Publications by authors named "Svend Aakhus"

142 Publications

Relationship of Mechanical Dyssynchrony and LV Remodeling With Improvement of Mitral Regurgitation After CRT.

JACC Cardiovasc Imaging 2021 Oct 7. Epub 2021 Oct 7.

Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium. Electronic address:

Objectives: The aim of this study was to explore the association between mechanical dyssynchrony of the left ventricle before cardiac resynchronization therapy (CRT) and improvement of mitral regurgitation (MR) after CRT.

Background: MR is very frequent among patients with dilated cardiomyopathy and conduction delay.

Methods: Echocardiograms (pre-CRT and 12 ± 3.8 months thereafter) of 314 patients with dilated cardiomyopathy and any degree of MR, who underwent CRT device implantation according to guidelines, were analyzed. Left ventricular (LV) mechanical dyssynchrony was assessed by apical rocking (ApRock) and septal flash (SF), while MR severity was graded from I to IV on the basis of vena contracta width, regurgitation jet size, and proximal isovelocity surface area.

Results: At baseline, 30% of patients presented with severe MR (grade III or IV). In 62% of patients, MR decreased after CRT, and these patients more frequently had left bundle branch block, had more severe MR, had more dilated left ventricles, had lower ejection fractions, and more often had ApRock and SF. Reverse remodeling was more frequent among patients with MR reduction (ΔLV end-systolic volume -35.5% ± 27.2% vs -4.1% ± 33.2%; P < 0.001). In a multivariable logistic stepwise regression, only ApRock (odds ratio [OR]: 3.8; 95% CI: 1.7-8.5; P = 0.001), SF (OR: 3.6; 95% CI: 1.6-7.9; P = 0.002), and baseline MR (OR: 1.4; 95% CI: 1.0-1.9; P = 0.046) remained significantly associated with MR reduction.

Conclusions: ApRock, SF, and severity of MR at baseline are strongly associated with MR reduction after CRT, while LV reverse remodeling is its underlying mechanism. Therefore, in patients with heart failure with LV dyssynchrony on optimal medical treatment, CRT should be the primary treatment attempt for relevant MR.
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http://dx.doi.org/10.1016/j.jcmg.2021.08.010DOI Listing
October 2021

Left Ventricular Systolic Function in Long-Term Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

JACC CardioOncol 2020 Sep 15;2(3):460-471. Epub 2020 Sep 15.

Department of Cardiology, Oslo University Hospital, Oslo, Norway.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a potentially curative therapy for malignant and nonmalignant diseases, is being increasingly used in younger patients. Although allo-HSCT survivors have an established increased risk of cardiovascular disease, there is limited knowledge of the long-term effects on cardiac function in survivors.

Objectives: The purpose of this study was to describe left ventricular (LV) systolic function in long-term allo-HSCT survivors treated in childhood, adolescence, or early adulthood.

Methods: Our cross-sectional cohort study included 104 patients (56% women), age 18 ± 10 years at time allo-HSCT with 17 ± 6 years of follow-up. Echocardiography included 2-dimensional (2D) and 3-dimensional (3D) analyses and speckle tracking imaging. In total, 55 healthy control subjects with a similar age, sex, and body mass index were used for comparison. Left ventricular systolic dysfunction (LVSD) was defined as reduced 2D left ventricular ejection fraction (LVEF) of <52% in men and <54% in women, and/or a reduced global longitudinal strain (GLS) of ≥-17%. Multivariable linear regression was used to determine independent predictors of 2D-LVEF and GLS.

Results: Allo-HSCT survivors had significantly reduced LV systolic function compared with control subjects: 2D-LVEF (55.2 ± 5.8% vs. 59.0 ± 2.9%; p < 0.001), 3D LVEF (54.0 ± 5.1% vs. 57.6 ± 2.7%; p < 0.001), and GLS (-17.5 ± 2.2% vs. -19.8 ± 1.4%; p < 0.001). LVSD was found in 44.2%, of whom 28.3% were symptomatic. Clinical factors independently associated with 2D-LVEF and/or GLS included age, anthracyclines, graft versus host disease (GVHD), heart rate, and hypertension. In the 45% of survivors pre-treated with anthracyclines, the effect of anthracyclines on 2D-LVEF and GLS was dose-dependent.

Conclusions: LVSD is common in long-term survivors of allo-HSCT treated in their youth. Pre-HSCT therapies with anthracyclines, age, heart rate, hypertension, and graft versus host disease are associated with measures of LV function.
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http://dx.doi.org/10.1016/j.jaccao.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352258PMC
September 2020

Risk scores for prediction of 30-day mortality after transcatheter aortic valve implantation: Results from a two-center study in Norway.

Health Sci Rep 2021 Jun 6;4(2):e283. Epub 2021 May 6.

Department of Cardiology University Hospital of North Norway Tromsø Norway.

Objectives: Transcatheter aortic valve implantation (TAVI)-specific risk scores have been developed based on large registry studies. Our aim was to evaluate how both surgical and novel TAVI risk scores performed in predicting all cause 30-day mortality. In addition, we wanted to explore the validity of our own previously developed model in a separate and more recent cohort.

Methods: The derivation cohort included patients not eligible for open surgery treated with TAVI at the University Hospital of North Norway (UNN) and Oslo University Hospital (OUS) from February 2010 through June 2013. From this cohort, a logistic prediction model (UNN/OUS) for all cause 30-day mortality was developed. The validation cohort consisted of patients not included in the derivation cohort and treated with TAVI at UNN between June 2010 and April 2017. EuroSCORE, Logistic EuroSCORE, EurosSCORE 2, STS score, German AV score, OBSERVANT score, IRRMA score, and FRANCE-2 score were calculated for both cohorts. The discriminative accuracy of each score, including our model, was evaluated by receiver operating characteristic (ROC) analysis and compared using DeLong test where < .05 was considered statistically significant.

Results: The derivation cohort consisted of 218 and the validation cohort of 241 patients. Our model showed statistically significant better accuracy than all other scores in the derivation cohort. In the validation cohort, the FRANCE-2 had a significantly higher predictive accuracy compared to all scores except the IRRMA and STS score. Our model showed similar results.

Conclusion: Existing risk scores have shown limited accuracy in predicting early mortality after TAVI. Our results indicate that TAVI-specific risk scores might be useful when evaluating patients for TAVI.
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http://dx.doi.org/10.1002/hsr2.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102057PMC
June 2021

Effect of Continuous Positive Airway Pressure on Arrhythmia in Atrial Fibrillation and Sleep Apnea: A Randomized Controlled Trial.

Am J Respir Crit Care Med 2021 09;204(5):573-582

Department of Cardiology, Rikshospitalet.

Sleep apnea (SA) is highly prevalent in patients with atrial fibrillation (AF), and both conditions are associated with adverse cardiovascular outcomes. To determine the effect of continuous positive airway pressure (CPAP) on AF burden. This open-label, parallel-group, randomized controlled trial included patients with paroxysmal AF and moderate to severe SA (apnea-hypopnea index ⩾15). A computerized system randomized eligible patients (1:1) to 5 months' treatment with CPAP plus usual care (CPAP,  = 55) or usual care alone (control,  = 54). The outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control groups in change of AF burden (percentage of time in AF) as measured by implantable loop recorder. A total of 579 patients with paroxysmal AF had respiratory polygraphy, of whom 244 (42%) had moderate to severe SA. Of these, 158 (65%) participated in the CPAP run-in period, of whom 39 (25%) patients did not tolerate the treatment. A total of 108 patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last 3 months of CPAP intervention and from 5.0% to 4.3% in the control group. The adjusted between-group difference at follow-up was -0.63 (95% confidence interval, -2.55 to 1.30) percentage points ( = 0.52). Seven serious adverse events (13%) occurred in the CPAP group, and two (4%) occurred in the control group. In patients with paroxysmal AF and SA, treatment with CPAP did not result in a statistically significant reduction in the burden of AF.Clinical trial registered with www.clinicaltrials.gov (NCT02727192).
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http://dx.doi.org/10.1164/rccm.202011-4133OCDOI Listing
September 2021

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2021 04;77(15):1845-1855

Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.

Objectives: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI.

Methods: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.

Results: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.

Conclusions: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).
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http://dx.doi.org/10.1016/j.jacc.2021.02.049DOI Listing
April 2021

Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy.

J Am Coll Cardiol 2021 02 18;77(4):392-401. Epub 2020 Nov 18.

Menzies Research Institute, Hobart, Tasmania, Australia; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. Electronic address:

Background: In patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT.

Objectives: This study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care.

Methods: In this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year.

Results: Of 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: -20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03).

Conclusions: Although the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628).
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http://dx.doi.org/10.1016/j.jacc.2020.11.020DOI Listing
February 2021

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

Circ Heart Fail 2020 10 23;13(10):e006643. Epub 2020 Sep 23.

Research Institute of Internal Medicine (F.A., A.A., A.E.M., T.L., S.H., B.H., A.V.F., L.-E.V., S.N., T.R., P.A., T.U.), Institute of Basic Medical Sciences, University of Oslo, Norway.

Background: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.

Methods: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.

Results: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, <0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], <0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).

Conclusions: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006643DOI Listing
October 2020

3D Myocardial Mechanical Wave Measurements: Toward In Vivo 3D Myocardial Elasticity Mapping.

JACC Cardiovasc Imaging 2021 08 26;14(8):1495-1505. Epub 2020 Aug 26.

Centre for Innovative Ultrasound Solutions, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.

Objectives: This study aimed to investigate the potential of a novel 3-dimensional (3D) mechanical wave velocity mapping technique, based on the natural mechanical waves produced by the heart itself, to approach a noninvasive 3D stiffness mapping of the left ventricle.

Background: Myocardial fibrosis is recognized as a pathophysiological substrate of major cardiovascular disorders such as cardiomyopathies and valvular heart disease. As fibrosis leads to increased myocardial stiffness, ultrasound elastography measurements could provide important clinical information.

Methods: A 3D high frame rate imaging sequence was implemented on a high-end clinical ultrasound scanner to achieve 820 volumes/s when gating over 4 consecutive cardiac cycles. Five healthy volunteers and 10 patients with various degrees of aortic stenosis were included to evaluate feasibility and reproducibility. Mechanical waves were detected using the novel Clutter Filter Wave Imaging approach, shown to be highly sensitive to the weak tissue displacements caused by natural mechanical waves.

Results: 3D spatiotemporal maps of mechanical wave velocities were produced for all subjects. Only the specific mechanical wave at atrial contraction provided a full 3D coverage of the left ventricle (LV). The average atrial kick propagation velocity was 1.6 ± 0.2 m/s in healthy volunteers and 2.8 ± 0.8 m/s in patients (p = 0.0016). A high correlation was found between mechanical wave velocity and age (R = 0.88, healthy group), septal wall thickness (R = 0.73, entire group), and peak jet velocity across the aortic valve (R = 0.70). For 3 of the patients, the higher mechanical wave velocity coexisted with the presence of late gadolinium enhancement on cardiac magnetic resonance.

Conclusions: In this study, 3D LV mechanical wave velocities were visualized and measured in healthy volunteers and patients with aortic stenosis. The proposed imaging sequence and measurement technique allowed, for the first time, the measurement of full spatiotemporal 3D elasticity maps of the LV using ultrasound. (Ultrasonic markers for myocardial fibrosis and prognosis in aortic stenosis; NCT03422770).
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http://dx.doi.org/10.1016/j.jcmg.2020.05.037DOI Listing
August 2021

Sex differences in circulating proteins in heart failure with preserved ejection fraction.

Biol Sex Differ 2020 08 24;11(1):47. Epub 2020 Aug 24.

Université de Lorraine, INSERM, Centre d'Investigation Clinique et Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce.

Methods: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models.

Results: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18.

Conclusion: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.
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http://dx.doi.org/10.1186/s13293-020-00322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444077PMC
August 2020

The association of mechanical dyssynchrony and resynchronization therapy with survival in heart failure with a wide QRS complex: a two-world study.

Int J Cardiovasc Imaging 2020 Aug 30;36(8):1507-1514. Epub 2020 Apr 30.

Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Catholic University Leuven, Herestraat 49, 3000, Leuven, Belgium.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35-0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups-they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17-0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22-0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25-0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.
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http://dx.doi.org/10.1007/s10554-020-01865-xDOI Listing
August 2020

Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction: insights from the MEDIA-DHF study (The Metabolic Road to Diastolic Heart Failure).

Biomarkers 2020 Mar 16;25(2):201-211. Epub 2020 Feb 16.

CHRU de Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre d'Investigation Clinique et Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes. Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression. Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 1. Patients in cluster 2 those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32,  = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism. Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.
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http://dx.doi.org/10.1080/1354750X.2020.1727015DOI Listing
March 2020

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies.

J Hypertens 2020 07;38(7):1347-1354

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet.

Objective: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental wingless (Wnt) pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia.

Methods: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study [n = 10 in each group, RNA sequencing (RNAseq)] to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months postpartum from an acute preeclampsia study (preeclampsia n = 34, normal pregnancy n = 61).

Results: We found circulating and placental mRNA levels of the secreted Wnt agonist R-spondin 3 (RSPO3) at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the noncanonical Ca/NFAT pathway. Finally, plasma dickkopf 3 was decreased in preeclampsia 6 months postpartum.

Conclusion: We identify a potential role for RSPO3 and activation of noncanonical Wnt signaling in preeclampsia.
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http://dx.doi.org/10.1097/HJH.0000000000002362DOI Listing
July 2020

Systolic Dysfunction in Systemic Sclerosis: Prevalence and Prognostic Implications.

ACR Open Rheumatol 2019 Jun 31;1(4):258-266. Epub 2019 May 31.

Oslo University Hospital, Oslo, Norway and University of Oslo Oslo Norway.

Objective: Primary cardiac involvement is presumed to account for a substantial part of disease-related mortality in systemic sclerosis (SSc). Still, there are knowledge gaps on the evolution and total burden of systolic dysfunction in SSc. Here we evaluated prospective left ventricular (LV) and right ventricular (RV) systolic function in an unselected SSc cohort and assessed the burden of systolic dysfunction on mortality.

Methods: From the Oslo University Hospital cohort, 277 SSc patients were included from 2003-2016 and compared with healthy controls. Serial echocardiographies were reevaluated in order to detect change in systolic function. Right heart catheterization was performed on patients suspected of pulmonary hypertension. Descriptive and regression analyses were conducted.

Results: At baseline, LV systolic dysfunction by ejection fraction less than 50%, or a global longitudinal strain greater than -17.0%, was found in 12% and 24%, respectively. RV systolic dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 17 mm was evident in 10%. Follow-up echocardiography was performed after a median of 3.3 years (interquartile range [IQR] 1.5-5.6). At follow-up, LV systolic function remained stable, whereas RV function evaluated by TAPSE deteriorated (mean 23.1 to 21.7 mm, = 0.005) equaling a 15% prevalence of RV systolic dysfunction. RV systolic function predicted mortality in multivariable models (hazard ratio 0.41, 95% confidence interval [CI] 0.19-0.90, value 0.027), whereas LV systolic function lost predictive significance when adjusted for TAPSE.

Conclusion: In this unselected and prospective study, systolic dysfunction of the LV and RV was a frequent complication of SSc. LV systolic function remained stable across the observation period, whereas RV function deteriorated and predicted mortality.
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http://dx.doi.org/10.1002/acr2.1037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857986PMC
June 2019

Rationale for the ASSAIL-MI-trial: a randomised controlled trial designed to assess the effect of tocilizumab on myocardial salvage in patients with acute ST-elevation myocardial infarction (STEMI).

Open Heart 2019;6(2):e001108. Epub 2019 Oct 15.

Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Introduction: Interleukin-6 (IL-6) may be involved in ischaemia-reperfusion injury and myocardial remodelling after myocardial infarction (MI). We have recently shown that IL-6 inhibition by tocilizumab attenuates systemic inflammation and troponin T-release in patients with acute non-ST elevation MI (NSTEMI). Experimental studies suggest that IL-6 inhibition can limit infarct size through anti-inflammatory mechanisms, but this has not been tested in clinical studies. With the essing the effect of nti--6 treatment in (ASSAIL-MI) trial, we aim to examine whether a single administration of the IL-6 receptor antagonist tocilizumab can increase myocardial salvage in patients with acute ST-elevation MI (STEMI).

Methods And Analysis: The ASSAIL-MI trial is a randomised, double blind, placebo-controlled trial, conducted at three high-volume percutaneous coronary intervention (PCI) centres in Norway. 200 patients with first-time STEMI presenting within 6 hours of the onset of chest pain will be randomised to receive tocilizumab or matching placebo prior to PCI. The patients are followed-up for 6 months. The primary endpoint is the myocardial salvage index measured by cardiac MRI (CMR) 3-7 days after the intervention. Secondary endpoints include final infarct size measured by CMR and plasma markers of myocardial necrosis. Efficacy and safety assessments during follow-up include blood sampling, echocardiography and CMR.

Ethics And Dissemination: Based on previous experience the study is considered feasible and safe. If tocilizumab increases myocardial salvage, further endpoint-driven multicentre trials may be initiated. The ASSAIL-MI trial has the potential to change clinical practice in patients with STEMI.

Registration: Clinicaltrials.gov, identifier NCT03004703.
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http://dx.doi.org/10.1136/openhrt-2019-001108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803013PMC
February 2021

Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis.

J Immunol 2019 10 6;203(7):1973-1980. Epub 2019 Sep 6.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway;

Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, = 123; population 2, = 436; population 3, = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.
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http://dx.doi.org/10.4049/jimmunol.1801244DOI Listing
October 2019

Combining Automatic Angle Correction and 3-D Tracking Doppler for the Assessment of Aortic Stenosis Severity.

IEEE Trans Ultrason Ferroelectr Freq Control 2019 09 10;66(9):1404-1412. Epub 2019 Jun 10.

Aortic valve stenosis (AS) is a narrowing of the aortic valve opening, which causes increased load on the left ventricle. Untreated, this condition can eventually lead to heart failure and death. According to current recommendations, an accurate diagnosis of AS mandates the use of multiple acoustic windows to determine the highest velocity. Furthermore, the optimal positioning of both patient and transducer to reduce the beam-to-flow angle is emphasized. Being operator dependent, the beam alignment is a potential source of uncertainty. In this work, we perform noncompounded 3-D plane wave imaging for retrospective estimation of maximum velocities in aortic jets with automatic angle correction. This is achieved by combining a hybrid 3-D speckle tracking method to estimate the jet direction and 3-D tracking Doppler to generate angle-corrected sonograms, using the direction from speckle tracking as input. Results from simulations of flow through an orifice show that 3-D speckle tracking can estimate the jet orientation with acceptable accuracy for signal-to-noise ratios above 10 dB. Results from 12 subjects show that sonograms recorded from a standard apical view using the proposed method yield a maximum velocity that matches continuous wave (CW) Doppler sonograms recorded from the acoustic window with the lowest angle within a ±10% margin, provided that a high enough pulse repetition frequency could be achieved. These results motivate further validation and optimization studies.
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http://dx.doi.org/10.1109/TUFFC.2019.2921818DOI Listing
September 2019

Predictors of early mortality after transcatheter aortic valve implantation.

Open Heart 2019;6(1):e000936. Epub 2019 Apr 23.

Department of Cardiology, University Hospital of North Norway, Tromsø, Norway.

Objectives: To investigate whether preoperative echocardiographic evaluation of ventricular function, especially right ventricular systolic and diastolic parameters including speckle-tracking analysis, could aid in the prediction of 30-day mortality after transcatheter aortic valve implantation (TAVI) in patients with aortic stenosis.

Methods: This is a prospective observational cohort study including 227 patients accepted for TAVI at the University Hospital of North Norway and Oslo University Hospital from February 2010 through June 2013. All patients underwent preoperative transthoracic echocardiography with retrospective speckle-tracking analysis. Primary endpoint was all-cause 30-day mortality.

Results: All-cause 30-day mortality was 8.7 % (n = 19). Independent predictors of 30-day mortality were systolic pulmonary arterial pressure (SPAP) > 60 mm Hg (HR: 7.7, 95% CI: 1.90 to 31.3), heart failure (HR: 2.9, 95% CI: 1.1 to 7.78), transapical access (HR: 3.8, 95% CI: 1.3 to 11.2), peripheral artery disease (HR: 6.0, 95% CI: 2.0 to 18.0) and body mass index (HR: 0.73, 95% CI: 0.61 to 0.87). C-statistic for the model generated was 0.91 (95% CI: 0.85 to 0.98). Besides elevated SPAP, no other echocardiographic measurements were found to be an independent predictor of early mortality.

Conclusion: Except for elevated systolic pulmonary artery pressure, our data suggests that clinical rather than echocardiographic parameters are useful predictors of 30-day mortality after TAVI.
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http://dx.doi.org/10.1136/openhrt-2018-000936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519416PMC
February 2021

Sex-specific difference in outcome after cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2019 May;20(5):504-511

Department of Cardiovascular Diseases, University Hospitals Leuven, University of Leuven, Herestraat 49, Leuven, Belgium.

Aims: Observation of better outcome in women after cardiac resynchronization therapy (CRT) has led to controversies about a potential sex-specific response. In this study, we investigated to which extent this sex-specific difference in CRT outcome could be explained by differences in baseline characteristics between both sexes.

Methods And Results: We retrospectively analysed data from a multicentre registry of 1058 patients who received CRT. Patients were examined by echocardiography before and 12 ± 6 months after implantation. Response was defined as ≥15% reduction of left ventricular end-systolic volume at follow-up. Patient's characteristics at baseline, including New York Heart Association class, ejection fraction, QRS width and morphology, ischaemic aetiology of cardiomyopathy (ICM), number of scarred segments, age at implantation, atrial fibrillation, and mechanical dyssynchrony (Dyss) were analysed. Patients were followed for a median duration of 59 months. Primary end point was all-cause mortality. Women (24% of the population) had less ICM (23% vs. 49%, P < 0.0001), less scarred segments (0.4 ± 1.3 vs. 1.0 ± 2.1, P < 0.0001), more left bundle branch block (LBBB; 87% vs. 80%, P = 0.01), and more Dyss at baseline (78% vs. 57%, P < 0.0001). Without matching baseline differences, women showed better survival (log rank P < 0.0001). After matching, survival was similar (log rank P = 0.58). In multivariable analysis, female sex was no independent predictor of neither volumetric response (P = 0.06) nor survival (P = 0.31).

Conclusion: Our data suggest that the repeatedly observed better outcome in women after CRT is mainly due to the lower rate ICM and smaller scars. When comparing patients with similar baseline characteristics, the response of both sexes to CRT is similar.
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http://dx.doi.org/10.1093/ehjci/jey231DOI Listing
May 2019

Treatment of sleep apnea in patients with paroxysmal atrial fibrillation: design and rationale of a randomized controlled trial.

Scand Cardiovasc J 2018 Dec 5;52(6):372-377. Epub 2019 Feb 5.

a Department of Cardiology , Oslo University Hospital, Rikshospitalet , Oslo , Norway.

Rationale: Atrial fibrillation is associated with increased mortality as well as morbidity. There is strong evidence for an association between atrial fibrillation and sleep apnea. It is not known whether treatment of sleep apnea with continuous positive airway pressure (CPAP) will reduce the burden of atrial fibrillation.

Objective: The Treatment of Sleep Apnea in Patients with Paroxysmal Atrial Fibrillation study will investigate the effects of CPAP in patients with paroxysmal atrial fibrillation and sleep apnea.

Design: The trial has a dual center, randomized, controlled, open-label, parallel design.

Methods: Two centers will enroll a total of 100 patients with both paroxysmal atrial fibrillation and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/h) who are scheduled for catheter ablation. Patients will be randomized in a 1:1 ratio to CPAP or control group (50 patients in each arm). The effects of CPAP treatment on atrial fibrillation will be determined using an implanted loop recorder (Reveal LINQ™, Medtronic) that detects all arrhythmia episodes. The primary endpoint is a reduction of the total burden of atrial fibrillation in the intervention group, after 5 months' follow-up (preablation). Reduction in the arrhythmia recurrence rate after ablation is the main secondary endpoint. All patients will be followed up for 12 months after ablation.

Conclusion: This study is the first randomized controlled trial that will provide data on the effects of CPAP therapy in patients with paroxysmal atrial fibrillation and sleep apnea. The results are expected to improve our understanding of the interaction between paroxysmal atrial fibrillation and sleep apnea. ClinicalTrials.gov Identifier. NCT02727192.
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http://dx.doi.org/10.1080/14017431.2019.1567933DOI Listing
December 2018

Arterial properties in adults with long-lasting active juvenile idiopathic arthritis compared to healthy controls.

Pediatr Rheumatol Online J 2018 Dec 29;16(1):85. Epub 2018 Dec 29.

Department of Circulation and Imaging, Faculty of Medicine and Health Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.

Background: The data on cardiovascular risk and systemic arterial properties in patients with long-lasting juvenile idiopathic arthritis (JIA) is limited. The objective of this study was to describe systemic arterial properties including characteristic impedance (Z), total arterial compliance (C), and peripheral vascular resistance (R) in patients with long-lasting active JIA compared with matched controls, and to assess the relation to JIA disease variables and traditional cardiovascular risk factors.

Findings: Methods: Eighty-one JIA patients (median age 38.6) with at least 15 years of active disease were reexamined after median 29 years of disease duration and compared to 41 healthy controls. With use of echocardiography and calibrated right common carotid artery tonometric pulse traces, noninvasive estimates of pressure and blood flow from the aortic root were obtained and used to estimate the systemic arterial parameters Z, C and R.

Results: The patients had higher Z as assessed by Windkessel model (mean ± SD 65.0 ± 30.1 versus 53.4 ± 18.8 10 mmHg/ml/s, p = 0.027), lower C as assessed by either Windkessel model or ratio of stroke volume and pulse pressure (1.57 ± 0.46 versus 1.80 ± 0.65 ml/mmHg, p = 0.030, 1.29 ± 0.37 versus 1.43 ± 0.34 ml/mmHg, p = 0.038), and similar R compared to the controls. Years on daily prednisolone and insulin resistance were the most important correlates of Z Metotrexat use, polyarticular disease course and erythrocyte sedimentation rate were also associated with a higher Z CONCLUSION: Our results indicate that JIA patients had altered arterial properties as compared to controls. Years on daily prednisolone and insulin resistance were the most important correlates of altered arterial properties.
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http://dx.doi.org/10.1186/s12969-018-0302-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310961PMC
December 2018

Espeland and co-workers respond.

Tidsskr Nor Laegeforen 2018 11 26;138(19). Epub 2018 Nov 26.

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http://dx.doi.org/10.4045/tidsskr.18.0865DOI Listing
November 2018

Myocardial fibrosis.

Tidsskr Nor Laegeforen 2018 10 12;138(16). Epub 2018 Oct 12.

Bakgrunn: Myokardfibrose oppstår sekundært til kardial belastning eller skade. I denne oversiktsartikkelen presenteres sentrale aspekter ved myokardfibrose.

Kunnskapsgrunnlag: Vi foretok 2 søk i PubMed som til sammen ga 417 treff. Artiklenes relevans ble vurdert på grunnlag av tittel, sammendrag og eventuell fulltekst. 44 sentrale artikler ble inkludert.

Resultater: Myokardfibrose klassifiseres som interstitiell fibrose og erstatningsfibrose. Fibrose kan forårsake ugunstige endringer i hjertets elektriske og mekaniske funksjon, og forverrer prognosen ved mange hjertesykdommer. Bildediagnostikk og forskning på biomarkører har forbedret mulighetene for å påvise fibrose. Det ultimate målet er å utvikle medikamenter som kan bremse eller reversere myokardfibrose.

Fortolkning: Moderne diagnostikk har forbedret mulighetene for å påvise myokardfibrose og økt forståelsen av fibrosens betydning ved hjertesykdommer. Utvikling av medikamenter som hemmer fibroseutviklingen, vil kunne få stor betydning for moderne hjertemedisin.
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http://dx.doi.org/10.4045/tidsskr.17.1027DOI Listing
October 2018

Left Ventricular Diastolic Dysfunction Predicts Mortality in Patients With Systemic Sclerosis.

J Am Coll Cardiol 2018 10;72(15):1804-1813

Department of Rheumatology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address:

Background: Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality.

Objectives: The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality.

Methods: SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted.

Results: Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84).

Conclusions: DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.
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http://dx.doi.org/10.1016/j.jacc.2018.07.068DOI Listing
October 2018

Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction.

Int J Cardiol 2018 Nov 29;271:1-7. Epub 2018 Jun 29.

Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.

Aim: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI).

Methods: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay.

Results: Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1β (MIP-1β), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (m), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β m, placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines.

Conclusions: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.
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http://dx.doi.org/10.1016/j.ijcard.2018.04.136DOI Listing
November 2018

Machine Learning Analysis of Left Ventricular Function to Characterize Heart Failure With Preserved Ejection Fraction.

Circ Cardiovasc Imaging 2018 04;11(4):e007138

Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain (S.S.-M., G.P., B.H.B.); Asclepios Research Group, Université Côte d'Azur, Inria, Sophia Antipolis, France (N.D.); Wales Heart Research Institute, Cardiff University, United Kingdom (T.E., A.G.F.); Department of Cardiology, Oslo University Hospital, Norway (G.K., S.A.); Department of Circulation and Imaging, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway (S.A.); Clinic of Cardiology, St. Olav Hospital, Trondheim, Norway (S.A.); Department of Cardiology, University of Eastern Piedmont, Novara, Italy (A.D., P.M.); Division of Cardiology, University Hospital "S.Maria della Misericordia", Perugia, Italy (E.C.); and Catalan Institution for Research and Advanced Studies, Barcelona, Spain (B.H.B.).

Background: Current diagnosis of heart failure with preserved ejection fraction (HFpEF) is suboptimal. We tested the hypothesis that comprehensive machine learning (ML) of left ventricular function at rest and exercise objectively captures differences between HFpEF and healthy subjects.

Methods And Results: One hundred fifty-six subjects aged >60 years (72 HFpEF+33 healthy for the initial analyses; 24 hypertensive+27 breathless for independent evaluation) underwent stress echocardiography, in the MEDIA study (Metabolic Road to Diastolic Heart Failure). Left ventricular long-axis myocardial velocity patterns were analyzed using an unsupervised ML algorithm that orders subjects according to their similarity, allowing exploration of the main trends in velocity patterns. ML identified a continuum from health to disease, including a transition zone associated to an uncertain diagnosis. Clinical validation was performed (1) to characterize the main trends in the patterns for each zone, which corresponded to known characteristics and new features of HFpEF; the ML-diagnostic zones differed for age, body mass index, 6-minute walk distance, B-type natriuretic peptide, and left ventricular mass index (<0.05) and (2) to evaluate the consistency of the proposed groupings against diagnosis by current clinical criteria; correlation with diagnosis was good (κ, 72.6%; 95% confidence interval, 58.1-87.0); ML identified 6% of healthy controls as HFpEF. Blinded reinterpretation of imaging from subjects with discordant clinical and ML diagnoses revealed abnormalities not included in diagnostic criteria. The algorithm was applied independently to another 51 subjects, classifying 33% of hypertensive and 67% of breathless controls as mild-HFpEF.

Conclusions: The analysis of left ventricular long-axis function on exercise by interpretable ML may improve the diagnosis and understanding of HFpEF.
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http://dx.doi.org/10.1161/CIRCIMAGING.117.007138DOI Listing
April 2018

Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2019 01;20(1):66-74

Department of Cardiovascular Diseases, University Hospitals Leuven, University of Leuven, Herestraat 49, Leuven, Belgium.

Aim: To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines.

Methods And Results: Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37-86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines.

Conclusion: Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony.
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http://dx.doi.org/10.1093/ehjci/jey029DOI Listing
January 2019

Determinants and Outcome of Decision Making Among Patients with Severe Aortic Stenosis.

J Heart Valve Dis 2017 07;26(4):413-422

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway.

Background And Aim Of The Study: Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aortic stenosis (AS), but despite clear indications for surgical treatment a significant proportion of patients do not undergo AVR. The study aim was to identify clinical variables associated with the decision to perform AVR, and to assess the prognostic effect of surgery versus medical treatment in patients with severe AS adjusted for significant confounders and effect modifiers.

Methods: A prospective observational study of consenting patients aged >18 years who were under consideration for AVR at the authors' tertiary teaching hospital was conducted. The main outcomes of the study were treatment decisions and survival.

Results: Among 480 patients with severe AS who were evaluated, 351 had surgical AVR, 38 had transcatheter AVR, and 91 were declined operative treatment. Typically, non-operated patients were older, were in a lower NYHA class, had fewer symptoms, a lower peak aortic jet velocity, a higher NT-proBNP level, and a lower physical summary score (SF-36). Higher age showed the strongest correlation against AVR (OR 0.91; 95% CI 0.87-0.94). One-, three-, and five-year cumulative survival rates, respectively, were 95%, 87%, and 73% among operated patients, and 82%, 47%, and 27% among non-operated patients. The median survival time was 1,604 days (95% CI 1,554-1,655) in operated patients versus 1,090 days (95% CI 954-1,226) in non-operated patients (p <0.001). The effect of operation on mortality was shown to depend on the interaction with diabetes, when adjusted for significant confounders (i.e., age, atrial fibrillation, NT-proBNP, hs-Troponin T, and NYHA class). An effect of AVR on mortality was found in patients without diabetes (HR 0.29; 95% CI 0.19-0.468; p <0.001), but not among patients with diabetes.

Conclusions: Supplemental and better parameters to improve patient selection are warranted. Surgical AVR shows a greater prognostic effect in patients without diabetes.
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July 2017

Timing of myocardial shortening determines left ventricular regional myocardial work and regional remodelling in hearts with conduction delays.

Eur Heart J Cardiovasc Imaging 2018 08;19(8):941-949

Department of Cardiovascular Diseases, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium.

Aims: The interaction between asynchronous regional myocardial activation and left ventricular (LV) wall remodelling has not been well established. We investigated the relationship between time of onset of longitudinal shortening (Tonset), regional myocardial work, and segmental LV wall thickness (SWT) in patients treated with cardiac resynchronization therapy (CRT).

Methods And Results: We analysed 26 patients with sinus rhythm, non-ischaemic cardiomyopathy (63 ± 9 years, 69% male, QRS duration 174 ± 18 ms) and positive response to CRT (15% reduction in end-systolic volume). Longitudinal strain was obtained by 2D speckle-tracking echocardiography before and after [14.5 (7-29) months] CRT. Tonset and SWT were measured in 18 segments per LV. Segmental myocardial work was calculated from non-invasive segmental stress-strain loop area. Before CRT, Tonset was the shortest in septal and anteroseptal and the longest in lateral and posterior walls (P < 0.001) and not different after CRT (P = 0.733). Before CRT, septal and anteroseptal walls were significantly thinner than lateral and posterior. After CRT, reverse remodelling increased thickness in septal and anteroseptal and thinned lateral and posterior segments (P < 0.001). Before CRT, non-uniformity in work distribution with reduced work in septal and anteroseptal and increased work in lateral and posterior walls (P < 0.001) was observed. After CRT, distribution of myocardial work was uniform (P = 0.215).

Conclusion: Dys-synchronous myocardial shortening is related to thinning of early and thickening of late activated segments in heart failure with conduction delay. Correction of dys-synchrony leads to regression of inhomogeneity towards more evenly distributed wall thickness. Regional differences in myocardial work load that are homogenized by successful CRT are considered as the underlying pathophysiological mechanism.
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http://dx.doi.org/10.1093/ehjci/jex325DOI Listing
August 2018

The association of volumetric response and long-term survival after cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2017 Oct;18(10):1109-1117

Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium.

Aims: Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT.

Methods And Results: In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 ± 3 months post-implantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 ± 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction ≥15%), and LV volume expansion (ESV increase ≥5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P < 0.001).

Conclusion: Volumetric response assessed at 1-year after CRT is strongly associated with long-term mortality. However, an optimal cut-off cannot be established. The association of the correction of mechanical dyssynchrony with survival was stronger than that of any volumetric cut-off.
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http://dx.doi.org/10.1093/ehjci/jex188DOI Listing
October 2017

Accuracy of Cuff-Measured Blood Pressure: Systematic Reviews and Meta-Analyses.

J Am Coll Cardiol 2017 Aug;70(5):572-586

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy.

Objectives: This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards.

Methods: Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP.

Results: A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval [CI]: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001) but overestimated intra-arterial diastolic BP (5.5 mm Hg; 95% CI: 3.5 to 7.5 mm Hg; p < 0.0001). Cuff and intra-arterial aortic SBP showed a small mean difference (0.3 mm Hg; 95% CI: -1.5 to 2.1 mm Hg; p = 0.77) but poor agreement (mean absolute difference 8.0 mm Hg; 95% CI: 7.1 to 8.9 mm Hg). Concordance between BP classification using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cuff BP (normal, pre-HTN, and HTN stages 1 and 2) compared with intra-arterial brachial BP was 60%, 50%, 53%, and 80%, and using intra-arterial aortic BP was 79%, 57%, 52%, and 76%, respectively. Using revised intra-arterial thresholds based on cuff BP percentile rank, concordance between BP classification using cuff BP compared with intra-arterial brachial BP was 71%, 66%, 52%, and 76%, and using intra-arterial aortic BP was 74%, 61%, 56%, and 65%, respectively.

Conclusions: Cuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adversely influences correct BP classification. These findings indicate that stronger accuracy standards for BP devices may improve cardiovascular risk management.
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http://dx.doi.org/10.1016/j.jacc.2017.05.064DOI Listing
August 2017
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