Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.

Click nanosponge - A novel amine-rich ß-cyclodextrin-based crosslinked polymer for heterogeneous catalysis.

Cyclodextrin-based nanosponges are promising materials for heterogeneous catalysis due to their inherent synthetic versatility, tunable porosity and nontoxicity. In this work, a primary amine-rich ß-cyclodextrin nanosponge was synthesized via click imine condensation reaction between 1,6-hexamethylamine-functionalized ß-cyclodextrin (CDAM) and glutaraldehyde (GLT) to afford CDGLAM, in mild conditions. The crosslinked polymer exhibited a BET surface area of 36.39 m2 g-1, an average pore diameter of 3.09 nm (as assessed by the BJH method), and thermal stability up to 253 °C. CDGLAM was tested as heterogeneous catalyst for the metal-free Henry and Knoevenagel reactions, between aromatic aldehydes and nitromethane or ethyl cyanoacetate, respectively, affording the products in moderate to very high yields. These results show the ease of preparation of ß-CD-based nanosponges from a green chemistry perspective, as well as their potential for future use in catalytic systems.

Data monitoring committees in pediatric randomized controlled trials registered in ClinicalTrials.gov.

BACKGROUND: Data monitoring committees advise on clinical trial conduct through appraisal of emerging data to ensure participant safety and scientific integrity. While consideration of their use is recommended for trials performed with vulnerable populations, previous research has shown that data monitoring committees are reported infrequently in publications of pediatric randomized controlled trials. We aimed to assess the frequency of reported data monitoring committee adoption in ClinicalTrials.gov registry records and to examine the influence of key trial characteristics. METHODS: We conducted a cross-sectional data analysis of all randomized controlled trials performed exclusively in a pediatric population and registered in ClinicalTrials.gov between 2008 and 2021. We used the Access to Aggregate Content of ClinicalTrials.gov database to retrieve publicly available information on trial characteristics and data on safety results. Abstracted data included reported trial design and conduct parameters, population and intervention characteristics, reasons for prematurely halting, serious adverse events, and mortality outcomes. We performed descriptive analyses on the collected data and explored the influence of clinical, methodological, and operational trial characteristics on the reported adoption of data monitoring committees. RESULTS: We identified 13,928 pediatric randomized controlled trial records, of which 39.7% reported adopting a data monitoring committee, 49.0% reported not adopting a data monitoring committee, and 11.3% did not answer on this item. While the number of registered pediatric trials has been increasing since 2008, we found no clear time trend in the reported adoption of data monitoring committees. Data monitoring committees were more common in multicenter trials (50.6% vs 36.9% for single-center), multinational trials (60.2% vs 38.7% for single-country), National Institutes of Health-funded (60.3% vs 40.1% for industry-funded or 37.5% for other funders), and placebo-controlled (47.6% vs 37.5% for other types of control groups). Data monitoring committees were also more common among trials enrolling younger participants, trials employing blinding techniques, and larger trials. Data monitoring committees were more common in trials with at least one serious adverse event (52.6% vs 38.4% for those without) as well as for trials with reported deaths (70.3% vs 38.9% for trials without reported deaths). In all, 4.9% were listed as halted prematurely, most often due to low accrual rates. Trials with a data monitoring committee were more often halted for reasons related to scientific data than trials without a data monitoring committee (15.7% vs 7.3%). CONCLUSION: According to registry records, the use of data monitoring committees in pediatric randomized controlled trials was more frequent than previously reported in reviews of published trial reports. The use of data monitoring committees varied across key clinical and trial characteristics based on which their use is recommended. Data monitoring committees may still be underutilized in pediatric trials, and reporting of this item could be improved.

Automated Operational Modal Analysis for Rotating Machinery Based on Clustering Techniques.

Many parameters can be used to express a machine's condition and to track its evolution through time, such as modal parameters extracted from vibration signals. Operational Modal Analysis (OMA), commonly used to extract modal parameters from systems under operating conditions, was successfully employed in many monitoring systems, but its application in rotating machinery is still in development due to the distinct characteristics of this system. To implement efficient monitoring systems based on OMA, it is essential to automatically extract the modal parameters, which several studies have proposed in the literature. However, these algorithms are usually developed to deal with structures that have different characteristics when compared to rotating machinery, and, therefore, work poorly or do not work with this kind of system. Thus, this paper proposes, and has as its main novelty in, a new automated algorithm to carry out modal parameter identification on rotating machinery through OMA. The proposed technique was applied in two different datasets to enable the evaluation of the robustness to different systems and test conditions. It is revealed that the proposed algorithm is suitable for the accurate extraction of frequencies and damping ratios from the stabilization diagram, for both the rotor and the foundation, and only one user defined parameter is required.

Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.

ß-Ketoenamine Covalent Organic Frameworks-Effects of Functionalization on Pollutant Adsorption.

Water pollution due to global economic activity is one of the greatest environmental concerns, and many efforts are currently being made toward developing materials capable of selectively and efficiently removing pollutants and contaminants. A series of ß-ketoenamine covalent organic frameworks (COFs) have been synthesized, by reacting 1,3,5-triformylphloroglucinol (TFP) with different C2-functionalized and nonfunctionalized diamines, in order to evaluate the influence of wall functionalization and pore size on the adsorption capacity toward dye and heavy metal pollutants. The obtained COFs were characterized by different techniques. The adsorption of methylene blue (MB), which was used as a model for the adsorption of pharmaceuticals and dyes, was initially evaluated. Adsorption studies showed that -NO2 and -SO3H functional groups were favorable for MB adsorption, with TpBd(SO3H)2-COF [100%], prepared between TFP and 4,4'-diamine- [1,1'-biphenyl]-2,2'-disulfonic acid, achieving the highest adsorption capacity (166 ± 13 mg g-1). The adsorption of anionic pollutants was less effective and decreased, in general, with the increase in -SO3H and -NO2 group content. The effect of ionic interactions on the COF performance was further assessed by carrying out adsorption experiments involving metal ions. Isotherms showed that nonfunctionalized and functionalized COFs were better described by the Langmuir and Freundlich sorption models, respectively, confirming the influence of functionalization on surface heterogeneity. Sorption kinetics experiments were better adjusted according to a second-order rate equation, confirming the existence of surface chemical interactions in the adsorption process. These results confirm the influence of selective COF functionalization on adsorption processes and the role of functional groups on the adsorption selectivity, thus clearly demonstrating the potential of this new class of materials in the efficient and selective capture and removal of pollutants in aqueous solutions.

Analysis of the Objective Internal Load in Portuguese Skydivers in the First Jump of the Day.

The general objective of this study was to identify the variation in heart rate (HR) of Portuguese skydivers during 6 moments in their first jump of the day, bearing in mind the variable level of experience. Thirty-one Portuguese skydivers, 28 men and 3 women, aged between 19 and 62, participated in the study, 12 had A and B licenses (less experienced) and 19 had C and D licences (more experienced). The instrument used to record the heart rate of the skydivers at the different moments of their first jump of the day was the WIMU PRO. A repeated measures analysis of variance was used to analyse HR at different moments in the jump and its relation with the variables level of experience. Bonferroni multiple comparisons were performed to study the importance of the differences observed in HR at the different moments. The effect size was evaluated with partial eta squared. The results showed that average HR in this group of skydivers was 130 bpm, in the different moments of the jump. HR increases from the value recorded at rest until the moment of jumping from the plane and opening the parachute, reaching the highest average at that moment, then decreasing until contact with the ground. Comparing the variable, we found that the less experienced had higher HR than the more experienced at all moments during the jump. Statistically significant differences were found at the different moments of the jump, regarding HR (Max: p < 0.001, ƞ2p = 0.820; Min: p < 0.001, ƞ2p = 0.821; AVG: p < 0.001, ƞ2p = 0.834) Level of experience with jumping moment interaction, we only verified differences related to HR Min (p = 0.007, ƞ2p = 0.056),. With regard to experience, the identified differences were not statistically significant. Skydiving triggers an acute adaptive cardiovascular response which is reflected in the increase in the HR, between the moment of boarding the plane and the moment at which the parachute opens, thereafter decreasing until contact with the ground. The most experienced parachutists recorded the highest HR at the moment of landing and the least experienced at the moment of free fall.

Confusion with the definition and diagnostic criteria for acute on chronic pancreatitis: review and recommendations.

OBJECTIVES: Chronic pancreatitis (CP) is a fibroinflammatory disease complicated by episodes of acute inflammation (acute on chronic pancreatitis (ACP)). This entity is common, variably defined and can reflect different pathological mechanisms that requires different interventions. The aim of this study is to conduct a systematic review of how ACP is described, defined and diagnosed in the literature. METHODS: A systematic search was conducted from January 1993 to June 2020. All articles that used a term to describe ACP in adults were reviewed and definitions and diagnostic criteria were sought. RESULTS: After reviewing 2271 abstracts, 848 articles included a term to describe ACP. The most common descriptions were 'acute on/in CP' (374), 'acute exacerbation of CP' (345) and 'flare(-up) of CP' (43). Among the 848 articles, 14 included a pragmatic definition of ACP, and only 2 papers stated diagnostic criteria. These covered both acute inflammation and acute exacerbation of chronic abdominal pain. CONCLUSION: There is no universally accepted term, definition or diagnostic criteria for ACP. A consensus definition is needed to improve quality and comparability of future articles as well as clinical management.

Covalent Organic Frameworks: Synthesis, Properties and Applications-An Overview.

Covalent Organic Frameworks (COFs) are an exciting new class of microporous polymers with unprecedented properties in organic material chemistry. They are generally built from rigid, geometrically defined organic building blocks resulting in robust, covalently bonded crystalline networks that extend in two or three dimensions. By strategically combining monomers with specific structures and properties, synthesized COF materials can be fine-tuned and controlled at the atomic level, with unparalleled precision on intrapore chemical environment; moreover, the unusually high pore accessibility allows for easy post-synthetic pore wall modification after the COF is synthesized. Overall, COFs combine high, permanent porosity and surface area with high thermal and chemical stability, crystallinity and customizability, making them ideal candidates for a myriad of promising new solutions in a vast number of scientific fields, with widely varying applications such as gas adsorption and storage, pollutant removal, degradation and separation, advanced filtration, heterogeneous catalysis, chemical sensing, biomedical applications, energy storage and production and a vast array of optoelectronic solutions. This review attempts to give a brief insight on COF history, the overall strategies and techniques for rational COF synthesis and post-synthetic functionalization, as well as a glance at the exponentially growing field of COF research, summarizing their main properties and introducing the numerous technological and industrial state of the art applications, with noteworthy examples found in the literature.

Analysis of clinical and methodological characteristics of early COVID-19 treatment clinical trials: so much work, so many lost opportunities.

BACKGROUND: The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. METHODS: First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. RESULTS: In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as "Completed", and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status "Not yet recruiting" or "Suspended", and 18 (3.1%) trials were prematurely stopped ("Terminated" or "Withdrawn") The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. CONCLUSIONS: Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

Parkinson's Disease Drug Development Since 1999: A Story of Repurposing and Relative Success.

BACKGROUND: A global overview of drug development programs in Parkinson's disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. OBJECTIVE: To indirectly assess drug development programs in Parkinson's disease, exploring some factors associated with compound attrition at different trial phases. METHODS: We assessed all Parkinson's disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. RESULTS: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. CONCLUSION: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

Clube Português do Pâncreas Recommendations for Chronic Pancreatitis: Medical, Endoscopic, and Surgical Treatment (Part II).

Chronic pancreatitis (CP) is a complex disease that should be treated by experienced teams of gastroenterologists, radiologists, surgeons, and nutritionists in a multidisciplinary environment. Medical treatment includes lifestyle modification, nutrition, exocrine and endocrine pancreatic insufficiency correction, and pain management. Up to 60% of patients will ultimately require some type of endoscopic or surgical intervention for treatment. However, regardless of the modality, they are often ineffective unless smoking and alcohol cessation is achieved. Surgery retains a major role in the treatment of CP patients with intractable chronic pain or suspected pancreatic mass. For other complications like biliary or gastroduodenal obstruction, pseudocyst drainage can be performed endoscopically. The recommendations for CP were developed by Clube Português do Pâncreas (CPP), based on literature review to answer predefined topics, subsequently discussed and approved by all members of CPP. Recommendations are separated in two parts: "chronic pancreatitis etiology, natural history, and diagnosis," and "chronic pancreatitis medical, endoscopic, and surgical treatment." This abstract pertains to part II.

Clube Português do Pâncreas Recommendations for Chronic Pancreatitis: Etiology, Natural History, and Diagnosis (Part I).

Chronic pancreatitis (CP) is a heterogeneous disease, with different causes and often a long delay between onset and full classic presentation. Clinical presentation depends on the stage of the disease. In earlier stages, recurrent episodes of acute pancreatitis are the major signs dominating clinical presentation. As the inflammatory process goes on, less acute episodes occur, and pain adopts different aspects or may even disappear. After 10-15 years from onset, functional insufficiency occurs. Then, a classic presentation with pain and pancreatic exocrine and endocrine insufficiency appears. Diagnosis remains challenging in the early stages of the disease, as its initial presentation is usually ill-defined and overlaps with other digestive disorders. Computed tomography and magnetic resonance cholangiopancreatography should be the first choice in patients with suspected CP. If the results are normal or equivocal but still there is a high suspicion of CP, the next option should be endoscopic ultrasound. Endoscopic retrograde cholangiopancreatography is mainly a therapeutic technique, and for the diagnostic purpose should only be used when all other imaging modalities and pancreatic function tests have been exhausted. Indirect tests are used to quantify the degree of insufficiency in already-established late CP. Recommendations on CP were developed by Clube Português do Pâncreas (CPP), based on literature review to answer predefined topics, subsequently discussed and approved by all members of CPP. Recommendations are separated in two parts: "chronic pancreatitis etiology, natural history, and diagnosis," and "chronic pancreatitis medical, endoscopic, and surgical treatment." This abstract pertains to part I.

A pancreatite crónica (PC) é uma doença heterogénea, com diferentes etiologias, muitas vezes, com um longo período entre o início de sintomatologia e a apresentação clínica clássica. A clínica depende do estadio da doença, sendo que nos estadios iniciais, predominam episódios recorrentes de pancreatite aguda; com a progressão da doença, os episódios agudos tornam-se menos frequentes, e a dor adota padrões diferentes, podendo inclusive desaparecer; a insuficiência funcional desenvolve-se 10 a 15 anos após o início, assumindo-se então, a apresentação clássica com dor, insuficiência pancreática exócrina e endócrina. O diagnóstico pode ser desafiador nos estadios iniciais da doença, já que a apresentação inicial é geralmente mal definida e se sobrepõe a outros patologias gastrointestinais. A TAC e CPRM devem ser os primeiros métodos de imagem em doentes com suspeita de PC. Se os resultados forem normais ou ambíguos, a próxima opção deve ser a ecoendoscopia. A CPRE é uma técnica principalmente terapêutica, sendo que para fins de diagnóstico, deve ser reservada para quando todas os outros exames de imagem/testes de função pancreática forem inconclusivos. Testes indiretos de função pancreática devem ser usados para quantificação do grau de insuficiência pancreática em doentes com PC já estabelecida. As recomendações sobre PC foram desenvolvidas pelo Clube Português do Pâncreas (CPP), com base numa revisão da literatura para responder a questões predefinidas, posteriormente discutidos e aprovados por todos os membros do CPP. As recomendações encontram-se separadas em duas partes: "etiologia da pancreatite crónica, história natural e diagnóstico" e "tratamento médico, endoscópico e cirúrgico da pancreatite crónica." Este resumo corresponde à parte I.

Electronic search strategies fail to identify randomized controlled trials (RCTs) in neurosurgery.

Randomized controlled trials (RCTs) are the gold standard studies to evaluate the efficacy of therapeutic interventions. Although they are frequently identified through open searches in electronic databases, no studies have evaluated how easy it is to identify RCTs in neurosurgery using electronic search strategies. The present study evaluated the sensitivity and specificity of different search strategies applied to commonly used databases to identify RCTs in neurosurgery. The total number of RCTs in neurosurgery published between 1960 and 2013 was determined through a detailed search involving open keyword searches in PubMed, Cochrane Library and Center for Reviews and Dissemination (CRD) databases, a PubMed search based on clinical entity-related keywords and hand-searches on the reference list of identified articles. The sensitivity and specificity were calculated for the open keyword searches on PubMed, the Cochrane Library and the CRD database and for the Cochrane's HSSS, based on the total number of the identified RCTs. Compared to the total of 1102 RCTs identified, PubMed open search yielded 4660 articles, among which 365 were RCTs (sensitivity: 33.1%; specificity: 7.8%). Cochrane open search yielded 621 among which 36 were RCTs (sensitivity: 3.2%; specificity: 5.8%) and CRD open search returned 78 articles, among which 4 were RCTs (sensitivity: 0.4% sensitivity; specificity: 5.1%). The Cochrane HSSS retrieved 10702 results, among which 340 were RCTs (sensitivity: 30.9%; specificity: 3.2%). Most RCTs in neurosurgery cannot be identified by commonly used search strategies, which emphasizes the need to improve their indexing.

Exposure to the UV Filter Octyl Methoxy Cinnamate in the Postnatal Period Induces Thyroid Dysregulation and Perturbs the Immune System of Mice.

Evidence demonstrates the bidirectional communication and regulation between the neuroendocrine and immune systems. Thyroid hormones play key roles in nervous system development and can exert influence on various immune cells contributing to pathophysiological conditions. Octyl methoxycinnamate (OMC) is one of the most commonly used UV filters, and in vitro and in vivo studies have found thyroid disrupting effects. The present study assessed whether OMC administration in mice dams during the lactational period can cause thyroid disruption and generate immunologic alterations in the offspring. Indirect exposure to the OMC (1,000 mg/kg) in the lactational period affected neurodevelopment parameters, such as delayed eye-opening and weight gain in mice of both sexes, and these alterations are corroborated by the decrease in the T4 levels present in the pups' blood. No significant changes were observed in the thymus of these pups, but the number of lymphocytes increased in the spleen of the animals exposed to OMC, similar to the animals treated with propyl-thiouracil (PTU), a well-known thyroid disruptor. OMC modulated the percentage of leukocyte populations in peripheral blood, and the number of circulating polymorphonuclear cells increased two-fold. In vitro, OMC exhibited an inhibitory effect on splenocyte proliferation and IL-2 production induced by anti-CD3 antibody; however, this effect was reversed with the addition of T4 in the cell culture. In summary, the results of the present study demonstrate the influence of OMC on thyroid dysregulation and its impact on the modulation of the immune system in mice pups.

Muscle metaboreflex-induced vasoconstriction in the ischemic active muscle is exaggerated in heart failure.

When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α1-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α1-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.

Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension.

Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after α1-adrenergic blockade (prazosin; 75 µg/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 ± 2.6 to 132.1 ± 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. NEW & NOTEWORTHY: We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. α1-Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction.