Measuring congestion with a non-invasive monitoring device in heart failure and haemodialysis: CONGEST-HF.

AIMS: We examined the effectiveness of a novel cardiopulmonary management wearable sensor (worn for less than 5 mins) at measuring congestion and correlated the device findings with established clinical measures of congestion. METHODS AND RESULTS: We enrolled three cohorts of patients: (1) patients with heart failure (HF) receiving intravenous diuretics in hospital; (2) patients established on haemodialysis, and (3) HF patients undergoing right heart catheterization (RHC). The primary outcomes in the respective cohorts were a Spearman correlation between (1) change in weight and change in thoracic impedance (TI) (from enrolment, 24 h after admission to discharge) in patients hospitalized for HF; (2) lung ultrasound B-lines and volume removed during dialysis with device measured TI, and (3) pulmonary capillary wedge pressure (PCWP) and sub-acoustic diastolic, third heart sound (S3) in the patients undergoing RHC. A total of 66 patients were enrolled. In HF patients (n = 25), change in weight was correlated with both change in device TI (Spearman correlation [rsp] = -0.64, p = 0.002) and change in device S3 (rsp = -0.53, p = 0.014). In the haemodialysis cohort (n = 21), B-lines and TI were strongly correlated before (rsp = -0.71, p < 0.001) and after (rsp = -0.77, p < 0.001) dialysis. Volume of fluid removed by dialysis was correlated with change in device TI (rsp = 0.49, p = 0.024). In the RHC cohort (n = 20), PCWP measured at one time point and device S3 were not significantly correlated (rsp = 0.230, p = 0.204). There were no device-related adverse events. CONCLUSIONS: A non-invasive device was able to detect changes in congestion in patients with HF receiving decongestion therapy and patients having fluid removed at haemodialysis. The cardiopulmonary management device, which measures multiple parameters, is a potentially useful tool to monitor patients with HF to prevent hospitalizations.

British societies guideline on the management of emergencies in implantable left ventricular assist device recipients in transplant centres.

An implantable left ventricular assist device (LVAD) is indicated as a bridge to transplantation or recovery in the United Kingdom (UK). The mechanism of action of the LVAD results in a unique state of haemodynamic stability with diminished arterial pulsatility. The clinical assessment of an LVAD recipient can be challenging because non-invasive blood pressure, pulse and oxygen saturation measurements may be hard to obtain. As a result of this unusual situation and complex interplay between the device and the native circulation, resuscitation of LVAD recipients requires bespoke guidelines. Through collaboration with key UK stakeholders, we assessed the current evidence base and developed guidelines for the recognition of clinical deterioration, inadequate circulation and time-critical interventions. Such guidelines, intended for use in transplant centres, are designed to be deployed by those providing immediate care of LVAD patients under conditions of precipitous clinical deterioration. In summary, the Joint British Societies and Transplant Centres LVAD Working Group present the UK guideline on management of emergencies in implantable LVAD recipients for use in advanced heart failure centres. These recommendations have been made with a UK resuscitation focus but are widely applicable to professionals regularly managing patients with implantable LVADs.

The atrial and ventricular myocardial proteome of end-stage lamin heart disease.

Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.

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.

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Graft function and incidence of cardiac allograft vasculopathy in donation after circulatory-determined death heart transplant recipients.

Experience in donation after circulatory-determined death (DCD) heart transplantation (HTx) is expanding. There is limited information on the functional outcomes of DCD HTx recipients. We sought to evaluate functional outcomes in our cohort of DCD recipients. We performed a single-center, retrospective, observational cohort study comparing outcomes in consecutive DCD and donation after brain death (DBD) HTx recipients between 2015 and 2019. Primary outcome was allograft function by echocardiography at 12 and 24 months. Secondary outcomes included incidence of cardiac allograft vasculopathy, treated rejection, renal function, and survival. Seventy-seven DCD and 153 DBD recipients were included. There was no difference in left ventricular ejection fraction at 12 months (59% vs 59%, P = .57) and 24 months (58% vs 58%, P = .87). There was no significant difference in right ventricular function at 12 and 24 months. Unadjusted survival between DCD and DBD recipients at 5 years (85.7% DCD and 81% DBD recipients; P = .45) was similar. There were no significant differences in incidence of cardiac allograft vasculopathy (odds ratio 1.59, P = .21, 95% confidence interval 0.77-3.3) or treated rejection (odds ratio 0.60, P = .12, 95% confidence interval 0.32-1.15) between DBD and DCD recipients. Post-transplant renal function was similar at 1 and 2 years. In conclusion, cardiac allografts from DCD donors perform similarly to a contemporary population of DBD allografts in the medium term.

Diagnostic quality electrocardiogram from a HeartMate 3 supported patient using a smartphone-based recording device.

Patients with implantable left ventricular assist devices (LVAD) are at risk of ventricular arrhythmias but these may be hemodynamically tolerated. An electrocardiogram (ECG) is essential to determine whether an LVAD-supported patient is experiencing a ventricular arrhythmia. Access to 12 lead ECG is predominantly in healthcare facilities. Implantable LVAD also cause significant electromagnetic interference leading to artefacts on ECG. We report a patient on Heartmate 3 LVAD with a diagnostic quality 6 lead ECG obtained with an AliveCor device during an episode of sustained palpitations. The AliveCor device may be used for remote identification of ventricular arrhythmias in LVAD patients.

Comparing Cardiac Mechanics and Myocardial Fibrosis in DBD and DCD Heart Transplant Recipients.

BACKGROUND: Heart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls. METHODS AND RESULTS: Consecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41-59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6-14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4-26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain -12.6 ± 3.1% vs -17.2 ± 1.8%, P < .0001; global circumferential strain -16.9 ± 3.1% vs -19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain -15.7 ± 4.5% vs -21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain -13.1 ± 3.0% vs -12.1 ± 3.1%, P = .14; global circumferential strain -17.3 ± 2.9% vs -16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain -15.9 ± 4.9% vs -15.5 ± 4.1%, P = .71) between DCD and DBD HTx. CONCLUSIONS: HTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable.

Lactate during ex-situ heart perfusion does not predict the requirement for mechanical circulatory support following donation after circulatory death (DCD) heart transplants.

BACKGROUND: Ex-situ heart perfusion (ESHP) is commonly used for the reanimation and preservation of hearts following donation after circulatory determined death (DCD). The only commercially available existing ESHP device promotes perfusate lactate levels for assessment of heart viability. The reliability of this marker is yet to be confirmed for DCD heart transplantation. METHODS: This is a single center, retrospective study examining DCD heart transplants from March 1, 2015 to June 30, 2020. Recipients were divided into 2 groups dependent upon their requirement for or absence of mechanical circulatory support post-transplant. Lactate profiles obtained during ESHP were analyzed. Hearts were procured using the direct procurement and perfusion (DPP) method. RESULTS: Fifty-one DCD heart transplant recipients were studied, of which 20 (39%) were dependent on mechanical circulatory support (MCS) following transplantation, (2% Ventricular Assist Device (VAD), 16% Extra Corporeal Membrane Oxygenation (ECMO) and 21% Intra-aortic balloon pumps (IABP). There was no difference in arterial lactate profiles on ESHP at any time point for those dependent upon MCS support (MCS) and those that were not (no MCS) post-transplant. After 3 hours of ESHP, the arterial lactate was >5mmol/L in 80% upon MCS vs 62% no MCS, p = .30. There was also no difference in ESHP rising arterial lactate concentrations, (15% MCS vs 13% non MCS, p = 1.00). CONCLUSION: For DCD hearts transplants retrieved using the DPP technique, lactate profiles do not seem to be a reliable predictor of mechanical circulatory support requirement post-transplant.

Validation of predicted heart mass equations by measurement of donor heart mass at time of heart transplantation.

Predicted heart mass (PHM) equations may be used in donor-recipient size matching in heart transplantation. We compared PHM and actual heart mass in 25 consecutive DBD heart transplants. There was a moderate positive correlation between actual heart mass and PHM. There was a similar moderate correlation between actual heart mass and donor weight or donor body surface area but not donor height. PHM was lower than actual heart mass for all donor hearts. Bland-Altman analysis showed a systematic bias between PHM and actual heart mass, with a mean difference of 190.9 ± 66.4 g. The utility of PHM equations is likely to be part of a multi-parametric assessment of the relative differences between donor and recipient, so the absolute difference is likely to be unimportant.

Cardiac Transplantation following Cobalt Cardiomyopathy from Bilateral Metal-on-Metal Hip Replacements.

A fifty-two-year-old man underwent heart transplantation at our centre after four years of developing progressive heart failure symptoms due to cobalt toxicity-related cardiomyopathy. Between the ages of forty and forty-two, he underwent bilateral metal-on-metal hip arthroplasties for early onset osteoarthritis. Six years later, he developed increasing fatigue and pericardial effusions. Following a prolonged period of deterioration without a clear cause, the diagnosis of cobalt toxicity-related cardiomyopathy due to cobalt-chromium alloy hip prostheses was eventually made. He underwent bilateral revision hip arthroplasties and was listed for heart transplantation. Metal-on-metal joint replacement is a rare cause of iatrogenic cobalt toxicity. Anaesthetists may encounter patients with unexplained symptoms of heart failure, having a high index of suspicion presenting an opportunity for early diagnosis and intervention before end-stage disease develops.

Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

An updated systematic review on heart failure treatments for patients with renal impairment: the tide is not turning.

Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend-55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001-2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001-2010 and 83.1% from 2011, P < 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.

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.

Real-world evidence in a national health service: results of the UK CardioMEMS HF System Post-Market Study.

AIMS: The CardioMEMS HF System Post-Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic-guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. METHODS AND RESULTS: COAST is a prospective, international, multicentre, open-label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic-guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system-related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72-88%] than the previous 12 months (0.27 vs. 1.52 events/patient-year, respectively, P < 0.0001). Freedom from device/system-related complications and pressure sensor failure at 2 years was 100% and 99%, respectively. CONCLUSIONS: Remote haemodynamic-guided HF management, using frequent assessment of pulmonary artery pressures, was successfully implemented at 14 specialist centres in the UK. Haemodynamic-guided HF management was safe and significantly reduced hospitalization in a group of high-risk patients. These results support implementation of this innovative remote management strategy to improve outcome for patients with symptomatic HF. Clinical registration number: ClinicalTrials.gov identifier: NCT02954341.

Size matching in heart transplantation: Is predicted heart mass the optimal method in a United Kingdom cohort?

Predicted heart mass (PHM) equations have been proposed as an alternative method for size matching in heart transplantation. We assessed association between donor-recipient size mismatch, defined using PHM equations, and survival post-heart transplant in the United Kingdom. Data from all adult patients who received a heart transplant between 1995 and 2017 were obtained from the United Kingdom Transplant Registry. PHM was calculated using published equations. Primary outcome was 1-year survival post-heart transplantation. Recipients of undersized organs had reduced 1-year survival (HR 1.31, 95% CI 1.03-1.67, p = .03). Oversizing had no impact on survival (HR 0.99, 95% CI 0.78-1.26, p = .96). Gender mismatching had no impact on survival in the cohort matched by PHM (HR 1.12, 95% CI 0.86-1.47, p = .4). In recipients without pulmonary hypertension, undersizing by PHM had no impact on 1-year survival (HR 0.95, 95% CI 0.61-1.49, p = .83). In recipients with pulmonary hypertension, oversizing donor RV by using PHM RV equation (PHMRV ) results in improved survival at 1 year (HR 0.65, 95% CI 0.5-0.83, p = .001). In conclusion, receiving an organ undersized by PHM was associated with decreased 1-year survival. Subgroup analyses demonstrated that undersizing only impacted survival in recipients with pulmonary hypertension and that these recipients had improved outcomes if they received an organ with an RV oversized by >10% by PHMRV .