In-hospital worsening heart failure: a clinically relevant endpoint?

Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In‐hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information.Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in‐hospital WHF.In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in‐hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes

Relation of microvascular dysfunction to exercise capacity and symptoms in patients with severe aortic stenosis

Objective: The aim of this study was to assess the impact of left ventricular hypertrophy, myocardial fibrosis, myocardial perfusion reserve (MPR) and diastolic dysfunction on objectively measured aerobic exercise capacity (peak VO$_{2}$) in severe aortic stenosis (AS). Background: The management of asymptomatic patients with severe AS remains controversial and clinical practice varies. Echocardiographic measures of severity do not discriminate between symptomatic status or predict exercise capacity. The purpose of this study was to investigate the mechanisms contributing to symptom generation and exercise intolerance. This needs to be fully understood to optimise the management of asymptomatic AS. Methods: Patients were prospectively enrolled from a single cardiac surgical centre. Inclusion criteria: age 18-85, isolated severe AS referred for valve replacement. Exclusion criteria: syncope; other moderate/severe valve disease, previous valve surgery, obstructive coronary artery disease (>50% luminal stenosis on invasive angiography), chronic obstructive pulmonary disease, atrial fibrillation, estimated glomerular filtration rate <30mL/min. Investigations and primary outcome measures; cardiac magnetic resonance (CMR) - left ventricular mass index (LVMI), MPR (calculated from absolute myocardial blood flow during adenosine hyperaemia and rest determined by model-independent deconvolution of signal intensity curves with an arterial input function), late gadolinium enhancement (LGE); echocardiography - AS severity, tissue Doppler-derived diastolic function; symptom-limited bicycle ergometer cardiopulmonary exercise testing (CPEX) - peak VO$_{2}$. Linear regression investigated possible predictors of continuous outcome measures. Stepwise selection methods were used to determine the most important predictors of outcome. Results: Four patients with variable LVMI, LGE and MPR are shown, Figure 1. Univariate analyses and results from the stepwise model selection for peak VO$_{2}$ are summarised in Table 1. Only MPR was of independent significance in predicting age and sex corrected peak VO$_{2}$. The relationship between peak VO$_{2}$ and MPR is shown, Figure 2. Patients with higher NYHA Class had lower MPR (p=0.001). Examining predictors of MPR the best stepwise model contained LVMI and LGE category as independent predictors, Table 2. Conclusions: MPR is a novel independent predictor of peak VO$_{2}$ and is inversely related to NYHA functional class in severe AS. Microvascular dysfunction is determined by a combination of factors including AS severity, LVMI, diastolic perfusion time, myocardial fibrosis and LV filling pressure. Further work is required to determine the clinical significance of microvascular dysfunction in AS

Community screening for left ventricular systolic dysfunction using plasma and urinary natriuretic peptides

ObjectivesWe sought to compare urinary and plasma N-terminal pro-brain natriuretic peptide (N-BNP) in left ventricular systolic dysfunction (LVSD) diagnosis.BackgroundPlasma N-BNP is elevated in LVSD. Renal tubule cells produce BNP. We tested the incremental value of urinary N-BNP in LVSD diagnosis.MethodsIn this prospective, community-screening study of undiagnosed LVSD, 1,360 subjects (45 to 80 years of age) were invited, and 1,308 had analyzable echocardiographic scans and urine and plasma specimens. The criterion standard for LVSD was defined as a wall motion score over 1.8 (ejection fraction ≤40%).ResultsTwenty-eight patients with LVSD had elevated urinary and plasma N-BNP levels compared with normal subjects (p < 0.0005). Receiver-operating characteristic (ROC) areas under the curve (AUCs) for urinary and plasma N-BNP were 0.831 and 0.840, respectively. Both tests had high negative predictive values (>99%) for excluding LVSD. Urinary N-BNP was more specific (67.2%) than plasma N-BNP (41%). The plasma/urinary N-BNP product yielded a higher ROC-AUC (0.923) and specificity (78%), reducing the number of cases to scan to detect one case of LVSD to 11.4 (compared with 16.6 [urinary N-BNP] and 29.0 [plasma N-BNP]). Sequential application of tests (urinary N-BNP, then plasma N-BNP in the urine-“positive” cases) achieved similar reductions in the number of cases to scan (10.8), while limiting the number of N-BNP tests to be performed. Urinary N-BNP performed poorly in detection of other cardiac abnormalities with preserved systolic function. It was less costly to test urinary N-BNP in the whole population as compared with other strategies, including scanning high-risk cases with N-BNP testing in the remainder.ConclusionsUrinary N-BNP used together with plasma N-BNP could reduce the echocardiographic burden in screening programs

Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome : analysis of the Myocardial Ischaemia National Audit Project

Aims To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS). Methods In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality. Results We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients. Conclusion There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients

Variation in outcome of hospitalised patients with out-of-hospital cardiac arrest from acute coronary syndrome : a cohort study

Background Each year, approximately 30,000 people have an out-of-hospital cardiac arrest (OHCA) that is treated by UK ambulance services. Across all cases of OHCA, survival to hospital discharge is less than 10%. Acute coronary syndrome (ACS) is a common cause of OHCA. Objectives To explore factors that influence survival in patients who initially survive an OHCA attributable to ACS. Data source Data collected by the Myocardial Ischaemia National Audit Project (MINAP) between 2003 and 2015. Participants Adult patients who had a first OHCA attributable to ACS and who were successfully resuscitated and admitted to hospital. Main outcome measures Hospital mortality, neurological outcome at hospital discharge, and time to all-cause mortality. Methods We undertook a cohort study using data from the MINAP registry. MINAP is a national audit that collects data on patients admitted to English, Welsh and Northern Irish hospitals with myocardial ischaemia. From the data set, we identified patients who had an OHCA. We used imputation to address data missingness across the data set. We analysed data using multilevel logistic regression to identify modifiable and non-modifiable factors that affect outcome. Results Between 2003 and 2015, 1,127,140 patient cases were included in the MINAP data set. Of these, 17,604 OHCA cases met the study inclusion criteria. Overall hospital survival was 71.3%. Across hospitals with at least 60 cases, hospital survival ranged from 34% to 89% (median 71.4%, interquartile range 60.7–76.9%). Modelling, which adjusted for patient and treatment characteristics, could account for only 36.1% of this variability. For the primary outcome, the key modifiable factors associated with reduced mortality were reperfusion treatment [primary percutaneous coronary intervention (pPCI) or thrombolysis] and admission under a cardiologist. Admission to a high-volume cardiac arrest hospital did not influence survival. Sensitivity analyses showed that reperfusion was associated with reduced mortality among patients with a ST elevation myocardial infarction (STEMI), but there was no evidence of a reduction in mortality in patients who did not present with a STEMI. Limitations This was an observational study, such that unmeasured confounders may have influenced study findings. Differences in case identification processes at hospitals may contribute to an ascertainment bias. Conclusions In OHCA patients who have had a cardiac arrest attributable to ACS, there is evidence of variability in survival between hospitals, which cannot be fully explained by variables captured in the MINAP data set. Our findings provide some support for the current practice of transferring resuscitated patients with a STEMI to a hospital that can deliver pPCI. In contrast, it may be reasonable to transfer patients without a STEMI to the nearest appropriate hospital. Future work There is a need for clinical trials to examine the clinical effectiveness and cost-effectiveness of invasive reperfusion strategies in resuscitated OHCA patients of cardiac cause who have not had a STEMI. Funding The National Institute for Health Research Health Services and Delivery Research programme

Activation of a novel natriuretic endocrine system in humans with heart failure

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function. In this prospective observational study, we recruited 243 patients with HF (151 men) and 72 healthy controls. In patients with HF, plasma levels of proguanylin [median, 7.2 (range, 0.9–79.0) μg/l] and prouroguanylin [8.3 (1.7–53.0 μg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4–22.3 μg/l) for proguanylin and 6.3 (2.5–16.9) μg/l for prouroguanylin]. In patients with HF, increased age, a history of hypertension, diabetes and atrial fibrillation, use of diuretics, a higher NYHA (New York Heart Association) class and a lower eGFR (estimated glomerular filtration rate) were significant univariate predictors of proguanylin and prouroguanylin levels. In multivariate analysis, a history of hypertension and low eGFR both had strong independent associations with proguanylin and prouroguanylin levels. Proguanylin and prouroguanylin varied significantly between NYHA class with a trend of increasing plasma concentrations with worsening severity of symptoms. In conclusion, plasma proguanylin and prouroguanylin are elevated in patients with HF. Elevated plasma proguanylin and prouroguanylin levels are associated with hypertension, renal impairment and increasing severity of HF. This novel endocrine system may contribute to the pathophysiology of HF