Impact of Donor Hemodynamics on Recipient Survival in Heart Transplantation.

BACKGROUND: Heart transplantation is the gold-standard therapy for end-stage heart failure, but rates of donor-heart use remain low due to various factors that are often not evidence based. The impact of donor hemodynamics obtained via right-heart catheterization on recipient survival remains unclear. METHODS: The United Network for Organ Sharing registry was used to identify donors and recipients from September 1999-December 2019. Donor hemodynamics data were obtained and analyzed using univariate and multivariable logistical regression, with the primary endpoints being 1- and 5-year post-transplant survival. RESULTS: Of the 85,333 donors who consented to heart transplantation during the study period, 6573 (7.7%) underwent right-heart catheterization, of whom 5531 eventually underwent procurement and transplantation. Donors were more likely to undergo right-heart catheterization if they had high-risk criteria. Recipients who had donor hemodynamic assessment had 1- and 5-year survival rates similar to those without donor hemodynamic assessment (87% vs 86%, 1 year). Abnormal hemodynamics were common in donor hearts but did not impact recipient survival rates, even when risk-adjusted in multivariable analysis. CONCLUSIONS: Donors with abnormal hemodynamics may represent an opportunity to expand the pool of viable donor hearts.

Hemodynamic Effects of High-dose Levothyroxine and Methylprednisolone in Brain-dead Potential Organ Donors.

BACKGROUND: Hormonal replacement therapy is administered to many brain-dead organ donors to improve hemodynamic stability. Previous clinical studies present conflicting results with several randomized studies reporting no benefit. METHODS: Consecutive adult donors (N = 199) were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both (Combo), or no hormonal therapy (Control). Vasopressor requirements using the vasoactive-inotropic score (VIS) were assessed at baseline, 4 h, and at procurement. Crossover to the Combo group was sufficient to require separate intention-to-treat and per-protocol analyses. RESULTS: In the intention-to-treat analysis, the mean (±SD) reduction in VIS from baseline to procurement was 1.6 ± 2.6, 14.9 ± 2.6, 10.9 ± 2.6, and 7.1 ± 2.6 for the levothyroxine, methylprednisolone, Combo, and Control groups, respectively. While controlling for the baseline score, the reduction in VIS was significantly greater in the methylprednisolone and Combo groups and significantly less in the levothyroxine group compared with controls. Results were similar in the per-protocol analysis. CONCLUSIONS: High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected.

Pulmonary Arterial Elastance and INTERMACS-Defined Right Heart Failure Following Left Ventricular Assist Device.

BACKGROUND: Acute right heart failure (RHF) after left ventricular assist device implantation remains a major source of morbidity and mortality, yet the definition of RHF and the preimplant variables that predict RHF remain controversial. This study evaluated the ability of (1) INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) RHF classification to predict post-left ventricular assist device survival and (2) preoperative characteristics and hemodynamic parameters to predict severe and severe acute RHF. METHODS AND RESULTS: An international, multicenter study at 4 large academic centers was conducted between 2008 and 2016. All subjects with hemodynamics measured by right heart catheterization within 30 days before left ventricular assist device implantation were included. RHF was defined using the INTERMACS definition for RHF. In total, 375 subjects were included (mean age, 57.4±13.2 years, 54% bridge-to-transplant). Mild RHF was most common (34%), followed by moderate RHF (16%), severe RHF (13%), and severe acute RHF (9%). Estimated on-device survival rates at 2 years were 72%, 71%, and 55% in the patients with none, mild-to-moderate, and severe-to-severe acute RHF, respectively (P=0.004). In addition, the independent hazard ratio for mortality was only increased in the patients with severe-to-severe acute RHF (hazard ratio, 3.95; 95% CI, 2.16-7.23; P<0.001). INTERMACS-defined RHF was superior to postimplant inotrope duration alone in the prediction of all-cause mortality. In multivariable analysis, older age, lower INTERMACS classes, and higher pulmonary arterial elastance (ratio of systolic pulmonary artery pressure to stroke volume) before left ventricular assist device, were identified as significant predictors of severe-to-severe acute RHF. Stratifying patients by ratio of systolic pulmonary artery pressure to stroke volume and right atrial pressure significantly improved the discrimination between patients at risk for severe-to-severe acute RHF. CONCLUSIONS: The INTERMACS RHF classification correctly identifies patients at risk for mortality, though this risk is only increased in patients with severe-to-severe acute RHF. Several predictors for RHF were identified, of which ratio of systolic pulmonary artery pressure to stroke volume was the strongest hemodynamic predictor. Coupling ratio of systolic pulmonary artery pressure to stroke volume with right atrial pressure may be most helpful in identifying patients at risk for severe-to-severe acute RHF.

Evaluation of anticoagulation and nonsurgical major bleeding in recipients of continuous-flow left ventricular assist devices.

Continuous-flow left ventricular assist device (LVAD) placement has become a standard of care in advanced heart failure treatment. Bleeding is the most frequently reported adverse event after LVAD implantation and may be increased by antithrombotic agents used for prevention of pump thrombosis. This retrospective cohort included 85 adult patients implanted with a Heartmate II LVAD. Major bleeding was defined as occurring >7 days after implant and included intracranial hemorrhage, events requiring 2 units of packed red blood cells within a 24-h period, and death from bleeding. Primary outcome was intensity of anticoagulation between patients with or without at least one incidence of nonsurgical major bleeding. Major bleeding occurred in 35 (41%) patients with 0.48 events per patient year and a median (IQR) time to first bleed of 134.5 (39.3, 368.5) days. The median (IQR) INR at time of bleed was 1.7 (1.4, 2.5). Median INR during follow-up did not differ between groups and patients with major bleeding were not more likely to have a supra-therapeutic INR. Patients who bled were more likely to have received LVAD for destination therapy, to have lower weight, worse renal function, and lower hemoglobin at baseline. Duration of LVAD support and survival were similar between groups with no difference in occurrence of thrombosis. Incidence of nonsurgical major bleeding was not significantly associated with degree of anticoagulation. Certain baseline characteristics may be more important than anticoagulation intensity to identify patients at risk for bleeding after LVAD implant. Modification of anticoagulation alone is not a sufficient management strategy and early intervention may be required to mitigate bleeding impact.

Effects of Percutaneous LVAD Support on Right Ventricular Load and Adaptation.

Both operative and hemodynamic mechanisms have been implicated in right heart failure (RHF) following surgical left ventricular assist device (LVAD) implantation. We investigated the effects of percutaneous LVAD (pLVAD; Impella®, Abiomed) support on right ventricular (RV) load and adaptation. We reviewed all patients receiving a pLVAD for cardiogenic shock at our institution between July 2014 and April 2017, including only those with pre- and post-pLVAD invasive hemodynamic measurements. Hemodynamic data was recorded immediately prior to pLVAD implantation and up to 96 h post-implantation. Twenty-five patients were included. Cardiac output increased progressively during pLVAD support. PAWP improved early post-pLVAD but did not further improve during continued support. Markers of RV adaptation (right ventricular stroke work index, right atrial pressure (RAP), and RAP to pulmonary artery wedge pressure ratio (RAP:PAWP)) were unchanged acutely implant but progressively improved during continued pLVAD support. Total RV load (pulmonary effective arterial elastance; EA) and resistive RV load (pulmonary vascular resistance; PVR) both declined progressively. The relationship between RV load and RV adaptation (EA/RAP and EA/RAP:PAWP) was constant throughout. Median vasoactive-inotrope score declined after pLVAD placement and continued to decline throughout support. Percutaneous LVAD support in patients with cardiogenic shock did not acutely worsen RV adaptation, in contrast to previously described hemodynamic effects of surgically implanted durable LVADs. Further, RV load progressively declined during support, and the noted RV adaptation improvement was load-dependent as depicted by constant EA/RA and EA/RAP:PAWP relationships. These findings further implicate the operative changes associated with surgical LVAD implantation in early RHF following durable LVAD.

A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction.

AIMS: This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. CONCLUSIONS: BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.

A Ventricular Assist Device Recipient and Suicidality: Multidisciplinary Collaboration With a Psychiatrically Distressed Patient.

BACKGROUND: Ventricular assist device (VAD) recipients are at high risk of depression and anxiety, and poor psychosocial functioning is associated with worse medical outcomes. PURPOSE: We present a case of a 31-year-old depressed patient who demonstrated passive suicidal behavior through multiple episodes of noncompliance, including temporarily discontinuing warfarin (Coumadin) several months after VAD implantation. The patient's psychosocial and medical histories and outcomes are presented. CONCLUSIONS: This case underscores the importance of pre-VAD as well and ongoing psychosocial evaluation and management for this unique patient population. CLINICAL IMPLICATIONS: Medical teams who are treating patients with cardiovascular disease who are under consideration for VAD or heart transplantation need to be aware of the multitude of ways in which patients can express depressed and suicidal mood and work with a multidisciplinary team to treat such symptoms to optimize patients' success with VAD/heart transplantation.

Thyroid hormone use during cardiac transplant organ procurement.

BACKGROUND: Acute hypothyroidism after brain death results in hemodynamic impairments that limit availability of donor hearts. Thyroid hormone infusions can halt that process and lead to increased utilization of donor organs, but prolonged use of thyroid replacement has not been well studied. METHODS: We developed a 15-question survey regarding policies, procedures, and reporting of thyroid hormone use by organ procurement organizations (OPOs). The survey was posted for 5 weeks on the Association of OPOs Portal. RESULTS: We received 29 responses, representing 24 OPOs. Seventy-two percent reported their OPOs use thyroid hormone for all potential donors and 90% have a protocol for thyroid hormone use. There is a large variation in the maximum dose of thyroid hormone used, and many OPOs have no weaning protocol. Most OPOs do not collect data on total thyroid hormone administered during procurement and would favor more detailed report of thyroid hormone use. CONCLUSIONS: Thyroid hormone use can have important implications for organ selection and cardiac function before and after transplantation. Protocols vary widely with respect to why and how to use and wean thyroid hormone. We believe there should be more detailed reporting of thyroid hormone use for future studies to ensure appropriate donor management.

Accurate monitoring of intravascular fluid volume: A novel application of intrathoracic impedance measures for the guidance of volume reduction therapy.

BACKGROUND: A significant proportion of patients admitted for acute decompensated heart failure (ADHF) that undergo volume reduction therapy are discharged with unchanged or increased bodyweight suggesting that the endpoints for these therapies are not optimally defined. We aimed to identify vectors that can help monitor changes in intravascular fluid volume, that in turn may more accurately guide volume reduction therapy. METHODS: Data from six different impedance vectors and corresponding changes in intravascular volume derived from changes in hematocrit were obtained from 132 clinical congestion events in 56 unique patients enrolled in a multisite trial of early detection of clinical congestion events (DEFEAT PE). Mixed effects regression models were used to determine the relation between changes in impedance derived from six different vectors and changes in intravascular plasma volume. RESULTS: Changes in impedance were negatively associated with changes in plasma volume. Two vectors, the right atrial ring to left ventricular ring and the left ventricular ring to the right ventricular ring, were most closely associated with changes in intravascular plasma volume. CONCLUSION: Impedance vectors derived from a multivector monitoring system reflect changes in intravascular plasma volume. Two of these vectors most closely track changes in plasma volume and may be used to more accurately guide and optimize volume reduction therapy.

Analysis of different device-based intrathoracic impedance vectors for detection of heart failure events (from the Detect Fluid Early from Intrathoracic Impedance Monitoring study).

Detect Fluid Early from Intrathoracic Impedance Monitoring (DEFEAT-PE) is a prospective, multicenter study of multiple intrathoracic impedance vectors to detect pulmonary congestion (PC) events. Changes in intrathoracic impedance between the right ventricular (RV) coil and device can (RVcoil→Can) of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy ICDs (CRT-Ds) are used clinically for the detection of PC events, but other impedance vectors and algorithms have not been studied prospectively. An initial 75-patient study was used to derive optimal impedance vectors to detect PC events, with 2 vector combinations selected for prospective analysis in DEFEAT-PE (ICD vectors: RVring→Can + RVcoil→Can, detection threshold 13 days; CRT-D vectors: left ventricular ring→Can + RVcoil→Can, detection threshold 14 days). Impedance changes were considered true positive if detected <30 days before an adjudicated PC event. One hundred sixty-two patients were enrolled (80 with ICDs and 82 with CRT-Ds), all with ≥1 previous PC event. One hundred forty-four patients provided study data, with 214 patient-years of follow-up and 139 PC events. Sensitivity for PC events of the prespecified algorithms was as follows: ICD: sensitivity 32.3%, false-positive rate 1.28 per patient-year; CRT-D: sensitivity 32.4%, false-positive rate 1.66 per patient-year. An alternative algorithm, ultimately approved by the US Food and Drug Administration (RVring→Can + RVcoil→Can, detection threshold 14 days), resulted in (for all patients) sensitivity of 21.6% and a false-positive rate of 0.9 per patient-year. The CRT-D thoracic impedance vector algorithm selected in the derivation study was not superior to the ICD algorithm RVring→Can + RVcoil→Can when studied prospectively. In conclusion, to achieve an acceptably low false-positive rate, the intrathoracic impedance algorithms studied in DEFEAT-PE resulted in low sensitivity for the prediction of heart failure events.

Variations in institutional staffing and clinical practice are predictive of center-specific 1-year survival post-transplant.

BACKGROUND: The accuracy of various risk models to predict early post-transplant mortality is limited by the type, quality, and era of the data collected. Most models incorporate a large number of recipient-derived and donor-derived variables; however, other factors related to specific institutional practices likely influence early mortality. The goal of this study was to determine if the addition of institutional practice variables would improve the predictive accuracy of a recipient/donor risk model in a modern cohort of heart transplant recipients. METHODS: Between 1999 and 2007, 3,591 primary heart transplants were performed at the 26 institutions participating in the Cardiac Transplant Research Database. Multivariable regression analysis in the hazard domain was used to identify recipient, donor, and institutional practice variables that were predictive of 1-year mortality. The derived model was used to predict institutional outcomes and compare them with observed outcomes first without and then with the inclusion of the institutional practice variables. RESULTS: Eleven individual plus 2 interaction recipient variables and 2 individual plus 2 interaction donor variables were predictive of increased mortality. The addition of institutional practice variables to the model identified 4 variables associated with decreased mortality: greater number of transplant cardiologists, a thoracic surgery fellowship, a surgery or cardiology attending taking donor call, and routine surveillance for antibody-mediated rejection. By using a p-value > 0.10 as a robust measure of similarity, the addition of institutional practice variables increased the number of institutions with similar predicted vs. observed mortality from 18 of 26 institutions (69%) to 26 of 26 (100%), demonstrating improved predictive accuracy of the model. CONCLUSIONS: Multiple recipient and donor variables influence early survival but do not fully explain the difference in predicted and observed outcomes at the institutional level. Variations in staffing and clinical practice contribute to risk, and the addition of these variables to our risk model improved predictive accuracy.

Bayesian analysis of recurrent event with dependent termination: an application to a heart transplant study.

For a heart transplant patient, the risk of graft rejection and risk of death are likely to be associated. Two fully specified Bayesian models for recurrent events with dependent termination are applied to investigate the potential relationships between these two types of risk as well as association with risk factors. We particularly focus on the choice of priors, selection of the appropriate prediction model, and prediction methods for these two types of risk for an individual patient. Our prediction tools can be easily implemented and helpful to physicians for setting heart transplant patients' biopsy schedule.

Mediastinal lymphadenopathy in patients undergoing cardiac transplant evaluation.

BACKGROUND: We evaluated the association between hemodynamic parameters of chronic congestive heart failure (CHF) and mediastinal lymphadenopathy (MLA) in heart transplantation (HT) candidates and the effect of HT on MLA. We also described the results of lymph node (LN) biopsies of MLA in the patients. METHODS: Patients who underwent HT evaluation over an 8-year period and had chest CT scans were evaluated retrospectively. Data collected included LN sizes pre-HT and post-HT, echocardiographic measurements, radionuclide-derived ejection fraction, and right-sided heart catheterization hemodynamics. MLA was defined as LNs > 1 cm in smallest dimension. RESULTS: Of 118 patients, 53 patients had MLA. MLA had weak statistically significant correlations with elevated mean pulmonary artery pressure (MPAP), mitral regurgitation (MR), tricuspid regurgitation (TR), right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP). Thirty-six patients with MLA underwent HT, and nine of the 36 had post-HT chest CT scans. All nine patients showed a decrease in LN size post-HT (mean LN diameter pre-HT = 1.16 ± 0.137 cm, post-HT = 0.75 ± 0.32 cm). Seven of 53 patients with MLA underwent biopsies. Four had benign LNs, one had sarcoidosis, and two had lung cancer. CONCLUSIONS: MPAP, MR, TR, RAP, and PCWP had weak statistically significant correlations with MLA. HT led to regression of MLA in patients who underwent CT scans post-HT, implying that MLA is related to CHF. However, we also identified clinically important causes of MLA; therefore, biopsy should be considered if enlarged LNs fail to regress after maximal medical management of CHF.

Continuous versus intermittent infusion of furosemide in acute decompensated heart failure.

BACKGROUND: Despite advances in the treatment of chronic ambulatory heart failure, hospitalization rates for acute decompensated heart failure (ADHF) remain high. Although loop diuretics are used in nearly all patients with ADHF to relieve congestive symptoms, optimal dosing strategies remain poorly defined. METHODS AND RESULTS: This was a prospective, randomized, parallel-group study comparing the effectiveness of continuous intravenous (cIV) with intermittent intravenous (iIV) infusion of furosemide in 56 patients with ADHF. The dose and duration of furosemide as well as concomitant medications to treat ADHF were determined by physician preference. The primary end point of the study was net urine output (nUOP)/24 hours. Safety measures including electrolyte loss and hemodynamic instability were also assessed. Twenty-six patients received cIV and 30 patients received iIV dosing. The mean nUOP/24 hours was 2098+/-1132 mL in patients receiving cIV versus 1575+/-1100 mL in the iIV group (P=.086). The cIV group had significantly greater total urine output (tUOP) with 3726+/-1121 mL/24 hours versus 2955+/-1267 mL/24 hours in the iIV group (P=.019) and tUOP/mg furosemide with 38.0+/-31.0 mL/mg versus 22.2+/-12.5 mL/mg (P=.021). Mean weight loss was not significantly different between the groups. The cIV group experienced a shorter length of hospital stay (6.9+/-3.7 versus 10.9+/-8.3 days, P=.006). There were no differences in safety measures between the groups. CONCLUSIONS: The cIV of furosemide was well tolerated and significantly more effective than iIV for tUOP. In addition, continuous infusion appears to provide more efficient diuresis.

Rational use of diuretics in acute decompensated heart failure.

Chronic heart failure poses an enormous health care burden to the United States and other developed countries. Acute decompensated heart failure (ADHF) accounts for nearly half of the morbidity and expense of treating this disease. Most patients presenting with ADHF have symptomatic vascular congestion. Diuretics, especially loop diuretics, are the primary pharmacologic intervention used in this population. Despite their widespread use, scant data from randomized clinical trials are available to guide therapeutic choices. In addition, data from several large registries examining weight loss during hospitalization for ADHF suggest that efficacy with diuretic treatment is far from universal. Aggressive diuresis carries a significant risk of electrolyte and volume depletion, with subsequent arrhythmias, hypotension, and worsening renal function. These complications often translate into worse prognosis. Diuretic regimens used to treat ADHF must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations. This article summarizes older and more recent literature to provide a framework for making rational treatment choices in this difficult patient population.

Cardiac transplantation in South Carolina: 300 transplants.

For nearly 20 years, the Medical University's Heart Transplant Program has been providing the citizens of South Carolina with excellent results with a minimum of delay. We present here the results of our first 300 heart transplants, spanning the first 18 years of the Cardiac Transplant Program at the Medical University. Overall survival has been very good, with one, five and ten year survival rates in the adults being 92 +/- 2%, 78 +/- 3%, and 58 +/- 4%. The children's group showed survival rates of 94 +/- 5%, 79 +/- 11%, and 79 +/- 11% over the same lengths of time. Most recently, the federally sponsored Scientific Registry of Transplant Recipients (www.ustransplant.org, July 2005) reports for MUSC a one-year survival of 97.67% and three-year survival of 90.74%; both leading the Southeast. We attribute this success to the dedicated work of health care workers at all levels who believe in attention to detail and that the patient always comes first. It is our hope that we will be able to continue to provide expert, state-of-the-art, cardiac transplant services long into the future, while continuing to expand our heart failure management program as dictated by further developments in this rapidly evolving specialty.

Continuous aortic flow augmentation: a pilot study of hemodynamic and renal responses to a novel percutaneous intervention in decompensated heart failure.

BACKGROUND: Diminished aortic flow may induce adverse downstream vascular and renal signals. Investigations in a heart failure animal model have shown that continuous aortic flow augmentation (CAFA) achieves hemodynamic improvement and ventricular unloading, which suggests a novel therapeutic approach to patients with heart failure exacerbation that is inadequately responsive to medical therapy. METHODS AND RESULTS: We studied 24 patients (12 in Europe and 12 in the United States) with heart failure exacerbation and persistent hemodynamic derangement despite intravenous diuretic and inotropic and/or vasodilator treatment. CAFA (mean+/-SD 1.34+/-0.12 L/min) was achieved through percutaneous (n=19) or surgical (n=5) insertion of the Cancion system, which consists of inflow and outflow cannulas and a magnetically levitated and driven centrifugal pump. Hemodynamic improvement was observed within 1 hour. Systemic vascular resistance decreased from 1413+/-453 to 1136+/-381 dyne.s.cm(-5) at 72 hours (P=0.0008). Pulmonary capillary wedge pressure decreased from 28.5+/-4.9 to 19.8+/-7.0 mm Hg (P<0.0001), and cardiac index (excluding augmented aortic flow) increased from 1.97+/-0.44 to 2.27+/-0.43 L.min(-1).m(-2) (P=0.0013). Serum creatinine trended downward during treatment (overall P=0.095). There were 8 complications during treatment, 7 of which were self-limited. Hemodynamics remained improved 24 hours after CAFA discontinuation. CONCLUSIONS: In patients with heart failure and persistent hemodynamic derangement despite intravenous inotropic and/or vasodilator therapy, CAFA improved hemodynamics, with a reduction in serum creatinine. CAFA represents a promising, novel mode of treatment for patients who are inadequately responsive to medical therapy. The clinical impact of the observed hemodynamic improvement is currently being explored in a prospective, randomized, controlled trial.