Inhibition of angiogenesis in the management of refractory gastrointestinal bleeding in patients with LVAD support.

BACKGROUND: Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD-associated GIAD bleeding, and now present follow-up data on patients treated with IV bevacizumab and/or low-dose oral pazopanib. METHODS: All consecutive adult patients with LVAD-associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3-59.8 months). RESULTS: Eleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference - 2.87, p = 0.002), blood transfusions (median difference - 20.9, p = 0.01), and endoscopies (median difference - 6.95, p = 0.007) in patients pre- and post-anti-angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference - 2.75, p = 0.014), blood transfusions (median difference - 24.5, p = 0.047), and number of endoscopies (median differences -6.88, p = 0.006). CONCLUSION: Anti-angiogenic therapy with IV bevacizumab and/or low-dose oral pazopanib appears to provide benefits in patients with LVAD-associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Left Ventricular Hemodynamics and Relationship With Myocardial Recovery and Optimization in Patients Supported on CF-LVAD Therapy.

BACKGROUND: Despite interest in left ventricular (LV) recovery, there is an absence of data on the relationship between intrinsic LV hemodynamics and both reverse remodeling on a continuous flow LV assist device (CF-LVAD) therapy. We hypothesized that the markers of intrinsic LV function would be associated with remodeling, optimization, and outcomes. METHODS AND RESULTS: Patients with continuous flow LVADs between 2015 and 2019 who underwent combined left and right heart catheterization ramp protocol at a single institution were enrolled. Patients were stratified by response to continuous flow LV assist device therapy: full responders, partial responders, or nonresponders per the Utah-Inova criteria. Hemodynamic data, including LV hemodynamics of peak LV dP/dt and tau (τ) were obtained at each phase. The 1-year heart failure hospitalization-free survival was the primary end point. Among 61 patients included in the current study 38 (62%) were classified as nonresponders, 14 as partial responders (23%), and 9 as full responders (15%). The baseline LV dP/dt and τ varied by response status (P ≤ .02) and generally correlated with reverse remodeling on linear regression. Biventricular filling pressures varied with τ and there was an interaction effect of speed on the relationship between τ and pulmonary capillary wedge pressure (P = .04). Last, τ was a prognostic marker and associated with 1-year HF hospital-free survival (odds ratio 1.04, 95% confidence interval 1.00-1.07, P = .02 per millisecond increase). CONCLUSIONS: Significant correlations between τ and LV dP/dt and reverse remodeling were noted, with τ serving as a prognostic marker. A higher LVAD speed was associated with a greater reliance on LVAD for unloading. Future work should focus on defining the optimal level of LVAD support in relation to LV recovery.

Incidence, Risk Factors, and Outcomes of Stroke Following Cardiac Transplantation.

Background and Purpose: Less is known about the risk factors and outcomes associated with stroke in the current era of increasing heart transplantation (HT) being performed in older patients. The impact of immunosuppression on risk of stroke has not yet been previously studied. We aimed to determine the incidence, risk factors and outcomes of stroke after HT. Methods: We retrospectively analyzed the incidence of ischemic and hemorrhagic strokes and associated outcomes in all consecutive HT recipients transplanted between 1994 and 2016 at a single institution. Results: Of 529 patients who underwent HT, 57 (10.7%) developed stroke, 8.1% had an ischemic events and (2.6%) had a hemorrhagic stroke. Age at HT (adjusted hazard ratio [HR] 1.33; P=0.03) and diabetes (HR, 2.60; P=0.02) were associated with increased risk of ischemic events. Patients with stroke (any type) were more likely to have worse kidney function (HR, 1.81; P=0.02) whereas patients with ischemic events were more likely to undergo combined organ transplantation (HR, 2.01; P=0.05). Cytomegalovirus infection was found to be associated with increased risk of any stroke (HR, 2.09; P=0.02).Conversion from calcineurin inhibitor to sirolimus-based immunosuppression was not found to be associated with a significant change in stroke risk (HR, 1.39; P=0. 45) compared with calcineurin inhibitor maintenance therapy. Stroke of any type and ischemic events were independently associated with increased risk of death (HR, 1.90; P=0.001 and HR, 2.14; P<0.001, respectively). Conclusions: Stroke after HT is associated with increased mortality. Older age at HT, diabetes, renal dysfunction, and CMV infection were associated with greater risk of stroke.

Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients.

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation.

BACKGROUND: Enhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit. METHODS AND RESULTS: CAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16). CONCLUSIONS: Early ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events.

Malignancy among adult heart transplant recipients following patient-tailored dosing of anti-thymocyte globulin: a retrospective, nested case-control study of individualized dosing.

Post-transplant malignancy is diagnosed in approximately 18% of heart transplant patients and is a leading cause of death post-transplant. One modifiable risk factor is the type and amount of immunosuppression received. Contemporary rabbit anti-thymocyte globulin (rATG) dosing strategy using T-cell-guided dosing, and its effect on malignancy in heart transplant patients is unclear. This was a single-center, retrospective chart review of heart transplant recipients receiving rATG for induction. Patients diagnosed with malignancy post-transplant were matched 1:2 to controls using a nested case-control design. The primary endpoint was to determine the relative risk of rATG exposure with the actual incidence of malignancy post-transplant. The secondary endpoint was the impact of maintenance immunosuppression on malignancy risk. Of the 126 patients included in the study, 25 developed malignancy and were matched to 50 control patients. The median cumulative rATG dose in milligrams (mg) between groups was 365 mg in malignancy cases and 480 mg in controls (OR 0.90, 95% CI 0.75-1.08, P = 0.28). In both the univariate and multivariable analysis, there was no statistically significant difference in malignancy risk found with any maintenance immunosuppressant. The results of this study showed that patient-tailored rATG dosing strategies may not be associated with malignancy development as previously thought.

The influence of anti-hyperglycemic drug therapy on cardiovascular and heart failure outcomes in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (DM) are at a substantially increased risk of heart failure (HF) and HF mortality. Despite the lack of evidence that tight glycemic control reduces the incidence of cardiovascular (CV) events, a growing body of evidence suggests that the choice of glucose-lowering agents may influence outcomes including HF. Thiazolidinediones are associated with a significant risk of HF. For metformin, sulphonylureas and insulin, little data is available to indicate the impact on HF. The glucagon-like peptide-1 (GLP-1) agonists, liraglutide and semaglutide, have been shown to reduce major CV events, but did not affect rates of hospitalization for HF. Clinical trials have demonstrated diverse effects of Dipeptidyl peptidase-4 (DPP-4) inhibitors on HF; saxagliptin showed an increased risk of HF admissions, alogliptin was associated with higher rates of new HF admissions, while sitagliptin had a neutral effect. The sodium-glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have been recently shown to reduce the incidence of HF and cardiovascular mortality in patients with and without a history of HF. This review will summarize key findings of the impact of glucose-lowering agents on CV safety and HF-associated outcomes, present available data on the underlying mechanisms for the benefits of the SGLT2 inhibitors on HF, and discuss strategies to improve outcomes in patients with DM and high CV risk.

Elevated ST2 levels are associated with antibody-mediated rejection in heart transplant recipients.

Soluble ST2 (sST2) is a novel biomarker of inflammation and fibrosis. Elevated sST2 levels (≥35 ng/mL) are associated with worse outcomes in patients with heart failure (HF). There are sparse data regarding the significance of sST2 levels after heart transplantation (HTx). The study aims were to evaluate trends in soluble ST2 levels after the resolution of HF status with HTx and association between post-HTx sST2 levels and outcomes. Plasma sST2 levels were measured at baseline (median [IQR] of 118 days pre-HTx) and 12 months post-HTx in 62 subjects who were stratified into two groups by post-HTx sST2 levels < or ≥35 ng/mL: "Group 1" or "Group 2," respectively. Plasma sST2 levels were elevated in 58% of patients pre-HTx and in 50% of patients post-HTx. There was no association between elevated sST2 levels before and after HTx, and no significant differences in baseline characteristics between Group 1 and Group 2 patients. Group 2 as compared to Group 1 HTx recipients had significantly higher incidence of antibody-mediated rejection (AMR) for the entire post-transplant follow-up period (32% vs 4%, P = 0.006). There was no association between post-HTx sST2 level status and other post-HTx outcomes including survival. In conclusion, elevated plasma sST2 levels after HTx are associated with increased risk for AMR.

Psychosocial characteristics and outcomes in patients with left ventricular assist device implanted as destination therapy.

BACKGROUND: Psychosocial factors impact survival in patients undergoing cardiac transplantation, but it is unclear whether they affect outcomes in patients undergoing left ventricular assist device (LVAD) implantation as destination therapy (DT). METHODS: Patients undergoing DT LVAD at the Mayo Clinic in Rochester, MN, from February 2007 to December 2013 were included. Psychosocial characteristics at the time of LVAD implantation were abstracted from the medical record. Andersen-Gill and Cox models were used to examine the association between psychosocial characteristics and all-cause readmission and death, respectively. Patients were censored at death or last follow-up through September 2014. RESULTS: Among 136 patients (mean age. 64 years; 17% female), most were married/living with a partner (82%), half (55%) had post-high school education, and a history of depression was common (32%). Although most patients were former tobacco users (60%) only a small proportion were current tobacco users (10%) and had a history of alcohol abuse (16%) or illegal drug use (7%). After a mean follow-up of 2.2 ± 1.8 years, 78% of patients had been readmitted (range, 0-14 per person) and 49% had died. There were no statistically significant differences in the risk of death according to psychosocial characteristics. However, current tobacco users had lower risk of readmission (adjusted HR, 0.57; 95% CI, 0.38-0.88), while illegal drug use (HR, 1.55; 95% CI, 1.01-2.35) and depression (HR, 1.77; 95% CI, 1.40-2.22) were associated with higher readmission risk. CONCLUSIONS: Psychosocial characteristics are not significant predictors of death but are associated with readmission risk after DT LVAD.

Use of Post-acute Care Services and Readmissions After Left Ventricular Assist Device Implantation in Privately Insured Patients.

BACKGROUND: Very little is known about health care resource utilization, including post-acute care use and hospital readmissions, after left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: Administrative claims from a database of multiple United States health plans were used to identify patients that received an LVAD (ICD-9 code 37.66) and survived to hospital discharge from January 1-2006, through September 30-2013. Post-acute care use was defined as a skilled nursing facility or rehabilitation stay within 90 days after hospital discharge. Patients were censored at heart transplantation or end of coverage through December 31-2013. Of 583 patients (mean age 55 years, 77% male), 223 (38.3%) used post-acute care services, more commonly in patients with diabetes, who required hemodialysis, and who had LVADs implanted at hospitals in more populated areas, with more beds, and in the northeast region (P < .05 for each). The most common reasons for readmission were device complications, heart failure, and arrhythmia. Readmission risk was higher in patients who had diabetes, peripheral vascular disease, and longer hospital length of stay, but it did not differ by post-acute care use. CONCLUSIONS: Use of post-acute care services varies based on hospital characteristics. We found no association between post-acute care use and readmission risk after LVAD implantation.

Attenuation in peripheral endothelial function after continuous flow left ventricular assist device therapy is associated with cardiovascular adverse events.

BACKGROUND: Patients with heart failure (HF) have abnormal endothelial function. Although use of a continuous flow left ventricular assist device (CF-LVAD) results in significant hemodynamic improvement, the effects on systemic endothelial function are unclear. METHODS AND RESULTS: Eighteen HF patients with CF-LVAD implantation were included in this prospective observational study. We measured reactive hyperemia index (RHI) before and after CF-LVAD implantation to evaluate sequential changes in endothelial function. Patients were followed clinically for the occurrence of adverse cardiovascular events, a composite of death, thrombosis, bleeding, HF, renal failure, and arrhythmia. Preoperative RHI was 1.77±0.39. Early in the postoperative period (7-14 days after operation) RHI significantly decreased to 1.19±0.31 (P<0.001, compared with preoperative RHI). At first and second follow-up (4-6 weeks and 3-7 months after operation) RHI remained lower at 1.48±0.50 (P=0.030) and 1.26±0.37 (P=0.002), respectively, compared with preoperative RHI. The decrease in early postoperative RHI relative to preoperative RHI was significantly associated with adverse cardiovascular events after CF-LVAD (age-adjusted risk ratio for 0.25 decrease in RHI, 1.35; 95% confidence interval: 1.13-1.62, P=0.001). CONCLUSIONS: Peripheral endothelial function had a significant and persistent decline up to 5 months following implantation of CF-LVAD, and this decline was associated with adverse cardiovascular events. These findings may provide insight into some of the vascular complications following CF-LVAD in HF patients.

Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography.

AIMS: Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival following cardiac transplantation. Conventional imaging modalities such as angiography and intravascular ultrasound fail to characterize CAV plaque morphology. Our aim was to characterize CAV in vivo using the high spatial resolution of intracoronary optical coherence tomography (OCT). METHODS AND RESULTS: We prospectively enrolled 53 cardiac transplant patients to undergo OCT of the left anterior descending coronary artery (LAD) in addition to annual CAV screening by coronary angiography and intravascular ultrasound (IVUS). The proximal 30 mm of the LAD was divided into three segments of 10 mm each (n = 156). Segments with CAV plaque on IVUS were analysed by OCT for specific CAV morphological characteristics within the framework of three groups according to follow-up time after heart transplantation: (i) 0-3 months (n = 18), (ii) 12-36 months (n = 55), and (iii) ≥48 months (n = 83). The prevalence of atherosclerotic characteristics such as eccentric plaques, calcification, and lipid pools increased from 6, 0, and 6% in group 1 to 78, 42, and 61% in group 3, respectively (all P < 0.001). The prevalence of vulnerable plaque features such as thin-cap fibroatheroma, macrophages, and microchannels increased from 0% in group 1 to 12, 29, and 33% in group 3, respectively (P = 0.19, P = 0.006, and P = 0.003). Complicated coronary lesions such as intimal laceration, intraluminal thrombus, and layered complex plaque increased from 0% in group 1 to 18, 19, and 57% in group 3 (P = 0.009, P < 0.001, and P < 0.001). Plaque rupture was identified in 4% of group 3 segments. CONCLUSION: The current study gives new insight into CAV that extends far beyond the current concept of concentric and fibrosing vasculopathy, that is, the development of atherosclerosis with vulnerable plaque and complicated coronary lesions.

Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy.

AIMS: The pathogenesis of cardiac allograft vasculopathy (CAV) remains complex and may involve multiple mechanisms. We tested the hypothesis that the multilayer (ML) appearance, an intravascular ultrasound (IVUS) finding suggestive of repetitive thrombosis, is associated with plaque progression in heart transplant (HTx) recipients. METHODS AND RESULTS: Our study population consisted of 132 HTx recipients undergoing at least two grayscale and virtual histology (VH)-IVUS examinations. A retrospective serial analysis was performed between the first (baseline) and the last (follow-up) IVUS data during a median follow-up of 3.0 years. The subjects were divided into two groups based on the presence of the ML appearance on the baseline IVUS. At baseline, subjects with ML appearance (n = 38) had a longer time elapsed since transplant, larger vessel volume, and larger plaque volume than those without (n = 94) (all P < 0.01). Intraluminal thrombi and plaque ruptures were identified only in subjects with ML appearance (P < 0.01 vs. those without). More subjects with ML appearance at baseline developed subsequent ML formation compared with those without [21 (55%) vs. 22 (23%), P < 0.01] during follow-up. There was an increase in plaque volume, necrotic core volume, and dense calcium volume in subjects with ML appearance (all P < 0.01 vs. those without). Multivariable linear regression analysis showed that ML appearance was a potential predictor of plaque progression (regression coefficient 0.28, 95% CI 0.10-0.45, P < 0.01). CONCLUSIONS: The current study demonstrates that a finding of ML appearance, indicative of repeated episodes of mural thrombosis, is not infrequent in asymptomatic HTx recipients and possibly contributes to progression of CAV.

Cardiac transplantation after bridged therapy with continuous flow left ventricular assist devices.

INTRODUCTION: Cardiac transplantation is an effective surgical therapy for end-stage heart failure. Patients (pts) may need to be bridged with a continuous flow left ventricular assist device (CF-LVAD) while on the transplant list as logistic factors like organ availability are unknown. Cardiac transplantation post-LVAD can be a surgically challenging procedure and outcome in these pts is perceived to be poorer based on experience with earlier generation pulsatile flow pumps. Data from a single institution comparing these pts with those undergoing direct transplantation in the present era of continuous flow device therapy are limited. AIM: Evaluate results of cardiac transplantation in pts bridged with a CF-LVAD (BTx) and compare outcomes with pts undergoing direct transplantation (Tx) in a single institution. RESULTS: From June 2007 till January 2012, 106 pts underwent cardiac transplantation. Among these, 37 (35%) pts (51±11 years; 85% male) were bridged with a CF-LVAD (BTx), while 70 (65%) comprised the Tx group (53±12 years; 72% males). The median duration of LVAD support was 227 (153,327) days. During the period of LVAD support, 10/37 (27%) pts were upgraded to status 1A and all were successfully transplanted. Median hospital stay in the BTx (14 days) was slightly longer than the Tx group (12 days) but not statistically significant (p=0.21). In-hospital mortality in the BTx (5%) and Tx (1%) were comparable (p=0.25). Estimated late survival in the BTx cohort was 94±7, 90±10 and 83±16% at the end of one, two and three years, respectively which was comparable to 97±4%, 93±6% and 89±9% for the Tx group (p=0.50). CONCLUSION: Cardiac transplantation after LVAD implant can be performed with excellent results. Patients can be supported on the left ventricular assist device even for periods close to a year with good outcome after cardiac transplantation.

Reversibility of precapillary pulmonary hypertension and outcomes after heart transplantation bridged with left ventricular assist devices: Insight from the United Network for Organ Sharing.

BACKGROUND: In light of the updated lowered threshold for diagnosing pulmonary hypertension (PH), the reversibility of precapillary PH with left ventricular assist device (LVAD) and the associated post-heart transplantation (HT) outcomes remain unclear. METHODS: Using data from the United Network for Organ Sharing database, we aimed to investigate predictors of persistent precapillary PH in HT recipients bridged with LVAD and examine the interrelated post-HT survival using the updated pulmonary vascular resistance (PVR) cutoff of >2 Wood units for precapillary PH. RESULTS: Among 2169 HT recipients bridged with LVAD, 1299 had PVR >2 at baseline; 551 (42.4%) of whom normalized their PVR ≤2 and 748 (57.6%) remained with elevated PVR >2 after LVAD implantation. Female sex (adjusted odds ratio [aOR]; 2.22, 95% confidence interval [CI], 1.61-3.07; P < .001) and inotrope treatment at listing (aOR, 1.31; 95% CI, 1.03-1.66; P = .028) were associated with persistently elevated PVR after LVAD. Conversely, longer duration of LVAD support (aOR, 0.74; 95% CI, 0.65-0.84; P < .001) and use of HeartMate II (aOR, 0.74; CI, 0.59-0.93; P = .011) were found to be protective against persistently elevated PVR after LVAD. Persistently elevated PVR >2 after LVAD was associated with increased risk of death compared with those who normalized their PVR (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.01-1.57; P = .037). However, the normalized PVR post-LVAD group had comparable survival with those with PVR ≤2 at baseline (aHR, 0.76; 95% CI, 0.57-1.02; P = .07). CONCLUSIONS: Many recipients of HT bridged with LVAD remain with PVR >2 after LVAD implantation, which is associated with increased risk of death after HT compared with patients with normalized PVR after LVAD.

Using PAH-SYMPACT to assess quality of life in patients with pulmonary hypertension associated with chronic lung disease.

Chronic lung disease (CLD) is the second leading cause of pulmonary hypertension (PH) and is associated with significant morbidity and mortality. Although PH associated with CLD (PH-CLD) leads to impaired health-related quality of life (HRQOL), there are no validated tools to assess HRQOL in PH-CLD. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT) is an HRQOL instrument aimed at assessing the symptoms and impact of PH on overall function and well-being. We performed a single-center prospective cohort study using PAH-SYMPACT scores to compare symptoms, exercise capacity and HRQOL in patients with PAH and PH-CLD. One hundred and twenty-five patients (99 patients with idiopathic/heritable PAH and 26 with PH-CLD) completed the PAH-SYMPACT questionnaire which consists of 22 questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive/emotional (CE) impact. Higher scores indicate worse HRQOL. We compared patients with PAH and PH-CLD using a Wilcoxon rank sum or chi-squared test as appropriate. Multivariate linear regression analysis was used to assess the relationship between PH classification and SYMPACT scores. Compared to PAH, patients with PH-CLD were older, more likely to use oxygen and had worse functional class and exercise capacity. While there was no significant difference between the two groups in CP, CV, or CE domain scores, patients with PH-CLD had significantly worse PI scores by univariate (1.79 vs. 1.13, p < 0.001) and multivariate analysis (1.61 vs. 1.17, p = 0.02) and overall worse SYMPACT scores (1.19 vs. 0.91, p = 0.03). In conclusion, patients with PH-CLD have worse HRQOL as assessed by the PAH-SYMPACT questionnaire versus patients with PAH. Although PAH-SYMPACT has not been validated in PH-CLD, the results of this study can guide clinicians in understanding the symptoms and impact of PH-CLD relative to PAH.

Adult Congenital Heart Disease Transplantation: Does Univentricle Physiology Impact Early Mortality?

BACKGROUND: With congenital heart disease patients increasingly living into adulthood, there is a growing population of adult congenital heart disease (ACHD) patients suffering from heart failure. Limited data exist evaluating heart transplant in this population. METHODS: Retrospective review was performed of ACHD patients undergoing heart transplantation 11/1990-1/2023. Kaplan-Meier, cumulative incidence accounting for competing risk of death, and subgroup analyses comparing those with biventricular (BiV) and univentricular (UniV) physiology were performed. Data are presented as median (interquartile range) or counts (%). RESULTS: 77 patients with a median age of 36 years (27, 45) were identified, including 57 (74%) BiV and 20 (26%) UniV. Preoperatively, UniV patients were more likely to have cirrhosis (9/20 [45.0%] vs 4/57 [7.0%], p<0.001) and protein losing enteropathy (4/20 [20.0%] vs 1/57 [1.8%], p=0.015). Multiorgan transplantation was performed in 23 patients (30%) and more frequently in UniV patients (10 [50%] vs. 13[23%], p=0.04). Operative mortality was 6.5%, 2/20 (10%) among UniV and 2/57 (4%) among BiV patients, p=0.276. Median clinical follow-up was 6.0 (1.4, 13.1) years. Survival tended to be lower among UniV patients compared to BiV patients, particularly within the first year (p=0.09), but was similar for survivors beyond one year. At 5 years, incidence of rejection was 28% (17%, 38%) and coronary allograft vasculopathy was 16% (7%, 24%). CONCLUSIONS: Underlying liver disease and need for heart/liver transplantation were significantly higher among UniV patients. Survival tended to be lower among UniV, particularly within the first year, but was similar for survivors beyond one year.

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.

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation.

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.