Publications by authors named "Bernhard Gerber"

183 Publications

Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma.

Blood 2021 Oct 15. Epub 2021 Oct 15.

University of Milan & Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor meta-data and in genetically modified mouse models, and determined correlations with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcome, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
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http://dx.doi.org/10.1182/blood.2021012386DOI Listing
October 2021

Prevalence and risk factors for venous thromboembolic events in critically ill patients with SARS-CoV-2 infection: a prospective observational study.

Minerva Anestesiol 2021 Oct 11. Epub 2021 Oct 11.

Department of Intensive Care Medicine of the Ente Ospedaliero Cantonale, Bellinzona, Switzerland.

Background: The majority of prevalence studies on deep vein thrombosis (DVT) in severe COVID-19 patients are retrospective with DVT assessment based on clinical suspicion. Our aim was to prospectively and systematically estimate the occurrence of DVT in critically ill mechanically ventilated patients, and to identify potential risk factors for DVT occurrence and mortality.

Methods: All patients with COVID-19 admitted to our 45-beds intensive care unit (ICU) between March 6, 2020 and April 18, 2020 requiring invasive ventilatory support were daily screened for DVT with lower extremities and jugular veins ultrasonography. Univariate and multivariable logistic regression models were performed in order to identify predictors of DVT and mortality.

Results: Seventy-six patients were included in the final analysis (56 men, mean age 67 years, median SOFA 7 points, median SAPS II 41 points, median PaO2/Fi02 10.8 kPa). The period prevalence of DVT was 40.8%. Thirty-one DVTs were diagnosed. Twenty-five DVTs (80.6% of total DVTs) were catheter-related, mainly in the jugular veins. Twentysix DVTs (83.9%) occurred in patients receiving enhanced antithrombotic prophylaxis. No independent variable was predictive of DVT occurrence. Twenty-eight patients (36.8%) died during the ICU stay. Age and SOFA score were independently associated with mortality.

Conclusions: A high number of critically ill mechanically ventilated COVID-19 patients developed a DVT. The majority of DVTs were catheter-related and occurred under intensive prophylactic anticoagulation. Routine ultrasound of the jugular veins should be suggested in this patient population, and in particular in presence of a central venous catheter.
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http://dx.doi.org/10.23736/S0375-9393.21.15510-5DOI Listing
October 2021

Automated Thrombin Generation Assay for Rivaroxaban, Apixaban, and Edoxaban Measurements.

Front Cardiovasc Med 2021 9;8:717939. Epub 2021 Sep 9.

Department of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.

The thrombin generation assay (TG) is a promising approach to measure the degree of anticoagulation in patients treated with direct oral anticoagulants (DOAC). A strong association with plasma drug concentrations would be a meaningful argument for the potential use to monitor DOAC. We aimed to study the correlation of TG with rivaroxaban, apixaban, and edoxaban drug concentrations in a large, prospective multicenter cross-sectional study. Five-hundred and fifty-nine patients were included in nine tertiary hospitals. The Technothrombin® TG was conducted in addition to an anti-Xa assay; LC-MS/MS was performed as the reference standard. Correlation (r) between thrombin generation measurements and drug concentrations was -0.72 for peak thrombin generation (95% confidence interval, CI, -0.77, -0.66), -0.55 for area under the curve (AUC; 95% CI -0.61, -0.48), and 0.80 for lag time (95% CI 0.75, 0.84). In contrast, r was 0.96 with results of the anti-Xa activity (95% CI 0.95-0.97). Sensitivity with regard to the clinically relevant cut-off value of 50 μgL was 49% in case of peak thrombin generation (95% CI, 44, 55), 29% in case of AUC (95% CI, 24, 34), and 64% in case of lag time (95% CI, 58, 69). Sensitivity of the anti-Xa assay was 95% (95% CI, 92, 97). The correlation of thrombin generation measurements with DOAC drug concentrations was weak, and clinically relevant drug levels were not predicted correctly. Our results do not support an application of TG in the monitoring of DOAC.
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http://dx.doi.org/10.3389/fcvm.2021.717939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459937PMC
September 2021

Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab.

Blood Adv 2021 Sep 9. Epub 2021 Sep 9.

Laboratory of Experimental Hematology, Institute of Oncology Research; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland.

To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Utilizing the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib plus nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3 day 1. Overall, 172 ctDNA samples from 67 patients were analyzed using LyV4.0 ctDNA CAncer Personalized Profiling by deep Sequencing assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved by 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired C481S BTK mutations implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.
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http://dx.doi.org/10.1182/bloodadvances.2021004528DOI Listing
September 2021

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

J Am Coll Cardiol 2021 Aug;78(6):545-558

Department of Radiology and Nuclear Medicine, German Heart Center Munich, Munich, Germany.

Background: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined.

Objectives: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality.

Methods: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome.

Results: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m) and small (LVEDVi ≤55 mL/m) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort.

Conclusions: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.
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http://dx.doi.org/10.1016/j.jacc.2021.05.047DOI Listing
August 2021

Multimodality imaging of myocardial viability: an expert consensus document from the European Association of Cardiovascular Imaging (EACVI).

Eur Heart J Cardiovasc Imaging 2021 07;22(8):e97-e125

Department of Biomedical Imaging Science, Leeds, Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Clarendon Way, Leeds LS2 9JT, United Kingdom.

In clinical decision making, myocardial viability is defined as myocardium in acute or chronic coronary artery disease and other conditions with contractile dysfunction but maintained metabolic and electrical function, having the potential to improve dysfunction upon revascularization or other therapy. Several pathophysiological conditions may coexist to explain this phenomenon. Cardiac imaging may allow identification of myocardial viability through different principles, with the purpose of prediction of therapeutic response and selection for treatment. This expert consensus document reviews current insight into the underlying pathophysiology and available methods for assessing viability. In particular the document reviews contemporary viability imaging techniques, including stress echocardiography, single photon emission computed tomography, positron emission tomography, cardiovascular magnetic resonance, and computed tomography and provides clinical recommendations for how to standardize these methods in terms of acquisition and interpretation. Finally, it presents clinical scenarios where viability assessment is clinically useful.
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http://dx.doi.org/10.1093/ehjci/jeab053DOI Listing
July 2021

Diagnostic and Prognostic Accuracy of Aortic Valve Calcium Scoring in Patients With Moderate-to-Severe Aortic Stenosis.

Front Cardiovasc Med 2021 17;8:673519. Epub 2021 May 17.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.

Assessing the true severity of aortic stenosis (AS) remains a challenge, particularly when echocardiography yields discordant results. Recent European and American guidelines recommend measuring aortic valve calcium (AVC) by multidetector row computed tomography (MDCT) to improve this assessment. To define, using a standardized MDCT scanning protocol, the optimal AVC load criteria for truly severe AS in patients with concordant echocardiographic findings, to establish the ability of these criteria to predict clinical outcomes, and to investigate their ability to delineate truly severe AS in patients with discordant echocardiographic AS grading. Two hundred and sixty-six patients with moderate-to-severe AS and normal LVEF prospectively underwent MDCT and Doppler-echocardiography to assess AS severity. In patients with concordant AS grading, ROC analysis identified optimal cut-off values for diagnosing severe AS using different AVC load criteria. In these patients, 4-year event-free survival was better with low AVC load (60-63%) by these criteria than with high AVC load (23-26%, log rank < 0.001). Patients with discordant AS grading had higher AVC load than those with moderate AS but lower AVC load than those with severe high-gradient AS. Between 36 and 55% of patients with severe LG-AS met AVC load criteria for severe AS. Although AVC load predicted outcome in these patients as well, its prognostic impact was less than in patients with concordant AS grading. Assessment of AVC load accurately identifies truly severe AS and provides powerful prognostic information. Our data further indicate that patients with discordant AS grading consist in a heterogenous group, as evidenced by their large range of AVC load. MDCT allows to differentiate between truly severe and pseudo-severe AS in this population as well, although the prognostic implications thereof are less pronounced than in patients with concordant AS grading.
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http://dx.doi.org/10.3389/fcvm.2021.673519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165166PMC
May 2021

Multivendor comparison of global and regional 2D cardiovascular magnetic resonance feature tracking strains vs tissue tagging at 3T.

J Cardiovasc Magn Reson 2021 05 13;23(1):54. Epub 2021 May 13.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc UCL, Av Hippocrate 10/2806, 1200, Woluwe St. Lambert, Belgium.

Background: Cardiovascular magnetic resonance (CMR) 2D feature tracking (FT) left ventricular (LV) myocardial strain has seen widespread use to characterize myocardial deformation. Yet, validation of CMR FT measurements remains scarce, particularly for regional strain. Therefore, we aimed to perform intervendor comparison of 3 different FT software against tagging.

Methods: In 61 subjects (18 healthy subjects, 18 patients with chronic myocardial infarction, 15 with dilated cardiomyopathy, and 10 with LV hypertrophy due to hypertrophic cardiomyopathy or aortic stenosis) were prospectively compared global (G) and regional transmural peak-systolic Lagrangian longitudinal (LS), circumferential (CS) and radial strains (RS) by 3 FT software (cvi42, Segment, and Tomtec) among each other and with tagging at 3T. We also evaluated the ability of regional LS, CS, and RS by different FT software vs tagging to identify late gadolinium enhancement (LGE) in the 18 infarct patients.

Results: GLS and GCS by all 3 software had an excellent agreement among each other (ICC = 0.94-0.98 for GLS and ICC = 0.96-0.98 for GCS respectively) and against tagging (ICC = 0.92-0.94 for GLS and ICC = 0.88-0.91 for GCS respectively), while GRS showed inconsistent agreement between vendors (ICC 0.10-0.81). For regional LS, the agreement was good (ICC = 0.68) between 2 vendors but less vs the 3 (ICC 0.50-0.59) and moderate to poor (ICC 0.44-0.47) between all three FT software and tagging. Also, for regional CS agreement between 2 software was higher (ICC = 0.80) than against the 3rd (ICC = 0.58-0.60), and both better agreed with tagging (ICC = 0.70-0.72) than the 3rd (ICC = 0.57). Regional RS had more variation in the agreement between methods ranging from good (ICC = 0.75) to poor (ICC = 0.05). Finally, the accuracy of scar detection by regional strains differed among the 3 FT software. While the accuracy of regional LS was similar, CS by one software was less accurate (AUC 0.68) than tagging (AUC 0.80, p < 0.006) and RS less accurate (AUC 0.578) than the other two (AUC 0.76 and 0.73, p < 0.02) to discriminate segments with LGE.

Conclusions: We confirm good agreement of CMR FT and little intervendor difference for GLS and GCS evaluation, with variable agreement for GRS. For regional strain evaluation, intervendor difference was larger, especially for RS, and the diagnostic performance varied more substantially among different vendors for regional strain analysis.
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http://dx.doi.org/10.1186/s12968-021-00742-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117295PMC
May 2021

A universal anti-Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation.

Br J Haematol 2021 06 6;193(6):1203-1212. Epub 2021 May 6.

Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

A universal anti-Xa assay for the determination of rivaroxaban, apixaban and edoxaban drug concentrations would simplify laboratory procedures and facilitate widespread implementation. Following two pilot studies analysing spiked samples and material from 698 patients, we conducted a prospective multicentre cross-sectional study, including 867 patients treated with rivaroxaban, apixaban or edoxaban in clinical practice to comprehensively evaluate a simple, readily available anti-Xa assay that would accurately measure drug concentrations and correctly predict relevant levels in clinical practice. Anti-Xa activity was measured by an assay calibrated with low-molecular-weight heparin (LMWH) in addition to ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). As an external validation, LMWH-calibrated anti-Xa activity was also determined in nine external laboratories. The LMWH-calibrated anti-Xa activity correlated strongly with rivaroxaban, apixaban or edoxaban drug levels [r  = 0·98, 95% confidence interval (CI) 0·98-0·98]. The sensitivity for the clinically relevant cut-off levels of 30, 50 and 100 µg/l was 96·2% (95% CI 94·4-97·4), 96·4% (95% CI 94·4-97·7) and 96·7% (95% CI 94·3-98·1) respectively. Concordant results were obtained in the external validation study. In conclusion, a universal, LMWH-calibrated anti-Xa assay accurately measured rivaroxaban, apixaban and edoxaban concentrations and correctly predicted relevant drug concentrations in clinical practice.
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http://dx.doi.org/10.1111/bjh.17470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252105PMC
June 2021

Thrombotic storm under DOAC treatment in a patient with homozygous antithrombin Budapest III mutation.

Thromb Res 2021 05 9;201:161-163. Epub 2021 Apr 9.

Clinic of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.

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http://dx.doi.org/10.1016/j.thromres.2021.04.002DOI Listing
May 2021

Diagnosis and risk stratification in hypertrophic cardiomyopathy using machine learning wall thickness measurement: a comparison with human test-retest performance.

Lancet Digit Health 2021 01 3;3(1):e20-e28. Epub 2020 Dec 3.

Cardiac Imaging Department, Barts Heart Centre, St Bartholomew's Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK. Electronic address:

Background: Left ventricular maximum wall thickness (MWT) is central to diagnosis and risk stratification of hypertrophic cardiomyopathy, but human measurement is prone to variability. We developed an automated machine learning algorithm for MWT measurement and compared precision (reproducibility) with that of 11 international experts, using a dataset of patients with hypertrophic cardiomyopathy.

Methods: 60 adult patients with hypertrophic cardiomyopathy, including those carrying hypertrophic cardiomyopathy gene mutations, were recruited at three institutes in the UK from August, 2018, to September, 2019: Barts Heart Centre, University College London Hospital (The Heart Hospital), and Leeds Teaching Hospitals NHS Trust. Participants had two cardiovascular magnetic resonance scans (test and retest) on the same day, ensuring no biological variability, using four cardiac MRI scanner models represented across two manufacturers and two field strengths. End-diastolic short-axis MWT was measured in test and retest by 11 international experts (from nine centres in six countries) and an automated machine learning method, which was trained to segment endocardial and epicardial contours on an independent, multicentre, multidisease dataset of 1923 patients. Machine learning MWT measurement was done with a method based on solving Laplace's equation. To assess test-retest reproducibility, we estimated the absolute test-retest MWT difference (precision), the coefficient of variation (CoV) for duplicate measurements, and the number of patients reclassified between test and retest according to different thresholds (MWT >15 mm and >30 mm). We calculated the sample size required to detect a prespecified MWT change between pairs of scans for machine learning and each expert.

Findings: 1440 MWT measurements were analysed, corresponding to two scans from 60 participants by 12 observers (11 experts and machine learning). Experts differed in the MWT they measured, ranging from 14·9 mm (SD 4·2) to 19·0 mm (4·7; p<0·0001 for trend). Machine learning-measured mean MWT was 16·8 mm (4·1). Machine learning precision was superior, with a test-retest difference of 0·7 mm (0·6) compared with experts, who ranged from 1·1 mm (0·9) to 3·7 mm (2·0; p values for machine learning vs expert comparison ranging from <0·0001 to 0·0073) and a significantly lower CoV than for all experts (4·3% [95% CI 3·3-5·1] vs 5·7-12·1% across experts). On average, 38 (64%) patients were designated as having MWT greater than 15 mm by machine learning compared with 27 (45%) to 50 (83%) patients by experts; five (8%) patients were reclassified in test-retest by machine learning compared with four (7%) to 12 (20%) by experts. With a cutoff point of more than 30 mm for implantable cardioverter-defibrillator, three experts would have changed recommendations between tests a total of four times, but machine learning was consistent. Using machine learning, a clinical trial to detect a 2 mm MWT change would need 2·3 times (range 1·6-4·6) fewer patients.

Interpretation: In this preliminary study, machine learning MWT measurement in hypertrophic cardiomyopathy is superior to human experts with potential implications for diagnosis, risk stratification, and clinical trials.

Funding: European Regional Development Fund and Barts Charity.
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http://dx.doi.org/10.1016/S2589-7500(20)30267-3DOI Listing
January 2021

EACVI recommendations on cardiovascular imaging for the detection of embolic sources: endorsed by the Canadian Society of Echocardiography.

Eur Heart J Cardiovasc Imaging 2021 05;22(6):e24-e57

Cardiology Department, University of Medicine and Pharmacy 'Carol Davila', Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C. C. Iliescu', Sos. Fundeni 258, sector 2, 022328 Bucharest, Romania.

Cardioaortic embolism to the brain accounts for approximately 15-30% of ischaemic strokes and is often referred to as 'cardioembolic stroke'. One-quarter of patients have more than one cardiac source of embolism and 15% have significant cerebrovascular atherosclerosis. After a careful work-up, up to 30% of ischaemic strokes remain 'cryptogenic', recently redefined as 'embolic strokes of undetermined source'. The diagnosis of cardioembolic stroke remains difficult because a potential cardiac source of embolism does not establish the stroke mechanism. The role of cardiac imaging-transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE), cardiac computed tomography (CT), and magnetic resonance imaging (MRI)-in the diagnosis of potential cardiac sources of embolism, and for therapeutic guidance, is reviewed in these recommendations. Contrast TTE/TOE is highly accurate for detecting left atrial appendage thrombosis in patients with atrial fibrillation, valvular and prosthesis vegetations and thrombosis, aortic arch atheroma, patent foramen ovale, atrial septal defect, and intracardiac tumours. Both CT and MRI are highly accurate for detecting cavity thrombosis, intracardiac tumours, and valvular prosthesis thrombosis. Thus, CT and cardiac magnetic resonance should be considered in addition to TTE and TOE in the detection of a cardiac source of embolism. We propose a diagnostic algorithm where vascular imaging and contrast TTE/TOE are considered the first-line tool in the search for a cardiac source of embolism. CT and MRI are considered as alternative and complementary tools, and their indications are described on a case-by-case approach.
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http://dx.doi.org/10.1093/ehjci/jeab008DOI Listing
May 2021

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

Cardiovasc Diabetol 2021 02 19;20(1):48. Epub 2021 Feb 19.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc and Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Cardiovascular Division, Université Catholique de Louvain, Avenue Hippocrate, 10, 1200, Brussels, Belgium.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C).

Methods: We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves.

Results: Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels).

Conclusion: Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.
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http://dx.doi.org/10.1186/s12933-021-01242-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893869PMC
February 2021

Ventricular lead malposition after TAVR causing ischaemic stroke.

Acta Cardiol 2021 Jul 20;76(5):564-566. Epub 2021 Jan 20.

Department of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

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http://dx.doi.org/10.1080/00015385.2020.1858249DOI Listing
July 2021

Prognostic Value of Pulmonary Transit Time by Cardiac Magnetic Resonance on Mortality and Heart Failure Hospitalization in Patients With Advanced Heart Failure and Reduced Ejection Fraction.

Circ Cardiovasc Imaging 2021 01 13;14(1):e011680. Epub 2021 Jan 13.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc (L.H., M.S.A., G.C., S.M., M.F.R., S.A.A., J.-L.J.V., A.-C.P., B.L.G.).

Background: Pulmonary transit time (PTT) from first-pass perfusion imaging is a novel parameter to evaluate hemodynamic congestion by cardiac magnetic resonance (cMR). We sought to evaluate the additional prognostic value of PTT in heart failure with reduced ejection fraction over other well-validated predictors of risk including the Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause.

Methods: We prospectively followed 410 patients with chronic heart failure with reduced ejection fraction (61±13 years, left ventricular (LV) ejection fraction 24±7%) who underwent a clinical cMR to assess the prognostic value of PTT for a primary endpoint of overall mortality and secondary composite endpoint of cardiovascular death and heart failure hospitalization. Normal reference values of PTT were evaluated in a population of 40 asymptomatic volunteers free of cardiovascular disease. Results PTT was significantly increased in patients with heart failure with reduced ejection fraction as compared to controls (9±6 beats and 7±2 beats, respectively, <0.001), and correlated not only with New York Heart Association class, cMR-LV and cMR-right ventricular (RV) volumes, cMR-RV and cMR-LV ejection fraction, and feature tracking global longitudinal strain, but also with cardiac output. Over 6-year median follow-up, 182 patients died and 200 reached the secondary endpoint. By multivariate Cox analysis, PTT was an independent and significant predictor of both endpoints after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. Importantly in multivariable analysis, PTT in beats had significantly higher additional prognostic value to predict not only overall mortality (χ to improve, 12.3; hazard ratio, 1.35 [95% CI, 1.16-1.58]; <0.001) but also the secondary composite endpoints (χ to improve=20.1; hazard ratio, 1.23 [95% CI, 1.21-1.60]; <0.001) than cMR-LV ejection fraction, cMR-RV ejection fraction, LV-feature tracking global longitudinal strain, or RV-feature tracking global longitudinal strain. Importantly, PTT was independent and complementary to both pulmonary artery pressure and reduced RV ejection fraction<42% to predict overall mortality and secondary combined endpoints.

Conclusions: Despite limitations in temporal resolution, PTT derived from first-pass perfusion imaging provides higher and independent prognostic information in heart failure with reduced ejection fraction than clinical and other cMR parameters, including LV and RV ejection fraction or feature tracking global longitudinal strain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03969394.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011680DOI Listing
January 2021

Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab.

Swiss Med Wkly 2020 Dec 18;150:w20422. Epub 2020 Dec 18.

Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Introduction: Emicizumab (Hemlibra®, Hoffmann-La Roche, Switzerland) is now available for haemophilia A patients with or without factor VIII inhibitors. Management of bleeding events and replacement therapy for invasive procedures have to be adapted.

Objective: To provide a practical guidance for the management of breakthrough bleeding events and elective or urgent surgery in adult and paediatric patients with haemophilia A without inhibitors treated with emicizumab.

Methods: Based on the available literature and the experiences collected from adult and paediatric patients treated in Switzerland, the Working Party on Haemostasis of the Swiss Society of Haematology and the Swiss Haemophilia Network worked together to reach a consensus on the management of bleeding events and invasive procedures.

Results And Conclusion: Minor bleeding events and invasive procedures associated with low bleeding risk can be treated without factor replacement therapy in most cases, whereas major bleeding events and high-risk surgery require additional factor VIII replacement at usual doses, at least for the first days. Emicizumab treatment should be continued throughout the procedure and during the postoperative period. Elective major surgery should be planned according to emicizumab dosing for patients with a once-a-month posology. Of note, so far only few data are available on the management of major bleeds and surgery in patients with haemophilia A treated with emicizumab and this practical guidance will have to be regularly updated with growing experience.  .
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http://dx.doi.org/10.4414/smw.2020.20422DOI Listing
December 2020

Expert recommendation from the Swiss Amyloidosis Network (SAN) for systemic AL-amyloidosis.

Swiss Med Wkly 2020 Nov 5;150:w20364. Epub 2020 Dec 5.

Department of Cardiology, University Hospital, Zurich, Switzerland.

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis.
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http://dx.doi.org/10.4414/smw.2020.20364DOI Listing
November 2020

Structural and Functional Correlates of Gradient-Area Patterns in Severe Aortic Stenosis and Normal Ejection Fraction.

JACC Cardiovasc Imaging 2021 03 18;14(3):525-536. Epub 2020 Nov 18.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; Divisions of Cardiology and Cardiothoracic Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Objectives: The authors sought to characterize the functional and structural myocardial phenotypes of patients with moderate-to-severe aortic stenosis (AS) and to determine whether severe paradoxical low-gradient AS (LG-AS) is specifically associated with left ventricular (LV) remodeling and fibrosis.

Background: Recently, it was suggested that severe paradoxical LG-AS is a more advanced form of AS, with greater reduction of longitudinal deformation, adverse LV remodeling, and more interstitial fibrosis.

Methods: The study population includes 147 patients with moderate-to-severe AS and a normal LV ejection fraction, and 75 normal control subjects. They prospectively underwent 2-dimensional speckle-tracking echocardiography and cardiac magnetic resonance to evaluate myocardial deformation, LV remodeling, and age- and sex-adjusted extravascular volume fraction (ECV, %). Among AS patients, 18 had moderate AS, 74 had severe high-gradient AS (HG-AS), and 55 had severe paradoxical LG-AS.

Results: Reduced longitudinal and circumferential deformation was observed in 21% and 6% of the AS patients, respectively. Multivariate analyses identified increased ECV (ß = 1.99; p = 0.001) and the absence of normal LV geometry (ß = -1.37; p = 0.007) and as independent predictors of reduced longitudinal deformation. Increased ECV was an independent predictor of reduced circumferential deformation (ß = 2.19; p = 0.001). Over a median follow-up of 29 months, reduced longitudinal deformation (hazard ratio: 0.82; p = 0.023) and higher transvalvular gradients (hazard ratio: 1.05; p < 0.001) increased the risk of death or need for aortic valve replacement. LV hypertrophy was more frequently observed among patients with severe HG-AS (65%) than among the other AS patients (14%; p < 0.001). On average, ECV was within normal limits and did not differ among gradient-area subgroups. When present, increased ECV was associated with reduced longitudinal deformation.

Conclusions: This study's data show that patients with severe paradoxical LG-AS less frequently display reduced longitudinal deformation, LV hypertrophy, or myocardial fibrosis than patients with HG-AS. Also, interstitial fibrosis only occurs when reduced longitudinal deformation and severe HG-AS are present together. Finally, this study suggests that reduced longitudinal deformation and higher transvalvular gradients adversely affect patients' outcomes.
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http://dx.doi.org/10.1016/j.jcmg.2020.09.031DOI Listing
March 2021

Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Sep 9;21(1):770. Epub 2020 Sep 9.

Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Objectives: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation.

Trial Design: The OVID study is conducted as a multicentre open-label superiority randomised controlled trial.

Participants: Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study's background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis:  a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke,  b. previous VTE,  c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 10 cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals.

Intervention And Comparator: Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation.

Main Outcomes: Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization.

Secondary Outcomes: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment.

Randomisation: Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24).

Blinding (masking): In this open-label study, no blinding procedures will be used.

Numbers To Be Randomised (sample Size): The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1-β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group.

Trial Status: Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021.

Trial Registration: ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04678-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479300PMC
September 2020

Test-retest reliability of left and right ventricular systolic function by new and conventional echocardiographic and cardiac magnetic resonance parameters.

Eur Heart J Cardiovasc Imaging 2021 09;22(10):1157-1167

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. LucPôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Av Hippocrate 10/2806, B-1200 Woluwe St. Lambert, Brussels, Belgium.

Aims: Reproducible evaluation of left (LV) and right ventricular (RV) function is crucial for clinical decision-making and risk stratification. We evaluated whether speckle-tracking echocardiography (STE) and cardiac magnetic resonance feature-tracking (cMR-FT) global longitudinal (GLS) and circumferential strains allow better test-retest reproducibility of LV and RV systolic function than conventional cMR and echocardiographic parameters.

Methods And Results: Thirty healthy volunteers and 20 chronic heart failure patients underwent cMR and STE twice on separate days to evaluate test-retest coefficient of variation (CV), intraclass correlation coefficient (ICC) and estimated sample sizes for significant changes in LV and RV function. Among LV parameters, cMR-left ventricular ejection fraction (LVEF) had the highest reproducibility (CV = 6.7%, ICC = 0.98), significantly better than cMR-FT-GLS (CV = 15.1%, ICC = 0.84), global circumferential strains (CV = 11.5%, ICC = 0.94) and echocardiographic LVEF (CV = 11.3%, ICC = 0.93). STE-LV-GLS (CV = 8.9%, ICC = 0.94) had significantly better reproducibility than cMR-FT-LV-GLS. Among RV parameters, STE-RV-GLS (CV = 7.3%, ICC = 0.93) had significantly better CV than cMR-right ventricular ejection fraction (RVEF) (CV = 13%, ICC = 0.82). cMR-FT-RV-GLS (CV = 43%, ICC = 0.39) performed poorly with significantly lower reproducibility than all other RV parameters. Owing to their superior interstudy reproducibility, cMR-LVEF (n = 12), cMR-RVEF (n = 41), STE-LV-GLS and STE-RV-GLS (both n = 14) were the parameters allowing the lowest calculated sample sizes to detect 10% change in LV or RV systolic function.

Conclusion: STE-LV-GLS and STE-RV-GLS showed higher test-retest reliability than other echocardiographic measurements of LV and RV function. They also allowed smaller calculated sample sizes, supporting the use of STE-LV and RV-GLS for longitudinal follow-up of LV and RV function.
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http://dx.doi.org/10.1093/ehjci/jeaa206DOI Listing
September 2021

Heart failure with preserved ejection fraction in Belgium: characteristics and outcome of a real-life cohort.

Acta Cardiol 2021 Sep 17;76(7):697-706. Epub 2020 Jul 17.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc and Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.

Background: Due to aging of the population and the increase of cardiovascular risk factors, heart failure and preserved ejection fraction (HFpEF) is a rising health issue. Few data exist on the phenotype of HFpEF patients in Belgium and on their prognosis.

Objectives: We describe clinical characteristics and outcomes of Belgian HFpEF patients.

Methods: We prospectively enrolled 183 HFpEF patients. They underwent clinical examination, comprehensive biological analysis and echocardiography, and were followed for a combined outcome of all-cause mortality and first HF hospitalisation.

Results: Belgian patients with HFpEF were old (78 ± 8 years), predominantly females (62%) with multiple comorbidities. Ninety-five per cent were hypertensive, 38% diabetic and 69% overweight. History of atrial fibrillation was present in 63% of population, chronic kidney disease in 60% and anaemia in 58%. Over 30 ± 9 months, 55 (31%) patients died, 87 (49%) were hospitalised and 111 (63%) reached the combined outcome. In multivariate Cox analysis, low body mass index (BMI), NYHA class III and IV, diabetes, poor renal function and loop diuretic intake were independent predictors of the combined outcome ( < .05). BMI and renal function were also independent predictors of mortality, as were low haemoglobin, high E/e' and poor right ventricular function.

Conclusion: Belgian patients with HFpEF are elderly patients with a high burden of comorbidities. Their prognosis is poor with high rates of hospitalisation and mortality. Although obesity is a risk factor for developing HFpEF, low BMI is the strongest independent predictor of mortality in those patients.
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http://dx.doi.org/10.1080/00015385.2020.1770460DOI Listing
September 2021

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction.

ESC Heart Fail 2020 10 24;7(5):2494-2507. Epub 2020 Jun 24.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Avenue Hippocrate, 10, Brussels, 1200, Belgium.

Aims: Besides regulating calcium-phosphate metabolism, fibroblast growth factor 23 (FGF-23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF-23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF-23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients.

Methods And Results: We prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two-dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF-23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF-23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all-cause mortality and first HF hospitalization and a secondary endpoint of all-cause mortality. Median FGF-23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF-23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF-23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF-23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow-up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all-cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF-23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03], P < 0.001), FGF-23 (HR: 2.85 [1.26; 6.44], P = 0.012), and ECV (HR: 1.26 [1.03; 1.23], P = 0.008) were independent predictors of all-cause mortality.

Conclusions: Fibroblast growth factor 23 (FGF-23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF-23 was correlated with fibrosis evaluated by ECV. High levels of FGF-23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF-23 was a strong predictor of poor outcome (mortality and first HF hospitalization).
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http://dx.doi.org/10.1002/ehf2.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524237PMC
October 2020

Pulmonary hypertension due to left heart disease: diagnostic value of pulmonary artery distensibility.

Eur Radiol 2020 Nov 16;30(11):6204-6212. Epub 2020 Jun 16.

Division of Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Avenue Hippocrate 10, 1200, Brussels, Belgium.

Objectives: To evaluate how pulmonary artery (PA) distensibility performs in detecting pulmonary hypertension due to left heart disease (PH-LHD) in comparison with parameters from ungated computed tomography (CT) and echocardiography.

Methods: One hundred patients (79 men, mean age = 63 ± 17 years) with either severe heart failure with reduced ejection fraction (HFrEF), aortic stenosis, or primary mitral regurgitation prospectively underwent right heart catheterization, ungated CT, ECG-gated CT, and echocardiography. During the ECG-gated CT, the right PA distensibility was calculated. In ungated CT, dPA, dPA/AA, the ratio of dPA to the diameter of the vertebra, segmental PA diameter, segmental PA-to-bronchus ratio, and the main PA volume were measured; the egg-and-banana sign was recorded. During echocardiography, the tricuspid regurgitation (TR) gradient was measured. The areas under the ROC curves (AUC) of these signs were computed and compared with DeLong test. Correlation between PA distensibility and PA pressure (PAP) was investigated through Pearson's coefficient.

Results: PA distensibility was lower in patients with PH than in those without PH (11.4 vs. 21.2%, p < 0.001) and correlated negatively with mean PAP (r = - 0.72, p < 0.001). Age, PA size, and mean PAP were independent predictors of PA distensibility. PA distensibility < 18% detected PH-LHD with 96% sensitivity and 73% specificity; its AUC was 0.92, larger than that of any other sign at ungated CT and TR gradient (AUC ranging from 0.54 to 0.83, DeLong: p ranging from 0.020 to < 0.001).

Conclusion: PA distensibility on an ECG-gated CT can detect PH-LHD better than the parameters reflecting PA dilatation in ungated CT or TR gradient in the echocardiography of patients with severe HFrEF, aortic stenosis, or mitral regurgitation.

Key Points: • In left heart disease, pulmonary artery distensibility is lower in patients with PH than in those without pulmonary hypertension (11.4 vs. 21.2%, p < 0.001). • In left heart disease, pulmonary artery distensibility detects pulmonary hypertension with an area under the receiver operating curve of 0.92. • In left heart disease, the area under the receiver operating curve of pulmonary artery distensibility for detecting pulmonary hypertension is larger than that of all other signs at ungated CT (p from 0.019 to < 0.001) and tricuspid regurgitation gradient at echocardiography (p = 0.020).
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http://dx.doi.org/10.1007/s00330-020-06959-7DOI Listing
November 2020

Right Ventricular Global Longitudinal Strain and Outcomes in Heart Failure with Preserved Ejection Fraction.

J Am Soc Echocardiogr 2020 08 7;33(8):973-984.e2. Epub 2020 May 7.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Brussels, Belgium. Electronic address:

Background: Right ventricular (RV) strain has emerged as an accurate tool for RV function assessment and is a powerful predictor of survival in patients with heart failure with reduced ejection fraction. However, its prognostic impact in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. The aim of this study was to compare the prognostic value of RV global longitudinal strain (RVGLS) by two-dimensional speckle-tracking echocardiographic (STE) imaging in patients with HFpEF against conventional RV function parameters.

Methods: Patients with HFpEF were prospectively recruited, and 149 of 183 (81%) with analyzable STE RVGLS images constituted the final study population (mean age, 78 ± 9 years; 61% women), compared with 28 control subjects of similar age and sex. All control subjects and 120 patients also underwent cardiac magnetic resonance imaging. Patients were followed up for a primary end point of all-cause mortality and first heart failure hospitalization, and Cox regression analysis was performed.

Results: Mean STE RVGLS was significantly altered in patients with HFpEF compared with control subjects (-21.7 ± 4.9% vs -25.9 ± 4.2%, P < .001). STE RVGLS correlated well with RV ejection fraction by cardiac magnetic resonance (r = -0.617, P < .001). Twenty-eight patients with HFpEF (19%) had impaired STE RVGLS (>-17.5%). During a mean follow-up period of 30 ± 9 months, 91 patients with HFpEF (62%) reached the primary end point. A baseline model was created using independent predictors of the primary end point: New York Heart Association functional class III or IV, hemoglobin level, estimated glomerular filtration rate, and the presence of moderate or severe tricuspid regurgitation. Impaired STE RVGLS provided significant additional prognostic value over this model (χ to enter = 7.85, P = .005). Impaired tricuspid annular plane systolic excursion and fractional area change, however, did not.

Conclusions: In patients with HFpEF, impaired RVGLS has strong prognostic value. STE RVGLS should be considered for systematic evaluation of RV function to identify patients at high risk for adverse events.
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http://dx.doi.org/10.1016/j.echo.2020.02.016DOI Listing
August 2020

Usefulness of Cardiac Magnetic Resonance Imaging in Aortic Stenosis.

Circ Cardiovasc Imaging 2020 05 6;13(5):e010356. Epub 2020 May 6.

Department of Cardiology (Y.B., C.T.), Amiens University Hospital, France.

The objective of this review is to provide an overview of the role of cardiac magnetic resonance (CMR) in aortic stenosis (AS). Although CMR is undeniably the gold standard for assessing left ventricular volume, mass, and function, the assessment of the left ventricular repercussions of AS by CMR is not routinely performed in clinical practice, and its role in evaluating and quantifying AS is not yet well established. CMR is an imaging modality integrating myocardial function and disease, which could be particularly useful in a pathology like AS that should be considered as a global myocardial disease rather than an isolated valve disease. In this review, we discuss the emerging potential of CMR for the diagnosis and prognosis of AS. We detail its utility for studying all aspects of AS, including valve anatomy, flow quantification, left ventricular volumes, mass, remodeling, and function, tissue mapping, and 4-dimensional flow magnetic resonance imaging. We also discuss different clinical situations where CMR could be useful in AS, for example, in low-flow low-gradient AS to confirm the low-flow state and to understand the reason for the left ventricular dysfunction or when there is a suspicion of associated cardiac amyloidosis.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.010356DOI Listing
May 2020

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.

Blood 2020 05;135(21):1859-1869

University of Texas MD Anderson Cancer Center, Houston, TX.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.
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http://dx.doi.org/10.1182/blood.2019003453DOI Listing
May 2020
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