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Although continuous-flow left ventricular assist devices (CF-LVADs) provide an augmentation in systemic perfusion, there is a scarcity of in vivo data regarding systemic pulsatility on support. Patients supported on CF-LVAD therapy (n = 71) who underwent combined left/right catheterization ramp study were included. Aortic pulsatility was defined by the pulsatile power index (PPI), which was also calculated in a cohort of high-output heart failure (HOHF, n = 66) and standard HF cohort (n = 44). PPI was drastically lower in CF-LVAD-supported patients with median PPI of 0.006 (interquartile range [IQR], 0.002-0.012) compared with PPI in the HF population at 0.09 (IQR, 0.06-0.17) or HOHF population at 0.25 (IQR, 0.13-0.37; p0.0001 among groups). With speed augmentation during ramp, PPI values fell quickly in patients with higher PPI at baseline. PPI correlated poorly with left ventricular ejection fraction (LVEF) in all groups. In CF-LVAD patients, there was a stronger correlation with LV dP/dt (r = 0.41; p = 0.001) than LVEF (r = 0.21; p = 0.08; pint0.001). CF-LVAD support is associated with a dramatic reduction in arterial pulsatility as measured by PPI relative to HOHF and HF cohorts and decreases with speed. Further work is needed to determine the applicability to the next generation of device therapy.

AimsAn artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect ‘physiological age’. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx).Methods and resultsA total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P < 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P < 0.0001) and the recipient ages (R = 0.38, P < 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002].ConclusionElectrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.

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.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).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.

The survival benefits of pulmonary thromboendarterectomy (PTE) for the treatment of chronic thromboembolic pulmonary hypertension have been well described. However, the significance of right heart hemodynamic changes and their impact on survival remains poorly understood. We sought to characterize the effects of these changes. We conducted a single center, retrospective review of 159 patients who underwent PTE between 1993 and 2015. Echocardiographic and right heart catheterization data were compared longitudinally before and after PTE in order to establish the extent of hemodynamic response to surgery. Kaplan Meier estimates were used to characterize patient survival over time. Univariable and multivariable Cox proportional hazards regression models were used to assess factors associated with long-term mortality. Among the 159 patients studied, 74 (46.5%) were male with a median age of 55 (IQR: 42-66). One-, 5-, 10-, and 15-year survival was 91.0% (95% CI: 86.6-95.6), 79.6% (73.5-86.3), 66.5% (59.2-74.7), and 56.2% (48.1-65.8). Of the 9 candidate risk factors that were evaluated, only advanced age and increased cardiopulmonary bypass time were found to be significantly associated with increased risk of mortality. Pre- and postsurgical echocardiographic imaging data, when available, revealed a median reduction in right ventricular systolic pressure of 29.0 mm Hg (P0.0001) and improvement of tricuspid regurgitation (P0.0001), both of which appeared to be sustained across long-term follow-up. Improvements in right heart hemodynamics and tricuspid valvular regurgitation persist on long term surveillance following PTE. While patient selection is often driven by the distribution of disease, close postoperative follow up may improve outcomes.

Aims Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non‐heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation. Methods and results We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index

Small patella syndrome presents with small or absent patellae and may result in pulmonary arterial hypertension, typically in children. A pathogenic canonical splice site variant, c.1021+1G>A in the T-box transcription factor 4 (TBX4) gene, currently not included in commercial gene panel, was detected in an adult with pulmonary arterial hypertension and absent patellae. (Level of Difficulty: Advanced.), Central Illustration

Aims Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation. Methods and results A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements (median 3.0, interquartile range (IQR) [2.8, 3.1] years), and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACE) was defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression (odds ratio 0.58, 95% confidence interval [CI] [0.37, 0.92], p = 0.01) and MACE (hazard ratio [HR] 0.79, 95% CI [0.66, 0.99], p = 0.05) during a median (IQR) follow up of 8.0 years (7.2, 8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE (HR 1.26, 95% CI [1.03, 1.57], p = 0.02). Conclusions Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression. Translational perspective The results of the current study suggest lower levels of circulating CD34+CD133+ cell levels are associated with cardiac allograft vasculopathy progression and future adverse cardiovascular events, while higher OC+ cell levels are associated with a greater risk of future cardiovascular events. Further studies confirming our findings might elucidate the role of circulating progenitor cells in the pathophysiology of CAV. Moreover, our findings might support the use of circulating progenitors as biomarkers, as well as the notion of cell therapy as potential treatment option for CAV, a disease with severe burden and limited treatment options.

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.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).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.

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.

Pulse pressure (PP) has been linked to an increased risk of extent of coronary atherosclerosis and cardiovascular events. This study aimed to investigate the contribution of aortic PP on cardiac allograft vasculopathy (CAV) progression, and cardiovascular events after heart transplantation (HTx).A total of 330 HTx patients (mean age 49 ± 25 years, 70.0% male) undergoing routine serial coronary intravascular ultrasound (IVUS) studies and had invasive aortic PP were enrolled. The median time from HTx to first IVUS was 13.6 months. CAV progression was assessed by IVUS as the changes (Δ) in plaque volume divided by the segment length (PV/SL), adjusted for the time between IVUS (median, 3.99 years; interquartile range, 1.99-7.20 years), and was defined as ΔPV/SL ≥0.50 mmRecipient age, recipient sex, and renal dysfunction were independent determinant of high aortic PP (≥ 50 mmHg). High aortic PP was an independent determinant of CAV progression [odds ratio, 1.72; 95% confidence interval (CI), 1.01-2.93; p = 0.045]. Both high aortic PP (HR 1.46, 95% CI 1.01-2.11, p = 0.044) and high baseline CAV grade on angiogram (≥1, HR 1.50, 95% CI 1.03-2.21, p = 0.037) were independently associated with MACEs over 12 years.In post-HTx patients, high aortic PP was significantly associated with plaque progression. Both aortic PP and CAV grade are independently associated with MACE during long-term follow-up. These findings suggest that arterial stiffness and CAV can be important predictors of MACEs.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04–0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

The expanding use of continuous-flow left ventricular assist devices (CF-LVADs) for end-stage heart failure warrants familiarity with the physiologic interaction of the device with the native circulation. Contemporary devices utilize predominantly centrifugal flow and, to a lesser extent, axial flow rotors that vary with respect to their intrinsic flow characteristics. Flow can be manipulated with adjustments to preload and afterload as in the native heart, and ascertainment of the predicted effects is provided by differential pressure-flow (H-Q) curves or loops. Valvular heart disease, especially aortic regurgitation, may significantly affect adequacy of mechanical support. In contrast, atrioventricular and ventriculoventricular timing is of less certain significance. Although beneficial effects of device therapy are typically seen due to enhanced distal perfusion, unloading of the left ventricle and atrium, and amelioration of secondary pulmonary hypertension, negative effects of CF-LVAD therapy on right ventricular filling and function, through right-sided loading and septal interaction, can make optimization challenging. Additionally, a lack of pulsatile energy provided by CF-LVAD therapy has physiologic consequences for end-organ function and may be responsible for a series of adverse effects. Rheological effects of intravascular pumps, especially shear stress exposure, result in platelet activation and hemolysis, which may result in both thrombotic and hemorrhagic consequences. Development of novel solutions for untoward device-circulatory interactions will facilitate hemodynamic support while mitigating adverse events. © 2021 American Physiological Society. Compr Physiol 12:1-37, 2021.

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 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.

Background An artificial intelligence (AI) algorithm detecting age from 12-lead ECG has been suggested to signal “physiological age” of the individual. Importantly, increased physiological age gauged by an increased difference between ECG-age and chronological age has been associated with higher risk of cardiac events in non-transplant population. Purpose We sought to investigate the validity of the AI-derived ECG-age algorithm in patients who underwent heart transplantation and its relationship to major adverse cardiovascular events (MACE). Methods A total of 489 consecutive patients who had undergone heart transplantation in our institution between 1994 and 2018 were studied. AI-ECG age was calculated by a previously-trained artificial intelligence (AI) algorithm using a 12-lead ECG per patient. ECGs used in the training process of the algorithm were excluded. The average of the ECG-ages within one year before and one year after heart transplantation was used to represent pre- and post-transplant ECG-ages. MACE was defined as any incidence of revascularization, re-transplantation, and death. Results Pre-transplant ECG-age (mean 63±10 years) correlated significantly with recipient chronological age (mean 50±13 years, r=0.57, p Conclusion Post-transplant ECG-age correlates more faithfully with the donor's than the recipient's chronological age, suggesting that ECG-age more closely reflects cardiac age than the patient age. Furthermore, ECG-age derived cardiac aging after transplantation is associated with higher risk of MACE. Funding Acknowledgement Type of funding sources: None.

Background A higher serum phosphorus level, although within the normal range has been linked to coronary artery and aortic calcification in the non-transplant population. Coronary calcification is mostly associated with donor-derived lesions, and is uncommon within the first years after heart transplantation. Purpose We aimed to investigate the association of phosphorus levels with plaque calcification after heart transplantation. Methods A total of 156 patients who underwent virtual histology intravascular ultrasound (VH-IVUS) studies for cardiac allograft vasculopathy (CAV) surveillance and had fasting serum phosphorus levels Results Mean recipient and donor ages were 54±13 and 31±14 years, respectively. Mean serum phosphorus in recipients was 3.5±0.6 mg/dL, with median time after transplantation at the IVUS studies of 6 (3,10) years. There were no significant differences in %DC between phosphorus tertiles in patients who underwent IVUS within 6 years after transplantation (p=0.11, Fig. 1A). However, beyond 6 years after transplantation, we observed an incremental association between phosphorus levels and the extent of calcification (p=0.02, Fig. 1B). In this group, serum phosphorus levels significantly correlated with %DC (standardized β=0.29, P=0.008), and this correlation remained significant after adjustment for donor age, recipient age, and eGFR (standardized β=0.26, P=0.001). Conclusion Higher serum phosphorus levels were associated with a level-dependent increase in calcified coronary artery plaque in patients starting 6 years post heart transplant. Long-term exposure to higher serum phosphorus, even within the normal range, might promote plaque calcification after heart transplantation. Funding Acknowledgement Type of funding sources: None.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.

Background Invasive fungal infection (IFI) in heart transplant recipients is associated with poor outcomes. Estimated risk of 1-year IFI in heart transplant recipients is 3.4-8.6% with risk factors inconsistently identified in previous studies. The role of antifungal prophylaxis is unclear. The transplant program at Mayo Clinic provides 6 months of universal azole prophylaxis for those heart transplant recipients in Arizona. We sought to define risk factors for 1-year IFI and determine the effect of antifungal prophylaxis. Methods We conducted a retrospective cohort study of patients undergoing heart transplantation at Mayo Clinic from January 2000 to March 2019. We analyzed demographics, details of transplant hospitalization, antifungal prophylaxis, and fungal infection. Multivariable Cox analyses were performed to identify risk factors of 1-year IFI and impact of IFI on posttransplant mortality. Results A total of 966 heart transplant recipients were identified with a median age of 56 years (IQR 47, 62). A total of 444 patients received antifungal prophylaxis. Over 1-year follow-up, 62 patients developed IFI with a cumulative incidence of 6.4%. In multivariable analysis, factors associated with IFI were renal replacement therapy (RRT) (HR 3.24, 95% CI 1.65-6.39), allograft rejection (HR 2.33, 95% CI 1.25-4.34), and antifungal prophylaxis (HR 0.32, 95% CI 0.11-0.96). RRT was also associated with invasive mold infection (HR 3.00, 95% CI 1.29-6.97). Conclusions RRT and allograft rejection after transplantation are associated with 1-year IFI, and RRT is also associated with invasive mold infection. Antifungal prophylaxis appears to be protective and further study is needed in the heart transplant population.

Introduction: Long-term use of continuous-flow left ventricular assist devices may have negative consequences for autonomic, cardiovascular and gastrointestinal function. It has thus been suggested that non-invasive monitoring of arterial pulsatility in patients with a left ventricular assist device is highly important for ensuring patient safety and longevity. We have developed a novel, semi-automated frequency-domain-based index of arterial pulsatility that is obtained during suprasystolic occlusions of the upper arm: the ‘cuff pulsatility index’. Purpose: The purpose of this study was to evaluate the relationship between the cuff pulsatility index and invasively determined arterial pulsatility in patients with a left ventricular assist device. Methods: Twenty-three patients with a left ventricular assist device with end-stage heart failure (six females: age = 65 ± 9 years; body mass index = 30.5 ± 3.7 kg m−2) were recruited for this study. Suprasystolic occlusions were performed on the upper arm of the patient’s dominant side, from which the cuff pressure waveform was obtained. Arterial blood pressure was obtained from the radial artery on the contralateral arm. Measurements were obtained in triplicate. The relationship between the cuff pressure and arterial blood pressure waveforms was assessed in the frequency-domain using coherence analysis. A mixed-effects approach was used to assess the relationship between cuff pulsatility index and invasively determined arterial pulsatility (i.e. pulse pressure). Results: The cuff pressure and arterial blood pressure waveforms demonstrated a high coherence up to the fifth harmonic of the cardiac frequency (heart rate). The cuff pulsatility index accurately tracked changes in arterial pulse pressure within a given patient across repeated measurements. Conclusions: The cuff pulsatility index shows promise as a non-invasive index for monitoring residual arterial pulsatility in patients with a left ventricular assist device across time.

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Introduction: CD34+ progenitor cells play a role in vascular repair and plaque stability. However, their role in cardiac allograft vasculopathy (CAV), vessel remodeling, and changes in plaque morphology is incompletely understood. Hypothesis: We hypothesized that decreased levels of baseline CD34+ progenitor cells would be associated with Intravascular Ultrasound (IVUS)-defined vulnerable plaque characteristics and CAV progression. Methods: In heart transplant patients undergoing annual IVUS, CD34+ cells were counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcific). Positive remodeling was defined as expansion of external elastic membrane area on follow-up. Patients were divided into two groups by the median of the change (Δ) in necrotic core volume over the subsequent 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. Median time after transplant was 4.2 years at baseline. Average vessel area at baseline and three years were 15.8±4.6 and 15.3±5.4 mm, respectively (p=0.32). Twenty-four patients (44%) who showed positive remodeling at follow-up, compared to those who did not, had lower levels of baseline CD34+ progenitor cells (absolute count per 100,000 counts, 980 [690, 1460]) vs. 665 [438, 1015], p=0.02) (Fig. 1A). Patients with greater than median (>1.96 mm3) Δnecrotic core volume, as compared to those with below median Δ, also had lower baseline CD34+ cells (705 [483, 998] vs. 1180 [660, 1620] per 100,000 counts, p=0.04) (Fig. 1B). Conclusions: Lower levels of CD34+ progenitor cells are associated with long-term positive coronary vascular remodeling and increased plaque necrotic core volume in patients who underwent allograft heart transplant. This study supports the notion that circulating CD34+ progenitor cells play a role in CAV.

Introduction: Cardiac allograft vasculopathy (CAV) is a major determinant of long term graft survival. Endothelial progenitor cells (EPC) expressing osteocalcin (OC) have been linked to atherosclerosis. However, little is known regarding bone-forming osteoblast-lineage (OL) cells, and their role in atherosclerosis and CAV. Methods: Heart transplant patients undergoing serial Intravascular Ultrasound (IVUS) and progenitor cell studies were included in the study. OL cells, defined as cells positive for alkaline phosphatase (AP) and OC, were counted using flow cytometry on the day of baseline IVUS. A follow up IVUS was done 3 years later. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcified). Patients were divided into two groups by the median change (Δ) in necrotic core volume and plaque volume over 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. At baseline, median time after transplant was 4.2 years. Average vessel area at baseline and three years were 15.8 ±4.6 and 15.3 ±5.4 mm2, respectively (p=0.32). However, 24/55 patients (44%) had positive remodeling. The number of OL cells was positively correlated with Δvessel (r=0.36, p=0.01) and Δlumen areas. (r=0.30, p=0.02). Patients with greater Δplaque volume and Δnecrotic core volume had higher OL cell levels compared to those with below medians (Δplaque volume: 95 [30,348] vs. 30 [10, 90] OL per 100,000 counts, p=0.01; Δnecrotic core volume: 95 [22.5, 320] vs. 30 [10, 90] OL per 100,000 counts, p=0.03) (Fig. 1A and 1B). Conclusions: The number of OL cells in heart transplant patients correlates with positive vascular remodeling, accompanied by increased lumen area over 3 months. Furthermore, patients with unstable plaque features had higher OL cells, suggesting a possible role in pathologic plaque progression.

Background Heart transplant (HTx) patients can develop graft dysfunction (GD) without biopsy evidence of cell or antibody mediated rejection. Cardiac MRI (CMR) can detect inflammatory or infiltrative causes of cardiomyopathy however CMR findings in HTx recipients with GD have not been previously described. Purpose We sought to identify CMR characteristics of HTx patients with GD, and evaluate its additive value in its diagnosis and prognosis. Methods CMR has been performed routinely to evaluate GD at our institutions. There were 37 HTx recipients who presented with acute decline in left ventricular ejection fraction (LVEF) of 10% from baseline, with no biopsy evidence of rejection between 2007 and 2018. Coronary angiogram with IVUS was done to rule out allograft vasculopathy. Treatment of GD was per discretion of the treating clinician. Responders were defined as those with LVEF improvement >10% at 180 days or greater post-presentation. LV and RV indices, the presence and pattern of late gadolinium enhancement (LGE) were determined by CMR. Results There were 34% females and mean age at transplant was 49±13 years. Median time from HTx to GD was 1.2 years. Presenting symptoms were heart failure (n=25), cardiogenic shock (n=1) and 11 patients were asymptomatic. Mean LVEF at presentation was 37±12% and donor specific antibodies were detected in 38% patients. Most patients were treated with steroid bolus (n=29), and/or plasmapheresis (n=23). There were no major changes made in immunosuppression in 6 patients. Delayed enhancement MRI was performed with standard inversion-recovery (IR) gradient echo sequences, between 5 and 20 minutes after institutional-standard protocol administration of IV gadolinium contrast. Biventricular LGE was present in 18/37 (49%) patients with GD and was more prevalent in responders (57%, 13 of 23) than non-responders (35%, 5 of 14), although not statistically significant (p=0.21). There were two patterns of LGE noted: 1) Diffuse epicardial (10 patients out which 9 were responders) and 2) Patchy pattern with non-specific distribution (8 patients out of which 4 were responders). Myocardial edema by triple IR sequencing was seen in 6 patients, all having diffuse epicardial pattern of enhancement matching the delayed enhancement pattern. When comparing different treatment groups, among those treated for GD (n=31), 12 of 21 (57%) responders had LGE and 4 of 10 (40%) non-responders had LGE (p=0.37), a pattern similar to the broader population. Among those not treated for GD (n=6), 1 of 2 responders had LGE and 1 of 4 non-responders had LGE (p=0.5). Conclusion CMR identified inflammation as a potential cause of GD in approximately 50% of HTx patients. There are 2 distinct patterns of LGE observed in GD, diffuse epicardial (56%) and patchy (44%). Although the presence of LGE in itself is not associated with myocardial recovery, 90% of patients with a diffuse epicardial pattern have recovery of GD. Funding Acknowledgement Type of funding source: None

Background In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. Objectives The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. Methods Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. Results A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at 1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction. Conclusions A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

HeartMate II left ventricular assist device controllers provide data including pulsatility index, reflecting the relationship between pump function and hemodynamics. We propose that a higher pulsatility index at hospital discharge following implant may be associated with less vascular congestion and improved clinical outcomes. A retrospective analysis of 40 patients (age 59.2 ± 10.3 years) supported with the HeartMate II devices was conducted. Data revealed moderate Pearson correlations between pulsatility index at discharge and right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure, respectively, post-surgery (median of 377 days), demonstrating a stronger relationship when analyzed for the EPC controller (n = 28) only (r = −.57, p

International normalized ratio (INR) measurements manage risks of bleeding and clotting sequelae in the population with left ventricular assist device (LVAD). Studies suggest that point-of-care (POC) INR does not significantly differ from plasma INR (P-INR) values in other patient populations, although this has not been validated in a multicenter LVAD study. We sought to determine whether POC-INR and P-INR values differ significantly in the LVAD population and reviewed patients with permanent LVAD implantation at seven institutions internationally. Our cohort comprised of 279 paired POC-INR and P-INR checks in patients supported on average 630 ± 598 days postimplant with predominately HeartWare, HeartMate II, and HeartMate III devices. The population averaged 57.9 years of age, and there were 86.7% male. We found no statistically significant difference between POC-INR and P-INR values. International normalized ratio accuracy correlated weakly with the time between INR measurements (p < 0.001). When the time difference was less than 4 hours, the difference between INR pairs was significantly lower than measurements greater than 8 hours (p = 0.006). There was no statistically significant difference when comparing paired INR values and time after implant to INR check (p = 0.43), age (p = 0.12), known coagulopathy (p = 0.12), bleeding history (p = 0.22), or thrombosis history (p = 0.34). This is the first large multicenter international study comparing POC-INR and P-INR measurements in patients with LVAD and found no statistically significant difference between either methods, particularly when measured within less than 4 hours of each other.

The true prevalence of heart failure due to wild type transthyretin amyloidosis (ATTRwt) is likely underestimated. There is a paucity of data with regard to the management of ATTRwt-related advanced heart failure and the natural history of extracardiac ATTRwt.We conducted a retrospective cohort study of patients undergoing cardiac transplant (HTx) for ATTRwt at a single institution. Comprehensive clinical data, including baseline hemodynamic and echocardiographic characteristics, and posttransplant outcomes, were obtained.Seven patients with ATTRwt underwent HTx between 2007 and 2015. All patients were male with a mean age of 66 ± 9. Patients had a reduced ejection fraction (mean, 37 ± 14%) and elevated filling pressures pre-HTx (mean pulmonary capillary wedge pressure 22 ± 7 mm Hg) before HTx. Three-year survival was 100%; 1 patient died of pancreatic cancer 45 months post-HTx (1 death per 30.8 patient-years). Oxygen consumption (Δ +6.8 ± 4.9 mL·kg·min) and 6-minute walk distances (Δ +189 ± 60 m) improved. Symptomatic gastrointestinal involvement (n = 2) and peripheral nerve involvement (n = 4) by ATTRwt developed late.This is the first report of a series of ATTRwt patients receiving HTx in which excellent outcomes are demonstrated. Although cardiac death is averted, systemic manifestations of ATTRwt may develop posttransplantation.

AIM The lungs-and particularly the alveolar-capillary membrane-may be sensitive to continuous flow (CF) and pulmonary pressure alterations in heart failure (HF). We aimed to investigate long-term effects of CF pumps on respiratory function. METHODS AND RESULTS We conducted a retrospective study of patients with end-stage HF at our institution. We analysed pulmonary function tests [e.g. forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 )] and diffusing capacity of the lung for carbon monoxide (DLCO ) from before and after left ventricular assist device (LVAD) implantation and compared them with invasive haemodynamic studies. Of the 274 patients screened, final study analysis involved 44 patients with end-stage HF who had CF LVAD implantation between 1 February 2007 and 31 December 2015 at our institution. These patients [mean (standard deviation, SD) age, 50 (9) years; male sex, n = 33, 75%] received either the HeartMate II (Thoratec Corp.) pump (77%) or the HeartWare (HeartWare International Inc.) pump. The mean (SD) left ventricular ejection fraction was 21% (13%). At a median of 237 days post-LVAD implantation, we observed significant DLCO decrease (-23%) since pre-implantation (P

BACKGROUND Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation (HT). Uric acid (UA) may play a role in CAV due to its role in stimulating T-cell-mediated immunity. Sirolimus is associated with CAV attenuation through a number of mechanisms, including immune-mediated effects. We aimed to determine whether UA is an independent predictor of CAV and whether conversion to sirolimus as primary immunosuppression modulates UA levels. METHODS We retrospectively analyzed a cohort of 224 patients who underwent HT between 2004 and 2015 and had serial coronary intravascular ultrasound (IVUS) studies. Serum UA levels were measured at baseline and last follow-up IVUS in all participants. CAV progression was assessed by measuring the change in plaque volume (ΔPV) and plaque index (ratio of plaque volume to vessel volume [ΔPI]) between last follow-up and baseline IVUS after correction for time of follow-up. RESULTS Patients with high (≥7 mg/dl) compared with low ( 0.50 mm3/mm) (hazard ratio 2.2, 95% confidence interval 1.1 to 4.6; p = 0.037). Sirolimus resulted in decreased UA levels (5.8 ± 1.4 vs 5.2 ± 1.5; p = 0.002) and patients converted to sirolimus and had low UA levels had the least CAV progression (p < 0.001). After adjustment for potential confounders, change in UA level was also an independent predictor of CAV progression. CONCLUSIONS UA is an independent predictor of CAV after HT. Sirolimus is associated with decreased UA levels and may explain one of the mechanisms by which sirolimus attenuates CAV progression.

AIMS Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new-generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long-term CAV progression and clinical outcomes in a large contemporary HT cohort. METHODS AND RESULTS We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow-up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES ( 2 years after HT) groups. During a median follow-up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV-associated events (hazard ratio 0.48, 95% confidence interval: 0.27-0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all-cause mortality and CAV-associated events (hazard ratio 0.58, 95% confidence interval: 0.38-0.91; P = 0.019). CONCLUSIONS Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV-related events and mortality.

Background Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. Objectives The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. Methods A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. Results The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p 2 years) after HT. Conclusions Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.