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Background: Achieving a therapeutic international normalized ratio (INR) before hospital discharge is an important inpatient goal for patients undergoing mechanical cardiac valve replacement (MCVR). The use of clinical algorithms has reduced the time to achieve therapeutic INR (TTI) with warfarin therapy. Whether TTI prolongs length of stay (LOS) is unknown., Methods: Patients who underwent MCVR over a consecutive 42-month period were included. Clinical data were obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery database and electronic medical records. Therapeutic INR was defined as per standard guidelines. Warfarin dose was prescribed using an inpatient pharmacy-managed algorithm and computer-based dosing tool. International normalized ratio trajectory, procedural needs, and drug interactions were included in warfarin dose determination., Results: There were 708 patients who underwent MCVR, of which 159 were excluded for reasons that would preclude or interrupt warfarin use. Among the remainder of 549 patients, the average LOS was 6.4days and mean TTI was 3.5days. Landmark analysis showed that subjects in hospital on day 4 (n=542) who achieved therapeutic INR were more likely to be discharged by day 6 compared with those who did not achieve therapeutic INR (75% vs 59%, P<.001). Multivariable proportional hazards regression with TTI as a time-dependent effect showed a strong association with discharge (P=.0096, hazard ratio1.3) after adjustment for other significant clinical covariates., Conclusions: Time to achieve therapeutic INR is an independent predictor of LOS in patients requiring anticoagulation with warfarin after MCVR surgery. Alternative dosing and anticoagulation strategies will need to be adopted to reduce LOS in these patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Progressive renal failure is a frequent complication after heart transplantation (HTx). It may result in end-stage renal disease (ESRD), prompting consideration of kidney Tx after HTx (KAH)., Methods: We performed a retrospective single-center study of 268 HTx recipients to evaluate outcomes after KAH compared with HTx recipients with and without ESRD., Results: During a median follow-up of 76 months, ESRD developed in 51 patients (19), and 39 of them (76%) underwent KAH. The mean time from HTx to ESRD was 83 months. The incidence of switching to a calcineurin inhibitor (CNI)-free regimen based on sirolimus was significantly lower among recipients with ESRD (6% vs 57%, p = 0.0001), and prolonged exposure to CNI significantly increased the risk for ESRD (hazard ratio, 1.09; 95% confidence interval, 1.03-1.15; p < 0.005). Death-censored renal graft survival after KAH was 95%, 95%, and 83% at 1, 5, and 10 years, respectively. Median long-term survival of KAH patients was comparable to HTx recipients without ESRD (17.5 vs 17.1 years, p = 0.27) and significantly better compared with HTx recipients with ESRD (17.5 vs 7.3 years, p < 0.001)., Conclusions: Prolonged exposure to CNI immunosuppression medications significantly increases the risk for ESRD among HTx recipients. KAH is a good therapeutic option for HTx recipients with ESRD, with survival benefit comparable to HTx without ESRD., (Copyright © 2017. Published by Elsevier Inc.)

Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.

The aim of this study was to evaluate the impact of continuous-flow left ventricular assist devices (CF-LVAD) on subsequent rejection after heart transplantation (HT) by using cellular rejection score and antibody-mediated rejection score (AMRS) and correlating with subsequent allograft outcomes. We retrospectively analyzed 108 consecutive patients who underwent HT without (n = 67) or with (n = 41) previous CF-LVAD in 2008 to 2014. The 24 months cumulative effect of rejection was calculated by using cellular rejection scores and AMRS, based on the total number of rejections divided by valid biopsy samples. Vasculopathy was assessed both by routine coronary angiogram and intravascular ultrasound. Patients who underwent pretransplant CF-LVAD demonstrated a significant increase in the number of cellular rejection episodes as compared with the nonbridged patients, for 1 and 2 years of follow-up (p = 0.026 and p = 0.016), respectively. There were no differences in AMRS (p >0.05) and allograft outcomes, such as vasculopathy and overall survival (p >0.05) over the period of follow-up. Implantation of a CF-LVAD before HT impacts cellular rejection during the post-transplant period. Despite these findings, CF-LVAD does not translate to differences in allograft outcomes after transplant, such as vasculopathy and overall survival over the period of the study. In conclusion, whether this affects longer term outcomes than studied remains to be determined., (Copyright © 2016 Elsevier Inc. All rights reserved.)

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: This study evaluated changes in serum levels of galectin (Gal)-3 before and after heart transplantation (HTx) and assessed the role of pre-HTx Gal-3 as a biomarker for post-HTx outcomes., Background: Gal-3 is a novel biomarker that reflects cardiac remodeling and fibrosis. Elevated serum Gal-3 levels are associated with poor prognosis in heart failure patients. Whether Gal-3 levels change following HTx and the significance of post-HTx outcomes are unknown., Methods: Serum Gal-3 levels were measured in 62 patients at 118 days (Interquartile Range [IQR]: 23 to 798 days) before and 365 days (IQR: 54 to 767 days) post HTx. Cardiac tissue taken during routine post-HTx endomyocardial biopsy was evaluated to assess the correlation between tissue Gal-3 staining and serum Gal-3 levels and with the presence of myocardial hypertrophy and fibrosis., Results: Serum Gal-3 levels remained significantly elevated (>17.8 ng/ml) in 35 patients (56%) post HTx. There was a significant inverse correlation between Gal-3 levels and glomerular filtration rate measured before and after HTx (p > 0.005). There was no association between Gal-3 serum level and Gal-3 staining of myocardial tissue or with the presence of myocyte hypertrophy and interstitial fibrosis post HTx. Elevated pre-HTx Gal-3 levels were associated with reduced post-HTx exercise capacity, but this association was not significant after adjustment for age, body mass index, and glomerular filtration rate., Conclusions: This is the first study to demonstrate the fact that Gal-3 levels remain elevated in the majority of patients despite HTx and is associated with renal dysfunction. Our findings suggest Gal-3 is a systemic rather than cardiac-specific biomarker., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Annona coriacea Mart. (araticum) is a widely distributed tree in the cerrado. Its value is attributed principally to the consumption of its fruit which possesses a large nutritive potential. The objective was to identify the chemical profile and evaluate the antimicrobial and cytoprotective activity of the hydroethanol extract of A. coriacea Mart. (HEAC) leaves against the toxicity of mercury chloride., Materials and Methods: The characterization of components was carried out using high-performance liquid chromatography (HPLC). The minimum inhibitory concentration (MIC) was determined by microdilution method in broth with strains of Staphylococcus aureus , Escherichia coli , and Pseudomonas aeruginosa . For evaluation of the modulatory and cytoprotective activity of aminoglycoside antibiotics (gentamicin and amikacin) and mercury chloride (HgCl 2 ), the substances were associated with the HEAC at subinhibitory concentrations (MIC/8)., Results and Discussion: The HPLC analysis revealed the presence of flavonoids such as Luteolin (1.84%) and Quercetin (1.19%) in elevated concentrations. The HEAC presented an MIC ≥512 μg/mL and significant antagonistic action in aminoglycosides modulation, and it also showed cytoprotective activity to S. aureus (significance P < 0.0001) and E. coli (significance P < 0.05) bacteria against the mercury chloride heavy metal with significance, this action being attributed to the chelating properties of the flavonoids found in the chemical identification., Conclusions: The results acquired in this study show that the HEAC presents cytoprotective activity over the tested strains in vitro and can also present antagonistic effect when associated with aminoglycosides, reinforcing the necessity of taking caution when combining natural and pharmaceutical products., Summary: The hydroalcoholic extract of A. coriacea Mart. presents in vitro cytoprotective activity against the toxic effect of Hg. Abbreviations Used : HPLC-DAD: High-performance liquid chromatography with a diode array detector; MIC: Minimum inhibitory concentration; DMSO: Dimethyl sulfoxide.

Background: Left ventricular assist devices (LVADs) improve survival, quality of life (QOL), and functional capacity (FC) among patients with end-stage heart failure. Few data are available regarding characteristics associated with QOL and FC response., Methods and Results: Patients enrolled in the Heartmate II clinical trials that were alive with ongoing LVAD support at 6 months were included. QOL response criteria included scoring above the lowest quartile on either the Minnesota Living With Heart Failure Questionnaire or the Kansas City Cardiomyopathy Questionnaire. FC responder criteria included improvement in 6-minute walk distance (6MWD) >70 meters from baseline, a 6MWD >220 meters at 6 months, or New York Heart Association functional class I or II. Independent variables associated with QOL nonresponse included history of diabetes (odds ratio [OR] 1.82, 95% confidence interval [CI] 1.20-2.78), lower mean pulmonary arterial pressure (OR 0.97, 95% CI 0.95-0.99), or a Heartmate II right ventricular risk score >2 (OR 1.77, 95% CI 1.00-3.12). Variables associated with FC nonresponse included history of COPD (OR 1.92, 95% CI 1.22-3.03) or diabetes (OR 1.52, 95% CI 1.01-2.27). Compared with responders, QOL and FC nonresponders had reduced long-term survival., Conclusions: Preoperative comorbidities, including diabetes, COPD, and right heart failure, may limit the QOL and FC response to LVAD therapy and should be considered during the shared decision-making process., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients., Methods: The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx)., Results: Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx ( P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men ( P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012)., Conclusions: Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV., Competing Interests: The authors declare no conflicts of interest.

Myocarditis is a polymorphic disease characterized by great variability in clinical presentation and evolution. Patients presenting with severe left ventricular dysfunction and life-threatening arrhythmias represent a demanding challenge for the clinician. Modern techniques of cardiovascular imaging and the exhaustive molecular evaluation of the myocardium with endomyocardial biopsy have provided valuable insight into the pathophysiology of this disease, and several clinical registries have unraveled the disease's long-term evolution and prognosis. However, uncertainties persist in crucial practical issues in the management of patients. This article critically reviews current information for evidence-based management, offering a rational and practical approach to patients with myocarditis. For this review, we searched the PubMed and MEDLINE databases for articles published from January 1, 1980, through December 31, 2015, using the following terms: myocarditis, inflammatory cardiomyopathy, and endomyocardial biopsy. Articles were selected for inclusion if they represented primary data or were review articles published in high-impact journals. In particular, a risk-oriented approach is proposed. The different patterns of presentation of myocarditis are classified as low-, intermediate-, and high-risk syndromes according to the most recent evidence on prognosis, clinical findings, and both invasive and noninvasive testing, and appropriate management strategies are proposed for each risk class., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Neurohormonal blockade drug therapy (NHBDT) is the cornerstone therapy in heart failure (HF) management for promoting reverse cardiac remodeling and improving outcomes. It's utility in left ventricular assist device (LVAD) supported patients remains undefined. Sixty-four patients who received continuous flow LVAD at our institution were retrospectively reviewed and divided into 2 groups: no-NHBDT group (n = 33) received LVAD support only and NHBDT group (n = 31) received concurrent NHBDT based on the clinical judgment of the attending physicians. Cardiac remodeling (echocardiographic parameters and biomarkers) and clinical outcome (functional status, HF-related hospital readmissions, and mortality) data were collected. A statistically significant increase in ejection fraction, decrease in LV end-diastolic diameter index and LV mass index, and a sustained reduction in N-terminal pro B-type natriuretic peptide (NTproBNP) were observed in the NHBDT group at 6 months after LVAD implant (p <0.05). NHBDT-treated patients experienced significantly greater improvement in New York Heart Association functional classification and 6-minute-walk distance throughout the study. The combined end point of cardiovascular death or HF hospitalization was significantly reduced in patients receiving NHBDT (p = 0.013) associated primarily with a 12.1% absolute reduction in HF-related hospitalizations (p = 0.046). In conclusion, NHBDT in LVAD-supported patients is associated with a significant reversal in adverse cardiac remodeling and a reduction in morbidity and mortality compared with LVAD support alone., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Computerized survival prediction in healthcare identifying the risk of disease mortality, helps healthcare providers to effectively manage their patients by providing appropriate treatment options. In this study, we propose to apply a classification algorithm, Contrast Pattern Aided Logistic Regression (CPXR(Log)) with the probabilistic loss function, to develop and validate prognostic risk models to predict 1, 2, and 5year survival in heart failure (HF) using data from electronic health records (EHRs) at Mayo Clinic. The CPXR(Log) constructs a pattern aided logistic regression model defined by several patterns and corresponding local logistic regression models. One of the models generated by CPXR(Log) achieved an AUC and accuracy of 0.94 and 0.91, respectively, and significantly outperformed prognostic models reported in prior studies. Data extracted from EHRs allowed incorporation of patient co-morbidities into our models which helped improve the performance of the CPXR(Log) models (15.9% AUC improvement), although did not improve the accuracy of the models built by other classifiers. We also propose a probabilistic loss function to determine the large error and small error instances. The new loss function used in the algorithm outperforms other functions used in the previous studies by 1% improvement in the AUC. This study revealed that using EHR data to build prediction models can be very challenging using existing classification methods due to the high dimensionality and complexity of EHR data. The risk models developed by CPXR(Log) also reveal that HF is a highly heterogeneous disease, i.e., different subgroups of HF patients require different types of considerations with their diagnosis and treatment. Our risk models provided two valuable insights for application of predictive modeling techniques in biomedicine: Logistic risk models often make systematic prediction errors, and it is prudent to use subgroup based prediction models such as those given by CPXR(Log) when investigating heterogeneous diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In this study we examined the impact of continuous-flow left ventricular assist device (CF-LVAD) support on proximal thoracic aorta dimensions., Methods: Aortic root and ascending aorta diameter were measured from serial echocardiograms before and after CF-LVAD implantation in patients with ≥6 months of support, and correlated with the development of >mild aortic valve insufficiency (AI)., Results: Of 162 patients included, mean age was 58 ± 11 years and 128 (79%) were male. Seventy-nine (63%) were destination therapy patients. Mean aortic root and ascending aorta diameters at baseline, 1 month, 6 months, 12 months and long-term follow-up (mean 2.0 ± 1.4 years) were 3.5 ± 0.4, 3.5 ± 0.3, 3.9 ± 0.3, 3.9 ± 0.2 and 4.0 ± 0.3, and 3.3 ± 0.2, 3.3 ± 0.3, 3.6 ± 0.2, 3.6 ± 0.3 and 3.6 ± 0.3 cm, respectively. Only change in aortic root diameter from 1-month to 6-month follow-up reached statistical significance (p = 0.03). Nine (6%) patients had accelerated proximal thoracic aorta expansion (>0.5 cm/year), occurring predominantly in the first 6 months after implantation. These patients were older and more likely to have hypertension and baseline proximal thoracic aorta dilation. Forty-five (28%) patients developed >mild AI at long-term follow-up, including 7 of 9 (78%) of those with accelerated proximal thoracic aorta expansion. All 7 had aortic valves that remained closed throughout the cardiac cycle, and this, along with duration of CF-LVAD support and increase in aortic root diameter, were significantly associated with developing >mild AI., Conclusion: CF-LVAD patients have small increases in proximal thoracic aorta dimensions that predominantly occur within the first 6 months after implantation and then stabilize. Increasing aortic root diameter was associated with AI development., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Identifying populations of heart failure (HF) patients is paramount to research efforts aimed at developing strategies to effectively reduce the burden of this disease. The use of electronic medical record (EMR) data for this purpose is challenging given the syndromic nature of HF and the need to distinguish HF with preserved or reduced ejection fraction. Using a gold standard cohort of manually abstracted cases, an EMR-driven phenotype algorithm based on structured and unstructured data was developed to identify all the cases. The resulting algorithm was executed in two cohorts from the Electronic Medical Records and Genomics (eMERGE) Network with a positive predictive value of >95 %. The algorithm was expanded to include three hierarchical definitions of HF (i.e., definite, probable, possible) based on the degree of confidence of the classification to capture HF cases in a whole population whereby increasing the algorithm utility for use in e-Epidemiologic research.

Consensus practice guidelines and the implementation of clinical therapeutic advances are usually based on the results of large, randomized clinical trials (RCTs). However, RCTs generally inform us on an average treatment effect for a presumably homogeneous population, but therapeutic interventions rarely benefit the entire population targeted. Indeed, multiple RCTs have demonstrated that interindividual variability exists both in drug response and in the development of adverse effects. The field of pharmacogenomics promises to deliver the right drug to the right patient. Substantial progress has been made in this field, with advances in technology, statistical and computational methods, and the use of cell and animal model systems. However, clinical implementation of pharmacogenetic principles has been difficult because RCTs demonstrating benefit are lacking. For patients, the potential benefits of performing such trials include the individualization of therapy to maximize efficacy and minimize adverse effects. These trials would also enable investigators to reduce sample size and hence contain costs for trial sponsors. Multiple ethical, legal, and practical issues need to be considered for the conduct of genotype-based RCTs. Whether pre-emptive genotyping embedded in electronic health records will preclude the need for performing genotype-based RCTs remains to be seen.

Background: Restrictive cardiomyopathy (RCM) patients have poor prognosis due to progressive heart failure characterized by impaired ventricular filling of either or both ventricles. The goal of this study was to evaluate the outcome of end-stage RCM patients after left ventricular assist device (LVAD) implantation and to determine factors that may be associated with improved survival., Methods: This investigation is a retrospective study of prospectively collected data that include 28 consecutive patients with end-stage RCM who received continuous-flow LVADs at the Mayo Clinic, Rochester, Minnesota. Outcome was assessed by survival with LVAD support until heart transplantation or all-cause mortality., Results: The mean follow-up time post-LVAD implantation was 448 ± 425 days. The mean hospitalization time was 29 ± 19 days and was complicated mainly by post-operative right ventricular (RV) failure requiring short-term medical support. The short-term in-hospital mortality was 14%. Ten patients underwent heart transplantation with 100% survival post-transplant during the follow-up period. One-year survival for patients with LVADs without transplantation was 64%, and was not significantly different between amyloidosis and non-amyloidosis patients. Larger left ventricle (LV) end-diastolic and end-systolic dimensions were significantly associated with improved survival rates (RR = 0.94 and 0.95, p < 0.05, respectively), and left ventricular end-diastolic diameter (LVEDD) ≤46 mm was associated with increased mortality post-LVAD implantation., Conclusions: LVAD is a feasible, life-saving therapy for end-stage heart failure related to RCM, especially as a bridge to transplant and in patients with larger LV dimensions., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility., Methods and Results: Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP1-98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein (P=0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P<0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P=0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P=0.004)., Conclusions: This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA-NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community., (© 2014 American Heart Association, Inc.)

Electronic Health Records (EHRs) contain a wealth of information about an individual patient's diagnosis, treatment and health outcomes. This information can be leveraged effectively to identify patients who are similar to each for disease diagnosis and prognosis. In recent years, several machine learning methods have been proposed to assessing patient similarity, although the techniques have primarily focused on the use of patient diagnoses data from EHRs for the learning task. In this study, we develop a multidimensional patient similarity assessment technique that leverages multiple types of information from the EHR and predicts a medication plan for each new patient based on prior knowledge and data from similar patients. In our algorithm, patients have been clustered into different groups using a hierarchical clustering approach and subsequently have been assigned a medication plan based on the similarity index to the overall patient population. We evaluated the performance of our approach on a cohort of heart failure patients (N=1386) identified from EHR data at Mayo Clinic and achieved an AUC of 0.74. Our results suggest that it is feasible to harness population-based information from EHRs for an individual patient-specific assessment.

Left ventricular assist devices (LVADs) acutely decrease left ventricular wall stress. Thus, early postoperative levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) should decrease. This study investigated postoperative changes in NT-proBNP levels, the parameters related to changes, and the possible association with complications by performing a retrospective analysis of changes in daily NT-proBNP (pg/ml) levels from admission to discharge both before and after LVAD implantation in a tertiary referral center. For 72 patients implanted with HeartMate II LVADs, baseline NT-proBNP levels were elevated at 3,943 ng/ml (interquartile range 1,956 to 12,964). Preoperative stabilization led to marked decreases in NT-proBNP. Levels peaked 3 days after surgery and subsequently decreased. Patients with complicated postoperative courses had higher early postoperative elevations. By discharge, NT-proBNP decreased markedly but was still 2.83 (1.60 to 5.76) times the age-based upper limit of normal. The 26% reduction in NT-proBNP between admission and discharge was due mostly to the preoperative reductions and not those induced by the LVAD itself. The decrease was not associated with decreases in LV volume. In conclusion, preoperative treatment reduces NT-proBNP values. The magnitude of early postoperative changes is related to the clinical course. Levels at discharge remain markedly elevated and similar to values after preoperative stabilization despite presumptive acute LV unloading., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cardiac output (CO) assessment is important in treating patients with heart failure. Durable left ventricular assist devices (LVADs) provide essentially all CO. In currently used LVADs, estimated device flow is generated by a computerized algorithm. However, LVAD flow estimate may be inaccurate in tracking true CO. We correlated LVAD (HeartMate II) flow with thermodilution CO during postoperative care (day 2-10 after implant) in 81 patients (5,616 paired measurements). Left ventricular assist device flow and CO correlated with a low correlation coefficient (r = 0.42). Left ventricular assist device readings were lower than CO measurements by approximately 0.36 L/min, trending for larger difference with higher values. Left ventricular assist device flow measurements showed less temporal variability compared with CO. Grouping for simultaneous measured blood pressure (BP < 60, 60-70, 70-80, 80-90, and ≥90), the correlation of CO with LVAD flow differed (R = 0.42, 0.67, 0.48, 0.32, 0.32, respectively). Indicating better correlation when mean blood pressure is 60 to 70 mm Hg. Left ventricular assist device flow generally trends with measured CO, but large variability exists, hence flow measures should not be assumed to equal with CO. Clinicians should take into account variables such as high CO, BP, and opening of the aortic valve when interpreting LVAD flow readout. Direct flow sensors incorporated in the LVAD system may allow for better estimation.

Background: Reduced exercise tolerance from impaired cardiac output is an important criterion for left ventricular assist device (LVAD) implantation. However, little is known about how exercise capacity changes after LVAD and how changes compare with patients undergoing heart transplantation., Methods and Results: We compared changes in cardiopulmonary exercise testing performed pre- and postoperatively in patients who underwent HeartMate II LVAD implantation (n = 25) and heart transplantation (n = 74) at the Mayo Clinic in Rochester, Minnesota, between 2007 and 2012. Preoperatively, patients undergoing LVAD and transplant had markedly reduced exercise time (mean 5.1 minutes [45% predicted] and 5.0 minutes [44% predicted], respectively), low peak oxygen consumption (VO2; mean 11.5 mL · kg · min [43% predicted] and 11.9 mL · kg · min [38% predicted]), and abnormal ventilatory gas exchange (ratio of minute ventilation to carbon dioxide production [VE/VCO2] nadir 39.4 and 37.4). After LVAD and transplant, there were similar improvements in exercise time (mean Δ +1.2 vs. 1.7 minutes, respectively, P = .27) and VE/VCO2 nadir (mean Δ -3.7 vs. -4.2, P = .74). However, peak VO2 increased posttransplant but did not change post-LVAD (mean Δ +5.4 vs. +0.9 mL · kg · min, respectively, P < .001). Most patients (72%) had a peak VO2 < 14 mL · kg · min post-LVAD., Conclusions: Although improvements in exercise capacity and gas exchange are seen after LVAD and heart transplant, peak VO2 doesn't improve post-LVAD and remains markedly abnormal in most patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Acute allograft dysfunction (AAD) is an important cause of morbidity among heart transplant recipients. The role of donor-specific antibodies (DSAs) in AAD, with the increasing use of single antigen bead (SAB) assays that have improved the ability to detect DSA, remains unclear., Methods: We retrospectively reviewed 329 heart transplant recipients followed up at our institution. AAD was defined as an acute decline in left ventricular ejection fraction to less than 50% and a decrement of 10% or higher compared to baseline in the absence of cellular rejection. Patients with AAD were compared with matched 30 heart transplant controls., Results: There were 10 (3%) patients with AAD, 4 (40%) had DSA detectable by SAB assay compared to 16 (53%) controls (P=0.43). Peak DSA mean fluorescent intensity (MFI) levels were significantly higher at baseline (class I and class II) in AAD compared to controls. DSA MFI values increased at the time of AAD and returned to baseline values during follow-up for these patients with AAD (P<0.05) but remained unchanged over time for controls. Six (60%) patients with AAD and 1 (3%) control had antibody-mediated rejection (AMR) by endomyocardial biopsy (P<0.01). There were 4 (40%) patients with AAD with no DSA or AMR., Conclusions: AAD after heart transplant is a heterogeneous process characterized by 1) AMR and DSA, 2) AMR but no DSA, and 3) no AMR or DSA. The presence of DSA is not associated with AAD, but the quantity assessed by MFI levels may play a role.

Dowling-Degos disease is a rare sporadic or autosomal dominant pigmentary entity, in which clusters of papules and reticulate macules slowly develop with predominance in flexural regions. This entity is due to mutations in the keratin 5 gene, and is related with other cutaneous disorders. We report the sporadic form of Dowling-Degos disease in an elderly man with multiple seborrheic keratosis in a "Christmas tree" pattern. Worthy of note in this case study is the lesions evolved for over than 30 years. The aim is to describe the association of these keratoses with Dowling-Degos disease in a healthy man.

Heart failure (HF) is an important public health problem, and strategies are needed to improve outcomes and decrease health care resource utilization and costs. Its prevalence has increased as the population ages, and HF continues to be associated with a high mortality rate and frequent need for hospitalization. The total cost of care for patients with HF was $30.7 billion in 2012, and it is estimated to more than double to $69.8 billion by 2030. Given this reality, there has been recent investigation into ways of identifying and preventing HF in patients at risk (stage A HF) and those with cardiac structural and functional abnormalities but no clinical HF symptoms (stage B). For patients who have symptoms of HF (stage C), there has been important research into the most effective ways to decongest patients hospitalized with acute decompensated HF and prevent future hospital readmissions. Successful strategies to treat patients with HF and preserved ejection fraction, which has increased in prevalence, continue to be sought. We are in the midst of a rapid evolution in our ability to care for patients with end-stage HF (stage D) because of the introduction of and improvements in mechanical circulatory support. Left ventricular assist devices used as destination therapy offer an important therapeutic option to patients who do not qualify for heart transplant because of advanced age or excessive comorbidity. This review provides a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged during the past several years., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Increased interventricular septal (IVS) thickness on echocardiography is a diagnostic criterion for cardiac amyloidosis and classically precedes decrement in left ventricular ejection fraction (LVEF). The investigators describe patients with histologically confirmed cardiac amyloidosis who had significant myocardial dysfunction (LVEF ≤ 40%) despite having normal IVS thickness., Methods: All patients with systemic amyloidosis and LVEFs ≤ 40% were analyzed to identify the prevalence of normal IVS thickness. Patients with known histories of cardiomyopathy or coronary artery disease were excluded. Histologic evaluation of tissue included assessment of amyloid burden and average myocyte diameter., Results: There were 255 patients with amyloidosis with LVEFs ≤ 40%, of whom seven (3%) had normal IVS thickness and histologic confirmation of cardiac involvement. Of these, six had immunoglobulin light chain amyloidosis, and one had senile amyloidosis. A majority of patients (86%) presented with new-onset cardiac dysfunction associated with edema and/or dyspnea. Electrocardiographic findings included low voltage (43%) and a pseudoinfarct pattern (29%). The 1-year survival from initial tissue diagnosis in the cohort with normal IVS thickness was similar to matched patients with amyloidosis with increased IVS thickness and LVEF ≤ 40% (21% vs 18%, respectively, P = .32). Myocardial tissue amyloid burden and average myocyte diameter were significantly reduced in cases compared with controls., Conclusions: Cardiac amyloidosis can uncommonly present with normal IVS thickness despite significant myocardial dysfunction. The prognosis of these patients is as poor as those with increased IVS thickness. Amyloidosis should be considered in the differential diagnosis of patients with cardiomyopathy and reduced LVEFs despite normal IVS thickness., (Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Objectives: To evaluate the impact of a functional genetic variant in the natriuretic peptide clearance receptor, NPR3, on circulating natriuretic peptides (NPs) and myocardial structure and function in the general community., Background: NPR3 plays an important role in the clearance of NPs and through direct signaling mechanisms modulates smooth muscle cell function and cardiac fibroblast proliferation. A NPR3 nonsynonymous single nucleotide polymorphism (SNP) rs2270915, resulting in a N521D substitution in the intracellular catalytic domain that interacts with Gi could affect receptor function. Whether this SNP is associated with alterations in NPs levels and altered cardiac structure and function is unknown., Methods: DNA samples of 1931 randomly selected residents of Olmsted County, Minnesota were genotyped. Plasma NT-proANP1-98, ANP1-28, proBNP1-108, NT-proBNP1-76, BNP1-32 and BNP3-32 levels were measured. All subjects underwent comprehensive echocardiography., Results: Genotype frequencies for rs2270915 were as follows: (A/A 60%, A/G 36%, G/G 4%). All analyses performed were for homozygotes G/G versus wild type A/A plus the heterozygotes A/G. Diastolic dysfunction was significantly more common (p = 0.007) in the homozygotes G/G (43%) than the A/A+A/G (28%) group. Multivariate regression adjusted for age, sex, body mass index and hypertension demonstrated rs2270915 to be independently associated with diastolic dysfunction (odds ratio 1.94, p = 0.03). There was no significant difference in NPs levels between the 2 groups suggesting that the clearance function of the receptor was not affected., Conclusions: A nonsynonymous NPR3 SNP is independently associated with diastolic dysfunction and this association does not appear to be related to alterations in circulating levels of natriuretic peptides.

Continuous flow left ventricular assist devices (LVADs) are used with good outcome. However, acute intravascular hemolysis due to thrombus in the pump remains a clinical challenge. We screened for LVAD-related intravascular hemolysis among 115 consecutive patients surviving HeartMateII implantation and investigated the role of medical therapy in resolving the hemolysis. Hemolytic events were identified in 7% of patients, 2-26 months after implant, manifested by peak lactate dehydrogenase (LDH) levels >6 times normal. With the institution of heparin and enhanced antiplatelet therapy, LDH levels receded rapidly reaching a stable trough level near baseline within 2 weeks with the resolution of clinical symptoms except in one patient who required additional therapy with tissue plasminogen activator (tPA). Complications included transient renal failure, one splenic infarct, and a cerebrovascular attack after tPA. The acute event of hemolysis resolved with medical therapy, and all were successfully discharged. However, recurrent hemolysis was common (6/8 patients over the next 1-7 months). At the end of follow-up, three patients were transplanted, one patient died refusing LVAD exchange for recurrent hemolysis, and 4 remained alive on LVAD support. Medical treatment with intensification of anticoagulation can be effective in resolving the acute hemolytic event. However, a definitive long-term strategy should be planned because the recurrence rate is high.

Objectives: Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA., Participants and Methods: We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies., Results: There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P<0.001), and the total rejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0)., Conclusion: HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.

Objectives: This study sought to characterize the echocardiographic findings of patients presenting with intravascular hemolysis (IVH) due to suspected continuous-flow left ventricular assist device (LVAD) pump thrombosis., Background: LVAD patients who develop pump thrombosis often present with IVH. Echocardiography may be able to detect device dysfunction in this setting., Methods: Continuous-flow LVAD patients presenting with IVH due to suspected pump thrombosis were identified. Patients underwent echocardiography with cannula Doppler flow velocity interrogation. Findings were compared with baseline and follow-up studies, and with 49 stable LVAD control patients., Results: Of 145 patients, 14 (10%) had IVH due to suspected pump thrombosis. The mean age was 55 ± 15 years, 93% were men, and 50% received LVAD as destination therapy. Mean duration between implantation and IVH was 231 ± 218 days. Eleven (79%) patients presented with hemoglobinuria, 9 (64%) with jaundice, and 5 (36%) with acute heart failure. Reduced cannula diastolic flow velocity and increased systolic/diastolic (S/D) flow velocity ratio were the only echocardiographic parameters significantly different from controls (outflow cannula 0.3 ± 0.2 m/s vs. 0.8 ± 0.3 m/s, p = 0.03, and 5.9 ± 2.8 vs. 1.7 ± 0.7, p < 0.01, respectively), and were worse for IVH patients with acute heart failure compared with those without (outflow cannula 0.2 ± 0.1 m/s vs. 0.5 ± 0.2 m/s, p = 0.04, and 7.2 ± 3.3 vs. 5.3 ± 2.0, p = 0.02, respectively). Outflow cannula diastolic flow velocity and S/D flow velocity ratio changed significantly from baseline (p = 0.01 and p < 0.01, respectively) in IVH patients, whereas systolic flow velocity did not change (p = 0.59). Odds ratios for outflow cannula diastolic flow velocity and S/D flow velocity ratio for predicting IVH were 0.60 (95% confidence interval [CI]: 0.51 to 0.73), p = 0.02, and 2.45 (95% CI: 2.37 to 2.52) p < 0.01, respectively. Corresponding inflow cannula values were similarly significant. Pump thrombosis was confirmed in 7 (50%) patients after LVAD retrieval., Conclusions: Reduced cannula diastolic flow velocity and increased S/D flow velocity ratio identified continuous-flow LVAD dysfunction in patients with IVH due to suspected pump thrombosis better than other echocardiographic parameters., (Copyright © 2013. Published by Elsevier Inc.)

Background: Left ventricular assist devices (LVAD) as a bridge (BTT) to heart transplantation (HTX) may be limited by the formation of anti-human leukocyte antigen antibodies. Whether sensitization occurs with continuous axial flow LVAD implant as assessed by single antigen bead (SAB) assay is unknown., Methods: Cytotoxic panel-reactive antibody (PRA) and SAB assays were analyzed in HTX recipients undergoing LVAD implant as a BTT. Sensitization was defined as peak anti-human leukocyte antigen antibody values of more than 2000 mean fluorescence intensity because these values have been found to correlate with flow cytometric crossmatch results., Results: LVADs were implanted as BTT in 30 patients. There were 7% (2 of 30) of patients before LVAD implant and no patients after LVAD implant with PRA more than 10%. However, 20% (6 of 30) of patients before LVAD and 53% (16 of 30) after LVAD were sensitized as measured by SAB (P=0.024). At HTX, 47% (14 of 30) of patients remained sensitized. A positive virtual crossmatch was observed in 28% (4 of 14) of the sensitized patients at HTX. There was no difference between the sensitized and nonsensitized groups (P>0.4 for all) in usage of blood products (6411 vs. 6339 units) and time to HTX (28,663 vs. 25,748 days), and 1 year after HTX, there were no differences in rejection (total rejection score 0.30 vs. 0.37) and survival (93% vs. 88%)., Conclusion: Allosensitization after LVAD is common despite cytotoxic PRA being negative. One year after HTX, this sensitization does not translate into increased acute cellular or antibody-mediated rejection or reduced survival.

Background: Proper identification of cardiac amyloid type is essential for patient management, and has historically relied upon immunohistochemical- or immunofluorescence-based methods, often correlated with serum and urine protein electrophoresis (SPEP and UPEP) with immunofixation electrophoresis (IFE), and/or free light chain immunoassay (FLC). The recent implementation of mass spectrometry-based proteomic analysis for clinical amyloid typing allows us to determine the validity of these tests to predict amyloid type. Validity of SPEP/UPEP/IFE and FLC assays in cardiac amyloid prediction was examined., Methods: Retrospective analysis of two tertiary care populations (n=143, 2001-2010), of cardiac biopsy-proven amyloidosis, was performed., Results: Amyloid of transthyretin (ATTR) type was found in 81 (57%) of 143 patients and immunoglobulin light chain amyloid was found in the remaining 62 (43%). SPEP/UPEP/IFE detected a monoclonal gammopathy in 76 individuals, 56 with AL and 20 with ATTR amyloid and was overall a poor predictor of AL amyloid in this patient population: specificity (75%; 95% CI, 65-83%) and positive predictive value (PPV 74%; 95% CI, 63-82%). The FLC assay detected an abnormal kappa/lambda ratio in 61 patients, 53 with AL and 8 with ATTR amyloid and was a better predictor of AL amyloid type in this patient population: specificity (90%, 95% CI, 82-95%) and PPV (87%, 95% CI, 76-93%)., Conclusions: ATTR was the predominant amyloid type in this large cohort of endomyocardial biopsies characterized by mass spectrometry. Although FLC performs better than SPEP/UPEP/IFE, the performance of blood and urine studies for monoclonal proteins are not adequate to classify amyloid type., Summary: This large-scale retrospective analysis of cardiac amyloidosis shows that blood and urine monoclonal protein studies are not, by themselves, robust predictors of cardiac amyloid type in patients undergoing endomyocardial biopsy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

BACKGROUND- The primary role of natriuretic peptide receptor-3 (NPR3) or NPR-C is in the clearance of natriuretic peptides that play an important role in modulating intravascular volume and vascular tone. Genetic variation in NPR3 has been associated with variation in blood pressure and obesity. Despite the importance of NPR3, sequence variation in the gene has not been addressed using DNA from different ethnic populations. We set out to identify and functionally characterize genetic variation in NPR3 in 3 ethnic groups. METHODS AND RESULTS- DNA samples from 96 European American, 96 African American, and 96 Han Chinese American healthy subjects were used to resequence NPR3 exons, splice junctions, and flanking regions. We identified 105 polymorphisms, 50 of which were novel, including 8 nonsynonymous single-nucleotide polymorphisms, 7 were novel. Expression constructs were created for the nonsynonymous single-nucleotide polymorphisms. HEK293 cells were transfected with constructs for wild type and variant allozymes; and recombinant proteins were measured by quantitative Western blot analysis. The most significant change in NPR3 protein was observed for the Arg146 variant allozyme, with 20% of wild-type protein, primarily because of autophagy-dependent degradation. NPR3 structural modeling confirmed that the Arg146 variant protein was not compatible with wild-type conformation and could result in protein misfolding or instability. CONCLUSIONS- Multiple novel NPR3 genetic polymorphisms were identified in 3 ethnic groups. The Arg146 allozyme displayed a significant decrease in protein quantity because of degradation mediated predominantly by autophagy. This genetic variation could have a significant effect on the metabolism of natriuretic peptides with potential clinical implications.

Background: We evaluated whether combined heart and liver transplant (H+LTx) can protect the heart graft from the development of cardiac allograft vasculopathy using coronary three-dimensional (3D) volumetric intravascular ultrasound (IVUS)., Methods: From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 H+LTx recipients in whom two coronary 3D IVUS studies were performed 1 year apart. Baseline 3D IVUS was performed at 0.22 (0.17-1.16) years after transplantation, with follow-up 3D IVUS exams performed after baseline exam (0.96 [0.83-1.08])., Results: Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+LTx group (0.3±1.1 vs. 1.5±2.9 mm/mm; P=0.08 and 0.01±0.03 vs. 0.1±0.1; P=0.004, respectively). Rejection burden was much lower in the H+LTx patients. Outcome analysis in 66 consecutive patients (56 HTx and 10 H+LTx) was performed irrespective of performance of second coronary IVUS. H+LTx was associated with reduced rate of cardiac events (P=0.04), which remained significant when adjusted for the difference in the primary etiology for heart disease (P=0.05)., Conclusions: Our preliminary serial 3D coronary IVUS data show that H+LTx attenuates cardiac allograft vasculopathy by decreasing the rate of plaque volume and plaque index progression and improves coronary-related outcomes. Because of the small numbers and the differences in etiology of heart disease, our data should be interpreted cautiously, and larger clinical trials would be required to recommend H+LTx for improved coronary remodeling.

Background: Although a link between donor-specific antibodies against human leukocyte antigens type II (DSA II+) and transplant glomerulopathy has been clearly established, its role in cardiac allograft vasculopathy (CAV) is unclear., Methods: Donor-specific antibodies were evaluated using solid-phase single-antigen bead assay before transplantation in 51 heart transplant recipients. Coronary angiography and three-dimensional intravascular ultrasound were performed at baseline and approximately 1 year after the baseline examination., Results: There were 4 (7.8 %), 11 (21.5%), and 2 (3.9%) patients who had DSA against donor class I (DSA I+), DSA II+, or both, respectively. All patients had negative complement-dependent cytotoxic crossmatch. There was accelerated progression of CAV in the DSA II+ group demonstrated by accelerated progression in plaque index (plaque volume/vessel volume) compared to patients with no DSA II+ antibodies (13.8% [12%] vs. -7.9% [37%], P=0.01). The development of any angiographic CAV was also more common in DSA II+ patients as compared to the DSA- patients at 4 years (100% [0%] vs. 64.2% [10%], P=0.05). All other traditional risk factors for CAV or immunosuppression were similar between the groups (P>0.2 for all)., Conclusions: This is the first preliminary study demonstrating that heart transplant recipients with preformed class II DSA may be at an increased risk for accelerated CAV as detected by consecutive volumetric three-dimensional intravascular ultrasound.

Objectives: The purpose of this study was to determine the occurrence and causes of readmissions after implantation of axial flow left ventricular assist device (LVAD)., Background: Based on the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) study experience, readmissions after LVAD implantation are thought to be frequent., Methods: We retrospectively analyzed admissions to our facility in a cohort of 115 patients implanted between January 2008 and July 2011 with the HeartMate II axial flow LVAD, of whom 42 were bridged to transplant. To account for repeated events, Andersen-Gill models were used to determine possible predictors., Results: The patients were followed for 1.4 ± 0.9 years. There were 224 readmissions in 83 patients. The overall readmission rate was 1.64 ± 1.97 per patient-year of follow-up. The readmission rate for the first 6 months was 2.0 ± 2.3 and decreased to 1.2 ± 2.1 during subsequent follow-up. Leading causes were bleeding (66 readmissions in 34 patients), mostly gastrointestinal bleed (51 in 27 patients), cardiac (51 in 36 patients, most for HF or arrhythmia), infections (32 in 25 patients) of which 6 were pump related, and thrombosis (20 in 15 patients) including 13 readmissions due to hemolysis. Preoperative variables associated with (fewer) readmissions in a multivariate model include residence within our hospital-extended referral zone of Minnesota and the neighboring states (hazard ratio: 0.66; 95% confidence interval: 0.48 to 0.91; p = 0.011), hemoglobin (hazard ratio: 0.91, 95% confidence interval: 0.84 to 0.99; p = 0.027) and N-terminal pro-B-type natriuretic peptide (hazard ratio: 0.98; 95% confidence interval: 0.96 to 1.0 per 1,000-unit increase, p = 0.022). C-statistic for the model: 0.63., Conclusions: Readmission rates after axial flow LVAD implantation decrease during the first 6 months and then stabilize. The leading causes are bleeding, cardiac (heart failure and arrhythmia), infections, and thrombosis., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The goal of this study was to describe the predictors and significance of poor exercise tolerance after left ventricular assist device (LVAD) implantation. Despite LVAD therapy, some patients continue to exhibit exercise intolerance. The predictors and outcomes of these patients are unknown. A retrospective review of 65 LVAD recipients who performed 6-minute walk tests was conducted. Patients walking <300 m were considered to have poor exercise tolerance. Twenty patients exhibited poor exercise tolerance (221 ± 45 m), compared to 45 patients with better exercise tolerance (406 ± 76 m). Postoperatively, poor performers were not easily identified by functional symptoms alone, because 42% of these patients reported New York Heart Association functional class I or II symptoms. Preoperative New York Heart Association class, inotrope therapy, and intra-aortic balloon pump use were similar between the 2 groups. Multivariate analysis using all adequately powered (n >50) univariate predictors identified diabetes mellitus (odds ratio 10.493, p = 0.003) and elevated 1-month right atrial pressure (odds ratio 2.985 for every 5 mm Hg, p = 0.003) as significant predictors of poor performance (<300 m; area under the curve 0.85). The poorly performing group had increased mortality (p = 0.011), with 21% increased risk for overall mortality for every 10 m short of 300 m (fitted Cox model: hazard ratio 1.211, p = 0.0001). The distance walked in meters in a postoperative 6-minute walk test was the strongest predictor of late post-LVAD mortality (p = 0.0002). In conclusion, despite similar severity of heart failure preoperatively, some LVAD recipients may have persistent exercise intolerance postoperatively as assessed by the 6-minute walk test that is independently associated with subsequent reduced survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Left thoracotomy was used as an approach for the implantation of pulsatile ventricular assist devices. Avoiding the standard approach of median sternotomy is attractive in patients undergoing complicated redo cardiac surgery, especially with prior mediastinal radiation. We report a case of the use of left thoracotomy for the implantation of the HeartMate II axial-flow pump., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality., Methods and Results: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002)., Conclusions: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Background: Operative mortality after left ventricular assist device (LVAD) implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we treat our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables 1 month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes after the initial successful LVAD implantation., Methods and Results: We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device for their association with a compound end point (90-day mortality, readmission for heart failure, or New York Heart Association class III or higher at the end of the 90-day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, interventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E-wave deceleration time, and the ratio of deceleration time to E-wave velocity (mitral deceleration index [MDI]). Four patients died during the 30- to 90-day period, 6 patients were readmitted for heart failure, and 25 patients were considered to have New York Heart Association class III or higher at the end of the 90-day period. Variables associated with adverse outcome included increased ELAP (odds ratio, 1.30 [1.16-1.48]; P<0.0001), MDI <2 ms/[cm/s] (odds ratio, 4.4 implantation [1.22-18]; P=0.02) and decreased tricuspid lateral annulus velocity (odds ratio, 0.70 implantation [0.48-0.95]; P=0.02). A leftward deviation of interventricular septum was associated with a worse outcome (odds ratio, 3.03 implantation [1.21-13.3]; P=0.01)., Conclusions: Mortality and heart failure after LVAD surgery appear to be predominantly determined by echocardiographic evidence of inefficient unloading of the left ventricle and persistence of right ventricular dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.

Background: Exercise performance, an important aspect of quality of life, remains limited after heart transplantation (HTx). This study examines the effect of cardiac allograft remodeling on functional capacity after HTx., Methods: The total cohort of 117 HTx recipients, based on echocardiographic determination of left ventricle mass and relative wall thickness at 1 year after HTx, was divided into 3 groups: (1) NG, normal geometry; (2) CR, concentric remodeling; and (3) CH, concentric hypertrophy. Cardiopulmonary exercise testing was performed 5.03 ± 3.08 years after HTx in all patients. Patients with acute rejection or significant graft vasculopathy were excluded., Results: At 1 year post-HTx, 30% of patients had CH, 55% had CR and 15% had NG. Exercise tolerance, measured by maximum achieved metabolic equivalents (4.62 ± 1.44 vs 5.52 ± 0.96 kcal/kg/h), normalized peak Vo(2) (52 ± 14% vs 63 ± 12%) and Ve/Vco(2) (41 ± 17 vs 34 ± 6), was impaired in the CH group compared with the NG group. A peak Vo(2) ≤14 ml/kg/min was found in 6%, 22% and 48% of patients in the NG, CR and CH groups, respectively (p = 0.01). The CH pattern was associated with a 7.4-fold increase in relative risk for a peak Vo(2) ≤14 ml/kg/min compared with NG patients (95% confidence interval 1.1 to 51.9, p = 0.001). After multivariate analysis, a 1-year CH pattern was independently associated with a reduced normalized peak Vo(2) (p = 0.018) and an elevated Ve/Vco(2) (p = 0.035)., Conclusions: The presence of CH at 1 year after HTx is independently associated with decreased normalized peak Vo(2) and increased ventilatory response in stable heart transplant recipients. The identification of CH, a potentially reversible mechanism of impairment in exercise capacity after HTx, may have major clinical implications., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent., Methods: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days., Results: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11)., Conclusions: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Background: We analyzed the results of combined heart-kidney transplantation (CHKTx) over a 10-year period., Methods: Between September 1996 and May 2007 at Mayo Clinic, 12 patients (age 52 ± 12.2 years) underwent CHKTx as a simultaneous procedure in 10 recipients and as a staged procedure in two recipients with unstable hemodynamics after heart transplantation., Results: There was no operative mortality. Patient survival rates for the CHKTx recipients at 1 and 3 months and 6 years were 91%, 83%, and 83% and did not differ from isolated heart transplantation (IHTx) recipients (97%, 95%, and 79%, P = 0.61). The freedom from cardiac allograft rejection (≥ grade 2) at 3 months was 73% for CHKTx and had not changed during further follow-up; for IHTx, freedom from rejection at 3 months and 1 and 6 years was 61%, 56%, and 42% (P = .08). Heart and renal allograft survival was 100% with and left ventricular ejection fraction 66% ± 8.4% and glomerular filtration rate 61 ± 25 at last follow-up. There were no signs of cardiac allograft vasculopathy in the CHKTx recipients., Conclusion: CHKTx yields favorable long-term outcome, with a low incidence of cardiac rejection and vasculopathy. Simultaneous CHKTx appears feasible, if hemodynamics is satisfactory. This approach expands the selection criteria for transplantation in patients with coexisting end-stage cardiac and renal disease., (Published by Elsevier Inc.)

Background: The purpose of this study was to describe the normal values for strain (S), systolic strain rate (SRs) and synchrony by speckle-tracking echocardiography (STE) in heart transplant (HTx) recipients who had normal left ventricular ejection fraction (LVEF) and no clinically significant complications., Methods: We evaluated S and SRs in 40 HTx patients at 1 year after transplant and 82 healthy controls with STE using velocity vector imaging., Results: Mean (SD) global longitudinal S and SRs, respectively, were lower in the transplant group compared with controls [-13.43% (2.39%) vs -17.28% (2.30%), p < 0.001; -0.83 (0.15) s(-1) vs -0.96 (0.13) s(-1), p < 0.001]. These variables were good for differentiating between groups: area under the curve was 0.88 for S and 0.73 for SRs. The differences remained significant after adjustment for other clinical variables. Global circumferential S and SRs were similar between groups. The standard deviation of the global longitudinal S time to peak of the 16 segments for HTx and control groups, respectively, was 41.67 (13.53) milliseconds vs 32.57 (12.81) milliseconds (p < 0.001). With 58.2 milliseconds as a cutoff value to define left ventricular synchrony, only 3 (8%) of the HTx patients and 4 (5%) of the control subjects were above that value (p = 0.6)., Conclusion: To our knowledge, this is the first study describing normal values for S and SRs and synchrony by STE in a HTx population with normal LVEF: longitudinal S and SRs were reduced; circumferential deformation indexes were normal; and left ventricular synchrony was preserved., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)