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BACKGROUND: Heart failure (HF) biomarkers have prognostic value. The aim of this study was to combine HF biomarkers into an objective classification system for risk stratification of patients with HF.METHODS: HF biomarkers were analyzed in a population of HF outpatients and expressed relative to their cut-off values (N-terminal pro-B-type natriuretic peptide [NT-proBNP] >1,000 pg/mL, soluble suppression of tumorigenesis-2 [ST2] >35 ng/mL, growth differentiation factor-15 [GDF-15] >2,000 pg/mL, and fibroblast growth factor-23 [FGF-23] >95.4 pg/mL). Biomarkers that remained significant in multivariable analysis were combined to devise the Heartmarker score. The performance of the Heartmarker score was compared to the widely used New York Heart Association (NYHA) classification based on symptoms during ordinary activity.RESULTS: HF biomarkers of 245 patients were analyzed, 45 (18%) of whom experienced the composite endpoint of HF hospitalization, appropriate implantable cardioverter-defibrillator shock, or death. HF biomarkers were elevated more often in patients that reached the composite endpoint than in patients that did not reach the endpoint. NT-proBNP, ST2, and GDF-15 were independent predictors of the composite endpoint and were thus combined as the Heartmarker score. The event-free survival and distance covered in 6 minutes of walking decreased with an increasing Heartmarker score. Compared with the NYHA classification, the Heartmarker score was better at discriminating between different risk classes and had a comparable relationship to functional capacity.CONCLUSIONS: The Heartmarker score is a reproducible and intuitive model for risk stratification of outpatients with HF, using routine biomarker measurements.

Importance: Diagnosis of heart failure with preserved ejection fraction (HFpEF) among dyspneic patients without overt congestion is challenging. Multiple diagnostic approaches have been proposed but are not well validated against the independent gold standard for HFpEF diagnosis of an elevated pulmonary capillary wedge pressure (PCWP) during exercise. Objective: To evaluate H 2FPEF and HFA-PEFF scores and a PCWP/cardiac output (CO) slope of more than 2 mm Hg/L/min to diagnose HFpEF. Design, Setting, and Participants: This retrospective case-control study included patients with unexplained dyspnea from 6 centers in the US, the Netherlands, Denmark, and Australia from March 2016 to October 2020. Diagnosis of HFpEF (cases) was definitively ascertained by the presence of elevated PCWP during exertion; control individuals were those with normal rest and exercise hemodynamics. Main Outcomes and Measures: Logistic regression was used to evaluate the accuracy of HFA-PEFF and H 2FPEF scores to discriminate patients with HFpEF from controls. Results: Among 736 patients, 563 (76%) were diagnosed with HFpEF (mean [SD] age, 69 [11] years; 334 [59%] female) and 173 (24%) represented controls (mean [SD] age, 60 [15] years; 109 [63%] female). H 2FPEF and HFA-PEFF scores discriminated patients with HFpEF from controls, but the H 2FPEF score had greater area under the curve (0.845; 95% CI, 0.810-0.875) compared with the HFA-PEFF score (0.710; 95% CI, 0.659-0.756) (difference, -0.134; 95% CI, -0.177 to -0.094; P 2FPEF score. Use of the PCWP/CO slope to redefine HFpEF rather than exercise PCWP reclassified 20% (117 of 583) of patients, but patients reclassified from HFpEF to control by this metric had clinical, echocardiographic, and hemodynamic features typical of HFpEF, including elevated resting PCWP in 66% (46 of 70) of reclassified patients. Conclusions and Relevance: In this case-control study, despite requiring fewer data, the H 2FPEF score had superior diagnostic performance compared with the HFA-PEFF score and PCWP/CO slope in the evaluation of unexplained dyspnea and HFpEF in the outpatient setting..

AimsTo date, potential differences in outcomes for immigrants and non-immigrants with a cardiac resynchronization therapy (CRT), in a European setting, remain underutilized and unknown. Hence, we examined the efficacy of CRT measured by heart failure (HF)-related hospitalizations and all-cause mortality among immigrants and non-immigrants.Methods and resultsAll immigrants and non-immigrants who underwent first-time CRT implantation in Denmark (2000–2017) were identified from nationwide registries and followed for up to 5 years. Differences in HF related hospitalizations and all-cause mortality were evaluated by Cox regression analyses. From 2000 to 2017, 369 of 10 741 (3.4%) immigrants compared with 7855 of 223 509 (3.5%) non-immigrants with a HF diagnosis underwent CRT implantation. The origins of the immigrants were Europe (61.2%), Middle East (20.1%), Asia-Pacific (11.9%), Africa (3.5%), and America (3.3%). We found similar high uptake of HF guideline-directed pharmacotherapy before and after CRT and a consistent reduction in HF-related hospitalizations the year before vs. the year after CRT (61% vs. 39% for immigrants and 57% vs. 35% for non-immigrants). No overall difference in 5-year mortality among immigrants and non-immigrants was seen after CRT [24.1% and 25.8%, respectively, P-value = 0.50, hazard ratio (HR) = 1.2, 95% confidence interval (CI): 0.8–1.7]. However, immigrants of Middle Eastern origin had a higher mortality rate (HR = 2.2, 95% CI: 1.2–4.1) compared with non-immigrants. Cardiovascular causes were responsible for the majority of deaths irrespective of immigration status (56.7% and 63.9%, respectively).ConclusionNo overall differences in efficacy of CRT in improving outcomes between immigrants and non-immigrants were identified. Although numbers were low, a higher mortality rate among immigrants of Middle Eastern origin was identified compared with non-immigrants. AIMS: To date, potential differences in outcomes for immigrants and non-immigrants with a cardiac resynchronization therapy (CRT), in a European setting, remain underutilized and unknown. Hence, we examined the efficacy of CRT measured by heart failure (HF)-related hospitalizations and all-cause mortality among immigrants and non-immigrants. METHODS AND RESULTS: All immigrants and non-immigrants who underwent first-time CRT implantation in Denmark (2000-2017) were identified from nationwide registries and followed for up to 5 years. Differences in HF related hospitalizations and all-cause mortality were evaluated by Cox regression analyses. From 2000 to 2017, 369 of 10 741 (3.4%) immigrants compared with 7855 of 223 509 (3.5%) non-immigrants with a HF diagnosis underwent CRT implantation. The origins of the immigrants were Europe (61.2%), Middle East (20.1%), Asia-Pacific (11.9%), Africa (3.5%), and America (3.3%). We found similar high uptake of HF guideline-directed pharmacotherapy before and after CRT and a consistent reduction in HF-related hospitalizations the year before vs. the year after CRT (61% vs. 39% for immigrants and 57% vs. 35% for non-immigrants). No overall difference in 5-year mortality among immigrants and non-immigrants was seen after CRT [24.1% and 25.8%, respectively, P-value = 0.50, hazard ratio (HR) = 1.2, 95% confidence interval (CI): 0.8-1.7]. However, immigrants of Middle Eastern origin had a higher mortality rate (HR = 2.2, 95% CI: 1.2-4.1) compared with non-immigrants. Cardiovascular causes were responsible for the majority of deaths irrespective of immigration status (56.7% and 63.9%, respectively). CONCLUSION: No overall differences in efficacy of CRT in improving outcomes between immigrants and non-immigrants were identified. Although numbers were low, a higher mortality rate among immigrants of Middle Eastern origin was identified compared with non-immigrants.

Objectives Accurate prediction of heart failure (HF) patients at high risk of atrial fibrillation (AF) represents a potentially valuable tool to inform shared decision making. No validated prediction model for AF in HF is currently available. The objective was to develop clinical prediction models for 1-year risk of AF.Methods Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed from 2008 to 2018 and without history of AF. Administrative data sources provided the predictors. We used a cause-specific Cox regression model framework to predict 1-year risk of AF. Internal validity was examined using temporal validation.Results The population included 27 947 HF patients (mean age 69 years; 34% female). Clinical experts preselected sex, age at HF, NewYork Heart Association (NYHA) class, hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, chronic obstructive pulmonary disease and myocardial infarction. Among patients aged 70 years at HF, the predicted 1-year risk was 9.3% (95% CI 7.1% to 11.8%) for males and 6.4% (95% CI 4.9% to 8.3%) for females given all risk factors and NYHA III/IV, and 7.5% (95% CI 6.7% to 8.4%) and 5.1% (95% CI 4.5% to 5.8%), respectively, given absence of risk factors and NYHA class I. The area under the curve was 65.7% (95% CI 63.9% to 67.5%) and Brier score 7.0% (95% CI 5.2% to 8.9%).Conclusion We developed a prediction model for the 1-year risk of AF. Application of the model in routine clinical settings is necessary to determine the possibility of predicting AF risk among patients with HF more accurately and if so, to quantify the clinical effects of implementing the model in practice ObjectivesAccurate prediction of heart failure (HF) patients at high risk of atrial fibrillation (AF) represents a potentially valuable tool to inform shared decision making. No validated prediction model for AF in HF is currently available. The objective was to develop clinical prediction models for 1-year risk of AF.MethodsUsing the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed from 2008 to 2018 and without history of AF. Administrative data sources provided the predictors. We used a cause-specific Cox regression model framework to predict 1-year risk of AF. Internal validity was examined using temporal validation.ResultsThe population included 27 947 HF patients (mean age 69 years; 34% female). Clinical experts preselected sex, age at HF, NewYork Heart Association (NYHA) class, hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, chronic obstructive pulmonary disease and myocardial infarction. Among patients aged 70 years at HF, the predicted 1-year risk was 9.3% (95% CI 7.1% to 11.8%) for males and 6.4% (95% CI 4.9% to 8.3%) for females given all risk factors and NYHA III/IV, and 7.5% (95% CI 6.7% to 8.4%) and 5.1% (95% CI 4.5% to 5.8%), respectively, given absence of risk factors and NYHA class I. The area under the curve was 65.7% (95% CI 63.9% to 67.5%) and Brier score 7.0% (95% CI 5.2% to 8.9%).ConclusionWe developed a prediction model for the 1-year risk of AF. Application of the model in routine clinical settings is necessary to determine the possibility of predicting AF risk among patients with HF more accurately and if so, to quantify the clinical effects of implementing the model in practice.

Background We aimed to examine the impact of gender and specific type of cardiovascular disease (CVD) diagnosis (ischemic heart disease [IHD], heart failure, peripheral artery disease [PAD] or stroke) on time-to-initiation of either a sodium glucose cotransporter 2 inhibitor or glucagon-like peptide 1 analogue (collectively termed cardioprotective GLD) after a dual diagnosis of type 2 diabetes (T2DM) and CVD. Methods In a nationwide cohort study, we identified patients with a new dual diagnosis of T2DM and CVD (January 1, 2012 and December 31, 2018). Cumulative user proportion (CUP) were assessed. Poisson models were used to estimate the initiation rate of cardioprotective GLDs. The final analyses were adjusted for potential confounders. Results In total, we included 70,538 patients with new-onset T2DM and CVD (38% female, mean age 70 ± 12 years at inclusion). During 183,256 person-years, 6,276 patients redeemed a prescription of a cardioprotective GLD. One-year CUPs of cardioprotective GLDs were lower in women than men. Initiation rates of GLDs were lower in women (female-to-male initiation-rate-ratio crude: 0.76, 95% CI 0.72–0.81); adjusted 0.92, 95% CI 0.87–0.97). In CVD-stratified analysis, the adjusted initiation rate ratio was lower in female patients with IHD and heart failure (IHD: 0.91 [95% CI 0.85–0.98], heart failure: 0.85 [95% CI 0.73–1.00], PAD: 0.92 [95% CI 0.78–1.09], and stroke: 1.06 [95% CI 0.93–1.20]). Conclusions Among patients with a new dual diagnosis of T2DM and CVD, female gender is associated with lower initiation rates of cardioprotective GLDs, especially if the patient has IHD or heart failure.

Background The objective of this international multicenter study was to investigate both early and late outcomes of cardiac resynchronization therapy (CRT) in patients with a systemic right ventricle (SRV) and to identify predictors for congestive heart failure readmissions and mortality. Methods and Results This retrospective international multicenter study included 13 centers. The study population comprised 80 adult patients with SRV (48.9% women) with a mean age of 45±14 (range, 18–77) years at initiation of CRT. Median follow‐up time was 4.1 (25th–75th percentile, 1.3–8.3) years. Underlying congenital heart disease consisted of congenitally corrected transposition of the great arteries and dextro‐transposition of the great arteries in 63 (78.8%) and 17 (21.3%) patients, respectively. CRT resulted in significant improvement in functional class (before CRT: III, 25th–75th percentile, II–III; after CRT: II, 25th–75th percentile, II–III; P =0.005) and QRS duration (before CRT: 176±27; after CRT: 150±24 milliseconds; P =0.003) in patients with pre‐CRT ventricular pacing who underwent an upgrade to a CRT device (n=49). These improvements persisted during long‐term follow‐up with a marginal but significant increase in SRV function (before CRT; 30%, 25th–75th percentile, 25–35; after CRT: 31%, 25th–75th percentile, 21–38; P =0.049). In contrast, no beneficial change in the above‐mentioned variables was observed in patients who underwent de novo CRT (n=31). A quarter of all patients were readmitted for heart failure during follow‐up, and mortality at latest follow‐up was 21.3%. Conclusions This international experience with CRT in patients with an SRV demonstrated that CRT in selected patients with SRV dysfunction and pacing‐induced dyssynchrony yielded consistent improvement in QRS duration and New York Heart Association functional status, with a marginal increase in SRV function.

Aims Prior studies have reported conflicting results on digoxin’s impact on clinical outcomes and quality of life, and there are limited data from Asia. The aim of this study is to evaluate the use of digoxin and its impact on clinical outcomes and quality of life in a high-risk cohort of elderly Chinese atrial fibrillation (AF) patients. Methods and results The Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry is a prospective, multicentre nationwide study conducted from October 2014 to December 2018. Endpoints of interest were the composite outcome of all-cause death/any thromboembolism (TE), all-cause death, cardiovascular death, sudden cardiac death, and TE events, as well as the quality of life. The eligible cohort for this analysis included 6391 individuals, of whom 751 (11.8%) patients were treated with digoxin. On multivariate analysis, the use of digoxin was associated with a higher odds ratio (OR) of composite outcome [OR: 1.71; 95% confidence interval (CI): 1.32–2.22], all-cause death (OR: 1.62; 95% CI: 1.23–2.14), and any TE (OR: 1.78; 95% CI: 1.08–2.95). Results were consistent in a subgroup of patients with diagnosed heart failure (HF) and patients with permanent AF. The use of digoxin was associated with worse health-related quality of life (mean EQ index: 0.76 ± 0.19 vs. 0.84 ± 0.18; P < 0.001). Conclusions In this nationwide cohort study, digoxin use was associated with an overall higher risk of the composite outcome of all-cause death/any TE, all-cause death, and any TE, regardless of HF diagnosis. Patients treated with digoxin had a worse health-related quality of life.

Background: Perioperative myocardial infarction is a serious cardiovascular complication of noncardiac surgery. The clinical course of perioperative myocardial infarction, other than all-cause mortality, is largely unknown. We examined long-term fatal and nonfatal outcomes of perioperative myocardial infarction compared with nonoperative myocardial infarction. Methods: We conducted a population-based cohort study of first-time myocardial infarction in Denmark from 2000 to 2016. We calculated cumulative incidence of all-cause mortality, cardiac mortality, recurrent myocardial infarction, heart failure, stroke, venous thromboembolism, acute kidney injury, and kidney failure with replacement therapy. We computed 5-year risk ratios adjusted for age, sex, year of diagnosis, educational level, and comorbidities. Results: We identified 5068 patients with perioperative myocardial infarction and 137 862 patients with nonoperative myocardial infarction. The 5-year risk of all-cause mortality was 67.5% (95% CI, 66.1%–69.0%) for perioperative myocardial infarction patients and 38.0% (95% CI, 37.7%–38.3%) for nonoperative myocardial infarction patients. The adjusted risk ratio of all-cause mortality was 1.13 (95% CI, 1.11–1.16) at 5 years. After adjustment, we found no association between patients with perioperative myocardial infarction and 5-year cardiac mortality, recurrent myocardial infarction, heart failure, stroke, or kidney failure with replacement therapy when compared with nonoperative myocardial infarction patients. Perioperative myocardial infarction patients had a higher relative risk of venous thromboembolism (5-year risk ratio, 1.21 [95% CI, 1.01–1.46]) and acute kidney injury (5-year risk ratio, 1.37 [95% CI, 1.22–1.53]). Conclusions: Compared with nonoperative myocardial infarction patients, perioperative myocardial infarction patients had elevated risk of all-cause mortality, venous thromboembolism, and acute kidney failure. In addition to the myocardial infarction component of perioperative myocardial infarction, this poor prognosis seemed associated with the surgery or underlying comorbidities. These findings warrant further research on strategies to reduce the risk of perioperative myocardial infarction and on strategies to manage perioperative myocardial infarction.

Background Patients diagnosed with ischemic heart disease (IHD) are becoming increasingly multi-morbid, and studies designed to analyze the full spectrum are few. Methods Disease trajectories, defined as time-ordered series of diagnoses, were used to study the temporality of multi-morbidity. The main data source was The Danish National Patient Register (NPR) comprising 7,179,538 individuals in the period 1994–2018. Patients with a diagnosis code for IHD were included. Relative risks were used to quantify the strength of the association between diagnostic co-occurrences comprised of two diagnoses that were overrepresented in the same patients. Multiple linear regression models were then fitted to test for temporal associations among the diagnostic co-occurrences, termed length two disease trajectories. Length two disease trajectories were then used as basis for constructing disease trajectories of three diagnoses. Results In a cohort of 570,157 IHD disease patients, we identified 1447 length two disease trajectories and 4729 significant length three disease trajectories. These included 459 distinct diagnoses. Disease trajectories were dominated by chronic diseases and not by common, acute diseases such as pneumonia. The temporal association of atrial fibrillation (AF) and IHD differed in different IHD subpopulations. We found an association between osteoarthritis (OA) and heart failure (HF) among patients diagnosed with OA, IHD, and then HF only. Conclusions The sequence of diagnoses is important in characterization of multi-morbidity in IHD patients as the disease trajectories. The study provides evidence that the timing of AF in IHD marks distinct IHD subpopulations; and secondly that the association between osteoarthritis and heart failure is dependent on IHD.

Background: Data on the association between quality of heart failure (HF) care and outcomes among patients with incident HF are sparse. We examined the association between process performance measures and clinical outcomes in patients with incident HF with reduced ejection fraction. Methods: Patients with incident HF with reduced ejection fraction (n=10 966) between January 2008 and October 2015 were identified from the Danish HF Registry. Data from public registries were linked. Multivariable regression analyses were used to assess the association between 6 guideline-recommended HF care processes (New York Heart Association assessment, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, exercise training, and patient education) and all-cause and HF readmission, all-cause and HF hospital days, and mortality within 3 to 12 months after HF diagnosis. The associations were analyzed according to the percentages of all relevant performance measures fulfilled for the individual patient (0%–50% [reference group], >50%–75%, and >75%–100%) and for the individual performance measures. Results: Fulfilling >75% to 100% of the performance measures (n=5341 [48.7%]) was associated with lower risk of all-cause readmission (adjusted hazard ratio, 0.78 [95% CI, 0.68–0.89]) and HF readmission (adjusted hazard ratio, 0.71 [95% CI, 0.54–0.92]), lower use of all-cause hospital days (adjusted mean ratio, 0.73 [95% CI, 0.70–0.76]) and HF hospital days (adjusted mean ratio, 0.79 [95% CI, 0.70–0.89]), and lower mortality (adjusted hazard ratio, 0.42 [95% CI, 0.32–0.53]). A dose-response relationship was observed between fulfilling more performance measures and mortality (adjusted hazard ratio, 0.62 [95% CI, 0.49–0.77] fulfilling >50%–75% of the measures). Fulfilling individual performance measures, except mineralocorticoid receptor antagonist therapy, was associated with lower adjusted all-cause readmission, lower adjusted use of all-cause and HF hospital days, and lower adjusted mortality. Conclusions: Fulfilling more process performance measures was associated with better clinical outcomes in patients with incident HF with reduced ejection fraction.

Background Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. Methods This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. Results A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. Conclusion Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

Significant advances have been made in 2021 in the areas of interventional cardiology, heart failure, cardiac imaging, electrophysiology and congenital heart disease. In addition to improving the screening, diagnosis and management of many heart diseases, these advances will change our daily practice. Moreover, the European Society of Cardiology has updated its guidelines on heart failure, valve disease, cardiac pacing and cardiovascular disease prevention. As in previous years, members of the Cardiology division of Lausanne University Hospital (CHUV) came together to select and present to you the papers that they considered to be the most important of the past year.

BackgroundBaseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long‐term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6 months based on 2 serial NP measurements.Methods and ResultsConsecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6 months using either BNP (B‐type natriuretic peptide) or NT‐proBNP (N‐terminal pro‐BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6‐month follow‐up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient‐years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6 months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT‐proBNP, PConclusionsSerial NP measurements improved prediction of imminent cardiovascular death or HFH in patients with coronary artery disease and type 2 diabetes. The absolute risk estimates provided may aid clinicians in decision‐making and help patients understand their short‐term risk profile. Background Baseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long-term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6 months based on 2 serial NP measurements. Methods and Results Consecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6 months using either BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal pro-BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6-month follow-up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient-years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6 months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT-proBNP, P

Natriuretic peptides (NP) play a key role in the regulation of the body's water and salt balance and may effectively contribute to the diagnosis of patients with heart failure. NP-measurements are increasingly used internationally, but despite being available for more than ten years, neither a rational implementation nor clinical guidelines for use exist in Denmark. In this review, we present a practical approach to the use of NP in general practice and in the emergency department based on a newly published position paper from the Danish Society of Cardiology.

Background: Factors determining referral for advanced heart failure (HF) evaluation are poorly studied. We studied the influence of socioeconomic aspects on the referral process in Denmark, which has a taxpayer-funded national health care system. Methods: We identified all patients aged 18 to 75 years with a first diagnosis of HF during 2010 to 2018. Hospitalized patients had to be discharged alive and were then followed for the outcome of undergoing a right heart catheterization (RHC) used as a surrogate marker of advanced HF work-up. Results: Of 36 637 newly diagnosed patients with HF, 680 (1.9%) underwent RHC during the follow-up period (median time to RHC of 280 days [interquartile range, 73–914]). Factors associated with a higher likelihood of RHC included the highest versus lowest household income quartile (HR, 1.56 [95% CI, 1.19–2.06]; P =0.001), being diagnosed with HF at a tertiary versus nontertiary hospital (HR, 1.68 [95% CI, 1.37–2.05]; P P Conclusions: Higher household income, HF diagnosis during hospitalization, and first admission at a tertiary hospital were associated with increased likelihood of subsequent referral for RHC independent of other demographic and clinical variables. Greater attention may be required to ensure timely referral for advanced HF therapies in lower income groups.

BACKGROUND: Pulmonary congestion is a key component of heart failure (HF) that chest computed tomography (CT) can detect. However, no guideline describes which of many anticipated CT signs are most associated with HF in patients with undifferentiated dyspnea.METHODS: In a prospective observational single-center study, we included consecutive patients ≥ 50 years admitted with acute dyspnea to the emergency department. Patients underwent immediate clinical examination, blood sampling, echocardiography, and CT. Two radiologists independently evaluated all images. Acute HF (AHF) was adjudicated by an expert panel blinded to radiology images. Lasso and logistic regression identified the independent CT signs of AHF.RESULTS: Among 232 patients, 102 (44%) had AHF. Of 18 examined CT signs, 5 were associated with AHF (multivariate odds ratio, 95% confidence interval): enlarged heart (20.38, 6.86-76.16), bilateral interlobular thickening (11.67, 1.78-230.99), bilateral pleural effusion (6.39, 1.98-22.85), and increased vascular diameter (4.49, 1.08-33.92). Bilateral ground-glass opacification (2.07, 0.95-4.52) was a consistent fifth essential sign, although it was only significant in univariate analysis. Eighty-eight (38%) patients had none of the five CT signs corresponding to a 68% specificity and 86% sensitivity for AHF, while two or more of the five CT signs occurred in 68 (29%) patients, corresponding to 97% specificity and 67% sensitivity. A weighted score based on these five CT signs had an 0.88 area under the curve to detect AHF.CONCLUSIONS: Five CT signs seem sufficient to assess the risk of AHF in the acute setting. The absence of these signs indicates a low probability, one sign makes AHF highly probable, and two or more CT signs mean almost certain AHF.

BACKGROUND AND AIMS: It is still unclear whether a healthy diet can prevent heart failure (HF). Therefore, this study aimed to investigate the association between adherence to a Mediterranean-style diet, reflected by modified Mediterranean Diet Scores (mMDS), and the incidence of HF in men and women. METHODS AND RESULTS: This observational study comprised 9316 men and 27,645 women from the EPIC-NL cohort free from cardiovascular disease at baseline. Dietary intakes were assessed using a validated food frequency questionnaire. mMDS was calculated using a 9-point scale based on consumption of vegetables, legumes, fruit, nuts, seeds, grains, fish, fat ratio, dairy, meat and alcohol. HF events were ascertained by linkage to nation-wide registries. Multivariable Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression models. Over a median follow-up of 15 years (IQR 14-16), 633 HF events occurred: 144 in men (1.5%) and 489 in women (1.8%). The median mMDS was 4 (IQR 3-5). There was significant effect modification by sex (P-value for interaction

Background: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.Methods: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.Results: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).Conclusion: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.

BackgroundThe family perspective on heart failure (HF) has an important role in patients’ self-care patterns, adjustment to the disease and quality of life. Little is known about families’ experiences of living with HF, particularly in ethnic minority families. This study describes the experiences of Iranian families living with HF as an ethnic minority family in Denmark.MethodsIn this descriptive qualitative study, we conducted eight face-to-face joint family interviews of Iranian patients with HF and their family members living in Denmark. We used content analysis with an inductive approach for data analysis.ResultsWe identified three categories: family daily life, process of independence and family relationships. Families were faced with physical restrictions, emotional distress and social limitations in their daily lives that threatened the patients’ independence. Different strategies were used to promote independence. One strategy was normalisation and avoiding the sick role; another strategy was accepting and adjusting themselves to challenges and limitations. The independence process itself had an impact on family relationships. Adjusting well to the new situation strengthened the relationship, while having problems in adjustment strained the relationship within the family.ConclusionsThis study highlights the process of independence as perceived by families living with HF. It is crucial to both families and healthcare professionals to maintain a balance between providing adequate support and ensuring independence when dealing with patients with HF. Understanding patients’ stories and their needs seems to be helpful in gaining this balance.

Background Patients with heart failure (HF) may be at increased risks of cancer, but the magnitude of risk for various cancer subtypes is insufficiently investigated. Method Using the Danish Nationwide administrative databases between 1997 and 2017, we estimated the prevalence, incidence and relative risk for all-cause cancer in new-diagnosed HF vs. age and sex-matched controls (up to 5 controls per HF case) before and after adjustment for comorbidities. Results Among the 167,633 people in the heart failure group and 837,126 individuals in the control group, there was a higher prevalence of several comorbidities, including cancer (17% vs. 10%) in the HF group; odds ratio 1.72 (1.70–1.75). Patients with heart failure also had higher cancer incidence (cancer incidence rate 3.02 [2.97–3.07] per 100 person-years), compared with controls (cancer incidence rate 1.89 [1.88–1.90]); hazards ratio 1.38 (1.36–1.40). However, after adjustment for comorbidities the increased risk of malignancy was greatly attenuated (hazards ratio 1.14 [1.12–1.16] for incident all-cause cancer) and dissipated altogether after additional adjustment for medications (multivariable adjusted hazards ratio 0.93 [0.91–0.96] for all-cause cancer). In a homogeneous cohort of patients with ischemic heart disease, the increased risk of all-cause cancer was only marginally increased after adjustment for baseline comorbidities (hazards ratio 1.05 [1.02–1.08]). Conclusion Patients with heart failure had a slightly increased risk of various cancer subtypes, but the risks were mainly driven by comorbidities.

Objectives: To assess the cost effectiveness of home telemonitoring (HTM) and nurse telephone support (NTS) compared with usual care (UC) in the management of patients with chronic heart failure, from a third-party payer's perspective. Methods: We developed a Markov model with a 20-year time horizon to analyze the cost effectiveness using the original study (Trans-European Network-Home-Care Management System) and various data sources. A probabilistic sensitivity analysis was performed to assess the decision uncertainty in our model. Results: In the original scenario (which concerned the cost inputs at the time of the original study), HTM and NTS interventions yielded a difference in quality-adjusted life-years (QALYs) gained compared with UC: 2.93 and 3.07, respectively, versus 1.91. An incremental net monetary benefit analysis showed (sic)7,697 and (sic)13,589 in HTM and NTS versus UC at a willingness-to-pay (WTP) threshold of (sic)20,000, and (sic)69,100 and (sic)83,100 at a WTP threshold of (sic)80,000, respectively. The incremental cost-effectiveness ratios were (sic)12,479 for HTM versus UC and (sic)8,270 for NTS versus UC. The current scenario (including telenurse cost inputs in NTS) yielded results that were slightly different from those for the original scenario, when comparing all New York Heart Association (NYHA) classes of severity. NTS dominated HTM, compared with UC, in all NYHA classes except NYHA IV. Conclusions: This modeling study demonstrated that HTM and NTS are viable solutions to support patients with chronic heart failure. NTS is cost-effective in comparison with UC at a WTP of (sic)9000/QALY or higher. Like NTS, HTM improves the survival of patients in all NYHA classes and is cost-effective in comparison with UC at a WTP of (sic)14,000/QALY or higher.

Aims: There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death.Methods and results: Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker as a time-dependent variable. From 2007 to 2012, 2935 first-time ICD devices were implanted. During follow-up, 399 patients experienced VT/VF, 728 HF hospitalizations and 361 died. As compared with patients not on beta-blockers, low, intermediate, and high dose had significantly reduced risk of HF hospitalizations {hazard ratio (HR) = 0.68 [0.54-0.87], P = 0.002; HR = 0.53 [0.42-0.66], P Conclusion: In primary prevention ICD patients, beta-blocker therapy was associated with significantly reduced risk of all endpoints, as compared with patients not on beta-blocker, with the suggestion of a dose-dependent effect. No detectable difference was found between comparable doses of carvedilol and metoprolol.

Aims: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community. Methods and results: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78). Conclusions: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF

International audience; Background - The first European Cardiac Resynchronization Therapy (CRT) Survey, conducted in 2008-2009, showed considerable variations in guideline adherence and implantation practice. A second prospective survey (CRT Survey II) was then performed to describe contemporary clinical practice regarding CRT among 42 European countries. Aim - To compare the characteristics of French CRT recipients with the overall European population of CRT Survey II. Methods - Demographic and procedural data from French centres recruiting all consecutive patients undergoing either de novo CRT implantation or an upgrade to a CRT system were collected and compared with data from the European population. Results - A total of 11,088 patients were enrolled in CRT Survey II, 754 of whom were recruited in France. French patients were older (44.7% aged≥75 years vs 31.1% in the European group), had less severe heart failure symptoms, a higher baseline left ventricular ejection fraction and fewer co-morbidities. Additionally, French patients had a shorter intrinsic QRS duration (19.1% had a QRS

Aims Randomized clinical trials investigating a possible outcome effect of remote monitoring in patients with implantable defibrillators have shown conflicting results. This study analyses the information flow and workflow details from the IN-TIME study and discusses whether differences of message content, information speed and completeness, and workflow may contribute to the heterogeneous results. Methods and results IN-TIME randomized 664 patients with an implantable cardioverter/defibrillator indication to daily remote monitoring vs. control. After 12 months, a composite clinical score and all-cause mortality were improved in the remote monitoring arm. Messages were received on 83.1% of out-of-hospital days. Daily transmissions were interrupted 2.3 times per patient-year for more than 3 days. During 1 year, absolute transmission success declined by 3.3%. Information on medical events was available after 1 day (3 days) in 83.1% (94.3%) of the cases. On all working days, a central monitoring unit informed investigators of protocol defined events. Investigators contacted patients with a median delay of 1 day and arranged follow-ups, the majority of which took place within 1 week of the event being available. Conclusion Only limited data on the information flow and workflow have been published from other studies which failed to improve outcome. However, a comparison of those data to IN-TIME suggest that the ability to see a patient early after clinical events may be inferior to the set-up in IN-TIME. These differences may be responsible for the heterogeneity found in clinical effectiveness of remote monitoring concepts.