Wanpen Vongpatanasin

The cellular properties of mechanosensitive sensory neurons innervating skeletal muscle remain incompletely understood. We show that retrogradely labeled skeletal muscle-innervating small DRG neurons exhibit lower mechanical thresholds and greater responsiveness to the Piezo1 agonist Yoda-1 than unlabeled neurons. These findings identify enhanced mechanosensitivity and Piezo1-related functional signaling as characteristics of skeletal muscle-innervating sensory neurons.

BACKGROUND: Abnormal mechanoreflex function from skeletal muscle significantly contributes to the heightened circulatory response during exercise in type 2 diabetes (T2DM). However, the underlying mechanisms remain unclear. We hypothesized that the abnormal cardiovascular responses in T2DM are mediated by mechanoreflex-induced exaggerations resulting from enhanced Piezo1-mediated mechanosensitivity of muscle afferents. METHODS: T2DM rats (Sprague-Dawley rats) were given a high-fat diet in combination with a low dose of streptozotocin. Using an in vivo decerebrated rat model and an ex vivo single-fiber recording preparation, we measured muscle mechanoreflex responses, mechanosensitivity of muscle afferents, and Piezo1-mediated responses. Piezo1 protein levels in the membrane fraction were detected by Western blotting in human embryonic kidney 293 (HEK293) cells. RESULTS: Blood pressure and sympathetic nerve activity responses to mechanoreflex activation, as well as group IV muscle afferent firing to mechanical stimulation and the Piezo1 agonist (Yoda1), were significantly greater in T2DM rats. More importantly, Piezo1 agonist-induced blood pressure changes and group IV afferent firing were significantly potentiated by administration of lipopolysaccharide, a gut-derived inflammatory endotoxin. Furthermore, lipopolysaccharide significantly increased Piezo1 protein in the cell membrane, which was attenuated by a PKA (protein kinase A) inhibitor. CONCLUSIONS: These findings suggest that activation of the lipopolysaccharide-Piezo1 pathway may contribute to enhanced responsiveness of group IV muscle afferents and may be associated with exaggerated circulatory responses to muscle mechanoreflex activation in T2DM.

Background: Hypertension remains one of the leading causes of cardiovascular morbidity and mortality worldwide, yet blood pressure (BP) control rates remain suboptimal despite available therapeutic options. Patients with difficult-to-control or resistant hypertension face elevated cardiovascular risk and require intensive, coordinated management that addresses measurement accuracy, medication adherence, and treatment intensification. Multidisciplinary collaboration has emerged as a highly effective approach, with systematic reviews demonstrating significant BP reductions and increases in control rate vs usual care. Methods: This review discusses evidence supporting collaborative care models, including advanced practice provider-physician partnerships, physician-pharmacist collaborative management, nurse-led interventions, and community health worker programs. Key implementation strategies include standardized treatment protocols, home BP monitoring with clinical support, and health information technology integration. Results: Despite demonstrated cost-effectiveness, significant barriers to collaborative care persist, including inadequate reimbursement, organizational inertia, and workforce limitations. The advanced practice provider-physician model shows promise, with advanced practice providers managing routine and complex hypertension, allowing physicians to focus on more challenging cases. Specialized centers, including American Heart Association Certified Comprehensive Hypertension Centers, provide multidisciplinary expertise for difficult-to-control hypertension. Conclusions: Future directions include sustainable payment models and leveraging technology to enhance team communication and patient engagement. Optimizing interprofessional collaboration represents an evidence-based strategy to close the gap between evidence-based management and real-world BP control.

Hypertension remains a major public health concern globally. Accumulating evidence suggests that dietary phosphate (Pi) and fibroblast growth factor 23 (FGF23), a phosphaturic hormone, are involved in blood pressure regulation. Experimental studies have shown that excess Pi consumption, largely from inorganic Pi used as a preservative or flavor enhancer in processed foods, and increased FGF23 may contribute to vascular abnormalities, thereby promoting hypertension. Importantly, recent animal studies have demonstrated that peripheral FGF23 can cross the blood–brain barrier and stimulate FGF receptor 4 (FGFR4)-calcineurin signaling in the brain, contributing to sympathetic overactivation and hypertensive responses during high Pi loading. Additionally, dietary Pi loading leads to suppression of Klotho, which may further contribute to hypertension. Such mechanisms are potentially relevant to chronic kidney disease (CKD), a condition characterized by Pi retention, massively elevated FGF23, sympathetic overactivity, and hypertension. This review highlights current evidence linking Pi-induced FGF23 pathogenically to hypertension, with focus on FGF23 translocation to and FGFR4 signaling in the central nervous system as a potential mechanism and therapeutic target for hypertension associated with high Pi intake and CKD.

Aims: Blood pressure (BP) control remains suboptimal among US patients with hypertension. Single-pill combination (SPC) therapies are commonly used to improve adherence; however, their effectiveness for achieving early and sustained intensive BP control is unclear. Methods and results: We performed a post hoc analysis of Systolic Blood Pressure Intervention Trial (SPRINT) including 2736 participants propensity matched in a 1:2 ratio to compare effects of SPCs with equivalent multi-pill therapy. The estimated marginal odds of achieving target BP control were derived using generalized linear mixed models with repeated measures (LMMRMs). The association between time-updated SPC use and BP change in short- (≤6 months) and long-term (>6 months) follow-up was assessed with LMMRM and SPC * time interaction term. Multivariable Cox models evaluated the association of SPC use with cardiovascular events and serious adverse events (SAEs). Among SPRINT participants (n = 8623), 9.3% (n = 803) were prescribed SPC at baseline with greater use in the intensive vs. usual care group (5.79 vs. 3.90 per 100 person-months; P-diff < 0.001). Among matched pairs [SPC (n = 912); multi-pill therapy (n = 1824)], SPC use was associated with 22% increased likelihood of achieving target BP by 6 months [odds ratio (95% confidence interval), 1.22 (1.05, 1.42)]. Participants receiving SPCs (vs. multi-pills) experienced more rapid BP reduction in the first 6 months (−2.0 vs. −1.2 mmHg monthly change; P-diff < 0.001). Over long-term follow-up, participants using SPCs achieved significantly lower SBP at each time point. The risk of the primary CV composite endpoint and SAEs were not significantly different between groups. Conclusion: Single-pill combination use resulted in greater likelihood of achieving target BP control and more rapid, sustained BP reduction without an increase in SAEs.

Background Current guidelines recommend a blood pressure (BP) goal ≤130/80 mm Hg in peripheral artery disease (PAD) even though few PAD patients were enrolled in the landmark BP-lowering trials. Moreover, intensive BP control can worsen limb perfusion and none of the trials adjudicated limb events. Methods Using data from a longitudinal registry of US Veterans, we identified 91,296 patients (>2.7 million BP values) with a new diagnosis of PAD during 2015-2020. Multivariable Cox regression models evaluated the association between longitudinal BP values (time-varying exposure) and risk of cardiovascular (CV: myocardial infarction, stroke) and limb (chronic limb threatening ischemia, major amputation) events. Results Mean age was 70.5 years, 97.3% were men and 18.5% were Black race. At baseline, the mean (SD) systolic BP was 133 (19) mm Hg and diastolic BP was 73 (11) mm Hg. Over a median 4.1 years, the incidence of CV and limb events was 4.6 per-100 patient-years and 5.0 per 100-patient-years, respectively. In adjusted Cox models, systolic BP ≥140 mm Hg was strongly associated with higher risk of CV events with increasing risk across BP categories (130-139 mm Hg [reference]; 140-149 mm Hg: hazard ratio [HR]: 1.28 [95%CI: 1.16-1.41]; 150-159 mm Hg: HR 1.54 [1.39-1.72]; >160 mm Hg: 2.22 [2.02-2.44]). However, there was no association between systolic BP below 130 mm Hg and risk of CV events. In contrast, the association between systolic BP and limb events was U-shaped with the highest hazard of limb events at both low (Conclusion Current recommendations for BP goal in PAD patients are associated with optimizing risk of CV events but associated with a higher risk of limb events. Our findings highlight the need to better define BP goals for PAD patients, especially those at an increased risk of limb events.