“Pure” severe aortic stenosis without concomitant valvular heart diseases:echocardiographic and pathophysiological features

Purpose!#!In echocardiography the severity of aortic stenosis (AS) is defined by effective orifice area (EOA), mean pressure gradient (mPG!##!Methods and results!#!Patients (n = 306) with asymptomatic (n = 133) and symptomatic (n = 173) 'pure' severe AS (mean age 78 ± 9.5 years) defined by indexed EOA < 0.6 cm!##!Conclusion!#!In patients with 'pure' AS according to current guidelines the presence of combined LVH, DD and PAH as accepted pathophysiological sequelae of severe AS cannot be confirmed. Probably, the detection of these secondary cardiac alterations might improve the diagnostic algorithm to avoid overestimation of AS severity

Diagnostic Line Emission from EUV and X-ray Illuminated Disks and Shocks around Low Mass stars

Extreme ultraviolet (EUV, 13.6 eV < h\nu \lta 100 eV) and X-rays in the 0.1-2 keV band can heat the surfaces of disks around young, low mass stars to thousands of degrees and ionize species with ionization potentials greater than 13.6 eV. Shocks generated by protostellar winds can also heat and ionize the same species close to the star/disk system. These processes produce diagnostic lines (e.g., [NeII] 12.8 $\mu$m and [OI] 6300 \AA) that we model as functions of key parameters such as EUV luminosity and spectral shape, X-ray luminosity and spectral shape, and wind mass loss rate and shock speed. Comparing our models with observations, we conclude that either internal shocks in the winds or X-rays incident on the disk surfaces often produce the observed [NeII] line, although there are cases where EUV may dominate. Shocks created by the oblique interaction of winds with disks are unlikely [NeII] sources because these shocks are too weak to ionize Ne. Even if [NeII] is mainly produced by X-rays or internal wind shocks, the neon observations typically place upper limits of \lta 10^{42} s$^{-1}$ on the EUV photon luminosity of these young low mass stars. The observed [OI] 6300 \AA line has both a low velocity component (LVC) and a high velocity component. The latter likely arises in internal wind shocks. For the former we find that X-rays likely produce more [OI] luminosity than either the EUV layer, the transition layer between the EUV and X-ray layer, or the shear layer where the protostellar wind shocks and entrains disk material in a radial flow across the surface of the disk. Our soft X-ray models produce [OI] LVCs with luminosities up to $10^{-4}$ L$_\odot$, but may not be able to explain the most luminous LVCs.Comment: 51 pages, 10 figures, accepted to Ap

Planetary nebulae in M33: probes of AGB nucleosynthesis and ISM abundances

We have obtained deep optical spectrophotometry of 16 planetary nebulae in M33, mostly located in the central two kpc of the galaxy, with the Subaru and Keck telescopes. We have derived electron temperatures and chemical abundances from the detection of the [OIII]4363 line for the whole sample. We have found one object with an extreme nitrogen abundance, 12+log(N/H)=9.20, accompanied by a large helium content. After combining our data with those available in the literature for PNe and HII regions, we have examined the behavior of nitrogen, neon, oxygen and argon in relation to each other, and as a function of galactocentric distance. We confirm the good correlation between Ne/H and O/H for PNe in M33. Ar/H is also found to correlate with O/H. This strengthens the idea that at the metallicity of the bright PNe analyzed in M33, which is similar to that found in the LMC, these elements have not been significantly modified during the dredge-up processes that take place during the AGB phase of their progenitor stars. We find no significant oxygen abundance offset between PNe and HII regions at any given galactocentric distance, despite the fact that these objects represent different age groups in the evolution of the galaxy. Combining the results from PNe and HII regions, we obtain a representative slope of the ISM alpha-element (O, Ar, Ne) abundance gradient in M33 of -0.025 +/- 0.006 dex/kpc. Both PNe and HII regions display a large abundance dispersion at any given distance from the galactic center. We find that the N/O ratio in PNe is enhanced, relative to the HII regions, by approximately 0.8 dex.Comment: 21 pages, 20 figures. Accepted for publication in MNRA

Direct and indirect effect of the COVID-19 pandemic on patients with cardiomyopathy

Objectives: (i) To evaluate the prevalence and hospitalisation rate of COVID-19 infections amongst patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) in the Royal Brompton & Harefield Hospital Cardiovascular Research Centre (RBHH CRC) Biobank. (ii) To evaluate the indirect impact of the pandemic on patients with cardiomyopathy through the Heart Hive COVID-19 study. (iii) To assess the impact of the pandemic on national cardiomyopathy-related hospital admissions. Methods: (i) 1,236 patients (703 DCM, 533 HCM) in the RBHH CRC Biobank were assessed for COVID-19 infections and hospitalisations; ii) 207 subjects (131 cardiomyopathy, 76 without heart disease) in the Heart Hive COVID-19 study completed online surveys evaluating physical health, psychological wellbeing, and behavioural adaptations during the pandemic; (iii) 11,447 cardiomyopathy-related hospital admissions across NHS England were studied from NHS Digital Hospital Episode Statistics over 2019-2020. Results: A comparable proportion of patients with cardiomyopathy in the RBHH CRC Biobank had tested positive for COVID-19 compared with the UK population (1.1% vs 1.6%, p=0.14), but a higher proportion of those infected were hospitalised (53.8% vs 16.5%, p=0.002). In the Heart Hive COVID-19 study, more patients with cardiomyopathy felt their physical health had deteriorated due to the pandemic than subjects without heart disease (32.3% vs 13.2%, p=0.004) despite only 4.6% of the cardiomyopathy cohort reporting COVID-19 symptoms. A 17.9% year-on-year reduction in national cardiomyopathy-related hospital admissions was observed in 2020. Conclusion: Patients with cardiomyopathy had similar reported rates of testing positive for COVID-19 to the background population, but those with test-proven infection were hospitalised more frequently. Deterioration in physical health amongst patients could not be explained by COVID-19 symptoms, inferring a significant contribution of the indirect consequences of the pandemic

Urinary drug metabolite testing in chronic heart failure patients indicates high levels of adherence with life-prolonging therapies

Aims Despite medical therapy for heart failure (HF) having proven benefits of improving quality of life and survival, many patients remain under-treated. This may be due to a combination of under-prescription by medical professionals and poor adherence from patients. In HF, as with many other chronic diseases, adherence to medication can deteriorate over time particularly when symptoms are well controlled. Therefore, detecting and addressing non-adherence has a crucial role in the management of HF. Significant flaws and inaccuracies exist in the methods currently used to assess adherence such as patient reporting, pill counts, and pharmacy fill records. We aim to use high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS) to detect metabolites of HF medications in the urine samples of chronic HF patients. Methods and results Urine samples were collected from 35 patients in a specialist HF clinic. Patients were included if they had an ejection fraction <45% and were taking at least two disease-modifying HF medications. They were excluded if they had been admitted to hospital for HF in the 3 months preceding clinic attendance. These samples were sent for HPLC-MS and tested for all HF medications prescribed for that patient. A high rate of complete adherence of 89% was detected in these patients, with 94% being partially adherent (at least one HF medication detected) to therapy (at least one HF medication detected). This analysis also highlighted that mineralocorticoid antagonists represent both the most under-prescribed (67%) and poorly adhered (75%) medication class. Conclusions This analysis revealed a surprisingly high level of adherence to disease-modifying therapy in chronic HF patients and highlights that most of our ‘total’ under-treatment is likely to be from a failure to prescribe rather than a failure to adhere. Testing for metabolites of disease-modifying HF drugs in urine using HPLC-MS is feasible and is a useful adjunct to a specialist HF service. At present, the distinction between treatment failure and failure to take treatment is not always clear, which is important because the investigation and potential solutions are different. The former needs initiation of additional therapies and consideration of additional diagnoses, whereas the latter requires strategies to understand reasons underlying poor adherence and collaborative working to improve this: the wrong strategy will be ineffective

The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of aetiology in dilated cardiomyopathy

Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology. Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step. Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68). Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy

Objective The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. Methods Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrollment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. Results DCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared to patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group– n =92, 94% vs n =306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in mid-wall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 0.73 to 2.26, p=0.38) during median follow up of 3.9 years. Conclusion Dilated cardiomyopathy patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with dilated cardiomyopathy

CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation

Purpose Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (http://www.cardioclassifier.org), a semiautomated decision-support tool for inherited cardiac conditions (ICCs). Methods CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. Results We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher’s P = 1.1  ×  10−18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. Conclusion CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines

Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction

Background—Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD. Methods—We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation. Results—Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (95% CI 1.3-18.9) and 11.8 (95% CI 4.3-32.3) respectively. Conclusions—Mid-wall LGE identifies a group of patients with DCM and LVEF≥40% at increased risk of SCD and low-risk of non-sudden death who may benefit from ICD implantation

Phenotype, outcomes and natural history of early-stage non-ischaemic cardiomyopathy

Aims To characterize the phenotype, clinical outcomes and rate of disease progression in patients with early-stage non-ischaemic cardiomyopathy (early-NICM). Methods and results We conducted a prospective observational cohort study of patients with early-NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early-NICM H−/D+), non-dilated left ventricular cardiomyopathy (early-NICM H+/D−), or early dilated cardiomyopathy (early-NICM H+/D+). Clinical follow-up for major adverse cardiovascular events (MACE) included non-fatal life-threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early-NICM (median age 46 years [interquartile range 36–58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52–59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early-NICM H−/D+, higher in early-NICM H+/D− and highest in early-NICM H+/D+ (p = 0.03). Over a median follow-up of 7.9 (5.5–10.0) years, 28 patients (11%) experienced MACE. Non-sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36–11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73–8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73–15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early-NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11–34) months. Conclusion Early-NICM is not benign. Fibrosis develops early in the phenotypic course. In-depth characterization enhances risk stratification and might aid clinical management