Stabilization of Rapidly Progressive Cardiac Allograft Vasculopathy Using mTOR Inhibition After Heart Transplantation.

BACKGROUND: Inhibition of the mammalian target of rapamycin (mTor) pathway after heart transplantation has been associated with reduced progression of coronary allograft vasculopathy (CAV). The application of low-dose mTOR inhibition in the setting of modern immunosuppression, including tacrolimus, remains an area of limited exploration. METHODS: This retrospective study included patients who received heart transplantation between January 2009 and January 2019 and had baseline, 1-year and 2-3-year coronary angiography with intravascular ultrasound (IVUS). Intimal thickness in 5 segments along the left anterior descending artery was compared across imaging time points in patients who were transitioned to low-dose mTOR inhibitor (sirolimus) vs standard treatment with mycophenolate on a background of tacrolimus. Long-term adverse cardiovascular outcomes (revascularization, severe CAV, retransplant, and cardiovascular death) were also assessed. RESULTS: Among 216 patients (mean age 51.5 ± 11.9 years, 77.8% men, 80.1% white), 81 individuals (37.5%) were switched to mTOR inhibition. mTOR inhibition was associated with a reduction in intimal thickness by 0.05 mm (95% CI 0.02-0.07; P < 0.001). This reduction was driven by patients who met the criteria for rapidly progressive CAV 1-year post-transplant (0.12 mm; P = 0.016 for interaction). After a median follow-up of 8.6 (IQR 6.6-11) years, 40 patients had major adverse cardiovascular outcomes. The use of mTOR inhibitors was not significantly associated with cardiovascular outcomes (P = 0.669). CONCLUSION: Transitioning patients after heart transplantation to an immunosuppression regimen composed of low-dose mTOR inhibition and tacrolimus was associated with a lack of progression of CAV, particularly in those with rapidly progressive CAV at 1 year, but not with long-term cardiovascular outcomes.

Beta-Blocker Use and Heart Failure Outcomes in Mildly Reduced and Preserved Ejection Fraction.

BACKGROUND: Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to examine the association of beta-blockers with heart failure (HF) hospitalization and death in patients with HF and EF ≥40% METHODS: Beta-blocker use was assessed at first encounter in outpatients ≥65 years of age with HFmrEF and HFpEF in the U.S. PINNACLE Registry (2013-2017). The associations of beta-blockers with HF hospitalization, death, and the composite of HF hospitalization/death were assessed using propensity-score adjusted multivariable Cox regression models, including interactions of EF × beta-blocker use. RESULTS: Among 435,897 patients with HF and EF ≥40% (HFmrEF, n = 75,674; HFpEF = 360,223), 289,377 (66.4%) were using a beta-blocker at first encounter; more commonly in patients with HFmrEF vs HFpEF (77.7% vs 64.0%; P < 0.001). There were significant interactions between EF × beta-blocker use for HF hospitalization, death, and composite of HF hospitalization/death (P < 0.001 for all), with higher risk with beta-blocker use as EF increased. Beta-blockers were associated with decreased risk of HF hospitalization and death in patients with HFmrEF but a lack of survival benefit and a higher risk of HF hospitalization in patients with HFpEF, particularly when EF was >60%. CONCLUSIONS: In a large, real-world, propensity score-adjusted cohort of older outpatients with HF and EF ≥40%, beta-blocker use was associated with a higher risk of HF hospitalization as EF increased, with potential benefit in patients with HFmrEF and potential risk in patients with higher EF (particularly >60%). Further studies are needed to understand the appropriateness of beta-blocker use in patients with HFpEF in the absence of compelling indications.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors in heart transplant patients with type 2 diabetes: Initial report from a cardiometabolic center of excellence.

Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates.

BACKGROUND: Statins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation. METHODS AND RESULTS: We identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8-9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8-3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102-148 mg/dL) to 55 mg/dL (IQR, 35-74 mg/dL) after starting PCSK9i (P < .001), with 72% of patients achieving a low-density lipoprotein cholesterol of <70 mg/dL after treatment. There were also significant reductions of total cholesterol, non-high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area. CONCLUSIONS: Among heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.

Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients.

BACKGROUND: Gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single-center experience of combined GEP and dd-cfDNA testing for AR surveillance. METHODS: GEP and dd-cfDNA are tested together starting at 2 months post-OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd-cfDNA. This approach was compared to using a GEP-only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd-cfDNA usage. RESULTS: A total of 153 OHT patients over a 13-month period underwent 495 combined GEP/dd-cfDNA tests. 82.2% of dd-cfDNA tests were below threshold. Above threshold results identified high-risk patients who developed AR. 378 combined tests ≥6 months post-OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody-mediated rejection episodes, and no significant AR ≥6 months. CONCLUSION: Routine dd-cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re-classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd-cfDNA identified patients at higher risk for AR.

Comparison of Outcomes Among Patients With Cardiogenic Shock Admitted on Weekends Versus Weekdays.

Cardiogenic shock (CS) is associated with high mortality and often requires involvement of a multidisciplinary provider team to deliver timely care. Care coordination is more difficult on weekends, which may lead to a delay in care. We sought to assess the effect of weekend admissions on outcomes in patients admitted with CS. Patients admitted with CS were identified from 2005 to 2014 in the National Inpatient Sample using ICD9 code 785.51. Baseline demographics, in-hospital procedures, and outcomes were obtained and compared by day of admission. A multivariable model was used to assess the impact of weekend admission on in-hospital mortality. A total of 875,054 CS admissions were identified (age 67.4 ± 15.1 years, 40.2% female, 72.1% Caucasian), with 23% of patients being admitted on weekends. Baseline co-morbidities were similar between groups. Weekend admissions were associated with higher in-hospital mortality (40.6% vs 37.5%) and cardiac arrest (20.3% vs 18.1%, p < 0.001 for both) consistently over the study period. Use of temporary and permanent mechanical support devices and heart transplantation were slightly less common for weekend admissions. In a multivariable model adjusting for relevant confounders, weekend admission was associated with a 10% increased mortality in patients with CS. In conclusion, patients with CS admitted on weekends had higher in-hospital mortality and were slightly less likely to receive mechanical support and advanced therapies compared with those admitted on weekdays. Future studies and health system initiatives should focus on rectifying these disparities with around-the-clock multidisciplinary coordinated care for CS.

Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis.

BACKGROUND: Donor-transmitted atherosclerosis (DTA) and rapidly progressive cardiac allograft vasculopathy (CAV) at 1 year are intravascular ultrasound (IVUS)-derived measures shown to predict adverse cardiovascular outcomes in the setting of early generation immunosuppressive agents. Given the paucity of data on the prognostic value of IVUS-derived measurements in the current era, we sought to explore their association with adverse outcomes after heart transplantation. METHODS AND RESULTS: This is a retrospective cohort analysis of patients who underwent heart transplantation at our center between January 2009 and June 2016 with baseline and 1-year IVUS. Five IVUS sections were prospectively analyzed for intimal thickness and lumen area. DTA was defined as maximum intimal thickness of 0.5 mm or greater at baseline, and rapidly progressive CAV as an increase in maximum intimal thickness by 0.5 mm or more at 1 year. Our primary analysis assessed the relationship of IVUS and other clinical data on a composite outcome: coronary intervention, CAV stage 2 or 3 (defined by the International Society for Heart and Lung Transplantation 2010 nomenclature), or cardiovascular death. Among 249 patients (mean age 51.0 ± 12.2 years and 74.3% male) included in the analysis, DTA was detected in 118 patients (51.4%). Over a median follow-up of 6.1 years (interquartile range 4.2-8.0 years), 45 patients met the primary end point (23 percutaneous coronary intervention, 11 CAV 2 or 3, and 11 cardiovascular deaths as first event). DTA and rapidly progressive CAV were not associated with the primary end point, all-cause mortality, or retransplantation. In an additional analysis including post-transplant events, incident rejection was strongly associated with poor outcomes, although cytomegalovirus infection was not. CONCLUSIONS: In this contemporary cohort, IVUS-derived DTA and rapidly progressive CAV were not associated with medium- to long-term adverse events after heart transplantation.

Evolution of Diagnostic and Treatment Patterns of Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) may impart substantial morbidity and mortality, and novel imaging modalities are now available to aid in early diagnosis of this clinically silent disease. A better understanding of the clinical experience with CS is important. Twenty-eight patients were diagnosed with the aid of multimodality imaging techniques and were treated by a multidisciplinary team. Demographics, symptomatology, imaging, and therapeutic interventions were compiled from our referral center. In patients with CS, nuclear and MR techniques were often the first studies performed. Echocardiographic findings differed widely. Immunosuppressive therapy and cardiac devices were frequently used. Importantly, isolated CS was not an infrequent finding.

Do Sex Differences Exist in the Establishment of "Do Not Attempt Resuscitation" Orders and Survival in Patients Successfully Resuscitated From In-Hospital Cardiac Arrest?

Background Women have higher utilization of "do not attempt resuscitation" (DNAR) orders during treatment for critical illness. Occurrence of sex differences in the establishment of DNAR orders after resuscitation from in-hospital cardiac arrest is unknown. Whether differences in DNAR use by sex lead to disparities in survival remains unclear. Methods and Results We identified 71 820 patients with return of spontaneous circulation (ROSC) after in-hospital cardiac arrest from the Get With The Guidelines-Resuscitation registry. Multivariable models evaluated the association between de novo DNAR (anytime after ROSC, within 12 hours of ROSC, or within 72 hours of ROSC) by sex and the association between sex and survival to discharge accounting for DNAR. All models accounted for clustering of patients within hospital and adjusted for demographic and cardiac arrest characteristics. The cohort included 30 454 (42.4%) women, who were slightly more likely than male participants to establish DNAR orders anytime after ROSC (45.0% versus 43.5%; adjusted relative risk: 1.15 [95% CI, 1.10-1.20]; P<0.0001). Of those with DNAR orders, women were more likely to be DNAR status within the first 12 hours (51.8% versus 46.5%; adjusted relative risk: 1.40 [95% CI, 1.30-1.52]; P<0.0001) and within 72 hours after ROSC (75.9% versus 70.9%; adjusted relative risk: 1.35 [95% CI, 1.26-1.45]; P<0.0001). However, no difference in survival to hospital discharge between women and men (34.5% versus 36.7%; adjusted relative risk: 1.00 [95% CI, 0.99-1.02]; P=0.74) was appreciated. Conclusions In patients successfully resuscitated from in-hospital cardiac arrest, there was no survival difference between men and women while accounting for DNAR. However, women had a higher rate of DNAR status early after resuscitation (<12 and <72 hours) in comparison to men.

Association between hospital rates of early Do-Not-Resuscitate orders and favorable neurological survival among survivors of inhospital cardiac arrest.

BACKGROUND: Current guidelines recommend deferring prognostication for 48 to 72 hours after resuscitation from inhospital cardiac arrest. It is unknown whether hospitals vary in making patients who survive an arrest Do-Not-Resuscitate (DNR) early after resuscitation and whether a hospital's rate of early DNR is associated with its rate of favorable neurological survival. METHODS: Within Get With the Guidelines-Resuscitation, we identified 24,899 patients from 236 hospitals who achieved return of spontaneous circulation (ROSC) after inhospital cardiac arrest between 2006 and 2012. Hierarchical models were constructed to derive risk-adjusted hospital rates of DNR status adoption ≤12 hours after ROSC and risk-standardized rates of favorable neurological survival (without severe disability; Cerebral Performance Category ≤2). The association between hospitals' rates of early DNR and favorable neurological survival was evaluated using correlation statistics. RESULTS: Of 236 hospitals, 61.7% were academic, 83% had ≥200 beds, and 94% were urban. Overall, 5577 (22.4%) patients were made DNR ≤12 hours after ROSC. Risk-adjusted hospital rates of early DNR varied widely (7.1%-40.5%, median: 22.7% [IQR: 19.3%-26.1%]; median OR of 1.48). Significant hospital variation existed in risk-standardized rates of favorable neurological survival (3.5%-44.8%, median: 25.3% [IQR: 20.2%-29.4%]; median OR 1.72). Hospitals' risk-adjusted rates of early DNR were inversely correlated with their risk-standardized rates of favorable neurological survival (r=-0.179, P=.006). CONCLUSIONS: Despite current guideline recommendations, many patients with inhospital cardiac arrest are made DNR within 12 hours after ROSC, and hospitals vary widely in rates of early DNR. Higher hospital rates of early DNR were associated with worse meaningful survival outcomes.

Palliative Care Clinicians Caring for Patients Before and After Continuous Flow-Left Ventricular Assist Device.

Left ventricular assist devices (LVADs) are an available treatment option for carefully selected patients with advanced heart failure. Initially developed as a bridge to transplantation, LVADs are now also offered to patients ineligible for transplantation as destination therapy (DT). Individuals with a DT-LVAD will live the remainder of their lives with the device in place. Although survival and quality of life improve with LVADs compared with medical therapy, complications persist including bleeding, infection, and stroke. There has been increased emphasis on involving palliative care (PC) specialists in LVAD programs, specifically the DT-LVAD population, from the pre-implantation process through the end of life. Palliative care specialists are well poised to provide education, guidance, and support to patients, families, and clinicians throughout the LVAD journey. This article addresses the complexities of the LVAD population, describes key challenges faced by PC specialists, and discusses opportunities for building collaboration between PC specialists and LVAD teams.

Changes in disease-specific versus generic health status measures after left ventricular assist device implantation: Insights from INTERMACS.

BACKGROUND: Quantifying quality of life (QoL) after left ventricular assist device (LVAD) remains challenging. Heart failure (HF)-specific health status measures are ideal for assessing symptoms of HF; however, if patients' QoL is limited by other factors, they may experience improved HF-specific QoL but no concurrent improvement in generic QoL. We sought to examine and predict discrepancies between disease-specific and generic QoL measures after LVAD. METHODS: We examined HF-specific and generic QoL with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol-5D Visual Analog Scale (VAS), respectively, among 1,888 patients with advanced heart failure who underwent LVAD implantation from 2012 to 2014 as part of the INTERMACS registry. RESULTS: Both measures showed substantial improvement, on average, at 6 months after LVAD, with mean changes of 32.7 ± 25.0 and 27.6 ± 27.4, respectively. Among the 1,539 patients (81.5%) with moderate/large improvement in KCCQ, 334 (21.7%) had discordant changes in generic QoL (i.e., VAS did not substantially increase despite improvement in KCCQ). In a multivariable logistic regression model, baseline VAS score was the strongest predictor of KCCQ-VAS discordance, whereas post-LVAD complications were not significant predictors of discordance. CONCLUSIONS: Most patients have major improvements in both HF-specific and generic QoL after LVAD implantation, and discordance in these measures after LVAD is uncommon. When it did occur, discordance was primarily observed in patients who reported good generic QoL on the VAS before LVAD (despite substantial impairment due to congestive HF). These results support the continued use of HF-specific health status measures to monitor QoL before and after LVAD implantation.

Association of global and disease-specific health status with outcomes following continuous-flow left ventricular assist device implantation.

BACKGROUND: The prognostic value of heart failure specific and global health status before and after left ventricular assist device (LVAD) implantation in the usual care setting is not well studied. METHODS: We included 3,836 continuous-flow LVAD patients in the INTERMACS registry. Health status was measured pre-operatively and 3 months post-LVAD using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol visual analog scale (VAS). Primary outcomes were mortality/rehospitalization. Inverse propensity weighting was used to minimize bias from missing data. RESULTS: Pre-operative global and heart failure-specific health status were very poor: KCCQ median 34.6 (IQR 21.4-50.5); VAS median 43 (interquartile range (IQR) 25-65). Health status measures improved 3 months after LVAD placement: KCCQ median 69.3 (IQR 54.2-82.3); VAS median 75 (IQR 60-85). Pre-operative health status was not associated with death (unadjusted HR for lowest vs. highest score quartiles: 1.09 (0.85-1.41) KCCQ; 1.12 (0.85-1.49) VAS) or rehospitalization (unadjusted HR 0.83 (0.72-0.96) KCCQ; 0.99 (0.85-1.16) VAS). Three-month KCCQ was associated with mortality (unadjusted HR 2.17 (1.47-3.21); VAS was not (1.43 (0.94-2.17). Three-month KCCQ added incremental discriminatory value to the HeartMate II Risk Score for death (c-stat 0.60 to 0.66); VAS did not (c-stat 0.59 to 0.60). Three-month health status was associated with rehospitalization (unadjusted HR 1.31 (1.15-1.57) KCCQ; 1.24 (1.05-1.46) VAS), but did not add incremental discriminatory value (c-stat 0.52 to 0.55 and 0.54, respectively). CONCLUSIONS: These real-world data suggest that pre-operative health status has limited association with outcomes after LVAD. However, persistently low health status after surgery may independently signal higher risk for subsequent death. Further study is needed to determine the clinical utility of routinely collected health status data after LVAD implantation.

Global Outcome in Patients With Left Ventricular Assist Devices.

Left ventricular assist devices (LVADs) improve survival and quality of life (QOL) for most, but not all, patients with advanced heart failure. We described a broader definition of poor outcomes after LVAD, using a novel composite of death, QOL, and other major adverse events. We evaluated the frequency of poor global outcome at 1 year after LVAD among 164 patients (86% Interagency Registry for Mechanically Assisted Circulatory Support profile 1 to 2; shock or declining despite inotropes) at a high-volume center. Poor global outcome (comprising death, poor QOL [Kansas City Cardiomyopathy Questionnaire <45], recurrent heart failure [≥2 heart failure readmissions], or severe stroke) occurred in 58 patients (35%): 37 died, 17 had poor QOL, 3 had recurrent heart failure, and 1 had a severe stroke. Patients with poor global outcomes were more likely designated for destination therapy (46% vs 24%, p = 0.01), spent more days hospitalized per month alive (median [interquartile range] 18.6 [5.0 to 31.0] vs 3.7 [1.8 to 8.3], p <0.001), and had higher intracranial (12% vs 2%, p = 0.031) and gastrointestinal (44% vs 28%, p = 0.056) hemorrhage rates over the year after implant. Although LVADs often improve survival and QOL, ∼1/3 of high-acuity patients experienced a poor global outcome over the year after LVAD. In conclusion, composite outcomes may better capture events that matter to patients with LVADs and thus support informed decisions about pursuing LVAD therapy.

Health Status Trajectories Among Outpatients With Heart Failure.

CONTEXT: Health status (i.e., symptoms, function, and quality of life) is an important palliative care outcome in patients with heart failure; however, patterns of health status over time (i.e., trajectories) are not well described. OBJECTIVES: The objective of this study was to identify health status trajectories in outpatients with heart failure and assess whether depression, symptom burden, or sense of peace predict health status trajectory. METHODS: This is an observational study utilizing data from the Patient-Centered Disease Management for Heart Failure trial. Participants completed Kansas City Cardiomyopathy Questionnaires at baseline, three, six, and 12 months. Latent class growth analysis identified health status trajectories; multinomial logistic regression models identified predictors of trajectory membership. RESULTS: Patients (n = 384) were primarily men (97%) and older (mean age 67.6 ± 10.1). Three health status trajectories were identified. All three trajectories improved at three months; however, the marked improvement health status trajectory (n = 19) showed progressive improvement over one year, whereas the poor (n = 119) and moderate (n = 246) health status trajectories had little change after three months. In adjusted analyses, worse baseline depression (odds ratio 1.10; 95% confidence interval 1.01-1.20), symptom burden (1.45; 1.15-1.83), and sense of peace (0.41; 0.22-0.75) predicted membership in the poor vs. moderate health status trajectory. CONCLUSION: We identified three one-year health status trajectories in patients with heart failure, with the two most common trajectories characterized by early improvement followed by limited change. Future research should assess these findings in nonveterans and women and explore whether treatment of depression, high symptom burden, and low sense of peace leads to improved long-term heart failure health status trajectory.