Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer.

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin. METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy. RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013). CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Characterization of the Myocardial Inflammatory Response in Acute Stress-Induced (Takotsubo) Cardiomyopathy.

Takotsubo cardiomyopathy is an acute stress-induced heart failure syndrome for which the exact pathogenic mechanisms are unclear, and consequently, no specific treatment exists. In an experimental model of stress-induced takotsubo-like cardiomyopathy, the authors describe the temporal course of a chronic inflammatory response post-induction, with an initial early influx of neutrophils into myocardial tissue followed by macrophages that are typical of a proinflammatory M1 phenotype, and a nonsignificant increase in systemic inflammatory cytokines. Post-mortem myocardium from the more complex clinical takotsubo patients share features of the study's experimental model. These findings suggest modulators of inflammation could be a potential therapeutic option.

Dental occlusion and temporomandibular disorders.

Data sourcesMedline, Scopus and Google Scholar.Study selectionTwo reviewers selected studies independently. English language clinical studies assessing the association between temporomandibular disorders (TMD) and features of dental occlusion were considered.Data extraction and synthesisStudy quality was assessed based on the Newcastle-Ottawa Scale (NOS) and a narrative synthesis was presented.ResultsIn all 25 studies (17 case-control, eight comparative) were included. Overall there was a high variability between occlusal features and TMD diagnosis. Findings were consistent with a lack of clinically relevant association between TMD and dental occlusion. Only two studies were associated with TMD in the majority (≥50%) of single variable analyses in patient populations. Only mediotrusive interferences are associated with TMD in the majority of multiple variable analyses.ConclusionsThe findings support the absence of a disease-specific association, there is no ground to hypothesise a major role for dental occlusion in the pathophysiology of TMDs. Dental clinicians are thus encouraged to move forward and abandon the old-fashioned gnathological paradig.

Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST segment elevation myocardial infarction (FAMOUS-NSTEMI) developmental trial: cost-effectiveness using a mixed trial- and model-based methods.

BACKGROUND: In the Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST elevation myocardial infarction (FAMOUS) clinical trial, FFR was shown to significantly reduce coronary revascularisation, compared to visual interpretation of standard coronary angiography without FFR. We estimated the cost-effectiveness from a UK National Health Service perspective, based on the results of FAMOUS. METHODS: A mixed trial- and model-based approach using decision and statistical modelling was used. Within-trial (1-year) costs and QALYs were assembled at the individual level and then modelled on subsequent management strategy [coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or medical therapy (MT)] and major adverse coronary events (death, MI, stroke and revascularisation). One-year resource uses included: material, hospitalisation, medical, health professional service use and events. Utilities were derived from individual EQ5D responses. Unit costs were derived from the literature. Outcomes were extended to a lifetime on the basis of MACE during the 1st year. Costs and QALYs were modelled using generalized linear models whilst MACE was modelled using logistic regression. The analysis adopted a payer perspective. Costs and outcomes were discounted at 3.5 %. RESULTS: Costs were related to the subsequent management strategy and MACE whilst QALYs were not. FFR led to a modest cost increase, albeit an imprecise increase, over both the trial [£112 (-£129 to £357)] and lifetime horizons [£133 (-£199 to £499)]. FFR led to a small, albeit imprecise, increase in QALYs over both the trial [0.02 (-0.03 to 0.06)] and lifetime horizons [0.03 (-0.21 to 0.28)]. The mean ICER was £7516/QALY and £4290/QALY over the trial and lifetime horizons, respectively. Decision remained high; FFR had 64 and 59 % probability of cost-effectiveness over trial and lifetime horizons, respectively. CONCLUSIONS: FFR was cost-effective at the mean, albeit with considerable decision uncertainty. Uncertainty can be reduced with more information on long-term health events.

Right ventricular septal pacing as alternative for failed left ventricular lead implantation in cardiac resynchronization therapy candidates.

AIMS: To compare the effects on left ventricular (LV) function of right ventricular (RV) septal pacing vs. cardiac resynchronization therapy (CRT) in patients with an indication for the latter. Cardiac resynchronization therapy is an effective therapy in patients with drug-refractory heart failure. Despite advances in implantation techniques, LV lead placement can be impossible in up to 10% of cases. We, therefore, assessed the effects of RV septal pacing from mid septum (RVmIVS) and outflow tract (RVOT) on cardiac performance, in comparison with CRT. METHODS AND RESULTS: Twenty-two patients scheduled for CRT underwent dual-chamber temporary pacing. The ventricular lead was placed at the RV apex (RVA), RVmIVS, and RVOT in random order. Comprehensive echocardiography was performed in a baseline AAI mode and then at each RV position in dual chamber pacemaker function (D pacing, D sensing, D dual responses) mode and repeated on the next day following CRT implantation. Right ventricular apex pacing did not change any of the assessed echocardiography parameters. Both RVmIVS and RVOT pacing increased LV ejection fraction (EF): 29 ± 7% at baseline vs. 32 ± 6% (P = 0.02) and 32 ± 5% (P = 0.04) with RVmIVS and RVOT pacing, respectively. Similarly, the dyssynchrony index (Ts-SD) decreased: 50 ± 19 ms at baseline vs. 39 ± 17 ms (P = 0.04) and 37 ± 17 ms (P = 0.006) with RVmIVS and RVOT pacing, respectively. Cardiac resynchronization therapy further improved LVEF and Ts-SD to 36 ± 7% and 34 ± 15 ms, respectively, however, only LVEF was significantly higher compared with RVmIVS and RVOT pacing (P = 0.03 and P = 0.01 respectively). There were no significant differences in either LVEF or Ts-SD between RVmIVS and RVOT. CONCLUSION: Right ventricular septal pacing from mid septum or RVOT pacing improves LVEF and LV synchrony in CRT candidates. Further improvement in LVEF was achieved by CRT, which remains the 'gold standard' therapy in these patients. However, RV septal pacing is worthy of further study as an alternative strategy when LV lead implantation fails.

A novel technique for accurate Poller (blocking) screw placement.

Achieving good results with intramedullary nailing of oblique long bone fractures at the metaphyseal-diaphyseal junction can be difficult. There is a strong tendency for axial displacement and an association with characteristic malalignment of the short fragment. Poller or blocking screws have been shown to be effective in aiding fracture reduction. While several papers describe methods for screw placement, these are confusing to understand, difficult to follow in clinical practice and not always applicable. Here we describe a new, simple, reproducible and easy to use method for ensuring accurate Poller screw placement, in order to maximise the benefits of their use and achieve good overall results.

Comparison of sample types for N-terminal pro-B-type natriuretic peptide measured on the Siemens Immulite 2500 and Dimension Vista LOCI methods.

BACKGROUND: Measurement of serum natriuretic peptides is recommended in patients with suspected heart failure. Assays for N-terminal pro-B-type natriuretic peptide (NT-proBNP) are available on several platforms and can be measured in serum or heparinized plasma. Siemens Healthcare Diagnostics do not recommend the use of serum for the Immulite NT-proBNP assay. Serum offers some practical advantages over plasma. We investigated the suitability of serum for use with the Immulite and Dimension Vista LOCI methods. METHODS: Paired serum and heparinized plasma samples were drawn from patients in the Cardiology Department over a 48-h period. Samples spanning the NT-proBNP concentration range 50-60,000 ng/L were analysed using the Siemens Immulite 2500 and Dimension Vista LOCI methods. RESULTS: There was no significant difference between serum NT-proBNP concentrations on either platform (P = 0.0665). Plasma NT-proBNP measured using the Immulite were moderately higher than on Vista (P < 0.0001). There was a small but statistically significant difference between plasma and serum NT-proBNP measured using the Immulite (P = 0.0002) with plasma values higher than serum. A similar comparison between plasma and serum NT-proBNP measured using the Vista showed no difference (P = 0.3662). CONCLUSIONS: We have demonstrated the suitability of serum for use on the Immulite 2500. Bland-Altman comparative analysis indicated minimal bias between both serum methods near the clinical cut-off level below which heart failure is considered unlikely (400 ng/L) up to the highest concentration tested (60,000 ng/L).

Impact of temporary right ventricular pacing from different sites on echocardiographic indices of cardiac function.

AIMS: To assess the impact of pacing from different right ventricular (RV) pacing sites on left ventricular (LV) function. Chronic apical RV pacing may induce heart failure. To reduce this RV, mid-septum and outflow tract are suggested as alternative pacing sites. We therefore assessed cardiac performance during temporary RV pacing from apical vs. mid-septum or outflow tract sites, using echocardiography and electrocardiography. METHODS AND RESULTS: Patients scheduled for a permanent pacemaker underwent temporary pacing in dual-chamber mode (DDD) and with atrio-ventricular delay optimized. The ventricular lead was moved to either the RV apex, mid-septum or outflow tract. Comprehensive echocardiography was performed in each position. Twenty-two patients completed the study. The baseline data was collected at atrial pacing mode (AAI). QRS duration lengthened with RV apical pacing (97 ± 22 ms AAI vs. 154 ± 18 ms RV apical, P < 0.001) and shortened with mid-septum or outflow tract pacing (147 ± 14 ms RV mid-septum and 136 ± 16 ms RV outflow tract, P = 0.001 and P < 0.001, respectively, vs. RV apical). Right ventricular apical pacing was associated with reductions in stroke volume and LV ejection fraction (54 ± 6% AAI vs. 48 ± 5% RV apical, P = 0.001). Right ventricular mid-septum (52 ± 5%) and outflow tract (54 ± 6%) pacing improved LV ejection fraction in comparison with apical pacing (P < 0.01 for both). Pacing at all sites induced dyssynchrony. In comparison with RV apical pacing dyssynchrony was reduced by mid-septum or outflow tract pacing. CONCLUSIONS: Right ventricular pacing at the mid-septum or outflow tract results in narrower QRS complexes, less dyssynchrony, and better LV systolic function than RV apical pacing.

Evolution of allometry in antirrhinum.

Correlated variation in shape and size (allometry) is a major component of natural diversity. We examined the evolutionary and genetic basis for allometry using leaves and flower petals of snapdragon species (Antirrhinum). A computational method was developed to capture shape and size variation in both types of organ within the Antirrhinum species group. The results show that the major component of variation between species involves positively correlated changes in leaf and petal size. The correlation was maintained in an F2 population derived from crossing two species with organs of different sizes, suggesting that developmental constraints were involved. Identification of the underlying genes as quantitative trait loci revealed that the larger species carried alleles that increased organ size at all loci. Although this was initially taken as evidence that directional selection has driven diversity in both leaf and petal size, simulations revealed that evolution without consistent directional selection, an undirected walk, could also account for the parental distribution of organ size alleles.

Food-the way to a man's heart: a mini-case series of Campylobacter perimyocarditis.

Campylobacter jejuni enteritis is 1 of the most common causes of food poisoning. Although an infrequent complication, Campylobacter associated perimyocarditis can have fatal consequences. This article illustrates 2 cases. We examine the types of Campylobacter jejuni responsible and report the observed male preponderance of this complication.