Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity.

BACKGROUND: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. OBJECTIVES: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. METHODS: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. RESULTS: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized ß: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). CONCLUSIONS: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk.

BACKGROUND: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear. OBJECTIVES: The purpose of this study was to evaluate whether the association between ACl/m and MACE is mediated by decreased SNA. METHODS: Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively). RESULTS: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 ACl/m. Over a median follow-up of 3.4 years, 1,914 experienced MACE. ACl/m (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, ACl/m (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of ACl/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, ACl/m associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003). CONCLUSIONS: ACl/m associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol's potential health detriments, new interventions with similar effects on SNA are needed.

A Care Management Intervention for Noncardiac Chest Pain: Treatment Development and Feasibility Assessment.

ABSTRACT.Objective: Noncardiac chest pain is common and can cause distress, impair quality of life, and lead to recurrent evaluation. It is often multifactorial in etiology and influenced by psychological factors. The objective of this study was to describe the development, implementation, and preliminary feasibility of an 8-week multicomponent care management intervention.Methods: Participants with noncardiac chest pain were recruited from primary care clinics, ambulatory cardiac stress testing, and the emergency department (ED) at an urban academic hospital from March 2019 to November 2019. The care management team consisted of a nurse, cardiologist, and psychiatrist. Following a 1-time consultation visit with the cardiologist and nurse, evaluation and treatment recommendations were conveyed to the participant's primary care physician. The nurse completed 8 weekly phone calls with the participant to provide support, introduce therapeutic principles, and assist with care coordination under the supervision of a psychiatrist. Intervention feasibility was assessed on 7 domains. To examine preliminary efficacy, the number of ED visits was recorded, and participants completed pre-post measures of psychological health and health-related quality of life and Likert scales of chest pain symptom severity, frequency, and impact.Results: The intervention was developed and implemented in 3 patients who completed 100% of the consultation visits and a mean of 95.8% of study phone calls. There were no adverse events or ED visits. Mean scores for chest pain severity, chest pain frequency, chest pain impact, depression, anxiety, and somatization all improved. No other trends were observed.Conclusions: The findings suggest that a care management intervention may be feasible with potential to improve chest pain symptoms and psychological outcomes. A larger, randomized trial is needed to explore the efficacy of this intervention.Trial Registration: ClinicalTrials.gov identifier: NCT04904198.

A neurobiological link between transportation noise exposure and metabolic disease in humans.

BACKGROUND: Chronic transportation noise exposure associates with cardiovascular events through a link involving heightened stress-associated neurobiological activity (as amygdalar metabolic activity, AmygA) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Increased AmygA also associates with greater visceral adipose tissue (VAT) and type 2 diabetes mellitus (DM). While relationships between noise exposure and VAT and DM have been reported, the underlying mechanisms remain incompletely understood. We tested whether: (1) transportation noise exposure associates with greater (a) baseline and gains in VAT and (b) DM risk, and (2) heightened AmygA partially mediates the link between noise exposure and these metabolic diseases. METHODS: VAT was measured in a retrospective cohort (N = 403) who underwent clinical 18F-FDG-PET/CT. AmygA was measured in those with brain imaging (N = 238). Follow-up VAT was remeasured on available imaging (N = 67). Among individuals (N = 224) without baseline DM, incident DM was adjudicated over 2 years from clinical records. Noise (24-h average) was modeled at each individual's home address. Linear regression, survival, and mediation analyses were employed. RESULTS: Higher noise exposure (upper tertile vs. others) associated with greater: baseline VAT (standardized ß [95% confidence interval (CI)]= 0.230 [0.021, 0.438], p = 0.031), gains in VAT (0.686 [0.185, 1.187], p = 0.008 adjusted for baseline VAT), and DM (hazard ratio [95% CI]=2.429 [1.031, 5.719], p = 0.042). The paths of: ↑noise exposure→↑AmygA→↑baseline VAT and ↑noise exposure→↑AmygA→↑subsequent DM were significant (p < 0.05). CONCLUSIONS: Increased transportation noise exposure associates with greater VAT and DM. This relationship is partially mediated by stress-associated neurobiological activity. These findings suggest altered neurobiology contributes to noise exposure's link to metabolic diseases.

Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome.

AIMS: Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest. METHODS AND RESULTS: Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028). CONCLUSION: Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Choosing Appropriate Technique for Nasal Reconstruction in Challenging Cases of Panfacial Burn: Treatment Algorithm.

The nose is one of the most challenging facial parts to reconstruct. Its asymmetries, defects, or disharmonies are easily noticeable. The complex contours, highlights, shadows, and special shape of its subunits make nasal reconstruction more difficult in panfacial burn than that of nonburned ones. This retrospective study was conducted at Zare Hospital. Twenty-five panfacial burn cases with nasal defects were studied from 2010 to 2019. Profile photos were manipulated by Adobe Photoshop. Based on the difference between the burn-related shortened nasal length and the expected photoshopped one, the severity of the short nose was detected, and the strategy of the surgery was determined. Of the 25 cases, 10 cases with normal nasal length and projection, or mild short nose with minimal alar rim, tip and/or columellar defect underwent nasal reconstruction with skin and/or composite graft. Nine patients with normal nasal length or mild to moderate short nose but moderate to severe alar defect underwent reconstruction with turndown flap plus skin and/or composite graft. Pre-expanded forehead flap (n = 1) and delayed scarred or skin grafted forehead flap (n = 5) were used for six patients with severe short nose defect. There are several procedural alternatives for the reconstruction of burn-related mild to moderate nasal deformity. For severe and deep panfacial burn, delayed forehead flap seems safe with acceptable color and texture harmony. Our designed algorithm could potentially improve the selection of proper nasal reconstruction techniques and assist novice surgeons.

A case series of concomitant burn and COVID-19.

BACKGROUND: The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) has become a human pandemic. Heightened inflammation, vascular hyperpermeability, acute lung injury, coagulopathy, and cardiovascular abnormalities are among the SARS-CoV-2 infection-related complications. Major burn is also associated with metabolic derangements, vascular leak, and hemodynamic instability. Burn patients are at high risk for infections and developing sepsis. COVID-19 in burn victims might worsen the clinical outcome and make their medical management challenging. RESULT: Here, we present four cases of concomitant burn and COVID-19 with different degrees of complications. They had no (three out of four) or multiple (one out of four) baseline comorbidities and all were admitted to hospital for further management. Three out of four cases demonstrated acute respiratory failure and were intubated (no longer than 7 days). It seems that one of them had COVID-19 on arrival, the other apparently contracted at outside hospital, and the last two infected during the index hospitalization. CONCLUSION: Concomitant severe burn and COVID-19 might complicate the clinical presentation and hospital course. Such combination was associated with poor outcome in a case with baseline comorbidities, beyond what was expected from the severity of burn injury. However, a more comprehensive study with larger sample size is required to make a valid conclusion. With an ongoing COVID-19 global pandemic, SARS-CoV-2 infection might be a concurrent disease with other illnesses or traumas such as burn. This dictate multidisciplinary approaches to risk stratify, screen, assess, and manage coexisting diseases. Additionally, appropriate preparations and careful precautions need to be executed in burn units to prevent COVID-19 exposure and transmission to limit potential adverse outcomes.

A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans.

AIMS: Air pollution [i.e. particulate matter with diameter <2.5 µm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE. METHODS AND RESULTS: Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual's home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE. CONCLUSIONS: Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

A neurobiological mechanism linking transportation noise to cardiovascular disease in humans.

AIMS: Chronic noise exposure associates with increased cardiovascular disease (CVD) risk; however, the role of confounders and the underlying mechanism remain incompletely defined. The amygdala, a limbic centre involved in stress perception, participates in the response to noise. Higher amygdalar metabolic activity (AmygA) associates with increased CVD risk through a mechanism involving heightened arterial inflammation (ArtI). Accordingly, in this retrospective study, we tested whether greater noise exposure associates with higher: (i) AmygA, (ii) ArtI, and (iii) risk for major adverse cardiovascular disease events (MACE). METHODS AND RESULTS: Adults (N = 498) without CVD or active cancer underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Amygdalar metabolic activity and ArtI were measured, and MACE within 5 years was adjudicated. Average 24-h transportation noise and potential confounders were estimated at each individual's home address. Over a median 4.06 years, 40 individuals experienced MACE. Higher noise exposure (per 5 dBA increase) predicted MACE [hazard ratio (95% confidence interval, CI) 1.341 (1.147-1.567), P < 0.001] and remained robust to multivariable adjustments. Higher noise exposure associated with increased AmygA [standardized ß (95% CI) 0.112 (0.051-0.174), P < 0.001] and ArtI [0.045 (0.001-0.090), P = 0.047]. Mediation analysis suggested that higher noise exposure associates with MACE via a serial mechanism involving heightened AmygA and ArtI that accounts for 12-26% of this relationship. CONCLUSION: Our findings suggest that noise exposure associates with MACE via a mechanism that begins with increased stress-associated limbic (amygdalar) activity and includes heightened arterial inflammation. This potential neurobiological mechanism linking noise to CVD merits further evaluation in a prospective population.

Psychosocial Stress and Cardiovascular Disease.

PURPOSE OF REVIEW: This manuscript reviews the epidemiological data linking psychosocial stress to cardiovascular disease (CVD), describes recent advances in understanding the biological pathway between them, discusses potential therapies against stress-related CVD, and identifies future research directions. RECENT FINDINGS: Metabolic activity of the amygdala (a neural center that is critically involved in the response to stress) can be measured on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) yielding a neurobiological signal that independently predicts subsequent CVD events. Furthermore, a serial pathway from ↑amygdalar activity → ↑hematopoietic tissue activity → ↑arterial inflammation → ↑CVD events has been elucidated, providing new insights into the mechanism linking stress to CVD. Psychosocial stress and stress conditions are independently associated with CVD in a manner that depends on the degree and duration of stress as well as the individual response to a stressor. Nevertheless, the fundamental biology remains incompletely defined, and stress is often confounded by adverse health behaviors. Thus, most clinical guidelines do not yet recognize psychosocial stress as an independent CVD risk factor or advocate for its treatment in CVD prevention. Clarification of this neurobiological pathway provides a better understanding of the underlying pathophysiology and suggests opportunities to develop novel preventive strategies and therapies.

Early transcriptional response to chloroquine of the Plasmodium falciparum antioxidant defence in sensitive and resistant clones.

Resistance to chloroquine (CQ) in Plasmodium falciparum has a major impact on malaria control worldwide. To gain insight into early parasite stress response, mRNA expression profiles were determined for a set of 10 antioxidant defence genes in synchronized CQ-sensitive (3D7) and CQ-resistant (Dd2) clones under transient IC50 CQ-exposure (Dd2, 200 nM; 3D7, 14 nM). Upon 2-h CQ challenge, the mRNA upregulation detected was greater in 3D7 (six genes overexpressed at 1/3 of the intraerythrocytic cycle) than in Dd2 clone (three genes responding), providing evidence of an early transcriptional response to CQ-induced oxidative stress which might underlie some of the parasite's metabolic adaptation to the drug.

Synchronous culture of Plasmodium falciparum at high parasitemia levels.

This protocol describes a method for preparing cultures of Plasmodium falciparum synchronized at any intraerythrocytic stage. Using this method, around 60% parasitized cells may be obtained. On the basis of Trager and Jensen's original continuous culture method, our approach relies on the use of fresh human blood not older than 2 weeks, a low hematocrit between 0.8 and 1.5%, a starting frozen inoculum of 10% ring-stage parasitemia, human serum replaced with AlbuMAX I and alternating sorbitol and Percoll synchronization methods to shorten the cycle window to 4-6 h and reduce sorbitol toxicity. From our synchronized high parasite density cultures, 3-5 ml of infected red blood cells can be obtained in 1 week, corresponding to 1.2 mg of total parasite protein per ml of harvested culture. On the basis of the variables parasitemia and packed cell volume, we provide an equation to accurately calculate the amount of complete medium required every 24 h corrected for the cycle stage and capacity of the culture flask. Ten days suffice to complete the protocol from a frozen stock of parasites.

Chloroquine mediates specific proteome oxidative damage across the erythrocytic cycle of resistant Plasmodium falciparum.

Resistance of Plasmodium falciparum to chloroquine hinders malaria control in endemic areas. Current hypotheses on the action mechanism of chloroquine evoke its ultimate interference with the parasite's oxidative defence systems. Through carbonyl derivatization by 2,4-dinitrophenylhydrazine and proteomics, we compared oxidatively modified proteins across the parasite's intraerythrocytic stages in untreated and transiently IC(50) chloroquine-treated cultures of the chloroquine-resistant P. falciparum strain Dd2. Functional plasmodial protein groups found to be most oxidatively damaged were among those central to the parasite's physiological processes, including protein folding, proteolysis, energy metabolism, signal transduction, and pathogenesis. While an almost constant number of oxidized proteins was detected across the P. falciparum life cycle, chloroquine treatment led to increases in both the extent of protein oxidation and the number of proteins oxidized as the intraerythrocytic cycle progressed to mature stages. Our data provide new insights into early molecular effects produced by chloroquine in the parasite, as well as into the normal protein-oxidation modifications along the parasite cycle. Oxidized proteins involved in the particular parasite drug-response suggest that chloroquine causes specific oxidative stress, sharing common features with eukaryotic cells. Targeting these processes might provide ways of combating chloroquine-resistance and developing new antimalarial drugs.

Protein processing in Plasmodium falciparum?

Los genomas de los organismos del género Plasmodium, agente causante de la malaria humana y animal, se caracterizan por un alto contenido en A+T e inserciones de baja complejidad en sus proteínas. La enzima glucosa-6-fosfato deshidrogenasa- 6-fosfogluconolactonasa (G6PD-6PGL) de las especies de Plasmodium posee unas características estructurales y bifuncionales únicas. En el presente trabajo analizamos la expresión de la G6PD-6PGL de P. faciparum a lo largo del ciclo intraeritrocítico mediante análisis inmunológico con anticuerpos frente a sus dominios N- y C- terminal. La modificación del tamaño del patrón de bandas en los diferentes estadios del desarrollo del parásito sugiere un procesamiento intracelular de la proteína que implicaría que la forma nativa bifuncional genera dos fragmentos principales. El silenciamiento in vitro del gen PfG6PD-6PGL, mediante ARN de interferencia, durante el desarrollo a corto plazo del parásito, también reveló la aparente modificación intracelular de la proteína dependiente del estadio de su ciclo vital. El tamaño de los fragmentos fue consistente con la separación de las dos funciones catalíticas de la enzima. Aunque en P. falciparum no se ha identificado la maquinaria proteolítica de este procesamiento específico de PfG6PD- 6PGL, nuestros resultados sugieren la existencia de mecanismos especializados para el procesamiento intracelular de este tipo de proteínas de estructura única y de función esencial, y que han podido aparecer como consecuencia de la particular evolución de su genoma

The genomes from the organisms of the Plasmodium genus, the causative agents of human and animal malaria, are characterized by an extreme high A+T content and an associated abundant low complexity inserts within their proteins. The enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (G6PD- 6PGL) found in Plasmodium species has unique structural and bifunctional characteristics. Here, we report the expression analysis of P. faciparum G6PD- 6PGL along the intraerythrocytic cycle by immunological analysis with antibodies raised against its N- and C- terminal domains. The pattern modification of band sizes at the different stages of parasite development suggest intracellular protein processing involving the cleavage of the native bifunctional form to produce two main fragments. In vitro RNA-mediated PfG6PD-6PGL gene silencing, studied along short-term parasite development also revealed the apparent intracellular protein modification dependent on the parasite stage. Fragment sizes were consistent with separating both catalytic functions of the enzyme. The proteolytic machinery underlying this specific PfG6PD-6PGL proccesing is still unknown in P. falciparum but suggests the existence of distinctive mechanisms in the parasite to deal with unique protein structures of essential function resulting from its genome evolution