Publications by authors named "Maarten J Cramer"

164 Publications

Echocardiographic deformation imaging unmasks global and regional mechanical dysfunction in patients with idiopathic ventricular fibrillation: A multicenter case-control study.

Heart Rhythm 2021 May 28. Epub 2021 May 28.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Idiopathic ventricular fibrillation (IVF) has been diagnosed in patients with sudden onset of ventricular fibrillation of unidentified origin. New diagnostic tools that can detect subtle abnormalities are needed to diagnose and treat patients with an underlying substrate.

Objective: The purpose of this study was to explore echocardiographic deformation characteristics in IVF patients.

Methods: Echocardiograms were analyzed with deformation imaging by 2-dimensional speckle tracking. Global and regional measurements of the left ventricle (LV) and right ventricle (RV) were performed. Regional LV deformation patterns were evaluated for the presence of postsystolic shortening. Regional RV deformation patterns were classified as type I (normal) or type II/III (abnormal).

Results: In total, 47 IVF patients (mean age 45 years; left ventricular ejection fraction [LVEF] 56%) and 47 healthy controls (mean age 41 years; LVEF 60%) were included. IVF patients showed more global deformation abnormalities as indicated by lower LV global longitudinal strain (18.5% ± 2.6% vs 21.6% ± 1.8%; P <.001) and higher LV mechanical dispersion (41 ± 12 ms vs 26 ± 6 ms; P <.001). In addition, IVF patients showed more regional LV postsystolic shortening compared to healthy controls (50% vs 11%; P <.001). Abnormal RV deformation patterns were observed in 16% of IVF patients and in none of the control subjects (P <.001).

Conclusion: We were able to show both regional and global echocardiographic deformation abnormalities in IVF patients. This study provides evidence that localized myocardial disease is present in a subset of IVF patients.
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http://dx.doi.org/10.1016/j.hrthm.2021.05.030DOI Listing
May 2021

Optimizing lead placement for pacing in dyssynchronous heart failure: The patient in the lead.

Heart Rhythm 2021 Jun 16;18(6):1024-1032. Epub 2021 Feb 16.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Cardiac resynchronization therapy (CRT) greatly reduces morbidity and mortality in patients with dyssynchronous heart failure. However, despite tremendous efforts, response has been variable and can be further improved. Although optimizing left ventricular lead placement (LVLP) is arguably the cornerstone of CRT, the procedure of LVLP using the transvenous approach has remained largely unchanged for more than 2 decades. Improvements have been developed using scar location and electrical and/or mechanical mapping, and interest in conduction system pacing as an alternative to biventricular pacing has emerged recently. Conduction system pacing is promising but may not be suitable for all patients with dyssynchronous heart failure. This review underscores the importance of a patient-tailored approach and discusses the potential applications of both conduction system pacing and targeted biventricular CRT.
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http://dx.doi.org/10.1016/j.hrthm.2021.02.011DOI Listing
June 2021

Early detection of small volume stroke and thromboembolic sources with computed tomography: Rationale and design of the ENCLOSE study.

Eur Stroke J 2020 Dec 23;5(4):432-440. Epub 2020 Oct 23.

Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Computed tomography is the most frequently used imaging modality in acute stroke imaging protocols. Detection of small volume infarcts in the brain and cardioembolic sources of stroke is difficult with current computed tomography protocols. Furthermore, the role of computed tomography findings to predict recurrent ischemic stroke is unclear. With ENCLOSE, we aim to improve (1) the detection of small volume infarcts with thin slice computed tomography perfusion (CTP) images and thromboembolic source with cardiac computed tomography techniques in the acute stage of ischemic stroke and (2) prediction of recurrent ischemic stroke with computed tomography-derived predictors.Methods/design: ENCLOSE is a prospective multicenter observational cohort study, which will be conducted in three Dutch stroke centers (ClinicalTrials.gov Identifier: NCT04019483). Patients (≥18 years) with suspected acute ischemic stroke who undergo computed tomography imaging within 9 h after symptom onset are eligible. Computed tomography imaging includes non-contrast CT, CTP, and computed tomography angiography (CTA) from base of the heart to the top of the brain. Dual-energy CT data will be acquired when possible, and thin-slice CTP reconstructions will be obtained in addition to standard 5 mm CTP data. CTP data will be processed with commercially available software and locally developed model-based methods. The post-processed thin-slice CTP images will be compared to the standard CTP images and to magnetic resonance diffusion-weighted imaging performed within 48 h after admission. Detection of cardioembolic sources of stroke will be evaluated on the CTA images. Recurrence will be evaluated 90 days and two years after the index event. The added value of imaging findings to prognostic models for recurrent ischemic stroke will be evaluated.

Conclusion: The aim of ENCLOSE is to improve early detection of small volume stroke and thromboembolic sources and to improve prediction of recurrence in patients with acute ischemic stroke.
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http://dx.doi.org/10.1177/2396987320966420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856586PMC
December 2020

Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias.

JACC Cardiovasc Imaging 2021 May 10;14(5):900-910. Epub 2021 Feb 10.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address:

Objectives: This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA).

Background: Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared.

Methods: We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest.

Results: We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 [95% confidence interval: 1.47 to 5.00] per class step-up, and 1.26 [95% confidence interval: 1.07 to 1.49]/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01).

Conclusions: We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.
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http://dx.doi.org/10.1016/j.jcmg.2020.12.028DOI Listing
May 2021

Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy.

Int J Cardiovasc Imaging 2021 Feb 5. Epub 2021 Feb 5.

University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands.

Purpose: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT.

Methods: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dt) during CRT-implantation. The acute change in dP/dt, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined.

Results: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dt 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination.

Conclusion: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.
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http://dx.doi.org/10.1007/s10554-021-02174-7DOI Listing
February 2021

Discovering and Visualizing Disease-Specific Electrocardiogram Features Using Deep Learning: Proof-of-Concept in Phospholamban Gene Mutation Carriers.

Circ Arrhythm Electrophysiol 2021 02 5;14(2):e009056. Epub 2021 Jan 5.

Department of Cardiology, University Medical Center Utrecht, the Netherlands (R.R.v.d.L., K.T., M.N.B., J.F.v.d.H., M.J.C., R.J.H., P.v.d.H., P.A.D., F.W.A., R.v.E.).

Background: ECG interpretation requires expertise and is mostly based on physician recognition of specific patterns, which may be challenging in rare cardiac diseases. Deep neural networks (DNNs) can discover complex features in ECGs and may facilitate the detection of novel features which possibly play a pathophysiological role in relatively unknown diseases. Using a cohort of PLN (phospholamban) p.Arg14del mutation carriers, we aimed to investigate whether a novel DNN-based approach can identify established ECG features, but moreover, we aimed to expand our knowledge on novel ECG features in these patients.

Methods: A DNN was developed on 12-lead median beat ECGs of 69 patients and 1380 matched controls and independently evaluated on 17 patients and 340 controls. Differentiating features were visualized using Guided Gradient Class Activation Mapping++. Novel ECG features were tested for their diagnostic value by adding them to a logistic regression model including established ECG features.

Results: The DNN showed excellent discriminatory performance with a c-statistic of 0.95 (95% CI, 0.91-0.99) and sensitivity and specificity of 0.82 and 0.93, respectively. Visualizations revealed established ECG features (low QRS voltages and T-wave inversions), specified these features (eg, R- and T-wave attenuation in V2/V3) and identified novel PLN-specific ECG features (eg, increased PR-duration). The logistic regression baseline model improved significantly when augmented with the identified features (<0.001).

Conclusions: A DNN-based feature detection approach was able to discover and visualize disease-specific ECG features in PLN mutation carriers and revealed yet unidentified features. This novel approach may help advance diagnostic capabilities in daily practice.
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http://dx.doi.org/10.1161/CIRCEP.120.009056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892204PMC
February 2021

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms.

JACC Cardiovasc Imaging 2021 May 18;14(5):885-896. Epub 2020 Nov 18.

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.

Background: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.

Methods: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.

Results: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).

Conclusions: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.
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http://dx.doi.org/10.1016/j.jcmg.2020.09.030DOI Listing
May 2021

Early- and late anthracycline-induced cardiac dysfunction: echocardiographic characterization and response to heart failure therapy.

Cardiooncology 2020 13;6:23. Epub 2020 Oct 13.

Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, E03.511, PO Box 85500, 3508 GA Utrecht, The Netherlands.

Background: Anthracycline-induced cardiac dysfunction (ACD) is a notorious side effect of anticancer treatment. It has been described as a phenomenon of a continuous progressive decline of cardiac function, eventually leading to dilated cardiomyopathy (DCM). This progressive nature suggests that patients with a delayed ACD diagnosis have greater compromise of cardiac function and more adverse remodeling, with a poor response to heart failure (HF) treatment. This study aimed to delineate the impact of a delayed ACD diagnosis on echocardiographic characteristics and response to HF treatment.

Methods And Results: From the population of our cardio-oncology outpatient clinic, 92 ACD patients were included in this study (age 51.6 ± 16.2 years, median cumulative anthracycline dose 329 [200-329] mg/m), and a median follow-up of 25.0 [9.6-37.2] months after ACD diagnosis. Median time to ACD diagnosis for patients diagnosed early (< 1 year) and late (> 1 year) was 4.0 vs. 47.7 months respectively. There were no echocardiographic differences between patients diagnosed early vs. late (LVEF 43.6 ± 4.9% vs. 43.0 ± 6.2% and iEDV 63.6 vs. 62.9 mL/m). Eighty-three percent of patients presented with mild LV dysfunction and in 79% the LV was not dilated. Patients diagnosed early were more likely to have (partial) recovery of cardiac function upon HF treatment initiation ( = 0.015).

Conclusions: In the setting of a cardio-oncology outpatient clinic, patients with ACD presented with a hypokinetic non-dilated cardiomyopathy, rather than typical DCM. Timing of ACD diagnosis did not impact HF disease severity. However, in patients receiving an early diagnosis, cardiac function was more likely to recover upon HF treatment.
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http://dx.doi.org/10.1186/s40959-020-00079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557080PMC
October 2020

Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2.

Front Cardiovasc Med 2020 28;7:115. Epub 2020 Jul 28.

Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.

Rheumatic heart disease (RHD) is common in developing countries and poses a big medical challenge and burden. The pathogenesis of RHD is influenced by the triad of host, agent, and environment. Autoantigens generated from Group A Streptococcus (GAS) infection are captured by the resident dendritic cells (DCs) in the heart's valvular endothelium. DCs differentiate into antigen presenting cells (APC) in the valve interstices. APC induces activation of autoreactive T cells, which triggers inflammation and tissue fibrosis. Cardiac fibrosis is promoted through the activation of Mitogen activated protein kinases (MAPKs) and its downstream signaling, including its interaction with transforming growth factor-β (TGF-β) and Smad proteins. TGF-β-induced phosphorylation of Smad2 complexes with Smad3 and Smad4, and translocates into the nucleus. Angiotensin II enhances the migration, maturation, and presentation of DC. In RHD, Angiotensin II induces fibrosis via the stimulation of TGF-β, which further increases the binding of IL-33 to sST2 but not ST2L, resulting in the upregulation of Angiotensin II and progression of cardiac fibrosis. This cascade of inflammation and valvular fibrosis causes calcification and stiffening of the heart valves in RHD. Angiotensin converting enzyme inhibitors (ACEIs) inhibit Angiotensin II production, which in turn decreases TGF-β expression and the onset of overt inflammatory response. This condition leads to a reduction in the sST2 as the decoy receptor to "steal" IL-33, and IL-33 binds to ST2L and results in cardioprotection against cardiac fibrosis in the pathogenesis of RHD.
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http://dx.doi.org/10.3389/fcvm.2020.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399157PMC
July 2020

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury.

Sci Rep 2020 08 18;10(1):13945. Epub 2020 Aug 18.

Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R 0.04, R = 0.21, p = 0.001, 95% CI 0.103-0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.
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http://dx.doi.org/10.1038/s41598-020-70848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435264PMC
August 2020

Rheumatic heart disease anno 2020: Impacts of gender and migration on epidemiology and management.

Eur J Clin Invest 2020 Dec 29;50(12):e13374. Epub 2020 Aug 29.

Division of Heart and Lung, Department of Cardiology, Faculty of Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: The epidemiology and management of diseases can be influenced by social demographic factors. Gender and migration are among these factors.

Methods: We aimed at reviewing the impacts of gender and migration on rheumatic heart disease (RHD) epidemiology and management by a nonsystematic literature review of published studies on RHD worldwide. Our PubMed search terms included RHD pathophysiology, diagnosis, complications, management or prevention, combined with words 'rheumatic mitral stenosis (MS)', 'outcomes after percutaneous balloon mitral valvuloplasty (PBMV)', 'gender or sex difference' and 'migration'. The reporting of this study conforms to SANRA (the Scale for Assessment of Narrative Review Articles) guidelines.

Results: We retrieved eight studies about the impact of sex on outcomes after PBMV. All of these studies showed a female predominance for RHD. Two studies showed that there is no impact, three studies showed female sex as a predictor of poor outcomes, and the other three showed male sex a predictor of poor outcomes. Although RHD is reported to be eradicated in the developed countries, 2.1% of refugees recently screened for RHD in Italy were found to have subclinical RHD. This prevalence is similar to those found in India (2.0%), Cambodia (2.2%) and Mozambique (3%).

Conclusions: There are contradicting results for outcomes after PBMV between males and females. It is not clear whether sex difference plays a role in pathophysiology, diagnosis, management and prognosis of MS. Migration has impacts on epidemiology and management of RHD. Further studies are required in these two fields to explore their relationship to RHD.
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http://dx.doi.org/10.1111/eci.13374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757241PMC
December 2020

The value of septal rebound stretch analysis for the prediction of volumetric response to cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2021 Jan;22(1):37-45

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

Aims: Patient selection for cardiac resynchronization therapy (CRT) may be enhanced by evaluation of systolic myocardial stretching. We evaluate whether systolic septal rebound stretch (SRSsept) derived from speckle tracking echocardiography is a predictor of reverse remodelling after CRT and whether it holds additive predictive value over the simpler visual dyssynchrony assessment by apical rocking (ApRock).

Methods And Results: The association between SRSsept and change in left ventricular end-systolic volume (ΔLVESV) at 6 months of follow-up was assessed in 200 patients. Subsequently, the additive predictive value of SRSsept over the assessment of ApRock was evaluated in patients with and without left bundle branch block (LBBB) according to strict criteria. SRSsept was independently associated with ΔLVESV (β 0.221, P = 0.002) after correction for sex, age, ischaemic cardiomyopathy, QRS morphology and duration, and ApRock. A high SRSsept (≥optimal cut-off value 2.4) also coincided with more volumetric responders (ΔLVESV ≥ -15%) than low SRSsept in the entire cohort (70.0% and 56.4%), in patients with strict LBBB (83.3% vs. 56.7%, P = 0.024), and non-LBBB (70.7% vs. 46.3%, P = 0.004). Moreover, in non-LBBB patients, SRSsept held additional predictive information over the assessment of ApRock alone since patients that showed ApRock and high SRSsept were more often volumetric responder than those with ApRock but low SRSsept (82.8% vs. 47.4%, P = 0.001).

Conclusion: SRSsept is strongly associated with CRT-induced reduction in left ventricular end-systolic volume and holds additive prognostic information over QRS morphology and ApRock. Our data suggest that CRT patient selection may be improved by assessment of SRSsept, especially in the important subgroup without strict LBBB.

Clinical Trial Registration: The MARC study was registered at clinicaltrials.gov: NCT01519908.
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http://dx.doi.org/10.1093/ehjci/jeaa190DOI Listing
January 2021

Intimal and medial calcification in relation to cardiovascular risk factors.

PLoS One 2020 13;15(7):e0235228. Epub 2020 Jul 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Purpose: To assess specific risk factors and biomarkers associated with intimal arterial calcification (IAC) and medial arterial calcification (MAC).

Methods: We conducted a cross-sectional study in patients with or at risk of vascular disease from the SMART study(n = 520) and the DCS cohort(n = 198). Non-contrast computed tomography scanning of the lower extremities was performed and calcification in the femoral and crural arteries was scored as absent, predominant IAC, predominant MAC or indistinguishable. Multinomial regression models were used to assess the associations between cardiovascular risk factors and calcification patterns. Biomarkers for inflammation, calcification and vitamin K status were measured in a subset of patients with IAC(n = 151) and MAC(n = 151).

Results: Femoral calcification was found in 77% of the participants, of whom 38% had IAC, 28% had MAC and 11% were scored as indistinguishable. The absolute agreement between the femoral and crural arteries was high(69%). Higher age, male sex, statin use and history of coronary artery disease were associated with higher prevalences of femoral IAC and MAC compared to absence of calcification. Smoking and low ankle-brachial-index (ABI) were associated with higher prevalence of IAC and high ABI was associated with less IAC. Compared to patients with IAC, patients with MAC more often had diabetes, have a high ABI and were less often smokers. Inactive Matrix-Gla Protein was associated with increased MAC prevalence, while osteonectin was associated with decreased risk of MAC, compared to IAC.

Conclusions: When femoral calcification is present, the majority of the patients have IAC or MAC throughout the lower extremity, which have different associated risk factor profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357737PMC
September 2020

Parameter subset reduction for patient-specific modelling of arrhythmogenic cardiomyopathy-related mutation carriers in the CircAdapt model.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190347. Epub 2020 May 25.

Department of Biomedical Engineering, Maastricht University CARIM School for Cardiovascular Diseases, Maastricht, Limburg, The Netherlands.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Patient-specific computational models could help understand the disease progression and may help in clinical decision-making. We propose an inverse modelling approach using the CircAdapt model to estimate patient-specific regional abnormalities in tissue properties in AC subjects. However, the number of parameters ( = 110) and their complex interactions make personalized parameter estimation challenging. The goal of this study is to develop a framework for parameter reduction and estimation combining Morris screening, quasi-Monte Carlo (qMC) simulations and particle swarm optimization (PSO). This framework identifies the best subset of tissue properties based on clinical measurements allowing patient-specific identification of right ventricular tissue abnormalities. We applied this framework on 15 AC genotype-positive subjects with varying degrees of myocardial disease. Cohort studies have shown that atypical regional right ventricular (RV) deformation patterns reveal an early-stage AC disease. The CircAdapt model of cardiovascular mechanics and haemodynamics has already demonstrated its ability to capture typical deformation patterns of AC subjects. We, therefore, use clinically measured cardiac deformation patterns to estimate model parameters describing myocardial disease substrates underlying these AC-related RV deformation abnormalities. Morris screening reduced the subset to 48 parameters. qMC and PSO further reduced the subset to a final selection of 16 parameters, including regional tissue contractility, passive stiffness, activation delay and wall reference area. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
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http://dx.doi.org/10.1098/rsta.2019.0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287326PMC
June 2020

Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction.

PLoS One 2020 6;15(5):e0232399. Epub 2020 May 6.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202634PMC
July 2020

Development of an algorithm for automatic classification of right ventricle deformation patterns in arrhythmogenic right ventricular cardiomyopathy.

Echocardiography 2020 05 3;37(5):698-705. Epub 2020 May 3.

Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

Background: Different disease stages of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be identified by right ventricle (RV) longitudinal deformation (strain) patterns. This requires assessment of the onset of shortening, (systolic) peak strain, and postsystolic index, which is time-consuming and prone to inter- and intra-observer variability. The aim of this study was to design and validate an algorithm to automatically classify RV deformation patterns.

Methods: We developed an algorithm based on specific local characteristics from the strain curves to detect the parameters required for classification. Determination of the onset of shortening by the algorithm was compared to manual determination by an experienced operator in a dataset containing 186 RV strain curves from 26 subjects carrying a pathogenic plakophilin-2 (PKP2) mutation and 36 healthy subjects. Classification agreement between operator and algorithm was solely based on differences in onset shortening, as the remaining parameters required for classification of RV deformation patterns could be directly obtained from the strain curves.

Results: The median difference between the onset of shortening determined by the experienced operator and by the automatic detector was 5.3 ms [inter-quartile range (IQR) 2.7-8.6 ms]. 96% of the differences were within 1 time frame. Both methods correlated significantly with ρ = 0.97 (P < .001). For 26 PKP2 mutation carriers, there was 100% agreement in classification between the algorithm and experienced operator.

Conclusion: The determination of the onset of shortening by the experienced operator was comparable to the algorithm. Our computer algorithm seems a promising method for the automatic classification of RV deformation patterns. The algorithm is publicly available at the MathWorks File Exchange.
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http://dx.doi.org/10.1111/echo.14671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317368PMC
May 2020

Cardiovascular adverse events in patients with non-Hodgkin lymphoma treated with first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP): a systematic review and meta-analysis.

Lancet Haematol 2020 Apr 2;7(4):e295-e308. Epub 2020 Mar 2.

Department of Cardiology, Division of Heart and Lungs, University Medical Centre Utrecht, University of Utrecht, Utrecht, Netherlands; Netherlands Heart Institute, Utrecht, Netherlands; Health Data Research UK, Institute of Health Informatics and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.

Background: Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen.

Methods: We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3-4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex.

Findings: Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5-52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3-4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81-2·93; heterogeneity test Q=326·21; τ=0·0042; I=71·40%; p<0·0001). For heart failure, the pooled proportion, based on 38 studies (n=5936 patients), was 4·62% (2·25-7·65; heterogeneity test Q=527·33; τ=0·0384; I=95·05%; p<0·0001), with a significant increase in reported heart failure from 1·64% (95% CI 0·82-2·65) to 11·72% (3·00-24·53) when cardiac function was evaluated post-chemotherapy (p=0·017). 53 (39%) of 137 studies were rated as having high risk of bias for incomplete outcome data and 54 (39%) for selective reporting.

Interpretation: The considerable increase of reported heart failures with cardiac monitoring, indicates that this complication often remains undiagnosed in patients with non-Hodgkin lymphoma who received first-line R-CHOP or CHOP. Our findings are of importance to raise awareness of this complication among clinicians treating patients with non-Hodgkin lymphoma and stresses the need for cardiac monitoring during and after chemotherapy. Prompt initiation of treatment for heart failure in the presymptomatic phase can mitigate the progression to more advanced heart failure stages.

Funding: None.
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http://dx.doi.org/10.1016/S2352-3026(20)30031-4DOI Listing
April 2020

Strategies to Improve Selection of Patients Without Typical Left Bundle Branch Block for Cardiac Resynchronization Therapy.

JACC Clin Electrophysiol 2020 02;6(2):129-142

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Cardiac resynchronization therapy (CRT) is becoming increasingly controversial in patients without typical left bundle branch block (LBBB). Yet, several recent studies displayed that a distinct subpopulation of patients with non-LBBB does benefit from CRT. Patients with non-LBBB should, therefore, not as a group be withheld from a potentially very beneficial therapy. Unfortunately, current clinical practice lacks validated selection criteria that may identify possible CRT responders in the non-LBBB subgroup. Consequently, clinical decision making in these patients is often challenging. A few studies, strongly differing in design, have proposed additive selection criteria for improved response prediction in patients with non-LBBB. There is accumulating evidence that more sophisticated echocardiographic dyssynchrony markers, taking into account the underlying electrical substrate responsive to CRT, can aid in the selection of patients with a non-LBBB who may benefit more favorably from CRT. Furthermore, it is important that cardiologists are aware of the shortcomings of current electrocardiographic selection criteria for CRT. Whereas these criteria provide an evidence-based approach for selecting patients for CRT, they do not necessarily guarantee the most optimal strategy for patient selection. Parameters obtained with vectorcardiography, such as QRS area, show potential to overcome the shortcomings of conventional electrocardiographic selection criteria and may improve response prediction regardless of QRS morphology.
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http://dx.doi.org/10.1016/j.jacep.2019.11.018DOI Listing
February 2020

Added Value of Interactive 3-D Stereo Vision Echocardiography in the Heart Valve Team: A Post Hoc Analysis for Optimal Decision Making in Patients With Mitral Valve Regurgitation.

Innovations (Phila) 2020 Jan/Feb;15(1):36-42. Epub 2020 Jan 7.

8124 University Medical Center Utrecht, The Netherlands.

Objective: We assessed the added value of advanced echocardiography post hoc analysis for optimal decision-making in the Heart Valve Team (HVT) using an interactive, dynamic, live visualization system with true three-dimensional (3-D) stereo vision.

Methods: HVT scrutinized the incremental value of 3 consecutive methods of presentation of full-volume echocardiographic data sets in terms of diagnosis and possibility of repair in 11 selected patients having mitral regurgitation (MR)(Table 1). The questionnaire investigated consecutively (a) standard two-dimensional (2-D) transesophageal echocardiography, (b) single-beat 3-D zoom of the surgical view of the mitral valve, and (c) advanced 3-D volumetric rendering technology (Personal Space Station, Vesalius 3D software, PS-Medtech, Netherlands).

Results: In 4 of 11 reviews (36%), single-beat 3-D zoom had additional value over 2-D echocardiography in terms of mechanism/adjustments or adjustment of confirmation of diagnosis. Single-beat 3-D zoom had no additional value over 2-D echocardiography in terms of proposal/probability of repair. In 7 out of 11 (64%) reviews, true stereo 3-D visualization had additional value in terms of mechanism of pathology compared to 2-D and 3-D zoom and in 5 out of 11 (45%) reviews in confirmation of diagnosis. In 3 out of 11 (27%) reviews, true stereo 3-D visualization had additional value in terms of proposal of repair and in 4 of 11 (36%) in probability of repair over 2-D and 3-D zoom.

Conclusions: Advanced easy-to-use true 3-D echocardiography limited differences in interpretation and strengthened the confidence in understanding the mechanisms and suitability for repair of mitral valve regurgitation, typically in more complex valve pathology.
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http://dx.doi.org/10.1177/1556984519887973DOI Listing
December 2020

Mitral valve prolapse, a familial condition worth screening for?

Eur J Prev Cardiol 2020 02 12;27(3):269-271. Epub 2019 Dec 12.

UMC Utrecht, Department of Cardiology, The Netherlands.

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http://dx.doi.org/10.1177/2047487319893368DOI Listing
February 2020

Clinical research study implementation of case-finding strategies for heart failure and chronic obstructive pulmonary disease in the elderly with reduced exercise tolerance or dyspnea: A cluster randomized trial.

Am Heart J 2020 02 1;220:73-81. Epub 2019 Sep 1.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care Department, University Medical Center, Utrecht University, Utrecht, the Netherlands.

Background: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) often remain undiagnosed in older individuals, although both disorders inhibit functionality and impair health. The aim of the study was to assess the effectiveness of a case-finding strategy of these disorders.

Methods: This is a clustered randomized trial; 18 general practices from the vicinity of Utrecht, the Netherlands, were randomly allocated to a case-finding strategy or usual care. Multimorbid community subjects (≥65 years) with dyspnea or reduced exercise tolerance were eligible for inclusion. The case-finding strategy consisted of history taking, physical examination, blood tests, electrocardiography, spirometry, and echocardiography. Subsequent treatment decisions were at the discretion of the general practitioner. Questionnaires regarding health status and functionality were filled out at baseline and after 6 months of follow-up. Information regarding changes in medication and health care use during the 6 months follow-up was extracted.

Results: A total of 829 participants were randomized: 389 in the case-finding strategy group and 440 in the usual care group. More patients in the case-finding group received a new diagnosis of HF or COPD than the usual care group (cumulative incidence 34% vs 2% and 17% vs. 2%, respectively). Scores for health status, functionality, and health care use were similar between the 2 strategies after 6 months of follow-up.

Conclusions: A case-finding strategy applied in primary care to multimorbid older people with dyspnea or reduced exercise tolerance resulted in a number of new diagnoses of HF and COPD but did not result in short-term improvement of health status compared to usual care.
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http://dx.doi.org/10.1016/j.ahj.2019.08.021DOI Listing
February 2020

Dissociation between hypertrophy and fibrosis in the left ventricle early after experimental kidney transplantation.

J Hypertens 2020 03;38(3):489-503

Department of Nephrology & Hypertension, University Medical Center Utrecht.

Objective: Left ventricular (LV) hypertrophy is the most common cardiac alteration in patients with chronic kidney disease (CKD). Normalization of hypertension in CKD patients receiving a healthy kidney allograft often reverses LV hypertrophy, but effects on LV fibrosis remain unclear. To study causal interactions between graft and environment on LV hypertrophy, fibrosis and inflammation, we applied cross-kidney transplantation METHODS:: Orthotopic transplantation was performed after inducing CKD in rats by two-third bilateral ablation of kidney mass: Healthy kidney (K) donor to healthy heart (H) recipient (healthy-K→healthy-H); CKD-K→healthy-H; healthy-K→CKD-H; CKD-K→CKD-H; N= 6 per group.

Results: At week 6 after transplantation, mean arterial pressure (MAP) and LV mass index (LVMI) increased in CKD-K versus healthy-K irrespective of recipient. Contrarily, LV fibrosis was more severe in CKD-H versus healthy-H recipients irrespective of graft. Indeed, MAP and plasma creatinine correlated with LVMI but not with LV fibrosis. Increased LVMI in CKD-K→CKD-H not accompanied by cardiomyocyte cross-sectional area gain is consistent with eccentric remodelling. Cardiac RNA sequencing found a strong transcriptional response associated with LV fibrosis but only sparse changes associated with LV hypertrophy. This response was, among others, characterized by changes in extracellular matrix (ECM) and inflammatory gene expression.

Conclusion: LVMI reversed and MAP and renal function were normalized early after transplantation of a healthy kidney. However, LV fibrosis persisted, dissociating LV hypertrophy from LV fibrosis within 6 weeks. Elucidating cardiac ECM dynamics in CKD patients, although challenging, appears promising.
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http://dx.doi.org/10.1097/HJH.0000000000002285DOI Listing
March 2020

Normal-range thyroid-stimulating hormone levels and cardiovascular events and mortality in type 2 diabetes.

Diabetes Res Clin Pract 2019 Nov 16;157:107880. Epub 2019 Oct 16.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. Electronic address:

Aims: Thyroid dysfunction is a risk factor for cardiovascular disease. Whether thyroid function within the normal range is a risk factor for cardiovascular disease remains uncertain. The aim of this study is to evaluate whether plasma thyroid-stimulating hormone (TSH) levels in the normal range are a risk factor for cardiovascular disease and mortality in participants with type 2 diabetes mellitus with high cardiovascular risk.

Methods: We included 1265 participants with high cardiovascular risk, type 2 diabetes, and TSH within the normal range (0.35-5.00 mIU/L) from the Second Manifestations of ARTerial disease cohort. The primary outcome was major cardiovascular events (MACE; vascular death, stroke and myocardial infarction). Secondary outcomes of interest were the separate vascular outcomes and all-cause mortality. Cox proportional hazard models were used to evaluate the risk of plasma TSH levels on all outcomes.

Results: A total of 191 MACE occurred during a total follow-up of 8183 years. Plasma TSH levels were not associated with MACE (hazard ratio (HR) per mIU/L TSH increase 0.93; 95% confidence interval (95%CI) 0.80-1.08). With a total of 54 strokes during the study period, plasma TSH was associated with a lower risk of stroke (HR per mIU/L 0.64, 95% CI 0.45-0.89). There was no association between plasma TSH levels and risk of myocardial infarction, vascular death, or all-cause mortality.

Conclusions: Higher TSH levels within the normal range are associated with a lower risk of stroke in high-risk patients with type 2 diabetes, but not associated with the risk of other cardiovascular events or mortality.
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http://dx.doi.org/10.1016/j.diabres.2019.107880DOI Listing
November 2019

Hemodynamic Optimization in Cardiac Resynchronization Therapy: Should We Aim for dP/dt or Stroke Work?

JACC Clin Electrophysiol 2019 09 31;5(9):1013-1025. Epub 2019 Jul 31.

Department of Cardiology, and Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands. Electronic address:

Objectives: This study evaluated the acute effect of dP/dt- versus stroke work (SW)-guided cardiac resynchronization therapy (CRT) optimization and the related acute hemodynamic changes to long-term CRT response.

Background: Hemodynamic optimization may increase benefit from CRT. Typically, maximal left ventricular (LV) pressure rise dP/dt is used as an index of ventricular performance. Alternatively, SW can be derived from pressure-volume (PV) loops.

Methods: Forty-one patients underwent CRT implantation followed by invasive PV loop measurements. The stimulation protocol included 16 LV pacing configurations using each individual electrode of the quadripolar lead with 4 atrioventricular (AV) delays. Conventional CRT was defined as pacing from the distal electrode with an AV delay of approximately 120 ms.

Results: Compared with conventional CRT, dP/dt-guided optimization resulted in a one-third additional dP/dt increase (17 ± 11% vs. 12 ± 9%; p < 0.001). Similarly, SW-guided optimization resulted in a one-third additional SW increase (80 ± 55% vs. 53 ± 48%; p < 0.001). Comparing both optimization strategies, dP/dt favored contractility (8 ± 12% vs. 5 ± 10%; p = 0.015), whereas SW optimization improved ventricular-arterial (VA) coupling (45% vs. 32%; p < 0.001). After 6 months, mean LV ejection fraction (LVEF) change was 10 ± 9% with 23 (56%) patients becoming super-responders to CRT (≥10% LVEF improvement). Although acute changes in SW were predictive for long-term CRT response (area under the curve: 0.78; p = 0.002), changes in dP/dt were not (area under the curve: 0.65; p = 0.112).

Conclusions: PV-guided hemodynamic optimization in CRT results in approximately one-third SW improvement on top of conventional CRT, caused by a mechanism of enhanced VA coupling. In contrast, dP/dt optimization favored LV contractility. Ultimately, acute changes in SW showed larger predictive value for long-term CRT response compared with dP/dt.
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http://dx.doi.org/10.1016/j.jacep.2019.05.020DOI Listing
September 2019

Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease.

J Am Heart Assoc 2019 08 17;8(16):e011130. Epub 2019 Aug 17.

Department of Internal Medicine and Dermatology University of Utrecht University Medical Center Utrecht Utrecht the Netherlands.

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.
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http://dx.doi.org/10.1161/JAHA.118.011130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759901PMC
August 2019

Limited synergy of obesity and hypertension, prevalent risk factors in onset and progression of heart failure with preserved ejection fraction.

J Cell Mol Med 2019 10 31;23(10):6666-6678. Epub 2019 Jul 31.

Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands.

Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction. To clarify if and how interaction between these comorbidities contributes to development of diastolic dysfunction, lean and obese ZSF1 rats were treated with deoxycorticosterone acetate implants and a high-salt diet (DS) to induce severe hypertension, or with placebo. In addition to echocardiographic, metabolic and hemodynamic analyses, immunohistochemistry and RNAseq were performed on left ventricular tissue. Obesity negatively affected cardiac output, led to an elevated E/e' ratio and mildly reduced ejection fraction. DS-induced hypertension did not affect cardiac output and minimally elevated E/e' ratio. Diastolic derangements in placebo-treated obese rats developed in absence of inflammation and fibrosis, yet in presence of oxidative stress and hypertrophic remodelling. In contrast, hypertension triggered apoptosis, inflammation and fibrosis, with limited synergy of the comorbidities observed for inflammation and fibrosis. Transcriptional data suggested that these comorbidities exerted opposite effects on mitochondrial function. In placebo-treated obese rats, genes involved in fatty acid metabolism were up-regulated, whereas DS-induced a down-regulation of genes involved in oxidative phosphorylation. Overall, limited interaction was observed between these comorbidities in development of diastolic dysfunction. Importantly, differences in obesity- and hypertension-induced cardiac remodelling emphasize the necessity for comorbidity-specific phenotypical characterization.
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http://dx.doi.org/10.1111/jcmm.14542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787495PMC
October 2019

Comparison of MAGGIC and MECKI risk scores to predict mortality after cardiac rehabilitation among Dutch heart failure patients.

Eur J Prev Cardiol 2020 12 26;27(19):2126-2130. Epub 2019 Jul 26.

Radboud Institute for Health Sciences, Department of Physiology, Radboud University Medical Centre, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1177/2047487319865730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734558PMC
December 2020

Mediation analysis of the relationship between type 2 diabetes and cardiovascular events and all-cause mortality: Findings from the SMART cohort.

Diabetes Obes Metab 2019 08 23;21(8):1935-1943. Epub 2019 May 23.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Aim: To quantify the magnitude and specific contributions of known cardiovascular risk factors leading to higher cardiovascular risk and all-cause mortality caused by type 2 diabetes (T2D).

Methods: Mediation analysis was performed to assess the relative contributions of known classical risk factors for vascular disease in T2D (insulin resistance, systolic blood pressure, renal function, LDL-cholesterol, triglycerides and micro-albuminuria), and what proportion of the effect of T2D on cardiovascular events and all-cause mortality these factors mediate in the Second Manifestations of ARTerial disease (SMART) cohort consisting of 1910 T2D patients.

Results: Only 35% (95% CI 15-71%) of the excess cardiovascular risk caused by T2D is mediated by the classical cardiovascular risk factors. The largest mediated effect was through insulin resistance [proportion of mediated effect (PME) 18%, 95% CI 3-37%], followed by elevated triglycerides (PME 8%, 95% CI 4-14%) and micro-albuminuria (PME 7%, 95% CI 3-17%). Only 42% (95% CI 18-73%) of the excess mortality risk was mediated by the classical risk factors considered. The largest mediated effect was by micro-albuminuria (PME 18%, 95% CI 10-29%) followed by insulin resistance (PME 15%, 95% CI 1-33%).

Conclusion: A substantial amount of the increased cardiovascular risk and all-cause mortality caused by T2D cannot be explained by traditional vascular risk factors. Future research should focus on identifying non-classical pathways that might further explain the increased cardiovascular and mortality risk caused by T2D.
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http://dx.doi.org/10.1111/dom.13759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767388PMC
August 2019

Effectiveness of the European Society of Cardiology/Heart Failure Association website 'heartfailurematters.org' and an e-health adjusted care pathway in patients with stable heart failure: results of the 'e-Vita HF' randomized controlled trial.

Eur J Heart Fail 2019 02 28;21(2):238-246. Epub 2018 Nov 28.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Background: Efficient incorporation of e-health in patients with heart failure (HF) may enhance health care efficiency and patient empowerment. We aimed to assess the effect on self-care of (i) the European Society of Cardiology/Heart Failure Association website 'heartfailurematters.org' on top of usual care, and (ii) an e-health adjusted care pathway leaving out 'in person' routine HF nurse consultations in stable HF patients.

Methods And Results: In a three-group parallel-randomized trial in stable HF patients from nine Dutch outpatient clinics, we compared two interventions ( heartfailurematters.org website and an e-health adjusted care pathway) to usual care. The primary outcome was self-care measured with the European Heart Failure Self-care Behaviour Scale. Secondary outcomes were health status, mortality, and hospitalizations. In total, 450 patients were included. The mean age was 66.8 ± 11.0 years, 74.2% were male, and 78.8% classified themselves as New York Heart Association I or II at baseline. After 3 months of follow-up, the mean score on the self-care scale was significantly higher in the groups using the website and the adjusted care pathway compared to usual care (73.5 vs. 70.8, 95% confidence interval 0.6-6.2; and 78.2 vs. 70.8, 95% confidence interval 3.8- 9.4, respectively). The effect attenuated, until no differences after 1 year between the groups. Quality of life showed a similar pattern. Other secondary outcomes did not clearly differ between the groups.

Conclusions: Both the heartfailurematters.org website and an e-health adjusted care pathway improved self-care in HF patients on the short term, but not on the long term. Continuous updating of e-health facilities could be helpful to sustain effects.

Clinical Trial Registration: ClinicalTrials.gov ID NCT01755988.
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http://dx.doi.org/10.1002/ejhf.1354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607483PMC
February 2019