Prognostic value of three iron deficiency definitions in patients with advanced heart failure.

AIMS: There is uncertainty about the definition of iron deficiency (ID) and the association between ID and prognosis in patients with advanced heart failure. We evaluated three definitions of ID in patients referred for heart transplantation. METHODS AND RESULTS: Consecutive patients assessed for heart transplantation at a single UK centre between January 2010 and May 2022 were included. ID was defined as (1) serum ferritin concentration of <100 ng/ml, or 100-299 ng/ml with transferrin saturation <20% (guideline definition), (2) serum iron concentration ≤13 µmol/L, or (3) transferrin saturation <20%. The primary outcome measure was a composite of all-cause mortality, urgent heart transplantation or need for mechanical circulatory support. Overall, 801 patients were included, and the prevalence of ID was 39-55% depending on the definition used. ID, defined by either serum iron or transferrin saturation, was an independent predictor of the primary outcome measure (hazard ratio [HR] 1.532, 95% confidence interval [CI] 1.264-1.944, and HR 1.595, 95% CI 1.323-2.033, respectively), but the same association was not seen with the guideline definition of ID (HR 1.085, 95% CI 0.8827-1.333). These findings were robust in multivariable Cox regression analysis. ID, by all definitions, was associated with lower 6-min walk distance, lower peak oxygen consumption, higher intra-cardiac filling pressures and lower cardiac output. CONCLUSIONS: Iron deficiency, when defined by serum iron concentration or transferrin saturation, was associated with increased frequency of adverse clinical outcomes in patients with advanced heart failure. The same association was not seen with guideline definition of ID.

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.

Low Pulmonary Artery Pulsatility Index Is Associated With Adverse Outcomes in Ambulatory Patients With Advanced Heart Failure.

BACKGROUND: The pulmonary artery pulsatility index (PAPi) is a composite measure of right heart function, and low PAPi is associated with increased likelihood of mortality in patients hospitalized with cardiogenic shock. Our aim was to determine how PAPi correlates with other measures of right heart function and whether PAPi is associated with outcomes in ambulatory outpatients with advanced heart failure. METHODS: We assessed 673 consecutive ambulatory outpatients for heart transplantation over 10 years. The median age was 52 years, 72% were male, and dilated cardiomyopathy was the most common cause. All patients underwent detailed assessment, including right heart catheterization, and PAPi was calculated. The coprimary endpoints were death, urgent heart transplantation and mechanical circulatory support. RESULTS: Median PAPi was 2.2 (interquartile range 1.42-3.62), and variation was predominantly due to variation in right atrial pressure. PAPi was well correlated with the right atrial pressure to pulmonary capillary wedge pressure ratio (rho -0.766) but less well correlated with the right ventricular stroke work index (rho 0.561) and tricuspid annular plane systolic excursion (rho 0.292). Patients in the lowest PAPi quartile (0.16-1.41) had lower event-free survival at 1 year (68.7%) and 3 years (45.6%) compared with all other PAPi quartiles (log rank P = 0.0286). CONCLUSIONS: PAPi offers a composite measure of right heart function that differs from other right heart catheter or echocardiographic measures. A PAPi of less than 1.41 is associated with adverse clinical outcomes in ambulatory outpatients with advanced heart failure.

Improving anticoagulation of patients with an implantable left ventricular assist device.

Patients supported with implantable left ventricular assist devices (LVAD) have a significant risk of bleeding and thromboembolic complications. All patients require anticoagulation with warfarin, aiming for a target international normalised ratio (INR) of 2.5 and most patients also receive antiplatelet therapy. We found marked variation in the frequency of INR measurements and proportion of time outside the therapeutic INR range in our LVAD-supported patients. As part of a quality improvement initiative, home INR monitoring and a networked electronic database for recording INR results and treatment decisions were introduced. These changes were associated with increased frequency of INR measurement. We anticipate that changes introduced in this quality improvement project will reduce the likelihood of adverse events during long-term LVAD support.

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.

High-Sensitivity Cardiac Troponin and New-Onset Heart Failure: A Systematic Review and Meta-Analysis of 67,063 Patients With 4,165 Incident Heart Failure Events.

OBJECTIVES: The aim of this study was to systematically collate and appraise the available evidence regarding the association between high-sensitivity cardiac troponin (hs-cTn) and incident heart failure (HF) and the added value of hs-cTn in HF prediction. BACKGROUND: Identification of subjects at high risk for HF and early risk factor modification with medications such as angiotensin-converting enzyme inhibitors may delay the onset of HF. Hs-cTn has been suggested as a prognostic marker for the incidence of first-ever HF in asymptomatic subjects. METHODS: PubMed, Embase, and Web of Science were systematically searched for prospective cohort studies published before January 2017 that reported associations between hs-cTn and incident HF in subjects without baseline HF. Study-specific multivariate-adjusted hazard ratios (HRs) were pooled using random-effects meta-analysis. RESULTS: Data were collated from 16 studies with a total of 67,063 subjects and 4,165 incident HF events. The average age was 57 years, and 47% were women. Study quality was high (Newcastle-Ottawa score 8.2 of 9). In a comparison of participants in the top third with those in the bottom third of baseline values of hs-cTn, the pooled multivariate-adjusted HR for incident HF was 2.09 (95% confidence interval [CI]: 1.76 to 2.48; p < 0.001). Between-study heterogeneity was high, with an I2 value of 80%. HRs were similar in men and women (2.29 [95% CI: 1.64 to 3.21] vs. 2.18 [95% CI: 1.68 to 2.81]) and for hs-cTnI and hs-cTnT (2.09 [95% CI: 1.53 to 2.85] vs. 2.11 [95% CI: 1.69 to 2.63]) and across other study-level characteristics. Further adjustment for B-type natriuretic peptide yielded a similar HR of 2.08 (95% CI: 1.64 to 2.65). Assay of hs-cTn in addition to conventional risk factors provided improvements in the C index of 1% to 3%. CONCLUSIONS: Available prospective studies indicate a strong association of hs-cTn with the risk of first-ever HF and significant improvements in HF prediction.

Retained pacemaker and implantable cardioverter-defibrillator components after heart transplantation are common and may lead to adverse events.

Aims: Many patients have a cardiac implantable electronic device (CIED) extracted at the time of heart transplantation. CIED components may be retained after heart transplantation, but their frequency, nature, and clinical significance is uncertain. Methods and results: Consecutive patients that underwent heart transplantation over 10 years from 1 January 2007 until 1 January 2017 were identified from the unit database. Pre- and post-operative chest radiographs were reviewed by two independent observers for the presence of CIED components. Adverse events relating to any retained CIED component were recorded. Two hundred and six patients had a CIED removed at the time of transplantation. Retained CIED components were present in 86 (42%) patients. The most common retained CIED components were suture sleeves and superior vena cava (SVC) coils of dual coil implantable cardioverter-defibrillator (ICD) leads. An SVC coil was retained in 25% of patients that had a dual coil ICD lead. Seven adverse events were associated with CIED removal or retained CIED components, including one fatal event. However, retained CIED components were not associated with reduced long-term survival after heart transplantation. Conclusion: Retained CIED components were seen in 42% of patients that had a CIED prior to transplantation, may be associated with serious adverse events but are not associated with reduced long-term survival. Cardiac surgeons should be aware of all CIED system components and be familiar with techniques for their complete removal at the time of transplantation.

Intravascular ultrasound of the proximal left anterior descending artery is sufficient to detect early cardiac allograft vasculopathy.

OBJECTIVE: Cardiac allograft vasculopathy (CAV) can be detected early with intravascular ultrasound (IVUS), but there is limited information on the most efficient imaging protocol. METHODS: Coronary angiography and IVUS of the three coronary arteries were performed. Volumetric IVUS analysis was performed, and a Stanford grade determined for each vessel. RESULTS: Eighteen patients were included 18 (range 12-24) months after transplantation. Angiographic CAV severity ranged from none (CAV0) to mild (CAV1), whereas IVUS CAV severity ranged from none (Stanford grade I) to severe (grade IV). Maximal intimal thickness measured with IVUS was significantly greater in the LAD (0.84 ± 0.48 mm) than in the LCX (0.46 ± 0.32 mm) or the RCA (0.53 ± 0.41 mm, P = .005). Diagnostic accuracy of IVUS in the left anterior descending artery was 100% (18 of 18 Stanford grades matched the patient's highest overall Stanford grade), 66% in the right coronary artery (12 of 18), and 56% in the left circumflex artery (11 of 18). The minimal required length of left anterior descending artery pullbacks to attain 100% accuracy was 36 mm (range 3-36 mm) distal from the guide catheter ostium. CONCLUSIONS: These data suggest that focal IVUS imaging of the proximal LAD followed by volumetric analysis may suffice when screening for transplant vasculopathy.

Socioeconomic Deprivation and Survival After Heart Transplantation in England: An Analysis of the United Kingdom Transplant Registry.

BACKGROUND: Socioeconomic deprivation (SED) is associated with shorter survival across a range of cardiovascular and noncardiovascular diseases. The association of SED with survival after heart transplantation in England, where there is universal healthcare provision, is unknown. METHODS AND RESULTS: Long-term follow-up data were obtained for all patients in England who underwent heart transplantation between 1995 and 2014. We used the United Kingdom Index of Multiple Deprivation (UK IMD), a neighborhood level measure of SED, to estimate the relative degree of deprivation for each recipient. Cox proportional hazard models were used to examine the association between SED and overall survival and conditional survival (dependant on survival at 1 year after transplantation) during follow-up. Models were stratified by transplant center and adjusted for donor and recipient age and sex, ethnicity, serum creatinine, diabetes mellitus, and heart failure cause. A total of 2384 patients underwent heart transplantation. There were 1101 deaths during 17 040 patient-year follow-up. Median overall survival was 12.6 years, and conditional survival was 15.6 years. Comparing the most deprived with the least deprived quintile, adjusted hazard ratios for all-cause mortality were 1.27 (1.04-1.55; P=0.021) and 1.59 (1.22-2.09; P=0.001) in the overall and conditional models, respectively. Median overall survival and conditional survival were 3.4 years shorter in the most deprived quintile than in the least deprived. CONCLUSIONS: Higher SED is associated with shorter survival in heart transplant recipients in England and should be considered when comparing outcomes between centers. Future research should seek to identify modifiable mediators of this association.

The management of patients with aortic regurgitation and severe left ventricular dysfunction: a systematic review.

A systematic search of Medline, EMBASE and CINAHL electronic databases was performed. Original research articles reporting all-cause mortality following surgery in patients with aortic regurgitation and severe left ventricular systolic dysfunction (LVSD) were identified. Nine of the 10 eligible studies were observational, single-center, retrospective analyses. Survival ranged from 86 to 100% at 30 days; 81 to 100% at 1 year and 68 to 84% at 5 years. Three studies described an improvement in mean left ventricular ejection fraction (LVEF) following aortic valve replacement (AVR) of 5-14%; a fourth study reported an increase in mean left ventricular ejection fraction (LVEF) of 9% in patients undergoing isolated AVR but not when AVR was combined with coronary artery bypass graft and/or mitral valve surgery. Three studies demonstrated improvements in functional New York Heart Association (NYHA) class following AVR. Additional studies are needed to clarify the benefits of AVR in patients with more extreme degrees of left ventricular systolic dysfunction (LVSD) and the potential roles of cardiac transplantation and transaortic valve implantation.

Interventricular lead separation is critical for NT-proBNP reduction after cardiac resynchronization therapy.

AIMS: Effective cardiac resynchronization therapy may depend upon the distance between left ventricular (LV) and right ventricular (RV) pacing leads. We assessed the influence of lead separation upon circulating NT-proBNP. MATERIALS & METHODS: In total, 132 patients underwent assessment, including NT-proBNP assay, before and after cardiac resynchronization therapy. 3D lead separation was calculated from postero-anterior and lateral chest radiography. RESULTS: Lead separation correlated with NT-proBNP reduction (r = 0.25; p = 0.004). Circulating NT-proBNP only fell in those with lead separation in the upper two quartiles. Deteriorating NT-proBNP occurred in 44 patients. Lead separation was less in these patients compared with those with an improvement (corrected 3D lead separation: 148.0 ± 5.38 and 170.5 ± 4.21 mm, respectively; p = 0.0018). CONCLUSION: Left ventricular-right ventricular lead separation correlates with postcardiac resynchronization therapy improvements in circulating NT-proBNP, a powerful marker of heart failure status and prognosis. Attention should be paid to achieving maximal lead separation at implantation.

How many patients fulfil the surface electrocardiogram criteria for subcutaneous implantable cardioverter-defibrillator implantation?

AIMS: To determine the number of patients with a primary or secondary prevention implantable cardioverter-defibrillator (ICD) indication who are eligible for subcutaneous ICD (S-ICD) implantation according to the S-ICD manufacturer's surface electrocardiogram (ECG) screening template. METHODS AND RESULTS: One hundred and ninety-six ICD patients with a non-paced ventricle were assessed using erect and supine ECG limb lead recordings to simulate the three S-ICD sensing vectors. Each ECG lead was scrutinized by two independent observers. Subcutaneous ICD eligibility required two or more leads to satisfy the S-ICD screening template in both erect and supine positions. Overall, 85.2% of patients [95% confidence interval (CI): 80.2-90.2%] fulfilled surface ECG screening criteria. The proportion of patients with 3, 2, 1, and 0 qualifying leads were 37.2% (95% CI: 30.4-44.0%), 48.0% (95% CI: 41.0-55.0%), 11.2% (95% CI: 6.8-15.6%), and 3.6% (95% CI: 1.0-6.2%). The S-ICD screening template was satisfied more often by Lead III (primary vector, 83.7%, 95% CI: 78.5-88.9%) and Lead II (secondary vector, 82.7%, 95% CI: 77.4-88.0%) compared with Lead I (alternate vector, 52.6%, 95% CI: 45.6-59.6%). A prolonged QRS duration was the only baseline characteristic independently associated with ineligibility for S-ICD implantation. There was 92.9% agreement between the two independent observers in assessment of eligibility using the S-ICD screening template. CONCLUSION: About 85.2% of patients with an indication for a primary or secondary prevention ICD have a surface ECG that is suitable for S-ICD implantation when assessed with an S-ICD screening template. There is minor inter-observer variation in assessment of eligibility using the S-ICD screening template.

Deactivation of implantable cardioverter-defibrillators at end of life.

It is inevitable that all patients with implantable cardioverter-defibrillators (ICDs) will die during extended follow-up. End-of-life care planning may become appropriate as a patient's condition deteriorates. There is concern about multiple futile shocks in the final hours of life, although the incidence of this problem has been estimated at only 8-16%. Despite broad consensus that ICD deactivation should be discussed as part of end-of-life care planning, the effect of ICD deactivation, in particular whether life expectancy is altered, is uncertain. Many clinicians are reluctant to discuss ICD deactivation. Many patients have misconceptions regarding ICD function and value longevity above quality of life. As such, ICD deactivation is often discussed late or not at all. The management of ICDs in patients approaching death is likely to become a major problem in the coming years. This article will discuss directions in which clinical practice might develop and areas for future research.

Clinical experience of subcutaneous and transvenous implantable cardioverter defibrillators in children and teenagers.

BACKGROUND: Subcutaneous implantable cardioverter defibrillator (S-ICD) systems have no components in contact with the heart and may avoid complications such as lead fracture, venous obstruction, or endocarditis that occur with transvenous leads. Concerns have been raised regarding inappropriate shocks and pocket erosion with S-ICD systems. We have compared the performance of S-ICD and transvenous ICD systems in children and teenagers. METHODS: We studied consecutive patients <20 years of age who received an ICD over a 4-year period in two Scottish centers. Baseline characteristics, complications, and ICD therapy were recorded. The primary outcome measure was survival. The secondary outcome measure was survival-free from inappropriate ICD therapy or system revision. RESULTS: Nine S-ICD were implanted in nine patients. Eight transvenous ICD were implanted in six patients; two were redo procedures. Baseline characteristics were well matched. Median duration of follow-up was lower for S-ICD (20 months) than for transvenous ICD (36 months, P = 0.0262). Survival was 100% in both groups. Survival free of inappropriate therapy or system revision was 89% for S-ICD and 25% for transvenous ICD systems (log-rank test, P = 0.0237). No S-ICD were extracted, but three transvenous ICD were extracted due to infection (n = 1) and lead failure (n = 2). CONCLUSIONS: In real-world use in children and teenagers, S-ICD may offer similar survival benefit to transvenous ICD, with a lower incidence of complications requiring reoperation. In the absence of randomized trials, S-ICD should be compared prospectively with transvenous ICD in large multicenter registries with comparable periods of follow-up.