Publications by authors named "Anne Raafs"

11 Publications

  • Page 1 of 1

The prognostic impact of mechanical atrial dysfunction and atrial fibrillation in heart failure with preserved ejection fraction.

Eur Heart J Cardiovasc Imaging 2021 Dec;23(1):74-84

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+ (MUMC+), PO Box 616, 6200 MD Maastricht, the Netherlands.

Aims: This study assessed the prognostic implications of mechanical atrial dysfunction in heart failure with preserved ejection fraction (HFpEF) patients with different stages of atrial fibrillation (AF) in detail.

Methods And Results: HFpEF patients (n = 258) systemically underwent an extensive clinical characterization, including 24-h Holter monitoring and speckle-tracking echocardiography. Patients were categorized according to rhythm and stages of AF: 112 with no history of AF (no AF), 56 with paroxysmal AF (PAF), and 90 with sustained (persistent/permanent) AF (SAF). A progressive decrease in mechanical atrial function was seen: left atrial reservoir strain (LASr) 30.5 ± 10.5% (no AF), 22.3 ± 10.5% (PAF), and 13.9 ± 7.8% (SAF), P < 0.001. Independent predictors for lower LASr values were AF, absence of chronic obstructive pulmonary disease, higher N-terminal-pro hormone B-type natriuretic peptide, left atrial volume index, and relative wall thickness, lower left ventricular global longitudinal strain, and echocardiographic signs of elevated left ventricular filling pressure. LASr was an independent predictor of adverse outcome (hazard ratio per 1% decrease =1.049, 95% confidence interval 1.014-1.085, P = 0.006), whereas AF was not when the multivariable model included LASr. Moreover, LASr mediated the adverse outcome associated with AF in HFpEF (P = 0.008).

Conclusion: Mechanical atrial dysfunction has a possible greater prognostic role in HFpEF compared to AF status alone. Mechanical atrial dysfunction is a predictor of adverse outcome independently of AF presence or stage, and may be an underlying mechanism (mediator) for the worse outcome associated with AF in HFpEF. This may suggest mechanical atrial dysfunction plays a crucial role in disease progression in HFpEF patients with AF, and possibly also in HFpEF patients without AF.
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http://dx.doi.org/10.1093/ehjci/jeab222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685598PMC
December 2021

A global longitudinal strain cut-off value to predict adverse outcomes in individuals with a normal ejection fraction.

ESC Heart Fail 2021 10 17;8(5):4343-4345. Epub 2021 Jul 17.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, PO Box 5800, Maastricht, 6202 AZ, The Netherlands.

Aims: Global longitudinal strain (GLS) has become an alternative to left ventricular ejection fraction (LVEF) to determine systolic function of the heart. The absence of cut-off values is one of the limitations preventing full clinical implementation. The aim of this study is to determine a cut-off value of GLS for an increased risk of adverse events in individuals with a normal LVEF.

Methods And Results: Echocardiographic images of 502 subjects (52% female, mean age 48 ± 15) with an LVEF ≥ 55% were analysed using speckle tracking-based GLS. The primary endpoint was cardiovascular death or cardiac hospitalization. The analysis of Cox models with splines was performed to visualize the effect of GLS on outcome. A cut-off value was suggested by determining the optimal specificity and sensitivity. The median GLS was -22.2% (inter-quartile range -20.0 to -24.9%). In total, 35 subjects (7%) had a cardiac hospitalization and/or died because of cardiovascular disease during a follow-up of 40 (5-80) months. There was a linear correlation between the risk for adverse events and GLS value. Subjects with a normal LVEF and a GLS between -22.9% and -20.9% had a mildly increased risk (hazard ratio 1.01-2.0) for cardiac hospitalization or cardiovascular mortality, and the risk was doubled for subjects with a GLS of -20.9% and higher. The optimal specificity and sensitivity were determined at a GLS value of -20.0% (hazard ratio 2.49; 95% confidence interval: 1.71-3.61).

Conclusions: There is a strong correlation between cardiac adverse events and GLS values in subjects with a normal LVEF. In our single-centre study, -20.0% was determined as a cut-off value to identify subjects at risk. A next step should be to integrate GLS values in a multi-parametric model.
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http://dx.doi.org/10.1002/ehf2.13465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497344PMC
October 2021

Post-discharge arrhythmic risk stratification of patients with acute myocarditis and life-threatening ventricular tachyarrhythmias.

Eur J Heart Fail 2021 Dec 21;23(12):2045-2054. Epub 2021 Jul 21.

Cardiothoracovascular Department, Azienda Sanitaria Universitaria Integrata di Trieste and University of Trieste, Trieste, Italy.

Aims: The outcomes of patients presenting with acute myocarditis and life-threatening ventricular arrhythmias (LT-VA) are unclear. The aim of this study was to assess the incidence and predictors of recurrent major arrhythmic events (MAEs) after hospital discharge in this patient population.

Methods And Results: We retrospectively analysed 156 patients (median age 44 years; 77% male) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death or successfully defibrillated ventricular fibrillation, or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up was 23 months [first to third quartile (Q1-Q3) 7-60]. Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated with MAEs were presentation with sVT [hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.38-6.11]; late gadolinium enhancement involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53), and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR.

Conclusions: Among patients discharged with a diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmia recurrence.
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http://dx.doi.org/10.1002/ejhf.2288DOI Listing
December 2021

Identification of sex-specific biomarkers predicting new-onset heart failure.

ESC Heart Fail 2021 10 22;8(5):3512-3520. Epub 2021 Jun 22.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands.

Aims: Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF.

Methods And Results: A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P < 0.013). E-selectin and interleukin 1 receptor antagonist were more female-specific, whereas IL17A and CHIT1 tended to be male sex-specific for incident HF.

Conclusions: The majority of biomarkers associated with incident HF did not significantly differ between women and men, despite clear differences in biomarkers at baseline.
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http://dx.doi.org/10.1002/ehf2.13476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497379PMC
October 2021

The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy.

Eur J Heart Fail 2021 06 24;23(6):933-944. Epub 2021 Jun 24.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients.

Methods And Results: We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles.

Conclusion: The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
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http://dx.doi.org/10.1002/ejhf.2201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362085PMC
June 2021

Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double-blind, randomized, placebo-controlled clinical trial.

Eur J Heart Fail 2021 02 7;23(2):302-309. Epub 2021 Jan 7.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.

Aims: Previous uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled, single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence.

Methods And Results: Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6-min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end-diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573], MLHFQ [IVIg 0 (-7;5) vs. placebo -2 (-6;6), P = 0.904] and LVEDV (IVIg -16 ± 49 mL/m vs. placebo -29 ± 40 mL/m ; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.

Conclusion: Intravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.

Clinical Trial Registration: ClinicalTrials.gov ID NCT00892112.
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http://dx.doi.org/10.1002/ejhf.2082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048650PMC
February 2021

Implications of Genetic Testing in Dilated Cardiomyopathy.

Circ Genom Precis Med 2020 10 3;13(5):476-487. Epub 2020 Sep 3.

Department of Clinical Genetics (J.A.J.V., I.P.C.K., P.W., G.R.F.C., E.K.V., A.v.d.W., H.G.B.).

Background: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome.

Methods: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias.

Results: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM (=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM (<0.001).

Conclusions: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.
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http://dx.doi.org/10.1161/CIRCGEN.120.003031DOI Listing
October 2020

Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review.

Eur J Heart Fail 2020 09 7;22(9):1586-1597. Epub 2020 Aug 7.

Department of Cardiology, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands.

Aim: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB).

Methods And Results: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed.

Conclusion: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.
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http://dx.doi.org/10.1002/ejhf.1944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689920PMC
September 2020

Contemporary use of devices in chronic heart failure in the Netherlands.

ESC Heart Fail 2020 08 12;7(4):1771-1780. Epub 2020 May 12.

Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.

Aims: Despite previous surveys regarding device implantation rates in heart failure (HF), insight into the real-world management with devices is scarce. Therefore, we investigated device implantation rates in HF with reduced left ventricular ejection fraction (LVEF) in 34 Dutch centres.

Methods And Results: A cross-sectional outpatient registry was conducted in 6666 patients with LVEF < 50% and with information about device implantation available [74 (66-81) years of age; 64% male]. Patients were classified into conventional pacemakers (PM, n = 562), implantable cardioverter defibrillators (ICD, n = 1165), and cardiac resynchronization therapy with defibrillator function (CRT-D, n = 885) or pacemaker function only (CRT-P, n = 248), or no device (n = 3806). Centres were divided into ICD-implanting and CRT-implanting and referral centres. Overall, 17.5% had an ICD, 13.3% CRT-D, 3.7% CRT-P, and 8.4% PM. Of those with LVEF ≤ 30%, 42.5% had ICD or CRT-D therapy. A large variation in implantation rates existed between centres: 3-51% for ICD therapy, 0.3-44% for CRT-D therapy, 0-11% for CRT-P therapy, and 0-25% PM therapy. Implantation centres showed higher implantation rates of ICD, CRT-D, and CRT-P compared with referral centres [36% vs. 25% for defibrillators (ICD or CRT-D) and 17% vs. 9% for CRT devices (CRT-D or CRT-P), respectively, P < 0.001], independently of other factors. A large number of clinical factors were predictive for device usage. Among other, LVEF < 40% and male sex were independent positive predictors for ICD/CRT-D use [odds ratio (OR) = 3.33, P < 0.001; OR = 1.87, P = 0.019, respectively]. Older age was independently associated with less ICD/CRT-D (OR = 0.96 per year, P < 0.001) and more CRT-P/PM use (OR = 1.03 per year, P = 0.006).

Conclusions: In this large Dutch HF registry, less than half of the patients with reduced LVEF received an ICD or CRT, even if LVEF was ≤30%, and a large variation between centres existed. Patients from implantation centres had more often ICD or CRT. More uniformity regarding guideline-based use of device therapy in clinical practice is needed.
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http://dx.doi.org/10.1002/ehf2.12740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373943PMC
August 2020

Balance of Active, Passive, and Anatomical Cardiac Properties in Doxorubicin-Induced Heart Failure.

Biophys J 2019 12 29;117(12):2337-2348. Epub 2019 Jul 29.

Department of Biomedical Engineering, St Thomas's Hospital, King's College London, London, United Kingdom. Electronic address:

Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. To link doxorubicin-induced changes in cardiac cellular and tissue mechanical properties to overall cardiac function, we apply a multiscale biophysical biomechanics model of the heart to measure the plausibility of changes in model parameters representing the passive, active, or anatomical properties of the left ventricle for reproducing measured patient phenotypes. We create representative models of healthy controls (N = 10) and patients with HF induced by (N = 22) or unrelated to (N = 25) doxorubicin therapy. The model predicts that HF in the absence of doxorubicin is characterized by a 2- to 3-fold stiffness increase, decreased tension (0-20%), and ventricular dilation (of order 10-30%). HF due to doxorubicin was similar but showed stronger bias toward reduced active contraction (10-30%) and less dilation (0-20%). We find that changes in active, passive, and anatomical properties all play a role in doxorubicin-induced cardiotoxicity phenotypes. Differences in parameter changes between patient groups are consistent with doxorubicin cardiotoxicity having a greater dependence on reduced cellular contraction and less anatomical remodeling than HF not caused by doxorubicin.
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http://dx.doi.org/10.1016/j.bpj.2019.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990149PMC
December 2019
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