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Background: Recent studies indicate that donor innate immune responses participate in initiating and accelerating innate responses and allorecognition in the recipient. These immune responses negatively affect recipient outcomes and predispose recipients to cardiovascular death (CV death). We hypothesized that a donor cause of death (COD) associated with higher levels of innate immune response would predispose recipients to more adverse outcomes post-transplant, including CV death. Methods: We performed a single-institution retrospective analysis comparing donor characteristics and COD to recipient adverse cardiovascular outcomes. We analyzed the medical records of local adult donors (age 18–64) in a database of donors where adequate data was available. Donor age was available on 706 donors; donor sex was available on 730 donors. We linked donor characteristics (age and sex) and COD to recipient CV death. The data were analyzed using logistic regression, the log-rank test of differences, and Tukey contrast. Results: Donor age, female sex, and COD of intracranial hemorrhage were significantly associated with a higher incidence of recipient CV death. Conclusions: In this single institution study, we found that recipients with hearts from donors over 40 years, donors who were female, or donors who died with a COD of intracranial hemorrhage had a higher frequency of CV death. Donor monitoring and potential treatment of innate immune activation may decrease subsequent recipient innate responses and allorecognition stimulated by donor-derived inflammatory signaling, which leads to adverse outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Cardiac allograft vasculopathy (CAV) continues to hinder the long-term success of heart transplant recipients. Redo-transplantation is currently the only definitive treatment for advanced CAV. We examined whether these patients are at similar CAV-risk with the second transplant. Methods: Heart recipients from 1985 to 2011 at the UTAH program were included in the study and those with CAV as an indication for redo-transplantation were identified. CAV diagnosis was made by coronary angiography and based on the 2010 ISHLT standardized nomenclature for CAV. Patient demographics, rejection history, and CAV incidence were analyzed. Results: Of the 1,169 eligible patients, 135 (11.5%) developed CAV post their first transplant; 78 cases within 10 years and 54 beyond 10 years. The mean time to CAV was 6.58 years. Of the 135 patients who developed CAV, only 21 (15.5%) ended up requiring a redo-transplant. Of the 21 retransplanted patients, 4 (19.0%) developed CAV again; 2 patients within 10 years and 2 patients beyond 10 years indicating a similar risk for CAV occurrence for first and redo-transplant. Conclusions: Our results indicate that CAV is as likely to develop in redo-transplants despite recent advances in immunosuppression and the standardized use of lipid-lowering agents. Although outcomes in redo-transplantation for the indication of CAV are favorable, efforts to better understand and minimize CAV are needed, especially in the face of scarce donor organs. [ABSTRACT FROM AUTHOR]

Aims Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous-flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS. Methods and results Patients with chronic HF requiring LVAD support were prospectively enrolled. Paired myocardial tissue samples were obtained prior to LVAD implantation and at transplantation for histopathology. The Meds group comprised patients treated with neurohormonal blocking therapy (concurrent beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and aldosterone antagonist), and the No Meds group comprised patients on none of these. Both the Meds (n=37) and No Meds (n=44) groups experienced significant improvements in cardiac structure and function over the 6 months following LVAD implantation. The degree of improvement was greater in the Meds group, including after adjustment for baseline differences. There were no differences between the two groups in arrhythmias, end-organ injury, or neurological events. In patients with high baseline pre-LVAD myocardial fibrosis, treatment with HF drug therapy was associated with a reduction in fibrosis. Conclusions Clinical and histopathological evidence showed that adjuvant HF drug therapy was associated with additional favourable effects on the structure and function of the unloaded myocardium that extended beyond the beneficial effects attributed to LVAD-induced unloading alone. Adjuvant HF drug therapy did not influence the incidence of major post-LVAD adverse events during the follow-up period. [ABSTRACT FROM AUTHOR]

Aims: Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous-flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS.Methods and Results: Patients with chronic HF requiring LVAD support were prospectively enrolled. Paired myocardial tissue samples were obtained prior to LVAD implantation and at transplantation for histopathology. The Meds group comprised patients treated with neurohormonal blocking therapy (concurrent beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and aldosterone antagonist), and the No Meds group comprised patients on none of these. Both the Meds (n = 37) and No Meds (n = 44) groups experienced significant improvements in cardiac structure and function over the 6 months following LVAD implantation. The degree of improvement was greater in the Meds group, including after adjustment for baseline differences. There were no differences between the two groups in arrhythmias, end-organ injury, or neurological events. In patients with high baseline pre-LVAD myocardial fibrosis, treatment with HF drug therapy was associated with a reduction in fibrosis.Conclusions: Clinical and histopathological evidence showed that adjuvant HF drug therapy was associated with additional favourable effects on the structure and function of the unloaded myocardium that extended beyond the beneficial effects attributed to LVAD-induced unloading alone. Adjuvant HF drug therapy did not influence the incidence of major post-LVAD adverse events during the follow-up period. [ABSTRACT FROM AUTHOR]

Background Ventricular assist devices ( VADs) have a proven survival benefit in select patients with advanced heart failure, yet many patients considered for implantation are declined for various reasons. The outcome of these patients is obscure owing to their exclusion from recent VAD studies. We aim to compare the outcomes of patients who received a VAD to those who did not. Methods For this study, the Artificial Heart Program's database at Intermountain Medical Center was queried from 2006 to 2012 for patients referred for a VAD. Kaplan-Meier survival analysis was performed with log-rank test determining significance. Results Of 232 patients included, 118 patients received a VAD and 114 patients did not. The prevailing reason for VAD decline in eligible and willing patients was due to pre-existing illness (39%). Mortality was higher in non- VAD vs. VAD patients (58.8% vs. 35.6%, p < 0.001) with a median time-to-death of 67 ( IQR:12-314) and 301 ( IQR:136-694) d, respectively (p = 0.007). Conclusions In the current era of non-pulsatile VADs, mortality of patients who are considered but not implanted remains high. Additionally, mortality of these patients occurred much sooner. Educational efforts ensuring timely referral for VAD therapy are important to maximize the number of patients who may benefit. [ABSTRACT FROM AUTHOR]

Background The elevated baseline heart rate ( HR) of a heart transplant recipient has previously been considered inconsequential. However, we hypothesized that a resting HR above 100 beats per minute (bpm) may be associated with morbidity and mortality. Methods The U.T.A.H. Cardiac Transplant Program studied patients who received a heart transplant between 2000 and 2011. Outpatient HR values for each patient were averaged during the first year post-transplant. The study cohort was divided into two groups: the tachycardic ( TC) ( HR >100 bpm) and the non- TC group ( HR ≤100 bpm) in which mortality, incidence of rejection, and cardiac allograft vasculopathy were compared. Results Three hundred and ten patients were included as follows: 73 in the TC and 237 in the non- TC group. The TC group had a higher risk of a 10-yr all-cause mortality (p = 0.004) and cardiovascular mortality (p = 0.044). After adjustment for donor and recipient characteristics in multivariable logistic regression analysis, the hazard ratio was 3.9, (p = 0.03, CI: 1.2-13.2) and 2.6 (p = 0.02, CI: 1.2-5.5) for cardiovascular mortality and all-cause mortality, respectively. Conclusion Heart transplant recipients with elevated resting HR appear to have higher mortality than those with lower resting HR. Whether pharmacologically lowering the HR would result in better outcomes warrants further investigation. [ABSTRACT FROM AUTHOR]

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy ( n = 14) and from normal donors ( n = 5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary ( D1), secondary ( D2) and tertiary ( D3) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively ( P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients ( r) between collagen content and FA, MD, D2 and D3 were -0.51, 0.59, 0.56 and 0.62 ( P < 0.05), respectively. The correlation between D1 and collagen content was not significant ( r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The Intermountain Risk Score (IMRS), composed of the complete blood count (CBC) and basic metabolic profile (BMP), predicts mortality and morbidity in medical and general populations. Whether longitudinal repeated measurement of IMRS is useful for prognostication is an important question for its clinical applicability. Methods: Females (N = 5,698) and males (N = 5,437) with CBC and BMP panels measured 6 months to 2.0 years apart (mean 1.0 year) had baseline and follow-up IMRS computed. Survival analysis during 4.0±2.5 years (maximum 10 years) evaluated mortality (females: n = 1,255 deaths; males: n = 1,164 deaths) and incident major events (myocardial infarction, heart failure [HF], and stroke). Results: Both baseline and follow-up IMRS (categorized as high-risk vs. low-risk) were independently associated with mortality (all p<0.001) in bivariable models. For females, follow-up IMRS had hazard ratio (HR) = 5.23 (95% confidence interval [CI] = 4.11, 6.64) and baseline IMRS had HR = 3.66 (CI = 2.94, 4.55). Among males, follow-up IMRS had HR = 4.28 (CI = 3.51, 5.22) and baseline IMRS had HR = 2.32 (CI = 1.91, 2.82). IMRS components such as RDW, measured at both time points, also predicted mortality. Baseline and follow-up IMRS strongly predicted incident HF in both genders. Conclusions: Repeated measurement of IMRS at baseline and at about one year of follow-up were independently prognostic for mortality and incident HF among initially hospitalized patients. RDW and other CBC and BMP values were also predictive of outcomes. Further research should evaluate the utility of IMRS as a tool for clinical risk adjustment. [ABSTRACT FROM AUTHOR]

Objective: To evaluate soluble (s) ST2 as a biomarker of rejection, allograft vasculopathy and mortality after orthotopic heart transplantation (OHT). Methods: sST2 concentrations were measured in 241 patients following OHT. Results: Elevated sST2 was associated with cellular rejection (CR) ≥1R, with highest rates of CR in the 4th sST2 quartile ( p = 0.003). No significant association between sST2 and antibody-mediated rejection or allograft vasculopathy was found. sST2 ≥30 ng/mL independently predicted death over 7-year follow-up (HR = 2.01; 95% CI 1.15-3.51; p = 0.01). Conclusion: Concentrations of sST2 are associated with the presence of CR and predict long-term mortality following OHT. [ABSTRACT FROM AUTHOR]

Nixon JL, Kfoury AG, Brunisholz K, Horne BD, Myrick C, Miller DV, Budge D, Bader F, Everitt M, Saidi A, Stehlik J, Schmidt TC, Alharethi R. Impact of high-dose inotropic donor support on early myocardial necrosis and outcomes in cardiac transplantation. Clin Transplant 2011 DOI: 10.1111/j.1399-0012.2011.01504.x. © 2011 John Wiley & Sons A/S. Abstract: Background: Cardiac donors routinely require vasoactive agents for circulatory stability after brain death. Nevertheless, inotropes have been associated with direct cardiac toxicity. Our study evaluated whether the use of high-dose inotropic support in potential donors was associated with increased early myocardial necrosis (MN) and worse clinical outcomes after cardiac transplantation. Methods: The UTAH Cardiac Transplant Program (UCTP) and Intermountain Donor Services databases were queried for records between 1996 and 2009. The high-dose donor inotropic support (HDIS) group was defined as patients on dopamine >10 μg/kg/min. The incidence of early MN, intensive care unit (ICU) length of stay, length of ventilator support, and mortality was evaluated. Results: Two hundred and forty-four recipients undergoing transplant met study criteria. The average donor age was 27 yr. The incidence of MN in the HDIS (n = 29) and non-HDIS (n = 204) groups was 14.8% and 6.7%, respectively, OR 2.67. Total ischemic time, ventilator support time, ICU stay, and actuarial survival were similar between both groups. Conclusion: The use of high-dose inotropic support to maintain donor stability appears to have a higher trend for early post-transplant MN without an impact on clinical outcomes. With the current growing shortage of organ donors, it appears reasonable to use donors on high-dose inotropic support. [ABSTRACT FROM AUTHOR]

Ventura PA, Alharethi R, Budge D, Reid BB, Horne BD, Mason NO, Stoker S, Caine WT, Rasmusson B, Doty J, Clayson SE, Kfoury AG. Differential impact on post-transplant outcomes between pulsatile- and continuous-flow left ventricular assist devices. Clin Transplant 2011: 25: E390-E395. © 2011 John Wiley & Sons A/S. Abstract: Background: The HeartMate II (HMII) left ventricular assist device (LVAD) has proven reliable and durable and has become the preferred choice for bridge to transplant therapy (BTT) when compared with the pulsatile HeartMate XVE (XVE). In this study, we compared the post-transplant (PTx) outcomes between XVE and HMII using a large national data registry. Methods: The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) Thoracic Registry database was queried for all patients implanted with either an XVE or an HMII as BTT during 2004-2009. Statistical analysis between XVE and HMII were performed using Kaplan-Meier survival analysis and Cox regression analyses. Results: A total of 673 patients were implanted with the XVE and 484 with HMII. When adjusted for age, gender, ethnicity, intra-aortic balloon pump, ventilator, inotropes, dialysis, body mass index, creatinine, bilirubin, transfusion, pulmonary capillary wedge, and pulmonary arterial pressures, the HMII had similar one- and three-yr survival (hazard ratio = 0.95, CI = 0.64, 1.42) and rejection-free survival PTx compared to XVE. The XVE group had more early incidences of allograft rejection (AR) and hospitalization for infection (HI). Conclusions: Compared to XVE, patients with HMII have similar one- and three-yr survival after heart transplantation with less risk of early graft rejection and significant infection. With a strong shift toward use of continuous-flow LVADs, PTx outcomes are expected to continue to improve. [ABSTRACT FROM AUTHOR]

Aims The complete blood count (CBC) and basic metabolic profile are common, low-cost blood tests, which have previously been used to create and validate the Intermountain Risk Score (IMRS) for mortality prediction. Mortality is the most definitive clinical endpoint, but medical care is more easily applied to modify morbidity and thereby prevent death. This study tested whether IMRS is associated with clinical morbidity endpoints. Methods and results Patients seen for coronary angiography (n = 3927) were evaluated using a design similar to a genome-wide association study. The Bonferroni correction for 102 tests required a P-value of ≤ 4.9 × 10−4 for significance. A second set of angiography patients (n = 10 413) was used to validate significant findings from the first patient sample. In the first patient sample, IMRS predicted heart failure (HF) (Ptrend = 1.6 × 10−26), coronary disease (Ptrend = 2.6 × 10−11), myocardial infarction (MI) (Ptrend = 3.1 × 10−25), atrial fibrillation (Ptrend = 2.5 × 10−20), and chronic obstructive pulmonary disease (Ptrend = 4.7 × 10−4). Even more, IMRS predicted HF readmission [hazard ratio (HR) = 2.29/category, Ptrend = 1.2 × 10−6), incident HF (HR = 1.88/category, Ptrend = 0.02), and incident MI (HR = 1.56/category, Ptrend = 4.7 × 10−4). These findings were verified in the second patient sample. Conclusion Intermountain Risk Score, a predictor of mortality, was associated with morbidity endpoints that often lead to mortality. Further research is required to fully characterize its clinical utility, but its low-cost CBC and basic metabolic profile composition may make it ideal for initial risk estimation and prevention of morbidity and mortality. An IMRS web calculator is freely available at http://intermountainhealthcare.org/IMRS. [ABSTRACT FROM AUTHOR]

Endomyocardial biopsy is the gold standard to diagnose cardiac allograft rejection, although a noninvasive modality such as brain natriuretic peptide (BNP) is attractive. The authors examined the correlation of BNP levels with rejection patterns and allograft function in cardiac allograft recipients followed up to 8 years. One hundred forty-four consecutive patients underwent endomyocardial biopsy, right heart catheterization, and blood sampling. BNP levels decreased during the first 6 months after transplant but then reached a plateau. Time-dependent correlations were made between BNP levels and allograft rejection, left ventricular ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, and serum creatinine. BNP levels were not different between patients with any rejection pattern and no rejection prior to or after 6 months following transplant. BNP levels did not correlate with ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, or creatinine in the first 6 months after transplant. Statistically significant correlations existed between BNP and these parameters after 6 months following transplant. In cardiac transplant recipients, BNP levels decrease in the first 6 months following transplant and then reach a plateau regardless of the presence, type, or severity of allograft rejection. BNP levels do predict allograft rejection but correlate with allograft function after 6 months following transplant. [ABSTRACT FROM AUTHOR]

Abstract: Background: Heart failure (HF) patients may require cardiac assist device implantation prior to transplantation (Tx) because of either acute cardiogenic shock (ACS), with no prior history of HF, or for progression of pump failure in the setting of chronic HF. Aims: To investigate whether patients implanted with a cardiac assist device for ACS, have similar post-Tx outcomes as those who underwent cardiac assist device implantation because of progressive chronic HF. Methods and results: We compared post-Tx outcomes of consecutive patients bridged due to ACS (Acute Group) with the outcomes of patients bridged due to deterioration of chronic HF (Chronic Group). Seventy-three patients had a cardiac assist device implanted and underwent subsequent cardiac Tx. Thirty-five patients (48%) had a cardiac assist device implanted due to ACS, most often caused by massive acute myocardial infarction, and 38 patients (52%) because of progressive chronic HF. Despite greater compromise at the time of implantation, the Acute Group recovered satisfactorily and underwent Tx with similar post-Tx survival rates as the Chronic Group patients [1-year survival: 88.6% vs 86.8%, p =0.80, actuarial survival (mean follow-up 4.2 years): 80.0% vs 81.6%, p =0.86)]. Furthermore, no significant differences were observed between the 2 groups in various post-Tx events. Conclusion: Patients with ACS who underwent emergency cardiac assist device implantation as bridge to Tx had similar post-Tx outcomes as their more chronically ill counterparts who underwent device implantation on a non-urgent basis. [Copyright &y& Elsevier]

Background: Increased homocysteine (HCY) is associated with increased risk of vascular disease. Whether HCY affects development of congestive heart failure (CHF) independent of coronary artery disease (CAD) is uncertain. We evaluated whether increased HCY predicts low ejection fraction or clinical CHF. Methods: Patients (n = 2,842) undergoing coronary angiography had HCY measured between 1994 and 1999 and were prospectively studied. Left ventricular dysfunction (LVD) was defined as ejection fraction ≤40%. Multivariable regressions assessed predictive strength of HCY for LVD or LVD/CHF. Results: The average age was 64 ± 12 years; 69% were men, and 74% had CAD. LVD was present in 12% and the combination of either LVD or clinical CHF was present in 21.9%. Quartiles of HCY were: ≤10.5 (Q1), 10.5–13.2 (Q2), 13.3–17.0 (Q3) and ≥17.1 μmol/l (Q4). LVD and LVD/CHF were more prevalent in Q3 (15, 25%) and Q4 (15, 27%) than in Q1 HCY (8.4, 18%; p < 0.001 vs. Q4). After adjustment, Q3 and Q4 HCY independently predicted LVD (OR = 1.7, 95% CI 1.2–2.5, p = 0.004; OR = 1.8, 95% CI 1.3–2.6, p = 0.002) or LVD/CHF (OR = 1.4, 95% CI 1.04–1.8, p = 0.03; OR = 1.7, 95% CI 1.3–2.2, p < 0.001). Findings did not differ by disease etiology: for Q4 among non-CAD patients, OR = 1.7 for LVD and OR = 1.7 for LVD/CHF. Further, there was no interaction of results with gender. Conclusion: High HCY levels (Q3/4 ≥13.3 μmol/l) are associated with LVD and combined endpoint of LVD/clinical CHF. This relationship is independent of CHF etiology and gender. Further research is indicated to distinguish between a causal or noncausal mechanism for this association. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) has been associated with atherosclerotic complications, and we hypothesized that CRP levels might also predict death in non-ischemic patients with left ventricular dysfunction. Two hundred and three patients with non-ischemic left ventricular dysfunction undergoing cardiac catheterization were included and were followed for 2.4 ± 1.4 years to determine the incidence of fatal events. Death occurred in 15% of patients with low CRP (1st and 2nd tertiles) and 30% of patients with high CRP (3rd tertile). After adjustment for 11 covariates, high CRP (p = 0.037, hazard ratio = 2.0) significantly and independently predicted mortality. Even in the absence of coronary artery disease, patients with left ventricular dysfunction are at increased risk of mortality based on their baseline CRP concentrations. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial demonstrated increased 1-and 2-year survival and improved quality of life for end-stage heart failure patients implanted with the HeartMate VE Left Ventricular Assist Device (LVAD) (Thoratec Corporation, Pleasanton, CA) compared with optimal medical management. This is the first report of Destination Therapy (DT) experience since REMATCH and incorporates improvements with the HeartMate XVE LVAD and patient management. Forty-two patients with end-stage heart failure at higher volume institutions were supported with the LVAD over a duration of 26.7 patient years (mean 232 days). Compared with REMATCH, DT patients had a 40% lower rate of death (0.49 vs. 0.84 deaths per patient year). Kaplan-Meier estimates of survival in the DT and REMATCH LVAD groups at 30 days were 90% and 81%, and at 1 year were 61% and 52%. The death rate due to sepsis was 8.3 times lower in DT patients (risk ratio, 0.12; 95% confidence interval, 0.02-0.90). DT patients were 2.1 times less likely to experience an adverse event (risk ratio, 0.47; 95% confidence interval, 0.35-0.63). These results demonstrate continued improvement with outcomes in long-term DT with LVADs. Given that these DT patients were similar to those in the REMATCH trial, the improved outcomes likely reflect improvements in the HeartMate XVE LVAD and experience with patient management. [ABSTRACT FROM AUTHOR]