Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart.

BACKGROUND: Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). METHODS: We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. RESULTS: Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). CONCLUSIONS: Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation.

Surveillance Endomyocardial Biopsy in the Modern Era Produces Low Diagnostic Yield for Cardiac Allograft Rejection.

BACKGROUND: The changing epidemiology of cardiac allograft rejection has prompted many to question the yield of surveillance endomyocardial biopsy (EMB) in heart transplantation (HT) patients. We sought to determine the yield of EMB in the modern era. METHODS: We evaluated 2597 EMBs in 182 consecutive HT patients who survived to their first EMB. The EMBs were categorized as asymptomatic or clinically driven and were compared based on era of antiproliferative therapy use at our center (early azathioprine era: 1990-2000 vs modern mycophenolate era: 2000-2011). RESULTS: In the modern era, patients had a higher prevalence of risk factors for developing rejection (≥ International Society of Heart and Lung Transplantation grade 2R); however, the frequency of rejection was decreased at all times (0-6 months: 60.2% vs 21.5%, P < 0.001, 6-12 months: 26.8% vs 1.8%, P < 0.001, 12-36 months: 32.3% vs 10.5%, P = 0.006). The yield of asymptomatic EMB decreased in the modern era between 0 and 6 months (10.9% vs 3.12%), 6 to 12 months (17% vs 0%), and years 2 to 3 (6.1% vs 1.5%). In the early era, the odds ratio of rejection during asymptomatic EMB compared to a clinically driven EMB was 0.47 (95% confidence interval, 0.31-0.71) and was decreased in the modern era (0.17 [0.07-0.42], P = 0.04). The probability of detecting rejection on asymptomatic EMB was significantly reduced in the modern era, even after adjustment for tacrolimus and induction therapy (1% vs 8%, P < 0.001). CONCLUSIONS: The clinical yield of surveillance EMB has decreased in the modern era. The EMB in asymptomatic patients longer than 6 months after HT warrants further scrutiny.

In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

Right ventricular dysfunction: lessons learned from mechanical circulatory assist devices.

Congestive heart failure represents a disease process of epidemic proportions in the United States, with 900,000 annual hospitalizations for New York Heart Association class III to IV symptoms. The inexorable deterioration of this group of patients has, until recently, been delayed by pharmacotherapy and by the use of automated implantable cardioverter defibrillators and cardiac resynchronization therapy. The authors propose that a major component of the downhill course of New York Heart Association class IV left heart failure is secondary to right heart failure and present the major predictors of right ventricular dysfunction. This, together with the limited availability of heart transplant donors, has led to the development of the left ventricular assist devices and the total artificial heart. Contrasting and comparing these devices have permitted insight into the importance of right ventricular function in the pathophysiology of heart failure, especially in the decision to proceed with left ventricular assist device placement, which is limited by right heart dysfunction or biventricular replacement with the total artificial heart.

A pilot study of an Internet walking program and pedometer in COPD.

BACKGROUND: Higher levels of physical activity are associated with better functional status, fewer hospital admissions, and lower mortality. In this pilot study, we examined the feasibility and safety of a novel program that combines a pedometer with a website to increase walking. METHODS: 27 persons with stable COPD wore the Omron HJ-720ITC pedometer and used the website for 90 days. They uploaded step-count data to the study server using their home computer and received an email each week with their individualized step-count goal. The website provided step-count feedback, education, and motivational content. Subjects participated in a monthly semi-structured interview by telephone. Subjects reported changes in medical condition by telephone or on the website. Paired T-tests assessed change in daily step counts. RESULTS: Subjects were males, mean age 72 ± 8 years, with moderate COPD, FEV(1) 1.57 ± 0.48 L (55 ± 16% predicted). 87% and 65% reported no problems using the pedometer and website, respectively. At month 3, 96% reported it was true that they knew their step count goal every day, and 52% reported that they were able to reach their goal. 95% of participants said they would recommend the walking program to another person with COPD. Eight subjects experienced breathing problems unrelated to the intervention. In 24 subjects with step counts at baseline and month 3, there was a significant increase of 1263 steps per day (approximately 1.0 km), p = 0.0054. CONCLUSIONS: The use of a website and pedometer was feasible and safe, and persons increased their daily walking.

Persistent anemia after implantation of the total artificial heart.

BACKGROUND: The total artificial heart (TAH) replaces the heart with 2 pneumatic pumps and 4 tilting disk mechanical valves. It was hypothesized that patients receiving TAH support have persistent hemolysis that resolves after heart transplantation (HT). METHODS AND RESULTS: Hematocrit (HCT) was compared in patients on TAH to left ventricular assist device (LVAD) support for bridge to HT. Data were compared with t tests. The TAH (n = 36; mean age 47 ± 13 years) and LVAD patients (n = 14; mean age 53 ± 12 years) were supported for a median of 83 (interquartile range [IQR] 43-115) and 106 days (IQR 84-134), respectively. Hematocrit was similar between the TAH and LVAD patients (34 ± 6% vs 37 ± 5%; P = .07) at baseline. After placement, TAH patients had lower HCT at 2 (20 ± 2% vs 24 ± 3%), 4 (22 ± 3% vs 26 ± 3%), 6 (22 ± 4% vs 30 ± 4%), and 8 weeks (23 ± 4% vs 33 ± 5%; P < .001 for all). There were no differences in HCT at 1 (30 ± 4% vs 29 ± 7%; P = .42) and 3 months (35 ± 7% vs 35 ± 4%; P = .98) after removal of the devices for HT. TAH patients had undetectable haptoglobin in 96% of assessments, increased lactate dehydrogenase (1,128 ± 384 units/L), and detectable plasma free hemoglobin in 40% of measurements (21 ± 15 mg/dL). High sensitivity C-reactive protein (52 ± 50 mg/dL) was elevated, and reticulocyte production index was decreased (1.6 ± 0.6). CONCLUSIONS: Patients implanted with a TAH have persistent anemia that resolves only after HT. The association of hemolysis, ineffective erythropoiesis, and inflammation with the TAH warrants further study.

Phosphodiesterase inhibitors, congestive heart failure, and sudden death: time for re-evaluation.

A 42-year-old diabetic man was admitted with systolic heart failure and pulmonary hypertension being treated with sildenafil for the previous year. With an increase in creatinine, he experienced 3 episodes of ventricular tachycardia and ventricular fibrillation. Withdrawal of the phosphodiesterase (PDE) inhibitor resulted in no further episodes of dysrhythmias. The basic pharmacology of PDE inhibitors is presented and the use of PDE-3 inhibitors for the treatment of heart failure causing an increase in sudden death is also reviewed. There have been several cases of sudden death associated with sildenafil use and with its increasing use in patients with severe pulmonary hypertension and decompensated heart failure. The authors also reviewed the electrophysiologic effects of PDE-5 inhibitors associated with their use. The crossover between PDE-3 and PDE-5 inhibitors is also discussed and caution is urged when contemplating the use of PDE-5 inhibitors in patients with systolic heart failure and pulmonary hypertension.

Evaluating heart failure after implantation of mechanical circulatory support devices.

The medical community has seen an explosive rise in the utilization of implantable mechanical circulatory support devices for late-stage cardiomyopathy. Care for these complex patients requires a basic understanding of device physiology and potential complications. This review focuses on an algorithm that incorporates a careful clinical history and examination with diagnostic modalities for the evaluation of a patient who is failing therapy with a continuous-flow left ventricular assist device, as well as the general management and optimization of patients implanted with an artificial heart.

Exercise blood pressure response during assisted circulatory support: comparison of the total artificial [corrected] heart with a left ventricular assist device during rehabilitation.

BACKGROUND: The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). METHODS: We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. RESULTS: In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (ß = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: ß = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. CONCLUSIONS: During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Integrating an internet-mediated walking program into family medicine clinical practice: a pilot feasibility study.

BACKGROUND: Regular participation in physical activity can prevent many chronic health conditions. Computerized self-management programs are effective clinical tools to support patient participation in physical activity. This pilot study sought to develop and evaluate an online interface for primary care providers to refer patients to an Internet-mediated walking program called Stepping Up to Health (SUH) and to monitor participant progress in the program. METHODS: In Phase I of the study, we recruited six pairs of physicians and medical assistants from two family practice clinics to assist with the design of a clinical interface. During Phase II, providers used the developed interface to refer patients to a six-week pilot intervention. Provider perspectives were assessed regarding the feasibility of integrating the program into routine care. Assessment tools included quantitative and qualitative data gathered from semi-structured interviews, surveys, and online usage logs. RESULTS: In Phase I, 13 providers used SUH and participated in two interviews. Providers emphasized the need for alerts flagging patients who were not doing well and the ability to review participant progress. Additionally, providers asked for summary views of data across all enrolled clinic patients as well as advertising materials for intervention recruitment. In response to this input, an interface was developed containing three pages: 1) a recruitment page, 2) a summary page, and 3) a detailed patient page. In Phase II, providers used the interface to refer 139 patients to SUH and 37 (27%) enrolled in the intervention. Providers rarely used the interface to monitor enrolled patients. Barriers to regular use of the intervention included lack of integration with the medical record system, competing priorities, patient disinterest, and physician unease with exercise referrals. Intention-to-treat analyses showed that patients increased walking by an average of 1493 steps/day from pre- to post-intervention (t = (36) = 4.13, p < 0.01). CONCLUSIONS: Providers successfully referred patients using the SUH provider interface, but were less willing to monitor patient compliance in the program. Patients who completed the program significantly increased their step counts. Future research is needed to test the effectiveness of integrating SUH with clinical information systems over a longer evaluation period.

Implantable mechanical circulatory support: demystifying patients with ventricular assist devices and artificial hearts.

Engineering advancements have expanded the role for mechanical circulatory support devices in the patient with heart failure. More patients with mechanical circulatory support are being discharged from the implanting institution and will be seen by clinicians outside the immediate surgical or heart-failure team. This review provides a practical understanding of device design and physiology, general troubleshooting, and limitations and complications for implantable left ventricular assist devices (pulsatile-flow and continuous-flow pumps) and the total artificial heart.

An online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trial.

BACKGROUND: Approximately half of American adults do not meet recommended physical activity guidelines. Face-to-face lifestyle interventions improve health outcomes but are unlikely to yield population-level improvements because they can be difficult to disseminate, expensive to maintain, and inconvenient for the recipient. In contrast, Internet-based behavior change interventions can be disseminated widely at a lower cost. However, the impact of some Internet-mediated programs is limited by high attrition rates. Online communities that allow participants to communicate with each other by posting and reading messages may decrease participant attrition. OBJECTIVE: Our objective was to measure the impact of adding online community features to an Internet-mediated walking program on participant attrition and average daily step counts. METHODS: This randomized controlled trial included sedentary, ambulatory adults who used email regularly and had at least 1 of the following: overweight (body mass index [BMI] ≥ 25), type 2 diabetes, or coronary artery disease. All participants (n = 324) wore enhanced pedometers throughout the 16-week intervention and uploaded step-count data to the study server. Participants could log in to the study website to view graphs of their walking progress, individually-tailored motivational messages, and weekly calculated goals. Participants were randomized to 1 of 2 versions of a Web-based walking program. Those randomized to the "online community" arm could post and read messages with other participants while those randomized to the "no online community" arm could not read or post messages. The main outcome measures were participant attrition and average daily step counts over 16 weeks. Multiple regression analyses assessed the effect of the online community access controlling for age, sex, disease status, BMI, and baseline step counts. RESULTS: Both arms significantly increased their average daily steps between baseline and the end of the intervention period, but there were no significant differences in increase in step counts between arms using either intention-to-treat or completers analysis. In the intention-to-treat analysis, the average step count increase across both arms was 1888 ± 2400 steps. The percentage of completers was 13% higher in the online community arm than the no online community arm (online community arm, 79%, no online community arm, 66%, P = .02). In addition, online community arm participants remained engaged in the program longer than no online community arm participants (hazard ratio = 0.47, 95% CI = 0.25 - 0.90, P = .02). Participants with lower baseline social support posted more messages to the online community (P < .001) and viewed more posts (P < .001) than participants with higher baseline social support. CONCLUSION: Adding online community features to an Internet-mediated walking program did not increase average daily step counts but did reduce participant attrition. Participants with low baseline social support used the online community features more than those with high baseline social support. Thus, online communities may be a promising approach to reducing attrition from online health behavior change interventions, particularly in populations with low social support. TRIAL REGISTRATION: NCT00729040; http://clinicaltrials.gov/ct2/show/NCT00729040 (Archived by WebCite at http://www.webcitation.org/5v1VH3n0A).

Antithrombotic therapy for the CardioWest temporary total artificial heart.

The CardioWest temporary total artificial heart serves as a viable bridge to orthotopic heart transplantation in patients who are experiencing end-stage refractory biventricular heart failure. This device is associated with a low, albeit still substantial, risk of thrombosis. Platelet interactions with artificial surfaces are complex and result in continuous activation of contact proteins despite therapeutic anticoagulation. We searched the medical literature (publication dates, January 1962-October 2009) in order to evaluate means of mitigating adverse events that have occurred after implantation of the CardioWest temporary total artificial heart.We conclude that the use of a multitargeted antithrombotic approach, involving anticoagulation (bivalirudin and warfarin) and antiplatelet therapy (dipyridamole and aspirin), can mitigate the procoagulative effects of mechanical circulatory assist devices, particularly those that are associated with the CardioWest temporary total artificial heart. Careful monitoring with use of a variant multisystem approach, involving efficacy tests (thrombelastography and light transmittance aggregometry), safety tests (laboratory analyses), and warfarin genomics, may maximize the therapeutic actions and minimize the bleeding risks that are associated with the multitargeted antithrombotic approach. The development and monitoring of individualized antithrombotic regimens require that informed health professionals appreciate the complexities and grasp the hazards that are associated with these therapies.

Barriers encountered during enrollment in an internet-mediated randomized controlled trial.

BACKGROUND: Online technology is a promising resource for conducting clinical research. While the internet may improve a study's reach, as well as the efficiency of data collection, it may also introduce a number of challenges for participants and investigators. The objective of this research was to determine the challenges that potential participants faced during the enrollment phase of a randomized controlled intervention trial of Stepping Up to Health, an internet-mediated walking program that utilized a multi-step online enrollment process. METHODS: We conducted a quantitative content analysis of 623 help tickets logged in a participant management database during the enrollment phase of a clinical trial investigating the effect of an automated internet-mediated walking intervention. Qualitative coding was performed by two trained coders, and 10% of the sample was coded by both coders to determine inter-coder reliability. Quantitative analyses included standard descriptive statistics on ticket characteristics and theme frequency, and a Poisson regression analysis identified characteristics of potential participants who reported more frequent problems during enrollment. RESULTS: In total, 880 potential participants visited the study website and 80% completed the enrollment screening. Of the potential participants who visited the study website, 38% had help tickets logged in the participant management database. The total number of help tickets associated with individual potential participants ranged from 0 to 7 (M = .71). Overall, 46% of help tickets were initiated by email and 54% were initiated by phone. The most common help ticket theme was issues related to the study process (48%). The next most prominent theme was discussion related to obtaining medical clearance (34%), followed by issues related to pedometers and uploading (31%). Older individuals, women, and those with lower self-rated internet ability were more likely to report problems during the enrollment process. CONCLUSION: Prospective participants in an online clinical trial encountered a number of barriers to enrollment that led them to request help from study staff. Questions about the complex enrollment process itself were common. In a complex multi-step enrollment process, providing personalized feedback to potential participants indicating their status within the enrollment process may be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT00729040.

Induction immunosuppression for orthotopic heart transplantation: a review.

OBJECTIVES: To describe the appropriateness and safety of induction immunosuppression for patients at risk for fatal rejection, and to describe the safety and effectiveness profiles of the induction regimens available in the United States. DATA SOURCES: MEDLINE/PubMed database, EMBASE database, Google Scholar; references from pertinent articles were also reviewed to identify additional data. STUDY SELECTION: A systematic literature review from January 1, 1980, through June 30, 2008, was performed. Included articles ranged from case series to prospective randomized controlled double-blind placebo-controlled trials that detailed the following topics with respect to induction immunosuppression: risk of fatal rejection, renal sparing, malignancy, OKT3, rabbit or equine antithymocyte globulin, daclizumab, basiliximab, and alemtuzumab. RESULTS: Patients at highest risk for fatal rejection experienced a survival benefit from induction immunosuppression, whereas all other patients experienced no benefit or harm. Most of the early data detail positive experiences with polyclonal antibody regimens. Several newer trials compare the use of polyclonal strategies with the use of anti-CD25 targeted monoclonal antibodies. Few researchers have assessed the usefulness of an anti-CD52 approach. Overall, induction therapy remains a poorly studied and widely variable practice among the major US heart transplant centers. CONCLUSION: At present, the unrestricted use of induction for all patients does not seem prudent. Induction should be individualized for each patient on the basis of a well-designed protocol, careful analysis of the transplant center's demographics, and the effectiveness and safety profiles of the regimens used.