Relationship Between Soluble Transferrin Receptor and Clinical Outcomes in Patients With Heart Failure According to Ejection Fraction Phenotype: The New Zealand PEOPLE Study.

BACKGROUND: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) but its impact on prognosis in HF with preserved ejection fraction (HFpEF) remains unclear. We assessed whether ID defined by soluble transferrin receptor (sTfR) criteria is independently associated with all-cause mortality in patients with HFpEF, and evaluated its comparative prognostic performance to ID definitions in common clinical use. METHODS AND RESULTS: Data were analyzed from 788 patients (36% HFpEF) in a prospective multicenter HF cohort study. Baseline plasma samples were analyzed with respect to 4 definitions of ID: sTfR of ≥1.59 mg/L (IDsTfR1), sTfR of ≥1.76 mg/L (IDsTfR2), ferritin of <100 µg/L, or ferritin of 100-300 µg/L + transferrin saturation of <20% (IDFerritin), and transferrin saturation of <20% (IDTsat). In multivariable Cox models IDsTfR2 (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.23-2.75) and IDTsat (HR, 1.69, 95% CI 1.10-2.59) were both independently associated with all-cause mortality in patients with HFpEF, whereas IDsTfR1 (HR 1.41, 95% CI 0.92-2.16) and IDFerritin (HR 1.19, 95% CI 0.77-1.85) were not. On inclusion of patients with HF with reduced EF, IDsTfR1 (HR 1.45, 95% CI 1.13-1.86) gained significance, but IDFerritin (HR 1.21, 95% CI 0.95-1.54) did not. For each pair of definitions intra-patient concordance was approximately 65%. CONCLUSION: ID defined by sTfR criteria is independently associated with all-cause mortality in patients with HFpEF. Poor concordance between ID definitions suggests that iron biomarkers do not reflect the same pathological process in the complex relationship between iron and HF. Therefore, which definition should guide iron replacement needs further evaluation.

Role of transthoracic echocardiogram in acute heart failure.

Acute Heart Failure (AHF) is an increasingly common condition with a poor prognosis. In contrast to CHF where advances in medical therapy and devices has led to significant improvement in morbidity and mortality, the prognosis for AHF has not changed significantly in the last few decades despite efforts to find effective treatment. There are multiple factors that contribute to the high mortality and morbidity of AHF; it can be a diagnostic challenge, determining whether decongestion has been achieved can be difficult, and persisting congestion is commonly present at discharge contributing to early decompensation and rehospitalisation. Transthoracic echocardiogram (TTE) is a unique imaging modality that is non-invasive, can be done at the bedside, in real time during procedures, is affordable and easy to access both in community and inpatient settings. Small hand held 'point of care' scans are increasingly available and being used as an adjunct to improve clinical examination. Consequently, the use of echocardiography to improve outcomes for patients with cardiac disease continues to evolve. In chronic heart failure TTE has established roles in the quantification of HF phenotype, and determination of treatment initiation, escalation and success. However, the role of echocardiogram in AHF is not as well established with society guidelines relying on expert consensus for their recommendations. Use of TTE at all stages of AHF has potential to reduce morbidity and mortality. This review discusses the evidence for use of TTE to improve the diagnosis, prognosis and management of AHF.

High-sensitivity Cardiac Troponin Is Not Associated With Acute Cellular Rejection After Heart Transplantation.

BACKGROUND: Acute cellular rejection (ACR) is common in the first year after cardiac transplantation, and regular surveillance endomyocardial biopsy (EMB) is required. An inexpensive, simple noninvasive diagnostic test would be useful. Prior studies suggest cardiac troponin (cTn) has potential as a "rule-out" test to minimize the use of EMB. Our aim was to determine whether a new high-sensitivity cardiac troponin I (hs-cTnI) assay would have utility as a "rule-out" test for ACR after heart transplantation. METHODS: Blood samples at patient follow-up visits were collected and stored over a period of 5 y. Serum cTnI concentrations were measured using the ARCHITECTSTAT hs-cTnI assay and compared with an EMB performed on the same day. Receiver-operator curve analysis based on mixed-effects logistic regression models that account for repeated measurements in individuals was performed to determine a serum troponin level below which ACR could be reliably excluded. RESULTS: One hundred seventy patients had 883 serum hs-cTnI results paired to a routine surveillance EMB. Fifty-one (6%) EMB showed significant ACR (grade ≥2R). Receiver-operator curve analysis approximated the null hypothesis area under the curve 0.509 (95% CI, 0.428-0.591). Sub-analysis including repeated hs-cTnI levels in a single individual, and early (<3 mo) EMB also showed no diagnostic utility of hs-cTnI measurement (area under the curve 0.512). CONCLUSIONS: In the largest published study to date, we found no association between hs-cTnI concentration and the presence of significant ACR on surveillance EMB. Measurement of hs-cTnI may not be a useful technique for diagnosis or exclusion of ACR after heart transplantation.

Impact of change in iron status over time on clinical outcomes in heart failure according to ejection fraction phenotype.

AIMS: The importance of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF) is unknown. In HF with reduced ejection fraction (HFrEF), ID is reported as an independent predictor of mortality in HF although not all published studies agree. Different definitions of ID have been assessed, and the natural history of untreated ID not established, which may explain the conflicting results. This study aimed to assess the relationship between ID and mortality in HFpEF, clarify which definition of ID correlates best with outcomes in HFrEF, and determine the prognostic importance of change in ID status over time. METHODS AND RESULTS: Analyses were conducted on data from 1563 patients participating in a prospective international cohort study comparing HFpEF with HFrEF. Plasma samples from baseline and 6 month visits were analysed for the presence of ID. Two ID definitions were evaluated: IDFerritin  = 'ferritin < 100 mcg/L or ferritin 100-300 mcg/L + transferrin saturation < 20%' and IDTsat  = 'transferrin saturation < 20%'. The risk of all-cause mortality and death/HF hospitalization associated with baseline ID (IDFerritin or IDTsat ) and change in ID status at 6 months (persistent, resolving, developing, or never present) was estimated in multivariable Cox proportional hazards models. Of 1563 patients, 1115 (71%) had HFrEF and 448 (29%) HFpEF. Prevalence of ID was similar in HFpEF and HFrEF (58%). Patients with ID were more likely to be female, diabetic, and have a higher co-morbid burden than patients without ID. ID by either definition did not confer independent risk for either all-cause mortality or death/HF hospitalization for patients with HFpEF [IDFerritin hazard ratio (HR) 0.65 (95% confidence interval 0.40-1.05), P = 0.08; IDTsat HR 1.16 (0.72-1.87), P = 0.55]. In the overall study cohort (HFrEF + HFpEF) and HFrEF subgroup, IDFerritin was inferior to IDTsat in prediction of all-cause mortality [overall cohort: HR 1.21 (0.95-1.53), P = 0.12 vs. HR 1.95 (1.52-2.51), P < 0.01; HFrEF: HR 1.12 (0.85-1.48), P = 0.43 vs. HR 1.57 (1.15-2.14), P < 0.01]. Persistence of IDTsat at 6 months was strongly associated with poor outcomes compared with never having IDTsat [HR 2.22 (1.42-3.46), P < 0.01] or having IDTsat at baseline self-resolve by 6 months [HR 1.40 (1.06-1.86), P = 0.02]. CONCLUSIONS: Iron deficiency is equally prevalent in HFpEF and HFrEF but is negatively prognostic only in HFrEF. The natural history of ID is important; persistent ID is strongly associated with mortality whereas resolution is not. IDTsat is the superior definition of ID and should inform future trials investigating the efficacy of intravenous iron replacement in patients with HFrEF.

Utility of troponin assays for exclusion of acute cellular rejection after heart transplantation: A systematic review.

BACKGROUND: Acute cellular rejection (ACR) is a common complication in the first year after heart transplantation (HT). Routine surveillance for ACR is undertaken by endomyocardial biopsy (EMB). Measurement of cardiac troponins (cTn) in serum is an established diagnostic test of cardiac myocyte injury. This systematic review aimed to determine whether cTn measurement could be used to diagnose or exclude ACR. METHODS: PubMed, Google Scholar and the JHLT archive were searched for studies reporting the result of a cTn assay and a paired surveillance EMB. Significant ACR was defined as International Society for Heart and Lung Transplantataion (ISHLT) Grade ≥3a/≥2R. Considerable heterogeneity between studies precluded quantitative meta-analysis. Individual study sensitivity and specificity data were examined and used to construct a pooled hierarchical summary receiver-operator characteristic (ROC) curve. RESULTS: Twelve studies including 993 patients and 3,803 EMBs, of which 3,729 were paired with cTn levels, had adequate data available for inclusion. The overall rate of significant ACR was 12%. There was wide variation in diagnostic performance. cTn assays demonstrated sensitivity of 8% to 100% and specificity of 13% to 88% for detection of ACR. The positive predictive value (PPV) was low but the negative predictive value (NPV) was relatively high (79% to 100%). High-sensitivity cTn assays had greater sensitivity and NPV than conventional cTn assays for detection of ACR (sensitivity: 82% to 100% vs 8% to 77%; NPV: 97% to 100% vs 81% to 95%, respectively). CONCLUSIONS: cTn assays do not have sufficient specificity to diagnose ACR in place of EMB. However, hs-cTn assays may have sufficient sensitivity and negative predictive value to exclude ACR and limit the need for surveillance EMB. Further research is required to assess this strategy.

Digital devices for teaching cardiac auscultation - a randomized pilot study.

BACKGROUND: Competent cardiac auscultation is a declining skill. Digital stethoscopes and hand-held echocardiography (HHE) are modern devices which may improve the accuracy of heart murmur recognition and diagnosis. Their incremental value compared to conventional examination has not been evaluated in depth. OBJECTIVES: Our aim was to quantify the utility of digital stethoscopes and HHE as teaching aids to improve medical students' diagnostic accuracy in the evaluation of heart murmurs using a novel clinically weighted scoring system. DESIGN: This pilot study involved eight medical students and eight patients with heart murmurs. Four patients were examined at 2 sessions, 1 week apart. Medical students were randomised into two groups: the 'intervention group' examined patients with a standard and digital stethoscope, and then received demonstration of the valvular lesion with HHE to illustrate the diagnosis. The 'control group' used a standard stethoscope only and were taught using traditional methods. Students' scores were compared to a 'gold standard' derived from a consensus of auscultation findings of three cardiologists. RESULTS: Overall the mean percent correct of total possible score was 65.4% (SD8.4). Using a mixed models ANOVA approach to repeated measures, the mean [95% CI] increase from training to validation period for the control group was 2.5% [-11.5, 16.5] P(Tukey) = 0.95 and 15.8% [1.7,29.8] P(Tukey) = 0.027 for the intervention group. Between the validation and training sessions for both groups, there was an increase of 9.1% [1.82, 16.4] in scores (p = 0.018). The mean [95% CI] difference in scores of the control and intervention groups was 1.9% [-5.4, 9.2] (p = 0.59). The Cohen's effect size estimate was 0.9. CONCLUSION: Digital stethoscopes and hand-held echo may be useful devices for teaching cardiac auscultation. This pilot study provides a novel study design, a heart murmur grading system, and data that will help develop definitive studies to assess new teaching techniques for cardiac auscultation using digital technology.

Iron deficiency in patients with heart failure.

Iron deficiency (ID) is a commonly present co-morbidity in patients with heart failure (HF). In iron deficient but otherwise healthy individuals, correction of ID restores exercise capacity and endurance regardless of the presence of anaemia. Recently, iron replacement in patients with HF with reduced ejection fraction has been shown to improve symptoms and exercise capacity. This article reviews the clinical relevance of ID in HF and evidence for iron replacement.