Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

BACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.

A novel intrapericardial pulsatile device for individualized, biventricular circulatory support without direct blood contact.

OBJECTIVE: Due to severely limited donor heart availability, durable mechanical circulatory support remains the only treatment option for many patients with end-stage heart failure. However, treatment complexity persists due to its univentricular support modality and continuous contact with blood. We investigated the function and safety of reBEAT (AdjuCor GmbH), a novel, minimal invasive mechanical circulatory support device that completely avoids blood contact and provides pulsatile, biventricular support. METHODS: For each animal tested, an accurately sized cardiac implant was manufactured from computed tomography scan analyses. The implant consists of a cardiac sleeve with three inflatable cushions, 6 epicardial electrodes and driveline connecting to an electro-pneumatic, extracorporeal portable driver. Continuous epicardial electrocardiogram signal analysis allows for systolic and diastolic synchronization of biventricular mechanical support. In 7 pigs (weight, 50-80 kg), data were analyzed acutely (under beta-blockade, n = 5) and in a 30-day long-term survival model (n = 2). Acquisition of intracardiac pressures and aortic and pulmonary flow data were used to determine left ventricle and right ventricle stroke work and stroke volume, respectively. RESULTS: Each implant was successfully positioned around the ventricles. Automatic algorithm electrocardiogram signal annotations resulted in precise, real-time mechanical support synchronization with each cardiac cycle. Consequently, progressive improvements in cardiac hemodynamic parameters in acute animals were achieved. Long-term survival demonstrated safe device integration, and clear and stable electrocardiogram signal detection over time. CONCLUSIONS: The present study demonstrates biventricular cardiac support with reBEAT. Various demonstrated features are essential for realistic translation into the clinical setting, including safe implantation, anatomical fit, safe device-tissue integration, and real-time electrocardiogram synchronized mechanical support, result in effective device function and long-term safety.

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Anticoagulation in syncardia total artificial heart recipients: anti-factor Xa or activated partial thromboplastin time?

Although the activated partial thromboplastin time (aPTT) has historically been the method of choice for anticoagulation monitoring in patients undergoing mechanical circulatory support with intravenous unfractionated heparin, it is being progressively superseded by the anti-factor Xa (anti-Xa) method. A retrospective single-arm, single-centre analysis of 20 patients who underwent total artificial heart implantation entailed simultaneous determinations of aPTT and anti-Xa. Agreement between these parameters was assessed using the Bland-Altman method. Despite a positive correlation between aPTT and anti-Xa, normal target ranges were poorly aligned: from 5th to 30th postoperative day, for anti-Xa values of 0.2 and 0.4 U/ml corresponding aPTT values were 52.1 and 65.2 s, 7.9 and 14.8 lower than predicted values, respectively. This was not associated with thromboembolic sequalae. It was not possible to demonstrate a significant relationship between the predictor variables (postoperative day; white blood cell count; C-reactive protein concentration; alanine transaminase and alkaline phosphatase level; bilirubin; haemoglobin; albumin and total protein concentration) and the agreement between aPTT and anti-Xa levels. In summary, when anti-Xa levels were used to guide anticoagulation therapy, corresponding aPTT levels were low with respect to target range. Methodology applied in this study is generalizable to other forms of mechanical circulatory support.

Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.

OBJECTIVE: Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period. DESIGN: Retrospective case-note review. PATIENTS: All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing. MEASUREMENTS: The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing. RESULTS: 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively. CONCLUSIONS: Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years.

Impaired Baseline Renal Function May Not Influence Outcomes and Survival After Left Ventricular Assist Device Implantation.

BACKGROUND: We investigated changes in estimated glomerular filtration rate (eGFR) after left ventricular assist device (LVAD) implant and the impact on long-term outcomes. METHODS: A retrospective analysis was conducted for 255 patients with LVADs, divided into 2 groups based on preimplant eGFR (<60 or >60 mL/min/1.73 m2) and into 6 grades (grade 1, >90 mL/min/1.73 m2 normal; grade 2, 60-89 mild dysfunction; grade 3, 45-59 moderate; grade 4, 30-44 moderate to severe; grade 5, 15-29 severe; or grade 6, <15 kidney failure). Changes in eGFR and the impact on long-term outcome and survival were analyzed. RESULTS: One-month postimplant eGFR of the total cohort increased from a baseline of 75.19 ± 34.35 to 118.97 ± 67.62 mL/min/1.73 m2(P < .001). eGRF 4 years postimplant was higher than baseline but not significantly (P = .48). Patients with a preimplant eGFR > 60 followed the same pattern as the entire cohort. The preimplant eGFR < 60 group had a significant increase at 1 month (P < .001), eGFR remained significantly higher than baseline 4 years postimplant (P = .032), and there was a sustained transition to improved distribution of renal function grade after LVAD implant. Post-LVAD implant survival at 1, 3, and 5 years for baseline eGFR > 60 was 76%, 54%, and 48% and for eGFR < 60 was 71%, 60%, and 48%, respectively (P = .92). CONCLUSIONS: Patients with a low preimplant eGFR derive benefit from LVAD therapy, with eGFR remaining elevated above preimplant levels. Preimplant renal dysfunction did not impact negatively on long-term morbidity and mortality.

Evolution of a rapid onsite evaluation (ROSE) service for endobronchial ultrasound guided (EBUS) fine needle aspiration (FNA) cytology in a UK Hospital: A 7 year audit.

OBJECTIVE: Endobronchial ultrasound fine needle aspiration (EBUS FNA) is a well-established procedure for the diagnosis and staging of lung cancer. We review our provision of this service at the Royal Devon and Exeter NHS Foundation Trust and the role of rapid onsite evaluation (ROSE) with the increasing demand for molecular markers in this era of personalized medicine. METHODS: A review of the changes in the Endoscopy clinic over the 7 years from the introduction of EBUS at the end of 2010 until 2017 was carried out. This included the availability of material obtained for diagnosis, accurate subtyping, and molecular testing. We also assessed the success of molecular genetics DNA techniques from EBUS material versus formalin fixed paraffin embedded tissue (FFPE). RESULTS: A total of 1218 EBUS cases with ROSE were reported between 2011 and 2017 Percentage diagnostic rates were calculated as 83, 82, 84, 92, 93, 94, and 92 for 2011, 2012, 2013, 2014, 2015, 2016, and 2017, respectively. Availability of material for immunocytochemistry ranged from 86 to 100% over the 7 years. Molecular testing was successfully performed for EGFR in 89-100% of requested cases and ALK testing in 87-100% of requested cases. EBUS sourced material gave on average twice the amount of DNA and fewer amplicon repeats per patient compared to FFPE material. CONCLUSION: ROSE at EBUS FNA provides access to suitable material for molecular testing with increased yields in the form of needle washings for EGFR with FFPE materials for ALK and PDL1 testing.

Direct Heart Procurement After Donation After Circulatory Death With Ex Situ Reperfusion.

The most extended technique of heart procurement from donors after circulatory death involves direct procurement and reperfusion in an ex situ normothermic platform using the Organ Care System (TransMedics, Inc, Andover, MA). This report describes a modified technique (at the Harefield Hospital, London, United Kingdom) with rapid donor blood drainage using a cell-saving device and synchronized perfusion on the Organ Care System.

Atrophy of anterior digastric muscle detected during ultrasound of the neck--a prospective clinical study.

Anatomical variants that affect both the anterior and posterior digastric muscles are well described, and include duplications and variable origin or sites of insertion. Although agenesis or atrophy of the anterior digastric occurs in up to 40% of patients with hemifacial microsomia, to our knowledge, it has been reported only rarely in those without this syndrome. To minimise observer bias and to establish the incidence of anomalies and atrophy of this muscle, a prospective 6-year study was conducted by an experienced consultant radiologist in all patients referred for ultrasound of the head and neck. Unilateral atrophy or absence of the anterior digastric muscle was seen in 3 of 1484 patients (0.2%). All 3 were female, and they had no symptoms or clinical signs related to the finding. One subsequently had a magnetic resonance scan. Non-syndromic absence or atrophy of the anterior digastric muscle is rare, and seems to be a unilateral phenomenon. Recognition of this variant could be important before operations in which it may be used as a landmark, or during procedures in which it is used, for example, for reanimation of a static lip or during reconstruction with a submental island flap.

A UK Single Centre Retrospective Analysis of the Relationship between Haemodynamic Changes and Outcome in Patients Undergoing Prolonged Left Ventricular Assist Device Support.

PURPOSE: Despite their efficacy, LVADs remain associated with serious complications. The relationship between haemodynamic changes during support and outcome remains inadequately characterised. This association was investigated in LVAD recipients undergoing prolonged support. METHODS: Forty patients receiving LVAD therapy for >2 years were reviewed retrospectively (mean support duration was 38.62 ± 15.28). Pre- and on-LVAD haemodynamic data were assessed in three groups: (1) those receiving ongoing support (n = 24); (2) those who underwent cardiac transplantation (n = 4); (3) those who died during support (n = 12). RESULTS: For group 1 and 2, LVAD support achieved a decrease in mean PAP, mean PCWP, TPG, and PVR and an increase in thermodilution blood flow (TBF) with significance at ≤5% level. For group 3, there were non-significant changes in TPG and PVR at the 5% level but for mean PAP, mean PCWP, and TBF the changes were similar to Groups 1 and 2 with significance at ≤5% level. Aggregated data from all three groups showed a 58% increase in TBF on LVAD support. CONCLUSION: Highly significant and favourable haemodynamic changes were found. However, group 3 did not undergo decrease in TPG and PVR possibly because of suboptimal LVAD flow, right heart dysfunction and unavoidable prolongation of support.

Evaluation of the organ care system in heart transplantation with an adverse donor/recipient profile.

BACKGROUND: A severe shortage of available donor organs has created an impetus to use extended criteria organs for heart transplantation. Although such attempts increase donor organ availability, they may result in an adverse donor-recipient risk profile. The TransMedics Organ Care System (OCS) (TransMedics, Inc, Boston) allows preservation of the donor heart by perfusing the organ at 34°C in a beating state, potentially reducing the detrimental effect of cold storage and providing additional assessment options. We describe a single-center experience with the OCS in high-risk heart transplant procedures. METHODS: Thirty hearts were preserved using the OCS between February 2013 and January 2014, 26 of which (86.7%) were transplanted. Procedures were classified as high risk based on (1) donor factors, ie, transport time more than 2.5 hours with estimated ischemic time longer than 4 hours, left ventricular ejection fraction (LVEF) less than 50%, left ventricular hypertrophy (LVH), donor cardiac arrest, alcohol/drug abuse, coronary artery disease or (2) recipient factors, ie, mechanical circulatory support or elevated pulmonary vascular resistance (PVR), or both. RESULTS: Donor and recipient age was 37 ± 12 years and 43 ± 13 years, respectively. Allograft cold ischemia time was 85 ± 17 minutes and OCS perfusion time was 284 ± 90 minutes. The median intensive care unit stay was 6 days. One death (3.8%) was observed over the follow-up: 257 ± 116 (109-445 days). There was preserved allograft function in 92% of patients, with a mean LVEF of 64% ± 5%. CONCLUSIONS: Use of the OCS is associated with markedly improved short-term outcomes and transplant activity by allowing use of organs previously not considered suitable for transplantation or selection of higher risk recipients, or both.

Simple and non-invasive techniques to evaluate the function of CircuLite Synergy.

OBJECTIVES: The Synergy CircuLite micropump is a novel partial-support miniature left ventricular assist device that propels 2-3 l/min blood from the left atrium into the right subclavian artery. The ability of currently available investigative modalities to confirm Synergy pump malfunction is limited. The Synergy speed fluctuates periodically (at 10-s intervals) from the baseline to a transient decrease followed by a transient increase (alternating speed algorithm, ASA) with the purpose of changing the blood flow behaviour, thereby reducing thrombogenicity. The aim of this study was to develop a simple non-invasive monitoring technique to assess pump function based on the detection of the ASA in the peripheral microcirculation. METHODS: Between February 2012 and July 2013, 10 patients with advanced chronic heart failure underwent Synergy implantation at our institution. The pump function was assessed by echocardiography and invasive monitoring according to standard protocols; additionally, the pump speed and power consumption were monitored. During the pump function assessment, the pulse oximeter waveform was recorded from the index fingers of the left and right hand with simultaneous pump auscultation using a stethoscope positioned on the pump (right infra-clavicular pocket). RESULTS: The pulse oximeter waveform was readily detectable from the right and left hand of all study patients. If the Synergy function was normal, there was a significant difference in the morphology of the pulse oximeter waveform from each hand: the ASA algorithm produced a more pronounced variation (giant wave) in the trace from the right hand than from the left. The giant waves invariably coincided with the sound variation associated with the ASA algorithms, which were detected regularly at 10-s intervals. CONCLUSIONS: We describe a simple, readily applicable, inexpensive, non-invasive technique that allows evaluation of Synergy pump function and may have diagnostic utility under conditions of suspected pump thrombus/malfunction. This technique is readily applicable from the early post-implant period throughout support and allows clinical personnel to verify blood flow variation through the Synergy, thereby providing a novel method of assessing device function.

Outcomes after implantation of partial-support left ventricular assist devices in inotropic-dependent patients: Do we still need full-support assist devices?

OBJECTIVES: Partial-support left ventricular assist devices (LVADs) represent a novel strategy for heart failure treatment. The Synergy Pocket Micro-pump (HeartWare Inc, Framingham, Mass), the smallest surgically implanted long-term LVAD, provides partial flow up to 4.25 L/min and was primarily designed for "less sick" patients with severe heart failure. This device is implanted minimally invasively without sternotomy or cardiopulmonary bypass. Early implantation in patients with Interagency Registry for Mechanically Assisted Circulatory Support class 4 and higher was shown to be feasible and associated with significantly improved hemodynamics and quality of life. The aim of this study was to present our experience with implementation of long-term partial circulatory support as a bridge to transplantation in patients with more advanced heart failure who were dependent preoperatively on inotropic support or intra-aortic balloon pump. METHODS: In this observational study, only inotropic or intra-aortic balloon pump-dependent patients with end-stage heart failure were included (n = 12). These patients underwent Synergy device implantation between February 2012 and August 2013. RESULTS: The mean preoperative Interagency Registry for Mechanically Assisted Circulatory Support class was 2.17 ± 0.84 (class 1, 25%; class 2, 33%; class 3, 42%). The mean age was 46 ± 15 years, and 33% were female. Preoperatively, 4 patients (33%) had at least 1 previous sternotomy, 3 patients (25%) were supported with a balloon pump, 1 patient (8%) had a previous full-support LVAD, and 4 patients (33%) had cerebrovascular events in the past. After device implantation, there were no right ventricular failures, device-related infections, hemorrhagic strokes, arterial or venous thromboembolisms, or worsenings of aortic and mitral regurgitation observed over the follow-up. The mean follow up was 174 ± 171 days (range, 5-764 days; cumulative, 3199 days). One patient (8%) died, 3 patients (25%) successfully underwent transplantation, 1 device (8%) was explanted after myocardial recovery, and 5 patients (42%) are still on ongoing support. Two patients (17%) were upgraded to a full-support LVAD after 65 days of mean support. A total of 11 of 12 patients (92%) were discharged from the hospital and are presently alive. Left ventricular end-diastolic diameter was significantly reduced 3 months after device implantation. CONCLUSIONS: Partial LVAD support may be clinically efficacious in inotropic and intra-aortic balloon pump-dependent patients. On the basis of our experience and evidence of previous research, such patients may benefit from minimally invasive access, no need for sternotomy and cardiopulmonary bypass, a short implantation time, an easy exchange if necessary, and a lower risk of subsequent heart transplantation. Because the implantation is performed without sternotomy, device upgrade is feasible with a comparatively low operative risk and good clinical outcome. Our preliminary results show that partial-support devices may have the potential to replace full-support LVADs in the near future.

De novo aortic regurgitation after continuous-flow left ventricular assist device implantation.

BACKGROUND: Significant aortic regurgitation (AR) after continuous-flow left ventricular assist device (cf-LVAD) placement affects device performance and patient outcomes. This study examined the development of AR and long-term results after implantation of cf-LVADs. METHODS: The study included all patients with no or less than mild AR who underwent HeartMate II (58 [62%]; Thoratec Corp, Pleasanton, CA) or HeartWare (35 [38%]; HeartWare International, Framingham, MA) implantation at our institute from July 2006 to July 2012. Serial echocardiograms were obtained preoperatively, at 1, 3 and 6 months postoperatively, and then at a minimum of 4-month intervals in patients with longer-term support. Kaplan-Meier estimates for freedom from moderate or greater AR were generated. Logistic regression analysis was used to define independent predictors of AR after cf-LVAD implantation. RESULTS: Median duration of LVAD support was 527 days (25(th), 75(th): 289, 907; range, 60 to 2,433 days). Mild AR developed in 48 patients (51.6%) over a median duration of 126 days, with progression to moderate AR in 13 (14%) over 493 days and to severe AR in 2 (2.1%) over 1,231 days. The incidence of mild or greater AR was 43.1% in HeartMate II vs 65.7% in HeartWare recipients (p = 0.035). Overall freedom from moderate or greater AR was 94.7% ± 2.6% at 1 year, 86.9% ± 4.5% at 2 years, 82.8% ± 5.9% at 3 years, and 31% ± 16.9% at 4 years. Independent predictors of AR were duration of support (odds ratio, 1.002; 95% confidence interval, 1.000 to 1.004; p = 0.017) and a persistently closed aortic valve (odds ratio, 0.193; 95% confidence interval, 0.097 to 0.382; p < 0.001). CONCLUSIONS: AR is associated with longer cf-LVAD support duration and persistent aortic valve closure. Incidence of moderate or greater AR after cf-LVAD implantation increases significantly after 3 years. The clinical implications of these data may warrant consideration of prophylactic aortic valve replacement at the time of cf-LVAD implantation, particularly with expected longer duration of support and in patients with preexisting AR that is more than mild.

Central extracorporeal life support with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure.

BACKGROUND: The purpose of this prospective study was to evaluate the effects and functional outcome of central extracorporeal life support (ECLS) with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure. METHODS: Between August 2010 and August 2013, 12 consecutive patients (2 female) with a mean age of 31.6 ± 15.1 years received central ECLS with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure. Underlying disease was acute cardiac decompensation due to dilated cardiomyopathy (n = 3, 25%), coronary artery disease with acute myocardial infarction (AMI) (n = 3, 25%), and acute myocarditis (n = 6, 50%). We routinely implemented ECLS by cannulating the ascending aorta, right atrium and inserting a left ventricular decompression cannula vent via the right superior pulmonary vein. RESULTS: All patients were successfully bridged to either recovery (n = 3, 25%), long-term biventricular support (n = 6, 50%) or cardiac transplantation (n = 3, 25%). Seven patients (58.3%) were discharged after a mean hospital stay of 42 ± 11.9 days. The overall survival from ECLS implantation to the end of the study was 58.3%. The cumulative ICU stay was 23.1 ± 9.6 days. The length of support was 8.0 ± 4.3 days (range 3-17 days). CONCLUSIONS: We strongly recommend left ventricular decompression in refractory cardiogenic shock and lung failure to avoid pulmonary edema, left heart distension and facilitate myocardial recovery.

Surgical treatment of infective endocarditis in active intravenous drug users: a justified procedure?

BACKGROUND: Infective endocarditis is a life threatening complication of intravenous drug abuse, which continues to be a major burden with inadequately characterised long-term outcomes. We reviewed our institutional experience of surgical treatment of infective endocarditis in active intravenous drug abusers with the aim of identifying the determinants long-term outcome of this distinct subgroup of infective endocarditis patients. METHODS: A total of 451 patients underwent surgery for infective endocarditis between January 1993 and July 2013 at the University Hospital of Heidelberg. Of these patients, 20 (7 female, mean age 35 ± 7.7 years) underwent surgery for infective endocarditis with a history of active intravenous drug abuse. Mean follow-up was 2504 ± 1842 days. RESULTS: Staphylococcus aureus was the most common pathogen detected in preoperative blood cultures. Two patients (10%) died before postoperative day 30. Survival at 1, 5 and 10 years was 90%, 85% and 85%, respectively. Freedom from reoperation was 100%. Higher NYHA functional class, higher EuroSCORE II, HIV infection, longer operating time, postoperative fever and higher requirement for red blood cell transfusion were associated with 90-day mortality. CONCLUSIONS: In active intravenous drug abusers, surgical treatment for infective endocarditis should be performed as extensively as possible and be followed by an aggressive postoperative antibiotic therapy to avoid high mortality. Early surgical intervention is advisable in patients with precipitous cardiac deterioration and under conditions of staphylococcal endocarditis. However, larger studies are necessary to confirm our preliminary results.

Adult human heart slices are a multicellular system suitable for electrophysiological and pharmacological studies.

Electrophysiological and pharmacological data from the human heart are limited due to the absence of simple but representative experimental model systems of human myocardium. The aim of this study was to establish and characterise adult human myocardial slices from small patients' heart biopsies as a simple, reproducible and relevant preparation suitable for the study of human cardiac tissue at the multicellular level. Vibratome-cut myocardial slices were prepared from left ventricular biopsies obtained from end-stage heart failure patients undergoing heart transplant or ventricular assist device implantation, and from hearts of normal dogs. Multiple slices were prepared from each biopsy. Regular contractility was observed at a range of stimulation frequencies (0.1-2 Hz), and stable electrical activity, monitored using multi-electrode arrays (MEA), was maintained for at least 8 h from slice preparation. ATP/ADP and phosphocreatine/creatine ratios were comparable to intact organ values, and morphology and gap junction distribution were representative of native myocardium. MEA recordings showed that field potential duration (FPD) and conduction velocity (CV) in human and dog slices were similar to the values previously reported for papillary muscles, ventricular wedges and whole hearts. Longitudinal CV was significantly faster than transversal CV, with an anisotropic ratio of 3:1 for human and 2.3:1 for dog slices. Importantly, slices responded to the application of E-4031, chromanol and 4-aminopyridine, three potassium channel blockers known to affect action potential duration, with an increase in FPD. We conclude that viable myocardial slices with preserved structural, biochemical and electrophysiological properties can be prepared from adult human and canine heart biopsies and offer a novel preparation suitable for the study of heart failure and drug screening.

Midterm experience with the Jarvik 2000 axial flow left ventricular assist device.

OBJECTIVE: Rotary axial flow pumps have several potential advantages and disadvantages over pulsatile pumps. The Jarvik 2000 is distinctive in being intracardiac. We report our experience in 22 patients. METHODS: The Jarvik 2000 was implanted in 15 men and 7 women. Mean age was 38.8 (range 23-59) years, preoperative diagnosis was dilated cardiomyopathy in 16, postpartum cardiomyopathy in 3, ischemic heart disease in 2, and chronic allograft failure in 1. Twenty-one patients were in New York Heart Association class IV, and 1 patient was in class III. Nineteen patients were on inotropic support, 6 were supported with an intra-aortic balloon pump, and 2 patients had been salvaged with a Centrimag (Levitronix) ventricular assist device. The median pulmonary vascular resistance was 3 Wood units; median pulmonary capillary wedge pressure was 26.6 mm Hg; and mean Cardiac Index was 1.5 L/min/m2. RESULTS: There were 2 early deaths and 6 late deaths. The average postoperative ventilation time and Intensive Treatment Unit stay was 2.2 and 10 days, respectively. One patient required a right ventricular assist device for short-term support and another for medium-term support. Seven patients were bridged to transplant, 3 had myocardial recovery, and 4 are ongoing. Mean and total duration of support was 280.5 and 6172 days, respectively. Driveline failures were noted in 3, but there were no pump infections or failure. CONCLUSION: The Jarvik 2000 provides satisfactory intermediate-term results as a bridge to transplant or recovery. It appears to be associated with a low rate of serious driveline or pump infections and technical failure. However, bleeding complications due to the required anticoagulation treatment frequently occurred.

Left ventricular assist device and drug therapy for the reversal of heart failure.

BACKGROUND: In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation. METHODS: We enrolled 15 patients with severe heart failure due to nonischemic cardiomyopathy and with no histologic evidence of active myocarditis. All had markedly reduced cardiac output and were receiving inotropes. The patients underwent implantation of left ventricular assist devices and were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling. Once regression of left ventricular enlargement had been achieved, the beta2-adrenergic-receptor agonist clenbuterol was administered to prevent myocardial atrophy. RESULTS: Eleven of the 15 patients had sufficient myocardial recovery to undergo explantation of the left ventricular assist device a mean (+/-SD) of 320+/-186 days after implantation of the device. One patient died of intractable arrhythmias 24 hours after explantation; another died of carcinoma of the lung 27 months after explantation. The cumulative rate of freedom from recurrent heart failure among the surviving patients was 100% and 88.9% 1 and 4 years after explantation, respectively. The quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire score at 3 years was nearly normal. Fifty-nine months after explantation, the mean left ventricular ejection fraction was 64+/-12%, the mean left ventricular end-diastolic diameter was 59.4+/-12.1 mm, the mean left ventricular end-systolic diameter was 42.5+/-13.2 mm, and the mean maximal oxygen uptake with exercise was 26.3+/-6.0 ml per kilogram of body weight per minute. CONCLUSIONS: In this single-center study, we found that sustained reversal of severe heart failure secondary to nonischemic cardiomyopathy could be achieved in selected patients with the use of a left ventricular assist device and a specific pharmacologic regimen.