Publications by authors named "Kenneth Dickstein"

317 Publications

Perceived risk profile and treatment optimization in heart failure: an analysis from BIOlogy Study to TAilored Treatment in chronic heart failure.

Clin Cardiol 2021 May 7. Epub 2021 May 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.

Background: Achieving target doses of angiotensin-converting-enzyme inhibitor/angiotensin-receptor blockers (ACEi/ARB) and beta-blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT-CHF) study, many patients were not up-titrated for which no clear reason was reported. Therefore, we hypothesized that perceived-risk profile might influence treatment optimization.

Methods: We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up-titration (after a 3-month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses.

Results: For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta-blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta-blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups.

Conclusions: Patients in whom clinicians did not give a reason why up-titration was missed were older and had more co-morbidities. Patients in whom up-titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up-titration was missed cannot be determined.
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http://dx.doi.org/10.1002/clc.23576DOI Listing
May 2021

Impaired High-Density Lipoprotein Function in Patients With Heart Failure.

J Am Heart Assoc 2021 May 17;10(9):e019123. Epub 2021 Apr 17.

Department of Pediatrics University of Groningen Groningen The Netherlands.

Background We recently showed that, in patients with heart failure, lower high-density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow-up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti-inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti-inflammatory capacity declined (both <0.001). In contrast, antioxidative capacity increased (<0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT-CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71-0.92; =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow-up, independent of HDL cholesterol. HDL cholesterol efflux and anti-inflammatory capacity declined during follow-up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.
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http://dx.doi.org/10.1161/JAHA.120.019123DOI Listing
May 2021

Global Differences in Burden and Treatment of Ischemic Heart Disease in Acute Heart Failure: REPORT-HF.

JACC Heart Fail 2021 May 7;9(5):349-359. Epub 2021 Apr 7.

University of Bergen, Stavanger University Hospital, Stavanger, Norway. Electronic address:

Objectives: The primary aim of the current study was to investigate global differences in prevalence, association with outcome, and treatment of ischemic heart disease (IHD) in patients with acute heart failure (AHF) in the REPORT-HF (International Registry to Assess Medical Practice With Longitudinal Observation for Treatment of Heart Failure) registry.

Background: Data on IHD in patients with AHF are primarily from Western Europe and North America. Little is known about global differences in treatment and prognosis of patients with IHD and AHF.

Methods: A total of 18,539 patients with AHF were prospectively enrolled from 44 countries and 365 centers in the REPORT-HF registry. Patients with a history of coronary artery disease, an ischemic event causing admission for AHF, or coronary revascularization were classified as IHD. Clinical characteristics, treatment, and outcomes of patients with and without IHD were explored.

Results: Compared with 8,766 (47%) patients without IHD, 9,773 (53%) patients with IHD were older, more likely to have a left ventricular ejection fraction <40% (heart failure with reduced ejection fraction [HFrEF]), and reported more comorbidities. IHD was more common in lower income compared with high-income countries (61% vs. 48%). Patients with IHD from countries with low health care expenditure per capita or without health insurance less likely underwent coronary revascularization or used anticoagulants at discharge. IHD was independently associated with worse cardiovascular death (hazard ratio: 1.21; 95% confidence interval: 1.09 to 1.35). The association between IHD and cardiovascular death was stronger in HFrEF compared with heart failure with preserved ejection fraction (p <0.001).

Conclusions: In this large global contemporary cohort of patients with AHF, IHD was more common in low-income countries and conveyed worse 1-year mortality, especially in HFrEF. Patients in regions with the greatest burden of IHD were less likely to receive coronary revascularization and treatment for IHD.
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http://dx.doi.org/10.1016/j.jchf.2020.12.015DOI Listing
May 2021

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

Eur J Heart Fail 2021 Mar 23. Epub 2021 Mar 23.

Department of Cardiovascular Science, University of Leicester, NIHR Leicester Biomedical Research Centre, Cardiovascular Unit and University Hospitals of Leicester NHS Trust, Leicester, UK.

Aims: Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).

Methods And Results: This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and β-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to β-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome.

Conclusion: Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.
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http://dx.doi.org/10.1002/ejhf.2160DOI Listing
March 2021

Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure.

Eur J Heart Fail 2021 Mar 20. Epub 2021 Mar 20.

University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Aims: Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.

Methods And Results: Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3-227.7) vs. 120.7 IU/mL (IQR 34.74-338.9), P < 0.001, for Q1-3 vs. Q4] and aldosterone [88 (IQR 44-179) vs. 116 IU/mL (IQR 46-241), P < 0.001, for Q1-3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log-alanine aminotransferase, log-total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor-23 and N-terminal pro-B-type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.

Conclusions: In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.
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http://dx.doi.org/10.1002/ejhf.2158DOI Listing
March 2021

The value of spot urinary creatinine as a marker of muscle wasting in patients with new-onset or worsening heart failure.

J Cachexia Sarcopenia Muscle 2021 Mar 20. Epub 2021 Mar 20.

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

Background: Muscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new-onset or worsening HF (WHF).

Methods: In BIOSTAT-CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new-onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland.

Results: Median spot urinary creatinine concentrations were 5.2 [2.7-9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09-1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04-1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P < 0.001) and predicted a higher rate for all-cause mortality [hazard ratio (HR) = 1.27, 95% CI = 1.17-1.38 per log decrease; P < 0.001] and the combined endpoints HF hospitalization or all-cause mortality (HR = 1.23, 95% CI = 1.15-1.31 per log decrease; P < 0.001). Significance was lost after addition of the BIOSTAT risk model. Analyses of the validation cohort yielded similar findings.

Conclusions: Lower spot urinary creatinine is associated with smaller body dimensions, renal dysfunction, and more severe HF in patients with new-onset/WHF. Additionally, lower spot urinary creatinine is associated with an increased risk of weight loss and a poorer exercise capacity/quality of life. Urinary creatinine could therefore be a novel, easily obtainable marker to assess (risk of) muscle wasting in HF patients.
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http://dx.doi.org/10.1002/jcsm.12690DOI Listing
March 2021

Quality of life in men and women with heart failure: association with outcome, and comparison between the Kansas City Cardiomyopathy questionnaire and the EuroQol 5 dimensions questionnaire.

Eur J Heart Fail 2021 Mar 16. Epub 2021 Mar 16.

Department of Cardiology, University of Groningen, Groningen, The Netherlands.

Aims: We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ-5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF).

Methods And Results: From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) we compared KCCQ and EQ-5D at baseline and after 9 months in 1276 men and 373 women with new-onset or worsening symptoms of HFrEF, who were sub-optimally treated and in whom there was an anticipated up-titration of guideline-derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ-OS, 44 vs. 53, P < 0.001) and EQ-5D utility score (0.62 vs. 0.73, P < 0.001). QoL improved equally in women and men at follow-up. All summary measures of QoL were independently associated with all-cause mortality, with KCCQ-OS showing the most remarkable association with mortality up to 1 year compared to the EQ-5D scores (C-statistic 0.650 for KCCQ-OS vs. 0.633 and 0.599 for EQ-5D utility score and EQ-5D visual analogue scale, respectively). QoL was associated with all outcomes analysed, both in men and women (all P for interaction with sex >0.2).

Conclusion: Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ-OS in particular, showed the strongest independent association with outcome.
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http://dx.doi.org/10.1002/ejhf.2154DOI Listing
March 2021

Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction.

Eur J Heart Fail 2021 Mar 2. Epub 2021 Mar 2.

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

Aims: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers.

Methods And Results: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patients with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patient subgroups based on their biomarker profiles: cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels; and cluster 4 with highest prevalence of ischaemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or heart failure hospitalization was highest in clusters 1 and 4 (62.1% and 62.8%, respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival.

Conclusion: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathways.
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http://dx.doi.org/10.1002/ejhf.2144DOI Listing
March 2021

Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials.

Am Heart J 2021 Feb 20;237:45-53. Epub 2021 Feb 20.

Department of Medicine, University of Mississippi, Jackson, MS.

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known.

Objective: To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations.

Methods: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors.

Results: A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months.

Conclusions: The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.
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http://dx.doi.org/10.1016/j.ahj.2021.02.015DOI Listing
February 2021

Non-fatal cardiovascular events preceding sudden cardiac death in patients with an acute myocardial infarction complicated by heart failure: insights from the high-risk myocardial infarction database.

Eur Heart J Acute Cardiovasc Care 2021 Apr;10(2):127-131

National Institute of Health and Medical Research Center for Clinical Multidisciplinary Research, INSERM U1116, Université de Lorraine, Inserm, Centre d'Investigations cliniques-plurithématique 1433, Inserm U1116; CHRU Nancy; F-CRIN INI-CRCT network, Nancy, France.

Aims: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD).

Methods And Results: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death).

Conclusion: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.
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http://dx.doi.org/10.1093/ehjacc/zuaa012DOI Listing
April 2021

Optimized Implementation of cardiac resynchronization therapy - a call for action for referral and optimization of care.

Europace 2021 Feb 5. Epub 2021 Feb 5.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heartfailure hospitalization rates and reduces all-cause mortality. Nevertheless, up to two-thirds ofeligible patients are not referred for CRT. Furthermore, post implantation follow-up is oftenfragmented and suboptimal, hampering the potential maximal treatment effect. This jointposition statement from three ESC Associations, HFA, EHRA and EACVI focuses onoptimized implementation of CRT. We offer theoretical and practical strategies to achievemore comprehensive CRT referral and post-procedural care by focusing on four actionabledomains; (I) overcoming CRT under-utilization, (II) better understanding of pre-implantcharacteristics, (III) abandoning the term 'non-response' and replacing this by the concept ofdisease modification, and (IV) implementing a dedicated post-implant CRT care pathway.
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http://dx.doi.org/10.1093/europace/euab035DOI Listing
February 2021

Is acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF.

Eur J Heart Fail 2021 Jan 22;23(1):43-57. Epub 2021 Jan 22.

Momentum Research, Inc., Durham, NC, USA.

Aims: This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.

Methods And Results: The BIOSTAT-CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6-month mortality was 12.3% for acute HF and 4.7% for worsening HF in chronic outpatients). Multivariable models predicting 180-day mortality and 180-day HF readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C-index of 0.71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C-index of 0.913 in the index cohort and 0.901 in the validation cohort.

Conclusions: This study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.
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http://dx.doi.org/10.1002/ejhf.2077DOI Listing
January 2021

Current clinical practice of cardiac resynchronization therapy in Turkey: Reflections from Cardiac Resynchronization Therapy Survey-II.

Anatol J Cardiol 2020 Dec;24(6):382-396

Division of Cardiology, Stavanger University Hospital; Stavanger-Norway; Institute of Internal Medicine, University of Bergen; Bergen-Norway.

Objective: Cardiac resynchronization therapy (CRT) has been shown to reduce mortality in selected patients with heart failure with reduced ejection fraction (HFrEF). CRT Survey-II was a snapshot survey to assess current clinical practice with regard to CRT. Herein, we aimed to compare Turkish data with other countries of European Society of Cardiology (ESC).

Methods: The survey was conducted between October 2015 and December 2016 in 42 ESC member countries. All consecutive patients who underwent a de novo CRT implantation or a CRT upgrade were eligible.

Results: A total of 288 centers included 11,088 patients. From Turkey, 16 centers recruited 424 patients representing 12.9% of all implantations. Compared to the entire cohort, Turkish patients were younger with a lower proportion of men and a higher proportion with ischemic etiology. Electrocardiography (ECG) showed sinus rhythm in 81.5%, a QRS duration of <130 ms in 10.1%, and ≥150 ms in 63.8% of patients. Left bundle branch block (LBBB) was more common. Median left ventricular ejection fraction (LVEF) was 25%, lower than in the overall ESC cohort, but NYHA class was more often II. Most common indication for CRT implantation was HF with a wide QRS (70.8%). Almost 98.3% of devices implanted were CRT-D, in contrast to the overall cohort. Fluoroscopy time was longer, but duration of overall procedure was shorter. LV lead implantation was unsuccessful in 2.6% patients. Periprocedural complication rate was 6.3%. The most common complication was bleeding. Remote monitoring was less utilized.

Conclusion: These are the first observational data reflecting the current CRT practice in Turkey and comparing it with other countries of Europe. Findings of this study may help detect gaps and provide insights for improvement.
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http://dx.doi.org/10.14744/AnatolJCardiol.2020.02680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791302PMC
December 2020

Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care: A joint position statement from the Heart Failure Association (HFA), European Heart Rhythm Association (EHRA), and European Association of Cardiovascular Imaging (EACVI) of the European Society of Cardiology.

Eur J Heart Fail 2020 12;22(12):2349-2369

Cardiologie, CHU Rennes - LTSI Inserm UMR 1099, Université Rennes-1, Rennes, France.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway.
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http://dx.doi.org/10.1002/ejhf.2046DOI Listing
December 2020

Differences in biomarkers and molecular pathways according to age for patients with HFrEF.

Cardiovasc Res 2020 Oct 1. Epub 2020 Oct 1.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.

Methods And Results: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged > 75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) - that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.

Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.

Translational Perspective: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. Using a large set of circulating proteins, elderly patients had higher concentrations of proteins associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas pathways that may point to cell proliferation and tumorigenesis were down-regulated. WAP Four-Disulfide-Core-Domain-2 was associated with older age and had the strongest association with an increased risk of all outcomes. Understanding the underlying pathophysiological processes associated with aging in HFrEF may potentially lead to targeted therapies in this vulnerable population.
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http://dx.doi.org/10.1093/cvr/cvaa279DOI Listing
October 2020

A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure.

Nutrients 2020 Aug 21;12(9). Epub 2020 Aug 21.

Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.
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http://dx.doi.org/10.3390/nu12092541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551091PMC
August 2020

Second European Society of Cardiology Cardiac Resynchronization Therapy Survey: the Italian cohort.

J Cardiovasc Med (Hagerstown) 2020 Sep;21(9):634-640

Heart and Vascular Theme, Karolinska University Hospital, Stockholm, and Karolinska Institutet, Stockholm, Sweden.

Aim: Adherence to guidelines was not homogeneous in Europe, according to the survey on cardiac resynchronization therapy conducted in 2008-2009. The aim of our study was to compare the results in the Italian and European cohorts of the Second European Cardiac Resynchronization Therapy Survey.

Methods: Patients' characteristics, procedural data and follow-up were collected. Italian records were compared with European countries.

Results: Italian hospitals enrolled 526 patients. The italian cohort was older (71.6 ± 9.5 vs. 68.4 ± 10.8; P < 0.00001), had less severe NYHA class (>II 47.2 vs. 59.6%; P < 0.00001), higher ejection fraction (30.3 ± 7.4 vs. 28.4 ± 8.2%; P < 0.00001), and less atrial fibrillation prevalence (34.4 vs. 41.2%; P = 0.00197) than the European cohort. Italian patients were more frequently hospitalized for heart failure in the previous year (51.9 vs. 46.2%; P = 0.01118) and had lower mean QRS duration (151 ± 26 vs. 157 ± 27 ms; P < 0.0001). CRT-D were more often implanted in Italian patients (79.3 vs. 69.3%; P < 0.00001). The complication rate was similar (4.6% vs. 5.6%; ns). The rate of use of ACEi/ARBs in Italy was lower than in Europe (77.2 vs. 86.9%; P < 0.00001). Patients were followed up in the implantation centre (92.1 vs. 86%; P = 0.00014), but rarely with remote monitoring (25.9 vs. 30%; P = 0.04792).

Conclusion: The survey demonstrates important similarities as well as substantial differences regarding most of the aspects evaluated. Efforts to implement adherence to guidelines will be endorsed in Italy.
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http://dx.doi.org/10.2459/JCM.0000000000001035DOI Listing
September 2020

Remote monitoring of cardiac implanted electronic devices: legal requirements and ethical principles - ESC Regulatory Affairs Committee/EHRA joint task force report.

Europace 2020 11;22(11):1742-1758

School of Medicine, Cardiff University, Cardiff, UK.

The European Union (EU) General Data Protection Regulation (GDPR) imposes legal responsibilities concerning the collection and processing of personal information from individuals who live in the EU. It has particular implications for the remote monitoring of cardiac implantable electronic devices (CIEDs). This report from a joint Task Force of the European Heart Rhythm Association and the Regulatory Affairs Committee of the European Society of Cardiology (ESC) recommends a common legal interpretation of the GDPR. Manufacturers and hospitals should be designated as joint controllers of the data collected by remote monitoring (depending upon the system architecture) and they should have a mutual contract in place that defines their respective roles; a generic template is proposed. Alternatively, they may be two independent controllers. Self-employed cardiologists also are data controllers. Third-party providers of monitoring platforms may act as data processors. Manufacturers should always collect and process the minimum amount of identifiable data necessary, and wherever feasible have access only to pseudonymized data. Cybersecurity vulnerabilities have been reported concerning the security of transmission of data between a patient's device and the transceiver, so manufacturers should use secure communication protocols. Patients need to be informed how their remotely monitored data will be handled and used, and their informed consent should be sought before their device is implanted. Review of consent forms in current use revealed great variability in length and content, and sometimes very technical language; therefore, a standard information sheet and generic consent form are proposed. Cardiologists who care for patients with CIEDs that are remotely monitored should be aware of these issues.
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http://dx.doi.org/10.1093/europace/euaa168DOI Listing
November 2020

Prevalence and incidence of intra-ventricular conduction delays and outcomes in patients with heart failure and reduced ejection fraction: insights from PARADIGM-HF and ATMOSPHERE.

Eur J Heart Fail 2020 12 14;22(12):2370-2379. Epub 2020 Sep 14.

BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials.

Methods And Results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) 'mildly abnormal' QRS (110-129 ms) and 6506 (54.9%) QRS <110 ms. During a median follow-up of 2.5 years, the risk of the primary composite endpoint was higher among those with a wide QRS, irrespective of morphology: hazard ratios (95% confidence interval) LBBB 1.36 (1.23-1.50), RBBB 1.54 (1.31-1.79), non-specific IVCD 1.65 (1.40-1.94) and QRS 110-129 ms 1.35 (1.23-1.47), compared with QRS duration <110 ms. A total of 1234 (15.6%) patients developed new-onset QRS widening ≥130 ms (6.1 per 100 patient-years). Incident LBBB occurred in 495 (6.3%) patients (2.4 per 100 patient-years) and was associated with a higher risk of the primary composite outcome [hazard ratio 1.42 (1.12-1.82)].

Conclusion: In patients with HFrEF, a wide QRS was associated with worse clinical outcomes irrespective of morphology. The annual incidence of new-onset LBBB was around 2.5%, and associated with a higher risk of adverse outcomes, highlighting the importance of repeat electrocardiogram review.

Trial Registration: ClinicalTrials.gov Identifier NCT0083658 (ATMOSPHERE) and NCT01035255 (PARADIGM-HF).
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http://dx.doi.org/10.1002/ejhf.1972DOI Listing
December 2020

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT-CHF.

Eur J Heart Fail 2020 08 30;22(8):1486-1490. Epub 2020 Jul 30.

Department of Cardiovascular Sciences, University of Leicester, Leicester, NIHR Leicester Biomedical Research Centre, Leicester, UK.

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http://dx.doi.org/10.1002/ejhf.1951DOI Listing
August 2020

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries.

Eur J Heart Fail 2020 08 25;22(8):1472-1482. Epub 2020 Jun 25.

National Heart Centre Singapore, Singapore, Singapore.

Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.

Methods And Results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).

Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.
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http://dx.doi.org/10.1002/ejhf.1869DOI Listing
August 2020

Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.

Eur Heart J 2020 05;41(19):1810-1817

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

Aims: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.

Methods And Results: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.

Conclusion: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.
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http://dx.doi.org/10.1093/eurheartj/ehaa373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239195PMC
May 2020

The prevalence and importance of frailty in heart failure with reduced ejection fraction - an analysis of PARADIGM-HF and ATMOSPHERE.

Eur J Heart Fail 2020 11 30;22(11):2123-2133. Epub 2020 Apr 30.

BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).

Methods And Results: Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001).

Conclusion: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF.
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http://dx.doi.org/10.1002/ejhf.1832DOI Listing
November 2020

Adherence to ESC cardiac resynchronization therapy guidelines: findings from the ESC CRT Survey II.

Europace 2020 06;22(6):932-938

Cardiology Division, Stavanger University Hospital, Postboks 8100, 4068 Stavanger, Norway.

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure (HF) and electrical dyssynchrony. The European Society of Cardiology (ESC) Guidelines provide evidence-based recommendations indicating optimal patient selection for CRT implantation in both the 2013 European Heart Rhythm Association (EHRA) and the 2016 Heart Failure Association (HFA) Guidelines. We assessed the adherence to guidelines and identified factors associated with guideline adherence.

Methods And Results: In 2016, the HFA and EHRA conducted the CRT Survey II in 42 ESC countries. The data collected were sufficient to evaluate adherence to guidelines in 8021 patients. Of these, 67% had a Class I guideline indication for CRT implantation, which was significantly correlated with female gender (1.70, P < 0.0001), age <75 years (1.55, P < 0.0001), non-ischaemic HF aetiology (1.22, P < 0.0001), and elective admission (1.87, P < 0.0001). A further 26% of implants had a Class IIa indication, 5% IIb and only 2% a contraindication to CRT-a Class III indication. Patients implanted under Level IIa indications were much more likely to have more comorbidities than patients implanted under Level I indications. However, there were large variations in guideline adherence between ESC countries.

Conclusion: Implanters in ESC member states demonstrate a high degree of adherence to ESC guidelines with 98% of implants having a documented Class I, IIa or IIb indication. Cardiac resynchronization therapy implantation without a Class I indication was more likely in men, patients age ≥75 years, with HF of ischaemic origin and in patients admitted to hospital acutely.
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http://dx.doi.org/10.1093/europace/euaa067DOI Listing
June 2020

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure.

Eur J Heart Fail 2020 05 3;22(5):821-833. Epub 2020 Apr 3.

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

Aims: Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non-ischaemic HF, it is important to better understand differences in underlying molecular mechanisms.

Methods And Results: We performed a biological physical protein-protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT-CHF study, 715 of whom had ischaemic HF and 445 had non-ischaemic HF. Second, we constructed an enriched physical protein-protein interaction network, followed by a pathway over-representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non-ischaemic HF patients. We found 21/92 proteins to be up-regulated and 2/92 down-regulated in ischaemic relative to non-ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin-like growth factor binding protein-1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort.

Conclusions: Pathophysiological pathways distinguishing patients with ischaemic HF from those with non-ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.
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http://dx.doi.org/10.1002/ejhf.1811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319432PMC
May 2020

Heart failure treatment up-titration and outcome and age: an analysis of BIOSTAT-CHF.

Eur J Heart Fail 2021 Mar 25;23(3):436-444. Epub 2020 Mar 25.

Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.

Aims: Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up-titration of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta-blockers on outcome across the age spectrum in HFrEF patients.

Methods And Results: We analysed HFrEF patients on sub-optimal doses of ACEI/ARB and/or beta-blockers from the BIOSTAT-CHF study stratified by age. Patients underwent a 3-month up-titration period. We used inverse probability weighting to adjust for the likelihood of successful up-titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow-up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta-blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI-ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91-0.94, P < 0.001; beta-blocker: HR 0.98, 95% CI 0.95-1.00, P = 0.046], with a significant interaction with age seen for beta-blockers but not ACEI/ARB (P = 0.034 and P = 0.22, respectively).

Conclusions: Achieving higher doses of ACEI/ARB was associated with improved outcome regardless of age. However, achieving higher doses of beta-blockers was only associated with improved outcome in younger, but not in older patients.
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http://dx.doi.org/10.1002/ejhf.1799DOI Listing
March 2021

Hyperglycaemia, ejection fraction and the risk of heart failure or cardiovascular death in patients with type 2 diabetes and a recent acute coronary syndrome.

Eur J Heart Fail 2020 07 25;22(7):1133-1143. Epub 2020 Mar 25.

Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Aims: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF.

Methods And Results: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow-up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27-1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03-4.98, P < 0.001).

Conclusion: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF.
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http://dx.doi.org/10.1002/ejhf.1790DOI Listing
July 2020

Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

ESC Heart Fail 2020 06 13;7(3):953-963. Epub 2020 Mar 13.

INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Université de Lorraine, Nancy, France.

Aims: Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF.

Methods And Results: We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile = 28-247) μIU/mL and 9.4 (percentile = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies.

Conclusions: Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.
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http://dx.doi.org/10.1002/ehf2.12634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261568PMC
June 2020