Dapagliflozin versus sacubitril-valsartan for heart failure with mildly reduced or preserved ejection fraction.

Background and aim: Heart failure with preserved ejection fraction (HFpEF) is associated with an increased risk of heart failure (HF) hospitalizations and cardiovascular death (CVD). Both dapagliflozin and sacubitril-valsartan have recently shown convincing reductions in the combined risk of CVD and HF hospitalizations in patients with HF and mildly reduced ejection fraction (HFmrEF) or HFpEF. We aimed to investigate the cost-per-outcome implications of dapagliflozin vs sacubitril-valsartan in the treatment of HFmrEF or HFpEF patients. Methods: We compared the annualized cost needed to treat (CNT) to prevent the composite outcome of total HF hospitalizations and CVD with dapagliflozin or sacubitril-valsartan. The CNT was estimated by multiplying the annualized number needed to treat (aNNT) by the annual cost of therapy. The aNNT was calculated based on data collected from the DELIVER trial for dapagliflozin and a pooled analysis of the PARAGLIDE-HF and PARAGON-HF trials for sacubitril-valsartan. Costs were based on 2022 US prices. Scenario analyses were performed to attenuate the differences in the studies' populations. Results: The aNNT with dapagliflozin in DELIVER was 30 (95% confidence interval [CI]: 21-62) versus 44 (95% CI: 25-311) with sacubitril-valsartan in a pooled analysis of PARAGLIDE-HF and PARAGON-HF, with an annual cost of $4,951 and $5,576, respectively. The corresponding CNTs were $148,547.13 (95% CI: $103,982.99-$306,997.39) for dapagliflozin and $245,346.77 (95% CI: $139,401.58-1,734,155.60) for sacubitril-valsartan for preventing the composite outcome of CVD and HF hospitalizations. The CNT for preventing all-cause mortality was lower for dapagliflozin than sacubitril-valsartan $1,128,958.15 [CI: $401,077.24-∞] vs $2,185,816.71 [CI: $607,790.87-∞]. Conclusion: Dapagliflozin provides a better monetary value than sacubitril-valsartan in preventing the composite outcome of total HF hospitalizations and CVD among patients with HFmrEF or HFpEF.

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.

Perimyocarditis Associated with Immune Checkpoint Inhibitors: A Case Report and Review of the Literature.

Patient prognoses have been significantly enhanced by immune checkpoint inhibitors (ICIs), altering the standard of care in cancer treatment. These novel antibodies have become a mainstay of care for metastatic non-small-cell lung cancer (mNSCLC) patients. Several types of adverse events related to ICIs have been identified and documented as a result of the launch of these innovative medicines. We present here a 74-year-old female patient with a stage IV lung adenocarcinoma, treated with nivolumab plus ipilimumab, who developed perimyocarditis two weeks after receiving the third cycle of immune checkpoint inhibitor therapy. The patient was diagnosed using troponin levels, computed tomography (CT) angiography, and echocardiography. After hospitalization, her cardiac condition was successfully resolved with corticosteroids, colchicine, and symptomatic treatment. To the best of our knowledge, this is one of the rarest cases to be reported of perimyocarditis as a toxicity of immunotherapy in a patient treated for adenocarcinoma of the lung.

Cardiac magnetic resonance imaging in heart transplant recipients with biopsy-negative graft dysfunction.

AIMS: Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. METHODS AND RESULTS: HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by >5% and LVEF < 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF < 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4-6.8) vs. 0.8 (0.3-1.2) years, P < 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37-55%) and LGE-positive groups (32-55%) (P = 0.16). CONCLUSIONS: Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.

Amiodarone and pulmonary toxicity in atrial fibrillation: a nationwide Israeli study.

BACKGROUND AND AIMS: Amiodarone-related interstitial lung disease (ILD) is the most severe adverse effect of amiodarone treatment. Most data on amiodarone-related ILD are derived from periods when amiodarone was given at higher doses than currently used. METHODS: A nationwide population-based study was conducted among patients with incident atrial fibrillation (AF) between 1 December 1999 and 31 December 31 2021. Amiodarone-exposed patients were matched 1:1 with controls unexposed to amiodarone based on age, sex, ethnicity, and AF diagnosis duration. The final patient cohort included only matched pairs where amiodarone therapy was consistent throughout follow-up. Directed acyclic graphs and inverse probability treatment weighting (IPTW) modelling were used. Patients with either prior ILD or primary lung cancer (PLC) were excluded. The primary outcome was the incidence of any ILD. Secondary endpoints were death and PLC. RESULTS: The final cohort included 6039 amiodarone-exposed patients who were matched with unexposed controls. The median age was 73.3 years, and 51.6% were women. After a mean follow-up of 4.2 years, ILD occurred in 242 (2.0%) patients. After IPTW, amiodarone exposure was not significantly associated with ILD [hazard ratio (HR): 1.45, 95% confidence interval (CI): 0.97, 2.44, P = 0.09]. There was a trivial higher relative risk of ILD among amiodarone-exposed patients between Years 2 and 8 of follow-up [maximal risk ratio (RR): 1.019]. Primary lung cancer occurred in 97 (0.8%) patients. After IPTW, amiodarone was not associated with PLC (HR: 1.18, 95% CI: 0.76, 2.08, P = 0.53). All-cause death occurred in 2185 (18.1%) patients. After IPTW, amiodarone was associated with reduced mortality risk (HR: 0.65, 95% CI: 0.60, 0.72, P < 0.001). The results were consistent across a variety of sensitivity analyses. CONCLUSION: In a contemporary AF population, low-dose amiodarone was associated with a trend towards increased risk of ILD (15%-45%) but a clinically negligible change in absolute risk (maximum of 1.8%), no increased risk of PLC, and a lower risk of all-cause mortality.

Sex differences in ventricular arrhythmia, atrial fibrillation and atrioventricular block complicating acute myocardial infarction.

Background: Acute myocardial infarction (AMI) complicated by tachyarrhythmias or high-grade atrioventricular block (HAVB) may lead to increased mortality. Purpose: To evaluate the sex differences in patients with AMI complicated by tachyarrhythmias and HAVB and their associated outcomes. Materials and methods: We analyzed the incidence rates of arrhythmias following AMI from the Acute Coronary Syndrome Israeli Survey database from 2000 to 2018. We assessed the differences in arrhythmias incidence and the associated mortality risk between men and women. Results: This cohort of 14,280 consecutive patients included 3,159 (22.1%) women and 11,121 (77.9%) men. Women were less likely to experience early ventricular tachyarrhythmia (VTA), (1.6% vs. 2.3%, p = 0.034), but had similar rates of late VTA (2.3% vs. 2.2%, p = 0.62). Women were more likely to experience atrial fibrillation (AF) (8.6% vs. 5.0%, p < 0.001) and HAVB (3.7% vs. 2.3%, p < 0.001). The risk of early VTAs was similar in men and women [adjusted Odds Ratio (aOR) = 0.76, p = 0.09], but women had a higher risk of AF (aOR = 1.27, p = 0.004) and HAVB (aOR = 1.30, p = 0.03). Early [adjusted hazard ratio (aHR) = 2.84, p < 0.001] and late VTA (aHR =- 4.59, p < 0.001), AF (aHR = 1.52, p < 0.001) and HAVB (aHR = 2.83, p < 0.001) were associated with increased 30-day mortality. Only late VTA (aHR = 2.14, p < 0.001) and AF (aHR = 1.44, p = 0.002) remained significant in the post 30 days period. Conclusions: During AMI women experienced more AF and HAVB but fewer early VTAs than men. Early and late VTAs, AF, and HAVB were associated with increased 30-day mortality. Only late VTA and AF were associated with increased post-30-day mortality.

Dapagliflozin versus empagliflozin in patients with chronic kidney disease.

Background and Aim: Dapagliflozin and empagliflozin have demonstrated favorable clinical outcomes among patients with chronic kidney disease (CKD). However, their comparative monetary value for improving outcomes in CKD patients is unestablished. We examined the cost-per-outcome implications of utilizing dapagliflozin as compared to empagliflozin for prevention of renal and cardiovascular events in CKD patients. Methods: For calculation of preventable events we divided the allocated budget by the cost needed to treat (CNT) for preventing a single renal or cardiovascular event. CNT was derived by multiplying the annualized number needed to treat (aNNT) by the annual therapy cost. The aNNTs were determined based on data from the DAPA-CKD and EMPEROR-KIDNEY trials. The budget limit was defined based on the threshold recommended by the United States' Institute for Clinical and Economic Review. Results: The aNNT was 42 both dapagliflozin (95% confidence interval [CI]: 34-59) and empagliflozin (CI: 33-66). The CNT estimates for the prevention of one primary event for dapagliflozin and empagliflozin were comparable at $201,911 (CI: $163,452-$283,636) and $209,664 (CI: $164,736-$329,472), respectively. However, diabetic patients had a higher CNT with dapagliflozin ($201,911 [CI: $153,837-$346,133]) than empagliflozin ($134,784 [CI: $109,824-$214,656]), whereas non-diabetic patients had lower CNT for dapagliflozin ($197,103 [CI: $149,029-$346,133]) than empagliflozin ($394,368 [CI: $219,648-$7,093,632]). The CNT for preventing CKD progression was higher for dapagliflozin ($427,858 [CI: $307,673-$855,717]) than empagliflozin ($224,640 [CI: $169,728-$344,448]). For preventing cardiovascular death (CVD), the CNT was lower for dapagliflozin ($1,634,515 [CI: $740,339-∞]) than empagliflozin ($2,990,208 [CI: $1,193,088-∞]). Conclusion: Among patients with CKD, empagliflozin provides a better monetary value for preventing the composite renal and cardiovascular events in diabetic patients while dapagliflozin has a better value for non-diabetic patients. Dapagliflozin provides a better monetary value for the prevention of CVD, whereas empagliflozin has a better value for the prevention of CKD progression.

Depression among Patients with an Implanted Left Ventricular Assist Device: Uncovering Pathophysiological Mechanisms and Implications for Patient Care.

Depression is a common and devastating mental illness associated with increased morbidity and mortality, partially due to elevated rates of suicidal attempts and death. Select patients with end-stage heart failure on a waiting-list for a donor heart undergo left ventricular assist device (LVAD) implantation. The LVAD provides a circulatory flow of oxygenated blood to the body, mimicking heart functionality by operating on a mechanical technique. LVAD improves functional capacity and survivability among patients with end-stage heart failure. However, accumulating data suggests that LVAD recipients suffer from an increased incidence of depression and suicide attempts. There is scarce knowledge regarding the pathological mechanism and appropriate treatment approach for depressed LVAD patients. This article summarizes the current evidence on the association between LVAD implantation and occurrence of depression, suggesting possible pathological mechanisms underlying the device-associated depression and reviewing the current treatment strategies. The summarized data underscores the need for a rigorous pre-(LVAD)-implantation psychiatric evaluation, continued post-implantation mental health assessment, and administration of antidepressant treatment as necessary.

Cardiac Transplantation: Physiology and Natural History of the Transplanted Heart.

Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short- and long-term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long-term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health-related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age-matched healthy subjects. Several factors, including alterations in central hemodynamics, HT-related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high-intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719-4765, 2023.

Effect of Dapagliflozin Versus Empagliflozin on Cardiovascular Death in Patients with Heart Failure Across the Spectrum of Ejection Fraction: Cost per Outcome Analysis.

BACKGROUND: Dapagliflozin and empagliflozin have shown clinical benefits in patients with heart failure (HF). Their comparative monetary value remains undetermined, and we therefore sought to compare the cost-per-outcome implications of utilizing dapagliflozin versus empagliflozin to prevent cardiovascular death (CVD) in patients with HF across the spectrum of ejection fraction. METHODS: We estimated the cost needed to treat (CNT) to prevent one CVD with either dapagliflozin or empagliflozin. CNT was estimated by multiplying the annualized number needed to treat (aNNT) by the annual cost of therapy. The aNNTs were calculated based on data from the DAPA-HF and DELIVER trials for dapagliflozin, and the EMPEROR-Reduced and EMPEROR-Preserved trials for empagliflozin. Drug costs were calculated as 75% of the 2022 US National Average Drug Acquisition Cost. RESULTS: The aNNT to prevent one event of CVD was 110 (95% confidence interval [CI] 58-∞) for dapagliflozin in a pooled analysis of DAPA-HF and DELIVER versus 204 (95% CI 71-∞) for empagliflozin in a pooled analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials. The annual costs of therapy were $4807 and $4992, respectively. The corresponding CNTs were $528,770 (95% CI $278,806-∞) for dapagliflozin and $1,018,368 (95% CI $354,432-∞) for empagliflozin. This remained consistent in Europe, using the price estimates in Germany, with CNT (€77,490 for dapagliflozin and €143,708 for empagliflozin). CONCLUSION: In incorporating data from all four outcomes trials of sodium-glucose cotransporter 2 inhibitors, dapagliflozin provides better monetary value for preventing CVD events in patients with HF across the spectrum of ejection fraction.

Vascular Function in Continuous Flow LVADs: Implications for Clinical Practice.

Left ventricular assist devices (LVADs) have been increasingly used in patients with advanced heart failure, either as a destination therapy or as a bridge to heart transplant. Continuous flow (CF) LVADs have revolutionized advanced heart failure treatment. However, significant vascular pathology and complications have been linked to their use. While the newer CF-LVAD generations have led to a reduction in some vascular complications such as stroke, no major improvement was noticed in the rate of other vascular complications such as gastrointestinal bleeding. This review attempts to provide a comprehensive summary of the effects of CF-LVAD on vasculature, including pathophysiology, clinical implications, and future directions.

Nonobstructive coronary atherosclerosis is associated with adverse prognosis among patients diagnosed with myocardial infarction without obstructive coronary arteries.

BACKGROUND AND AIMS: The prognostic impact of nonobstructive coronary artery disease (CAD), as opposed to normal coronary arteries, on long-term outcomes of patients with myocardial infarction with no obstructive coronary arteries (MINOCA) is unclear. We aimed to address the association between nonobstructive-CAD and major adverse events (MAE) following MINOCA. METHODS: We conducted a retrospective cohort study of consecutive MINOCA patients admitted to a large referral medical center between 2005 and 2018. Patients were classified according to coronary angiography as having either normal-coronaries or nonobstructive-CAD. The primary outcome was MAE, defined as the composite of all-cause mortality and recurrent acute coronary syndrome (ACS). RESULTS: Of the 1544 MINOCA patients, 651 (42%) had normal coronaries, and 893 (58%) had CAD. The mean age was 61.2 ± 12.6 years, and 710 (46%) were females. Nonobstructive-CAD patients were older and less likely to be females, with higher rates of diabetes, hypertension, dyslipidemia, atrial fibrillation, and chronic renal-failure (p < 0.05). At a median follow-up of 7 years, MAE occurred in 203 (23%) patients and 67 (10%) patients in the nonobstructive-CAD and normal-coronaries groups, respectively (p < 0.01). In multivariable models, nonobstructive -CAD was significantly associated with long-term MAE [adjusted-hazard-ratio (aHR):1.67, 95% confidence-interval (95%CI):1.25-2.23; p < 0.001]. Other factors associated with a higher MAE-risk were older-age (aHR:1.05,95%CI:1.03-1.06; p < 0.001) and left ventricular ejection-fraction<40% (aHR:3.04,95%CI:2.03-4.57; p < 0.001), while female-sex (aHR:0.72, 95%CI: 0.56-0.94; p=0.014) and sinus rhythm at presentation (aHR:0.66, 95%CI: 0.44-0.98; p=0.041) were associated with lower MAE-risk. CONCLUSIONS: In MINOCA, nonobstructive-CAD is independently associated with a higher MAE-risk than normal-coronaries. This finding may promote risk-stratification of patients with nonobstructive-CAD-MINOCA who require tighter medical follow-up and treatment optimization.

Characteristics, Predictors, and Outcomes of Early mTOR Inhibitor Use After Heart Transplantation: Insights From the UNOS Database.

Background The clinical characteristics of mTOR (mammalian target of rapamycin) inhibitors use in heart transplant recipients and their outcomes have not been well described. Methods and Results We compared patients who received mTOR inhibitors within the first 2 years after heart transplantation to patients who did not by inquiring the United Network for Organ Sharing (UNOS) database between 2010 and 2018. The primary end point was all-cause mortality with retransplantation as a competing event. Rejection, malignancy, hospitalization for infection, and renal transplantation were secondary end points. There were 1619 (9%) and 15 686 (81%) mTOR inhibitors+ and mTOR inhibitors- patients, respectively. Body mass index, induction, cardiac allograft vasculopathy, calculated panel reactive antibody, and fewer days in 1A status were independently associated with mTOR inhibitors+ status. Over a follow-up of 10.4 years, there was no difference in all-cause mortality after adjusting for donor and recipient characteristics (adjusted subdistribution hazard ratio, 1.03 [0.90-1.19]; P=0.66). mTOR inhibitors+ were independently associated with increased risk for rejection (odds ratio [OR], 1.43 [1.11-1.83]; P=0.005) and basal skin cancer (OR, 1.35 [1.19-1.51]; P=0.012) but not for infection or renal transplantation. Conclusions mTOR inhibitors are used in <10% patients in the first 2 years after heart transplantation and are noninferior to contemporary immunosuppression regimens in terms of all-cause mortality, infection, malignancy, or renal transplantation. They are associated with risk for rejection.

Aspirin with Low-Dose Ticagrelor or with Low-Dose Rivaroxaban for Secondary Prevention: A Cost per Outcome Analysis.

INTRODUCTION: Secondary prevention of cardiovascular events among patients with diagnosed cardiovascular disease and high ischemic risk poses a significant challenge in clinical practice. The combinations of aspirin with low-dose (LD) ticagrelor or LD rivaroxaban have shown superiority in preventing major adverse cardiovascular events (MACE) compared with aspirin treatment alone. The comparative value for money of these two regimens remains unexplored. METHODS: We analyzed each regimen's annual cost needed to treat (CNT) by multiplying the annualized number needed to treat (aNNT) by the annual cost of each drug. The aNNTs were based on outcome data from PEGASUS TIMI-54 and COMPASS trials. Scenario analyses were performed to overcome variances in terms of population risk. Costs were calculated as 75% of US National Average Drug Acquisition Cost (NADAC), extracted in January 2022. The primary outcome was defined as CNT to prevent one MACE across the two regimens. Secondary value analysis was performed for myocardial infarction (MI), stroke, and cardiovascular death as separate outcomes. RESULTS: The aNNTs to prevent MACE with LD ticagrelor and with LD rivaroxaban were 229 [95% confidence interval (CI) 141-734] and 147 (95% CI 104-252), respectively. At an annual cost of US$3726 versus US$4533, the corresponding CNTs were US$853,254 (95% CI 525,366-2,734,884) with LD ticagrelor and US$666,351 (95% CI 471,432-1,142,316) with LD rivaroxaban. CONCLUSION: Combining aspirin with LD rivaroxaban provides better value for money than with LD ticagrelor for secondary prevention of MACE.

Post-transplant Lymphoproliferative Disorder Following Cardiac Transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid conditions frequently associated with the Epstein Barr Virus (EBV) and the use of potent immunosuppressive drugs after solid organ transplantation. PTLD remains a major cause of long-term morbidity and mortality following heart transplantation (HT). Epstein-Barr virus (EBV) is a key pathogenic driver in many PTLD cases. In the majority of PTLD cases, the proliferating immune cell is the B-cell, and the impaired T-cell immune surveillance against infected B cells in immunosuppressed transplant patients plays a key role in the pathogenesis of EBV-positive PTLD. Preventive screening strategies have been attempted for PTLD including limiting patient exposure to aggressive immunosuppressive regimens by tailoring or minimizing immunosuppression while preserving graft function, anti-viral prophylaxis, routine EBV monitoring, and avoidance of EBV seromismatch. Our group has also demonstrated that conversion from calcineurin inhibitor to the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, as a primary immunosuppression was associated with a decreased risk of PTLD following HT. The main therapeutic measures consist of immunosuppression reduction, treatment with rituximab and use of immunochemotherapy regimens. The purpose of this article is to review the potential mechanisms underlying PTLD pathogenesis, discuss recent advances, and review potential therapeutic targets to decrease the burden of PTLD after HT.

Outcomes after heart transplantation in patients with cardiac sarcoidosis.

BACKGROUND: The number of patients with sarcoidosis requiring heart transplantation (HT) is increasing. The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy and compare them to recipients with non-ischaemic restrictive or dilated cardiomyopathy. METHODS AND RESULTS: Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Rejection was evaluated using logistic regression analysis. We also reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single centre. A total of 30 160 HT recipients were included in the present study (n = 239 sarcoidosis, n = 1411 non-ischaemic restrictive cardiomyopathy, and n = 28 510 non-ischaemic dilated cardiomyopathy). During a total of 194 733 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischaemic dilated cardiomyopathy [adjusted subhazard ratio (aSHR) 1.46, 95% confidence intervals (CIs): 0.9-2.4, P = 0.12] or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, P = 0.67). Accordingly, multivariable analysis suggested that 1 year mortality was not significantly different between sarcoidosis and non-ischaemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, P = 0.12) or restrictive cardiomyopathy (aSHR 1.15, 95% CI: 0.61-2.18, P = 0.66). No differences were observed regarding 30 day mortality, treated and hospitalized acute rejection, and 30 day death from graft failure after HT. Thirty-day mortality did not improve significantly in more recent HT eras whereas there was a trend towards improved 1 year mortality in the latest HT era (P = 0.06). Data from the single-centre case review showed excellent long-term outcomes with sirolimus-based immunosuppression. CONCLUSIONS: Short-term and long-term post HT outcomes among patients with sarcoid cardiomyopathy are similar to those with common types of non-ischaemic cardiomyopathy.

Identifying patients with atrial fibrillation with a single CHA2DS2-VASC risk factor who are at higher risk of stroke.

AIMS: Management of patients with a single CHA2DS2-VASc score risk factor is controversial. We attempt to identify the "truly low risk" AF patients who will not benefit from oral anticoagulation (OAC) treatment. METHODS: Retrospective cohort analysis, all incident non-valvular AF (NVAF) cases between 2004 and 2015, and age 21 and older, with up to one thromboembolic risk factor besides sex (CHA2DS2-VASc score of up to 1 for men and up to 2 for women). A "low risk" score was created for these patients using a logistic regression model on the incidence of stroke within 30-2500 days following the NVAF diagnosis. RESULTS: We identified 15,621 patients. Average age was 53.7 ± 12.3 years, 56.6% male. Mean follow-up was 5.5 years. Significant predictors of ischemic stroke were age 65-74 and diabetes (2 points each), hypertension, vascular disease, and chronic kidney disease stage 2-3 (1 point each). Stroke incidence ranged from 0.8% for score 0 and up to 3.4% for scores ≤ 2. Odds ratio for stroke among patient group with a score ≤ 2 was 4.3 (2.9-6.6) compared with score 0. Our risk score's area-under-the-curve (AUC) for prediction of stroke was 0.68 (0.65-0.71), compared with 0.60 (0.57-0.62) for the CHAD2S2-VASc score, within this low-risk group. CONCLUSION: Patients considered at low or intermediate risk using traditional risk stratification schemes, with ≥ 2 points using this proposed low-risk index (65-74 years old, diabetics or a combination of chronic renal failure and an additional risk factor), had an overall stroke risk that may justify anticoagulation therapy.

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.

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.