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Background Heart failure (HF) is a progressive symptomatic illness with reports suggesting that patients experience multiple symptoms. Symptom clusters constitute symptoms that co-occur, are related, and influence outcomes. Objectives The specific aims of this study were to (1) examine prevalent symptoms experienced by persons with HF, (2) identify symptoms forming clusters, and (3) evaluate the impact of HF symptom clusters on quality of life (QOL). Methods 117 participants (62% male; 50% black; age = 56) were recruited. Prevalent symptoms were evaluated; principle components analysis (PCA) was used to extract symptom clusters; regression analysis was used to evaluate factors influencing QOL, defined as life satisfaction. Results Three symptom clusters–sickness behavior, discomforts of illness, and GI distress–were extracted. Sickness behavior significantly influenced QOL (β = −0.603 p = 0.0001), explaining 40% of the variance (F = 75.12; R2 = 0.404; p = 0.0001). Conclusions The Sickness Behavior cluster had a negative impact on QOL and suggests that incorporating an evaluation of these symptoms may facilitate identification and treatment of symptoms having an additive and detrimental influence on QOL. Studies to examine the stability of the clusters are warranted.

AIM Our study aimed to examine factors that contribute to cognitive dysfunction in patients with heart failure (HF). BACKGROUND Although a majority of patients with HF have mild to moderate cognitive impairment, little is known about factors that influence progressive cognitive decline in this population. METHODS We examined the influence of physiological factors (NYHA functional class II - IV, ejection fraction, co-morbidity burden, polypharmacy), psychosocial factors (anxiety, depression, evaluation for advanced therapy), and associated toxicities (anticholinergic drug burden), on cognitive dysfunction. Data were analyzed using mean (SE) for continuous variables and frequency and percent for categorical variables. Differences between NYHA functional classification (Class II vs. Class III/IV) were examined using Chi Square. Linear regression models were used to assess associations among model variables. RESULTS Of the 113 participants with HF, Class III-IV HF were more cognitively impaired than those with NYHA Class II (p

Background We studied longitudinal levels of angiotensin-II type 1 receptor antibody (AT1R-Ab) and their effects on adverse events (death, treated rejection and cardiac allograft vasculopathy) in patients who were bridged to heart transplant using a continuous flow left ventricular assist device (LVAD). Methods and Results Sera of 77 patients bridged to heart transplant (from 2009 to 2017) were tested for AT1R-Ab and CRP before and after LVAD. Elevated AT1R-Ab was defined as >10.0 U/mL. The median follow-up after transplant was 3.6 years (interquartile range, 2.2–5.6 years). After LVAD, AT1R-Ab levels increased from baseline and remained elevated until transplant. Freedom from adverse events at 5 years was lower in those with elevated AT1R-Ab levels at time of transplant. In an adjusted, multivariable Cox analysis, an AT1R-Ab level of >10 U/mL was associated with developing the primary end point (adjusted hazard ratio 3.4, 95% confidence interval 1.2–9.2, P = .017). Although C-reactive protein levels were high before and after LVAD placement, C-reactive protein did not correlate with AT1R-Ab. Conclusions In LVAD patients bridged to heart transplant, an increased AT1R-Ab level at time of transplant was associated with poor outcomes after heart transplant. Post-LVAD AT1R-Ab elevations were not correlated with serum markers of systemic inflammation. Larger studies are needed to examine the pathologic role of AT1R-Ab in heart transplant.

Purpose Heart Transplant recipients previously exposed to CMV infection are considered intermediate risk for post-transplant CMV complications. Many centers therefore utilize "universal" prophylaxis for 3-6 months to mitigate this risk. However, it remains unclear how long prophylaxis should be continued post-transplant in this population. In the present analysis, we compared post-transplant CMV outcomes in patients receiving 3 vs. 6 months of valganciclovir prophylaxis in a multicenter, retrospective analysis. Methods Retrospective analysis of 321 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 treated with universal prophylaxis with valganciclovir for either 3 months (n = 277) or 6 months (n = 44). The primary endpoint was the development of CMV viremia or end-organ disease resulting in the escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. Results Of the 321 patients in the analysis, 13.4% (n = 43) developed CMV viremia or end-organ infection requiring escalation of anti-CMV therapy, and 3.4% (n = 11) were hospitalized for CMV infection. Overall, there was no significant difference in the primary endpoint in patients treated with 3 months of valganciclovir compared to 6 months (12.6% vs. 18.2%, p = 0.316; Figure 1A). There was a trend toward reduction in CMV hospitalization in the 6-month treatment group (Figure 1B), but this did not achieve statistical significance (3.6% vs. 2.3%, p = 0.651), potentially due to a low number of events. Conclusion We found no difference in the risk of CMV viremia or hospitalization for CMV using either a 3-month or 6-month regimen for prophylaxis in HTx recipients at intermediate risk for CMV (R+).

Purpose Heart transplant recipients with prior exposure to CMV (R+) are considered intermediate risk for CMV-related complications, and current guidelines allow for either universal prophylaxis or a pre-emptive approach to prophylaxis. Some centers prefer a preemptive approach to mitigate the cost and risks of prophylaxis, most notably the risk of leukopenia. In the present study, we evaluate the risks of leukopenia with each prophylaxis approach. Methods Retrospective analysis of 440 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018, treated with either universal prophylaxis (73%, n = 323) or preemptive therapy (27%, n = 117). The primary endpoint was the development of leukopenia (WBC Results Of the 440 patients in the analysis, 177 (40%) developed leukopenia (WBC Conclusion Leukopenia occurs in 40% of heart transplant recipients. Although CMV prophylaxis has been associated with leukopenia, there is no difference in this risk when comparing a universal vs. preemptive prophylaxis strategy for CMV.

Purpose Heart transplant recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Current guidelines allow for a pre-emptive approach to CMV prophylaxis (i.e. “watch and wait” strategy) in these patients; however, it remains unclear if this is a safe and effective strategy to mitigate the risks of CMV reactivation. In the present study, we assessed the utility of a pre-emptive approach to CMV prophylaxis compared to a universal prophylaxis strategy in an intermediate risk population. Methods Multi-center, retrospective analysis of 564 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 with 18 months of follow-up. The primary endpoint was the development of CMV viremia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. Results Of 564 intermediate risk (CMV R+) patients in the analysis, 123 (21.8%) were treated with a pre-emptive CMV prophylaxis strategy. Patient's treated with a pre-emptive approach had a significantly higher risk of both the primary (p Conclusion The use of a pre-emptive prophylaxis approach in intermediate risk CMV HTx recipients (CMV R+) is associated with a significantly higher risk of both the need for therapy escalation and hospitalization for CMV-related complications.

Purpose Induction therapy with either thymoglobulin or basiliximab is used in approximately 50% of patients at the time of heart transplant. While the use of thymoglobulin has been reported to increase the risk of CMV reactivation, it remains unclear if this risk is also seen with basiliximab. In the present analysis, we compared post-transplant CMV outcomes in patients receiving basiliximab vs. no induction in a multicenter, retrospective analysis. We also assess the effects of universal prophylaxis on any attendant risk. Methods Retrospective analysis of 439 intermediate risk (CMV R+) HTx recipients from 6 U.S. centers between 2010-2018 treated with either basiliximab induction (63%, n = 276) or no induction (37%, n = 163). The primary endpoint was the development of CMV viremia or end-organ disease resulting in the escalation of anti-CMV therapy. The secondary endpoint was hospitalization for CMV-related infection. Results Of 439 patients in the analysis, 18.9% (n = 83) developed CMV viremia or end-organ infection requiring escalation of anti-CMV therapy, and 5.7% (n = 25) were hospitalized for CMV infection. Patients who received induction with basiliximab were more likely to meet the primary endpoint (22.8% vs. 12.3%, p = 0.006) and had a trend towards higher risk for CMV hospitalization (7.2% vs. 3.1%, p = 0.068) in the overall group. However, in patients receiving universal CMV prophylaxis, there was no difference in the primary (14.7% vs. 13.1%, p = 0.672) or secondary endpoint (4.1% vs. 3.3%, p = 0.687) when basiliximab was used compared to no induction. Alternatively, 36% of patients receiving basiliximab induction reached the primary endpoint when a preemptive therapy approach to prophylaxis was used (vs. 0% in no induction, p = 0.021). Conclusion Although basiliximab induction increases the risk of CMV viremia/end organ damage and CMV-related hospitalizations, this risk is eliminated when a universal CMV prophylaxis strategy is used.

PURPOSE: To assess and compare the prevalence of medication nonadherence (MNA) (implementation and persistence) to immunosuppressants and co-medications in heart transplant recipients. METHODS: MNA prevalence was assessed using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (self-report) and compared using logistic regression in a 4-continent sample of 1397 heart transplant recipients from 36 heart transplant centers in 11 countries. FINDINGS: MNA was significantly (α = 0.05) higher to co-medications than to immunosuppressants (taking nonadherence: 23.9% vs 17.3%; odds ratio [OR] = 1.5; 95% CI, 1.30-1.73; drug holiday: 5.7% vs 1.9%; OR = 3.17; 95% CI, 2.13-4.73; dose alteration: 3.8% vs 1.6%; OR = 2.46; 95% CI, 1.49-4.06; and discontinuation: 2.6% vs 0.5%; OR = 5.15; 95% CI, 2.36-11.20). IMPLICATIONS: The observed MNA necessitates adherence-enhancing interventions encompassing the entire post-heart transplant medication regimen. ClinicalTrials.gov identifier: NCT01608477. ispartof: CLINICAL THERAPEUTICS vol:41 issue:1 pages:130-136 ispartof: location:United States status: published

Purpose Nearly 30% of heart transplant recipients develop de novo donor-specific antibodies post-transplant, leading to an increased risk of antibody mediated rejection, graft failure, and death. Given poor response rates to therapies targeting dnDSA once present, therapies preventing dnDSA altogether could impact transplant outcomes. It remains unclear if the use of induction therapy at the time of transplant mitigates the risk of dnDSA development. The present study attempts to address this question in a multicenter, retrospective analysis. Methods Multicenter, retrospective analysis of 319 heart transplant recipients from 4 participating centers in the U.S. The primary endpoint was the development of dnDSA. Results In the overall cohort, 206 of 319 (65%) patients received induction therapy at the time of transplant, with 200 (62%) receiving basiliximab and 6 (3%) receiving thymoglobulin. Overall 93 of 319 (29%) patients developed dnDSA post-transplant. The use of induction therapy reduced the risk of dnDSA (Kaplan Meier log rank p = 0.009, Figure 1). When assessing induction type, basiliximab reduced the risk of dnDSA compared to no induction, whereas thyroglobulin did not (Figure 2). However, in a multivariable Cox Regression model incorporating the use of an LVAD as BTT, the use of any induction was no longer statistically significant. Conclusion Although induction therapy, particularly with basiliximab, reduces the risk of dnDSA post-heart transplant in univariate analysis, this effect is no longer significant in a model incorporating LVAD as BTT.

Purpose Antibody to angiotensin-II type 1 receptor (AT1R-Ab) may be implicated in allograft dysfunction in patients who are bridged to heart transplant (BTT) with a continuous flow left ventricular assist device (VAD). We studied AT1R-Ab level following VAD implantation on event-free survival in BTT patients and whether AT1R-Ab elevation is independent from inflammation as measured through C-reactive protein (CRP). Methods Sera of 77 BTT patients from 2009 to 2017 were tested for AT1R-Ab and CRP prior to and after VAD placement. Elevated AT1R-Ab level was defined as greater than 10.0 U/mL. For statistical analysis, the value of 40 U/mL was assigned to AT1R-Ab level greater than 40 U/mL. Events were defined as acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy, reduced EF, and death. Results Median follow-up time after transplant was 3.3 years (range 0.4-9.0 years). After VAD implantation, AT1R-Ab was increased as compared to baseline (Fig 1A). Univariate regression analysis revealed that age, female gender, African-American race, time to transplant, type of VAD, HLA sensitization, and positive donor specific antibodies were not risk factors for AT1R-Ab sensitization. The elevated post-VAD AT1R-Ab cohort had more events than the normal AT1R-Ab group (61% vs 29%, Fig 1B). On Kaplan Meier analysis, there was a statistically decrease in 5-year event-free survival in patients who had elevated AT1R-Ab levels (Fig 1C). Multivariate Cox regression analysis showed increased post-VAD AT1R-Ab as an independent risk factor for developing events. Though CRP was high before and after VAD implantation, CRP had no statistically significant correlation with AT1R-Ab level (Fig 1D). Conclusion Increase in AT1R-Ab was seen in BTT patients after VAD implantation and was associated with adverse outcomes after heart transplant. The AT1R-Ab elevation does not appear to be an epiphenomenon related to CRP, a marker of inflammation.

The changing epidemiology of cardiac allograft rejection has prompted many to question the yield of surveillance endomyocardial biopsy (EMB) in heart transplantation (HT) patients. We sought to determine the yield of EMB in the modern era.We evaluated 2597 EMBs in 182 consecutive HT patients who survived to their first EMB. The EMBs were categorized as asymptomatic or clinically driven and were compared based on era of antiproliferative therapy use at our center (early azathioprine era: 1990-2000 vs modern mycophenolate era: 2000-2011).In the modern era, patients had a higher prevalence of risk factors for developing rejection (≥ International Society of Heart and Lung Transplantation grade 2R); however, the frequency of rejection was decreased at all times (0-6 months: 60.2% vs 21.5%, P0.001, 6-12 months: 26.8% vs 1.8%, P0.001, 12-36 months: 32.3% vs 10.5%, P = 0.006). The yield of asymptomatic EMB decreased in the modern era between 0 and 6 months (10.9% vs 3.12%), 6 to 12 months (17% vs 0%), and years 2 to 3 (6.1% vs 1.5%). In the early era, the odds ratio of rejection during asymptomatic EMB compared to a clinically driven EMB was 0.47 (95% confidence interval, 0.31-0.71) and was decreased in the modern era (0.17 [0.07-0.42], P = 0.04). The probability of detecting rejection on asymptomatic EMB was significantly reduced in the modern era, even after adjustment for tacrolimus and induction therapy (1% vs 8%, P0.001).The clinical yield of surveillance EMB has decreased in the modern era. The EMB in asymptomatic patients longer than 6 months after HT warrants further scrutiny.

Purpose Previous reports have suggested an association between pre-transplant mechanical circulatory support (MCS) and an increased risk for post-transplant de novo donor specific antibodies (dnDSA). However, it is unclear if specific MCS devices pose a greater risk for dnDSA. The present study seeks to better understand the risk of dnDSA posed by a variety of MCS devices in a multicenter, collaborative study. Methods Multicenter, retrospective analysis of 319 heart transplant recipients from 4 U.S. centers between 2011 - 2017. The primary outcome was the development of post-transplant dnDSA. Results 145 of 319 (45%) patients were supported with durable MCS devices prior to transplant, including 47 Heartware (HVAD), 73 Heartmate II (HM2), and 25 total artificial hearts (TAH). MCS patients had a higher risk of dnDSA compared to those transplanted without mechanical support (37% vs. 23%, p = 0.006; Kaplan Meier log rank p Conclusion Pre-transplant MCS is associated with higher risk for dnDSA. Similar risk is seen regardless of device type; however, the risk associated with TAH was not significantly increased compared to no MCS.

The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD).We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period.In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time.During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Figure 1 Laboratory evidence of severe persistent hemolysis in a patient supported witha TAH for 130 days. A 62-year-old man with non-ischemic cardiomyopathy developed cardiogenic shock, and a total artificial heart (TAH) was implanted due to profound biventricular failure. Within days of device implantation the patient developed severe hemolysis. Over the subsequent weeks, despite aggressive anticoagulation with bivalirudin, aspirin, dipyridamole and pentoxyfilline, he continued to have hemolytic anemia (mean hemoglobin [Hb] 5.7 g/dl, nadir Hb 3.1 g/dl; mean lactate dehydrogenase [LDH] 1,693 U/liter, peak LDH 2,628 U/liter) (Figure 1), receiving 37 units of packed red blood cells (RBC) and several infusions of intravenous iron sucrose over the 130 days of TAH support. The TAH parameters were within normal limits. No device malfunction or thrombosis was detected on intracardiac echocardiography or upon direct inspection of the TAH at the time of heart transplantation. Post-transplantation recovery was uneventful. Later, the patient presented with a febrile illness. Computer tomography of the abdomen revealed a hepatic lesion. Abdominal magnetic resonance imaging (MRI) demonstrated secondary hemochromatosis to the liver and spleen. The previously identified hepatic lesion represented an area of normal tissue sparing. The pancreas was not affected, favoring a secondary, rather than primary, etiology of hemochromatosis (Figure 2). In addition, iron deposition was noted in the renal cortex, a finding specific to intravascular hemolysis (Figure 3). Ferritin concentration was markedly elevated. Liver function studies showed mild transaminitis that normalized within 1 week. Because total iron concentration and transferrin saturation remained within normal limits, and there was no liver dysfunction, both hematology and hepatology consultants did not recommend treatment with phlebotomy or iron chelation as long as no further blood transfusions were required. We retrospectively identified a 68-year-old woman who was supported with TAH for 254 days. The patient had chronic hemolytic anemia, alveolar hemorrhage and

s S285 < 50% were excluded. Transmitral flow velocity variables were utilized (peak velocity during early (E) and late (A) filling, medial and lateral annular diastolic velocities (e medial, e lateral). Estimated PCWP was calculated using the following formula (ePCWP = 1.24 * (E /e lateral) + 1.9) whereas invasive PCWP (iPCWP) was calculated using pulmonary artery catheter. Results: In our cohort (age, median 56 years (45-63), 57 male (80%), mean EF (63 ± 7%), mean iPCWP was 12 ± 4 mmHg and mean ePCWP was 13 ± 3 mmHg. Strong correlation was noted between iPCWP and E (r= 0.5, P= < 0.0001), E/e lateral (r= 0.53, P= < 0.0001), but weak correlation with E/e medial (r= 0.34, P= 0.002). Using linear regression analysis, a strong significant correlation existed between iPCWP and ePCWP (r= 0.53, P= < 0.0001). Conclusion: In heart transplant recipients, ePCWP correlates with iPCWP, and E/e lateral was the strongest among diastolic echocardiographic indices.

Background. Sustained maintenance on left ventricular assist device (LVAD) is associated with an increased frequency of severe infections. Although temporary changes in cellular immunity are seen immediately after implantation, the consequence of sustained LVAD treatment on immunity is unknown. Methods. In vitro functional and phenotypic markers of T cell activation and 6 month clinical outcome were compared between patients with >6-month LVAD therapy and heart failure control patients. Results. Recipients of LVADs had more infections (45.5% versus 0%; p < 0.05) and mortality (54% versus 16%; p < 0.05) than control patients. T-cell proliferative responses were lower among LVAD recipients than control patients when challenged with phytohemagglutinin (3.4 4.7 versus 28.5 19.6; p < 0.01), anti-CD3 (4.3 4.5 versus 16.4 17; p < 0.01), and staphylococcal enterotoxin B (7.2 6.3 versus 26.1 15.6; p 0.002). Proliferative hyporesponsiveness among LVAD recipients was not caused by apoptosis (2.6% 2.7% versus 2.7% 2.1%; p 0.94) or insufficient CD4 cells (42.1% 11.3% versus 40.2% 7.5%; p 0.71) relative to control patients. Instead, CD3 cells from LVAD patients expressed less interleukin 2 (2.5% 1.5% versus 5.2% 3.1%; p 0.03) and tumor necrosis factor- (6.0% 3.5% versus 25.8% 8.7%; p < 0.001) and more interleukin 10 (5.8% 6.1% versus 2.6% 2.1%; p < 0.05). In addition, suppressive T-regulatory cells were more prevalent in LVAD patients than control patients (12.9% 3.2% versus 1.2% 1.1%; p < 0.001). Conclusions. Cellular immunity is compromised among long-term LVAD recipients because of a downregulatory cytokine imbalance and emergence of suppressive T-regulatory cells. (Ann Thorac Surg 2008;85:1656‐61) © 2008 by The Society of Thoracic Surgeons

Purpose Heart failure (HF) is a progressive, symptomatic illness with reports suggesting that pts. experience 2 to 9 symptoms. Symptom clusters (SCs) are symptoms that co-occur, are related, and influence outcomes. Thus, the purpose of this study was to examine 9 prevalent symptoms of HF, identify SCs, and examine the effects on quality of life (QOL). Methods and Materials This study was conducted at a health sciences center with a HF/HTx Program. We studied 117 HF pts. (age=56; 62% male; 50% AA) and examined prevalence and severity of 9 symptoms: anxiety, depression, dyspnea, fatigue, pain, swelling, daytime sleepiness, cognitive dysfunction, and GI disturbances. Instruments were valid and reliable and had acceptable psychometric properties. Descriptive statistics were used to describe the sample, co-morbidities, and symptoms. Principle components analysis (PCA) was used to extract related symptoms, aggregate components, and calculate SC scores. Multiple regression was used to examine effects of SCs on QOL. Results Approx. 51% of pts. were NYHA Class III/IV and had an EF of 25%. Over half (62%) had an ICD and 9% were receiving IV inotropes. The most prevalent symptoms included: dyspnea in the past 2 weeks (100%), decreased hunger (95%), decreased appetite (85%), daytime sleepiness (54%), fatigue (73%), swelling (73%), and pain (62%). Least frequently occurring included depression (21%). Three SCs were extracted in a PCA: Sickness Behavior (anxiety, depression, daytime sleepiness, cognitive dysfunction, fatigue), Discomforts (dyspnea, edema, pain), and GI Disturbamces (appetite/hunger). Sickness Behavior was the only predictor (β=-0.635; p= Conclusions Sickness Behaviors had a significant negative effect on QOL and suggests that incorporating an evaluation of each of these symptoms may facilitate identification and treatment of symptoms having an additive and detrimental impact on QOL. Future studies to examine the stability of the cluster are warranted.

Background Hyperhomocysteinemia has been implicated as an independent risk factor for atherosclerotic cardiovascular disease. Both cardiac transplantation and diabetes are associated with accelerated coronary artery disease. We therefore, designed this study to determine serum homocysteine levels in cardiac transplant recipients and patients with diabetes. We also sought to determine the relationship between hyperhomocysteinemia and renal insufficiency and its response to oral supplementation with folic acid.