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Background: This study aimed to identify heart failure (HF) subphenotypes using 92 repeatedly measured circulating proteins in 250 patients with heart failure with reduced ejection fraction, and to investigate their clinical characteristics and prognosis. Methods: Clinical data and blood samples were collected tri-monthly until the primary endpoint (PEP) or censoring occurred, with a maximum of 11 visits. The Olink Cardiovascular III panel was measured in baseline samples and the last two samples before the PEP (in 66 PEP cases), or the last sample before censoring (in 184 PEP-free patients). The PEP comprised cardiovascular death, heart transplantation, Left Ventricular Assist Device implantation, and hospitalization for HF. Cluster analysis was performed on individual biomarker trajectories to identify subphenotypes. Then biomarker profiles and clinical characteristics were investigated, and survival analysis was conducted. Results: Clustering revealed three clinically diverse subphenotypes. Cluster 3 was older, with a longer duration of, and more advanced HF, and most comorbidities. Cluster 2 showed increasing levels over time of most biomarkers. In cluster 3, there were elevated baseline levels and increasing levels over time of 16 remaining biomarkers. Median follow-up was 2.2 (1.4–2.5) years. Cluster 3 had a significantly poorer prognosis compared to cluster 1 (adjusted event-free survival time ratio 0.25 (95%CI:0.12–0.50), p < 0.001). Repeated measurements clusters showed incremental prognostic value compared to clusters using single measurements, or clinical characteristics only. Conclusions: Clustering based on repeated biomarker measurements revealed three clinically diverse subphenotypes, of which one has a significantly worse prognosis, therefore contributing to improved (individualized) prognostication.

Background Infective endocarditis is a severe and potentially lethal cardiac disease. Recognition of the clinical features of endocarditis, such as distant embolisation, and adequate treatment should be initiated promptly given the grim perspective of upcoming virulent pathogens. Methods We report on our registry-based experience with outcomes of consecutive patients with infective endocarditis with distant embolisation. We aimed to describe the patient characteristics of infective endocarditis complicated by distant organ embolisation and the safety aspects of continuing endocarditis treatment at home in these patients. Results From November 2018 through April 2022, 157 consecutive patients were diagnosed with infective endocarditis. Of them, 38 patients (24%) experienced distant embolisation, either in the cerebrum (n = 18), a visceral organ (n = 5), the lungs (n = 7) or the myocardium (n = 8). Pathogens identified in blood cultures were predominantly streptococcal variants (43%), with only one culture-negative endocarditis case. Of the 18 patients with cerebral embolisation, 12 had neurological complaints and most often discrete abnormal findings on neurological examination. Six of the 8 cardiac embolism patients experienced chest pain before admission. Visceral organ and pulmonary embolism occurred silently. Of the 38 patients with distant embolisation, 17 could be discharged earlier by providing antibiotic treatment at home without complications. Conclusion This registry-based single-centre experience showed an incidence of distant embolisation in daily care of 24%. Cerebral and coronary embolisation provoked symptoms, while visceral emboli remained silent. Pulmonary emboli may present with inflammatory signs. Distant embolisation was not in itself a contra-indication for outpatient endocarditis@home treatment.

We recently showed more severe diastolic dysfunction at the time of myectomy in female compared to male patients with obstructive hypertrophic cardiomyopathy. Early recognition of aberrant cardiac contracility using cardiovascular magnetic resonance (CMR) imaging may identify women at risk of cardiac dysfunction. To define myocardial function at an early disease stage, we studied regional cardiac function using CMR imaging with tissue tagging in asymptomatic female gene variant carriers. CMR imaging with tissue tagging was done in 13 MYBPC3, 11 MYH7 and 6 TNNT2 gene carriers and 16 age-matched controls. Regional peak circumferential strain was derived from tissue tagging images of the basal and midventricular segments of the septum and lateral wall. Left ventricular wall thickness and global function were comparable between MYBPC3, MYH7, TNNT2 carriers and controls. MYH7 gene variant carriers showed a different strain pattern as compared to the other groups, with higher septal peak circumferential strain at the basal segments compared to the lateral wall, whereas MYBPC3, TNNT2 carriers and controls showed higher strain at the lateral wall compared to the septum. Only subtle gene-specific changes in strain pattern occur in the myocardium preceding development of cardiac hypertrophy. Overall, our study shows that there are no major contractile deficits in asymptomatic females carrying a pathogenic gene variant, which would justify the use of CMR imaging for earlier diagnosis.

Contains fulltext : 233789.pdf (Publisher’s version ) (Open Access) AIMS: In non-ischaemic dilated cardiomyopathy (DCM), concomitant right ventricular (RV) dysfunction is frequently observed. This study sought to determine the correlation of RV dysfunction with several cardiac magnetic resonance (CMR) imaging characteristics in patients with DCM, and the prognostic value of RV dysfunction on all-cause mortality and ventricular arrhythmias (VA) was evaluated. METHODS AND RESULTS: Consecutive patients with DCM and left ventricular (LV) dysfunction (ejection fraction

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

Aims: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). Methods and Results: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47–2.98), P < 0.001], TRAP [0.62 (0.43–0.90), P = 0.009], GRN [2.46 (1.64–3.84), P < 0.001], SPON1 [3.94 (2.50–6.50), P < 0.001], and PGLYRP1 [1.62 (1.14–2.31), P = 0.006]. Conclusions: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.

Background Activation of the inflammatory response in heart failure (HF) may initially serve as a compensatory mechanism. However, on the longer term, this physiological phenomenon can become disadvantageous. Temporal patterns of inflammatory proteins other than CRP have not yet been investigated in patients with stable HF. Purpose We aimed to evaluate the association of 17 serially measured cytokines and cytokine receptors with clinical outcome in patients with stable heart failure. Methods In 263 patients, 1984 serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (IQR: 1.4–2.5) years. The primary endpoint (PE) composed of cardiovascular mortality, HF-hospitalization, heart transplantation, and LVAD. We selected baseline blood samples in all patients, as well as the two samples closest to the primary endpoint, and the last sample available in event-free patients. Thus, in 567 samples we measured 17 cytokines and cytokine receptors using the Olink Proteomics Cardiovascular III multiplex assay. Associations between biomarkers and PE were investigated by joint modelling. Results Median age was 68 (IQR: 59–76) years, with 72% men, 74% NYHA class I-II and a median ejection fraction of 30% (23–38%). 70 patients reached a PE. After adjustment for clinical characteristics (age, sex, diabetes, atrial fibrillation, NYHA class at baseline, diuretics and systolic blood pressure), 7 biomarkers were associated with the PE (Figure). Interleukin-1 receptor type 1 (IL1RT1) showed the strongest association: HR 2.65 [95% CI: 1.78–4.21]) per standard deviation change in level (NPX) at any point in time during follow-up, followed by Tumor necrosis factor receptor 1 (TNF-R1): 2.25 [1.66–3.08], and C-X-C motif chemokine 16 (CXCL16): 2.18 [1.59–3.04]. After adjustment for baseline N-terminal pro–B-type natriuretic peptide, high-sensitive troponin T and C-reactive protein however, only IL1RT1 and TNF-R1 remained significantly associated with the PE. Conclusion Repeatedly measured levels of several cytokines and cytokine receptors are independently associated with clinical outcome in stable HF patients. These results suggest that repeated measurements of these biomarkers, in addition to established cardiac biomarkers, may contribute to personalized risk assessment and herewith better identify high-risk patients. Figure 1. Associations between levels of cytokines and cytokine receptors and the primary endpoint. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by the Jaap Schouten Foundation and the Noordwest Academie.

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype–phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM). We performed non-quantitative direct-infusion high-resolution mass spectrometry-based untargeted metabolomics on serum from fasted asymptomatic gene variant carriers, symptomatic HOCM patients and healthy controls (n = 31, 14 and 9, respectively). Biomarker panels that discriminated the groups were identified by performing multivariate modeling with gradient-boosting classifiers. For all three group-wise comparisons we identified a panel of 30 serum metabolites that best discriminated the groups. These metabolite panels performed equally well as advanced cardiac imaging modalities in distinguishing the groups. Seven metabolites were found to be predictive in two different comparisons and may play an important role in defining the disease stage. This study reveals unique metabolic signatures in serum of preclinical carriers and HOCM patients that may potentially be used for HCM risk stratification and precision therapeutics.

Background Physicians can be reluctant to prescribe antithrombotic agents in frail elderly patients with frequent falls due to the fear for severe bleeding, mainly for intracranial haemorrhage (ICH). Presently, there is only a limited amount of inconclusive data available on the topic. Purpose Identification of risk factors for ICH within a cohort of geriatric patients with repeated falls. Methods All patients of 65 years of age and older with repeated falls at our day clinic were eligible. If an MRI of the brain was performed as part of the assessment, patients were included in this analysis. Baseline characteristics including medical, functional, and cognitive state were collected, a Frailty Index (FI) was calculated [1,2]. Cerebral small vessel disease was described and evaluated as proposed in a position paper in 2013 [3]. Follow-up data concerning major bleeding events were retrieved from the electronic medical files. Odds ratios (OR) with confidence intervals (CI) were calculated. Results 670 patients were eligible; an MRI was performed in 486 patients. The average age was 80 years, 50% was severely frail at the time of inclusion. 83 patients (17%) used OAC (mainly Vitamin K antagonists prescribed for atrial fibrillation), 165 patients (34%) used anti platelet agents (APA), 1 patient used both OAC and APA. In total, 29 major bleeding events (MB) occurred, of which 13 were ICH. Among patients using OAC, 8 MB occurred, of which 2 were ICH. The patient with both OAC and APA did not experience a bleeding event. Well known risk factors for ICH such as hypertension, diabetes mellitus and cognitive impairment were not predictive for ICH in this cohort, nor were the use APA (OR 0.86, 95% CI 0.26–2.84), or vitamin K antagonists (OR 0.88, 95% CI 0.19–4.05). However, a composite factor of using either APA or OAC, heightened the risk for MB (OR 3.24, 95% CI 1.35–7.74), but not for ICH (OR 0.83, 95% 0.27–2.49). Of cerebral small vessel disease, predictive factors for ICH were the presence of lacunes (OR 3.81, 95% CI 1.25–11.56), and relevant white matter hyperintensities (WMH) (defined as a Fazekas score of 2 or more) (OR 11.3, 95% CI 1.45–87.3). Furthermore, cognitive decline defined as an MMSE score of ≤26 heightened the risk of MB (OR 2.28, 95% CI 1.05–4.96). The low number of ICH did not allow for a multivariate analysis. Conclusion This analysis has several important findings. First, despite the long follow up of a cohort of severely frail patients that frequently fall, a low number of MB and ICH was observed. Second, well known risk factors for MB do not seem predictive of ICH in this cohort of very elderly patients. Finally, cognitive decline was predictive for MB, and WMH and lacunes were predictive for ICH. Adding cognitive screening and brain imaging to the diagnostic work up of patients with an indication for OAC could be of value when assessing the future risk for major bleeding events. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Frail older persons with falls are often undertreated for atrial fibrillation (AF) due to fear of bleeding complications of oral anticoagulants (OAC). However, the safety of OAC use in frail elderly with AF and falls is not investigated extensively. Purpose The aim of the study was to investigate whether frail older persons with falls and OAC for AF have more bleeding complications than patients without OAC and to investigate the association between frailty, OAC therapy (including bleeding complications), and mortality. Methods This observational study included frail patients aged 65 years or older who were evaluated for falls between November 2011 and December 2019. Patients using OAC for AF were compared with similar patients without using OAC. Primary outcomes were death, major bleeding and intracranial bleeding. Secondary outcomes were frailty measured by the Frailty Index and cause of death. Results Of the 645 included patients, 132 had AF and used OAC. Patients with AF were more often severely frail (67% vs. 47%, p Conclusions Elderly with falls and AF using OAC are frailer and have a tendency to a higher mortality risk than patients without AF. These frail elderly patients with falls had no more bleeding complications during OAC treatment than comparable patients without OAC. Therefore, withholding OAC out of fear for major bleeding complications is not justified. It is unclear why elderly persons with AF and OAC are frailer and die sooner, since the incidence of major bleedings and fatal bleedings is equal. Further research should focus why older frail persons with AF are more prone to die. Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. Background Cardiac magnetic resonance (CMR) plays a major role in both the diagnostic process and prognostic stratification in acute myocarditis. Presence of late gadolinium enhancement (LGE) and left ventricular (LV) ejection fraction (EF) are known predictors of major adverse cardiovascular events (MACE). However, in daily clinical practice it remains challenging to distinguish ‘the good from the bad’. The prognostic value of CMR feature tracking (FT) derived strain, with respect to LGE and LVEF, remains unclear. Purpose To evaluate the incremental prognostic value of left atrial (LA) phasic function, LV and right ventricular (RV) strain using CMR-FT in patients with CMR-proven acute myocarditis. Methods In this multicenter observational study, patients with CMR-proven acute myocarditis were included and followed with regard to MACE including all-cause mortality (ACM), heart-failure hospitalizations (HFH), and life-threatening arrhythmias (LTA). Using FT-derived strain, LV global longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS), RV GLS and LA phasic function were measured. Uni- and multivariable analysis including clinical and CMR parameters were performed to assess the association with MACE. Results A total of 162 patients were included (75% male, 41 ±17 years). MACE occurred in 29 patients (18%, ACM n = 18, HFH n = 7, LTA n = 11) during a median follow-up of 5.5 (2.2-8.3) years. Forty-six percent had a STEMI-like presentation (combination of chest pain, elevated troponin, and ST-elevation, n = 74). LGE was present in 90% of patients and mean LVEF was 51 ± 12%. Patients with LVEF Conclusions LV strain parameters are independent and incremental predictors of prognosis in patients with acute myocarditis, while RV strain and LA phasic function are not. Therefore, LV strain is a promising novel parameter for risk stratification in acute myocarditis.

Dilated cardiomyopathy (DCM) is characterized by enlargement of the heart with associated reduced left ventricular function. From an imaging perspective, important requirements are to exclude other pathologies, assess disease severity, guide therapeutic management, and identify complications. Establishing the imaging diagnosis of DCM is key to guiding the management of DCM. In this chapter we discuss how to use imaging to make an accurate diagnosis of DCM, and review how to exclude coronary artery disease (CAD) and valvular disease as these are two important differentials with differing management strategies. We then review the diagnostic and prognostic capabilities of echocardiography, cardiovascular magnetic resonance imaging (CMR) and nuclear techniques including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in DCM, with a focus on where imaging can identify particular causes of DCM.

Background In survivors of sudden cardiac arrest with obstructive coronary artery disease, it remains challenging to distinguish ischemia as a reversible cause from irreversible scar‐related ventricular arrhythmias. We aimed to evaluate the value of implantable cardioverter‐defibrillator (ICD) implantation in sudden cardiac arrest survivors with presumably reversible ischemia and complete revascularization. Methods and Results This multicenter retrospective cohort study included 276 patients (80% men, age 67±10 years) receiving ICD implantation for secondary prevention. Angiography was performed before ICD implantation. A subgroup of 166 (60%) patients underwent cardiac magnetic resonance imaging with late gadolinium enhancement before implantation. Patients were divided in 2 groups, (1) ICD‐per‐guideline, including 228 patients with incomplete revascularization or left ventricular ejection fraction ≤35%, and (2) ICD‐off‐label, including 48 patients with complete revascularization and left ventricular ejection fraction >35%. The primary outcome was time to appropriate device therapy (ADT). During 4.0 years (interquartile range, 3.5–4.6) of follow‐up, ADT developed in 15% of the ICD‐off‐label group versus 43% of the ICD‐per‐guideline group. Time to ADT was comparable in the ICD‐off‐label and ICD‐per‐guideline groups (hazard ratio (HR), 0.46; P =0.08). No difference in mortality was observed (HR, 0.95; P =0.93). Independent predictors of ADT included age (HR, 1.03; P =0.01), left ventricular end‐diastolic volume HR, (1.05 per 10 mL increase; P P =0.04). Conclusions This study demonstrates that sudden cardiac arrest survivors with coronary artery disease remain at high risk of recurrent ventricular arrhythmia, even after complete revascularization and with preserved left ventricular function. Late gadolinium enhancement–cardiac magnetic resonance imaging derived left ventricular volumes and extent of myocardial scar were independently associated with.

BACKGROUND: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients.METHODS: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation.RESULTS: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR.CONCLUSION: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.

Objective Viral myocarditis (VM) can induce changes in myocardial electrical conduction and arrhythmia. However, their relationship with myocarditis-associated arrhythmic substrates in the heart such as inflammation and fibrosis is relatively unknown. This we have analyzed in the present study. Methods C3H mice were infected with 1×105 plaque-forming units Coxsackievirus B3 (CVB3, n=68) and were compared with uninfected control mice (n=10). Electrocardiograms (ECGs) were recorded in all conscious mice shortly before sacrifice and included heart rate; P-R interval; QRS duration; QTc interval and R-peak amplitude of lead II and aVF. Mice were sacrificed at 4, 7, 10, 21, 35 or 49 days post-infection. Cardiac lesion size, calcification, fibrosis and cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells were quantitatively determined in cross-sections of the ventricles. Putative relations between ECG changes and lesion size and/or cardiac inflammation were then analyzed. Results Significant transient reductions in QRS duration and R-peak amplitude occurred between 4 and 14 days post-infection and returned to baseline values thereafter. The magnitude of these ECG changes strongly correlated to the extent of lymphocyte (days 7 and 14), macrophage (days 7 and 10) and neutrophil (days 7) infiltration. The ECG changes did not significantly correlate with lesion size and fibrosis. Conclusion VM induces transient changes in myocardial electrical conduction that are strongly related to cellular inflammation of the heart. These data show that even in mild VM, with relatively little cardiac damage, the inflammatory infiltrate can form an important arrhythmogenic substrate.

Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology & results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4–2.5) years in 263 CHF patients. Seventy patients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23–2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04–2.06]) and LDLR (HR: 0.66 [0.49–0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12–1.76] per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61–0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538 . https://clinicaltrials.gov/ct2/show/NCT01851538 .

Background: We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF. Methods: We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5–10) urine and 9 (5–10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached. Results: A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17–21.93), men: HR(95%CI) 3.14 (2.09–4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18–22.46), men: HR(95%CI) 4.91 (2.58–9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43–19.53), men: HR(95%CI) 3.29 [2.27–5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women. Conclusion: Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences.

Background Hypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin‐filament variant present with milder hypertrophy than carriers of thick‐filament variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in TNNT 2 (troponin T gene) variant carriers. Methods and Results Fourteen individuals with TNNT 2 variants (genotype positive), without left ventricular hypertrophy (G+/ LVH −; n=6) and with LVH (G+/ LVH +; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and [ 11 C]‐acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/ LVH − and G+/ LVH +. Lower myocardial external efficiency in G+/ LVH − is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/ LVH + is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/ LVH + compared with G+/ LVH −. Although LV ejection fraction was higher in G+/ LVH +, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall. Conclusions Using cardiac magnetic resonance and [ 11 C]‐acetate positron emission tomography imaging, we show that G+/ LVH − have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/ LVH +. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant–mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.

Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is a characteristic finding in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse cardiac events. QRS-prolongation in DCM is also frequently present and a predictor of arrhythmic events and mortality. Since the His-Purkinje fibres are located in the interventricular septum, QRS-prolongation may directly result from septal fibrosis, visualized by LGE. Our aim was to study the correlation of the presence and extent of septal midwall LGE and QRS-duration. Methods: DCM-patients with left ventricular (LV) dysfunction (LVEF

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4&ndash, 2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59&ndash, 76) years, with 72% men and 74% New York Heart Association class I&ndash, II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66&ndash, 3.16) per SD difference in level, followed by JAM-A (2.10, 1.42&ndash, 3.23) and C1qR (1.90, 1.36&ndash, 2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients.

Objectives This review and meta-analysis reviews the prognostic value of cardiac magnetic resonance (CMR) in nonischemic dilated cardiomyopathy (DCM). Background Late gadolinium-enhanced (LGE) CMR is a noninvasive method to determine the underlying cause of DCM and previous studies reported the prognostic value of the presence of LGE to identify patients at risk of major adverse cardiovascular events. Methods PubMed was searched for studies describing the prognostic implication of LGE in patients with DCM for the specified endpoints cardiovascular mortality, major ventricular arrhythmic events including appropriate implantable cardioverter-defibrillator therapy, rehospitalization for heart failure, and left ventricular reverse remodeling. Results Data from 34 studies were included, with a total of 4,554 patients. Contrast enhancement was present in 44.8% of DCM patients. Patients with LGE had increased cardiovascular mortality (odds ratio [OR]: 3.40; 95% confidence interval [CI]: 2.04 to 5.67), ventricular arrhythmic events (OR: 4.52; 95% CI: 3.41 to 5.99), and rehospitalization for heart failure (OR: 2.66; 95% CI: 1.67 to 4.24) compared with those without LGE. Moreover, the absence of LGE predicted left ventricular reverse remodeling (OR: 0.15; 95% CI: 0.06 to 0.36). Conclusions The presence of LGE on CMR substantially worsens prognosis for adverse cardiovascular events in DCM patients, and the absence indicates left ventricular reverse remodeling.

To evaluate different patterns of orthostatic hypotension (OH) and its relation to mortality in older patients with unexplained falls or syncope. This is an observational cohort study in consecutive patients aged ≥ 65 years with unexplained falls or syncope at a Fall Syncope day clinic November 2011 until May 2016. OH is defined as a decrease in systolic blood pressure (BP) ≥ 20 mmHg and/or in diastolic BP ≥ 10 mmHg during standing test. Main outcomes are the baseline characteristics and prevalence of patients with classical OH (decrease BP until 3 min), delayed OH (decrease of BP from 5 to 10 min) and continuous OH (decrease of BP for 10 min). Secondary outcome is the relation between different OH patterns and mortality. Of 374 patients with a mean age of 80 year (SD 6.6), 56% of the patients had OH: 16% had classical OH, 8% delayed OH, 32% had continuous OH and 44% had no OH. Patients with continuous OH and patients with delayed OH tended to have a higher mortality compared to patients with classical OH, 14 vs. 5% (P = 0.07) and 17 vs. 5% (P = 0.06). This possible relation between OH patterns and mortality could not be confirmed in multivariate analysis. In these very old patients, there are various patterns of decline in standing BP. Delayed and continuous OH will be missed if BP is measured only for 3 min during standing. This is important because patients with continuous OH and delayed OH might have a relation with mortality. Our results encourage additional studies investigating the relation between different OH patterns and mortality.

We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.

Introduction The prevalence of psychiatric symptoms has hardly been investigated in elderly syncope patients. The aim of this study was to investigate the prevalence of psychiatric symptoms in elderly syncope patients in comparison with elderly patients with falls. Materials and methods Observational cohort study including consecutive patients aged ≥ 65 with syncope and/or unexplained falls at an outpatient fall and syncope clinic. Main outcomes were the prevalence of depressive and anxiety symptoms. Secondary outcomes were the prevalence of fear of falling (FOF), 15-item Geriatric Depression Scale, 2-item Patient Health Questionnaire, use of psychotropic medication, and functional activity. Results We included 194 syncope patients and 184 fall patients (mean age of 79.7 ± 6.5 [SD] years). Depressive symptoms, including sadness, occurred frequently (33% in syncope group and 23% in fall group, P = 0.05). Symptoms of anxiety were present in 20% of both syncope and fall patients. The prevalence of FOF was 68% in the syncope group and 67% in the fall group. Compared with patients without FOF, patients with FOF more often had depressive symptoms ( P = 0.01), used more antidepressants ( P = 0.03) and benzodiazepines ( P = 0.00), and scored worse on the handgrip strength test (19.3 ± 8.4 vs. 22.6 ± 10.2, P = 0.01). Conclusions Psychiatric symptoms may be common in elderly patients with syncope or falls, occurring in one fifth to one third of these patients. Physicians taking care of older patients with syncope should be aware of the high prevalence of FOF with its associated functional decline, depressive symptoms, and high use of psychotropic medications.

Background: Several studies have suggested circulating microRNAs (miRs) are associated with heart failure, but these studies were small, and limited to single miR measurements.We examined 7 miRs which were previously linked to heart failure, and tested whether their temporal expression level predicts prognosis in a prospective cohort of chronic heart failure (CHF) patients.Methods and results: In 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3 months, we measured 7 miRs. The primary endpoint (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation and LVAD implantation. Associations between temporal miR patterns and the PE were investigated by joint modelling, which combines mixed models with Cox regression.Mean age was 67 +/- 13 years, 72% were men and 27% NYHA classes III-IV. We obtained 873 blood samples (median 3 [IQR 2-5] per patient). The PE was reached in 41 patients (16%) during a median follow-up of 0.9 [0.6-1.4] years. The temporal pattern of miR-22-3pwas independently associatedwith the PE (HR [95% CI] per doubling of level: 0.64 [0.47-0.77]). The instantaneous change in level (slope of the temporal miR pattern) of miR-22-3p was also independently associated with the PE (HR [95% CI] per doubling of slope: 0.33 [0.20-0.51]). These associations remained statistically significant after adjustment for temporal patterns of NT-proBNP, Troponin T and CRP.Conclusions: The temporal pattern of circulating miR-22-3p contains important prognostic and independent information in CHF patients. This concept warrants further investigation in larger series with extended follow-up. (C) 2017 The Authors. Published by Elsevier B.V.

Background In nonischemic dilated cardiomyopathy (DCM), diagnosis and prognosis is based on left ventricular function. Although concomitant right ventricular (RV) dysfunction is frequently observed, the underlying mechanism is currently not fully understood. Purpose We aimed to describe the characteristics of right ventricular function in DCM patients with cardiac magnetic resonance (CMR) imaging using cine and late-gadolinium enhancement (LGE) imaging. Methods Patients with DCM and left ventricular (LV) dysfunction (ejection fraction (EF) Results The study included 214 DCM patients (42% female, age 58±14 years) with a mean LVEF of 34±12% and RVEF of 46±12%. RV systolic dysfunction was present in 39% and was associated with the presence of septal midwall LGE (OR 1.96 (95% CI 1.09–3.54) p=0.026). In patients with RV dysfunction, LV dilation was more severe (LV end diastolic volume (EDV) 242±97mL vs. 212±58mL, p=0.011) and LVEF was lowere (26±12% vs. 39±8%, p In patients with RV dysfunction, left atrial volumes were enlarged (56±23mL/m2 vs. 46±14mL/m2, p RVEF in DCM patients Conclusion In DCM, reduced RVEF predominantly occurred in patients with a) LVEF lower than 30%, b) septal midwall enhancement, indicating progressive LV remodeling, c) LA dilation and d) LA dysfunction. This suggests that RV dysfunction in advanced DCM is drive by LV diastolic dysfunction resulting in increased afterload of the RV.

Background Cardiovascular inflammation and vascular endothelial dysfunction are present in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. The temporal patterns of the blood biomarkers involved could provide further insights into these processes. Purpose We aimed to evaluate the prognostic value of the temporal patterns of blood biomarkers of cell adhesion in stable patients with CHF. Methods In 263 patients, a median of 9 (IQR: 5–10) serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (IQR: 1.4–2.5) years. The composite primary endpoint (PE) of cardiovascular mortality, HF-hospitalization, heart transplantation and LVAD was reached in 70 patients. For efficiency, we selected all baseline samples, the two samples closest to a PE, and the last sample available for event-free patients. Thus, in 567 samples we measured twelve biomarkers of cell adhesion using the Olink Proteomics Cardiovascular III multiplex assay. Associations between biomarkers and first PE were investigated by combining linear mixed effect models and Cox regression (so-called joint model). Results Median age was 68 (IQR: 59–76) years, with 72% men and 74% NYHA class I-II. Levels of CD93 (Complement component C1q receptor), CDH5 (VE cadherin), CHI3L1 (Chitinase-3-like protein 1), EPHB4 (Ephrin type-B receptor 4) and JAM-A (Junctional adhesion molecule A) differed at baseline already. The average biomarker evolutions of these markers, and additionally of ICAM-2 (Intercellular adhesion molecule-2), showed different patterns in patients approaching the PE versus those who remained event-free (Figure 1). Repeatedly measured levels of these biomarkers were independently associated with the PE. Corresponding HRs [95% CI] per 1SD increase in log2 level (arbitrary unit) were: CD93: 1.85 [1.29–2.70], CDH5: 1.72 [1.23–2.44], CHI3L1: 2.45 [1.73–3.56], EPHB4: 1.83 [1.33–2.55], ICAM2: 1.74 [1.24–2.46] and JAM-A: 2.07 [1.39–3.18], adjusted for clinical characteristics (age, sex, diabetes, atrial fibrillation, baseline NYHA class, diuretics, systolic blood pressure and eGFR). Figure 1. Average temporal patterns of cell adhesion biomarkers during follow-up. Conclusion CD93, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A show different patterns as adverse events approach in CHF patients, and their temporal patterns strongly predict clinical outcome. These findings demonstrate the incremental value of repeated measurements of biomarkers of cell adhesion in stable patients with CHF. Acknowledgement/Funding This work was supported by the Jaap Schouten Foundation and the Noordwest Academie.

Introduction Atrial fibrillation (AF) is the most common arrhythmia and its incidence rises with age. Especially geriatric patients are at high risk for the development of AF as well as its complications. These high risk patients might benefit the most of oral anticoagulation. AF is however often asymptomatic in these patients and might stay undiagnosed. Purpose To assess the outcomes of opportunistic screening on AF on a geriatric outpatient clinic with a hand held single lead ECG device. Methods All consecutive patients 60 years and older that visited the outpatient clinic between the 1st of June 2017 and the 1st of June 2018 were eligible. Patients who were not able or willing to give informed consent, or had a pacemaker (PM) or internal cardioverter defibrillator (ICD) were excluded. Patients were screened 2 or 3 times at every visit with the MyDiagnostick©, a hand held single lead ECG device with inbuilt algorithm that identifies AF [1]. At baseline all patients underwent a comprehensive geriatric assessment (CGA), including a 12 lead ECG, physical, cognitive and functional assessment and medication review. All baseline ECGs were reviewed by 1 cardiologist and all measurements with the single lead device were reviewed by 2 independent cardiologists. Disagreement about the rhythm on the measurements was resolved by discussion between the cardiologists. Results 498 consecutive patients were eligible for inclusion. We excluded 39 patients: 20 patients had a PM or ICD, 17 did not want to participate and of 2 the medical files were incomplete. A total of 459 patients participated in this study. The mean age was 78±7.3 years and ranged from 60 to 100 years, 245 patients (53%) were female. Patients were known with 5±3 morbidities and used 6±4 different drugs. At baseline 88 (19%) patients were known with AF and AF was first diagnosed in 24 (5%) patients, constituting to an overall prevalence of 23% within this ambulatory geriatric population. Of these 24 patients, 4 (1%) showed AF on their baseline ECG and in 20 (4%) patients AF was found using the handheld device. A total of 1345 measurement with the handheld device were performed, 14 measurements (1%) were of too low quality to use, 32 (2%) were of poor quality, 148 (11%) acceptable and 1151 (86%) were of good quality. Sensitivity of the hand held device for detecting AF is 83.9%, specificity 99.2%, negative predictive value 99.6%, and positive predictive value 72.2%. Conclusions Opportunistic screening for AF with a hand held ECG device has a 5 times higher yield than the standard CGA with an 12 lead ECG at the first visit only. Also, AF can be reliably excluded after a negative measurement. Because of the potential benefit of OAC we advocate screening geriatric patients for AF at every doctor's visit. However, considering the positive predictive value, a confirmatory ECG remains necessary to confirm the diagnosis of AF. Acknowledgement/Funding None

Background Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure ( CHF ) patients. However, temporal patterns during the course of CHF , and especially the trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio‐SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study. Methods and Results In 263 CHF patients, we performed trimonthly blood sampling during a median follow‐up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point ( PE ), or the last sample available for end point–free patients. Thus, in 567 samples, we measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2, 3, and 9, tissue inhibitor metalloproteinase‐4, perlecan, aminopeptidase‐N, caspase‐3, cathepsin‐D, cathepsin‐Z, and cystatin‐B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59–76) years with 72% men; 70 patients reached the PE . Repeatedly measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2 and 9, tissue inhibitor metalloproteinase‐4, perlecan, cathepsin‐D, and cystatin‐B levels were significantly associated with the PE , and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity‐2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI : 5.53–10.30), followed by growth differentiation factor‐15 (4.06, 2.98–5.54) and matrix metalloproteinase‐2 (3.59, 2.55–5.05). Conclusions Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01851538.

To evaluate different patterns of orthostatic hypotension (OH) and its relation to mortality in older patients with unexplained falls or syncope.This is an observational cohort study in consecutive patients aged ≥ 65 years with unexplained falls or syncope at a Fall Syncope day clinic November 2011 until May 2016. OH is defined as a decrease in systolic blood pressure (BP) ≥ 20 mmHg and/or in diastolic BP ≥ 10 mmHg during standing test. Main outcomes are the baseline characteristics and prevalence of patients with classical OH (decrease BP until 3 min), delayed OH (decrease of BP from 5 to 10 min) and continuous OH (decrease of BP for 10 min). Secondary outcome is the relation between different OH patterns and mortality.Of 374 patients with a mean age of 80 year (SD 6.6), 56% of the patients had OH: 16% had classical OH, 8% delayed OH, 32% had continuous OH and 44% had no OH. Patients with continuous OH and patients with delayed OH tended to have a higher mortality compared to patients with classical OH, 14 vs. 5% (P = 0.07) and 17 vs. 5% (P = 0.06). This possible relation between OH patterns and mortality could not be confirmed in multivariate analysis.In these very old patients, there are various patterns of decline in standing BP. Delayed and continuous OH will be missed if BP is measured only for 3 min during standing. This is important because patients with continuous OH and delayed OH might have a relation with mortality. Our results encourage additional studies investigating the relation between different OH patterns and mortality.

Aims The pathophysiology underlying aortic valve stenosis (AVS)-induced cardiac dysfunction and reduced exercise capacity is unclear. We hypothesize that improvement of myocardial external efficiency (MEE)—the ratio between external work and myocardial oxygen consumption (MVO2)—underlies functional improvement of AVS patients after aortic valve replacement (AVR). Therefore, the aim of this proof-of-concept study was to investigate whether myocardial efficiency is reduced in patients with cardiac hypertrophy caused by AVS and to assess the effect of AVR on myocardial efficiency in relation to exercise capacity. Methods and results Echocardiography, cardiopulmonary exercise test, [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging were performed in 10 AVS patients prior to (pre-AVR) and 4 months after AVR (post-AVR). Fourteen healthy individuals served as control group. MEE was significantly lower in pre-AVR patients (32 ± 7%) than in controls (49 ± 6%). AVR significantly decreased left ventricle mass and MVO2. Also, external work significantly decreased post-AVR reaching similar values as in controls. AVR significantly improved MEE from 32 ± 7 to 37 ± 5% ( P = 0.02). Moreover, significant correlations were present between the AVR-induced increase in MEE and changes in both exercise work ( r = 0.74, P = 0.01) and peak VO2 ( r = 0.67, P = 0.03). However, four AVS patients did not show improved MEE, which was associated with no or minimal improvement in exercise parameters. Conclusion MEE is significantly reduced in patients with AVS-induced hypertrophy. Improved MEE is an important predictor of AVR-induced improvement of exercise capacity in AVS patients. Future investigation is needed to confirm our observations in a large prospective, multicenter clinical trial.

This review and meta-analysis reviews the prognostic value of cardiac magnetic resonance (CMR) in nonischemic dilated cardiomyopathy (DCM).Late gadolinium-enhanced (LGE) CMR is a noninvasive method to determine the underlying cause of DCM and previous studies reported the prognostic value of the presence of LGE to identify patients at risk of major adverse cardiovascular events.PubMed was searched for studies describing the prognostic implication of LGE in patients with DCM for the specified endpoints cardiovascular mortality, major ventricular arrhythmic events including appropriate implantable cardioverter-defibrillator therapy, rehospitalization for heart failure, and left ventricular reverse remodeling.Data from 34 studies were included, with a total of 4,554 patients. Contrast enhancement was present in 44.8% of DCM patients. Patients with LGE had increased cardiovascular mortality (odds ratio [OR]: 3.40; 95% confidence interval [CI]: 2.04 to 5.67), ventricular arrhythmic events (OR: 4.52; 95% CI: 3.41 to 5.99), and rehospitalization for heart failure (OR: 2.66; 95% CI: 1.67 to 4.24) compared with those without LGE. Moreover, the absence of LGE predicted left ventricular reverse remodeling (OR: 0.15; 95% CI: 0.06 to 0.36).The presence of LGE on CMR substantially worsens prognosis for adverse cardiovascular events in DCM patients, and the absence indicates left ventricular reverse remodeling.