Impact of donor smoking history on post heart transplant outcomes: A propensity-matched analysis of ISHLT registry.

PURPOSE: Smoking is a major public health issue, and its effect on cardiovascular outcomes is well established. This study evaluates the impact of donor smoking on heart transplant (HT) outcomes. METHODS: HT recipients between January 1, 2005, and December 31, 2016, with known donor smoking status were queried from the International Society of Heart and Lung Transplantation (ISHLT) registry. The primary outcome was all-cause mortality, and secondary endpoints were graft failure, acute rejection, and cardiac allograft vasculopathy. We utilized propensity-score matching to identify cohorts of recipients with and without a history of donor smoking. Hazard ratios for post-transplant outcomes for the matched sample were estimated from separate Cox proportional hazard models. RESULTS: Of 26 390 patients in the cohort, 18.9% had history of donor smoking. Donors with history of smoking were older, predominantly male and had higher incidence of diabetes, hypertension, cocaine use, and "high-risk" status. In propensity-matched analysis, recipients with a history of donor smoking had increased risk of death (HR 1.11, 95% CI 1.03-1.20) and higher risk of graft failure (HR 1.11, 95% CI 1.03-1.20). CONCLUSION: Donor smoking was associated with increased mortality and higher incidence of graft failure following HT. Consideration of donor smoking history is warranted while evaluating donor hearts.

Elevated Heart Rate Following Heart Transplantation Is Associated With Increased Graft Vasculopathy and Mortality.

BACKGROUND: The effect of elevated heart rate (HR) on outcomes after heart transplantation (HT) has not been well established. The aim of this study was to assess predictors of elevated HR following HT and its impact on outcomes. METHODS AND RESULTS: We retrospectively evaluated 394 patients who underwent HT at 2 academic medical centers from 2005 to 2016. Patients were divided into 2 groups based on HR 1 year after HT: HR ≥95 beats/min (n = 162; 41%) and HR <95 beats/min (n = 232; 59%). Median follow-up time was 6.6 (interquartile range [IQR] 2.2-7.5) years. HR ≥95 beats/min 1 year after HT was associated with younger donor age, whereas HR <95 beats/min was associated with heavy donor alcohol use and African-American recipient race. Left ventricular (LV) end-diastolic dimension, mass, and ejection fraction were lower and E/E' higher in the HR ≥95 group at the time of the last follow up. HR ≥95 beats/min at 1 year after HT was independently associated with the development of cardiac allograft vasculopathy and increased mortality. CONCLUSIONS: HR ≥95 beats/min 1 year after HT is associated with a reduction in LV size and function, increased incidence of cardiac allograft vasculopathy, and reduced survival. Studies investigating the effect of medical HR reduction on post-HT outcomes are warranted.

The effect of donor alcohol abuse on outcomes following heart transplantation.

BACKGROUND: Current guidelines recommend against the use of hearts from donors that abuse alcohol. We explored the effect of donor alcohol abuse (AA) on cardiac allograft function and outcomes in heart transplant (HTx) recipients. METHODS: Overall, 370 HTx recipients were divided into two groups: (a) the alcoholic donor group (AD, n = 58) and (b) the non-alcoholic donor group (NAD, n = 312). RESULTS: Recipients in the AD group had a slower heart rate (86 ± 13 vs 93 ± 13, P = 0.004) and an increased incidence of early atrial fibrillation (AF) (30% vs 11%, P = 0.003). Echocardiographic left ventricular mass was higher among alcoholic donors (171.7 ± 66.7 vs 151.6 ± 54.7, P = 0.02). This difference remained present 1 year following HTx (185 ± 43 vs 166 ± 42, P = 0.007). E/E' was higher in the AD group (9.5 ± 3.9 vs 8.4 ± 2.9, P = 0.04) and a larger number of AD recipients had a ventilatory equivalent for VCO2  > 34 (50% vs 31%, P = 0.04) on cardiopulmonary exercise test. There was no significant difference in rejection, cardiac allograft vasculopathy (CAV), or survival between the groups. CONCLUSIONS: Our data suggest that donor AA does not impact rejection, CAV, or intermediate-term survival, but may cause increased incidence of post-HTx AF and impaired cardiac allograft diastolic function.

Gastrointestinal Bleeding With Left Ventricular Assist Devices (LVAD): Locating the Leak and Identifying Outcomes.

BACKGROUND AND GOALS: Gastrointestinal bleeding (GIB) is a significant complication following left ventricular assist device (LVAD) implantation. We evaluated the incidence, predictors, endoscopic findings, and outcomes of GIB in LVAD recipients. STUDY: Retrospective review of 205 adult patients undergoing HeartMate II LVAD implantation from January 2012 to June 2016. Patients were reviewed and separated into GIB (n=57; 28%) and non-GIB (n=148; 72%) groups. RESULTS: Median time to GIB was 55 (range, 3 to 730) days. The GIB group patients were older (61±12 vs. 56±13, P=0.0042), more often underwent concomitant tricuspid valve (TV) repair (16% vs. 4%, P=0.007), and a higher percentage were assigned for destination therapy (75% vs. 55%, P=0.01). Angioectasia (33%) was the most common identified cause of GIB. Median time to endoscopic intervention was 1 day. The total number of hospital readmissions after LVAD was higher in the GIB group (median of 5 vs. 3, P=0.001), as was the total number of blood products transfused after LVAD (29 vs. 13, P≤0.0001). GIB was associated with an increased risk of death (hazard ratio, 1.94; 95% confidence interval, 1.16-3.25; P=0.01) and the mortality rate during hospitalization for GIB was 11% (P=0.0004). Receiving a heart transplant was associated with a decreased hazard of death (hazard ratio, 0.40; 95% confidence interval, 0.19-0.85; P=0.016). CONCLUSIONS: Older age and destination therapy as implant strategy were found to be associated with an increased risk of GIB, consistent with previous studies. A unique finding in our study is the association of TV repair with a higher incidence of GIB. Further studies are needed to investigate possible mechanisms by which TV repair increases the incidence of GIB.

Left Ventricular Assist Devices in Pulmonary Hypertension Group 2 With Significantly Elevated Pulmonary Vascular Resistance: A Bridge to Cure.

BACKGROUND: Pulmonary hypertension secondary to left heart disease (WHO Group 2) is a known risk factor in patients with heart failure. The favourable effect of left ventricular assist devices (LVAD) on pulmonary hypertension has been demonstrated before, although this effect has not been well-studied in advanced pulmonary arterial bed disease with a significant elevation in pulmonary vascular resistance. METHODS: We reviewed the records of 258 LVAD patients in our institution. Patients with elevated mean pulmonary artery pressure (mPAP>25mmHg) and elevated pulmonary vascular resistance (PVR ≥3 Wood units) were included in the study. Patients were divided into two groups based on their baseline PVR (PVR=3-5 Wood units (WU) vs. PVR>5WU). The groups were studied for the changes in their pulmonary haemodynamics after the placement of LVAD. RESULTS: Fifty-one (51) patients were included in the study. All patients showed a significant improvement in their pulmonary haemodynamic parameters post LVAD placement. In the group with the higher PVR, mPAP dropped from a baseline of 43±7mmHg to 22±6mmHg post LVAD placement (p<0.001), while PVR dropped from 6.3±1.2 Wood units to 2.2±1.1 Wood units (p<0.001). In a subgroup of patients who underwent cardiac transplantation post LVAD (n=14), all patients maintained a normalised PVR (<3WU) one year post cardiac transplantation. CONCLUSIONS: Left ventricular assist devices can reverse pulmonary hypertension WHO Group 2 with significantly elevated PVR; this effect is not dependent on the baseline PVR, and is maintained up to one year post cardiac transplantation.

High tacrolimus trough level variability is associated with rejections after heart transplant.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Donor-recipient ethnic mismatching impacts short- and long-term results of heart transplantation.

BACKGROUND: The impact of donor-recipient ethnic matching on heart transplantation (HT) has been poorly studied with inconclusive results. We aimed to investigate the impact of ethnic matching on HT outcomes in Israeli multiethnic patients. METHODS: The study comprised 168 patients who underwent HT from 1990-2017. Patients and their donors were ethnically categorized to Jews and Arabs. Primary end points were all-cause in-hospital and late mortality; secondary end points included primary graft dysfunction (PGD), rejections, and vasculopathy. RESULTS: Donor-recipient ethnic matching was found in 111 patients, while 57 were ethnically mismatched. Baseline characteristics were similar in both groups. Ethnic mismatching was associated with >7-fold (P = 0.018) increased risk for in-hospital mortality and >8-fold (P < 0.001) increased risk for PGD. Kaplan-Meier survival analysis showed that overall survival at 10 years was significantly higher among matched patients (73% vs 43%, log-rank P < 0.001). Multivariate analysis showed that ethnic mismatching was associated with an approximately fourfold higher risk for death (P < 0.01). These findings were validated by propensity score analysis. The ethnic mismatched group experienced significantly higher rejection rates compared with the matched group with lower survival free of rejections (log-rank P = 0.029). No differences in vasculopathy were found. CONCLUSIONS: Donor-recipient ethnic mismatch is an important independent predictor of early- and long-term outcomes following HT, and is associated with increased risk for PGD, rejections, and mortality. These findings will help to design tailored treatment protocols leading to improved outcomes after HT.

Effect of diltiazem on exercise capacity after heart transplantation.

BACKGROUND: Sinus tachycardia (ST) is common after heart transplantation (HTx). The aim of the study was to evaluate the effect of diltiazem treatment during the first year after HTx on heart rate (HR), cardiac allograft function, and exercise capacity. METHODS: From the total cohort, 25 HTx recipients started diltiazem treatment 4±2 weeks after HTx and continued it for at least 1 year (diltiazem group). Each study case was matched to a control. All patients underwent hemodynamic assessment and cardiopulmonary exercise test (CPET) at 1 year after HTx. RESULTS: HR decreased in the diltiazem group from 99±11 bpm to 94±7 bpm (P=.03) and did not change in the controls (98±11 bpm vs 100±13 bpm, P=.14). The difference between the groups at 1 year after HTx was significant (P=.04). In the diltiazem group left ventricular (LV), stroke volume and ejection fraction increased (48±16 vs 55±17 mL, P=.02, and 60%±10% vs 62%±12% P=.03, respectively) but did not differ from controls. E/E' decreased (10.7±2.7 vs 7.3±1.9, P=.003) while cardiac index was higher (3.5±0.8 vs 3.1±0.5; P=.05) in the diltiazem group at 1-year follow-up. The absolute peak VO2 (21±4 vs 18±6 mL/kg/min; P=.05) and normalized peak VO2 (73%±17% vs 58%±14%; P=.004) were significantly higher in the diltiazem group. CONCLUSIONS: This study showed that diltiazem treatment reduces ST, may improve cardiac allograft function and exercise tolerance during the first year after HTx.

Sinus tachycardia is associated with impaired exercise tolerance following heart transplantation.

BACKGROUND: Sinus tachycardia often presents in heart transplantation (HTx) recipients, but data on its effect on exercise performance are limited. METHODS: Based on mean heart rate (HR) value 3 months after HTx, 181 patients transplanted from 2006 to 2015 at University of Nebraska Medical Center were divided into two groups: (i) HR<95 beats/min (bpm, n=93); and (ii) HR≥95 bpm (n=88). Cardiopulmonary exercise testing (CPET) was performed 1 year after HTx. RESULTS: Mean HR at 3 months post-HTx was 94±11 bpm and did not change significantly at 1 year post-HTx (96±11 bpm, P=.13). HR≥95 bpm at 3 months was associated with younger donor age (OR 1.1; CI 1.0-1.1, P=.02), female donors (OR -2.4; CI 1.16-5.24 P=.02), and lack of donors' heavy alcohol use (OR -0.43; CI 0.17-0.61; P=.04). HR≥95 bpm at 3 months post-HTx was independently associated with decreased exercise capacity in metabolic equivalent (P=.008), reduced peak VO2 (P=.006), and percent of predicted peak VO2 (P=.002) during CPET. CONCLUSIONS: HR≥95 at 3 months following HTx is associated with reduced exercise tolerance in stable HTx recipients. Medical HR reduction after HTx could improve exercise performance after HTx and merits further investigation.

Risk of early, intermediate, and late rejection following heart transplantation: Trends over the past 25 years and relation to changes in medical management. Tertiary center experience: The Sheba Heart Transplantation Registry.

AIM: To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management. METHODS: The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3 months (early), 3-12 months (intermediate), and 12+ months (late). HT era was dichotomized as follows: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, and everolimus) vs older therapies (AZA, CSA). RESULTS: Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR = 0.44 [95% CI 0.22-0.88]), intermediate (OR = 0.02 [95% CI 0.003-0.11]), and late rejections (OR = 0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%, 21%, 18%, respectively). In contrast, the risk reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period. CONCLUSIONS: Major rejection rates following HT have significantly declined over the past 2 decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients.

Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long-term follow-up.

AIM: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality after heart transplantation (HT). Enhanced platelet reactivity is a contributing factor. We aimed to investigate the association between early initiation of aspirin therapy post-HT and the 15-year risk of the development of CAV. METHODS: We studied 206 patients who underwent HT between 1991 and 2016. Multivariate Cox proportional hazards regression modeling was employed to evaluate the association between early aspirin initiation and the long-term risk of CAV. RESULTS: Ninety-seven patients (47%) received aspirin therapy. At 15 years of follow-up, the rate of CAV was lowered by sixfold in patients treated with aspirin compared with the non-treated patients: 7% vs 37% (log-rank P-value<.001). The corresponding rates of the combined end-point of CAV or death were also lower in patients treated with aspirin, compared with the non-treated patients: 42% vs 78% (log-rank P < .001). Consistently, multivariate analysis showed that early aspirin therapy was associated with a significant 84% (P < .001) reduction in CAV risk, and with a corresponding 68% (P < .0001) reduction in the risk of the combined end-point of CAV or death. We further validated these results using a propensity score-adjusted Cox model. CONCLUSIONS: Early aspirin initiation is independently associated with a significant reduction in the risk of CAV.

Targeted myocardial gene expression in failing hearts by RNA sequencing.

BACKGROUND: Myocardial recovery with left ventricular assist device (LVAD) therapy is highly variable and difficult to predict. Next generation ribonucleic acid (RNA) sequencing is an innovative, rapid, and quantitative approach to gene expression profiling in small amounts of tissue. Our primary goal was to identify baseline transcriptional profiles in non-ischemic cardiomyopathies that predict myocardial recovery in response to LVAD therapy. We also sought to verify transcriptional differences between failing and non-failing human hearts. METHODS: RNA was isolated from failing (n = 16) and non-failing (n = 8) human hearts. RNA from each patient was reverse transcribed and quantitatively sequenced on the personal genome machine (PGM) sequencer (Ion torrent) for 95 heart failure candidate genes. Coverage analysis as well as mapping the reads and alignment was done using the Ion Torrent Browser Suite™. Differential expression analyses were conducted by empirical analysis of digital gene expression data in R (edgeR) to identify differential expressed genes between failing and non-failing groups, and between responder and non-responder groups respectively. Targeted cardiac gene messenger RNA (mRNA) expression was analyzed in proportion to the total number of reads. Gene expression profiles from the PGM sequencer were validated by performing RNA sequencing (RNAseq) with the Illumina Hiseq2500 sequencing system. RESULTS: The failing sample population was 75% male with an average age of 50 and a left ventricular ejection fraction (LVEF) of 16%. Myosin light chain kinase (MYLK) and interleukin (IL)-6 genes expression were significantly higher in LVAD responders compared to non-responders. Thirty-six cardiac genes were expressed differentially between failing and non-failing hearts (23 decreased, 13 elevated). MYLK, Beta-1 adrenergic receptor (ADRB1) and myosin heavy chain (MYH)-6 expression were among those significantly decreased in failing hearts compared to non-failing hearts. Natriuretic peptide B (NPPB) and IL-6 were significantly elevated. Targeted gene expression profiles obtained from the Ion torrent PGM sequencer were consistent with those obtained from Illumina HiSeq2500 sequencing system. CONCLUSIONS: Heart failure is associated with a network of transcriptional changes involving contractile proteins, metabolism, adrenergic receptors, protein phosphorylation, and signaling factors. Myocardial MYLK and IL-6 expression are positively correlated with ejection fraction (EF) response to LVAD placement. Targeted RNA sequencing of myocardial gene expression can be utilized to predict responders to LVAD therapy and to better characterize transcriptional changes in human heart failure.

Inhaled Milrinone After Left Ventricular Assist Device Implantation.

BACKGROUND: Proven strategies to reduce right ventricular (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation are lacking. We sought to evaluate the tolerability, feasibility, efficacy, and pharmacokinetics of inhaled milrinone (iMil) delivery after CF-LVAD implantation. METHODS AND RESULTS: We prospectively evaluated fixed-dose nebulized iMil delivered into a ventilator circuit for 24 hours in 10 postoperative CF-LVAD (Heartmate-II) patients. Tolerability (arrhythmias, hypotension, and hypersensitivity reaction), efficacy (hemodynamics), pharmacokinetics (plasma milrinone levels), and cost data were collected.Mean age was 56 ± 9 years, 90% were male, and mean INTERMACS profile was 2.5 ± 0.8. No new atrial arrhythmia events occurred, although 3 (30%) ventricular tachycardia (1 nonsustained, 2 sustained) events occurred. Sustained hypotension, drug hypersensitivity, death, or need for right ventricular assist device were not observed. Invasive mean pulmonary arterial pressure from baseline to during iMil therapy was improved (P = .017). Mean plasma milrinone levels (ng/mL) at baseline, and 1, 4, 8, 12, and 24 hours were 74.2 ± 35.4, 111.3 ± 70.9, 135.9 ± 41.5, 205.0 ± 86.7, 176.8 ± 61.3 187.6 ± 105.5, respectively. Reduced institutional cost was observed when iMil was compared with nitric oxide therapy over 24 hours ($165.29 vs $1,944.00, respectively). CONCLUSIONS: iMil delivery after CF-LVAD implantation was well tolerated, feasible, and demonstrated favorable hemodynamic, pharmacokinetic, and cost profiles. iMil therapy warrants further study in larger clinical trials.

Worsening renal function in patients with acute decompensated heart failure treated with ultrafiltration: predictors and outcomes.

BACKGROUND: Ultrafiltration (UF) is used to treat patients with diuretic-resistant acute decompensated heart failure. The aim of this study was to identify predictors and the effect of worsening renal failure(WRF) on mortality in patients treated with UF. METHODS AND RESULTS: Based on changes in serum creatinine, 99 patients treated with UF were divided into WRF and control groups. Overall creatinine increased from 1.9 ± 0.7 to 1.2 ± 1.0 mg/dL (P!.001),and WRF developed in 41% of the subjects. The peak UF rate was higher in the WRF group in univariate analysis (174 ± 75 vs 144 ± 52 mL/h; P = .03). Based on multivariate analysis, aldosterone antagonist treatment (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.17-13.46, P = .04), heart rate ≤65 beats/min (OR 6.03, 95% CI 1.48-48.42; P = .03), and E/E0 ≥ 15 (OR 3.78, 95% CI 1.26-17.55; P 5 .04) at hospital admission were associated with WRF. Patients with baseline glomerular filtration rate (GFR) ≤60mg/dL who developed WRF during UF had a 75% 1-year mortality rate. CONCLUSIONS: WRF occurred frequently during UF. Increased LV filling pressures, lower heart rate, and treatment with aldosterone antagonist at hospital admission can identify patients at increased risk for WRF. Patients with baseline GFR ≤60 mg/dL and WRF during UF have an extremely high 1-year mortality rate.

Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation.

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.

Worsening renal function in patients with acute decompensated heart failure treated with ultrafiltration: predictors and outcomes.

BACKGROUND: Ultrafiltration (UF) is used to treat patients with diuretic-resistant acute decompensated heart failure. The aim of this study was to identify predictors and the effect of worsening renal failure (WRF) on mortality in patients treated with UF. METHODS AND RESULTS: Based on changes in serum creatinine, 99 patients treated with UF were divided into WRF and control groups. Overall creatinine increased from 1.9 ± 9.7 to 2.2 ± 2.0 mg/dL (P < .001), and WRF developed in 41% of the subjects. The peak UF rate was higher in the WRF group in univariate analysis (174 ± 45 vs 144 ± 42 mL/h; P = .03). Based on multivariate analysis, aldosterone antagonist treatment (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.17-13.46, P = .04), heart rate ≤65 beats/min (OR 6.03, 95% CI 1.48-48.42; P = .03), and E/E' ≥15 (OR 3.78, 95% CI 1.26-17.55; P = .04) at hospital admission were associated with WRF. Patients with baseline glomerular filtration rate (GFR) ≤60 mg/dL who developed WRF during UF had a 75% 1-year mortality rate. CONCLUSIONS: WRF occurred frequently during UF. Increased LV filling pressures, lower heart rate, and treatment with aldosterone antagonist at hospital admission can identify patients at increased risk for WRF. Patients with baseline GFR ≤60 mg/dL and WRF during UF have an extremely high 1-year mortality rate.

Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis.

BACKGROUND: Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis. METHODS AND RESULTS: Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months. CONCLUSIONS: This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Preoperative Right Heart Dysfunction and Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices.

Gastrointestinal bleeding (GIB) is a common cause of morbidity among patients supported by left ventricular assist devices (LVADs). The aim of this study was to identify if pre-LVAD right ventricular (RV) dysfunction is associated with risk of GIB after LVAD implantation. Of 398 patients implanted with LVADs between July 2008 and July 2016, 130 (33%) developed GIB at a median of 2.6 months following LVAD implantation. Arteriovenous malformations (AVMs) were found in 42 (34%) GIB patients. Patients with GIB were older and more likely to have hypertension, diabetes, and ischemic cardiomyopathy. On pre-LVAD echocardiography, GIB patients had increased RV diastolic dimension (4.7 ± 0.8 vs. 4.4 ± 0.9 cm, p = 0.02), a higher rate of greater than mild tricuspid valve (TV) regurgitation (73 [60%] vs. 120 [47%], p = 0.006), and underwent TV repair more often (38 [30%] vs. 43 [16%], p = 0.0006) during LVAD implantation. After multivariable adjustment, preoperative greater than mild RV enlargement (hazard ratio [HR] 2.32, 95% CI 1.12-5.03; p = 0.03), TV regurgitation (HR 1.83, CI 1.02-3.44; p = 0.01), and TV repair (HR 3.76, confidence interval [CI] 1.02-4.44; p = 0.01) remained associated with risk of GIB. This finding was driven by the AVM-GIB subgroup. Preoperative RV enlargement and TV regurgitation are associated with post-LVAD AVM-related GIB.

Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients.

AIMS: The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression. METHODS AND RESULTS: Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups. CONCLUSION: Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.