Pulmonary artery wave intensity analysis in pulmonary hypertension associated with heart failure and reduced left ventricular ejection fraction

Wave intensity analysis (WIA) uses simultaneous changes in pressure and flow velocity to determine wave energy, type, and timing of traveling waves in the circulation. In this study, we characterized wave propagation in the pulmonary artery in patients with pulmonary hypertension associated with left‐sided heart disease (PHLHD) and the effects of dobutamine. During right heart catheterization, pressure and velocity data were acquired using a dual‐tipped pressure and Doppler flow sensor wire (Combowire; Phillips Volcano), and processed offline using customized Matlab software (MathWorks). Patients with low cardiac output underwent dobutamine challenge. Twenty patients with PHLHD (all heart failure with reduced left ventricular ejection fraction) were studied. Right ventricular systole produced a forward compression wave (FCW), followed by a forward decompression wave (FDW) during diastole. Wave reflection manifesting as backward compression wave (BCW) following the FCW was observed in 14 patients. Compared to patients without BCW, patients with BCW had higher mean pulmonary artery pressure (28.7 ± 6.12 vs. 38.6 ± 6.5 mmHg, p = 0.005), and lower pulmonary arterial capacitance (PAC: 2.88 ± 1.75 vs. 1.73 ± 1.16, p = 0.002). Pulmonary vascular resistance was comparable. Mean pulmonary artery pressure of 34.5 mmHg (area under the curve [AUC]: 0.881) and PAC of 2.29 mL/mmHg (AUC: 0.833) predicted BCW. The magnitude of the FCW increased with dobutamine (n = 11) and correlated with pulmonary artery wedge pressure. Wave reflection in PHLHD is more likely at higher pulmonary artery pressures and lower PAC and the magnitude of reflected waves correlated with pulmonary artery wedge pressure. Dobutamine increased FCW but did not affect wave reflection

Maternal mental health:a key area for future research among women with congenital heart disease

In this viewpoint, we respond to the recently published national priorities for research in congenital heart disease (CHD) among adults, established through the James Lind Alliance Priority Setting Partnership, with specific attention to priority 3 (mental health) and priority 5 (maternal health). Our recent policy impact project explored how maternal mental health is currently addressed in adult congenital heart disease (ACHD) services in the National Health Service, identified gaps and discussed possible ways forward. Our multidisciplinary discussion groups, which included women with lived experience of CHD and pregnancy, cardiology and obstetrics clinicians and medical anthropologists, found that while pregnancy and the postnatal period increase the mental health challenges faced by women with CHD, current services are not yet equipped to address them. Based on this work, we welcome the prioritisation of both mental health and maternal health in ACHD, and suggest that future research should focus on the overlaps between these two priority areas

Acute leukaemoid reaction following cardiac surgery

Chronic myelomonocytic leukaemia is an atypical myeloproliferative disorder with a natural history of progression to acute myeloid leukaemia, a complex and poorly understood response by the bone marrow to stress. Cardiac surgery activates many inflammatory cascades and may precipitate a systemic inflammatory response syndrome. We present a case of undiagnosed chronic myelomonocytic leukaemia who developed rapidly fatal multi-organ dysfunction following cardiac surgery due to an acute leukaemoid reaction

Stereoselective handling of perhexiline:Implications regarding accumulation within the human myocardium

Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. Method: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. Results: Myocardial uptake of both (+) and (−) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (−) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (−) perhexiline were the plasma concentrations [(+) perhexiline: β = −0.256, p = 0.015; (−) perhexiline: β = −0.347, p = 0.001] and patients’ age [(+) perhexiline: β = 0.300, p = 0.004; (−) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (−) perhexiline varied inversely with simultaneous heart rate (β = −0.240, p = 0.015). Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (−) perhexiline may selectively modulate heart rate reduction

Bilateral Remote Ischemic Conditioning in Children:a two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis.Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants.Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 μg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 μg/L/h, n = 58) (mean difference, 13.2 μg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups.Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies