Incidence of cardiovascular mortality among head and neck cancer patients.

BACKGROUND: While treatment advancements have prolonged the lives of patients with head and neck cancer, the subgroups of these patients at higher risk for cardiovascular disease (CVD) mortality remain unclear. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with head and neck cancer from 2000 to 2019. We compared their CVD mortality against the general US population using standardized mortality ratios (SMRs). RESULTS: Our analysis included 474,366 patients, identifying that 14% of deaths were due to CVD, with an SMR of 1.19. Notably, patients under the age of 39 had a CVD SMR increase of over 100-fold. Those with distant tumor stages showed the highest CVD SMR of 1.52 (95% CI 1.50-1.54). An upward trend in SMR to 2.53 (95% CI 2.51-2.56) was observed from 2011 to 2019. Within the initial 5-year post-diagnosis, the SMR for CVD was 3.17 (95% CI 3.14-3.20), which exceeded the general population's rates but declined in the 5-20-year range after diagnosis. Patients who did not any therapy had the greatest CVD SMR of 2.26 (95% CI 2.24-2.28). Hypopharyngeal cancer patients exhibited the highest CVD SMR of 1.54 (95% CI 1.52-1.56). CONCLUSIONS: The study highlights that head and neck cancer patients, especially younger individuals and those with advanced disease stages, face substantial CVD mortality risks. The CVD SMR peaks within 5 years following diagnosis. Patients abstaining from treatment bear the highest risk of CVD mortality. Cardioprotective measures should be considered critical for this patient population.

Identification of a novel Scn3b mutation in a Chinese Brugada syndrome pedigree: implications for Nav1.5 electrophysiological properties and intracellular distribution of Nav1.5 and Navß3.

Background: The Scn3b gene encodes for Navß3, a pivotal regulatory subunit of the fast sodium channel in cardiomyocytes. However, its mutation status in the Chinese population suffering from Brugada Syndrome (BrS) has not been characterized, and the contributory pathophysiological mechanisms to disease pathology remain undefined. Methods and Results: A Scn3b (c.260C>T, p.P87l) mutation was identified in a patient with BrS of Chinese descent. Functional analyses demonstrated that sodium channel activation for the wild type, mutant samples, and co-expression of both commenced at -55 mv and peaked at -25 mv. The mutant group exhibited a notable reduction, approximately 60%, in peak sodium channel activation current (INa) at -25 mv. The parameters for half-maximal activation voltages (V1/2) and slope factors (k) showed no significant differences when comparing wild type, mutant, and combined expression groups (P = 0.98 and P = 0.65, respectively). Additionally, no significant disparities were evident in terms of the steady-state sodium channel inactivation parameters V1/2 and k (with P-values of 0.85 and 0.25, respectively), nor were there significant differences in the activation time constant τ (P = 0.59) and late sodium current density (P = 0.23) across the wild-type, mutant, and co-expressed groups. Confocal imaging and Western blot analysis demonstrated decreased plasma membrane localization of SCN3B and SCN5A in the P87l group. Computational simulations of cardiac action potentials suggested that SCN3B P87l can alter the morphology of the action potentials within the endocardium and epicardium while reducing the peak of depolarization. Conclusions: The pathogenic impact of the Scn3b P87l mutation predominantly originates from a reduction in peak INa activation current coupled with decreased cell surface expression of Nav1.5 and Navß3. These alterations may influence cardiac action potential configurations and contribute to the risk of ventricular arrhythmias in individuals with BrS.

Mitochondrial dysfunction-mediated decline in angiogenic capacity of endothelial progenitor cells is associated with capillary rarefaction in patients with hypertension via downregulation of CXCR4/JAK2/SIRT5 signaling.

BACKGROUND: Hypertensive patients exhibit decline in capillary density and endothelial progenitor cells (EPCs). However, whether capillary rarefaction in hypertension is associated with defect angiogenesis of EPCs remains unknown. We hypothesized that impaired mitochondrial function of late EPCs in hypertension is associated with the structural lack of capillary microcirculation via deficient CXCR4/JAK2/SIRT5 signaling. METHODS: We performed capillary microcirculation detection in hypertensive patients and healthy subjects. Angiogenic capacity and mitochondrial function of circulating EPCs were evaluated. The underlying mechanisms were further investigated by genetic inhibition and overexpression. FINDINGS: Capillary density of nail fold and eye fundus were significantly reduced in hypertensive patients, which was paralleled to decreased in vitro late EPC function and in vivo angiogenic capacity. Meanwhile the decline of EPC function in hypertension was accompanied by impaired mitochondrial ultrastructure, diminished mitochondrial membrane potential, reduced oxygen consumption, increased ROS generation and NADH level. Rotenone induced inhibition of oxygen consumption rate, excessive ROS generation and loss of MMP, which markedly decreased the in vitro functions of EPCs. Furthermore, SIRT5 expression of EPCs in hypertension was markedly reduced, which was correlated to mitochondrial dysfunction. CXCR4 gene transfer enhanced SIRT5 expression, improved mitochondrial functions and augmented angiogenic capacity of EPCs. The beneficial impacts of SIRT5 up-regulation on late EPC-mediated angiogenesis can be abrogated by blockade of CXCR4/JAK2/SIRT5 signaling pathway. INTERPRETATION: Mitochondrial dysfunction-mediated fall in angiogenic capacity due to deficient CXCR4/JAK2/SIRT5 signaling of late EPCs is probably responsible for the capillary rarefaction in hypertension. Our findings provide insight into the potential of EPC mitochondria as a novel target for the treatment of hypertension-related loss of microvascular density. FUNDS: National Nature Science Foundation of China, 973Program, the Nature Science Foundation of Guangdong.

Berberine-Promoted CXCR4 Expression Accelerates Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Persons with Prehypertension.

OBJECTIVE: To evaluate whether the berberine treatment can improve endothelial repair capacity of early endothelial progenitor cells (EPCs) from prehypertensive subjects through increasing CXC chemokine receptor 4 (CXCR4) signaling. METHODS: EPCs were isolated from prehypertensive and healthy subjects and cultured. In vivo reendothelialization capacity of EPCs from prehypertensive patients with or without in vitro berberine treatment was examined in a nude mouse model of carotid artery injury. The protein expressions of CXCR4/Janus kinase-2 (JAK-2) signaling of in vitro EPCs were detected by Western blot analysis. RESULTS: CXCR4 signaling and alteration in migration and adhesion functions of EPCs were evaluated. Basal CXCR4 expression was significantly reduced in EPCs from prehypertensive patients compared with normal subjects (P<0.01). Also, the phosphorylation of JAK-2 of EPCs, a CXCR4 downstream signaling, was significantly decreased (P<0.01). Berberine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs (P<0.01). Transplantation of EPCs pretreated with berberine markedly accelerated in vivo reendothelialization (P<0.01). The increased in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by CXCR4 neutralizing antibody or pretreatment with JAK-2 inhibitor AG490, respectively (P<0.01). CONCLUSION: Berberinemodified EPCs via up-regulation of CXCR4 signaling contributes to enhanced endothelial repair capacity in prehypertension, indicating that berberine may be used as a novel potential primary prevention means against prehypertension-related atherosclerotic cardiovascular disease.

Effect of Intensive Periodontal Therapy on Blood Pressure and Endothelial Microparticles in Patients With Prehypertension and Periodontitis: A Randomized Controlled Trial.

BACKGROUND: Although some studies show a positive association between periodontitis and blood pressure (BP) elevation, research on the effect of intensive periodontal treatment on decline in BP levels and endothelial microparticles (EMPs) without any antihypertensive management is lacking. Therefore, the present clinical trial explores whether intensive periodontal therapy would lower BP levels and EMPs of patients with prehypertension with periodontitis. METHODS: From a total 107 patients, 95 underwent randomization (47 assigned to control-treatment [CT] group and 48 assigned to intensive-treatment [IT] group) and completed the trial. Patients received intervention for 4 consecutive weeks and were followed for 6 months. Levels of BP and EMPs were evaluated at baseline and 1, 3, and 6 months after intervention. RESULTS: Periodontal conditions were significantly improved (P <0.05) 6 months after intensive periodontal treatment. In parallel, the primary outcomes including systolic and diastolic BP and EMPs were markedly reduced in the IT group compared with the CT group (absolute difference: 12.57 and 9.65 mm Hg and 581.59/µL, respectively; 95% confidence intervals: 10.45 to 14.69, 7.06 to 12.24, and 348.12 to 815.06, respectively; P <0.05). Reduction in BP levels and EMPs was related to improvement in probing depth (r = 0.358, 0.363, and 0.676, respectively, by the Pearson product-moment correlation; P = 0.009, 0.008, and P <0.001, respectively). CONCLUSION: To the best knowledge of the authors, the present study demonstrates for the first time that intensive periodontal intervention without any antihypertensive medication therapy may be an effective means to lower levels of BP and EMPs in patients with prehypertension with periodontitis.

CXCR7 upregulation is required for early endothelial progenitor cell-mediated endothelial repair in patients with hypertension.

Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in hypertension.

Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans.

BACKGROUND: Circulating endothelial microparticles (EMPs) lead to endothelial dysfunction by increasing oxidative stress. Berberine has a beneficial effect on endothelial function, but no data are available on the EMP-mediated oxidative stress. The present study tests the hypothesis that berberine contributes to the improvement of endothelial function in humans via inhibiting EMP-mediated oxidative stress in vascular endothelium. METHODS: Twelve healthy subjects received a 1-month berberine therapy and eleven healthy subjects served as control. Endothelium-dependent and -independent function in the brachial artery was assessed by flow-mediated vasodilation (FMD) and sublingual nitroglyceride-mediated vasodilation (NMD). Circulating EMPs and serum malondialdehyde (MDA) were measured before and after therapy. Furthermore, in vitro human umbilical vein endothelial cells (HUVECs) were stimulated by EMPs with or without presence of anti-oxidant compound apocynin or berberine. Intracellular reactive oxygen species (ROS), nitric oxide (NO) production and NADPH oxidase 4 (Nox4) protein expressions were examined, respectively. RESULTS: The levels of serum MDA and circulating CD31+/CD42- MPs were significantly reduced in the berberine group compared with the control group, which were associated with improvement of FMD. The EMPs in vitro facilitated ROS production and Nox4 protein expression and reduced NO synthesis in HUVECs. These alterations can be reversed by the presence of apocynin or berberine, respectively. CONCLUSION: The present study demonstrated for the first time that EMP-induced upregulation of Nox4 expression may enhance ROS production in HUVECs. Berberine treatment contributes to the amelioration of endothelial function through a partially reducing oxidative stress of vascular endothelium induced by circulating CD31+/CD42- microparticles in humans.

Shear stress-induced activation of Tie2-dependent signaling pathway enhances reendothelialization capacity of early endothelial progenitor cells.

Although endothelial progenitor cells (EPCs) play a pivotal role in the endothelial repair following arterial injury and shear stress has a beneficial effect on EPCs, however, the molecular mechanism underlying the influence of EPCs on the endothelial integrity and the regulation of shear stress on the EPC signaling remained to be studied. Here, we investigated the effects of laminar shear stress on the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2)-dependent signaling and its relation to in vivo reendothelialization capacity of human early EPCs. The human early EPCs were treated with shear stress. Shear stress in a dose-dependent manner increased angiopoietin-2 (Ang2)-induced migratory, adhesive and proliferatory activities of EPCs. Transplantation of EPCs treated by shear stress facilitated in vivo reendothelialization in nude mouse model of carotid artery injury. In parallel, the phosphorylation of Tie2 and Akt of EPCs in response to shear stress was significantly enhanced. With treatment of Tie2 knockdown or Akt inhibition, shear stress-induced phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) of EPCs was markedly suppressed. After Tie2/PI3K/Akt/eNOS signaling was blocked, the effects of shear stress on in vitro function and in vivo reendothelialization capacity of EPCs were significantly inhibited. The present findings demonstrate for the first time that Tie2/PI3k/Akt/eNOS signaling pathway is, at least in part, involved in the EPCs-mediated reendothelialization after arterial injury. The upregulation of shear stress-induced Tie2-dependent signaling contributes to enhanced in vivo reendothelialization capacity of human EPCs.

Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK-2 signaling in healthy men.

Endothelial progenitor cells (EPCs) play an important role in repairing endothelial injury. Aging is associated with EPC dysfunction. Physical exercise has a beneficial impact on EPC activity. However, whether physical exercise can enhance the endothelial repair capacity of EPCs in healthy men with aging is not clear. Here, we investigated the effects of physical exercise on reendothelialization capacity and CXC chemokine receptor four (CXCR4) signaling in human EPCs. Before and after 12-week exercise, EPCs were isolated from elderly and young men. In vitro function and in vivo reendothelialization capacity of EPCs in a mouse model of carotid artery injury were measured. The expression of CXCR4 and its downstream signaling target Janus kinase-2 (JAK-2) were determined. Before exercise, in vitro function and in vivo reendothelialization capacity of EPCs were significantly reduced in elderly men compared with young men. After exercise intervention, in vitro function and in vivo reendothelialization capacity of EPCs from elderly men were markedly enhanced. Physical exercise increased a higher CXCR4 protein expression and higher JAK-2 phosphorylation levels of EPCs. The augmentation in reendothelialization capacity of EPCs was closely correlated with the upregulation of CXCR4/JAK-2 signaling and improvement of endothelial function. This study demonstrates for the first time that physical exercise attenuates age-associated reduction in endothelium-reparative capacity of EPCs by increasing CXCR4/JAK-2 signaling. Our findings provide insight into the novel mechanisms of physical exercise as a lifestyle intervention strategy to promote vascular health in aging population.