Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

ECG-only explainable deep learning algorithm predicts the risk for malignant ventricular arrhythmia in phospholamban cardiomyopathy.

BACKGROUND: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model. OBJECTIVE: This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data. METHODS: A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression. RESULTS: The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai). CONCLUSION: Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up.

The Use of Oral Anticoagulation Is Not Independently Associated with Mortality in Frail Older Patients with Repeated Falls.

BACKGROUND: Particularly in frail patients, anticoagulation may be underused because of the fear of bleeding. OBJECTIVE: To determine whether the use of antithrombotic medication is an independent risk factor for mortality in frail elderly with repeated falls. METHODS: All patients aged 65 years or older at the Fall and Syncope Clinic were eligible. Frailty was calculated with a Frailty Index (FI) based on the accumulation of deficits model. Risks were calculated with a cox regression analysis, adjusted for age, sex, and Frailty Index. RESULTS: 663 patients were included in this analysis. The median age was 80 years, 438 were women (66%), 73% had polypharmacy, and 380 patients (57%) had cognitive impairment. The mean FI was 0.23 (sd 0.09), 182 patients were moderately frail (27.5%), and 259 (39.1%) were severely frail. A total of 140 (21%) used oral anticoagulation and 223 (34%) used antiplatelet agents. A total of 196 patients (29.6%) died during follow-up. In the adjusted cox regression model, the use of neither antiplatelets nor anticoagulation was associated with mortality. A strong association was found with frailty (HR 74.0, 95% CI 13.1-417.3) and a weak association with age (HR 1.05, 95% CI 1.03-1.08). A lower risk of mortality was seen in women (HR 0.5, 95% CI 0.3-0.6). CONCLUSIONS: In this cohort of frail older patients, there was no independent association between the use of antithrombotic medication and mortality. A strong association with mortality was found with frailty, a weak association was found with age, and a lower mortality risk was found in women. Our data indicate that the fear of bleeding or increased mortality in frail patients with an indication for oral anticoagulation may be unjustified.

Machine learning-based biomarker profile derived from 4210 serially measured proteins predicts clinical outcome of patients with heart failure.

Aims: Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF. Methods and results: In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c-index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c-index of 0.85 upon internal validation and c-indices up to 0.80 upon external validation. The c-index was higher than that of a model containing established risk factors (P = 0.021). Conclusion: Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.

Septal Midwall Late Gadolinium Enhancement in Ischemic Cardiomyopathy and Nonischemic Dilated Cardiomyopathy-Characteristics and Prognosis.

Septal midwall late gadolinium enhancement (LGE) is a characteristic finding on cardiac magnetic resonance imaging (CMR) in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse events. Its significance in ischemic cardiomyopathy (ICM) is unknown. With this multicenter observational study, we aimed to study the characteristics of septal midwall LGE and evaluate its prognostic value in ICM. A total of 1,084 patients with an impaired left ventricular (LV) ejection fraction (<50%) on LGE-CMR, either because of ICM (53%) or DCM, were included retrospectively. Septal midwall LGE was defined as midmyocardial stripe-like or patchy LGE in septal segments and was present in 10% of patients with ICM compared with 34% of patients with DCM (p <0.001). It was significantly associated with larger LV volumes and lower LV ejection fraction, irrespective of etiology. The primary endpoint was all-cause mortality and secondary endpoint was ventricular arrhythmias (VAs), including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter-defibrillator (ICD) therapy. During a median follow-up of 2.7 years, we found a significant association between septal midwall LGE and mortality in patients with DCM (hazard ratio [HR] 1.92, p = 0.03), but not in patients with ICM (HR 1.35, p = 0.39). Risk of VAs was significantly higher in patients with septal midwall LGE on CMR, both in DCM (HR 2.80, p <0.01) and in ICM (HR 2.70, p <0.01). In conclusion, septal midwall LGE, typically seen in DCM, was also present in 10% of patients with ICM and was associated with increased LV dilation and worse function, irrespective of etiology. When present, septal midwall LGE was associated with adverse outcome.

[Outpatient parenteral antimicrobial therapy for infective endocarditis]. / Thuisbehandeling van infectieuze endocarditis.

Bacterial endocarditis is associated with high morbidity and mortality and requires a long hospitalization due to long-term intravenous antimicrobial therapy. It is possible to partially treat selected and stable patients at home. We present 3 patients partially treated at home with intravenous antibiotics for proven complicated endocarditis. Patient A presented with a septic shock and mitral valve endocarditis. Patient B presented with an ICD lead endocarditis and patient C presented with an mitral valve endocarditis. All 3 patients had a complicated endocarditis and presented with extensive embolic dissemination. Following the initial complicated clinical course, the patients were discharged for antibiotic home treatment after clinical improvement. Subsequent treatment was successful and reduced their hospital stay with more than 14 days. Thanks to transmural cooperation with the home-care colleagues, we can safely provide antibiotic care at home so that stabilized endocarditis patients can be treated in their own habitat.

Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure.

BACKGROUND: Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes. METHODS: In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13-31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing. RESULTS: In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (Pinteraction < 0.001) and somatostatin (Pinteraction = 0.040) with the PEP was modified by sex, independent of clinical characteristics. Endothelin-1 was more strongly associated with the PEP in men (HR 2.62 [95%CI, 1.98, 3.46], p < 0.001) compared to women (1.14 [1.01, 1.29], p = 0.036). Somatostatin was positively associated with the PEP in men (1.23 [1.10, 1.38], p < 0.001), but inversely associated in women (0.33 [0.12, 0.93], p = 0.036). CONCLUSION: Baseline cardiovascular protein levels differ between women and men. However, the predictive value of repeatedly measured circulating proteins does not seem to differ except for endothelin-1 and somatostatin.

Distant embolisation in infective endocarditis: characteristics and outcomes.

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.

Comprehensive Cardiovascular Magnetic Resonance-Derived Myocardial Strain Analysis Provides Independent Prognostic Value in Acute Myocarditis.

Background Late gadolinium enhancement and left ventricular (LV) ejection fraction on cardiovascular magnetic resonance (CMR) are prognostic markers, but their predictive value for incident heart failure or life-threatening arrhythmias in acute myocarditis patients is limited. CMR-derived feature tracking provides a more sensitive analysis of myocardial function and may improve risk stratification in myocarditis. In this study, the prognostic value of LV, right ventricular, and left atrial strain in acute myocarditis patients is evaluated. Methods and Results In this multicenter retrospective study, patients with CMR-proven acute myocarditis were included. The primary end point was occurrence of major adverse cardiovascular events: all-cause mortality, heart transplantation, heart failure hospitalizations, and life threatening arrhythmias. LV global longitudinal strain, global circumferential strain and global radial strain, right ventricular-global longitudinal strain and left atrial strain were measured. Unadjusted and adjusted cox proportional hazard regression analysis were performed. In total, 162 CMR-proven myocarditis patients were included (41 ± 17 years, 75% men). Mean LV ejection fraction was 51 ± 12%, and 144 (89%) patients had presence of late gadolinium enhancement. Major adverse cardiovascular events occurred in 29 (18%) patients during a follow-up of 5.5 (2.2-8.3) years. All LV strain parameters were independent predictors of outcome beyond clinical features, LV ejection fraction and late gadolinium enhancement (LV-global longitudinal strain: hazard ratio [HR] 1.07, P=0.02; LV-global circumferential strain: HR 1.15, P=0.02; LV-global radial strain: HR 0.98, P=0.03), but right ventricular or left atrial strain did not predict outcome. Conclusions CMR-derived LV strain analysis provides independent prognostic value on top of clinical parameters, LV ejection fraction and late gadolinium enhancement in acute myocarditis patients, while left atrial and right ventricular strain seem to be of less importance.

Heart failure subphenotypes based on repeated biomarker measurements are associated with clinical characteristics and adverse events (Bio-SHiFT study).

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.

Dynamic personalized risk prediction in chronic heart failure patients: a longitudinal, clinical investigation of 92 biomarkers (Bio-SHiFT study).

The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .

Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy.

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.

Electrocardiographic changes are strongly correlated with the extent of cardiac inflammation in mice with Coxsackievirus B3-induced viral myocarditis.

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.

Reversible Cause of Cardiac Arrest and Secondary Prevention Implantable Cardioverter Defibrillators in Patients With Coronary Artery Disease: Value of Complete Revascularization and LGE-CMR.

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<0.01) and extent of transmural late gadolinium enhancement (HR, 1.12; 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.

Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers.

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.

Regional myocardial function at preclinical disease stage of hypertrophic cardiomyopathy in female gene variant carriers.

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.

Associations of serially measured PCSK9, LDLR and MPO with clinical outcomes in heart failure.

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.

Characteristics and prognostic value of right ventricular (dys)function in patients with non-ischaemic dilated cardiomyopathy assessed with cardiac magnetic resonance imaging.

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 < 50%) on CMR were included retrospectively. Left atrial (LA), LV, and RV volumes and function were quantified. RV systolic dysfunction was defined as RVEF<45%. The presence and pattern of late gadolinium enhancement (LGE) on CMR were assessed visually. Septal midwall LGE was defined as midmyocardial stripe-like or patchy hyperenhancement in the septal segments, and the extent was quantified using the full width at half maximum method. Primary endpoint was a composite of all-cause mortality and VA, including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter defibrillator therapy. Secondary endpoints were time to all-cause mortality alone and time to VA alone. A total of 216 DCM patients were included (42% female, age 58 ± 14 years). Mean RVEF was 46 ± 12%, and RV dysfunction was present in 38%. RVEF was moderately correlated with LA dilation (LA minimal volume ρ = -0.38, P < 0.001) and strongly correlated with LA and LV dysfunction (LA emptying fraction r = 0.58, P < 0.001 and LVEF ρ = 0.52, P < 0.001). Septal midwall LGE was more often observed in patients with RV dysfunction compared with patients with preserved RV function (respectively 40% vs. 26%, P = 0.04). No correlation was found between RVEF and the extent of septal midwall LGE (ρ = -0.12, P = 0.34). During a median follow-up of 2.2 years [IQR 1.6-2.8], 30 patients experienced the primary endpoint. RV dysfunction was significantly associated with shorter time to the composite primary endpoint (HR 3.19 [95% CI 1.49-6.84], P < 0.01) and to the secondary endpoint of VA alone (HR 6.48 [95% CI 1.83-22.98], P < 0.01). There was a trend towards increased mortality when RV dysfunction was present (HR 2.54 [95% CI 0.99-6.57], P = 0.05). CONCLUSIONS: Right ventricular dysfunction was predominantly observed in patients with DCM with advanced heart failure and pronounced myocardial remodelling, defined as increased LV and LA dilation and dysfunction and the presence of septal midwall LGE on CMR. During follow-up, RV dysfunction was associated with shorter time to all-cause mortality and ventricular arrhythmic events.

Serially Measured Cytokines and Cytokine Receptors in Relation to Clinical Outcome in Patients With Stable Heart Failure.

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment.

Renal tubular damage and worsening renal function in chronic heart failure: Clinical determinants and relation to prognosis (Bio-SHiFT study).

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-ß-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 m2 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 m2 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.