Remote noninvasive allograft rejection monitoring for heart transplant recipients: study protocol for the novel evaluation with home electrocardiogram and remote transmission (NEW HEART) study

Background: Acute allograft rejection is a major cause of early mortality in the first year after heart transplantation in adults. Although endomyocardial biopsy (EMB) is not a perfect "gold standard" for a correct diagnosis of acute allograft rejection, it is considered the best available test and thus, is the current standard practice. Unfortunately, EMB is an invasive and costly procedure that is not without risk. Recent evidence suggests that acute allograft rejection causes delays in ventricular repolarization and thereby increases the cellular action potential duration resulting in a longer QT interval on the electrocardiogram (ECG). No prospective study to date has investigated whether such increases in the QT interval could provide early detection of acute allograft rejection. Therefore, in the Novel Evaluation With Home Electrocardiogram And Remote Transmission (NEW HEART) study, we plan to investigate the potential benefit of daily home QT interval monitoring to predict acute allograft rejection. Methods/design: The NEW HEART study is a prospective, double-blind, multi-center descriptive research study. A sample of 325 adult heart transplant recipients will be recruited within six weeks of transplant from three sites in the United States. Subjects will receive the HeartView™ ECG recorder and its companion Internet Transmitter, which will transmit the subject's ECG to a Core Laboratory. Subjects will be instructed to record and transmit an ECG recording daily for 6 months. An increase in the QTC interval from the previous day of at least 25 ms that persists for 3 consecutive days will be considered abnormal. The number and grade of acute allograft rejection episodes, as well as all-cause mortality, will be collected for one year following transplant surgery. Discussion: This study will provide "real world" prospective data to determine the sensitivity and specificity of QTC as an early non invasive marker of cellular rejection in transplant recipients during the first post-transplant year. A non-invasive indicator of early allograft rejection in heart transplant recipients has the potential to limit the number and severity of rejection episodes by reducing the time and cost of rejection surveillance and by shortening the time to recognition of rejection. Trial Registration: ClinicalTrials.gov: NCT0136580

Feasibility and Compliance with Daily Home ECG Monitoring of the QT Interval in Heart Transplant Recipients

Background: Recent evidence suggests that acute allograft rejection after heart transplantation causes an increased QT interval on electrocardiogram (ECG). The aims of this pilot study were to (1) determine whether heart transplant recipients could achieve compliance in transmitting a 30-second ECG every day for 1 month using a simple ECG device and their home telephone, (2) evaluate the ease of device use and acceptability by transplant recipients, and (3) evaluate the quality of transmitted ECG tracings for QT-interval measurement. Methods: A convenience sample of adult heart transplant recipients were recruited and trained to use the device (HeartOne, Aerotel Medical Systems, Holon, Israel). Lead II was used with electrodes that were easy to slip on and off (expandable metal wrist watch-type electrode for right wrist and C-shaped band electrode for left ankle). Patients used a toll-free number with automated voice prompts to guide their ECG transmission to the core laboratory for analysis. Results: Thirty-one subjects (72% were male; mean age of 52 ± 17 years; 37% were nonwhite) achieved an ECG transmission compliance of 73.4% (daily) and 100% (weekly). When asked, how difficult do you think it was to record and transmit your ECG by phone, 90% of subjects replied “somewhat easy” or “extremely easy.” Of the total 644 ECGs that were transmitted by subjects, 569 (89%) were acceptable quality for QT-interval measurement. The mean QTc was 448 ± 44 ms (440 ± 41 ms for male subjects and 471 ± 45 ms for female subjects). Eleven subjects (35%) had an extremity tremor, and 19 subjects (55%) had ≥ 1+ left leg edema. Neither of these conditions interfered with ECG measurements. Conclusion: Transplant recipients are compliant with recording and transmitting daily and weekly ECGs

Cytochromes P450 involved in bacterial RiPP biosyntheses

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of secondary metabolites that have garnered scientific attention due to their complex scaffolds with potential roles in medicine, agriculture, and chemical ecology. RiPPs derive from the cleavage of ribosomally synthesized proteins and additional modifications, catalyzed by various enzymes to alter the peptide backbone or side chains. Of these enzymes, cytochromes P450 (P450s) are a superfamily of heme-thiolate proteins involved in many metabolic pathways, including RiPP biosyntheses. In this review, we focus our discussion on P450 involved in RiPP pathways and the unique chemical transformations they mediate. Previous studies have revealed a wealth of P450s distributed across all domains of life. While the number of characterized P450s involved in RiPP biosyntheses is relatively small, they catalyze various enzymatic reactions such as C-C or C-N bond formation. Formation of some RiPPs is catalyzed by more than one P450, enabling structural diversity. With the continuous improvement of the bioinformatic tools for RiPP prediction and advancement in synthetic biology techniques, it is expected that further cytochrome P450-mediated RiPP biosynthetic pathways will be discovered.SummaryThe presence of genes encoding P450s in gene clusters for ribosomally synthesized and post-translationally modified peptides expand structural and functional diversity of these secondary metabolites, and here, we review the current state of this knowledge

Electrocardiographic Correlates of Acute Allograft Rejection Among Heart Transplant Recipients.

BACKGROUND:Acute allograft rejection appears to be associated with increases in QT/QTc intervals. OBJECTIVES:To determine the relationship between acute allograft rejection and electrocardiogram changes in patients undergoing an orthotopic heart transplant. METHODS:The study population comprised 220 adult patients undergoing heart transplant and enrolled in the NEW HEART study. Electrocardiograms obtained within 72 hours of endomyocardial biopsy were analyzed; electrocardiograms obtained fewer than 10 days after transplant surgery were excluded. Repeated-measures analysis was performed with statistical models including effects for rejection severity (mild and moderate/severe) and time trends independent of rejection status. RESULTS:The 151 male and 69 female transplant recipients (mean age [SD], 54 [13] years) had 969 biopsy/electrocardiogram pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate to severe organ rejection was associated with significant increases in QRS duration (P < .001), QT (P = .009), QTc (P = .003), and PR interval (P = .03), as well as increased odds of right bundle block branch (P = .002) and fascicular block (P = .009) occurring. CONCLUSIONS:Moderate to severe acute allograft rejection was associated with electrocardiographic changes after transplant surgery. Studies are needed to assess the value of computerized electrocardiogram measurement algorithms for detecting acute allograft rejection

Electrocardiographic Correlates of Acute Allograft Rejection Among Heart Transplant Recipients.

BACKGROUND:Acute allograft rejection appears to be associated with increases in QT/QTc intervals. OBJECTIVES:To determine the relationship between acute allograft rejection and electrocardiogram changes in patients undergoing an orthotopic heart transplant. METHODS:The study population comprised 220 adult patients undergoing heart transplant and enrolled in the NEW HEART study. Electrocardiograms obtained within 72 hours of endomyocardial biopsy were analyzed; electrocardiograms obtained fewer than 10 days after transplant surgery were excluded. Repeated-measures analysis was performed with statistical models including effects for rejection severity (mild and moderate/severe) and time trends independent of rejection status. RESULTS:The 151 male and 69 female transplant recipients (mean age [SD], 54 [13] years) had 969 biopsy/electrocardiogram pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate to severe organ rejection was associated with significant increases in QRS duration (P < .001), QT (P = .009), QTc (P = .003), and PR interval (P = .03), as well as increased odds of right bundle block branch (P = .002) and fascicular block (P = .009) occurring. CONCLUSIONS:Moderate to severe acute allograft rejection was associated with electrocardiographic changes after transplant surgery. Studies are needed to assess the value of computerized electrocardiogram measurement algorithms for detecting acute allograft rejection

Feasibility and Compliance with Daily Home ECG Monitoring of the QT Interval in Heart Transplant Recipients

About 13% of adult heart transplant recipients do not survive to one year and a major cause of death is acute cellular allograft rejection.1,2 According to the 2009 annual United States data published from the International Society for Heart Lung Transplantation Registry, acute rejection occurs in 25 – 35% of transplant recipients within the first year following transplant surgery.3 In order to detect the early stages of rejection so that more aggressive and early immunosuppressant therapy can be initiated, frequent biopsies of heart tissue are performed (typically, weekly or every other week in the first 3 months and then monthly or every other month during the first year). Although endomyocardial biopsy (EMB) is not a perfect “gold standard” for a correct diagnosis of acute allograft rejection, it is considered the best available test and thus, it is the current standard practice. Unfortunately, EMB is an invasive and costly procedure that is not without risk.4,5 If a simple noninvasive biomarker could be identified to detect the early stages of acute rejection, it might be possible to reduce the number of invasive biopsy procedures and to initiate earlier therapy that might prevent death from severe rejection