data from nonpregnant adults aged 30 to 79 years without known ASCVD who participated in the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2023. The analysis included 4366 participants representing 154.5 million US adults. Data were analyzed from March to May 2026.
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The study compared statin eligibility under the 2026 dyslipidemia guideline with recommendations from the 2018 lipid guidelines. The investigators assessed the proportion of adults eligible for primary prevention statin therapy, including individuals qualifying based on low-density lipoprotein cholesterol (LDL-C) levels, diabetes, chronic kidney disease, or ASCVD risk estimation.
The study estimated that the 2026 guideline would expand primary prevention statin eligibility to 21.5 million US adults who were not previously recommended statin therapy. Overall, 87.5 million US adults (56.6% of the target population) were estimated to be eligible for statins under the new guideline.
Among the weighted sample, 5.5% (95% CI, 4.7%-6.6%) had untreated LDL-C below 70 mg/dL, 17.8% (95% CI, 16.3%-19.5%) reported current statin use, and 8.6% (95% CI, 7.6%-9.8%) met criteria for statin therapy independent of ASCVD risk estimation based on LDL-C of 190 mg/dL or greater, diabetes, or chronic kidney disease.
Eligibility increased substantially among older adults, with more than 93% of adults aged 70 to 79 years and 85% of adults aged 60 to 69 years meeting criteria for primary prevention statin therapy, compared with 11% of adults aged 30 to 39 years.
The newly eligible population generally represented younger and lower-risk adults compared with those previously recommended statins. The mean estimated 10-year ASCVD risk was 3.1% (95% CI, 2.7%-3.5%) among newly eligible individuals compared with 6.1% (95% CI, 5.8%-6.4%) among those previously eligible.
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Source: Anderson, T. S., Wilson, L. M., and Sussman, J. B. Implications of the 2026 Dyslipidemia Guideline for Primary Prevention Statin Therapy. JAMA. 2026; Published: July 20, 2026. DOI: 10.1001/jama.2026.11246
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