Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR.

Background: Measures that can detect large treatment effects are important for monitoring therapeutic effectiveness. The 2022 European Society of Cardiology/European Respiratory Society guidelines highlight the importance of imaging in monitoring disease status and treatment response in pulmonary arterial hypertension (PAH). Are the standardised treatment effect sizes (STES) of cardiac magnetic resonance imaging (cMRI) comparable with functional and haemodynamic variables? Methods: REPAIR (ClinicalTrials.gov: NCT02310672) was a prospective, multicentre, single-arm, open-label, 52-week phase 4 study evaluating the effect of macitentan 10 mg, with or without a phosphodiesterase 5 inhibitor (PDE5i), on right ventricular (RV) remodelling, cardiac function and cardiopulmonary haemodynamics. Both cMRI and functional assessments were performed at screening and at weeks 26 and 52; haemodynamic measurements were conducted at screening and week 26. In this post hoc analysis, STES were estimated using the parametric Cohen's d and non-parametric Cliff's delta tests. Results: At week 26, large STES (Cohen's d) were observed for 10 of the 20 cMRI variables assessed, including the prognostic measures of RV and left ventricular stroke volume and RV ejection fraction and the haemodynamic trial end-point, pulmonary vascular resistance; medium STES were observed for 6-min walk distance (6MWD). The STES were consistent in treatment-naïve patients and those escalating therapy and maintained at week 52. Similar results were obtained using the non-parametric Cliff's delta method. Conclusions: The treatment effect of macitentan, alone or in combination with a PDE5i, was comparable for several cMRI and haemodynamic variables with prognostic value in PAH, and greater than that of 6MWD in patients with PAH, highlighting the emerging relevance of cMRI in PAH.

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

INTRODUCTION: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. METHODS: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. RESULTS: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. CONCLUSIONS: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. TRIAL REGISTRATION NUMBER: REPAIR NCT02310672.

Comprehensive vasodilatation in women with acute heart failure: Novel insights from the GALACTIC randomized controlled trial.

AIMS: Sex-specific differences in acute heart failure (AHF) are both relevant and underappreciated. Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately. METHODS AND RESULTS: We performed a pre-defined sex-specific analysis in AHF patients randomized to a strategy of early intensive and sustained vasodilatation versus usual care in an international, multicentre, open-label, blinded endpoint trial. Inclusion criteria were AHF with increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100 mmHg, and plan for treatment in a general ward. Among 781 eligible patients, 288 (37%) were women. Women were older (median 83 vs. 76 years), had a lower body weight (median 64.5 vs. 77.6 kg) and lower estimated glomerular filtration rate (median 48 vs. 54 ml/min/1.73 m2 ). The primary endpoint, a composite of all-cause mortality or rehospitalization for AHF at 180 days, showed a significant interaction of treatment strategy and sex (p for interaction = 0.03; hazard ratio adjusted for female sex 1.62, 95% confidence interval 1.05-2.50; p = 0.03). The combined endpoint occurred in 53 women (38%) in the intervention group and in 35 (24%) in the usual care group. The implementation of rapid up-titration of renin-angiotensin-aldosterone system (RAAS) inhibitors was less successful in women versus men in the overall cohort and in patients with heart failure with reduced ejection fraction (median discharge % target dose in patients randomized to intervention: 50% in women vs. 75% in men). CONCLUSION: Rapid up-titration of RAAS inhibitors was less successfully implemented in women possibly explaining their higher rate of all-cause mortality and rehospitalization for AHF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT00512759.

Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure.

AIMS: Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF). METHODS AND RESULTS: This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT-proBNP plasma concentrations were applied: first, using currently recommended cut-offs; second, using cut-offs lowered by 33% with body mass index (BMI) of 30-34.9 kg/m2 and by 50% with BMI ≥ 35 kg/m2 . Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT-proBNP as quantified by the area under the receiver-operating characteristic curve was lower in obese versus non-obese patients (0.890 vs. 0.938). For rapid AHF rule-out in obese patients, the currently recommended cut-off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8-98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule-in, the age-dependent cut-off concentrations (age <50 years: 450 pg/ml; age 50-75 years: 900 pg/ml; age >75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8-88.9%). Proportionally lowering the currently recommended cut-offs by BMI increased sensitivity to 98.2% (95% CI 95.8-99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the 'gray zone' (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7-81.4%). CONCLUSIONS: Adjusting NT-proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF.

SARS-CoV-2 transmission from infected owner to household dogs and cats is associated with food sharing.

OBJECTIVES: Several cases of reverse transmission of SARS-CoV-2 from human to pets were reported during the first year of the COVID-19 pandemic. Accordingly, the World Organization for Animal Health has recommended to improve SARS-CoV-2 surveillance on household animals to assess the risk of transmission between species. After such recommendation, we studied the potential SARS-CoV-2 infection in household dogs and cats in the city of Guayaquil, the most populated city in Ecuador. METHODS: Oral and nasal swab samples were collected from dogs and cats within 10 days of a positive SARS-CoV-2 test result of their owners. Total ribonucleic acid was extracted and detection of viral gene targets N and ORF1ab was performed by quantitative reverse transcription polymerase chain reaction. RESULTS: From the 50 cats and dogs tested, 12 were SARS-CoV-2 positive, giving a total positivity rate of 24%. A total of 1 of 8 cats tested positive, whereas 11 of 42 dogs were positive, yielding a positivity rate of 12.5% and 26.2%, respectively. SARS-CoV-2 was confirmed by whole genome sequencing. In addition, we also found a statistically significant association between SARS-CoV-2 pet positivity and food sharing with infected owners. CONCLUSION: This study is the second active surveillance of SARS-CoV-2 in household dogs and cats in Latin America. Moreover, it is the first study to address the risk factors associated with potential anthropogenic SARS-CoV-2 transmission to domestic cats and dogs. Given the high presence of free-roaming dogs and cats in rural and urban areas in Latin American countries and the high capacity shown by coronaviruses for interspecies transmission, our findings support the view that SARS-CoV-2 surveillance in pets is necessary to better understand the role that pet-human interaction plays in the COVID-19 spread.

Effect of a strategy of comprehensive vasodilation versus usual care on health-related quality of life among patients with acute heart failure.

AIMS: We aimed to assess the long-term effect of a strategy of comprehensive vasodilation versus usual care on health-related quality of life (HRQL) among patients with acute heart failure (AHF). METHODS AND RESULTS: Health-related quality of life was prospectively assessed by the generic 3-levelled EQ-5D and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) among adult AHF patients enrolled in an international, multicentre, randomised, open-label blinded-end-point trial of a strategy that emphasized early intensive and sustained vasodilation using maximally tolerated doses of established oral and transdermal vasodilators according to systolic blood pressure. Changes in EQ-5D and KCCQ from admission to 180 day follow-up were individually compared between the intensive vasodilatation and the usual care group. Among 666 patients eligible for 180 day follow-up, 284 (43%, median age 79 years, 35% women) and 198 (30%, median age 77 years, 35% women) had completed the EQ-5D and KCCQ at baseline and follow-up, respectively. There was a significant improvement in HRQL as quantified by both, EQ-5D and KCCQ, from hospitalization to 180 day follow-up, with no significant differences in the change of HRQL between both treatment strategies. For instance, 39 (26%) versus 33 (25%) patients had an improvement by at least one level in at least two categories in the EQ-5D. Median increase in KCCQ overall summary score (KCCQ-OSS) was 17.6 (IQR 2.0-42.6) in the intervention group versus 18.5 (IQR 3.9-39.3) in the usual care group (P < 0.001 vs. baseline, P = 0.945 between groups). CONCLUSIONS: Among patients with AHF, long-term HRQL quantified by EQ-5D and KCCQ improved substantially, with overall no significant differences between a strategy of comprehensive vasodilation versus usual care.

Development of an electrocardiogram-based risk calculator for a cardiac cause of syncope.

OBJECTIVE: To develop an ECG-based tool for rapid risk assessment of a cardiac cause of syncope in patients ≥40 years. METHODS: In a prospective international multicentre study, 2007 patients ≥40 years presenting with syncope were recruited in the emergency department (ED) of participating centres ranging from large university hospitals to smaller rural hospitals in eight countries from May 2010 to July 2017. 12-Lead ECG recordings were obtained at ED presentation following the syncopal event. The primary diagnostic outcome, a cardiac cause of syncope, was centrally adjudicated by two independent cardiologists using all available clinical information including 12-month follow-up. ECG predictors for a cardiac cause of syncope were identified using penalised backward selection and a continuous-scale likelihood was calculated based on regression analysis coefficients. Findings were validated in an independent US multicentre cohort including 2269 patients. RESULTS: In the derivation cohort, a cardiac cause of syncope was adjudicated in 267 patients (16%). Seven ECG criteria were identified as predictors for this outcome: heart rate and QTc-interval (continuous predictors), rhythm, atrioventricular block, ST-segment depression, bundle branch block and ventricular extrasystole/non-sustained ventricular tachycardia (categorical predictors). Diagnostic accuracy of these combined predictors for a cardiac cause of syncope was high (area under the curve 0.80, 95% CI 0.77 to 0.83). Overall, 138 patients (8%) were rapidly triaged towards rule-out and 181 patients (11%) towards rule-in of a cardiac cause of syncope. External validation showed similar performance. CONCLUSION: In patients ≥40 years with a syncopal event, a combination of seven ECG criteria enabled rapid assessment of the likelihood that syncope was due to a cardiac cause. TRIAL REGISTRATION NUMBER: NCT01548352 (BASEL IX), NCT01802398 (SRS study).

Cardiac myosin-binding protein C in the diagnosis and risk stratification of acute heart failure.

AIMS: Cardiac myosin-binding protein C (cMyC) seems to be even more sensitive in the quantification of cardiomyocyte injury vs. high-sensitivity cardiac troponin, and may therefore have diagnostic and prognostic utility. METHODS AND RESULTS: In a prospective multicentre diagnostic study, cMyC, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations were measured in blinded fashion in patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists centrally adjudicated the final diagnosis. Diagnostic accuracy for acute heart failure (AHF) was quantified by the area under the receiver operating characteristic curve (AUC). All-cause mortality within 360 days was the prognostic endpoint. Among 1083 patients eligible for diagnostic analysis, 51% had AHF. cMyC concentrations at presentation were higher among AHF patients vs. patients with other final diagnoses [72 (interquartile range, IQR 39-156) vs. 22 ng/L (IQR 12-42), P < 0.001)]. cMyC's AUC was high [0.81, 95% confidence interval (CI) 0.78-0.83], higher than hs-cTnT's (0.79, 95% CI 0.76-0.82, P = 0.081) and lower than NT-proBNP's (0.91, 95% CI 0.89-0.93, P < 0.001). Among 794 AHF patients eligible for prognostic analysis, 28% died within 360 days; cMyC plasma concentrations above the median indicated increased risk of death (hazard ratio 2.19, 95% CI 1.66-2.89; P < 0.001). cMyC's prognostic accuracy was comparable with NT-proBNP's and hs-cTnT's. cMyC did not independently predict all-cause mortality when used in validated multivariable regression models. In novel multivariable regression models including medication, age, left ventricular ejection fraction, and discharge creatinine, cMyC remained an independent predictor of death and had no interactions with medical therapies at discharge. CONCLUSION: Cardiac myosin-binding protein C may aid physicians in the rapid triage of patients with suspected AHF.

Mortality and pathophysiology of acute kidney injury according to time of occurrence in acute heart failure.

AIMS: Acute kidney injury (AKI) during acute heart failure (AHF) is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanism appears to have prognostic relevance; however, the differentiation of true, structural AKI from hemodynamic pseudo-AKI remains a clinical challenge. METHODS AND RESULTS: The Basics in Acute Shortness of Breath Evaluation Study (NCT01831115) prospectively enrolled adult patients presenting with AHF to the emergency department. Mortality of patients was prospectively assessed. Haemoconcentration, transglomerular pressure gradient (n = 231) and tubular injury patterns (n = 253) were evaluated to investigate pathophysiological mechanisms underlying AKI timing (existing at presentation vs. developing during in-hospital period). Of 1643 AHF patients, 755 patients (46%) experienced an episode of AKI; 310 patients (19%; 41% of AKI patients) presented with community-acquired AKI (CA-AKI), 445 patients (27%; 59% of AKI patients) developed in-hospital AKI. CA-AKI but not in-hospital AKI was associated with higher mortality compared with no-AKI (adjusted hazard ratio 1.32 [95%-CI 1.01-1.74]; P = 0.04). Independent of AKI timing, haemoconcentration was associated with a lower two-year mortality. Transglomerular pressure gradient at presentation was significantly lower in CA-AKI compared to in-hospital AKI and no-AKI (P < 0.01). Urinary NGAL ratio concentrations were significantly higher in CA-AKI compared to in-hospital AKI (P < 0.01) or no-AKI (P < 0.01). CONCLUSIONS: CA-AKI but not in-hospital AKI is associated with increased long-term mortality and marked by decreased transglomerular pressure gradient and tubular injury, probably reflecting prolonged tubular ischemia due to reno-venous congestion. Adequate decongestion, as assessed by haemoconcentration, is associated with lower long-term mortality independent of AKI timing.

Diagnostic and prognostic values of the QRS-T angle in patients with suspected acute decompensated heart failure.

AIMS: The aim of this study was to investigate the diagnostic and prognostic utility of the QRS-T angle, an electrocardiogram (ECG) marker quantifying depolarization-repolarization heterogeneity, in patients with suspected acute decompensated heart failure (ADHF). METHODS AND RESULTS: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of ADHF. The QRS-T angle was automatically derived from a standard 12-lead ECG recorded at presentation. The primary diagnostic endpoint was a final adjudicated diagnosis of ADHF. The primary prognostic endpoint was all-cause mortality during 2 years of follow-up. Among the 1915 patients enrolled, those with higher QRS-T angles were older, were more commonly male, and had a higher rate of co-morbidities such as arterial hypertension, coronary artery disease, or chronic kidney disease. ADHF was the final adjudicated diagnosis in 1140 (60%) patients. The QRS-T angle in patients with ADHF was significantly larger than in patients with non-cardiac causes of dyspnoea {median 110° [inter-quartile range (IQR) 46-156°] vs. median 33° [IQR 15-57°], P < 0.001}. The diagnostic accuracy of the QRS-T angle as quantified by the area under the receiver operating characteristic curve (AUC) was 0.75 [95% confidence interval (CI) 0.73-0.77, P < 0.001], which was inferior to N-terminal pro-B-type natriuretic peptide (AUC 0.93, 95% CI 0.92-0.94, P < 0.001), but similar to that of high-sensitivity troponin T (AUC 0.78, 95% CI 0.76-0.80, P = 0.09). The AUC of the QRS-T angle for discrimination between ADHF and non-cardiac dyspnoea remained similarly high in subgroups of patients known to be diagnostically challenging, including patients older than 75 years [0.71 (95% CI 0.67-0.74)], renal failure [0.79 (95% CI 0.71-0.87)], and atrial fibrillation at presentation [0.68 (95% CI 0.60-0.76)]. Mortality rates according to QRS-T angle tertiles were 4%, 6%, and 10% after 30 days (P < 0.001) and 24%, 31%, and 43% after 2 years (P < 0.001). After adjustment for clinical, laboratory, and ECG parameters, the QRS-T angle remained an independent predictor for 2 year mortality with a 4% increase in mortality for every 20° increase in QRS-T angle (P = 0.02). CONCLUSIONS: The QRS-T angle is a readily available and inexpensive marker that can assist in the discrimination between ADHF and non-cardiac causes of acute dyspnoea and may aid in the risk stratification of these patients.

Clinical features of pericarditis with and without myocardial involvement diagnosed in the emergency department and factors associated with need for hospitalization. / Características clínicas de las pericarditis y miopericarditis diagnosticadas en urgencias y factores asociados con la necesidad de hospitalización.

OBJECTIVES: To analyze the clinical features of acute pericarditis diagnosed in the emergency department according to patient age and myocardial involvement (myopericarditis) and to determine factors associated with hospitalization. MATERIAL AND METHODS: Retrospective, descriptive, observational, single-center study of consecutive patients. We analyzed all cases of pericarditis diagnosed in the emergency department over a period of 10 years (2008-2017), reviewing clinical, electrocardiographic, and laboratory findings as well as ultrasound imaging for myocardial involvement. Characteristics were analyzed by age (under 50 years or 50 or older) and presence or not of myocardial involvement. Factors associated with hospitalization for both pericarditis and myopericarditis were identified by crude and adjusted odds ratios (ORs). RESULTS: A total of 983 patients were diagnosed with pericarditis (34% women, mean age, 42 years). The younger patients more often reported sharp chest pain modified by breathing or posture changes. Older patients had more concurrent cardiovascular disease and described chest pain as pressure (oppressive); acute coronary syndrome was suspected more often in the older patients. The only independent predictor of myopericarditis was a finding of electrocardiographic abnormalities, recorded in 72 cases (7%) (OR, 4.26; 95% CI, 1.89-9.59). Sixty-two patients (6%) were admitted for pericarditis. Associated factors were renal insufficiency (OR, 4.83; 95% CI, 1.66-14.05), pain modified by breathing or posture changes (OR, 0.54; 95% CI, 0.29-0.99), tachycardia (OR, 2.29; 95% CI, 1.15- 4.55), and myopericarditis (OR, 8.73; 95% CI, 4.65-16.38). Admission of 24 patients (33%) for myocarditis was related to focused cardiac ultrasound findings (OR, 13.72; 95% CI, 1.80-104). CONCLUSION: Age may affect the presentation of pericarditis. ST segment abnormalities on an electrocardiogram suggest myocardial involvement. Renal insufficiency, tachycardia, and myocardial involvement are the factors associated with a decision to admit patients with pericarditis. Ultrasound findings are associated with admission for myopericarditis.

OBJETIVO: Analizar los episodios de pericarditis aguda (PA) diagnosticados en urgencias en función de la edad y de la afectación miocárdica (miopericarditis, MioP), y determinar los factores asociados a hospitalización. METODO: Estudio observacional, descriptivo, unicéntrico de casos consecutivos, con análisis retrospectivo de todos los casos diagnosticados de PA en urgencias durante 10 años (2008-2017), y revisión de las características clínicas, ECG, analíticas y ecográficas (en MioP). Se compararon características clínicas según la edad (< 50 y $ 50 años) y existencia de MioP. Los factores asociados a hospitalización (PA y MioP) se identificaron de forma cruda y ajustada por las diferencias clínicas entre grupos. RESULTADOS: Se diagnosticaron 983 PA (34% mujeres, mediana de edad: 42 años). Los pacientes más jóvenes referían con mayor frecuencia dolor torácico (DT) punzante y modificable con la respiración o cambios posturales, y los más mayores tenían más comorbilidades cardiovasculares, refirieron más frecuentemente DT opresivo y generaron mayor sospecha de síndrome coronario agudo. Las alteraciones en el ECG (OR = 4,26; IC95% = 1,89-9,59) se asociaron a MioP (72 casos, 7%). Ingresaron 62 PA (6%), hecho asociado a antecedente de insuficiencia renal (OR = 4,83; IC95% = 1,66-14,05), DT que se modifica con movimientos respiratorios/posturales (OR = 0,54, IC95% = 0,29-0,99), taquicardia (OR = 2,29, IC95% = 1,15-4,55) y MioP (OR = 8,73, IC95% = 4,65-16,38). Ingresaron 24 MioP (33%), hecho asociado a alteraciones en la ecoscopia dirigida (protocolo FOCUS; OR = 13,72, IC95% = 1,80-104). CONCLUSIONES: La edad puede condicionar la presentación clínica en los pacientes con PA. Las alteraciones en el segmento ST en el ECG son sugestivos de implicación miocárdica. La insuficiencia renal, la taquicardia y la MioP son factores que incrementan la decisión de hospitalización en las PA; mientras que en las MioP, las alteraciones ecográficas.

Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure: The GALACTIC Randomized Clinical Trial.

Importance: Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF). Objective: To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF. Design, Setting, and Participants: Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019. Interventions: Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days. Results: Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%). Conclusions and Relevance: Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days. Trial Registration: ClinicalTrials.gov Identifier: NCT00512759.

Clinical Utility of Procalcitonin in the Diagnosis of Pneumonia.

BACKGROUND: The clinical utility of procalcitonin in the diagnosis and management of pneumonia remains controversial. METHODS: We assessed the clinical utility of procalcitonin in 2 prospective studies: first, a multicenter diagnostic study in patients presenting to the emergency department with acute dyspnea to directly compare the diagnostic accuracy of procalcitonin with that of interleukin 6 and C-reactive protein (CRP) in the diagnosis of pneumonia; second, a randomized management study of procalcitonin guidance in patients with acute heart failure and suspected pneumonia. Diagnostic accuracy for pneumonia as centrally adjudicated by 2 independent experts was quantified with the area under the ROC curve (AUC). RESULTS: Among 690 patients in the diagnostic study, 178 (25.8%) had an adjudicated final diagnosis of pneumonia. Procalcitonin, interleukin 6, and CRP were significantly higher in patients with pneumonia than in those without. When compared to procalcitonin (AUC = 0.75; 95% CI, 0.71-0.78), interleukin 6 (AUC = 0.80; 95% CI, 0.77-0.83) and CRP (AUC = 0.82; 95% CI, 0.79-0.85) had significantly higher diagnostic accuracy (P = 0.010 and P < 0.001, respectively). The management study was stopped early owing to the unexpectedly low AUC of procalcitonin in the diagnostic study. Among 45 randomized patients, the number of days on antibiotic therapy and the length of hospital stay were similar (both P = 0.39) in patients randomized to the procalcitonin-guided group (n = 25) and usual-care group (n = 20). CONCLUSIONS: In patients presenting with dyspnea, diagnostic accuracy of procalcitonin for pneumonia is only moderate and lower than that of interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. SUMMARY: Pneumonia has diverse and often unspecific symptoms. As the role of biomarkers in the diagnosis of pneumonia remains controversial, it is often difficult to distinguish pneumonia from other illnesses causing shortness of breath. The current study prospectively enrolled unselected patients presenting with acute dyspnea and directly compared the diagnostic accuracy of procalcitonin, interleukin 6, and CRP for the diagnosis of pneumonia. In this setting, diagnostic accuracy of procalcitonin for pneumonia was lower as compared to interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. CLINICALTRIALSGOV IDENTIFIER: NCT01831115.

Incidence and outcomes of unstable angina compared with non-ST-elevation myocardial infarction.

OBJECTIVE: Assess the relative incidence and compare characteristics and outcome of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI). DESIGN: Two independent prospective multicentre diagnostic studies (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] and High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]) enrolling patients with acute chest discomfort presenting to the emergency department. Central adjudication of the final diagnosis was done by two independent cardiologists using all clinical information including serial measurements of high-sensitivity cardiac troponin (hs-cTn). All-cause death and future non-fatal MI were assessed at 30 days and 1 year. RESULTS: 8992 patients were enrolled at 11 centres. UA was adjudicated in 8.9%(95% CI 8.0 to 9.7) and 2.8% (95% CI 2.3 to 3.3) patients in APACE and High-STEACS, respectively, and NSTEMI in 15.1% (95% CI 14.0 to 16.2) and 13.4% (95% CI 12.4 to 14.3). Coronary artery disease was pre-existing in 73% and 76% of patients with UA. At 30 days, all-cause mortality in UA was substantially lower as compared with NSTEMI (0.5% vs 3.7%, p=0.002 in APACE, 0.7% vs 7.4%, p=0.004 in High-STEACS). Similarly, at 1 year in UA all-cause mortality was 3.3% (95% CI 1.2 to 5.3) vs 10.4% (95% CI 7.9 to 12.9) in APACE, and 5.1% (95% CI 0.7 to 9.5) vs 22.9% (95% CI 19.3 to 26.4) in High-STEACS, and similar to non-cardiac chest pain (NCCP). In contrast, future non-fatal MI in APACE was comparable in UA and NSTEMI (11.2%, 95% CI 7.8 to 14.6 and 7.9%, 95% CI 5.7 to 10.2), and higher than in NCCP (0.6%, 95% CI 0.2 to 1.0). CONCLUSIONS: The relative incidence and mortality of UA is substantially lower than that of NSTEMI, while the rate of future non-fatal MI is similar.

Relative hypochromia and mortality in acute heart failure.

BACKGROUND: Relative hypochromia of erythrocytes defined as a reduced mean corpuscular hemoglobin concentration (MCHC) is a surrogate of iron deficiency. We aimed to evaluate the prevalence and prognostic impact of relative hypochromia in acute heart failure (AHF). METHODS: We prospectively characterized 1574 patients presenting with an adjudicated diagnosis of AHF to the emergency department. Relative hypochromia was defined as a MCHC ≤330 g/l and determined at presentation. The presence of AHF was adjudicated by two independent cardiologists. All-cause mortality and AHF-rehospitalization were the primary prognostic end-points. RESULTS: Overall, 455 (29%) AHF patients had relative hypochromia. Patients with relative hypochromia had higher hemodynamic cardiac stress as quantified by NT-proBNP concentrations (p < 0.001), more extensive cardiomyocyte injury as quantified by high-sensitive cardiac troponin T (hs-cTnT) concentrations (p < 0.001), and lower estimated glomerular filtration rate (eGFR; p < 0.001) as compared to AHF patients without hypochromia. Cumulative incidences for all-cause mortality and AHF-rehospitalization at 720-days were 50% and 55% in patients with relative hypochromia as compared to 33% and 39% in patients without hypochromia, respectively (both p < 0.0001). The association between relative hypochromia and increased mortality (HR 1.7, 95% CI 1.4-2-0) persisted after adjusting for anemia (HR 1.5, 95% CI 1.3-1.8), and after adjusting for hemodynamic cardiac stress (HR 1.46, 95% CI 1.21-1.76) and eGFR (HR 1.5, 95% CI 1.3-1.8, p < 0.001). CONCLUSIONS: Relative hypochromia is common and a strong and independent predictor of increased mortality in AHF. Given the direct link to diagnostic (endoscopy) and therapeutic interventions to treat functional iron deficiency, relative hypochromia deserves increased attention as an inexpensive and universally available biomarker.

External Validation of the MEESSI Acute Heart Failure Risk Score: A Cohort Study.

Background: The MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score was developed to predict 30-day mortality in patients presenting with acute heart failure (AHF) to emergency departments (EDs) in Spain. Whether it performs well in other countries is unknown. Objective: To externally validate the MEESSI-AHF score in another country. Design: Prospective cohort study. (ClinicalTrials.gov: NCT01831115). Setting: Multicenter recruitment of dyspneic patients presenting to the ED. Participants: The external validation cohort included 1572 patients with AHF. Measurements: Calculation of the MEESSI-AHF score using an established model containing 12 independent risk factors. Results: Among 1572 patients with adjudicated AHF, 1247 had complete data that allowed calculation of the MEESSI-AHF score. Of these, 102 (8.2%) died within 30 days. The score predicted 30-day mortality with excellent discrimination (c-statistic, 0.80). Assessment of cumulative mortality showed a steep gradient in 30-day mortality over 6 predefined risk groups (0 patients in the lowest-risk group vs. 35 [28.5%] in the highest-risk group). Risk was overestimated in the high-risk groups, resulting in a Hosmer-Lemeshow P value of 0.022. However, after adjustment of the intercept, the model showed good concordance between predicted risks and observed outcomes (P = 0.23). Findings were confirmed in sensitivity analyses that used multiple imputation for missing values in the overall cohort of 1572 patients. Limitations: External validation was done using a reduced model. Findings are specific to patients with AHF who present to the ED and are clinically stable enough to provide informed consent. Performance in patients with terminal kidney failure who are receiving long-term dialysis cannot be commented on. Conclusion: External validation of the MEESSI-AHF risk score showed excellent discrimination. Recalibration may be needed when the score is introduced to new populations. Primary Funding Source: The European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, and University Hospital Basel.

Circadian, weekly, seasonal, and temperature-dependent patterns of syncope aetiology in patients at increased risk of cardiac syncope.

AIMS: It is unknown whether cardiac syncope, and possibly also other syncope aetiologies exhibit circadian, weekly, seasonal, and temperature-dependent patterns. METHODS AND RESULTS: We prospectively recorded the exact time, date, and outside temperature of syncope of patients >40 years old presenting with syncope to the emergency department in a diagnostic multicentre study. Two independent cardiologists/emergency physicians adjudicated the final diagnosis based on all information becoming available during clinical work-up including 1-year follow-up. Among 1230 patients, the adjudicated aetiology was cardiac in 14.6%, reflex in 39.2%, orthostatic in 25.7%, other non-cardiac in 9.7%, and unknown in 10.8% of patients. All syncope aetiologies occurred much more frequently during the day when compared with the night (P < 0.01). While reflex and orthostatic syncope showed a broad peak of prevalence with 80.9% of these events occurring between 4 am and 4 pm, cardiac syncope showed a narrow peak of prevalence with 70.1% of all events occurring between 8 am and 2 pm. A weekly pattern was present for most syncope aetiologies, with events occurring mainly from Monday to Friday (P < 0.01). Reflex syncope displayed a seasonal rhythm and was more common in winter (P < 0.01), while cardiac syncope stayed constant over the year. Syncope occurred most often when the outside temperature was coldest. Overall the patterns observed for cardiac syncope were similar to the patterns observed for its differential diagnosis. CONCLUSION: Syncope aetiologies in patients >40 years old display circadian, weekly, seasonal, and temperature-dependent patterns. Unfortunately, these patterns do not allow to reliably differentiate cardiac syncope from other aetiologies.

Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction.

BACKGROUND: The safety of the European Society of Cardiology (ESC) 0/1-h algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin (hs-cTn) has been questioned. OBJECTIVES: This study aimed to validate the diagnostic performance of the 0/1-h algorithm in a large multicenter study. METHODS: The authors prospectively enrolled unselected patients in 6 countries presenting to the emergency department with symptoms suggestive of NSTEMI. Final diagnosis was centrally adjudicated by 2 independent cardiologists. Hs-cTnT and hs-cTnI blood concentrations were measured at presentation and after 1 h. Safety of rule-out was quantified by the negative predictive value (NPV) for NSTEMI, accuracy of rule-in by the positive predictive value (PPV), and overall efficacy by the proportion of patients triaged towards rule-out or rule-in within 1 h. RESULTS: Prevalence of NSTEMI was 17%. Among 4,368 patients with serial hs-cTnT measurements available, safety of rule-out (NPV 99.8%, 2,488 of 2,493), accuracy of rule-in (PPV 74.5%, 572 of 768), and overall efficacy were high by assigning three-fourths of patients either to rule-out (57%, 2,493 to 4,368) or rule-in (18%, 768 to 4,368). Similarly, among 3,500 patients with serial hs-cTnI measurements, safety of rule-out (NPV 99.7%, 1,528 of 1,533), accuracy of rule-in (PPV 62.3%, 498 of 800), and overall efficacy were high by assigning more than two-thirds of patients either to rule-out (44%, 1,533 of 3,500) or rule-in (23%, 800 of 3,500). Excellent safety was confirmed in multiple subgroup analyses including patients presenting early (≤3 h) after chest pain onset. CONCLUSIONS: The ESC 0/1-h algorithm using hs-cTnT and hs-cTnI is very safe and effective in triaging patients with suspected NSTEMI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT00470587; and Biomarkers in Acute Cardiac Care [BACC]; NCT02355457).