Pulmonary and systemic hypertension  are characterized by vasoconstriction and vascular remodeling resulting in increased vascular resistance and pulmonary/aortic artery pressures. The chronic stress leads to inflammation, oxidative stress, and infiltration by immune cells. Roles of metals in these diseases, particularly PH are largely unknown. This review first discusses the pathophysiology of PH including vascular oxidative stress, inflammation, and remodeling in PH; mitochondrial dysfunction and metabolic changes in PH; ion channel and its alterations in the pathogenesis of PH as well as PH-associated right ventricular (RV) remodeling and dysfunctions. This review then summarizes metal general features and essentiality for the cardiovascular system and effects of metals on systemic blood pressure. Lastly, this review explores non-essential and essential metals and potential roles of their dyshomeostasis in PH and RV dysfunction. Although it remains early to conclude the role of metals in the pathogenesis of PH, emerging direct and indirect evidence implicates the possible contributions of metal-mediated toxicities in the development of PH. Future research should focus on comprehensive clinical metallomics study in PH patients; mechanistic evaluations to elucidate roles of various metals in PH animal models; and novel therapy clinical trials targeting metals. These important discoveries will significantly advance our understandings of this rare yet fatal disease, PH. Pulmonary hypertension (PH) is currently defined as an increased mean pulmonary arterial pressure greater than 20 mmHg measured by right heart catheterization at rest. It can be further divided into pre-capillary and post-capillary PH based on other hemodynamic parameters, namely pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR). Pre-capillary PH, or pulmonary arterial hypertension (PAH), is defined as PAWP ≤ 15 and PVR > 2 Woods Units (WU). Conversely, isolated post-capillary PH uses PAWP > 15 and PVR ≤ 2 WU as its defining parameters and is associated with left-sided heart disease. Combined pre- and post-capillary PH is a combination of the two previous definitions with PAWP > 15 and PVR > 2WU Currently there is no consensus regarding how or why endothelial mitochondrial dysfunction occurs. One proposed mechanism comes from the interaction between the mitochondria and metals. Non-essential metal pollution from industrialization and urbanization, impacts everyone through the contamination of water, soil, and the atmosphere Although PH and systemic hypertension (SH) shared some similarity, they are two significantly different diseases in terms of etiology, risk factors, pathogenic target organs and pathogenic mechanisms Table . ConsideFigure 1. The chronic and mechanical stress experienced by endothelial cells leads to inflammation, and infiltration by immune cells that potentiates the inflammatory process. Cellular and molecular responses from many signaling pathways cause pulmonary vasoconstriction, remodeling, and in situ thrombosis, which lead to increased vascular resistance and pulmonary artery pressure. The right ventricular (RV) afterload increases in PH eventually leads to RV remodeling, right heart failure, and death The pathophysiology of PH is the combination of endothelial cell damage, immune dysregulation, oxidative stress, and maladaptive metabolism, eventually leading to remodeling of the cardiopulmonary vasculature, as shown in Increased blood flow through the pulmonary vasculature impacts pulmonary arterial fibroblasts (PAFBs), PAECs, and PASMCs. Each of these cell types communicate via paracrine and mechanical signaling. Fluid shear stress not only impacts these cells individually but affects them as a network Bone morphogenetic proteins (BMPs), as a member of the TGF-β superfamily of ligands, are involved in paracrine signaling. BMP type II (BMPR2) is a serine/threonine receptor kinase that binds to BMPs. BMPR2 is the first gene identified in families with PAH and its mutation accounts for around 70% to 80% of heritable PH cases Endothelial dysfunction decreases endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, decreases NO generation, increases vasoconstriction, and causes higher pressure in the pulmonary vasculature. BMPR2 dysregulation causes overproliferation and overmigration of PASMCs in the tunica media and disrupts the expression of vascular endothelial growth factor (VEGF) that reduces vascular formation and function in vascular adventitia. All these changes cause pulmonary vasculature to be more susceptible to hypoxia Oxidative stress and ROS result in mitochondrial dysfunction This metabolic dysregulation and mitochondrial dysfunction inhibit mitochondria-mediated apoptosis despite the release of pro-apoptotic factors (i.e.: cytochrome c), due in part to hyperpolarization of the mitochondrial membrane The conversion of superoxide anions to hydrogen peroxide by MnSOD affects potassium (Kv) channels—such as those encoded by KCNK3— in the plasma membrane of healthy cells. KCNK3 encodes a K leak channel that regulates smooth muscle contraction via establishment of a concentration gradient. Kv channels not only control the major influx and efflux of potassium ions, but also the calcium (Ca) ions of the PASMCs, which are required for normal function. Both experimental models and human PH demonstrate downregulation of Kv channels. Kv1.5 channels are especially susceptible, as they are expressed in the small blood vessels typically affected by PAH vascular remodeling 2+ and sodium influx in response to stretch in the vascular wall. In animal models, Piezo1 proteins and mRNA were upregulated in isolated pulmonary artery when compared to controls. Blocking Piezo1 signaling with an intraperitoneal injection of GsMTx4, a Piezo1 channel blocker, improved the PH in mouse models 2+ influx into the cytosol which increases the expression of mechanosensitive channels in the transient receptor potential (TRP) channel superfamily and leads to vasoconstriction. As one of the TRP channel superfamily members, TRPM4 is a Ca-activated nonselective cation channel and TRPM7 is magnesium -permeable and Mg-modulated cation channels. TRPM7 and TRPV4 channels had increased expression in IPAH patient when compared to controls. Inhibiting these channels decreases the vasoconstriction and vascular remodeling in PH patients Piezo1, a cation channel that responds to mechanical stress, is upregulated in PAECs of IPAH patients and animal models of PH. This channel mediates CaThe above discussions are the main pathogenic changes and associated mechanisms in the PAEC death and differentiation, PAMSC proliferation, and fibrotic responses. These changes lead to the remodeling of the arterial wall, arterial stiffness and loss of the normal vascular dilation and contraction Figure . In factCardiac hypertrophy characteristic of severe PAH is also affected by oxidative damage. The GATA binding protein 4 (GATA4) transcription factor has been implicated in PASMC growth and proliferation. RV hypertrophy in response to hypoxia and PH increases GATA4 expression. In PASMCs, serotonin (5-HT) activates GATA4, and produces hydrogen peroxide, a potential source of ROS/RNS. Therefore, PH activates GATA4 pathway-mediated oxidative stress and RV cardiac remodeling and dysfunction In summary, oxidative stress result in mitochondrial dysfunction and leads to metabolic dysregulation. High energy requirements, potentially exacerbated by PH, increase production of various free radicals that damage mitochondrial membranes and proteins involved in metabolic functions. Therefore, the pathogenesis of PH is significantly different from SH Table .Table 2. Heavy metals are those with either a high atomic weight or density Metals are categorized into different groups based on their various features: transient (transition) metals vs non-transition metals based on their chemical features; heavy metals vs non-heavy metals from atomic weight; and essential vs non-essential metals from their biological effects. Electrons of transition metals can participate in the formation of chemical bonds—in two shells instead of only one. Transition metals are shown in red font in Table 2 lists some commonly investigated non-essential and essential metals in the toxicological studies, with overlap among three categories. For instance, the heavy metals and transition metals include both non-essential and essential metals Metal toxicity can be caused by both non-essential metals and essential metals. When introduced into the human, nonessential metals cause toxic effects. Essential metals can also be toxic when these metals accumulate to excessive levels systemically or in specific tissues or organs. It should be noticed that if the essential metal levels are too low, which is called metal deficiency, it can cause specific symptoms related to the specific essential metal As mentioned above, mitochondria play an important role in ROS/RNS, ATP production, conversion, and transduction of information, and cell death process. The mitochondrial responses in exposure to heavy metals has been discussed for a few decades. To date, several metals are known to distribute to, and accumulate in, the mitochondria where trace amounts of metals may be required for normal functioning of biological membranes as well as enzyme systems, whereas excess levels may be toxic Figure 2, many experiments showed that heavy metals can cause mitochondrial damage, impair ROS clearance system, increase ROS production, lead to lipid peroxidation, cell signal protein oxidation, and even DNA strand breaks. Increased intracellular ROS contents can destroy the intracellular membranes ion conversion channel, leak Ca2+ out, cause mitochondrial membrane dysfunctions, increase oxidant production, and damage the mitochondria. Impaired mitochondria display morphological and functional changes and produce more oxidants and less ATP. The integrity of the mitochondrial membrane is prerequisite for normal progression of oxidative phosphorylation and ATP generation. The integrity of the mitochondrial inner membrane is important because the electrochemical gradient and proton gradient on both sides of the membrane must be maintained 2+ intake, causes mitochondrial transient potential (mPTP) opening, increases mitochondrial membrane permeability, affects the imbalance of ion exchange causes, and alters membrane potential. The inner mitochondrial membrane contains enzymes involved in the electron transport chain and ATP production. The energy of most human cells is produced by the mitochondria. Heavy metals aggravate the oxidative damage of the mitochondria by reducing the activity of NADH and ATP enzymes and by affecting key enzymes, leading to suppressed ATP generation and a substantial increase in ROS As illustrated in The National Health and Nutrition Examination Survey (NHANES) defined SH as systolic BP ≥ 130 mmHg and diastolic BP ≥ 90 mmHg. A systematic review concluded that prolonged exposure to high levels of Pb might cause SH in adults Associations of metals with SH were also estimated for both single and multiple metal models in 11,037 adults from the 2017-2018 China National Human Biomonitoring. Higher rates of pre-hypertension (defined as systolic BP between 120 - 139 mmHg and diastolic BP between 80 - 89 mm Hg) and hypertension (systolic BP/diastolic BP ≥ 140/90 mmHg) were both associated with elevated blood Pb or As levels, but more remarkable with mixtures of metals in the blood The toxicity of inhaled Cd leads to inflammation and fibrosis, especially around blood vessels near the alveoli, and destruction of the lung immune barrier. Early epidemiological studies investigated the elements in rainwater and their relation to the frequency of hospitalization for SH, in Opole Voivodship, Poland during 2000-2002, revealing a mild correlation between Cd and cases of SH with some sex differences Other metals' potential links to SH were relatively less investigated. Tungsten is an emerging contaminant in the environment primarily due to increased use of tungsten in industrial applications. Its potential impact on human health remains unknown In addition, it should be clear that the metals that are associated with SH are not only nonessential metals, in fact cross-sectional study in two rural areas of southwest China showed positive trends between SH and increasing quartiles of Fe in the Cd-polluted area and Mg, Ca and Cu in the unpolluted area. These findings suggest that exposure to Fe in the polluted area while Mg, Ca and Fe in the unpolluted area might increase the risk of SH or elevate blood pressure levels In summary, the harmful effects of metals on SH have been extensively reported via several mechanisms such as NO availability, upregulation of inflammatory pathways, and induction of ROS. Whether these metals may be contributors to the pathogenic effects of metals on the pulmonary vasculature, and whether exposure to nonessential metals disturb essential metal homeostasis that secondarily affects the pulmonary artery structures and induces PH, will be discussed in the following section.The pulmonary vasculature is one of the first capillary beds that encounters the environmental air pollution. The environmental pollution, tobacco smoking, and other particles may generate free radicals and damage vascular cells causing cellular dysfunction 2.5). These effects were attributed to proximity of workers to the dispersion of the PM2.5, particle size, and free silica content of the PM. Proposed damage to lungs with occupational exposure - intimal thickening, capillary damage, and permeability changes - were consistent with the changes seen in the mining workers 2.5 as well as household exposures Human studies also showed associations between heavy metals and PH. Workers in an open-pit Mn mine in Guangdong, China had worse lung functions than controls due to exposure to fine PM with a diameter less than 2.5 μm  pointed out that adult smokers with low dietary Zn intakes have a higher Cd burden and increased risk of developing chronic obstructive pulmonary disease (COPD) A case-control study supported the above notice, by demonstrating associations of circulatory Cd and COPD among 400 COPD patients and 400 control subjects. Circulatory Cd was inversely associated with pulmonary functions in COPD patients. Meanwhile, E-cadherin, one of epithelial biomarkers, was reduced in lung tissues of COPD patients with higher circulatory Cd, which was accompanied with reduced levels of pulmonary N-cadherin, Vimentin and α-SMA, three mesenchymal biomarkers 2-, urinary nitrate/nitrite, MDA, carbonyl level and decreased GSH production in rat blood and thoracic aorta tissues, leading to the arterial remodeling and stiffness, development of high arterial blood pressure, and cardiac dysfunction 2.5 and PM10 in juvenile, adult and senescent rats for 12 months with the average concentrations of 78.7 PM2.5 or 128.2 μg/m3 PM10 could destroy intrapulmonary and small artery endothelial functions, causing vasodilatory disorders. In these rats, PM2.5 and PM10 exposure caused PM to accumulate in the lungs, along with Cd accumulation in the liver and kidneys. Therefore, severe pulmonary and vascular disorders caused by ambient PM2.5 and PM10 might be related to Cd in PM Exposure to Cd leads to vascular remodeling via many mechanisms, including increased smooth muscle cells, NOS dysregulation, and ROS production One question is whether Ca is required for Cd-mediated pathogenesis of PH since intracellular Ca ion concentration (Ca2+) was associated with PH-related vascular remodeling and vasoconstriction In addition, platelet-derived growth factor (PDGF) also increases intracellular free Ca2+ in human dermal fibroblasts. However, PDGF stimulating effect was markedly inhibited by genistein that selectively inhibits tyrosine kinases. Genistein did not prevent Cd-stimulated Ca2+ mobilization into cytosol. These suggest that several stimuli such as Cd and PDGF can stimulate Ca2+ efflux or rapid increase at intracellular level through different signaling pathways. However, whether stimulation of intracellular Ca2+ result in the same pathogenic effects also depended on the status of intracellular Ca2+ clearance by plasma membrane Ca-ATPase (PMCA) Although exposure to chronic Cd may cause CVDs, including hypertension from the vascular endothelial cell damage, the matter of whether exposure to Cd directly induces or only exacerbates PH and RV remodeling and dysfunction remains unclear and warrants further investigation.Antimony is a chemical element and its air pollution and/or environmental contamination is derived from its wide application and associated products 2) In our recent pilot study, we evaluated Sb levels in the blood, plasma and urine of 20 PAH patients and 10 controls, which showed significantly higher blood and plasma levels of Sb in PAH patients when compared to controls. Sb blood and plasma levels were also significantly higher in both IPAH patients and non-IPAH when compared with controls. But these differences were not significantly observed in the urine levels of Sb. In addition, there was a significant correlation between plasma Sb levels and all the PAH prognostic hemodynamic parameters, including mean right atrial pressure (mRAP), CO, CI, PVR, and mixed venous oxygenation (SvOVanadium (V) is in the first transition series of the periodic table, specifically in the 5 group states. V is omnipresent in trace amounts in the environment and atmosphere. V is also present in the human body, where it might serve as a regulator for phosphate-dependent proteins. The unique chemical and physical features of V compounds make it a widely required material in many industries and medical fields. The wide use of V also leads to its release to, and therefore presence in, the environment. Occupational exposure to V was found to induce, e.g., acute respiratory symptoms in boiler makers 2.5 was associated with increased risk of respiratory symptoms in children Earlier studies have reported that exposure to V oxides attached to fine PMAs mentioned above, the potential link of tungsten to SH has been implicated In summary, we did not have direct evidence to indicate the causative role of these non-essential metals mentioned above in the pathogenesis of PH. However, whether exposure to these metals would worsen the outcomes of PH should be urgently investigated.Table 3.Essential metals are required for the biological functions, but their dyshomeostasis (i.e.: either too low [deficiency] or too much [excessive]) causes vascular injuries or remodeling, contributing to the development of PAH, RV remodeling, and cardiac dysfunction. These metals play key roles in NO metabolism dysregulation and production of ROS/RNS and free radicals. Metabolic disturbances, mediated by Cu ions, can induce DNA strand disruptions and oxidation of the DNA bases. Furthermore, Cu and Fe undergo Fenton reactions to produce free radicals Copper is a major component of non-exhaust traffic-related pollution. It is taken up by membrane protein Cu transporter (CTR1). Once absorbed, Cu serves as a critical element in the redox reactions necessary for hemoglobin synthesis, protective functions for DNA, and nervous and immune system functions 2.5, the long-term health effects may be great though more research is needed to elucidate these mechanisms In Toronto, long-term exposure to Cu with Fe was associated with increased ROS in lung epithelial fluid and worse mortality from respiratory diseases. COPD mortality was associated with higher levels of Cu exposure Mechanistically, Cu is a producer of ROS, but it also plays a role in anti-oxidative stress as Copper-Zinc superoxide dismutase (CuZn-SOD) Cu interacts with other heavy and essential metals. Cu deficiency can contribute to Zn toxicity and both Cu and Zn can interfere with Fe metabolism. In fact, Zn supplementation can alter the intestinal absorption of Cu and cause anemia 2+) to ferric (Fe3+) state Iron is an essential metal and involved in metabolic processes such as electron transport, nucleotide synthesis, and oxygen transport. Although essential for metabolism, Fe can be toxic if concentrations exceed a certain threshold. Therefore, Fe levels need to be held in tight regulation. In the human body, Fe is concentrated in hemoglobin, bound to ferritin or transferrin, embedded within intracellular proteins, and in a labile iron pool. This labile Fe pool, also referred to as non-transferrin bound Fe, is a reactive pool of relatively free-floating Fe. Iron in this non-bound state can form ROS, in this case a free radical as Fe is transformed from its ferrous  It is worth noticing that despite the connections between Fe homeostasis and PH, interventions targeting Fe pathways in PH patients have shown varying results. Application of Fe chelation as a main therapeutic approach for the patients with PH or PAH are not clinically applied. However, recent summary revealed that oral Fe supplementation with traditional formulation showed limited utility due to poor absorption. Newer oral formulations such as ferrous maltol and pyrophosphate sucrosomial Fe, with intrinsically improved bioavailability, have demonstrated possible clinical benefits, including improved exercise capacity measured by 6-min walk distance in vitroZn is a necessary component of many enzymes and play key roles in the enzymatic activity of alcohol dehydrogenase, DNA polymerases, and RNA transcriptase which highlights Zn's role in synthesis and maintenance of nucleic acids Figure 3. MTs as Zn storage and donor play important roles to bind free Zn and release its bound Zn to the Zn-contained proteins or kinases for their stable or functional conformation. As one of ZIP family members, ZIP12 has been appreciated for its expression and role in the nervous system. Normally, this transporter is undetectable in normoxic pulmonary tissues and cells; however, in hypoxic environments a marked increase in ZIP12 mRNA expression is present in multiple cell types related to pulmonary vascular remodeling, including vascular smooth muscle, endothelial, and interstitial cells Zn homeostasis is known to be regulated by different proteins involved in uptake, excretion and intracellular storage of Zn. These proteins belong to the ZIP  and ZnT  families as well as MTs Table 1 and major findings are summarized in Table 4. Promising evidence around MTs and other free radical-scavenging treatments suggest that these are possible avenues for future PH treatment.Currently, there are few definitive mechanisms identified in PH pathophysiology and even fewer efficacious treatments available for PH. Many factors  are used to determine a treatment plan for each patient. However, metal levels and exposures are not evaluated comprehensively in vitro cultured cells, we hypothesize that exposure to metals including cadmium and antimony may either directly cause PH, or enhance the risk of developing PH, indirectly accelerating the pathogenesis of PH. Future research should focus on comprehensive clinical metallomics study in PH patients, mechanistic evaluations to elucidate roles of various metals in PH animal models, and novel therapy clinical trials targeting metals. These important discoveries will significantly advance our understandings of this rare yet fatal disease.Based on the above indirect clinical evidence and preclinical studies with animal models and Through the investigation of metal impact on SH, it has been clear that exposure to metal cluster  are more significantly associated with CVDs


The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.  The human papillomavirus (HPV) group comprises members with a high affinity to the cutaneous and mucosal epithelium. Around two hundred genetic types of HPV have been described and grouped into five genera , according to the variability of the viral capsid protein gene L1 ., as well as other types, depending on the studied population. For example, in Asian populations, cervical cancer has been associated with HPV-52 and HPV-58 types in addition to HPV-16 . Ad. AdKCNS3patients .KCNQ1) plays important oncogenic roles, mainly in cell cycle, apoptosis, and autophagy . T. TTRPC6)motility . Its ove pathway .TRPV3  is mainly expressed in keratinocytes and is activated by repetitive thermal stimuli . T. TTRPV3 isorders . In OSCCisorders . TRPV6 (g cancer . In ESCChormones .TRPM2) is associated with oxidative stress and has been related to cardiovascular and neurodegenerative disorders [TRPM2 has a protective role via reducing oxidative stress, inflammation, and chromosomal instability, although in other cancers it may promote tumor progression [TRPM2 is highly expressed in cell lines and cancerous samples from patients, and its knock-down by shRNA inhibits cell survival and migration; thus, the channel is proposed as an alternative target in the treatment of OSCC [TRPM2 is increased compared to normal tissue [TRPM7  is important in the intracellular regulation of magnesium (Mg2+), zinc (Zn2+), and Ca2+ concentration via the modulation of SOCE [2+ current takes place via TRPM7, and its blocking or silencing reduces the growth and proliferation of cancer cells [TRPM7 is overexpressed in LUAD cell lines and samples from patients with the pathology and promotes the expression of stem cells markers. In addition, the reduction in gene expression by shRNA or channel block with waixenicin A inhibits cell viability (TRPA1), which is activated by a wide range of irritant substances that can be found in food or in the environment, is mainly expressed in neuronal cells and has nociceptive functions [SCLC, TRPA1 overexpression has been detected both in cell lines and patient tissue samples compared to non-malignant lung tissue, and its downregulation decreases the anchoring capacity of cancer cells [The transient receptor potential cation channel subfamily M member 2 unctions . In SCLCer cells .TRPP2  is involved in mechanical sensation and cell proliferation [TRPP2 silencing increases cell proliferation [feration . In headferation .The high incidence of HPV-associated cancers causes thousands of deaths worldwide. Thus, novel diagnostic, prognostic, and therapeutic tools are urgently needed. The expression and regulation of ion channels in HPV-associated cancers here reviewed represents a plethora of opportunities and potential solutions to this problem. + and HPV- tissues from the same patient or cancer type should be performed. This analysis should include information concerning the exposure of the patients to other cancer-associated factors, such as hormones, cigarette smoke, etc., to define the specific influence of each risk factor on ion- channel expression. It will be very interesting in a few decades to analyze ion channel expression in “HPV-associated cancers” in those patients who have been vaccinated against HPV. As mentioned above, this will help to resolve the controversy of the association of HPV infection with lung cancer and other malignancies. The investigation of more precise molecular mechanisms associating HPV-oncoproteins with the regulation of ion channels is necessary.Because cancer is a multifactorial disease and ion channels are regulated by a variety of cancer-associated factors, more studies are needed to determine whether changes in ion channel expression are solely or mainly associated with HPV infection. For instance, an RNA-Seq database analysis of ion channel expression from HPVA significant percentage of drugs commonly used in clinical settings target ion channels. Glibenclamide and antihistamines are examples of the extraordinary opportunity that ion channel inhibitors may provide for drug repurposing for the benefit of cancer patients. The study of the combination of ion channel inhibitors with usually prescribed anticancer drugs represents an exceptional area for cancer research. This approach may help to reduce drug-resistance and fight cancer cells via diverse molecular mechanisms and cellular pathways. The vast amount of research yet to be performed associating ion channels and HPV could help to find novel markers and targets to improve clinical outcomes in patients with these types of malignancies.


An excessive generation of reactive oxygen species (ROS) induces oxidative stress and subsequent inflammation, and is considered major drivers in the pathogenesis of renal and cardiovascular diseases (CVDs) . NuclearThis Research Topic contains 6 papers, including 5 original research articles and 1 review, reporting relevant information about the key role of NRF2 in the context of renal diseases and CVDs.Gonzalez-Carnicero et al., have reported that NRF2 activation prevents the pro-oxidant and pro-inflammatory effects induced by Interleukin-1β in vascular smooth muscle cells through downregulation of Toll-like receptor 4 (TLR4)-dependent pathway.Oxidative stress and inflammation have been identified as crucial in most of the key steps in the pathogenesis of CVDs . In thisMellitus (DM) is characterized by an increased risk of developing CVDs, mostly attributed to the adverse effects of hyperglycemia and oxidative stress on vascular and endothelial cells (Sonmez et al., the authors investigated the effects of sulfasalazine on endothelial dysfunction in the context of DM. Treatment with sulfasalazine reduced oxidative stress and cell injury induced by high glucose concentrations using isolated organ bath experiments. Molecular analyses revealed that the therapeutic potential of sulfasalazine was a consequence of inducing NRF2/HO-1 activity via the ERK and JNK pathways.Diabetes al cells . In the Wu et al., reported that tanshinone, a natural compound extracted from Salvia miltiorrhiza protected against oxidative stress-induced myocardial injury in mice. In vitro and in vivo models revealed tanshinone I reduced cardiomyocyte oxidative stress and subsequent apoptosis through NRF2 activation and MAPK signaling inhibition, indicating the potential therapeutic application of tanshinone I for oxidative stress–induced CVDs.Several studies have reported that a variety of natural products show protective effects against oxidative stress by activating NRF2 signaling pathway . In thisLi et al., in this Research Topic. Doxorubicin, an antibiotic widely used in the treatment of cancer, induces cardiotoxicity, limiting its clinical applications (in vivo and in vitro doxorubicin-induced cardiotoxicity by reduction of ferroptosis. Authors revealed that Fisetin reduces malondialdehyde levels, a biomarker of oxidative stress induced lipid peroxidation and increases glutathione levels through SIRT1/NRF2 signaling pathway activation. Overall, these studies indicate that natural products such as diterpenoids and flavonoids can be effective therapeutic tools against cardiotoxicity induced by oxidative stress.The protective effect of natural products against cardiac injury has also been evaluated by ications . This orAlthunibat et al., investigated the renoprotective effects of formononetin, a natural isoflavone found in several plants with anti-oxidant, anti-inflammatory, anti-apoptotic, and tissue-protective properties. They showed that formononetin prevent kidney injury and improves renal function in rats treated with gentamicin by decreasing lipid peroxidation and enhancing antioxidant capacity via NRF2/HO-1 axis.Gentamicin is an aminoglycoside antibiotic used to treat potentially severe Gram-negative bacterial infections. However, the therapeutic use of gentamicin is frequently restricted by the induction of nephrotoxicity . GentamiWu et al., reviewed the potential of NRF2 as a therapeutic target for the management of CVDs, focusing on its role in hypertension, atherosclerosis, myocardial ischemia, heart failure, peripheral artery disease, rheumatic heart disease, and other cardiomyopathies. In addition, the authors summarized the potential of different natural products and their molecular mechanisms targeting the NRF2 signaling pathway in protecting against CVDs.Finally, the article submitted by NRF2 Signaling Pathway: new Insights in the Field of Reno-Cardiovascular Health” has collected different studies focusing on the role of NRF2 in the pathophysiology of kidney and cardiovascular system and summarizing the impact of NRF2 signaling pathway as a therapeutic target. We hope that this Research Topic will improve our understanding of the molecular mechanisms of NRF2 and provide broad insights for future therapies in the context of reno-cardiovascular diseases.In summary, the Research Topic “Since our topic has focused on the importance of NRF2 signaling pathway in reno-cardiovascular health, the topic’s scope is restricted to targeting NRF2 transcription factor in renal diseases and CVDs. In the editorial, we have summarized the 6 articles that are published under the Research Topic. We anticipate the published articles in this Research Topic to be of interest to the readers and expect researchers to benefit from achieving further progress in understanding the role of NRF2 signaling mechanisms underlying renal diseases and CVDs and the development of novel therapeutics. However, considering the importance of NRF2 in the regulation of expression of several antioxidants and cytoprotective proteins and enzymes, it is worth investigating the role of this transcription factor in other physiological and pathological conditions.


Screening for early symptoms of cognitive impairment enables timely interventions for patients and their families. Despite the advances in dementia diagnosis, the current nosography of neurocognitive disorders (NCDs) seems to overlook some clinical manifestations and predictors that could contribute to understanding the conversion from an asymptomatic stage to a very mild one, eventually leading to obvious disease. The present review examines different diagnostic approaches in view of neurophysiological and neuropsychological evidence of NCD progression, which may be subdivided into: (1) preclinical stage; (2) transitional stage; (3) prodromal or mild stage; (4) major NCD. The absence of univocal criteria and the adoption of ambiguous or narrow labels might complicate the diagnostic process. In particular, it should be noted that: (1) only neuropathological hallmarks characterize preclinical NCD; (2) transitional NCD must be assessed through proactive neuropsychological protocols; (3) prodromal/mild NCDs are based on cognitive functional indicators; (4) major NCD requires well-established tools to evaluate its severity stage; (5) insight should be accounted for by both patient and informants. Therefore, the examination of evolving epidemiological and clinical features occurring at each NCD stage may orient primary and secondary care, allowing for more targeted prevention, diagnosis, and/or treatment of both cognitive and functional impairment. Major neurocognitive disorder, previously referred to as dementia, is a clinical condition entailing a significant decline in patients’ cognitive and daily living performances . ScreeniWithin any diagnostic approach, the professional will need to consider aging-related confounders and comorbidities, methodological deficiencies, and potential risks for clinical practice associated with “undetected” signs of dementia or cognitive impairment . On the The present paper is an attempt to present and examine the stages that might define the time span leading from a condition of apparent wellbeing to an overt symptomatology of cognitive–functional impairment. Although the categorical diagnosis of NCDs represents the current diagnostic standard, it primarily relies on quantitative criteria addressing the severity of the neurocognitive impairment. Given NCD heterogeneity, this work focuses on delineating the progression of neurocognitive decline based on multiple models retrieved from the literature while also incorporating NCD manifestations that may arise at specific stages of decline. To this end, this review focuses on the stages of neurocognitive decline that can be identified as: (1) preclinical stage; (2) transitional stage; (3) prodromal or mild stage; (4) major NCD. As shown in https://osf.io/84wnp/ (accessed on 10 September 2023).To yield a stadial progression of neurocognitive decline, a review of the most widely used criteria for NCDs ,9 and MCThe preclinical stage is characterized by neuropathological hallmarks of a specific disease  that do not translate into relevant or persistent cognitive symptoms. Research has focused on this phase to highlight potential risk factors of cognitive decline and the need to prevent the onset of NCD manifestations through primary prevention measures . Among tPreclinical Alzheimer’s disease (AD) consists of three distinct sub-stages that have been conceptualized based on in vivo studies : (1) asyOverall, preclinical AD is prevalent in the elderly population. Considering a sample composed of 450 subjects aged more than 65 years and expected to be “cognitively normal”, 43% showed no alterations (sub-stage 0), 16% fell into asymptomatic amyloidosis (sub-stage 1), 12% showed signs of neurodegeneration (sub-stage 2), 3% reported cognitive/behavioral alterations (sub-stage 3), 23% featured negative Aβ but positive neurodegeneration markers, and the remaining 3% were unclassified . This inBiomarkers emerging in preclinical AD can also contribute to differential diagnosis, as Aβ deposition detected by Aβ PET imaging and/or by low CSF Aβ1-42 levels represents a prerequisite  for clinical subjects to be included within the “Alzheimer continuum”. However, the diagnosis of AD requires additional investigations through 18-F-fluorodeoxyglucose (FDG)-PET, structural MRI (sMRI), cortical Tau PET, and CSF biomarkers. Reduced glucose metabolism in specific brain regions (AD “signature”), temporal medial atrophy and regional cortical atrophy consistent with typical or atypical disease phenotypes, decreased Aβ1-42 combined with increased total Tau, and increased p-Tau in CSF all can support the diagnosis; the combination of different abnormalities depends on the spatiotemporal neuropathology trajectory over several years ,20. HoweEvidence of neurodegeneration markers , in the absence of Aβ deposition demonstrated by Aβ cerebral PET and/or by low CSF Aβ1-42 levels, may instead characterize a wide range of clinical conditions called Suspected Non-Alzheimer Pathology (SNAP) . It shouNeurodegenerative diseases, notably the most common forms of AD, may progressively impact on cognition, starting from early clinical features, signs, and prodromes associated with an increased risk for conversion to dementia . During Within the transitional stage, early yet persistent shifts in behavior may arise, which can be isolated or associated with slight cognitive issues (including SCD). Such symptoms do not meet the minimum criteria of severity and specificity to be included in a diagnostic cluster of psychiatric disorders; however, they may fall into the broad category of mild behavioral impairment (MBI) . MBI affThe third stage  is characterized by cognitive and functional alterations corroborated by objective neuropsychological indicators, such as cognitive test scores, which allow for the detection of mental state impairments and domain-specific deficits over the neurocognitive continuum. In contrast to major NCDs, such alterations do not interfere with daily routine. In order to classify an array of mild clinical conditions, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition , has proIn the case of minor cognitive symptoms, it is also advisable to consider the clinical presentation of MCI  as it enMCI sub-types have been operationalized based on the number and types of cognitive domains that may be found to be spared or impaired in MCI subjects. In particular, memory impairment can lead to two different MCI sub-types, consisting of amnesic single-domain MCI (a-MCI-sd) and amnesic multiple-domain MCI (a-MCI-md). If memory is spared, it is possible to discriminate between non-amnesic single-domain MCI (na-MCI-sd) and non-amnesic multiple-domain MCI (na-MCI-md) based on the same criterion. The highly variable MCI prevalence estimates mainly depend on the sample examined, according to the use of MCI macro-categories  or more specific diagnostic labels . Indeed, the prevalence of MCI is still uncertain due to the heterogeneity of its diagnostic criteria and indices; however, there is agreement on its increased prevalence with advancing age, ranging from 2–5% (60 years of age) to 4–30% (over 90 years of age) . The incThe higher diagnostic specificity of mild NCD criteria (in terms of both number of impaired cognitive domains and etiologic hypotheses), compared to MCI criteria, results in different prevalence estimates regarding mild cognitive symptoms that may be smoothed through the harmonization of cognitive test scores for MCI . AccordiOne should note here that specific therapies for prodromal AD have provided disappointing or uncertain results that may also depend on misdiagnosis. Considering recent advances in the diagnosis of AD, such as the new discovery about Aβ plaques being a consequence (and not a cause) of cognitive impairment , the corThe DSM-5  has repl®) is one of the most used staging instruments to screen for patients’ degree of impairment across cognitive and functional domains [Given the lack of biomarkers for clinical differential diagnosis, the distinction between major and mild NCDs while patients are developing from early mild advanced disorder (late MCI) to initial major disorder is arbitrary. The differential process relies on the clinical and psychometric assessment of cognitive impairment and mostly depends on the tools and cut-off values adopted by clinicians. While test scores indicative of MCI generally fall within 1–1.5 standard deviation (SD), the cut-off proposed to discriminate between mild and major NCDs is conventionally set at 2 SDs below normative expectations . The ass domains  with the domains . In addi domains , also co® . Patien.5 years . The red.5 years .In addition to the aforementioned stages, it is also possible to contemplate further clinical entities ; age-associated cognitive decline (AACD); senescent forgetfulness; cognitive impairment no dementia (CIND)) ,32 that The phenomenology of CIND is so multifaceted that greater accuracy in defining the clinical characteristics and diagnostic criteria is required for this syndrome , consideTo advance the diagnosis and treatments for such diverse etiologies of cognitive impairment, systematization of the diagnostic criteria of the CIND has been proposed in the last decade  based onAlthough not exhaustive, this review intends to provide scholars as well as clinicians with a dimensional framework that stems from neurophysiological and neuropsychological approaches to the progression of neurocognitive decline. To this end, we focused on evolving epidemiologic and clinical features of cognitive impairment to orient primary care and secondary care in the early and differential diagnosis of NCDs through an integrated perspective. The detection, prevention, and/or treatment of such syndromes are indeed accompanied by new challenges and discoveries that may fit the above-described stages  and related neurocognitive profiles.While there is agreement about the prevalence of cognitive decline among the elderly population, the current diagnostic gold standard for NCD  adopts cThe models of NCDs reported in the literature hold a dynamic view of such conditions that still reveals ambiguous and unclear aspects underlying the current nosography for cognitive impairment. These aspects might delay and complicate the diagnostic process as it relies on diverse theoretical and methodological frameworks. Novel imaging techniques and CSF biomarkers have shown great utility in the detection of early NCD manifestations, yet not all the aforementioned protocols have been adopted and validated across outpatient settings, resulting in poor clinical translatability. Further limitations apply to the DSM-5, as the NCD cluster does not cover specific criteria for progressive conditions . Hence, the widespread adoption of stadial criteria may represent an opportunity to set or advance screening and treatment standards. This scope could be afforded through the achievement of evidence-based protocols and reliable indicators of NCD progression that can be spent in a broader range of clinical and research contexts, granting early and appropriate care throughout the neurocognitive continuum.Overall, the present stadial framework for NCDs may complement existing categorical diagnoses to offer practical benefits in the context of both primary and specialized care. This approach promotes early intervention through the identification of established hallmarks and symptoms that may convert to dementia, remain stable, or revert to a status of cognitive–functional wellbeing over time. Although no consensus on CIND makes it even harder to predict the prognosis of different “no dementia” syndromes, some proactive strategies can be adopted to counter mild-to-major conversion. Based on epidemiological data on the potential remissions of mild symptoms up to the prodromal stage, it becomes crucial to target the modifiable factors of dementia  aimed at fostering patients’ functioning and quality of life. While medications and cognitive-enhancing drugs can be effective in managing specific symptoms ,60, favoBy categorizing cognitive decline into stages, the healthcare system can also allocate resources efficiently, directing support to individuals at higher risk from the preclinical phase and evaluating cases where undergoing invasive exams can be avoided and integrated treatment strategies ,66,67,68The recognition and monitoring of individuals at the stages from preclinical to overt dementia are essential for optimizing clinical efforts against neurocognitive decline. These strategies may allow healthcare professionals to assess the progression of cognitive decline stepwise, orient care plans to evolving patient needs, and provide timely interventions to enhance their quality of life. In view of the validation of further assessment techniques and dementia biomarkers, the adoption of a perspective that accounts for clinical–temporal progression can enrich the diagnostic systems and supportive measures currently in use, ultimately advocating wellbeing and independence for individuals experiencing neurocognitive symptoms.


However, although various studies have investigated minimally invasive techniques for predicting response to NST, no technique has yet showed an acceptable false negative rate (FNR) for predicting pCR for the entire study cohort.8 The studies differed in radiologic response assessment and biopsy technique. Optimal radiologic assessment with magnetic resonance imaging (MRI), used in the MICRA trial, was associated with a higher FNR.9 Studies where more tissue was obtained with larger or > 12 biopsies showed lower FNRs.8Since the introduction of neoadjuvant systemic therapy (NST), there are increasing possibilities to de-escalate locoregional treatment. The usage and effectiveness of NST are on the rise, with high pathological complete response (pCR) rates observed, particularly in patients with triple-negative (TN) and HER2-positive breast cancer.11 several attempts are made to define a subgroup of excellent responders in which an acceptable FNR can be achieved.14 These results should be interpreted with caution, as the studies were not powered for post hoc subgroup analyses. Another approach in the attempt of lowering the FNR is the introduction of machine-learning techniques incorporating patient, imaging, tumor, and biopsy characteristics of previously conducted studies.17 While with an obtained FNR of only 0% this is a promising approach, further investigation is needed to determine its applicability in the clinical setting. Meanwhile, one trial is currently investigating the oncologic outcome of omission of surgery in patients with a pCR post-NST on the basis of vacuum assisted biopsies (VAB).18 Two-year follow-up of 31 participating patients showed no local recurrences.18 It should be noted that a mean of 15 VAB (9G) are obtained, and one might question whether this can be considered as a minimally invasive technique.Although the exact acceptable FNR for detection of pCR after NST is still under debate, as adjuvant systemic treatment improved survival in patients with (any) residual invasive disease,11 Although surgery may not attribute to local control or survival, it is still essential as diagnostic tool in these patients. In our opinion, the low risk of complications and morbidity associated with a diagnostic lumpectomy, where < 10 grams of tissue is removed, outweighs the accuracy of residual disease assessment in order not to withhold patients from adjuvant systemic treatment. Our pathology analysis of the MICRA study shows that limited but relevant residual invasive disease was missed in patients with TN or HER2-postive breast cancer when surgery was omitted.19 Therefore, it is time to consider alternative de-escalation strategies, such as omission of radiotherapy instead of surgery. The DESCARTES trial  aims to show the safety of omission of radiation treatment in cT1–2N0 patients achieving pCR after NST, detected with surgery.20Accurate assessment of the response to NST is of importance, especially in patients with TN and HER2-positive breast cancer, as they have a survival benefit from adjuvant systemic treatment in case of residual invasive disease.


Despite being uncommon, speech-induced atrial tachycardias carry significant morbidity and affect predominantly healthy individuals. Little is known about their mechanism, treatment, and prognosis. In this review, we seek to identify the underlying connections and pathophysiology between speech and arrhythmias while providing an informed approach to evaluation and management. Furthermore, insight into their mechanism holds potential for advancing our understanding of neural control of the heart. In this article, we review the literature on speech-induced tachycardias, propose possible mechanisms, describe their clinical features, and suggest a pathway to diagnosis and treatment.Initial presentations were similar in the cases reviewed. Patients were an average age of 59 years, and most (7/11) were male . All patThe hallmark electrocardiographic features of speech-induced AT include organized, irregular atrial activity at 150–250 bpm yielding a narrow-complex, long RP tachycardia triggered by the onset of speech. These broad electrocardiographic characteristics were described in all cases except for the 1 patient in whom AF was triggered by speaking.,,,The role of the ANS in modulation of cardiac electrophysiology and arrhythmogenesis has undergone extensive review because of great interest given both pathophysiological understanding and therapeutic potential.,Acknowledging that the extrinsic cardiac ANS ultimately is not dichotomous in its function or dysfunction, it generally consists of both sympathetic  and parasympathetic  components.,35Sympathetic signaling in the atria yields a surplus of calcium secondary to a spontaneous release of calcium from the sarcoplasmic reticulum, creating an environment of calcium handling dysfunction.,,,,The relationship between AF and the ANS offers an arguably analogous model to that of speech-induced tachycardias and thus adds further insight into the complex interplay between autonomic function and tachyarrhythmias. The dictum of “AF begets AF” is supported by contemporary evidence, which suggests that afferent signals such as rapid stimulation of the atria, whether in the form of a sustained tachyarrhythmia such as AF or in the laboratory with rapid atrial pacing, lead to perturbations in the ANS itself, resulting in a vulnerable arrhythmogenic substrate.Speech-induced tachyarrhythmias are supraventricular arrhythmias triggered by the onset of speech production with a propensity to terminate or wane with cessation of speaking. Various theories have been postulated regarding the mechanism of arrhythmogenesis, with most highlighting an association between cardiac and laryngeal autonomic connections mediated by the vagus nerve and its branches.,In the first published case of speech-induced tachycardia, Kan et al,,Medina et al,,,Electrophysiological studies performed during the reported cases showed a marked predilection for arrhythmogenic foci in areas susceptible to autonomic input associated with GPs, such as pulmonary vein ostia, right atrium–superior vena cava (SVC) junction, and SVC–aorta–right superior pulmonary vein junction. Of the 11 reported cases of speech-induced tachyarrhythmias, 5 were localized to the left atrium (4 involving the pulmonary veins) and underwent successful ablation10Given these reports, we propose that cases of speech-induced AT are due to an aberrantly conducted supramedullary signal that initially was intended for speech production but ultimately triggered vagal activation of intrinsic cardiac autonomic structures . This in turn exposed susceptible atrial tissue to both sympathetic and parasympathetic inputs, resulting in increased calcium availability and shortened action potentials, respectively, and leading to triggered activity as the mechanism for arrhythmogenesis. Importantly, the role of both efferent and interoceptive limbs of the cardiac–autonomic relationship also could be implicated, as evidenced by the onset of speech-induced AT before production of speech in relation to atrial stretch receptors.,Of the 3 patients treated with medications alone, only 1 experienced resolution of their arrhythmia with the use of medical therapy alone, 1 of whom had reported follow-up.Despite varying approaches to management, no recurrence was noted in cases with reported follow-up periods (6/11), which ranged from 6 months to 3 years. Although a publication bias toward cases in which no further tachyarrhythmias resulted could be implicated, it is important to note the trend toward an overall favorable prognosis. Initial workup should follow that typical for evaluating palpitations as the chief complaint. If speech is identified as the trigger for symptoms, then rhythm monitoring (ambulatory monitoring or inpatient telemetry depending on location of presentation) is appropriate and should reveal a consistent and predictable relationship between the initiation of speech and development of a long RP tachycardia. Importantly, the correlation between cessation of speech and return to normal sinus rhythm should be investigated. Attempting other maneuvers such as Valsalva, mouthing words, deep breaths, coughing, or swallowing, which probe associations between potential vagally mediated outputs and the tachycardia, further complements a thorough evaluation. Further probing with direct neurological testing was not reported in the published case reports, yet data gained from electroencephalograms and functional or static neuroimaging while performance of the aforementioned maneuvers stands to better inform relationships between supramedullary signals and the observed arrhythmia. Identification of all stimuli improves the ability to elicit and reproduce the arrhythmia in an electrophysiological study if later indicated. Evaluation of structural heart disease should be prioritized; an echocardiogram with or without cross-sectional imaging of the chest often suffices.,,Successful medical management alone was noted in only 3 reported cases, 1 of which described no recurrence at 3 years with metoprolol.Electrophysiological study with subsequent catheter ablation  was the most common and successful method of management (8/11), resulting in remission of the arrhythmia in all cases at their reported follow-up time (range 6 months to 3 years). Given consistent and immediate results, catheter ablation is reasonable in patients with recurrent symptomatic speech-induced AT, especially when pharmacologic therapy is not well tolerated or unsuccessful. Evidence of tachycardia-induced cardiomyopathy would be a clear indication for catheter ablation, regardless of symptoms. All but one of the catheter ablations were radiofrequency ablations. There are insufficient data to recommend one type of ablation over another.Speech-induced ATs are rare, quality-of-life–limiting arrhythmias. Their proposed mechanism likely involves an aberrantly conducted supramedullary signal that initially was intended for speech production but ultimately triggered vagal activation of intrinsic cardiac autonomic structures, leading to heightened autonomic atrial tone causing triggered activity yielding an AT while speaking. Importantly, cessation of speech stopped the tachyarrhythmia, suggesting a functional rather than anatomic or substrate-based abnormality. Although uncommon, the reviewed pathophysiology offers new insights into the complex interplay between ANS and cardiac pathophysiology.


Pulmonary hypertension (PH) frequently complicates chronic lung disease and is associated with high morbidity and poor outcomes. Individuals with interstitial lung disease and chronic obstructive pulmonary disease develop PH due to structural changes associated with the destruction of lung parenchyma and vasculature with concurrent vasoconstriction and pulmonary vascular remodeling similar to what is observed in idiopathic pulmonary arterial hypertension (PAH). Treatment for PH due to chronic lung disease is largely supportive and therapies specific to PAH have had minimal success in this population with exception of the recently FDA-approved inhaled prostacyclin analogue treprostinil. Given the significant disease burden of PH due to chronic lung diseases and its associated mortality, a great need exists for improved understanding of molecular mechanisms leading to vascular remodeling in this population. This review will discuss the current understanding of pathophysiology and emerging therapeutic targets and potential pharmaceuticals. Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance and high pulmonary artery pressures that ultimately leads to right heart failure and is associated with high morbidity. PH can occur de novo as either idiopathic or hereditary PAH, but often complicates other chronic conditions including chronic lung diseases. This entity of PH belongs to the Group 3 classification and is one of the highest leading causes of PH worldwide, second to PH associated with left-sided heart disease Group 2) . Of the  . Of theGroup 3 PH is defined similarly to Group 1 PAH and formal diagnosis is made by right heart catheterization (RHC) with measurements of mean pulmonary artery pressure (PAP) > 20 mm Hg, pulmonary capillary wedge pressure (PCWP) < 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 wood units. These findings must be in conjunction with the presence of underlying lung disease. Group 3 PH encompasses several diseases including obstructive, restrictive, or mixed lung disease, developmental lung diseases, and includes states of chronic hypoxia such as sleep-disordered breathing, alveolar hypoventilation disorders, and chronic exposure to high altitude. This review will focus on chronic lung diseases, specifically ILDs with emphasis on idiopathic pulmonary fibrosis (IPF) and COPD. Epidemiology is difficult to define in this patient population due to differing definitions of PH and the use of transthoracic echocardiography over RHC for diagnosis. In IPF patients, evidence of PH as defined by mean PAP > 25 mm Hg ranges between 8 and 15% at initial work-up, with a higher incidence of 30–50% in severe disease, and greater than 60% in patients at end-stage disease ,12,13,14The mechanisms leading to the development of Group 3 PH is not completely understood, but likely multifactorial with large contributions from the mechanisms that led to the development of underlying lung disease. Evaluations of explanted lungs of individuals with Group 3 PH demonstrate significant overlap with Group 1 PAH, suggesting a similar mechanistic process: injury to the pulmonary vascular endothelium leading to endothelial dysfunction and vascular remodeling, which in combination with sustained vasoconstriction leads to changes in pulmonary hemodynamics causing development and progression of PH.Vascular remodeling refers to the structural changes in the pulmonary circulation that increases vessel wall thickness, reduces vessel lumen diameter, and thus increases PVR. The pulmonary arterial circulation is composed of the endothelial-cell-lined intima, smooth muscle cell media, and fibroblast-composed adventitia. In PAH, intermediate and large vessels demonstrate hyperplasia and hypertrophy of all three layers which occur as a result of endothelial dysfunction, characterized by disorganized hyperproliferation of pulmonary artery endothelial cells . SimilarHypoxia contributes greatly to the development of PH in this population through the alteration of pulmonary hemodynamics, inciting endothelial dysfunction, and thus giving rise to pulmonary vascular remodeling. The structural changes of the lung parenchyma and concomitant vasculature lead to aberrant gas exchange in chronic lung diseases and often results in alveolar hypoxia. Alveolar hypoxia causes a depolarization of pulmonary smooth muscle cells and an influx of cytoplasmic calcium leading to contraction and sustained pulmonary vasoconstriction. This phenomenon is specific to the lungs, as reduced oxygen delivery in the systemic circulation leads to vasodilatation. Brief hypoxia exposures lead to prolonged increases in pulmonary vascular resistance with long-term exposure leading to structural changes of the pulmonary arterioles predominantly defined as medial hypertrophy .ILD is a disease of progressive scarring of the lung parenchyma leading to reduced gas exchange. The structural changes as well as pathophysiologic changes associated with ILD are thought to contribute to PH development as well . Pulmona2) and mean PAP in COPD patients [2 at the renal tubules leads to retained sodium and fluid through the sodium–hydrogen exchange. Additional fluid retention may occur through the vasodilatory effects of hypercapnia in the systemic circulation leading to neurohormonal activation of salt and water retention [COPD is a disease of airflow limitation that results in structural changes of the lung parenchyma and concomitant vasculature that leads to aberrant gas exchange. The development of PH in COPD is a result of both structural and functional causes that are inherent to chronic lung disease . Alveolapatients . There ipatients . Increasetention ,29. Fluietention .The structural changes that occur due to COPD also contribute to altered pulmonary hemodynamics. Emphysema is characterized by destruction of the alveoli and associated pulmonary microvasculature; the reduction in overall vascular cross-sectional area leads to increases in pulmonary vascular pressure . AdditioApproach to treatment of Group 3 PH patients is centered around guideline-directed therapy of the underlying lung disease and treatment of comorbid conditions that may also exacerbate PH, such as left-sided heart disease, sleep disordered breathing, and pulmonary thromboembolism ,32. PatiTreatment of PAH has largely been established by targeting vasodilator pathways of prostacyclin, endothelin-1, and nitric oxide (NO). All classes of PAH medications have been tested in patients with PH associated with ILD and COPD, yet with varying degrees of success .NO is a potent vasodilator that is synthesized in pulmonary vascular endothelial cells and functions in conjunction with other vasodilators and constrictors to maintain vascular tone in response to stress or oxygen levels . In indiSildenafil treatment in IPF patients demonstrated preferential vasodilatation in well-ventilated areas of the lung, improving gas exchange . These fRiociguat is a soluble guanylate cyclase stimulator that acts similarly through the NO pathway to increase production of cGMP and has been identified as a successful therapy in both primary PAH and CTEPH ,41. PrecThere have been more studies evaluating NO-targeted therapy in COPD patients, however results are inconclusive across trials. In patients with COPD and without PH, two studies of sildenafil showed opposing results, one with improvement in exercise capacity while sildenafil was associated with increased harm in the other ,48. BlanEndothelin-1 (ET-1) is a potent vasoconstrictor peptide produced predominately by endothelial cells. ET-1 acts via both autocrine and paracrine signaling on vascular endothelial and smooth muscle cells, mediated by ETA and ETB receptors to execute its vasoconstrictive and mitogenic functions. ET-1 activation of ETA and ETB receptors on smooth muscle cells leads to vasoconstriction, whereas activation of ETB receptors on endothelial cells stimulates production of vasodilatory compounds, NO and prostaglandin, and aids in pulmonary clearance of ET-1, thus the receptors are thought to function in mediating vasomotor tone . ET-1 coAs ET-1 influences fibroblast proliferation and inflammation, ET receptor antagonists have been tested in patients with IPF and PH. Ambistentan treatment in this population was not effective in treating disease progression, led to harm causing early termination of the ARTEMIS-IPF study, and is contraindicated in this patient population . BosentaBosentan treatment in severe COPD without severe PH did not improve pulmonary hemodynamics or lung function, but also worsened hypoxemia and functional status in this patient population . AnotherProstacyclin is an endogenous vasodilator produced by vascular endothelial cells. Prostacyclin binds to a G-protein-coupled receptor and results in downstream production of cyclic adenosine monophosphate (cAMP), leading to vasodilatation of vascular smooth muscle cells . ThroughSynthetic prostacyclin analogues have been developed in several formulations and function to cause direct vasodilatation of vascular beds and are approved for treatment of PAH. The INCREASE trial recently demonstrated that inhaled Treprostinil led to improvement in exercise capacity measured by 6MWD and reduced NT-pro-BNP levels and disease-related exacerbations in individuals with IPF and PH. Investigators note that inhaled administration allows for preferential blood flow to well-ventilated alveoli and minimizes V/Q mismatching from vasodilators in Group 3 patients . SubsequAs discussed previously, clinical trials for chronic lung disease have largely been undertaken to repurpose therapies that are efficacious in PAH by targeting one of the vasodilator pathways: prostacyclin, endothelin-1, and NO. In PAH, these therapies slow progression of disease, but were largely ineffective in patients with Group 3 PH until the recent INCREASE trial ,51,59,63Heterozygous BMPR2 mutations are implicated in 70–80% of heritable PAH cases and 10–20% of idiopathic PAH cases . This muPulmonary fibrosis not only causes obliteration of the alveoli, but also damages the pulmonary vasculature. Angiogenesis is the process of new vessel formation from existing vasculature and is an important mechanism after tissue damage to facilitate healing. The abundance or lack of pulmonary capillaries is thought to influence the development of PH in PF. In explanted lungs of IPF, vessel density is decreased in areas of fibrosis and increased in non-fibrotic areas, but overall results in reduced vessel density . AdditioInflammatory responses to environmental triggers are mediated by NF-κB signaling and thus activation of NF-κB is thought to play a role in the pathogenesis of asthma, COPD, and autoimmune diseases ,79,80,81Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates NF-κB signaling, reactive oxygen species, and overall generation of oxidative stress. Treatment with Nrf2 induction in a chronic hypoxia PAH murine model decreased vascular remodeling and RV hypertrophy . BardoxoRAS is a group of ligands and receptors that regulate several organ systems and has been a well-established therapeutic target for several disease processes. Activation of angiotensin II (Ang II), a potent vasoconstrictor, stimulates lung fibroblast growth, upregulates TGF-β, and stimulates pulmonary artery smooth muscle cell growth contributing to pathophysiology seen in both PF and PH ,93,94. TPeroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family that regulates inflammation and lipid and carbohydrate metabolism. These receptors are ubiquitous across many cell types and PPARγ is present predominantly in adipose tissue, but also found in lung parenchyma and immune cells with several pulmonary diseases, including PH demonstrating reduced PPARγ expression ,103,104.In pulmonary fibrosis, tissue injury through proinflammatory and abnormal growth factor production leads to the transition of mesenchymal cells to myofibroblasts which produce collagen and extracellular matrix proteins. PPARs are shown to have anti-fibrotic effects and decrease lung fibrosis in preclinical models ,109,110.Taken together, PPAR activation has demonstrated promising pre-clinical results and its synthetic ligands are well-studied therapeutics for a wide range of disease processes. Additionally, PPARγ’s therapeutic benefit has significant overlap with several of the previously discussed targets in this section, including BMPR2 and TGF-β signaling ,114,115 EndoMT is a process of cellular transdifferentiation where endothelial cells lose their barrier protective functions and gain mesenchymal characteristics such as contractility . EndoMT Dipeptidyl peptidase IV (DPP-4) is a serine protease that cleaves N-terminal dipeptides from substrates and is increased in inflammatory disease states. DPP-4 inhibition (DPP-4i) has been used in the treatment of diabetes and cardiovascular complications. It also has been shown to regulate endothelial and smooth muscle vascular cells. DPP4i attenuated pulmonary fibrosis in a sepsis lung murine model by decreasing the EndoMT process . DPP-4i In response to cellular injury, adenosine acts via extracellular signaling to regulate tissue repair. In chronic lung disease, elevated levels of adenosine are thought to contribute to remodeling and progression of disease, with findings of increased adenosine 2B receptor expression in patients with COPD and IPF ,127. NucIn the realm of COPD, a mouse model of airspace enlargement as seen in emphysema, is generated by adenosine deaminase (ADA) deficiency. ADA is an enzyme that metabolizes adenosine, and ADA is reduced in patients with COPD. Genetic deficiencies of ADA in mice leads to increased adenosine expression, airspace enlargement, and development of vascular remodeling and PH. Patients with COPD and PH have remodeled pulmonary vessels with smooth muscle and collagen deposition, and increased levels of ADORA2B correlate with PAP. Treatment of ADORA2B antagonist in this ADA-deficient COPD mouse model led to the attenuation of PH through a regulation of hyaluranon and hyaluranon synthase-2, suggesting that adenosine signaling influences lung extracellular matrix composition which leads to remodeling .Hypoxia-inducible factor signaling is known to be important in the development of PAH. HIF is a transcription factor that degrades in normoxia, but in response to low oxygen levels translocates to the nucleus and augments gene transcription. Although the mechanisms that result in fibrosis and lead to vascular remodeling are unclear, stabilization of HIF1α under hypoxic conditions could play a crucial role as hypoxia is an important feature of the disease. Studies have also suggested a potential dysregulation in oxygen sensing as HIF is often upregulated in normoxic conditions. Additionally, individuals exposed to hypoxia demonstrate a wide change in mean PAP, suggesting additional influencing factors in the development of PH related to hypoxia . InteresPulmonary hypertension is an important and deadly complication of chronic lung diseases, including ILD and COPD. There are both overlapping and distinct pathogenic mechanisms associated with the development of PH in these conditions. It remains imperative that we use the best standard of care to treat the underlying respiratory condition, yet the severe pathobiologic changes in the pulmonary circulation associated with the development of PH cannot be ignored. Vasoconstriction and vascular remodeling continue to be the areas that are considered to be the most ripe for targeted therapeutics; yet to date, only inhaled treprostinil has attained FDA approval for the treatment of PH associated with ILD and no targeted therapies are available for PH associated with COPD. We have reviewed many emerging therapeutic targets based on important molecular mechanisms in PH associated with both ILD and COPD, which include BMPR2, angiogenesis, NF-κB, RAS, PPARγ, EndoMT, adrenergic stimuli, and HIF signaling. While our understanding of these molecular targets and signaling pathways in Group 3 PH has grown exponentially, much of the work has remained in the preclinical stages of investigation. Continuing to develop our understanding of PH related to ILD and COPD, as well as bringing novel, targeted therapies into development and clinical studies should remain a priority with this deadly condition.


CSP usually involves His bundle pacing or left bundle branch area pacing (LBBAP). Distal right bundle branch pacing (RBBP) has only been described to date in a case report.A 71-year-old patient with chronic atrial fibrillation with symptomatic brady-tachy syndrome was scheduled for single-chamber pacemaker implantation with LBBAP in anticipation of possible future atrioventricular nodal ablation. Baseline QRS morphology was normal with 93 ms duration. CSP procedures are all filmed at our institution with simultaneous recordings of fluoroscopy, electrophysiology bay tracings, pacing system analyzer screen, and video of the operation field, allowing precise reconstitution of the entire procedure.After the tricuspid annulus had been identified by electrogram analysis , proximal LBBAP was initially attempted, using a Solia 60 cm lead and a Selectra 55 guiding catheter . The lead was positioned below the annulus at about 10 mm toward the apex in the right anterior oblique view A. Trauma1  in V6 of 65 ms , the following deductions may be made:(1)The initial lead position was on the proximal right bundle branch (RBB). The potential to QRS duration of 32 ms is in keeping with this hypothesis, which was later confirmed by selective RBBP with retrograde block and a typical left bundle branch block morphology at low output. This was owing to capture of conduction tissue distal to the site of traumatic RBBB. At higher output, the conduction tissue proximal to the block was also captured, narrowing the QRS.(2)6RWPT, which was surprisingly short.The lead had been repositioned on a more distal branch of the RBB, as indicated by the slight transition in QRS morphology with decrementing unipolar output, which is the hallmark of conduction tissue capture. Loss of RBB capture had, however, no impact on LV activation, as indicated by unchanged V(3)Left-sided conduction system capture seemed to be present at the site of the distal RBBP, already during pace mapping of the endocardial surface (before screwing in the lead).(4)After a deeper lead position had been obtained, RBBP was lost, as indicated by lack of QRS transitions with decrementing output. The end result was LBBAP.Based on analysis of lead position on fluoroscopy, intrinsic signals, paced QRS morphology at different outputs, and measurements of timing of RWPT in V6RWPT that is significantly longer than the potential to V6RWPT  during selective proximal RBBP in the presence of RBBB with retrograde block  explained the findings. Durrer and colleagues


A total of 75% of people with mental health disorders have an onset of illness between the ages of 12 and 24 years. Many in this age group report substantial obstacles to receiving quality youth-centered mental health care services. With the rapid development of technology and the recent COVID-19 pandemic, mobile health  has presented new opportunities for youth mental health research, practice, and policy.The research objectives were to (1) synthesize the current evidence supporting mHealth interventions for youths who experience mental health challenges and (2) identify current gaps in the mHealth field related to youth’s access to mental health services and health outcomes.Guided by the methods of Arksey and O’Malley, we conducted a scoping review of peer-reviewed studies that used mHealth tools to improve youth mental health (January 2016-February 2022). We searched MEDLINE, PubMed, PsycINFO, and Embase databases using the following key terms: (1) mHealth; (2) youth and young adults; and (3) mental health. The current gaps were analyzed using content analysis.The search produced 4270 records, of which 151 met inclusion criteria. Included articles highlight the comprehensive aspects of youth mHealth intervention resource allocation for targeted conditions, mHealth delivery methods, measurement tools, evaluation of mHealth intervention, and youth engagement. The median age for participants in all studies is 17 (IQR 14-21) years. Only 3 (2%) studies involved participants who reported their sex or gender outside of the binary option. Many studies  were published after the onset of the COVID-19 outbreak. Study types and designs varied, with 60 (40%) identified as randomized controlled trials. Notably, 143 out of 151 (95%) studies came from developed countries, suggesting an evidence shortfall on the feasibility of implementing mHealth services in lower-resourced settings. Additionally, the results highlight concerns related to inadequate resources devoted to self-harm and substance uses, weak study design, expert engagement, and the variety of outcome measures selected to capture impact or changes over time. There is also a lack of standardized regulations and guidelines for researching mHealth technologies for youths and the use of non–youth-centered approaches to implementing results.This study may be used to inform future work as well as the development of youth-centered mHealth tools that can be implemented and sustained over time for diverse types of youths. Implementation science research that prioritizes youths’ engagement is needed to advance the current understanding of mHealth implementation. Moreover, core outcome sets may support a youth-centered measurement strategy to capture outcomes in a systematic way that prioritizes equity, diversity, inclusion, and robust measurement science. Finally, this study suggests that future practice and policy research are needed to ensure the risk of mHealth is minimized and that this innovative health care service is meeting the emerging needs of youths over time. Mental health disorders are the leading cause of disability worldwide and are considered a global public health challenge ,2. GlobaA total of 75% of people with mental health disorders have an onset of illness between the ages of 12 and 24 years . This isIn 2022, mobile phone users reached 6.5 billion worldwide, accounting for approximately 80% of the global population. In developed countries such as Canada and the United States, 97% of people own a mobile phone and 85% use a smart phone ,18. SuchWhile the pace of new mHealth technologies is growing rapidly, the regulations and standards for their use have not yet followed. In a recent study of nearly 300 apps for mental health, less than one-third received input from a mental health expert . There iIn summary, the field of mHealth often presents a dichotomy of opportunity and risk. On the one hand, the lack of standards and regulation for mHealth apps presents global concerns for the safety of youths, notably personal security and the uptake of misinformation -25. On tThe purpose of this scoping review is to synthesize the current evidence supporting mHealth interventions for youths accessing support for mental health challenges. This will facilitate understanding of what is missing in the field of mHealth and support recommendations for research, practice, and policy. The specific objectives are to (1) synthesize the current evidence supporting mHealth interventions for youths who experience mental health challenges and (2) identify current gaps in the mHealth field, with an overarching goal of improving youths’ mental health service access, outcomes, and experiences.We conducted a scoping review to examine the extent, range, and nature of mHealth and to identify gaps in the existing literature on this emerging topic. This scoping study followed the 5 stages of Arksey and O’Malley’s scoping study framework  to (1) iWhat is known in the existing literature about the feasibility and effectiveness of mHealth intervention for youths, aged 12-24 years, facing mental health challenges?Under the guidance of a medical librarian, a comprehensive search of the following electronic databases was conducted: MEDLINE (Ovid), Embase (Ovid), PsycINFO (EBSCO), and PubMed (see The following inclusion criteria were considered: (1) published in English; (2) published between January 1, 2016, and February 7, 2022; (3) included human subjects, whose ages fall between 12 and 24 years; (4) included at least one mHealth intervention tool targeting 1 or more mental health conditions for youths; and (5) referenced literature from peer-reviewed journals and book chapters. Exclusion criteria were as follows: (1) editorial comments, commentaries, book reviews, and opinion articles; (2) incomplete studies ; (3) articles without full text available. Relevant systematic reviews were included in the study to serve as background literature but were excluded from the data extraction and analysis process to focus on intervention studies.Through careful review of the literature, the researchers (XD and SB) identified the key components and issues discussed in all relevant studies. This information was recorded in a data extraction sheet, along with information on each study .The information was synthesized and used to map out the scope and breadth of included literature on the topic of mHealth intervention for youths’ mental health challenges.As noted in As shown in As shown in All included studies have a general targeted age group of “young people,” “adolescent,” or “youth.” The median age for participants in all studies was 17 (IQR 14-21) years, with 2 outliers  papers did not provide any statistics on sex or gender. Only 3 (2%) studies involved participants who reported their sex or gender beyond binary options. One study focused on eating disorders and had 1 intersex participant . The othThe included studies took place in various settings. They were coded into the following 4 different categories, inspired by Marshall et al : (1) resAs noted in The number and percentage of health conditions targeted using mHealth interventions are summarized in A wide range of tools were employed to measure outcomes in mHealth intervention research . A detaiOf the 151 studies included within the given time period, 68 (45%) were published after the COVID-19 outbreak, with most  published in 2020. The numbers of studies published each year are as follows: 11 studies in 2016; 21 studies in 2017; 19 studies in 2018; 32 studies in 2019; 44 studies in 2020; 23 studies in 2021; and 1 study in February 2022.The following 8 studies directly addressed health conditions or service delivery modalities influenced by the pandemic: (1) treatment of eating disorders in adolescents ; (2) groThis scoping review provides a comprehensive synthesis of mobile mental health intervention research for youths. The study identified that the number of interventions is proliferating over time, with limited emphasis on study quality, youths’ engagement, youth-centered outcome assessment, implementation standards, or consideration for equity, diversity, and inclusion in research. Youths’ engagement was rarely mentioned as a part of any research study method, and most studies focused primarily on youths who identified within the gender binary. Few studies discussed the implementation and scale of interventions in diverse settings  and evenAmong the studies that met the inclusion criteria, depression , anxiety , and general mental health concerns  accounted for over half of the studies, and the remaining addressed 17 other mental health concern categories. According to a GBD systematic analysis of mental health conditions relevant to this study, the top concerns for all youths are self-harm, depressive disorders, interpersonal violence, anxiety disorders, HIV/AIDS, conduct disorder, and drug use disorder . The poiFrom a global health perspective, 95% (143/151) of studies came from developed countries. This result is not surprising, as mHealth resources are almost exclusively concentrated in high-income countries, although the prevalence of depression and anxiety in high-income countries is not significantly higher than in the rest of the world . TherefoWith respect to delivering mHealth interventions, most studies employed web pages  and smartphone apps , and these modes also had the largest number of randomized controlled trials conducted. The results show web-based mHealth tools have the strongest evidence for improving mental health conditions in youths, but the effectiveness of other intervention modes cannot be ruled out. Web-based intervention tools require youths to have internet access, and the use of computers may not be convenient in home and school settings, so the development of mHealth interventions has gradually evolved to include smartphones, smart devices, wearables, and newer technologies, including VR and augmented reality . HoweverThe measurement tools used in the studies  can be bThe percentage of positive results is considerably high among all included studies . Study aims included “feasibility,” “effect,” “acceptability,” “efficacy,” “fidelity,” “effectiveness,” and “cost-effectiveness,” with research designs including experiments, surveys, and interviews. Questions remain as to whether positive results translate to real-world applications or which types of outcomes possess high level of evidence in the knowledge translation process for health care services. In a Canadian study where participants were asked to rate mHealth apps objectively, results were highly variable, and 28% of reviewers were not even sure about the overall quality of the health product . The samSeveral included studies discuss how to support youths during the COVID-19 pandemic ,66. WithChilds and colleagues  illustraAnother youths’ mHealth intervention study showed the transition to virtual services was not always desired by clients. The authors presented a case where a participant refused to cooperate, and the telemedicine service increased the tension between the participant and family members . When deEngagement with mHealth interventions is thought to be important for intervention effectiveness by increasing acceptability, satisfaction, intervention adherence, and levels of attention and enjoyment . This caCurrent youth mHealth research often engages youths by asking for feedback in a survey or interview to test usability, feasibility, and acceptability ,70,71, oMore than two-thirds of the studies took place in a clinical setting, yet none of the studies reviewed provided systematic frameworks or models to help translate, scale, and sustain available mHealth tools to clinical practice. If health care stakeholders and policy makers aim to scale up and normalize mHealth services in the near future, it is essential to understand the feasibility and impact of implementing new mHealth tools in current models of care . Guidelines and standards may be critical to ensuring that mHealth interventions are trustworthy and can be value added to health services that are delivered to youths and their families.This review has a broad scope of attempting to draw a picture of existing mHealth intervention tools specifically designed for younger populations and how their effectiveness is being assessed. This scoping review addressed a broad term list and a large number of parameters. Inclusion and exclusion criteria were strictly set from the beginning and determined by experts in the field and a medical librarian, and diversity is presented for all included studies. There are unlimited possibilities for future work, particularly with the uncertainty of the COVID-19 pandemic and the ongoing response of the health care system to remote health access. Regarding weaknesses, the lack of critical appraisal is a widely recognized limitation for scoping reviews . The scoAs the need for mental health services continues to accelerate , mHealth