Search

Reduced exercise tolerance and fatigue are hallmark features in both breast cancer (BC) and heart failure with preserved ejection fraction (HFpEF) and are associated with decreased physical function and quality of life. This brief review focuses on the mechanisms of exercise intolerance in women with BC across the survivorship continuum and highlights how these disturbances within the oxygen transport cascade are similar to that of HFpEF patients. Specifically, the role that impaired cardiac, peripheral vascular and skeletal muscle function play in limiting peak oxygen uptake are discussed. We propose that women with BC are at increased risk of developing HFpEF potentially due to the adverse effects of chemotherapy and concurrent adverse lifestyle behaviors on cardiovascular and skeletal muscle function.

Background While cardiotoxic chemotherapy is known to negatively impact cardiac function and hemoglobin levels, the impact on skeletal muscle has been understudied among patients. The purpose was to longitudinally characterize myosteatosis (muscle fat), skeletal muscle metabolism, and oxygen (O2) consumption during cardiotoxic chemotherapy for breast cancer. Patients and Methods Thirty-four patients with stage I-III breast cancer were enrolled before trastuzumab-containing and/or anthracycline-containing chemotherapy. We used magnetic resonance imaging to non-invasively quantify thigh myosteatosis (fat-water imaging), and lower leg metabolism (31P spectroscopy), O2 consumption (custom techniques), and peak power output during single-leg plantarflexion exercise at pre-, mid-, end-chemotherapy, and 1-year. We also measured pulmonary VO2peak and maximal leg press strength. Results During chemotherapy, VO2peak and leg press strength decreased while peak plantarflexion power output was maintained. At mid-chemotherapy, hemoglobin decreased (16%) and lower leg blood flow increased (37%) to maintain lower leg O2 delivery; exercise Pi:PCr and myosteatosis increased. Between mid- and end-chemotherapy, lower leg O2 extraction (28%) and O2 consumption (21%) increased, while plantarflexion exercise efficiency (watts/O2 consumed) decreased. At one year, VO2peak and leg press strength returned to pre-chemotherapy levels, but lower leg exercise O2 extraction, consumption and Pi:PCr, and myosteatosis remained elevated. Conclusion Lower leg skeletal muscle blood flow and O2 extraction adapt to compensate for chemotherapy-related hemoglobin reduction for small muscle mass exercise but are insufficient to maintain large muscle mass exercise (pulmonary VO2peak, leg press strength). The excess O2 required to perform work, increased Pi:PCr ratio and myosteatosis together suggest suppressed fat oxidation during chemotherapy.

Background Despite the improved awareness of cardiac amyloidosis among clinicians, its incidence and prevalence is not well-described in a community setting. We sought to investigate the incidence and prevalence of cardiac amyloidosis in the community. Methods and Results In the adult population of Alberta, we examined 3 cohorts: (1) probable cases of cardiac amyloidosis: the presence of physician-assigned diagnosis of amyloidosis (International Classification of Diseases [ICD]-10 code E85; ICD-9 277.3) and 1 or more health care encounter for heart failure (HF) (ICD-10 I50; ICD-9 428); (2) possible cardiac amyloidosis: the presence of clinical phenotypes suggestive of amyloidosis; and (3) a comparator HF cohort without amyloidosis. Between 2004 and 2018, 982 of the 145,329 patients with HF were identified as probable cardiac amyloidosis. During the same period, the incidence rates of probable cardiac amyloidosis increased from 1.38 to 3.69 per 100,000 person-years and the prevalence rates increased from 3.42 to 14.85 per 100,000 person-years (Ptrend Conclusions The incidence and prevalence of cardiac amyloidosis has increased over the last decade. Given the advent of new therapies for cardiac amyloidosis and considering their high cost, it is imperative to devise strategies to screen, identify, and track patients with cardiac amyloidosis from administrative databases.

17 p.-5 fig.1 graph. abst., Taxanes are microtubule-stabilizing agents used in the treatment of many solid tumors, but they often involve side effects affecting the peripheral nervous system. It has been proposed that this could be related to structural modifications on the filament upon drug binding. Alternatively, laulimalide and peloruside bind to a different site also inducing stabilization, but they have not been exploited in clinics. Here, we use a combination of the parental natural compounds and derived analogs to unravel the stabilization mechanism through this site. These drugs settle lateral interactions without engaging the M loop, which is part of the key and lock involved in the inter-protofilament contacts. Importantly, these drugs can modulate the angle between protofilaments, producing microtubules of different diameters. Among the compounds studied, we have found some showing low cytotoxicity and able to induce stabilization without compromising microtubule native structure. This opens the window of new applications for microtubule-stabilizing agents beyond cancer treatment., This work was supported by Ministerio de Ciencia e Innovación PID2021-123399OB-I00 and PID2019-104545RBI00 to M.O.B. and J.F.D.;/AEI/10.13039/501100011033, Consejo Superior de Investigaciones Científicas PIE 201920E111, the European Commission-NextGenerationsEU (Regulation EU 2020/2094), through CSIC’s Global Health Plat-form (PTI Salud Global), and Proyecto de Investigación en Neurociencia Fundacion Tatiana Pérez de Guzmán el Bueno 2020 to J.F.D.; H2020-MSCA-ITN-2019 860070 TUBINTRAIN to J.F.D. and A.E.P.; Swiss National Science Foundation (31003A_166608) to M.O.S.; Ministerio de Universidades fellowship FPU15/03140 to J.E.G.; European Commission IHP Networks HPRN-CT-2000-18 and HPRN-CT-2000-00014 to I.P. and postdoctoral fellowship to D.M. We thank staff of beamlines BL11-NDC-SWEET (ALBA, CELLS, Cerdanyola del Vallès, Spain), X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen PSI, Switzerland), and ID30B of the European Synchrotron Radiation Facility (ESRF, Grenoble, France) for their support. We also thank Ganadería Fernando Díaz for calf brains supply and Escuela Hongaresa de Esgrima de Pontevedra for its private donation to the project.

Aims Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome. Methods and results A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow‐up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan–Meier analyses compared to those with no remodelling, log‐rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction. Conclusions Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long‐term outcomes whereas change in left ventricular ejection fraction did not.

Background This study investigated accuracy and consistency of epicardial adipose tissue (EAT) quantification in non-ECG-gated chest computed tomography (CT) scans. Methods EAT volume was semi-automatically quantified using a standard Hounsfield unit threshold (− 190, − 30) in three independent cohorts: (1) Cohort 1 (N = 49): paired 120 kVp ECG-gated cardiac non-contrast CT (NCCT) and 120 kVp non-ECG-gated chest NCCT; (2) Cohort 2 (N = 34): paired 120 kVp cardiac NCCT and 100 kVp non-ECG-gated chest NCCT; (3) Cohort 3 (N = 32): paired non-ECG-gated chest NCCT and chest contrast-enhanced CT (CECT) datasets (including arterial phase and venous phase). Images were reconstructed with the slice thicknesses of 1.25 mm and 5 mm in the chest CT datasets, and 3 mm in the cardiac NCCT datasets. Results In Cohort 1, the chest NCCT-1.25 mm EAT volume was similar to the cardiac NCCT EAT volume, while chest NCCT-5 mm underestimated the EAT volume by 7.5%. In Cohort 2, 100 kVp chest NCCT-1.25 mm were 13.2% larger than 120 kVp cardiac NCCT EAT volumes. In Cohort 3, the chest arterial CECT and venous CECT dataset underestimated EAT volumes by ~ 28% and ~ 18%, relative to chest NCCT datasets. All chest CT-derived EAT volumes were similarly associated with significant coronary atherosclerosis with cardiac CT counterparts. Conclusion The 120 kVp non-ECG-gated chest NCCT-1.25 mm images produced EAT volumes comparable to cardiac NCCT. Chest CT EAT volumes derived from consistent imaging settings are excellent alternatives to the cardiac NCCT to investigate their association with coronary artery disease.

Metabolic dysfunction and excess accumulation of adipose tissue are detrimental side effects from breast cancer treatment. Diet and physical activity are important treatments for metabolic abnormalities, yet patient compliance can be challenging during chemotherapy treatment. Time-restricted eating (TRE) is a feasible dietary pattern where eating is restricted to 8 h/d with water-only fasting for the remaining 16 h. The purpose of this study is to evaluate the effect of a multimodal intervention consisting of TRE, healthy eating, and reduced sedentary time during chemotherapy treatment for early-stage (I–III) breast cancer on accumulation of visceral fat (primary outcome), other fat deposition locations, metabolic syndrome and cardiovascular disease risk (secondary outcomes) compared with usual care. The study will be a two-site, two-arm, parallel-group superiority randomised control trial enrolling 130 women scheduled for chemotherapy for early-stage breast cancer. The intervention will be delivered by telephone, including 30–60-minute calls with a registered dietitian who will provide instructions on TRE, education and counselling on healthy eating, and goal setting for reducing sedentary time. The comparison group will receive usual cancer and supportive care including a single group-based nutrition class and healthy eating and physical activity guidelines. MRI, blood draws and assessment of blood pressure will be performed at baseline, after chemotherapy (primary end point), and 2-year follow-up. If our intervention is successful in attenuating the effect of chemotherapy on visceral fat accumulation and cardiometabolic dysfunction, it has the potential to reduce risk of cardiometabolic disease and related mortality among breast cancer survivors.

This study aimed to characterize peak exercise cardiac function and thigh muscle fatty infiltration and their relationships with VO2peak among anthracycline-treated breast cancer survivors (BCS). BCS who received anthracycline chemotherapy ~ 1 year earlier (n = 16) and matched controls (matched-CON, n = 16) were enrolled. Resting and peak exercise cardiac function, myocardial T1 mapping (marker of fibrosis), and thigh muscle fat infiltration were assessed by magnetic resonance imaging, and VO2peak by cycle test. Compared to matched-CON, BCS had lower peak SV (64 ± 9 vs 57 ± 10 mL/m2, p = 0.038), GLS (− 30.4 ± 2.2 vs − 28.0 ± 2.5%, p = 0.008), and arteriovenous oxygen difference (16.4 ± 3.6 vs 15.2 ± 3.9 mL/100 mL, p = 0.054). Mediation analysis showed: (1) greater myocardial T1 time (fibrosis) is inversely related to cardiac output and end-systolic volume exercise reserve; (2) greater thigh muscle fatty infiltration is inversely related to arteriovenous oxygen difference; both of which negatively influence VO2peak. Peak SV (R2 = 65%) and thigh muscle fat fraction (R2 = 68%) were similarly strong independent predictors of VO2peak in BCS and matched-CON combined. Post-anthracyclines, myocardial fibrosis is associated with impaired cardiac reserve, and thigh muscle fatty infiltration is associated with impaired oxygen extraction, which both contribute to VO2peak.

ObjectivesTo synthesise evidence on incidence rates and risk factors for myocarditis and pericarditis after use of mRNA vaccination against covid-19, clinical presentation, short term and longer term outcomes of cases, and proposed mechanisms.DesignLiving evidence syntheses and review.Data sourcesMedline, Embase, and the Cochrane Library were searched from 6 October 2020 to 10 January 2022; reference lists and grey literature (to 13 January 2021). One reviewer completed screening and another verified 50% of exclusions, using a machine learning program to prioritise records. A second reviewer verified all exclusions at full text, extracted data, and (for incidence and risk factors) risk of bias assessments using modified Joanna Briggs Institute tools. Team consensus determined certainty of evidence ratings for incidence and risk factors using GRADE (Grading of Recommendations, Assessment, Development and Evaluation).Eligibility criteria for selecting studiesLarge (>10 000 participants) or population based or multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after covid-19 mRNA vaccination; case series (n≥5, presentation, short term clinical course and longer term outcomes); opinions, letters, reviews, and primary studies focused on describing or supporting hypothesised mechanisms.Results46 studies were included (14 on incidence, seven on risk factors, 11 on characteristics and short term course, three on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines was highest in male adolescents and male young adults (age 12-17 years, range 50-139 cases per million (low certainty); 18-29 years, 28-147 per million (moderate certainty)). For girls and boys aged 5-11 years and women aged 18-29 years, incidence of myocarditis after vaccination with BNT162b2 (Pfizer/BioNTech) could be fewer than 20 cases per million (low certainty). Incidence after a third dose of an mRNA vaccine had very low certainty evidence. For individuals of 18-29 years, incidence of myocarditis is probably higher after vaccination with mRNA-1273 (Moderna) compared with Pfizer (moderate certainty). Among individuals aged 12-17, 18-29, or 18-39 years, incidence of myocarditis or pericarditis after dose two of an mRNA vaccine for covid-19 might be lower when administered ≥31 days compared with ≤30 days after dose one (low certainty). Data specific to men aged 18-29 years indicated that the dosing interval might need to increase to ≥56 days to substantially drop myocarditis or pericarditis incidence. For clinical course and short term outcomes, only one small case series (n=8) was found for 5-11 year olds. In adolescents and adults, most (>90%) myocarditis cases involved men of a median 20-30 years of age and with symptom onset two to four days after a second dose (71-100%). Most people were admitted to hospital (≥84%) for a short duration (two to four days). For pericarditis, data were limited but more variation than myocarditis has been reported in patient age, sex, onset timing, and rate of admission to hospital. Three case series with longer term (3 months; n=38) follow-up suggested persistent echocardiogram abnormalities, as well as ongoing symptoms or a need for drug treatments or restriction from activities in >50% of patients. Sixteen hypothesised mechanisms were described, with little direct supporting or refuting evidence.ConclusionsThese findings indicate that adolescent and young adult men are at the highest risk of myocarditis after mRNA vaccination. Use of a Pfizer vaccine over a Moderna vaccine and waiting for more than 30 days between doses might be preferred for this population. Incidence of myocarditis in children aged 5-11 years is very rare but certainty was low. Data for clinical risk factors were very limited. A clinical course of mRNA related myocarditis appeared to be benign, although longer term follow-up data were limited. Prospective studies with appropriate testing (eg, biopsy and tissue morphology) will enhance understanding of mechanism.

The security-migration nexus is ubiquitous throughout Europe and beyond. An avalanche of scholarship has explored the construction of migration as a security threat in general and, in the UK, the creation of the ‘hostile environment’ in particular – the problematic nature of each being well documented. Yet, far less attention has been paid to activities that contest this process. Deploying Balzacq's four modalities of contestation – desecuritisation, resistance, emancipation, and resilience – this article addresses the imbalance, exploring how asylum and refugee sector NGOs engage in and contest security-migration politics. Using Scotland (2018–19) as an illustrative case and analysing discursive and predominantly non-discursive activities, findings demonstrate that NGOs are successfully contesting the security-migration nexus in Scotland across four principal categories, supporting the ‘surviving’ and ‘thriving’ of asylum seeker and refugee communities, problematising previous conceptualisations of ‘UK’ asylum and refugee politics, with implications extending globally. The article helps refine the theorisation of contestation, demonstrating first, the need to move beyond studies of ‘desecuritisation’, with consequences for understandings of ‘success’ in securitisation, and second, the potential blindness of single-modality studies to vital, meaningful contestation, resulting in the production of less comprehensive visions of the security world.

Magnetic resonance imaging (MRI) is often considered the gold-standard test for characterizing cardiac as well as noncardiac structure and function. However, many patients with cardiac implantable electronic devices (CIEDs) and/or severe renal dysfunction are unable to undergo this test because of safety concerns. In the past 10 years, newer-generation CIEDs and gadolinium-based contrast agents (GBCAs) as well as coordinated care between imaging and heart rhythm device teams have mitigated risk to patients and improved access to MRI at many hospitals. The purpose of this statement is to review published data on safety of MRI in patients with conditional and nonconditional CIEDs in addition to patient risks from older and newer GBCAs. This statement was developed through multidisciplinary collaboration of pan-Canadian experts after a relevant and independent literature search by the Canadian Agency for Drugs and Technologies in Health. All recommendations align with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Key recommendations include: (1) the development of standardized protocols for patients with a CIED undergoing MRI; (2) patients with MRI nonconditional pacemakers and pacemaker dependency should be programmed to asynchronous mode and those with MRI nonconditional transvenous defibrillators should have tachycardia therapies turned off during the scan; and (3) macrocyclic or newer linear GBCAs should be used in preference to older GBCAs because of their better safety profile in patients at higher risk of nephrogenic systemic fibrosis.

Immune checkpoint inhibitor therapy has been shown to improve outcomes across many types of malignancies. However, immune checkpoint inhibitor has been associated with several immune-related adverse events including myocarditis. We describe the case of a 69-year-old man with fulminant myocarditis likely due to pembrolizumab therapy, complicated by biventricular failure with cardiogenic shock. Because of deterioration in hemodynamic status refractory to conventional immunosuppression, therapeutic plasma exchange was performed, resulting in a rapid reduction of serum pembrolizumab levels, and marked clinical, radiological, and biochemical improvement. To our knowledge, this is the first reported case on the successful use of plasma exchange for pembrolizumab-associated fulminant myocarditis.

Immune checkpoint inhibitor therapy has been shown to improve outcomes across many types of malignancies. However, immune checkpoint inhibitor has been associated with several immune-related adverse events including myocarditis. We describe the case of a 69-year-old man with fulminant myocarditis likely due to pembrolizumab therapy, complicated by biventricular failure with cardiogenic shock. Because of deterioration in hemodynamic status refractory to conventional immunosuppression, therapeutic plasma exchange was performed, resulting in a rapid reduction of serum pembrolizumab levels, and marked clinical, radiological, and biochemical improvement. To our knowledge, this is the first reported case on the successful use of plasma exchange for pembrolizumab-associated fulminant myocarditis. Résumé: Il a été montré que le traitement par un inhibiteur du point de contrôle immunitaire améliore les résultats dans de nombreux types de cancer. Un inhibiteur du point de contrôle immunitaire a toutefois été associé à plusieurs effets indésirables d'origine immunologique, y compris la myocardite. Nous vous présentons le cas d'un homme de 69 ans ayant présenté une myocardite fulminante, probablement causée par un traitement par le pembrolizumab, compliquée par une insuffisance biventriculaire accompagnée d'un choc cardiogénique. En raison de la détérioration de l'état hémodynamique réfractaire à une immunosuppression classique, un échange plasmatique thérapeutique a été effectué, lequel a entraîné une réduction rapide des taux sériques de pembrolizumab, et une amélioration marquée sur les plans clinique, radiologique et biochimique. À notre connaissance, il s'agit du premier cas signalé dans lequel un échange plasmatique a été utilisé avec succès pour traiter une myocardite fulminante associée au pembrolizumab.

The diverse and complex structures of polyketide natural products have stimulated the imagination of synthetic chemists for decades. Captivated by their often impressive biological activities and t...

The structural complexity and biological importance of macrolide natural products has inspired the development of innovative strategies for their chemical synthesis. With their dense stereochemical content, high level of oxygenation and macrocyclic cores, we viewed the efficient total synthesis of these valuable compounds as an aspirational driver towards developing robust methods and strategies for their construction. Starting out from the initial development of our versatile asymmetric aldol methodology, this personal perspective reflects on an adventurous journey, with all its trials, tribulations and serendipitous discoveries, across the total synthesis, in our group, of a representative selection of six macrolide natural products of marine and terrestrial origin - swinholide A, spongistatin 1, spirastrellolide A, leiodermatolide, chivosazole F and actinoallolide A.

The marine natural product hemicalide displays potent anticancer activity. While detailed NMR experiments established the planar carbon skeleton, its full configurational assignment proved enigmatic. This Review summarises ongoing synthetic efforts and NMR studies on hemicalide, which have succeeded in reducing the number of possible stereoisomers from more than one million to a more manageable eight structures, setting the stage for a focused total synthesis campaign.

With 21 unknown stereocentres embedded in spatially separated stereoclusters, the cytotoxic polyketide hemicalide represents a seemingly intractible structural assignment problem. Herein, through the targeted synthesis of configurationally defined fragments, as well as "encoded" mixtures of diastereomers, the stereochemical elucidation of the C31-C46 region of hemicalide is achieved. Detailed NMR spectroscopic analysis of candidate fragments and comparison with the related hemicalide data strongly supported a 31,32

The phosphoinositide 3-kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3′-hydroxyl group of inositol membrane lipids, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. This results in downstream effects, including cell growth, proliferation, and migration. The heart expresses three PI3K class I enzyme isoforms (α, β, and γ), and these enzymes play a role in cardiac cellular survival, myocardial hypertrophy, myocardial contractility, excitation, and mechanotransduction. The PI3K pathway is associated with various disease processes but is particularly important to human cancers since many gain-of-function mutations in this pathway occur in various cancers. Despite the development, testing, and regulatory approval of PI3K inhibitors in recent years, there are still significant challenges when creating and utilizing these drugs, including concerns of adverse effects on the heart. There is a growing body of evidence from preclinical studies revealing that PI3Ks play a crucial cardioprotective role, and thus inhibition of this pathway could lead to cardiac dysfunction, electrical remodeling, vascular damage, and ultimately, cardiovascular disease. This review will focus on PI3Kα, including the mechanisms underlying the adverse cardiovascular effects resulting from PI3Kα inhibition and the potential clinical implications of treating patients with these drugs, such as increased arrhythmia burden, biventricular cardiac dysfunction, and impaired recovery from cardiotoxicity. Recommendations for future directions for preclinical and clinical work are made, highlighting the possible role of PI3Kα inhibition in the progression of cancer-related cachexia and female sex and pre-existing comorbidities as independent risk factors for cardiac abnormalities after cancer treatment.