Publications by authors named "Stefan Janssens"

192 Publications

Exercise capacity, muscle strength and objectively measured physical activity in patients after heart transplantation.

Transpl Int 2021 Oct 13. Epub 2021 Oct 13.

KU Leuven-University of Leuven, University Hospitals Leuven, Department of Cardiovascular Sciences, B-3000, Leuven, Belgium.

Background: Maximal exercise capacity of patients after heart transplantation (HTX) remains limited, affecting their quality of life. Evidence on the evolution of muscle strength and physical activity (PA) post-HTX is lacking, but a prerequisite to tailor cardiac rehabilitation programs.

Methods: 45 consecutive patients were evaluated every 3 months during the first year post-HTX. Functional exercise capacity (Six minutes walking distance test (6MWD)), peripheral (Quadriceps strength (QF)) and respiratory (Maximal inspiratory strength (MIP)) muscle strength were evaluated. PA (number of steps (PAsteps), active time (PAactive) and sedentary time (PAsed)) was objectively measured.

Results: 6MWD, QF, MIP, PAsteps and PAactive significantly improved over time (p<0.001). No change in PAsed was noticed (p=0.129). Despite improvements in 6MWD and QF, results remained substantially below those of age-and gender matched healthy subjects. One year post-HTX, 30% of patients presented with peripheral muscle weakness. Baseline levels of 6MWD and QF were significantly higher in patients with pretransplant LVAD-implantation and this difference was maintained during follow-up.

Conclusions: cardiac rehabilitation, combining aerobic exercise training and peripheral muscle strength training, is mandatory in patients post-HTX. Inspiratory muscle training should be implemented when respiratory muscle weakness is present. Programs improving physical activity and reducing sedentary time post-HTX are essential.
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http://dx.doi.org/10.1111/tri.14139DOI Listing
October 2021

Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Aims: Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome.

Methods And Results: Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO (R  = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance.

Conclusion: Exercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.
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http://dx.doi.org/10.1002/ehf2.13514DOI Listing
September 2021

Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

JACC Basic Transl Sci 2021 Aug 23;6(8):631-646. Epub 2021 Aug 23.

Department of Cardiovascular Sciences, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.

The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in translates into significantly improved LV structural and functional remodeling at 4 weeks' follow-up. The early transcriptome of LV tissue from mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury.
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http://dx.doi.org/10.1016/j.jacbts.2021.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385568PMC
August 2021

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

N Engl J Med 2021 10 27;385(16):1451-1461. Epub 2021 Aug 27.

From the Department of Cardiology (CVK) and the Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin (S.D.A.), Universitätsklinikum des Saarlandes, Homberg (M. Böhm), RWTH Aachen University, Aachen (N.M.), Boehringer Ingelheim Pharma, Biberach (C.Z., S.S.), Boehringer Ingelheim International, Ingelheim (W.J., M. Brueckmann), and the Faculty of Medicine Mannheim, University of Heidelberg, Mannheim (M. Brueckmann) - all in Germany; the University of Mississippi Medical Center, Jackson (J.B.); National and Kapodistrian University of Athens School of Medicine, Athens (G.F.); Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, and INSERM Unité 1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) (J.P.F.), and Université de Lorraine, INSERM INI-CRCT, CHRU (F.Z.) - both in Nancy, France; the Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal (J.P.F.); Unidade de Insuficiência Cardíaca, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.B.); Maastricht University Medical Center and the School for Cardiovascular Disease CARIM - both in Maastricht, the Netherlands (H.-P.B.-L.R.); the Department of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea (D.-J.C.); Max Superspeciality Hospital, Saket, New Delhi, India (V.C.); the National Institute of Cardiology, Mexico City (E.C.-V.); McGill University Health Centre, Montreal (N.G.), and St. Michael's Hospital, University of Toronto, Toronto (S.V.) - both in Canada; the Cardiology Service, Fundación Valle del Lili, Universidad Icesi, Cali, Colombia (J.E.G.-M.); the Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium (S.J.); Massachusetts General Hospital and Baim Institute for Clinical Research, Boston (J.L.J.); University Hospital, Santiago de Compostela, Spain (J.R.G.-J.); Heart and Vascular Center, Semmelweiss University, Budapest, Hungary (B.M.); Victorian Heart Institute, Monash University, Melbourne, VIC, Australia (S.J.N.); Argentine Catholic University, and Medical Advisor in Heart Failure, Pulmonary Hypertension and Intrathoracic Transplant at FLENI and IADT Institute - both in Buenos Aires (S.V.P.); Central Michigan University, Mount Pleasant (I.L.P.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Cardiovascular Department, Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo (M.S.), and Università di Pisa, Pisa (S.T.) - both in Italy; National Heart Centre Singapore, Singapore (D.S.); the Internal Cardiology Department, St. Ann University Hospital and Masaryk University, Brno, Czech Republic (J.S.); the University of Leicester, Glenfield General Hospital, Leicester (I.S.), the University of Glasgow, Glasgow (N.S.), the London School of Hygiene and Tropical Medicine (S.J.P.), and Imperial College, London (M.P.) - all in the United Kingdom; Kyushu University, Fukuoka, Japan (H.T.); the University of Medicine and Pharmacy, Carol Davila University and Emergency Hospital, Bucharest, Romania (D.V.); the Heart Failure Center, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing (J.Z.); the Veterans Affairs Medical Center, Washington, DC (P.C.); National Heart Centre Singapore, Duke-National University of Singapore, Singapore (C.S.P.L.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (J.M.S.); and Baylor Heart and Vascular Institute, Dallas (M.P.).

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.

Methods: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.

Results: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.

Conclusions: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
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http://dx.doi.org/10.1056/NEJMoa2107038DOI Listing
October 2021

Antithrombotic Treatment After Surgical and Transcatheter Heart Valve Repair and Replacement.

Front Cardiovasc Med 2021 5;8:702780. Epub 2021 Aug 5.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

New antithrombotic drugs have been developed, new valve types have been designed and minimally invasive transcatheter techniques have emerged, making the choice of antithrombotic therapy after surgical or transcatheter heart valve repair and replacement increasingly complex. Moreover, due to a lack of large randomized controlled trials many recommendations for antithrombotic therapy are based on expert opinion, reflected by divergent recommendations in current guidelines. Therefore, decision-making in clinical practice regarding antithrombotic therapy for prosthetic heart valves is difficult, potentially resulting in sub-optimal patient treatment. This article compares the 2017 ESC/EACTS and 2020 ACC/AHA guidelines on the management of valvular heart disease and summarizes the available evidence. Finally, we established a convenient consensus on antithrombotic therapy after valve interventions based on over 800 annual cases of surgical and transcatheter heart valve repair and replacement and a multidisciplinary team discussion between the department of cardiovascular diseases and cardiac surgery of the University Hospitals Leuven, Belgium.
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http://dx.doi.org/10.3389/fcvm.2021.702780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375148PMC
August 2021

Rapid Exclusion of COVID Infection With the Artificial Intelligence Electrocardiogram.

Mayo Clin Proc 2021 08;96(8):2081-2094

Department of Cardiovascular Medicine, The University of Kansas Health System, Kansas City, KS.

Objective: To rapidly exclude severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using artificial intelligence applied to the electrocardiogram (ECG).

Methods: A global, volunteer consortium from 4 continents identified patients with ECGs obtained around the time of polymerase chain reaction-confirmed COVID-19 diagnosis and age- and sex-matched controls from the same sites. Clinical characteristics, polymerase chain reaction results, and raw electrocardiographic data were collected. A convolutional neural network was trained using 26,153 ECGs (33.2% COVID positive), validated with 3826 ECGs (33.3% positive), and tested on 7870 ECGs not included in other sets (32.7% positive). Performance under different prevalence values was tested by adding control ECGs from a single high-volume site.

Results: The area under the curve for detection of acute COVID-19 infection in the test group was 0.767 (95% CI, 0.756 to 0.778; sensitivity, 98%; specificity, 10%; positive predictive value, 37%; negative predictive value, 91%). To more accurately reflect a real-world population, 50,905 normal controls were added to adjust the COVID prevalence to approximately 5% (2657/58,555), resulting in an area under the curve of 0.780 (95% CI, 0.771 to 0.790) with a specificity of 12.1% and a negative predictive value of 99.2%.

Conclusion: Infection with SARS-CoV-2 results in electrocardiographic changes that permit the artificial intelligence-enhanced ECG to be used as a rapid screening test with a high negative predictive value (99.2%). This may permit the development of electrocardiography-based tools to rapidly screen individuals for pandemic control.
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http://dx.doi.org/10.1016/j.mayocp.2021.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327278PMC
August 2021

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

Semin Thromb Hemost 2021 Jun 23;47(4):362-371. Epub 2021 Apr 23.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

Background:  Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis.

Methods:  Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism.

Results:  Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported.

Conclusion:  In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.
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http://dx.doi.org/10.1055/s-0041-1727284DOI Listing
June 2021

Added Value of Quantitative Apparent Diffusion Coefficient Values for Neuroprognostication After Cardiac Arrest.

Neurology 2021 05 9;96(21):e2611-e2618. Epub 2021 Apr 9.

From the Departments of Neurology (A.W., L.S., S.P., R.L.), Radiology (R.P., S.C., P.D.), and Cardiology (S.J., K.A.), University Hospitals Leuven; Laboratory of Neurobiology (A.W., L.S., R.L.), Center for Brain & Disease Research, VIB; Department of Neurosciences (A.W., L.S., R.L.), Experimental Neurology and Leuven Brain Institute, University of Leuven, Belgium; Department of Neurology (A.W.), Academic Medical Center, University of Amsterdam, the Netherlands; Translational MRI, Department of Imaging and Pathology (R.P., S.C., P.D.), and Laboratory for Epilepsy Research, Department of Neurosciences (W.V.P.), KU Leuven, Belgium; Department of Cardiology (B.F., M.D., J.D., K.A.), Ziekenhuis Oost-Limburg, Genk; and Faculty of Medicine and Life Sciences (J.D., K.A.), Faculty of Medicine and Life Sciences, University Hasselt, Diepenbeek, Belgium.

Objective: To test the prognostic value of brain MRI in addition to clinical and electrophysiologic variables in patients post-cardiac arrest (CA), we explored data from the randomized Neuroprotect Post-CA trial (NCT02541591).

Methods: In this trial, brain MRIs were prospectively obtained. We calculated receiver operating characteristic (ROC) curves for the average apparent diffusion coefficient (ADC) value and percentage of brain voxels with an ADC value <650 × 10 mm/s and <450 × 10 mm/s. We constructed multivariable logistic regression models with clinical characteristics, EEG, somatosensory evoked potentials (SSEP), and ADC value as independent variables to predict good neurologic recovery.

Results: In 79/102 patients, MRI data were available and in 58/79 patients all other data were available. At 180 days post-CA, 25/58 (43%) patients had good neurologic recovery. In univariable analysis of all tested MRI measures, average ADC value in the postcentral cortex had the highest accuracy to predict good neurologic recovery, with an area under the ROC curve (AUC) of 0.78. In the most optimal multivariable model, which also included corneal reflexes and EEG, this measure remained an independent predictor of good neurologic recovery (AUC 0.96, false-positive 27%). This model provided a more accurate prediction compared to the most optimal combination of EEG, corneal reflexes, and SSEP ( = 0.03).

Conclusions: Adding information on brain MRI in a multivariable model may improve the prediction of good neurologic recovery in patients post-CA.

Classification Of Evidence: This study provides Class III evidence that MRI ADC features predict neurologic recovery in patients post-CA.
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http://dx.doi.org/10.1212/WNL.0000000000011991DOI Listing
May 2021

Relative and Absolute Risk to Guide the Management of Pulse Pressure, an Age-Related Cardiovascular Risk Factor.

Am J Hypertens 2021 09;34(9):929-938

Laboratory of Neurosciences, Faculty of Medicine, University of Zulia, Maracaibo, Zulia, Venezuela.

Background: Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan.

Methods: In 4,663 young (18-49 years) and 7,185 older adults (≥50 years), brachial PP was recorded over 24 hours. Total mortality and all major cardiovascular events (MACEs) combined were coprimary endpoints. Cardiovascular death, coronary events, and stroke were secondary endpoints.

Results: In young adults (median follow-up, 14.1 years; mean PP, 45.1 mm Hg), greater PP was not associated with absolute risk; the endpoint rates were ≤2.01 per 1,000 person-years. The adjusted hazard ratios expressed per 10-mm Hg PP increments were less than unity (P ≤ 0.027) for MACE (0.67; 95% confidence interval [CI], 0.47-0.96) and cardiovascular death (0.33; 95% CI, 0.11-0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mm Hg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1,000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P < 0.0001). The PP-related relative risks of death, MACE, and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3.

Conclusions: From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality.
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http://dx.doi.org/10.1093/ajh/hpab048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457427PMC
September 2021

Managing Patients With Short-Term Mechanical Circulatory Support: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 03;77(9):1243-1256

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

The use of mechanical circulatory support for patients presenting with cardiogenic shock is rapidly increasing. Currently, there is only limited and conflicting evidence available regarding the role of the Impella (a microaxial, continuous-flow, short-term, left or right ventricular assist device) in cardiogenic shock; further randomized trials are needed. Patient selection, timing of implantation, and post-implantation management in the cardiac intensive care unit are crucial elements for success. Particular challenges at the bedside include the practical management of anticoagulation, evaluation of correct device position, and the approach to use in a patient with signs of insufficient hemodynamic support. Profound knowledge of these issues is required to enable the maximal potential of the device. This review provides a comprehensive overview of the short-term assist device and describes a practical approach to optimize care for patients supported with the device.
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http://dx.doi.org/10.1016/j.jacc.2020.12.054DOI Listing
March 2021

Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies.

ESC Heart Fail 2021 06 2;8(3):2306-2309. Epub 2021 Mar 2.

Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERCV, Madrid, Spain.

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.
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http://dx.doi.org/10.1002/ehf2.13256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120359PMC
June 2021

Impact of Cardiac Resynchronization Therapy on Global and Cardiac Metabolism and Cardiac Mitochondrial Function.

J Card Fail 2021 Jun 24;27(6):706-715. Epub 2021 Feb 24.

Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Laboratory Medicine, KU Leuven, UZ Leuven, Leuven, Belgium; Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.

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http://dx.doi.org/10.1016/j.cardfail.2021.02.008DOI Listing
June 2021

Cardiologists' perceptions on multidisciplinary collaboration in heart failure care - a qualitative study.

BMC Health Serv Res 2021 Feb 23;21(1):170. Epub 2021 Feb 23.

Department of Public Health and Primary Care, KU Leuven, Kapucijnenvoer 33, Blok J, Bus 7001, 3000, Leuven, Belgium.

Background: Cardiologists play a key role in multidisciplinary care by guiding heart failure (HF) management in the hospital and in the community. Regional implementation of multidisciplinary health care interventions depends on how they perceive collaboration with other health care disciplines, yet research on this topic is limited. This study aimed to explore the views and opinions of cardiologists on multidisciplinary collaboration in HF care.

Methods: We conducted a qualitative study based on face-to-face semi-structured interviews with 11 Belgian cardiologists between September 2019 and February 2020. We used the Qualitative Analysis Guide of Leuven (QUAGOL) method as guidance for data analysis until data saturation was reached.

Results: Cardiologists consider the general practitioner (GP) and HF nurse as the most important partners in HF management. Cardiologists identified four problems in current multidisciplinary collaboration: the communication of a HF diagnosis to the patient, advanced care planning, titration of HF medication by the GP and electronic data exchange and communication. Three themes emerged as ideas for improvement of HF care: 1) expansion of the role of the HF nurse, 2) implementation of a structured, patient-centered, and flexible model of disease management program and 3) integrated data approaches.

Conclusion: Cardiologists value close cooperation with GPs in HF management. They advocate an expanded future role for the HF nurse, increased eHealth, and structured disease management to optimize current HF care.
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http://dx.doi.org/10.1186/s12913-021-06179-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901167PMC
February 2021

Left Impella®-device as bridge from cardiogenic shock with acute, severe mitral regurgitation to MitraClip®-procedure: a new option for critically ill patients.

Eur Heart J Acute Cardiovasc Care 2021 May;10(4):415-421

Department of Adult Intensive Care, Royal Brompton and Harefield NHS Foundation Trust, Sydney St, Chelsea, London SW3 6NP, UK.

Aims: Patients presenting with cardiogenic shock (CS) related to acute, severe mitral regurgitation (MR) are often considered too ill for immediate surgical intervention. Therefore, other less invasive techniques for haemodynamic stabilization should be explored. The purpose of this exploratory study was to investigate the feasibility and outcomes in patients with CS due to severe MR by using a novel approach combining haemodynamic stabilization with left Impella-support plus MR-reduction using MitraClip®.

Methods And Results: We analysed whether a combined left Impella®/MitraClip®-procedure in a rare population of CS-patients with acute MR requiring mechanical ventilation is a feasible strategy to recovery in patients who had been declined cardiac surgery. Six INTERMACS-1 CS-patients with acute MR were studied at two tertiary cardiac intensive care units. The mean EURO-II score was 39 ± 19% and age 66.8 ± 4.9 years. All patients had an initial pulmonary capillary wedge pressure >20 mmHg and pulmonary oedema necessitating invasive ventilation. Cardiac output was severely impaired (left ventricular outflow tract velocity time index 9.8 ± 1.8 cm), requiring mechanical circulatory support (MCS) (Impella®-CP; mean flow 2.9 ± 1.8 L per minute; mean support 9.7 ± 6.0 days). Despite MCS-guided unloading, weaning from ventilation failed due to persisting pulmonary oedema necessitating MR-reduction. In all cases, the severe MR was reduced to mild using percutaneous MitraClip®-procedure, followed by successful weaning from invasive ventilation. Survival to discharge was 86%, with all surviving and rare readmission for heart failure at 6 months.

Conclusions: A combined Impella®/MitraClip®-strategy appears a novel, feasible alternative for weaning CS-patients presenting with acute, severe MR. Upfront Impella®-stabilization facilitates safe bridging to Mitraclip®-procedure and the staged approach facilitates successful weaning from ventilatory support.
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http://dx.doi.org/10.1093/ehjacc/zuaa031DOI Listing
May 2021

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

Basic Res Cardiol 2021 02 9;116(1):10. Epub 2021 Feb 9.

Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium.

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.
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http://dx.doi.org/10.1007/s00395-021-00846-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873123PMC
February 2021

Long-term follow-up of patients with infective endocarditis in a tertiary referral center.

Int J Cardiol 2021 05 3;331:176-182. Epub 2021 Feb 3.

Department of Cardiology, KU Leuven, University Hospitals Leuven, 3000 Leuven, Belgium. Electronic address:

Background: Infective endocarditis (IE) remains a severe disease with high mortality. Most studies report on short-term outcome while real world long-term outcome data are scarce. This study reports reinfection rates and mortality data during long-term follow-up.

Methods: A total of 270 patients meeting the modified Duke criteria for definite IE admitted to a tertiary care center between July 2000 and June 2007 were analyzed retrospectively. Early reinfection was defined as a new IE episode within 6 months; late reinfection as a new IE episode beyond 6 months follow-up.

Results: Median follow-up was 8.5 years. Early reinfection occurred in 10 patients (3.7%), late reinfection in 18 patients (6.7%). Staphylococci (39.7%) were the most frequent causative microorganisms, followed by Streptococci (30.0%) and Enterococci (17.8%). Independent predictors of any reinfection were heart failure (HR 3.02, 95% CI 1.42-6.41), peripheral embolization (HR 4.00, 95% CI 1.58-10.17) and implanted pacemakers (HR 3.43, 95% CI 1.25-9.36). Survival rates were 71.1%, 55.2% and 43.3% at respectively 1-, 5- and 10-years follow-up. Independent predictors for mortality were age (HR 1.03, 95% CI 1.01-1.04), diabetes mellitus (HR 2.24, 95% CI 1.46-3.45), hemodialysis (HR 2.70, 95% CI 1.37-5.29), heart failure (HR 1.64, 95% CI 1.19-2.26), stroke (HR 1.73, 95% CI 1.18-2.52), antimicrobial treatment despite surgical indication (HR 5.53, 95% CI 3.59-8.49) and non-Streptococci causative microorganisms (HR 1.84, 95% CI 1.28-2.64).

Conclusions: Contemporary mortality rates of infective endocarditis remain high, irrespective of reinfection. Heart failure, peripheral embolization and presence of a pacemaker were predictors of reinfection.
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http://dx.doi.org/10.1016/j.ijcard.2021.01.048DOI Listing
May 2021

Cardiac Microvascular Endothelial Cells in Pressure Overload-Induced Heart Disease.

Circ Heart Fail 2021 01 19;14(1):e006979. Epub 2021 Jan 19.

Department of Cardiovascular Sciences (S.T., H.H., S.C., P.P., J.V.W., H.G., D.V., F.W., E.C., J.A.S., F.R., B. Meuris, B. Meyns, W.O., J.D., K.G., J.-U.V., M.-C.H., P.H., A.L., S.J.), KU Leuven, Belgium.

Background: Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS).

Methods: In mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac -MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women).

Results: In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of (), , , and were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS (<0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%-474%; =0.008) and procollagen secretion by 85% (mean [95% CI, 16%-154%]; <0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting (<0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS.

Conclusions: Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006979DOI Listing
January 2021

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Eur Heart J 2021 02;42(6):671-680

Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France.

Aims: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.

Methods And Results: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.

Conclusion: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.
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http://dx.doi.org/10.1093/eurheartj/ehaa968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878011PMC
February 2021

Impact of primary care involvement and setting on multidisciplinary heart failure management: a systematic review and meta-analysis.

ESC Heart Fail 2021 04 6;8(2):802-818. Epub 2021 Jan 6.

Department of Public Health and Primary Care, KU Leuven (KUL), Kapucijnenvoer 33, Blok J Bus 7001, Leuven, 3000, Belgium.

Multidisciplinary disease management programmes (DMPs) are a cornerstone of modern guideline-recommended care for heart failure (HF). Few programmes are community initiated or involve primary care professionals, despite the importance of home-based care for HF. We compared the outcomes of different multidisciplinary HF DMPs in relation to their recruitment setting and involvement of primary care health professionals. We conducted a systematic review and meta-analysis of randomized controlled trials published in MEDLINE, Embase, and Cochrane between 2000 and 2020 using Cochrane Collaboration methodology. Our meta-analysis included 19 randomized controlled trials (7577 patients), classified according to recruitment setting and involvement of primary care professionals. Thirteen studies recruited in the hospital (n = 5243 patients) and six in the community (n = 2334 patients). Only six studies involved primary care professionals (n = 3427 patients), with two of these recruited in the community (n = 225 patients). Multidisciplinary HF DMPs that recruited in the community had no significant effect on all-cause and HF readmissions nor on mortality, irrespective of primary care involvement. Studies that recruited in the hospital demonstrated a significant reduction in mortality (relative risk 0.87, 95% confidence interval [CI] [0.76, 0.98]), HF readmissions (0.70, 95% CI [0.54, 0.89]), and all-cause readmissions (0.72, 95% CI [0.60, 0.87]). However, the difference in effect size between recruitment setting and involvement of primary care was not significant in a meta-regression analysis. Multidisciplinary HF DMPs that recruit in the community have no significant effect on mortality or hospital readmissions, unlike DMPs that recruit in the hospital, although the difference in effect size was not significant in a meta-regression analysis. Only six multidisciplinary studies involved primary care professionals. Given demographic evolutions and the importance of integrated home-based care for patients with HF, future multidisciplinary HF DMPs should consider integrating primary care professionals and evaluating the effectiveness of this model.
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http://dx.doi.org/10.1002/ehf2.13152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006678PMC
April 2021

Association of Fatal and Nonfatal Cardiovascular Outcomes With 24-Hour Mean Arterial Pressure.

Hypertension 2021 01 8;77(1):39-48. Epub 2020 Dec 8.

From the Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium (J.D.M., W.-Y. Y, L.T., F.-F.W., J.A.S., Z.-Y.Z.).

Major adverse cardiovascular events are closely associated with 24-hour blood pressure (BP). We determined outcome-driven thresholds for 24-hour mean arterial pressure (MAP), a BP index estimated by oscillometric devices. We assessed the association of major adverse cardiovascular events with 24-hour MAP, systolic BP (SBP), and diastolic BP (DBP) in a population-based cohort (n=11 596). Statistics included multivariable Cox regression and the generalized R statistic to test model fit. Baseline office and 24-hour MAP averaged 97.4 and 90.4 mm Hg. Over 13.6 years (median), 2034 major adverse cardiovascular events occurred. Twenty-four-hour MAP levels of <90 (normotension, n=6183), 90 to <92 (elevated MAP, n=909), 92 to <96 (stage-1 hypertension, n=1544), and ≥96 (stage-2 hypertension, n=2960) mm Hg yielded equivalent 10-year major adverse cardiovascular events risks as office MAP categorized using 2017 American thresholds for office SBP and DBP. Compared with 24-hour MAP normotension, hazard ratios were 0.96 (95% CI, 0.80-1.16), 1.32 (1.15-1.51), and 1.77 (1.59-1.97), for elevated and stage-1 and stage-2 hypertensive MAP. On top of 24-hour MAP, higher 24-hour SBP increased, whereas higher 24-hour DBP attenuated risk (<0.001). Considering the 24-hour measurements, R statistics were similar for SBP (1.34) and MAP (1.28), lower for DBP than for MAP (0.47), and reduced to null, if the base model included SBP and DBP; if the ambulatory BP indexes were dichotomized according to the 2017 American guideline and the proposed 92 mm Hg for MAP, the R values were 0.71, 0.89, 0.32, and 0.10, respectively. In conclusion, the clinical application of 24-hour MAP thresholds in conjunction with SBP and DBP refines risk estimates.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720872PMC
January 2021

Insights into therapeutic products, preclinical research models, and clinical trials in cardiac regenerative and reparative medicine: where are we now and the way ahead. Current opinion paper of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine.

Cardiovasc Res 2021 05;117(6):1428-1433

Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Doctor Esquerdo 46, 28007 Madrid, Spain.

Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting.
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http://dx.doi.org/10.1093/cvr/cvaa337DOI Listing
May 2021

Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.

Eur J Heart Fail 2020 12;22(12):2383-2392

University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital, Bucharest, Romania.

Aims: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials.

Methods And Results: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists.

Conclusion: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021.
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http://dx.doi.org/10.1002/ejhf.2064DOI Listing
December 2020

Implementing standards of care for heart failure patients in general practice - the IMPACT-B study protocol.

Acta Cardiol 2021 Jul 9;76(5):486-493. Epub 2020 Nov 9.

Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Background: Heart failure (HF) is an important health problem. Most chronic HF management occurs in primary care. Although guidelines exist, there is an important implementation gap in current HF care in Belgium.

Methods: We will conduct a non-randomised, non-controlled prospective observational trial to implement guideline-recommended disease management interventions in primary care in Leuven, a region of ±100.000 inhabitants. These interventions include education of general practitioners, reimbursement of the analysis of circulating natriuretic peptides and audits in the electronic health record (EHR), training and implementation of HF educators in primary care, and a protocol to structure transition to primary care after discharge. The main objective is to study and implement interventions in an iterative implementation process.

Conclusions: We will evaluate the implementation of several guideline-recommended disease management interventions to optimise the diagnosis and treatment of heart failure in a real-world primary care setting.

Trial Registration: NCT04334447 (clinicaltrials.gov).
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http://dx.doi.org/10.1080/00015385.2020.1844504DOI Listing
July 2021

Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.

Circulation 2020 11 25;142(19):1831-1847. Epub 2020 Sep 25.

Advanced Genomics Laboratory (J.P.R., A.V.-Z., L.C.-L., P.S.M.-U., E.L.-V., D.L.-A.), Program of Hemato-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

Background: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function.

Methods: Collagen1α1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing.

Results: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-β signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy.

Conclusions: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies as a novel regulator of the healing scar process and a target for future translational studies.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730974PMC
November 2020

Impact of an extended audit on identifying heart failure patients in general practice: baseline results of the OSCAR-HF pilot study.

ESC Heart Fail 2020 Sep 24. Epub 2020 Sep 24.

Department of Cardiovascular Diseases, Universitair Ziekenhuis Gasthuisberg, KU Leuven (KUL), Leuven, Belgium.

Aims: Identifying heart failure (HF) patients in general practice is challenging, and little is known about the current quality of care. We implemented an extended audit from the electronic health records (EHRs) of general practitioners (GPs) to identify HF patients and investigate patient characteristics and quality of care.

Methods And Results: This study describes the baseline results of the OSCAR-HF pilot study in eight general practices (51 GPs) in Flanders, Belgium. This prospective trial ran for 6 months. Interventions included an extended audit, an N-terminal pro-B-type natriuretic peptide point-of-care test, and assistance of a specialist HF nurse. The extended audit searched on risk factors for HF, HF symptoms, signs, and medication in the GPs' EHR to generate a list of possible HF patients. GPs determined which patients had HF. Those HF patients constituted the OSCAR-HF study population. Each patient file was manually revised to extract biomarker measurements, echocardiography data, and quality indicators. An independent panel of experts assessed the validity of GPs' HF diagnoses. Feedback about the validity of the HF diagnosis was given to the GP. Out of 18 011 patients ≥ 40 years, we identified 310 patients with a registered HF diagnosis before the study start (HF prevalence: 1.7%). The extended audit led to a 74% increase in identified HF patients (n = 538, HF prevalence: 3.0%) with a mean age of 79 ± 11 years. The prevalence of HF with reduced ejection fraction (HFrEF) was 20% (n = 110). A high proportion of patients underwent echocardiography in the past 5 years (86%, n = 462). Natriuretic peptides were rarely available in patients' files (19%, n = 100). Medical specialists should improve communication about the HF diagnosis because a specialist diagnosis was present in only 225 patients (42%) while 67% (n = 359) of the HF diagnoses were judged objectified by a panel of experts. Assigning a diagnosis of HF was particularly difficult in HF patients with preserved EF (HFpEF). HFrEF treatment rates with renin-angiotensin-aldosterone system blockers (84%, n = 92) and beta-blockers (86%, n = 94) were very good; however, target doses were hardly reached (34% and 14%, respectively).

Conclusions: This study highlighted the need to improve case finding for HF in general practice and showed that an extended audit in the GPs' EHR was a successful strategy to do so. To improve the quality of HF care in general practice, specific strategies are needed to diagnose HFpEF and to reach target doses of disease-modifying drugs in HFrEF patients.
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http://dx.doi.org/10.1002/ehf2.12990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754725PMC
September 2020

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

N Engl J Med 2020 10 28;383(15):1413-1424. Epub 2020 Aug 28.

From Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.); Imperial College (M.P.) and the Department of Medical Statistics, London School of Hygiene and Tropical Medicine (S.J.P.), London, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow (N.S.), and the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Biomedical Research Centre, Glenfield Hospital, Leicester (I.S.) - all in the United Kingdom; the Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin (S.D.A.), Boehringer Ingelheim International, Ingelheim (M. Brueckmann, W.J.), Faculty of Medicine Mannheim, University of Heidelberg, Mannheim (M. Brueckmann), Boehringer Ingelheim Pharma, Biberach (C.Z.), Klinik für Innere Medizin III, Saarland University, Homburg-Saar (M. Böhm), and the Department of Medicine, University Hospital of Würzburg, Würzburg (C.W.) - all in Germany; the Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B.); National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens (G.F.); Washington DC Veterans Affairs Medical Center, Washington DC (P.C.); the Division of Cardiology, Harvard Medical School and Massachusetts General Hospital, Boston (J.J.); the Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto (S.V.), Boehringer Ingelheim Canada, Burlington, ON (K.K.), and the Division of Cardiology, McGill University and Health Centre, Montreal (N.G.) - all in Canada; the Department of Cardiovascular Medicine, Kyushu University, Higashi-ku, Fukuoka, Japan (H.T.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (J. Schnee, D.C.); Heart Institute, São Paulo University Medical School, São Paulo (E.B.); the Department of Medicine, Seoul National University, Seoul, South Korea (D.-J.C.); the Department of Cardiology, Max Super Speciality Hospital, Saket, New Delhi, India (V.C.); the Department of Clinical Cardiology, National Institute of Cardiology, Mexico City (E.C.); the Department of Cardiology, University Hospital Gasthuisberg of Leuven, Leuven, Belgium (S.J.); Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (J.Z.); the Cardiology Department, University Hospital, Santiago de Compostela, Spain (J.R.G.J.); the Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles (S.K.); Maastricht Heart and Vascular Center, Maastricht, the Netherlands (H.P.B.-L.R.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Victorian Heart Institute and Monash University, Melbourne, VIC, Australia (S.J.N.); Fleni Institute and Hospital El Cruce-Nestor Kirchner, Buenos Aires (S.P.); the Department of Medicine, Wayne State and Central Michigan Universities, Detroit (I.P.); the Center for Heart Diseases, Wrocław Medical University, Wrocław, Poland (P.P.); the Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo (M.S.), and the Department of Clinical and Experimental Medicine, University of Pisa, Pisa (S.T.) - both in Italy; the Department of Cardiology, University Hospital Jean Minjoz, Besançon (M.-F.S.), and Université de Lorraine, INSERM Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Régional Universitaire, Nancy (F.Z.) - both in France; and Internal Cardiology, University Hospital Brno, Brno, Czech Republic (J. Spinar).

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

Methods: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.

Results: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.

Conclusions: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
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http://dx.doi.org/10.1056/NEJMoa2022190DOI Listing
October 2020

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

Eur Heart J 2020 10;41(38):3702-3710

Department of Medicine III, Goethe University of Frankfurt, Frankfurt, Germany.

Aims: Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent.

Methods And Results: Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group.

Conclusions: Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.
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http://dx.doi.org/10.1093/eurheartj/ehaa651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666866PMC
October 2020

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

Eur J Heart Fail 2020 11 30;22(11):2093-2101. Epub 2020 Sep 30.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies.

Methods And Results: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA.

Conclusions: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.
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http://dx.doi.org/10.1002/ejhf.1984DOI Listing
November 2020

Optimum Blood Pressure in Patients With Shock After Acute Myocardial Infarction and Cardiac Arrest.

J Am Coll Cardiol 2020 08;76(7):812-824

Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Emergency Medicine and Services, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: In patients with shock after acute myocardial infarction (AMI), the optimal level of pharmacologic support is unknown. Whereas higher doses may increase myocardial oxygen consumption and induce arrhythmias, diastolic hypotension may reduce coronary perfusion and increase infarct size.

Objectives: This study aimed to determine the optimal mean arterial pressure (MAP) in patients with AMI and shock after cardiac arrest.

Methods: This study used patient-level pooled analysis of post-cardiac arrest patients with shock after AMI randomized in the Neuroprotect (Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients; NCT02541591) and COMACARE (Carbon Dioxide, Oxygen and Mean Arterial Pressure After Cardiac Arrest and Resuscitation; NCT02698917) trials who were randomized to MAP 65 mm Hg or MAP 80/85 to 100 mm Hg targets during the first 36 h after admission. The primary endpoint was the area under the 72-h high-sensitivity troponin-T curve.

Results: Of 235 patients originally randomized, 120 patients had AMI with shock. Patients assigned to the higher MAP target (n = 58) received higher doses of norepinephrine (p = 0.004) and dobutamine (p = 0.01) and reached higher MAPs (86 ± 9 mm Hg vs. 72 ± 10 mm Hg, p < 0.001). Whereas admission hemodynamics and angiographic findings were all well-balanced and revascularization was performed equally effective, the area under the 72-h high-sensitivity troponin-T curve was lower in patients assigned to the higher MAP target (median: 1.14 μg.72 h/l [interquartile range: 0.35 to 2.31 μg.72 h/l] vs. median: 1.56 μg.72 h/l [interquartile range: 0.61 to 4.72 μg. 72 h/l]; p = 0.04). Additional pharmacologic support did not increase the risk of a new cardiac arrest (p = 0.88) or atrial fibrillation (p = 0.94). Survival with good neurologic outcome at 180 days was not different between both groups (64% vs. 53%, odds ratio: 1.55; 95% confidence interval: 0.74 to 3.22).

Conclusions: In post-cardiac arrest patients with shock after AMI, targeting MAP between 80/85 and 100 mm Hg with additional use of inotropes and vasopressors was associated with smaller myocardial injury.
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http://dx.doi.org/10.1016/j.jacc.2020.06.043DOI Listing
August 2020

Opportunities of Antidiabetic Drugs in Cardiovascular Medicine: A Meta-Analysis and Perspectives for Trial Design.

Hypertension 2020 08 8;76(2):420-431. Epub 2020 Jul 8.

From the Department of Science and Technology, Beijing YouAn Hospital (C.Y., Y.-M.F.), Capital Medical University, China.

To identify potential application of GLP1-RAs (glucagon-like peptide-1 receptor agonists) and SGLT2-Is (sodium-dependent glucose cotrasnsporter-2 inhibitors) in cardiovascular medicine, we performed PubMed search until March 31, 2020 and selected placebo-controlled randomized trials (RCTs) in patients with type 2 diabetes mellitus. Twenty-four hour ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in glycated hemoglobin and body weight were aggregated across RCTs using random-effect models. In 2238 patients (7 RCTs), SGLT2-Is lowered 24-hour systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4-5.5/1.2-2.6 mm Hg), whereas 2 GLP1-RAs RCTs produced contradictory BP results. Over 1.3 to 5.4 years of follow-up of 56 004 patients (7 RCTs), aggregate hazard ratios associated with GLP1-RA treatment were 0.88 (0.84-0.93) for MACE, 0.84 (0.74-0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE end points (≤0.01). Across 5 SGLT2-Is RCTs, including 43 467 patients with 1.5 to 4.2 years follow-up, hazard ratios were 0.87 (0.82-0.93) for MACE, 0.68 (0.62-0.75) for HF, 0.82 (0.72-0.93) for cardiovascular death, 0.87 (0.79-0.96) for myocardial infarction, and 0.61 (0.56-0.67) for worsening CKD. The risk of HF and CKD, but not MACE, decreased with more BP lowering. Stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD. The aggregate effect sizes on systolic BP, body weight, and glycated hemoglobin were -1.61 mm Hg, -2.40 kg, and -0.69% for GLP1-RAs, and -2.53 mm Hg, -1.15 kg and -0.24%, for SGLT2-Is (<0.001). In conclusion, GLP1-RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14791DOI Listing
August 2020
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