Abstract
As rates of type 2 diabetes mellitus (T2DM) have risen, comorbidities of T2DM and cardiovascular disease (CVD) have similarly increased. The adoption of sodium-glucose cotransporter (SGLT) 2 inhibitors as a treatment for T2DM has provided an effective means of decreasing renal glucose reabsorption. In recent clinical trials, sotagliflozin, the first FDA-approved inhibitor of both isoforms of SGLT (SGLT1 and SGLT2), demonstrated a reduction in myocardial infarction and stroke in patients with T2DM at high cardiovascular risk. The cardiovascular protective effect of sotagliflozin compared to the SGLT2-selective inhibitor, empagliflozin, was investigated by evaluating effects on platelet activation and thrombus formation. Employing ex vivo models using blood from healthy donors or T2DM patients, and in vivo mouse models, we demonstrate an inhibitory effect on platelet activity and thrombus formation with sotagliflozin, while empagliflozin has minor to no effects. Further, no impact on hemostasis was observed with sotagliflozin. Finally, a platelet-specific deletion of SGLT1 via Slc5a1fl/fl Gp1ba-Cre⁺ mice resulted in reduced platelet integrin activation and thrombus formation. This study provides insight into a potential explanation for the cardiovascular protection conferred by sotagliflozin observed in patients with T2DM at risk of an ischemic event and reveals an added benefit to SGLT2-selective inhibitors.
Authors
Livia Stanger, Krista Goerger, Xu Zhang, Pooja Yalavarthi, Andrew Rickenberg, Adriana Yamaguchi, Mariane Flores Nascimento, Ashleigh Kilgore, Heeseo Kim, Xiaokang Wu, Yanhong Guo, Anna R. Dahlgren, Jifeng Zhang, Jordan A. Shavit, Bertram Pitt, Y. Eugene Chen, Michael Holinstat
Abstract
BACKGROUND. Supraventricular tachycardia (SVT) and Wolff-Parkinson-White (WPW) are potentially highly symptomatic and, rarely, lethal arrhythmias associated with atrioventricular accessory pathways. While the etiology of accessory pathways remains largely unknown, they are frequently observed with Ebstein’s Anomaly, a congenital heart disease associated with maternal medicinal lithium use. Therefore, we evaluated whether in utero exposure to lithium from environmental sources is associated with the prevalence of accessory pathways. METHODS. We conducted a county-level ecological comparison of lithium levels in drinking water versus prevalence of WPW diagnoses among patients < 18-years-old in California using multivariable logistic regression. Children were analyzed given their high likelihood to reside in the same county during fetal development. WPW cases were identified using diagnostic codes. Positive and negative controls, including falsification endpoints, were analyzed. RESULTS. Among 2,329,090 patients (mean age 8.2 ± 5.9 years, 47.8% female), 686 (0.03%) were diagnosed with WPW. Areas where lithium levels ≥ 75th percentile were associated with 71% greater odds of WPW (OR 1.71, 95% CI 1.44 to 2.03). Areas above the lithium health-based screening limit had 29% greater odds of WPW (OR 1.29, 95% CI 1.05 to 1.58). Similar results existed in a New York statewide cohort. In validation analyses, areas where lithium levels ≥ 75th percentile were associated with a higher prevalence of SVT, syncope, palpitations, and catheter ablation procedures. CONCLUSIONS. Higher lithium levels in drinking water were associated with a greater prevalence of childhood-diagnosed WPW, implicating a potentially modifiable risk factor for the development of accessory pathways.
Authors
Justin T. Teraoka, Anushree Agarwal, Janet J. Tang, Thomas A. Dewland, Gregory M. Marcus
Abstract
Atrial fibrillation (AF) is the most common sustained human cardiac arrhythmia and linked to a drastic increase in stroke and heart failure risk. While sequence variations in the PITX2 non-coding region are the strongest genetic signature of AF risk, the direct role of PITX2 in AF remains a topic of debate. Here, we generated a mouse model (Pitx2Pro41Ser) of a human PITX2 coding variant linked to increased AF risk in the Finnish population. The Pitx2Pro41Ser mice exhibit near-complete penetrance of pacing-induced AF, and transcriptional profiling indicates that Pitx2Pro41Ser is a loss-of-function mutation. In vivo cleavage under targets and tagmentation (CUT&Tag) reveals that PITX2 acts as a transcriptional repressor in developing left atrial cardiomyocytes independent of DNA methylation. Ectopic Pitx2 expression in postnatal right atrial cardiomyocytes via adeno-associated virus (AAV) delivery or genetic overexpression represses right atrial genes and induces a left atrial transcriptome, revealing unexpected plasticity of postnatal atrial cardiomyocytes. Strikingly, delivery of Pitx2 AAV into Pitx2Pro41Ser mice rescues AF inducibility uncovering a direct link between PITX2 activity and AF susceptibility.
Authors
Jeffrey D. Steimle, Yue Yuan, Shaohai Fang, Vaibhav Deshmukh, Christine Rodriguez, Fansen Meng, Taotao Tan, Md. Abul Hassan Samee, Yun Huang, Na Li, James F. Martin
Abstract
Chronic kidney disease (CKD) disrupts mineral homeostasis, leading to impaired skeletal mineralization and cardiovascular pathology, yet the mechanism linking these processes remains undefined. Here we identify glycerol-3-phosphate acyltransferase 2 (GPAT2) as a regulator that couples free fatty acid (FFA) partitioning in osteoblasts to systemic phosphate balance. In mouse and human CKD, elevated osteoblast GPAT2 routes FFA away from mitochondrial oxidation, limiting phosphate incorporation into bone, and toward lysophosphatidic acid synthesis, increasing production of the phosphaturic hormone fibroblast growth factor 23 (FGF23). By contrast, osteoblast-specific Gpat2 deletion restores osteoblast FFA oxidation and skeletal phosphate incorporation, lowers circulating phosphate and FGF23, and attenuates vascular calcification and cardiac hypertrophy in CKD. Further, a bone-targeted GPAT inhibitor recapitulates most of these beneficial effects. These findings establish a fundamental role for osteoblast lipid metabolism in mineral homeostasis and identify GPAT2 in bone as a promising therapeutic target for both skeletal and cardiovascular complications of CKD.
Authors
Petra Simic, Han Xie, Wen Zhou, Yu Fan, Renata C. Pereira, Fangcong Dong, Jason D. Roh, Isidro B. Salusky, Charandeep Singh, Russell P. Goodman, Ashok Khatri, Eugene P. Rhee
Abstract
Authors
Rong Tian, E. Douglas Lewandowski
Abstract
Authors
Chai-Wan Kim, Matthew A. Mitsche, Jay D. Horton
Abstract
Authors
Diwakar Turaga, Chang-Ru Tsai, Yuka Morikawa, Hanna J. Tadros, Yi Zhao, Lalita Wadhwa, Iki Adachi, Xiao Li, James F. Martin
Abstract
Authors
Diana B. Voss, Emily J. Shields, Andrey Poleshko, Li Li, Jun Li, Roger Wang, Mariacristina Calcagno, Rajan Jain, Cheryl L. Smith, Jonathan A. Epstein
Abstract
Authors
Seyi E. Elasoru, Christian Miccile, Jingwu Pan, Zhaoyang Zhang, Kalyanam Shivkumar, Herbert Herzog, Robert D. Harvey, Zhilin Qu, Olujimi A. Ajijola
Abstract
The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent endothelial-to-mesenchymal transition (Endo-MT). In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator of the endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.
Authors
Huijuan Wang, Haosheng Zhang, Leiyin Zheng, Peihan Zhang, Yuqian Wang, Sijia Ding, Wenping Liu, Yuanming Cheng, Zhongzhou Yang, Wen Luo
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)