Search

Abstract Aims Arterial hypertension (aHTN) plays a fundamental role in the pathogenesis and prognosis of heart failure with preserved ejection fraction (HFpEF). The risk of heart failure increases with therapy‐resistant arterial hypertension (trHTN), defined as inadequate blood pressure (BP) control ≥140/90 mmHg despite taking ≥3 antihypertensive medications including a diuretic. This study investigates the effects of the BP lowering baroreflex activation therapy (BAT) on cardiac function and morphology in patients with trHTN with and without HFpEF. Methods Sixty‐four consecutive patients who had been diagnosed with trHTN and received BAT implantation between 2012 and 2016 were prospectively observed. Office BP, electrocardiographic and echocardiographic data were collected before and after BAT implantation. Results Mean patients' age was 59.1 years, 46.9% were male, and mean body mass index (BMI) was 33.2 kg/m2. The prevalence of diabetes mellitus was 38.8%, atrial fibrillation was 12.2%, and chronic kidney disease (CKD) stage ≥3 was 40.8%. Twenty‐eight patients had trHTN with HFpEF, and 21 patients had trHTN without HFpEF. Patients with HFpEF were significantly older (64.7 vs. 51.6 years, P

Abstract Aims Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device‐based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well‐defined cohorts for innovative preclinical and clinical trials. Methods and results TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all‐cause mortality, to cardiovascular mortality, to heart failure mortality, to all‐cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. Conclusions TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure.

Abstract Objective Deep vein thrombosis (DVT) is discussed as a source of embolism for cerebral ischemia in the presence of patent foramen ovale (PFO). However, previous studies reported varying rates of DVT in stroke patients, and recommendations for screening are lacking. This study aimed to characterize patients with stroke or transient ischemic attack (TIA) and concomitant PFO and explore the rate of DVT and associated parameters. Methods Medical records were screened for patients with stroke or TIA and echocardiographic evidence of PFO. Concomitant DVT was identified according to compression ultrasonography of the lower limbs. A variety of demographic, clinical, and laboratory parameters, the RoPE and Wells scores were compared between patients with and without DVT. Results Three-hundred-thirty-nine patients (mean age 61.2 ± 15.4 years, 61.1% male) with stroke or TIA and PFO, treated between 01/2015 and 12/2020, were identified. Stroke and TIA patients did not differ for demographic and vascular risk factors. DVT was found in 17 cases out of 217 (7.8%) with compression ultrasonography. DVT was associated with a history of DVT, cancer, previous immobilization, calf compression pain, calf circumference difference, and a few laboratory abnormalities, e.g., increased D-dimer. A multivariate regression model with stepwise backward selection identified the Wells score (odds ratio 35.46, 95%-confidence interval 4.71–519.92) as a significant predictor for DVT. Conclusion DVT is present in a relevant proportion of patients with cerebral ischemia and PFO, which needs to be considered for the individual diagnostic workup. The Wells score seems suitable for guiding additional examinations, i.e., compression ultrasonography.

Blinding is an essential part of many randomized controlled trials. However, its quality is usually not checked, and when it is, common measures are the James index and/or the Bang index. In the present paper we discuss these two indices, providing examples demonstrating their considerable weaknesses and limitations, and propose an alternative method for measuring blinding. We argue that this new approach has a number of advantages. We also provide an R-package for computing our blinding index.

Background Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies.Objectives We investigated six blood biomarkers for predicting paroxysmal AF in general practice.Methods This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation.Results Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706).Conclusion Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed.

Background Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long‐term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross‐sectional studies. We analyzed ADMA, SDMA, and other L‐arginine metabolites to assess their association with AF in the Find‐AF trial. Methods and Results We included 280 patients presenting with acute cerebral ischemia. Patients presenting in sinus rhythm received 7‐day Holter‐ECG. Biomarkers were quantified by ultra‐performance liquid chromatography–tandem mass spectrometry. We also analyzed protein methylation and L‐arginine‐related metabolites in human induced pluripotent stem cell‐derived cardiomyocytes in vitro. ADMA and SDMA were elevated in 44 patients who presented with AF. SDMA, but not ADMA, was significantly elevated in patients newly diagnosed with AF in Holter‐ECG as compared with those in sinus rhythm. SDMA plasma concentration >0.571 μmol/L significantly predicted presence of AF in Holter‐ECG (area under the curve=0.676 [0.530–0.822]; P=0.029; sensitivity 0.786, specificity 0.572). SDMA levels further increased in patients with AF during the first 24 hours in hospital, and ADMA levels remained stable. In vitro, induced pluripotent stem cell‐derived cardiomyocytes showed increased symmetric protein methylation and elevated SDMA during rapid pacing (2.0 Hz versus 0.5 Hz), whereas asymmetric protein methylation and ADMA were unchanged. Conclusions SDMA at admission was significantly elevated in stroke patients presenting with AF and showed a moderate but significant prospective association with previously unrecognized AF. Thus, stroke patients with elevated SDMA concentration at admission may specifically benefit from extended Holter‐ECG monitoring.

Abstract Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54–0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Abstract ESCAPE Evaluation of a patient‐centred biopsychosocial blended collaborative care pathway for the treatment of multimorbid elderly patients. Therapeutic Area Healthcare interventions for the management of older patients with multiple morbidities. Aims Multi‐morbidity treatment is an increasing challenge for healthcare systems in ageing societies. This comprehensive cohort study with embedded randomized controlled trial tests an integrated biopsychosocial care model for multimorbid elderly patients. Hypothesis A holistic, patient‐centred pro‐active 9‐month intervention based on the blended collaborative care (BCC) approach and enhanced by information and communication technologies can improve health‐related quality of life (HRQoL) and disease outcomes as compared with usual care at 9 months. Methods Across six European countries, ESCAPE is recruiting patients with heart failure, mental distress/disorder plus ≥2 medical co‐morbidities into an observational cohort study. Within the cohort study, 300 patients will be included in a randomized controlled assessor‐blinded two‐arm parallel group interventional clinical trial (RCT). In the intervention, trained care managers (CMs) regularly support patients and informal carers in managing their multiple health problems. Supervised by a clinical specialist team, CMs remotely support patients in implementing the treatment plan—customized to the patients' individual needs and preferences—into their daily lives and liaise with patients' healthcare providers. An eHealth platform with an integrated patient registry guides the intervention and helps to empower patients and informal carers. HRQoL measured with the EQ‐5D‐5L as primary endpoint, and secondary outcomes, that is, medical and patient‐reported outcomes, healthcare costs, cost‐effectiveness, and informal carer burden, will be assessed at 9 and ≥18 months. Conclusions If proven effective, the ESCAPE BCC intervention can be implemented in routine care for older patients with multiple morbidities across the participating countries and beyond.

Abstract Background Higher plasma levels of natriuretic peptides (NPs) have been associated with reduced anxiety in experimental research and a number of patient samples. As NP levels are elevated in heart failure patients, we investigate whether this elevation is related to anxiety in patients with heart failure with preserved ejection fraction (HFpEF). Methods Post-hoc regression and mediation analyses were conducted, using data of 422 patients with HFpEF from the randomized, placebo-controlled, double-blinded, two-armed, multicentre aldosterone in diastolic heart failure trial, testing associations and their mediators between the N-terminal B-type natriuretic peptide (NT-proBNP) and anxiety at baseline and over 12-month follow-up. Anxiety was measured by the Hospital Anxiety and Depression Scale (HADS), social support by the ENRICHD Social Support Inventory and physical functioning by the Short Form 36 Health Survey. Results The mean age of the study population was 66.8 ± 7.6 years, 47.6% were male and 86.0% had NYHA class II. NT-proBNP showed a weak negative correlation with HADS anxiety scores at baseline (r = − 0.087; p = 0.092), which was significant (r = − 0.165; p = 0.028) in men but not in women. NT-proBNP also tended to predict lower anxiety at 12-months in men. On the other hand, higher anxiety at baseline was associated with lower NT-proBNP scores 12 months later (r = − 0.116; p = 0.026). All associations lost significance in multivariate regression for age, perceived social support (ESSI), physical function (SF-36) and study arm. Mediation analyses revealed that social support acts as a full mediator for the link between NT-proBNP levels and anxiety. Conclusion The mechanisms linking NT-proBNP to anxiety may be more complex than originally assumed. While effects of NT-proBNP on anxiety may be mediated by perceived social support, there may be an additional negative effect of anxiety on NT-proBNP. Future research should consider this possible bi-directionality of the association and assess the potential influence of gender, social support, oxytocin and vagal tone on the interaction of anxiety and natriuretic peptide levels. Trial Registration http://www.controlled-trials.com (ISRCTN94726526) on 07/11/2006. Eudra-CT-number: 2006–002,605-31.

Abstract Aims Chronic heart failure (HF) is a common disease and one of the leading causes of death worldwide. Heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF) are different diseases with distinct as well as comparable pathophysiologies and diverse responses to therapeutic agents. We aimed to identify possible pathobiochemical signalling pathways and biomarkers in HFpEF and HFrEF by using a broad proteomic approach. Methods and results A total of 180 biomarkers in the plasma of a representative subgroup (71 years old) of HFpEF (70% female) with a left ventricular ejection fraction (LVEF) ≥ 50% and HFrEF (18% female) with an LVEF ≤ 40% patients (n = 127) from the Prevalence and Clinical Course of Diastolic Dysfunction and Diastolic Heart Failure (DIAST‐CHF) trial were examined and compared with a healthy control group (n = 40; 48% female). We were able to identify 35 proteins that were expressed significantly different in both HF groups compared with the control group. We determine 29 unique proteins expressed in HFpEF and 33 unique proteins in HFrEF. Significantly up‐regulated trefoil factor 3 (TFF3) and down‐regulated contactin‐1 could be identified as previously unknown biomarkers for HF. However, TFF3 is also a predictive factor for the occurrence of a cardiovascular event in HFpEF patients. In HFpEF, serine protease 27 was found at reduced levels for the first time, which could offer a new therapeutic target. Additionally, network analyses showed a special role of platelet‐derived growth factor subunit A, Dickkopf‐related protein 1, and tumour necrosis factor receptor superfamily member 6 in HFpEF patients, whereas perlecan and junctional adhesion molecule A stood out in the HFrEF group. Overall, signalling pathways of metabolic processes, cellular stress, and iron metabolism seemed to be important for HFrEF, whereas for HFpEF, oxygen stress, haemostasis, cell renewal, cell migration, and cell proliferation are in the foreground. Conclusions The identified proteins and signalling pathways offer new therapeutic and diagnostic approaches for patients with chronic HF.

Abstract Aims Diabetes mellitus is associated with worse outcomes and lower attainment of disease‐modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co‐morbidity. Methods TRANSITION, a randomized, open‐label study compared sacubitril/valsartan initiation pre‐discharge vs. post‐discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10‐week and 26‐week post‐randomization. Results Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre‐discharge or post‐discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non‐diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non‐diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non‐diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre‐discharge or post‐discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non‐diabetes subgroups at 10 weeks, respectively: pre‐discharge (7.5% vs. 7.1%) or post‐discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT‐proBNP (P

Abstract Background Echocardiography is highly relevant in patients with ischemic stroke or TIA. Utilization of routine echocardiographic examinations [transthoracic (TTE) or transesophageal (TEE)] on stroke units remains however unknown. To representatively examine echocardiographic rates on stroke units in Germany and to evaluate structural factors that may influence the decision to conduct echocardiography. Methods A nationwide analysis was performed by using certification audit data of all primary and comprehensive stroke centers (pSC and cSC) in Germany. Results Structural and organizational requirements of 310 departments (cSCs: 42.6%) were extracted. Median TTE rate was 63.3% (IQR 39.3–80.8), median TEE rate 21.3% (IQR 16.4–29.5). A cardiological department on site was present in 74.2%, and they were associated with higher TEE rates. TTE rates decreased with increasing numbers of patients (p = 0.026). Likewise, TEE rates decreased with increasing numbers of patients (p = 0.006), mediated by departments with cSCs (p = 0.008 for cSCs vs p = 0.230 for pSCs). TTE rates were far more inhomogeneously distributed than TEE rates and higher in pSCs (p = 0.011). Overall, 12.9% of centers did not perform any echocardiographic examination in at least 50% of all stroke patients. Conclusion More detailed recommendations regarding echocardiography should be included in future guidelines. Moreover, evaluating the impact of echocardiographic examinations on long-term prognosis in stroke patients should be focus of further evaluations.

Summary: Background: Whether there is a subset of patients with heart failure with preserved ejection fraction (HFpEF) that benefit from spironolactone therapy is unclear. We applied a machine learning approach to identify responders and non-responders to spironolactone among patients with HFpEF in two large randomized clinical trials. Methods: Using a reiterative cluster allocating permutation approach, patients from the derivation cohort (Aldo-DHF) were identified according to their treatment response to spironolactone with respect to improvement in E/e’. Heterogenous features of response (‘responders’ and ‘non-responders’) were characterized by an extreme gradient boosting (XGBoost) algorithm. XGBoost was used to predict treatment response in the validation cohort (TOPCAT). The primary endpoint of the validation cohort was a combined endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Patients with missing variables for the XGboost model were excluded from the validation analysis. Findings: Out of 422 patients from the derivation cohort, reiterative cluster allocating permutation identified 159 patients (38%) as spironolactone responders, in whom E/e’ significantly improved (p = 0.005). Within the validation cohort (n = 525) spironolactone treatment significantly reduced the occurrence of the primary outcome among responders (n = 185, p log rank = 0.008), but not among patients in the non-responder group (n = 340, p log rank = 0.52). Interpretation: Machine learning approaches might aid in identifying HFpEF patients who are likely to show a favorable therapeutic response to spironolactone. Funding: See Acknowledgements section at the end of the manuscript.

Abstract Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline‐directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor‐neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM‐HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real‐world patient exposure is >5.5 million patient‐treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

Abstract Aims Although the number of patients suffering from heart failure with preserved ejection fraction (HFpEF) increases, the routine diagnosis remains a challenge. In the absence of a pathognomonic sign for HFpEF or specific treatment strategies, a prognosis‐based characterization of suspected patients remains promising for both the risk stratification of the patients and a disease definition. The Heart Failure Association (HFA) of the European Society of Cardiology has introduced an algorithm with different levels of likelihood regarding the diagnosis of HFpEF, the HFA‐PEFF score. We aimed to evaluate the predictive value of this algorithm in a large cohort regarding mortality, symptom burden, and the functional status. Methods and results DIAST‐CHF is a multicentre, population‐based, prospective, observational study in subjects with at least one risk factor for HFpEF between the age of 50 and 85. We calculated the HFA‐PEFF score (n = 1668) and analysed the risk groups for overall mortality, cardiovascular hospitalization, and submaximal functional capacity (6‐min walk distance) at baseline and after a follow‐up period of 10 years. Patients with high HFA‐PEFF score values 5&6 showed a higher mortality than those with an intermediate score (score values 2–4) and low score values (high 21.3% vs. intermediate 10.1% vs. low 4.3%, P

Background: Arrhythmia-induced cardiomyopathy (AIC) is characterized by the reversibility of left ventricular (LV) systolic dysfunction (LVSD) after rhythm restoration. This study is a cardiac magnetic resonance tomography substudy of our AIC trial with the purpose to investigate whether left ventricular fibrosis affects the time to recovery (TTR) in patients with AIC. Method: Patients with newly diagnosed and otherwise unexplainable LVSD and tachyarrhythmia were prospectively recruited. LV ejection fraction (LVEF) was measured by echocardiography at baseline and 2, 4, and 6 months after rhythm control, and stress markers were assessed. After initial rhythm control, LV fibrosis was assessed through late gadolinium enhancement (LGE). Patients were diagnosed with AIC if their LVEF improved by ≥15% (or ≥10% when LVEF reached ≥50%). Non-responders served as controls (non-AIC). Results: The LGE analysis included 39 patients, 31 of whom recovered (AIC). LV end-systolic diameters decreased and LVEF increased during follow-up. LV LGE content correlated positively with TTR (r = 0.63, p = 0.003), with less LGE favoring faster recovery, and negatively with ΔLVEF (i.e., LVEF at month 2 compared to baseline) as a marker of fast recovery (r = −0.55, p = 0.012), suggesting that LV fibrosis affects the speed of recovery. Conclusion: LV fibrosis correlated positively with the time to recovery in patients with AIC. This correlation may help in the estimation of the recovery period and in the optimization of diagnostic and therapeutic strategies for patients with AIC.

Abstract Aims Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is known that AF impairs the diagnostic accuracy of NT‐proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT‐proBNP for HF and AF in stable outpatients with cardiovascular risk factors. Methods and results Data were obtained from the DIAST‐CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population‐based cohorts using the same inclusion/exclusion criteria: LIFE‐Adult (n = 2869), SHIP (n = 2013), and SHIP‐TREND (n = 2408). Serum levels of NT‐proBNP were taken once at baseline. The DIAST‐CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT‐proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT‐proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver‐operating characteristic curves of NT‐proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79–0.88]) and for HF with EF 50% was significantly lower (0.61 [0.56–0.65]) than for AF (P = 0.001). During follow‐up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT‐proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75–0.83]) than of newly diagnosed HF (0.59 [0.55–0.63]; P 50% is very limited.

Background and Purpose Prolonged electrocardiography (ECG)-monitoring in stroke patients improves the detection of paroxysmal atrial fibrillation (pAF). However, most randomized studies only had short follow-up. We aimed to provide 3-year follow-up data for AF detection and stroke recurrence risk. Methods We randomized 402 patients aged ≥60 years with acute ischemic strokes without AF to either enhanced and prolonged monitoring (EPM; 3×10-day Holter-ECG-monitoring) or standard-of-care (≥24 hours ECG-monitoring). The endpoint of the current analysis was AF within 36 months analyzed by intention to treat. Long-term follow-up was performed for 36 months. Results Two hundred and seventy-four patients (80%) participated in the extended follow-up (median duration of follow-up was 36 months [interquartile range, 12 to 36]). During the first 6 months, more AF was documented in the EPM arm compared to the control arm (13.5% vs. 5.1%; 95% confidence interval, 2.9% to 14.4%; P=0.004). During months 6 to 36, AF was less detected in the EPM intervention arm than in the control arm (2.0% vs. 7.3%; 95% confidence interval, 0.7% to 9.9%; P=0.028). Overall, the detection rate of AF within 36 months was numerically higher within the EPM group (15.0% vs. 11.1%, P=0.30). Numerically less patients in the EPM arm had recurrent ischemic strokes (5.5% vs. 9.1%, P=0.18), transient ischemic attacks (3.0% vs. 4.5%, P=0.44) or died (4.5% vs. 6.6%, P=0.37). Conclusions Enhanced and prolonged ECG monitoring increased AF detection during the first six months, but there was significantly more clinical AF during months 6 to 36 observed in the usual-care arm. This suggests that EPM leads to an earlier detection of clinically relevant AF.

Abstract Aims To identify baseline parameters longitudinally influencing overall health‐related quality of life (HRQoL), physical function and mental health 1 year later in patients with chronic heart failure and preserved ejection fraction (HFpEF). Methods and results We performed post hoc analyses of the randomized aldosterone in diastolic heart failure (Aldo‐DHF) trial, including 422 patients with HFpEF and NYHA class II or III. Overall HRQoL, measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), physical functioning and mental health, both measured by the Short Form 36 Health Survey (SF‐36), after 12 months were predicted in correlation analyses and multivariate regression analyses with continuous values and worst versus three better HRQoL quartiles as dependent variables. The mean age of the study population was 66.8 ± 7.6 years, 52.4% were female, and 86.0% had NYHA class II. All HRQoL variables at 1 year were predicted by their respective baseline values (all P

Abstract Heart failure (HF) does not occur in a vacuum and is commonly defined and exacerbated by its co‐morbid conditions. Neurohormonal imbalance and systemic inflammation are some of the key pathomechanisms of HF but also commonly encountered co‐morbidities such as arterial hypertension, diabetes mellitus, cachexia, obesity and sleep‐disordered breathing. A cornerstone of HF management is neurohormonal blockade, which in HF with reduced ejection fraction has been tied to a reduction in morbidity and mortality. Pharmacological treatment effective in patients with HF with reduced ejection fraction did not show substantial effects in HF with preserved ejection fraction. Here, we review novel device‐based therapies using neuromodulation of extra‐cardiac targets to treat cardiometabolic disease.

Abstract Aims Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences. Methods and results We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF‐related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF‐related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; −29%), while the total number of HF‐related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in‐hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population). Conclusions Heart failure remains the most common cause of hospitalization and in‐hospital death throughout Germany. The increase in HF‐related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.

Abstract Aims Galectin‐3 (Gal‐3) predicts long‐term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal‐3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal‐3 and clinical manifestations of HFpEF, the relationship between Gal‐3 and all‐cause mortality, or the composite of cardiovascular hospitalization and death. Methods and results The observational Diast‐CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal‐3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non‐cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut‐off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal‐3, and the diagnostic power to detect HFpEF was superior to N‐terminal pro‐brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal‐3 was associated with risk factors for HF (P

Abstract Aims White matter lesions (WML) are common structural alterations in the white matter of the brain and their prevalence increases with age. They are associated with cerebral ischaemia and cognitive dysfunction. Patients with heart failure (HF) are at risk for cognitive decline. We hypothesized that the presence and duration of HF are associated with WML. Methods and results The LIFE‐Adult Study is a population‐based study of 10 000 residents of Leipzig, Germany. WML were quantitated in 2490 participants who additionally underwent cerebral MRI using the Fazekas score. Mean age was 64 years, and 46% were female; 2156 (86.6%) subjects had Fazekas score of 0–1, and 334 (13.4%) had Fazekas score of 2–3. Thirty participants had a medical history of HF, 1019 had hypertension, and 51 had a history of stroke. Median left ventricular ejection fraction of the participants with HF was 57% (interquartile ranges 54–62). Age, troponin T, NT‐proBNP, body mass index, history of acute myocardial infarction, stroke, HF, and diabetes were positively associated with WML in univariate analysis. On multivariate analysis, age, hypertension, stroke, and HF were independently associated with WML. The odd's ratio for the association of WML (Fazekas 2–3) with HF was 2.8 (95% CI 1.2–6.5; P = 0.019). WML increased with longer duration of HF (P = 0.036 for trend). Conclusions In addition to age, hypertension, and stroke, the prevalence and duration of HF are independently associated with WML. This observation sets the stage to investigate the prognostic value of WML in HF and the impact of HF therapies on WML.

Abstract Background Coronary heart disease (CHD) is the leading cause of death and years of life lost worldwide. While effective treatments are available for both acute and chronic disease stages there are unmet needs for effective interventions to support patients in health behaviors required for secondary prevention. Psychosocial distress is a common comorbidity in patients with CHD and associated with substantially reduced health-related quality of life (HRQoL), poor health behavior, and low treatment adherence. Methods In a confirmatory, randomized, controlled, two-arm parallel group, multicenter behavioral intervention trial we will randomize 440 distressed CHD patients with at least one insufficiently controlled cardiac risk factor to either their physicians' usual care (UC) or UC plus 12-months of blended collaborative care (TeamCare = TC). Trained nurse care managers (NCM) will proactively support patients to identify individual sources of distress and risk behaviors, establish a stepwise treatment plan to improve self-help and healthy behavior, and actively monitor adherence and progress. Additional e-health resources are available to patients and their families. Intervention fidelity is ensured by a treatment manual, an electronic patient registry, and a specialist team regularly supervising NCM via videoconferences and recommending protocol and guideline-compliant treatment adjustments as indicated. Recommendations will be shared with patients and their physicians who remain in charge of patients’ care. Since HRQoL is a recommended outcome by both, several guidelines and patient preference we chose a ≥ 50% improvement over baseline on the HeartQoL questionnaire at 12 months as primary outcome. Our primary hypothesis is that significantly more patients receiving TC will meet the primary outcome criterion compared to the UC group. Secondary hypotheses will evaluate improvements in risk factors, psychosocial variables, health care utilization, and durability of intervention effects over 18–30 months of follow-up. Discussion TEACH is the first study of a blended collaborative care intervention simultaneously addressing distress and medical CHD risk factors conducted in cardiac patients in a European health care setting. If proven effective, its results can improve long-term chronic care of this vulnerable patient group and may be adapted for patients with other chronic conditions. Trial registration: German Clinical Trials Register, DRKS00020824, registered on 4 June, 2020; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020824

Abstract Aims Patients with heart failure (HF) have impaired quality of life (QoL). The randomized controlled trial PHARM‐CHF investigated whether an interdisciplinary intervention consisting of regular contacts with the community pharmacy and weekly dosing aids improves medication adherence in patients with HF. It is unknown how an intervention involving frequent structured pharmacy visits affects QoL. Our aim was to explore adherence to the intervention and effects on QoL. Methods and results Among 237 patients, n = 110 were randomized to pharmacy care and n = 127 to usual care. The pharmacy care group received a medication review followed by (bi‐)weekly dose dispensing and counselling. The median follow‐up was 2.0 years [inter‐quartile range (IQR) 1.2–2.7]. Median interval between pharmacy visits was 8.4 days (IQR 8.0–10.3) and the visits lasted in median 14 min (IQR 10–15). Median adherence to the intervention was 96% (IQR 84–100). QoL at 365 days was predefined as a main secondary and at 730 days as another secondary endpoint in PHARM‐CHF. QoL was measured by the Minnesota Living with Heart Failure Questionnaire; and for 111 patients (n = 47 in the pharmacy care group and n = 64 in the usual care group), data were available at baseline, and after 365 and 730 days (mean age 74 years; 41% female). Improvement in QoL was numerically higher in the pharmacy care group after 365 days and was significantly better after 730 days (difference in total scores −7.7 points [−14.5 to −1.0]; P = 0.026) compared to the usual care group. In all subgroups examined, this treatment effect was preserved. Improvements in the physical and emotional dimensions were numerically higher in the pharmacy care group after 365 days and were significantly better after 730 days: −4.0 points [−6.9 to −1.2]; P = 0.006, and −1.9 points [−3.7 to −0.1]; P = 0.039, respectively. Conclusions A pharmacy‐based interdisciplinary intervention was well received by the patients and suggests clinically important improvements in QoL.

Abstract Background Galectin-3 promotes the proliferation of neural progenitor cells and is engaged in cell-cell adhesion, cell-matrix interactions, and macrophage activation. In addition, in patients with heart failure this carbohydrate-binding protein is a known prognostic marker for cardiovascular mortality. However, its association with psychological variables has not been investigated so far. Methods Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) trial, we studied in participants with cardiovascular risk factors (n = 1260, age 66.7 ± 8.0 years, males 51%, left ventricular ejection fraction 60.0 ± 8.1%) the relationship between serum concentrations of galectin-3 and anxiety. Galectin-3 levels were measured by means of a sandwich enzyme-linked immunosorbent assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS). Results In univariate analysis, there was a weak but significant inverse correlation between galectin-3 and HADS anxiety (rho = − 0.076; p = 0.008). Linear regression models adjusted for sex, age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-min walking distance, the 36-item Short-Form Health Survey (SF-36) subscale physical functioning, and known biomarkers for heart failure confirmed that serum galectin-3 significantly and independently predicted self-rated anxiety (B = -2.413; 95%CI = -2.413–-4.422; p = 0.019). Conclusion In patients with cardiovascular risk factors, serum concentrations of galectin-3 showed an inverse association with anxiety, which was independent of both the severity of physical impairment and established risk factors for the progression of heart failure.

Abstract Aims Atrial fibrillation (AF) is a frequent comorbidity in patients with heart failure (HF). HF patients with AF are characterized by high morbidity and increased risk of hospitalizations. We assessed the effects of remote patient management (RPM) in HF patients with AF compared with usual care (UC) in the TIM‐HF2 trial. Methods and results For this post‐hoc analysis, AF status at randomization was assessed in 1537 patients with HF. The primary outcome was the percentage of days lost due to unplanned cardiovascular hospital admissions or death of any cause. Around 966 patients had sinus rhythm (SR) and 571 had AF. The analysis showed a significant interaction between heart rhythm and all‐cause mortality (P for interaction = 0.001). AF patients had more days lost due to unplanned cardiovascular hospitalization than SR patients (7.53%, CI 6.01–9.05 vs. 4.90%, CI 3.98–5.82, ratio 1.54, P = 0.004) and higher all‐cause mortality (11.9%, CI 9.4–14.9 vs. 8.5%, CI 6.8–10.4, HR 0.66, CI 0.47–0.94, P = 0.029). Patients with AF randomized to RPM had significantly less days lost due to unplanned cardiovascular hospital admissions or all‐cause death (5.64%, CI 3.81–7.48) than patients with AF randomized to UC (9.37%, CI 6.98–11.76, ratio 0.60, P = 0.015). No difference was seen in SR patients (UC: 5.25%, CI 3.93–6.58, RPM: 4.55%, CI 3.27–5.83, ratio 0.87, P = 0.452). All‐cause mortality in AF patients was reduced with 9.2% (CI 6.1–13.2) in the RPM group compared with 14.5% (CI 10.7–18.1) in the UC group (HR 0.60, CI 0.36–1.00, P = 0.050). Conclusions For patients with atrial fibrillation at study entry, RPM was associated with increased days alive out of hospital. Our results identify HF patients with atrial fibrillation as a promising target population for RPM.

Abstract Aims The aim of this paper was to analyse heart failure (HF) signs and symptoms, hospital referrals, and prescription patterns in patients receiving sacubitril/valsartan (sac/val) in primary care and cardiology settings in Germany. Methods and results A retrospective cohort study of electronic medical records identified 1263 adults (aged ≥18 years) in the German IMS® Disease Analyzer database who were prescribed sac/val during 2016 and had at least 6 months of data following sac/val initiation. Clinical characteristics were collected during the 12 months before the first recorded sac/val prescription (index date) and 6 months post‐index. Details of sac/val dose and prescription patterns were also recorded in the 6 months post‐index. HF signs, symptoms, and all‐cause hospital referrals were evaluated for 90 days pre‐index and 30–120 days post‐index. Most patients (62%) were prescribed the lowest sac/val dose of 24/26 mg twice daily (b.i.d.) at index; only 14% of patients initiated on 24/26 mg or 49/51 mg b.i.d. were up‐titrated to the 97/103 mg b.i.d. target dose during the 6 months post‐index, while 6% of patients initiated on either 49/51 mg or 97/103 mg b.i.d. were stably down‐titrated. Evaluation of prescription patterns in relation to clinical characteristics did not clearly explain the reluctance to up‐titrate in the majority of patients. More patients experienced HF signs or symptoms or all‐cause referrals to hospital during the 90 days pre‐index than during the 30–120 days post‐index. Conclusions The majority of patients receiving sac/val are not up‐titrated, contrary to recommendations of the EU summary of product characteristics; this is not fully explained by patients' clinical characteristics. Further research is required to understand the reasons for clinician inertia.

Abstract Objective Identification of ischemic stroke patients at high risk for paroxysmal atrial fibrillation (pAF) during 72 hours Holter ECG might be useful to individualize the allocation of prolonged ECG monitoring times, currently not routinely applied in clinical practice. Methods In a prospective multicenter study, the first analysable hour of raw ECG data from prolonged 72 hours Holter ECG monitoring in 1031 patients with acute ischemic stroke/TIA presenting in sinus rhythm was classified by an automated software (AA) into “no risk of AF” or “risk of AF” and compared to clinical variables to predict AF during 72 hours Holter‐ECG. Results pAF was diagnosed in 54 patients (5.2%; mean age: 78 years; female 56%) and was more frequently detected after 72 hours in patients classified by AA as “risk of AF” (n = 21, 17.8%) compared to “no risk of AF” (n = 33, 3.6%). AA‐based risk stratification as “risk of AF” remained in the prediction model for pAF detection during 72 hours Holter ECG (OR3.814, 95% CI 2.024‐7.816, P

Abstract Aims Although the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin‐converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background‐medication‐based individualized comparators (BMICs) on N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial. Methods PARALLAX is a prospective, randomized, controlled, double‐blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II–IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co‐morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT‐proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden. Conclusions PARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co‐morbidities improves NT‐proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%.

Abstract Aims Whereas syncopal episodes are a frequent complication of cardiovascular disorders, including heart failure (HF), little is known whether syncopes impact the prognosis of patients with HF. We aimed to assess the impact of a history of syncope (HoS) on overall and hospitalization‐free survival of these patients. Methods and results We pooled the data of prospective, nationwide, multicentre studies conducted within the framework of the German Competence Network for Heart Failure including 11 335 subjects. Excluding studies with follow‐up periods

Abstract Aims Although heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause for hospitalization, its overall costs remain unclear. Therefore, we assessed the health care‐related costs of ambulatory HFpEF patients and the effect of spironolactone. Methods and results The aldosterone receptor blockade in diastolic HF trial is a multicentre, prospective, randomized, double‐blind, placebo‐controlled trial conducted between March 2007 and April 2011 at 10 sites in Germany and Austria that included 422 ambulatory patients [mean age: 67 years (standard deviation: 8); 52% women]. All subjects suffered from chronic New York Heart Association (NYHA) class II or III HF and preserved left ventricular ejection fraction of 50% or greater. They also showed evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209) with 12 months of follow‐up. We used a single‐patient approach to explore the resulting general cost structure and included medication, number of general practitioner and cardiologist visits, and hospitalization in both acute and rehabilitative care facilities. The average annual costs per patient in this cohort came up to €1, 118 (±2,475), and the median costs were €332. We confirmed that the main cost factor was hospitalization and spironolactone did not affect the overall costs. We identified higher HF functional class (NYHA), male patients with low haemoglobin level, with high oxygen uptake (VO2max) and coronary artery disease, hyperlipidaemia, and atrial fibrillation as independent predictors for higher costs. Conclusions In this relatively young, oligosymptomatic, and with regard to the protocol without major comorbidities patient cohort, the overall costs are lower than expected compared with the HFrEF population. Further investigation is needed to investigate the impact of, for example, comorbidities and their effect over a longer period of time. Simultaneously, this analysis suggests that prevention of comorbidities are necessary to reduce costs in the health care system.

The role of patent foramen ovale (PFO) in stroke was debated for decades. Randomized clinical trials (RCTs) have shown fewer recurrent events after PFO closure in patients with cryptogenic stroke (CS). However, in clinical practice, treating stroke patients with coexisting PFO raises some questions. This brief review summarizes current knowledge and challenges in handling stroke patients with PFO and identifies issues for future research. The rationale for PFO closure was initially based on the concept of paradoxical embolism from deep vein thrombosis (DVT). However, RCTs did not consider such details, limiting their impact from a pathophysiological perspective. Only a few studies explored the coexistence of PFO and DVT in CS with varying results. Consequently, the PFO itself might play a role as a prothrombotic structure. Transesophageal echocardiography thus appears most appropriate for PFO detection, while a large shunt size or an associated atrial septum aneurysm qualify for a high-risk PFO. For drug-based treatment alone, studies did not find a definite superiority of oral anticoagulation over antiplatelet therapy. Remarkably, drug-based treatment in addition to PFO closure was not standardized in RCTs. The available literature rarely considers patients with transient ischemic attack (TIA), over 60 years of age, and competing etiologies like atrial fibrillation. In summary, RCTs suggest efficacy for closure of high-risk PFO only in a small subgroup of stroke patients. However, research is also needed to reevaluate the pathophysiological concept of PFO-related stroke and establish strategies for older and TIA patients and those with competing risk factors or low-risk PFO.

Summary: Background: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. Methods: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36–50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. Findings: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57–73]); left ventricular ejection fraction 45% [40–48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40–11·78]; p

BackgroundThe contribution of left atrial disease and excessive supraventricular ectopic activity (ESVEA) to the risk for incident atrial fibrillation (AF) is incompletely understood.ObjectiveTo analyse the ten-year risk to develop AF in patients with cardiovascular risk factors and to define the impact of parameters of left atrial disease and ESVEA on AF risk.Methods148 patients from the Diast-CHF trial with at least one cardiovascular risk factor and free of AF at baseline were followed for 10 years. Left atrial disease was defined as left atrial volume index (LAVI) >35 ml/m2, P-terminal force in lead V1 (PTFV1) >4000 ms*μV or elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/ml. We analyzed the association of these parameters and ESVEA (either >720 premature atrial contractions (PAC) or one atrial run >20 beats per day) on AF-free survival.ResultsAfter ten years, AF was newly detected in twelve patients (13.4%) with signs of left atrial disease and two patients (3.4%) without signs of left atrial disease (p = 0.04). LAVI (p = 0.005), ESVEA (p = 0.016) and NT-proBNP (p = 0.010) were significantly associated with AF-free survival in univariate analysis. A combined Cox model of left atrial disease parameters showed associations for NT-proBNP (HR 3.56; 95%CI 1.33-5.31; p = 0.04) and PAC (HR 2.66; 95%CI 1.25-10.15; p = 0.01) but not for LAVI or PTFV1 with AF-free survival.ConclusionThe risk for AF is higher in patients with cardiovascular risk factors and signs of left atrial disease. NT-proBNP and premature atrial contractions independently predict AF-free survival. The role of excessive supraventricular ectopic activity for the assessment of AF risk may be underestimated and requires further study.

Abstract Aims Patients suffering from heart failure with preserved ejection fraction (HFpEF) report similar symptoms and reduction in quality of life to those with reduced ejection fraction but remain largely untreated. We conducted a preliminary evaluation of the acceptance, feasibility, and efficacy of a motivational interviewing (MI) intervention to support elderly patients suffering from HFpEF in maintaining or starting physical activity. Methods and results At the conclusion of the exercise training in diastolic heart failure parent trial that examined the effects of supervised exercise, patients with HFpEF were offered participation in a two‐group pilot study. Based on their preference, consenting patients were assigned to either a 6 month MI intervention group (n = 19) or their physicians' usual care (n = 20). To support participants in increasing and/or maintaining their physical activity, counsellors delivered a mean of 6.5 MI sessions (face to face and via telephone) and also provided a physical activity diary as self‐management tool. At baseline and 6 months, we assessed participants' physical activity motivation (Sportbezogene Selbstkonkordanz Scale) and their physical improvements with the 6 min walk test and a cardiopulmonary exercise test. Of the entire sample (N = 39), 46% were female, their mean age was 73, 90% were in New York Heart Association Class II, and the mean ejection fraction was 61.4%. The majority of MI participants rated the intervention as acceptable, 90% perceived MI as helpful in setting specific exercise goals and overcoming barriers concerning physical activity, and 58% considered the physical activity diary as very helpful. Three‐quarters of MI participants (79%) reported an increase in their physical activity compared with the previous year. Intervention participants showed a greater increase in median peak VO2 from baseline to 6 months (baseline: 18.4 mL/kg/min; 6 months: 20.4 mL/kg/min) compared with the control group (baseline: 20.0 mL/kg/min; 6 months: 19.2 mL/kg/min; P = 0.015). There was no significant change in motivation on the Sportbezogene Selbstkonkordanz Scale for either group (MI: 1.7 vs. 3, P = 0.55; control: 4.7 vs. 4, P = 0.26) nor did patients show any significant improvements in the 6 min walk test (MI: 549 vs. 540 m, P = 0.80; control: 572 vs. 580 m, P = 0.37). Counsellors rated the implementation of the MI intervention as feasible. Conclusions The results from this pilot study suggest that our MI intervention was well accepted by participants and deemed feasible. It also appears to be an effective treatment to increase and maintain physical activity and exercise capacity in patients suffering from HFpEF. Our findings need to be confirmed in a randomized clinical trial with larger and unselected patient cohorts.

Aims Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE). Methods Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. Results Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84–152) versus 102 (78–134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2–2.4) versus 1.3 (1.1–1.7); p

Background: Circulating long-chain (LCSFAs) and very long-chain saturated fatty acids (VLSFAs) have been differentially linked to risk of incident heart failure (HF). In patients with heart failure with preserved ejection fraction (HFpEF), associations of blood SFA levels with patient characteristics are unknown. Methods: From the Aldo-DHF-RCT, whole blood SFAs were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were 67 ± 8 years, 53% female, NYHA II/III (87%/13%), ejection fraction ≥50%, E/e’ 7.1 ± 1.5; and median NT-proBNP 158 ng/L (IQR 82–298). Spearman´s correlation coefficients and linear regression analyses, using sex and age as covariates, were used to describe associations of blood SFAs with metabolic phenotype, functional capacity, cardiac function, and neurohumoral activation at baseline and after 12-month follow-up (12 mFU). Results: In line with prior data supporting a potential role of de novo lipogenesis-related LCSFAs in the development of HF, we showed that baseline blood levels of C14:0 and C16:0 were associated with cardiovascular risk factors and/or lower exercise capacity in patients with HFpEF at baseline/12 mFU. Contrarily, the three major circulating VLSFAs, lignoceric acid (C24:0), behenic acid (C22:0), and arachidic acid (C20:0), as well as the LCSFA C18:0, were broadly associated with a lower risk phenotype, particularly a lower risk lipid profile. No associations were found between cardiac function and blood SFAs. Conclusions: Blood SFAs were differentially linked to biomarkers and anthropometric markers indicative of a higher-/lower-risk cardiometabolic phenotype in HFpEF patients. Blood SFA warrant further investigation as prognostic markers in HFpEF. One Sentence Summary: In patients with HFpEF, individual circulating blood SFAs were differentially associated with cardiometabolic phenotype and aerobic capacity.

Aims: High prevalence and lack of pharmacological treatment are making heart failure with preserved ejection fraction (HFpEF) a growing public health problem. No algorithm for the screening of asymptomatic patients with risk for HFpEF exists to date. We assessed whether HFA/ESC 2007 diagnostic criteria for HFpEF are helpful to investigate the cardiovascular outcome in asymptomatic patients. Methods and results: We performed an analysis of the Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that recruited patients with cardiovascular risk factors. All patients underwent a comprehensive diagnostic workup at baseline. Asymptomatic patients with preserved LVEF (>50%) were selected and classified according to HFA/ESC surrogate criteria for left ventricular elevated filling pressure (mean E/e’ >15 or E/e’ >8 and presence of either NT-proBNP > 220 ng/l, BNP > 200 ng/l or atrial fibrillation) into elevated filling pressure (FPe) or controls. Cardiovascular hospitalizations and all-cause death were assessed for both groups over a 10-year-follow-up.851 asymptomatic patients (age 65.5 ± 7.6 years, 44% female) were included in the analysis. FPe-patients were significantly older (p

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement.

BackgroundThe cardiac diagnostic workup of stroke patients, especially the value of echocardiography and enhanced and prolonged Holter-ECG monitoring, is still a matter of debate. We aimed to analyse the impact of pathologies detected by echocardiography and ECG monitoring on therapeutic decisions and prognosis.MethodsFind-AFRANDOMISED was a prospective multicenter study which randomised 398 acute ischemic stroke patients ≥ 60 years to enhanced and prolonged Holter-ECG monitoring or usual stroke unit care. This substudy compared therapeutic consequences of echocardiography and routine Holter-ECG or enhanced and prolonged Holter-ECG monitoring, respectively, and prognosis of patients with or without pathologic findings in echocardiography or Holter-ECG monitoring.Results50.3% received enhanced and prolonged Holter-ECG monitoring and 49.7% routine ECG monitoring. 82.9% underwent transthoracic echocardiography (TTE), 38.9% transesophageal echocardiography (TEE) and 25.6% both procedures. 14/89 TEE pathologies and 1/90 TTE pathology led to a change in therapy, resulting in a number needed to change decision (NNCD) of 12 and 330 (p < 0.001), respectively. In comparison, enhanced and prolonged Holter-ECG monitoring found atrial fibrillation (AF) in 27 of 200 patients, and routine ECG monitoring in twelve of 198 patients, leading to therapeutic changes in all patients (NNCD 8 and 17, respectively, p < 0.001).ConclusionsMost changes in therapeutic decisions were triggered by enhanced and prolonged Holter-ECG monitoring, which should therefore play a more prominent role in future guidelines. Echocardiography identifies a patient group at high cardiovascular risk, but rarely result in therapeutic changes. Whether this patient group requires further cardiovascular workup remains unknown. This should be further investigated by interdisciplinary neurocardiologic teams and in appropriate future trials.Trial registrationClinicalTrials.gov NCT01855035.

BackgroundPatients with retinal vascular occlusion disease have an increased risk for ischemic stroke and share some risk factors with cerebrovascular disease. The purpose of this study was to analyze the prevalence of atrial fibrillation (AF) in subjects with retinal vascular occlusive disease and anterior ischemic optic neuropathy and to compare these data to an ischemic stroke group.MethodsProspective, observational single-center trial. Subjects with retinal artery occlusion (RAO), retinal vein occlusion (RVO) and anterior ischemic optic neuropathy (AION) were included. Patients with ischemic stroke (IS) from a previous observational trial were used as control. Investigation included 7-day Holter ECG, echocardiography, duplex ultrasonography of the carotid arteries, and 24-hour blood pressure monitoring. Further vascular risk factors were documented.ResultsDuring the 1-year study period, 101 patients were recruited. The control group with ischemic stroke consisted of 272 subjects. At inclusion, the prevalence of AF was 12% (RAO), 10.2% (RVO), 11.1% (NAION) and 15.8% (IS). The final prevalence after Holter ECG rose to 16% (RAO), 18.4% (RVO), 14.8% (NAION) and 26.5% (IS). No significant difference was measured between groups.ConclusionsWe detected a similar prevalence of AF in all groups. RVO patients tended to exhibit a higher AF detection rate and lower number needed to screen than RAO and NAION. The detection of AF rose considerably via Holter ECG. As a consequence, we recommend prolonged ECG monitoring in patients with acute ophthalmic vascular diseases.

Background. Atrial fibrillation (AF) is an important cause of embolic stroke of undetermined source (ESUS). Imaging-patterns like multiple infarcts, simultaneous involvement of different circulations, infarcts of different ages, and isolated cortical infarcts are likely to indicate cardioembolic stroke. The aim of our study was to evaluate the association between embolic stroke patterns, ESUS, and the new diagnosis of AF. Methods. Stroke etiology and imaging characteristics from patients included in the Find-AF study were obtained. Embolic stroke patterns in CT- or MR-imaging were correlated with the diagnosis of ESUS as well as the short- (on baseline ECG and during 7-day Holter) and long-term (12-month follow-up) diagnosis of AF. Results. From 281 patients included in the Find-AF study, 127 (45.2%) patients with ischemic lesions detected in CT or MRI were included. 26 (20.5%) of these patients had ESUS. At least one embolic stroke pattern was detected in 67 (52.7%) patients. Embolic stroke patterns were not associated with ESUS (OR 1.57, 0.65–3.79, p=0.317), the short-term (OR 0.64, 0.26–1.58, p=0.327) or long-term diagnosis of AF (OR 0.72, 0.31–1.68, p=0.448). Conclusions. This secondary data analysis of the Find-AF study could not provide evidence for an association between embolic stroke patterns, ESUS, and the new diagnosis of AF.

BACKGROUND:The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety. METHODS:Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS:Among the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-CI] = 0.067-0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β) = 0.114, 95%-CI = 0.023-0.566, p = 0.008). CONCLUSIONS:Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

BackgroundDetecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run(24 h)), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a' (left atrial volume index/late diastolic tissue Doppler velocity).MethodsRetrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively.ResultsPAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run(24 h). PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤ 4 (p5) vs. ≤ 5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run(24 h = 10) [5]; [21] vs. 0 [0; 8] beats (both p4 and abnormal LAVI/a' showed high PAF-rates.ConclusionsESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a' in patients with cerebral ischemia. Normal LAVI/a'+PAC/h ≤ 4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a'+PAC/h >4.

Background and purposeDiagnosis of paroxysmal atrial fibrillation (AF) can be challenging, but it is highly relevant in patients presenting with sinus rhythm and acute cerebral ischemia. We aimed to evaluate prospectively whether natriuretic peptide levels and kinetics identify patients with paroxysmal AF.MethodsPatients with acute cerebral ischemia were included into the prospective observational Find-AF study. N-terminal pro brain-type natriuretic peptide (NT-proBNP), brain-type natriuretic peptide (BNP) and N-terminal pro atrial-type natriuretic peptide (NT-proANP) plasma levels were measured on admission, after 6 and 24 hours. Patients free from AF at presentation received 7 day Holter monitoring. We prospectively hypothesized that patients presenting in sinus rhythm with NT-proBNP>median were more likely to have paroxysmal AF than patients with NT-proBNPResults281 patients were included, of whom 237 (84.3%) presented in sinus rhythm. 220 patients naïve to AF with an evaluable prolonged Holter ECG were analysed. In patients with NT-proBNP>median (239 pg/ml), 17.9% had paroxysmal AF in contrast to 7.4% with NT-proBNPConclusionsBNP is independently predictive of paroxysmal AF detected by prolonged ECG monitoring in patients with cerebral ischemia and may be used to effectively select patients for prolonged Holter monitoring.

Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital.Methods Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.Results Among 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p