Autonomic Nerve Function Predicts Risk of Early Death after Discharge in Acute Medical Disease.

BACKGROUND: Heart rate variability, a marker of autonomic function, has shown promising prognostic results in specific populations, but has not been tested in a general medical population. We hypothesized that heart rate variability identifies high-risk medical patients early after admission to the hospital. METHODS: This was a single-center prospective cohort study of acutely admitted medical patients aged ≥18 years with a life expectancy ≥3 months, included between 2019-2023. Unstable patients needing direct admission to the intensive care unit were excluded. Heart rate variability was recorded within 24 hours of admission for 10 minutes. The standard deviation of normal-normal beats (SDNN) was the primary heart rate variability marker. Low SDNN was defined as the lowest tertile (≤22 ms). The primary outcome was 30-day all-cause mortality. The secondary outcome was 30-day readmission or mortality. RESULTS: Among 721 patients included, low SDNN carried an 8-fold greater risk of 30-day mortality in univariate analysis (hazard ratio [HR] 8.3; P = .001); in multivariate analyses a 4-fold greater risk (HR 3.8; P = .037). Low SDNN was associated with the combined outcome of 30-day mortality or readmission (HR 1.5; P = .03) in multivariate analysis. In receiver operating characteristics analyses, low SDNN improved the predictive accuracy of early warning score for 30-day mortality or readmission from 0.63 to 0.71 (P = .008) but did not improve the accuracy for 30-day mortality alone. CONCLUSIONS: In patients admitted due to acute medical illness, low heart rate variability predicted 30-day mortality and readmission, suggesting heart rate variability as a tool to identify patients at high and low risk of relevant endpoints.

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

AIMS: Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. METHODS: The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. RESULTS: The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. CONCLUSION: The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

In this study, we developed and examined the potential of the novel ASGARD risk score to tailor personalized follow-up intervals for diagnostic heart scans, incorporating updated heart rate and blood marker measurements along with the heart scan data from the previous year. Patients with the ASGARD risk score within the lowest 50% had a low annual risk of aortic valve-related events (less than 5%) for a minimum of 15 months.In clinical settings, the ASGARD score could provide a personalized and safe monitoring alternative to routine heart scans, prioritizing the diagnostic heart scans for high-risk patients.

Computed tomography or chest X-ray to assess pulmonary congestion in dyspnoeic patients with acute heart failure.

AIMS: While computed tomography (CT) is widely acknowledged as superior to chest radiographs for acute diagnostics, its efficacy in diagnosing acute heart failure (AHF) remains unexplored. This prospective study included consecutive patients with dyspnoea undergoing simultaneous low-dose chest CT (LDCT) and chest radiographs. Here, we aimed to determine if LDCT is superior to chest radiographs to confirm pulmonary congestion in dyspnoeic patients with suspected AHF. METHODS AND RESULTS: An observational, prospective study, including dyspnoeic patients from the emergency department. All patients underwent concurrent clinical examination, laboratory tests, echocardiogram, chest radiographs, and LDCT. The primary efficacy measure to compare the two radiological methods was conditional odds ratio (cOR). The primary outcome was adjudicated AHF, ascertained by comprehensive expert consensus. The secondary outcome, echo-bnp AHF, was an objective AHF diagnosis based on echocardiographic cardiac dysfunction, elevated cardiac filling pressure, loop diuretic administration, and NT-pro brain natriuretic peptide > 300 pg/mL. Of 228 dyspnoeic patients, 64 patients (28%) had adjudicated AHF, and 79 patients (35%) had echo-bnp AHF. Patients with AHF were older (78 years vs. 73 years), had lower left ventricular ejection fraction (36% vs. 55%), had higher elevated left ventricular filling pressures (98% vs. 18%), and had higher NT-pro brain natriuretic peptide levels (3628 pg/mL vs. 470 pg/mL). The odds to diagnose adjudicated AHF and echo-bnp AHF were up to four times greater using LDCT (cOR: 3.89 [2.15, 7.06] and cOR: 2.52 [1.45, 4.38], respectively). For each radiologic sign of pulmonary congestion, the LDCT provided superior or equivalent results as the chest radiographs, and the interrater agreement was higher using LDCT (kappa 0.88 [95% CI: 0.81, 0.95] vs. 0.73 [95% CI: 0.63, 0.82]). As first-line imaging modality, LDCT will find one additional adjudicated AHF in 12.5 patients and prevent one false-positive in 20 patients. Similar results were demonstrated for echo-bnp AHF. CONCLUSIONS: In consecutive dyspnoeic patients admitted to the emergency department, LDCT is significantly better than chest radiographs in detecting pulmonary congestion.

Frequency and risk factors of atrial fibrillation after acute abdominal surgery: A prospective cohort study.

BACKGROUND AND AIM: Scarce data exist on the true incidence of postoperative atrial fibrillation (POAF) after acute abdominal surgery and associated outcomes. The current study aimed to identify the frequencies of clinically recognized POAF and associated complications, along with their risk factors. METHODS: This study was a prospective, single-center cohort study of unselected adult patients referred for acute abdominal surgery during a 3-month period. Through careful review, demographics, comorbidity, and surgical characteristics were prospectively drawn from medical charts. The primary outcome was clinically recognized POAF occurring in-hospital. Logistic regression was used to determine the risk factors of POAF and associated complications. A subgroup was enrolled in a feasibility study of peri- and postoperative continuous cardiac rhythm monitoring. RESULTS: In total, 450 patients were enrolled. Clinically recognized in-hospital POAF was observed in 22 patients (4.9%). All cases were observed in patients aged ≥60 years, corresponding to 22 of 164 patients (13.4%). Multiple risk factors were observed, such as age, prior atrial fibrillation, heart failure, hypertension, diabetes mellitus, chronic renal disease, and major (vs. minor) surgery. POAF was associated with severe in-hospital complications (POAF group 45.5% vs. non-POAF group 8.6%, p < .001) and in-hospital mortality (POAF group 13.6% vs. non-POAF group 3.0%, p = .043). In total, 295 patients were monitored by continuous cardiac rhythm monitoring for 12,148 h, yielding five patients with asymptomatic AF. CONCLUSIONS: In conclusion, this prospective study of POAF in patients undergoing acute abdominal surgery showed that one in 20 patients developed clinically recognized in-hospital POAF. Multiple risk factors of POAF were identified. POAF was associated with severe complications up to 30 days after surgery.

Predicting risk of AF in ischaemic stroke using sinus rhythm ECG abnormalities: A meta-analysis.

OBJECTIVE: To identify ECG changes in sinus rhythm that may be used to predict subsequent development of new AF. METHOD: We identified prospective and retrospective cohort or case control studies evaluating ECG patterns from a 12-lead ECG in sinus rhythm taken in hospital or community predicting subsequent development of new AF. For each identified ECG predictor, we then identify absolute event rates and pooled risk ratios (RR) using an aggregate level random effects meta-analysis. RESULTS: We identified 609,496 patients from 22 studies. ECG patterns included P wave terminal force V1 (PTFV1), interatrial block (IAB) and advanced interatrial block (aIAB), abnormal P wave axis (aPWA), PR prolongation and atrial premature complexes (APCs). Pooled risk ratios reached significance for each of these; PTFV1 RR 1.48 (95% CI 1.04-2.10), IAB 2.54 (95% CI 1.64-3.93), aIAB 4.05 (95% CI 2.64-6.22), aPWA 1.89 (95% CI 1.25-2.85), PR prolongation 2.22 (95% CI 1.27-3.87) and APCs 3.71 (95% CI 2.23-6.16). Diabetes reduced the predictive value of PR prolongation. CONCLUSION: APC and aIAB were most predictive of AF, while IAB, PR prolongation, PTFV1 and aPWA were also significantly associated with development of AF. These support their use in a screening tool to identify at risk cohorts who may benefit from further investigation, or following stroke, with empirical anticoagulation.

The left atrial appendage closure by surgery-2 (LAACS-2) trial protocol rationale and design of a randomized multicenter trial investigating if left atrial appendage closure prevents stroke in patients undergoing open-heart surgery irrespective of preoperative atrial fibrillation status and stroke risk.

BACKGROUND: Current recommendations regarding the use of surgical left atrial appendage (LAA) closure to prevent thromboembolisms lack high-level evidence. Patients undergoing open-heart surgery often have several cardiovascular risk factors and a high occurrence of postoperative atrial fibrillation (AF)-with a high recurrence rate-and are thus at a high risk of stroke. Therefore, we hypothesized that concomitant LAA closure during open-heart surgery will reduce mid-term risk of stroke independently of preoperative AF status and CHA2DS2-VASc score. METHODS: This protocol describes a randomized multicenter trial. Consecutive participants ≥18 years scheduled for first-time planned open-heart surgery from cardiac surgery centers in Denmark, Spain, and Sweden are included. Both patients with a previous diagnosis of paroxysmal or chronic AF, as well as those without AF, are eligible to participate, irrespective of their CHA2DS2-VASc score. Patients already planned for ablation or LAA closure during surgery, with current endocarditis, or where follow-up is not possible are considered noneligible. Patients are stratified by site, surgery type, and preoperative or planned oral anticoagulation treatment. Subsequently, patients are randomized 1:1 to either concomitant LAA closure or standard care (ie, open LAA). The primary outcome is stroke, including transient ischemic attack, as assigned by 2 independent neurologists blinded to the treatment allocation. To recognize a 60% relative risk reduction of the primary outcome with LAA closure, 1,500 patients are randomized and followed for 2 years (significance level of 0.05 and power of 90%). CONCLUSIONS: The LAACS-2 trial is likely to impact the LAA closure approach in most patients undergoing open-heart surgery. TRIAL REGISTRATION: NCT03724318.

Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial.

Background: High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. Methods: In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint. Findings: Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, -0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18-1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23-2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event. Interpretation: hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Funding: Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Left atrial late gadolinium enhancement in patients with ischaemic stroke.

AIMS: To evaluate the extent of left atrial (LA) fibrosis in patients with a recent stroke without atrial fibrillation and controls without established cardiovascular disease. METHODS AND RESULTS: This prospectively designed study used cardiac magnetic resonance to detect LA late gadolinium enhancement as a proxy for LA fibrosis. Between 2019 and 2021, we consecutively included 100 patients free of atrial fibrillation with recent ischaemic stroke (<30 days) and 50 age- and sex-matched controls. LA fibrosis assessment was achieved in 78 patients and 45 controls. Blinded to the cardiac magnetic resonance results, strokes were adjudicated according to modified Trial of Org 10172 in Acute Stroke Treatment classification as undetermined aetiology (n = 42) or as attributable to large- or small-vessel disease (n = 36). Patients with stroke had a larger extent of LA fibrosis [6.9%, interquartile range (IQR) 3.6-15.4%] than matched controls (4.2%, IQR 2.3-7.5%; P = 0.007). No differences in LA fibrosis were observed between patients with stroke of undetermined aetiology and those with large- or small-vessel disease (6.6%, IQR 3.8-16.0% vs. 6.9%, IQR 3.4-14.6%; P = 0.73). CONCLUSION: LA fibrosis was more extensive in patients with stroke than in age- and sex-matched controls. A similar extent of LA fibrosis was observed in patients with stroke of undetermined aetiology and stroke classified as attributable to large- or small-vessel disease. Our findings suggest that LA structural abnormality is more frequent in patients with stroke than in controls independent of aetiological classification.

Remote dielectric sensing to detect acute heart failure in patients with dyspnoea: a prospective observational study in the emergency department.

Aims: Remote dielectric sensing (ReDS) enables quick estimation of lung fluid content. To examine if ReDS is superior to other methods in detecting acute heart failure. Methods and results: We included consecutive patients with dyspnoea from the emergency departments at Bispebjerg Hospital, Copenhagen, and performed ReDS, low-dose chest computed tomography (CT), echocardiogram, lung ultrasound, NT-Pro-brain natriuretic peptide (NT-proBNP), and a Boston score evaluation (chest X-ray and clinical signs). ReDS values >35% were used as a cut-off to diagnose pulmonary congestion. Acute heart failure was adjudicated by experts' review of health records but independently of ReDS values. Sub-analyses investigated ReDS in acute heart failure patients with congestion on CT. We included 97 patients within a median of 4.8 h from admittance: 25 patients (26%) were ReDS-positive and 39 (40%) had adjudicated acute heart failure (21 with and 18 without CT congestion). Heart failure patients had median ReDS 33%, left ventricular ejection fraction 48%, and NT-proBNP 2935 ng/L. A positive ReDS detected heart failure with 46% sensitivity, 88% specificity, and 71% accuracy. The AUC for ReDS was like the Boston score (P = 0.88) and the lung ultrasound score (P = 0.74). CT-congested heart failure patients had higher ReDS values than patients without heart failure (median 38 vs. 28%, P < 0.001). Heart failure patients without CT-congestion had ReDS values like patients without heart failure (mean 30 vs. 28%, P = 0.07). Conclusion: ReDS detects acute heart failure similarly to the Boston score and lung ultrasound score, and ReDS primarily identifies the acute heart failure patients who have congestion on a chest CT.

Parasympathetic tonus in type 2 diabetes and pre-diabetes and its clinical implications.

Autonomic imbalance reflected by higher resting heart rate and reduced parasympathetic tone may be driven by low-grade inflammation (LGI) and impaired glycemic control in type 2 diabetes mellitus (T2DM) and pre-diabetes. We examined the interaction of parasympathetic components of heart rate variability (HRV), variables of LGI, and glucose metabolism in people with T2DM, pre-diabetes, and normal glucose metabolism (NGM). We recorded HRV by Holter (48 h) in 633 community-dwelling people of whom T2DM n = 131, pre-diabetes n = 372, and NGM n = 130 and mean HbA1c of 7.2, 6.0 and 5.3%, respectively. Age was 55-75 years and all were without known cardiovascular disease except from hypertension. Fasting plasma glucose, fasting insulin, HOMA-IR, HbA1c and LGI (CRP, Interleukin-18 (IL-18), and white blood cells) were measured. Root-mean-square-of-normal-to-normal-beats (RMSSD), and proportion of normal-to-normal complexes differing by more than 50 ms (pNN50) are accepted measures of parasympathetic activity. In univariate analyses, RMSSD and pNN50 were significantly inversely correlated with level of HbA1c and CRP among people with T2DM and pre-diabetes, but not among NGM. RMSSD and pNN50 remained significantly inversely associated with level of HbA1c after adjusting for age, sex, smoking, and BMI among people with T2DM (ß = - 0.22) and pre-diabetes (ß = - 0.11); adjustment for LGI, HOMA-IR, and FPG did not attenuate these associations. In backward elimination models, age and level of HbA1c remained associated with RMSSD and pNN50. In people with well controlled diabetes and pre-diabetes, a lower parasympathetic activity was more related to age and HbA1c than to markers of LGI. Thus, this study shows that the driver of parasympathetic tonus may be more the level of glycemic control than inflammation in people with prediabetes and well controlled diabetes.

Left Atrial Volumes and Function, and Long-Term Incidence of Ischemic Stroke in the General Population.

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long-term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community-based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow-up of 16.5 years (interquartile range: 11.4-16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause-specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02-1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01-1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow-up (HR, 1.12 per 10% decrease [95% CI, 1.00-1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all-cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993172.

Atrial cardiomyopathy in patients with ischaemic stroke: a cross-sectional and prospective cohort study-the COAST study.

INTRODUCTION: Despite workup for the aetiology of ischaemic stroke, about 25% of cases remain unexplained. Paroxysmal atrial fibrillation is typically suspected but often not detected. Even if atrial fibrillation (AF) is detected, the quantitative threshold of clinically relevant AF remains unclear. Emerging evidence suggests that left atrial (LA) functional and structural abnormalities may convey a risk of ischaemic stroke in which AF is only one of several features. These abnormalities have been termed 'atrial cardiomyopathy'. This study uses cardiac magnetic resonance (CMR) to evaluate atrial cardiomyopathy among patients with stroke of undetermined aetiology compared with those with an attributable mechanism and controls without established cardiovascular disease. METHODS AND ANALYSIS: This cross-sectional and prospective cohort study included 100 patients with recent ischaemic stroke and 50 controls with no established cardiovascular disease. The study will assess LA structural and functional abnormalities with CMR. Inclusion began in March 2019, and follow-up is planned to be complete in January 2023. There are two scheduled follow-ups: (1) 18 months after individual inclusion, counting from the index diagnostic MRI of the brain, (2) end of study follow-up at 18 months after inclusion of the last patient, assessing the incidence of recurrent ischaemic stroke, AF and cardiovascular death. The primary endpoint is the extent of CMR-assessed atrial fibrosis in the LA at baseline. The study is powered to detect a difference of 6% fibrosis between stroke of undetermined aetiology and stroke of known mechanism with a SD of 9%, a significance level of 0.05, and power of 80%. ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics (H-18055313). All participants in the study signed informed consent. Results from the study will be published in peer-reviewed journals regardless of the outcome. TRIAL REGISTRATION NUMBER: NCT03830983.

Blood Pressure Drops During Hospitalization for Acute Heart Failure Treated With Serelaxin: A Patient-Level Analysis of 4 Randomized Controlled Trials.

BACKGROUND: Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients hospitalized with acute heart failure. We investigated whether SBP-drops are associated with outcomes in patients treated with serelaxin. METHODS: Patient-level retrospective analyses of 4 prospective trials investigating serelaxin in acute heart failure. Main inclusion criteria were SBP 125 to 180 mm Hg, pulmonary congestion, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide). SBP-drops were prospectively defined as SBP<100 mm Hg, or, if SBP remained >100 mm Hg, a drop from baseline of 40 mm Hg from baseline. Outcomes were a short-term composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality. RESULTS: Overall, 2559/11 226 (23%) patients had an SBP-drop. SBP-drop, versus no SBP-drop, was associated with a worse outcome: cumulative incidence of 180-day mortality (11% versus 9%, hazard ratio [HR]. 1.21 [95% CI, 1.05-1.39]; P=0.009) and the short-term outcome (11% versus 9%, HR, 1.29 [95% CI, 1.13-1.49]; P<0.001). Of the 2 SBP-drop components, an SBP<100 mm Hg was associated with the worst outcome compared with a 40 mm Hg drop: short-term outcome (11% versus 10%) and HRs of 1.32 (95% CI, 1.13-1.55; P=0.0005) and 1.22 (95% CI, 0.97-1.56; P=0.09), for each component respectively, with a P value for interaction of 0.05. SBP-drops were associated with a worse short-term outcome in the placebo group (HR, 1.46 [95% CI, 1.19-1.79]; P=0.0003), but not in the serelaxin-group (HR, 1.18 [95% CI, 0.97-1.42]; P=0.10); P interaction=0.003. CONCLUSIONS: SBP-drops in patients with acute heart failure and normal to high SBP at admission is associated with worse short- and long-term outcomes especially for SBP <100 mm Hg. However, in patients treated with the intravenous vasodilator serelaxin, SBP-drops seemed less harmful. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT02064868, NCT02007720, NCT01870778, NCT00520806.

Chest computed tomography features of heart failure: A prospective observational study in patients with acute dyspnea.

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.

Association of Annual N-Terminal Pro-Brain Natriuretic Peptide Measurements With Clinical Events in Patients With Asymptomatic Nonsevere Aortic Stenosis: A Post Hoc Substudy of the SEAS Trial.

IMPORTANCE: Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown. OBJECTIVE: To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS. DESIGN, SETTING, AND PARTICIPANTS: Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1. EXPOSURES: Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s. MAIN OUTCOMES AND MEASURES: Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes. RESULTS: Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001). CONCLUSIONS AND RELEVANCE: The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00092677.

Are Prolonged Ventricular Pauses in Atrial Fibrillation a Marker of Poor Prognosis?

BACKGROUND: In patients with atrial fibrillation (AF), the long-term prognosis of long electrocardiographic pauses in the ventricular action is not well studied. METHODS: Consecutive Holter recordings in patients with AF (n = 200) between 2009 and 2011 were evaluated, focusing on pauses of at least 2.5 s. Outcomes of interest were all-cause mortality and pacemaker implantation. RESULTS: Forty-three patients (21.5%) had pauses with a mean of 3.2 s and an SD of 0.9 s. After a median follow-up of 99 months (ranging 89-111), 47% (20/43) of the patients with and 45% (70/157) without pauses were deceased. Pauses of ≥2.5 s did not constitute a risk of increased mortality: HR = 0.75 (95% CI: 0.34-1.66); p = 0.48, neither did pauses of ≥3.0 s: HR = 0.43 (95% CI: 0.06-3.20); p = 0.41. Sixteen percent of patients with pauses underwent pacemaker implantation during follow-up. Only pauses in patients referred to Holter due to syncope and/or dizzy spells were associated with an increased risk of pacemaker treatment: HR = 4.7 (95% CI: 1.4-15.9), p = 0.014, adjusted for age, sex, and rate-limiting medication. CONCLUSION: In patients with AF, prolonged electrocardiographic pauses of ≥2.5 s or ≥3.0 s are not a marker for increased mortality in this real-life clinical study.

Systolic Blood Pressure and Outcome in Patients Admitted With Acute Heart Failure: An Analysis of Individual Patient Data From 4 Randomized Clinical Trials.

BACKGROUND In acute heart failure (AHF), systolic blood pressure (SBP) is an important clinical variable. This study assessed the association between SBP and short-term and long-term outcomes in a large cohort of patients with AHF. METHODS AND RESULTS This is an analysis of 4 randomized controlled trials investigating serelaxin versus placebo in patients admitted with AHF and SBPs from 125 to 180 mm Hg. Outcomes were 180-day all-cause mortality and a composite end point of all-cause mortality, worsening heart failure, or hospital readmission for heart failure the first 14 days. Left ventricular ejection fraction (LVEF) was examined as LVEF<40% and LVEF≥40%. Multivariable Cox regression models were adjusted for known confounders of outcomes in AHF. A total of 10 533 patients with a mean age of 73 (±12) years and a mean SBP of 145 (±7) mm Hg were included. LVEF was assessed in 9863 patients (93%); 4737 patients (45%) had LVEF<40%. Increasing SBP was inversely associated with 180-day mortality (adjusted hazard ratio [HRadjusted], 0.93; 95% CI, 0.89-0.98; P=0.008 per 10 mm Hg increase) and with the composite end point (HRadjusted, 0.90; 95% CI, 0.85-0.94; P<0.001 per 10 mm Hg increase). A significant interaction with LVEF was observed, revealing that SBP was not associated with mortality in patients with LVEF≥40% (HRadjusted, 0.98; 95% CI, 0.91-1.04; per 10 mm Hg increase), but was strongly associated with increased mortality in LVEF<40% (HRadjusted, 0.84; 95% CI, 0.77-0.92; per 10 mm Hg increase). CONCLUSIONS Elevated SBP is associated with favorable short-term and long-term outcomes in patients with AHF. In our predefined subgroup analysis, we found that baseline SBP was not associated with mortality in LVEF≥40%, but was strongly associated with mortality in patients with LVEF<40%.

Excessive supraventricular ectopic activity and risk of incident atrial fibrillation in a consecutive population referred to ambulatory cardiac monitoring.

BACKGROUND: Excessive supraventricular ectopic activity (ESVEA), defined as ≥720 premature atrial contractions (PAC) per day or any runs of ≥20 PACs, has been proposed as a surrogate marker for paroxysmal atrial fibrillation (PAF). OBJECTIVE: We aimed to estimate the prognostic impact of ESVEA on the future development of PAF in consecutive patients referred to ambulatory cardiac monitoring. METHODS: The cohort consists of a population with comorbidities referred to 48-hour ambulatory electrocardiogram aged 30-98 (n = 1316) between 2009 and 2011. After exclusion of known or current atrial fibrillation (AF) (n = 527) and patients with pacemakers (n = 7), 782 patients were included, with a median follow-up of 8.1 years. Events of incident AF and death were retrieved from patient records. RESULTS: Mean age was 58.6 ± 15.5 years and 56.5% were women. A total of 101 patients had ESVEA at baseline (12.9%). During follow-up, 69 (8.9%) developed incidental AF. Twenty-three patients with ESVEA developed AF (23%). Incidence rate of AF in patients with and without ESVEA was 37.1/1000 person-years and 9.1 per 1000 person-years, respectively (P < .001). ESVEA was associated with incident AF after adjustment for potential confounders in Cox regression analysis (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.40-4.09) and in competing risk analysis with death as competing risk (subdistribution HR: 2.35; 95% CI: 1.30-4.17). CONCLUSION: ESVEA increases the risk of incident AF substantially in a population referred to ambulatory cardiac monitoring.

A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

OBJECTIVES: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. METHODS: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. RESULTS: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. CONCLUSIONS: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.