Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Society for Cardiovascular Magnetic Resonance 2023 Cases of SCMR Case Series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2023 digital collection of cases are presented in this manuscript.

Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Percutaneous approach to left ventricular assist device decommissioning.

OBJECTIVE: To assess the outcomes of a single-center experience with percutaneous left ventricular assist device (LVAD) decommissioning. BACKGROUND: Patients with LVADs may eventually require their removal, either due to recovery of left ventricular function or recurrent complications. Traditionally, withdrawal of LVAD support has been managed with surgical device explantation, which carries significant procedural risks. Transcatheter LVAD decommissioning, with outflow graft occlusion and driveline transection, has recently been described as an alternative to surgical removal. METHODS: Here, we report on a retrospective cohort of five consecutive cases treated with transcatheter LVAD decommissioning. RESULTS: The procedure was effective in all cases, and no patient experienced procedure-related complications. At midterm follow-up, the three patients who had myocardial function recovery were alive and had not experienced heart failure-related symptoms or complications. CONCLUSION: Percutaneous LVAD decommissioning appears to be a safe and effective approach to LVAD treatment discontinuation.

An interventional approach to left ventricular assist device outflow graft obstruction.

BACKGROUND: LVADs provide life-sustaining treatment for patients with heart failure, but their complexity allows for complications. One complication, LVAD outflow graft obstruction, may be misdiagnosed as intraluminal thrombus, when more often it is extraluminal compression from biodebris accumulation. It can often be treated endovascularly with stenting. This case series describes diagnostic and procedural techniques for the treatment of left ventricular assist device (LVAD) outflow graft obstruction. METHODS: We present four patients with LVADs who developed LVAD outflow graft obstruction within the bend relief-covered segment. All were initially diagnosed with computed tomographic angiography (CTA). All underwent invasive evaluation with intravascular ultrasound (IVUS), then were treated with stenting. After misdiagnosing a twist, we developed the technique of balloon "graftoplasty" to ensure suitability for stent delivery in subsequent cases. RESULTS: All patients presented with low-flow alarms and symptoms of low output, and were diagnosed with outflow graft obstruction by CTA. In all four, IVUS confirmed an extraluminal etiology. Patient 1 was treated with stenting and had a good outcome. Patient 2's obstruction was from twisting, rather than biodebris accumulation, and had sub-optimal stent expansion and ultimately required surgery. Balloon "graftoplasty" was used in subsequent cases to ensure subsequent stent expansion. Patients 3 and 4 were successfully stented. All improved after treatment. CONCLUSIONS: In patients with LVAD outflow graft obstruction, IVUS can distinguish intraluminal thrombus from extraluminal compression. Balloon "graftoplasty" can ensure that the outflow graft will respond to stenting. Many cases of LVAD outflow graft obstruction should be amenable to endovascular treatment.

Disease-Modifying Treatments for Transthyretin Amyloidosis.

ABSTRACT: The transthyretin (TTR) amyloidoses result from misfolding of the protein leading to fibril formation and aggregation as amyloid deposits in predominantly the cardiovascular and nervous systems. Cardiac involvement can manifest as heart failure, arrhythmias, and valvular disease. Neurologic involvement can cause sensorimotor polyneuropathies, mononeuropathies, and dysautonomia. Previously, treatment has focused on management of these symptoms and disease sequelae, with a high rate of mortality due to the absence of disease-modifying therapies. In this article, we review novel treatments focusing on 3 mechanistic pathways: (1) silencing of the TTR gene to suppress production, (2) stabilizing of TTR tetramers to prevent misfolding, or (3) disrupting of existing TTR amyloid fibrils to promote reabsorption.

Predictors of Renal Failure in Patients Treated With the Total Artificial Heart.

BACKGROUND: The incidence of hemodialysis (HD)-dependent renal failure after total artificial heart (TAH) implantation is high. We sought to determine the preoperative predictors of HD after TAH implantation. METHODS AND RESULTS: We studied 87 patients after TAH implantation at our institution between April 2006 and March 2017. Baseline clinical data were obtained from the medical records, and patients were followed until death or heart transplantation. We performed logistic regression analysis to identify predictors of HD after TAH implantation. Of the patients, 24 (28%) required postimplantation HD. Those requiring HD were more likely to have histories of coronary artery disease (58% vs 29%; P = 0.01), required preoperative membrane oxygenation (33% vs 4.8%; P = 0.001) and had lower baseline estimated glomerular filtration rates (54 ± 29 vs 67 ± 24 mL/min/1.73m2; P = 0.04). Patients requiring HD were at a higher risk of death on device at 1 year (33% vs 5%, P = 0.001; log rank test: P =0.001, hazard ratio 6.6 [95% CI:1.8-23], P = 0.003). CONCLUSIONS: The incidence of postimplantation HD is high and is associated with increased likelihood of mortality. Lower baseline estimated glomerular filtration rates, histories of coronary artery disease and preoperative membrane oxygenation support are predictors of postimplantation requirement of HD. These data may help to identify patients at risk for adverse outcomes after TAH implantation.

Elevated AT1R Antibody and Morbidity in Patients Bridged to Heart Transplant Using Continuous Flow Left Ventricular Assist Devices.

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.

Impact of Socioeconomic Factors on Patient Desire for Early LVAD Therapy Prior to Inotrope Dependence.

BACKGROUND: Worsening heart failure (HF) and health-related quality of life (HRQOL) have been shown to impact the decision to proceed with left ventricular assist device (LVAD) implantation, but little is known about how socioeconomic factors influence expressed patient preference for LVAD. METHODS AND RESULTS: Ambulatory patients with advanced systolic HF (n=353) reviewed written information about LVAD therapy and completed a brief survey to indicate whether they would want an LVAD to treat their current level of HF. Ordinal logistic regression analyses identified clinical and demographic predictors of LVAD preference. Higher New York Heart Association (NYHA) class, worse HRQOL measured by Kansas City Cardiomyopathy Questionnaire, lower education level, and lower income were significant univariable predictors of patients wanting an LVAD. In the multivariable model, higher NYHA class (OR [odds ratio]: 1.43, CI [confidence interval]: 1.08-1.90, P = .013) and lower income level (OR: 2.10, CI: 1.18 - 3.76, P = .012 for <$40,000 vs >$80,000) remained significantly associated with wanting an LVAD. CONCLUSION: Among ambulatory patients with advanced systolic HF, treatment preference for LVAD was influenced by level of income independent of HF severity. Understanding the impact of socioeconomic factors on willingness to consider LVAD therapy may help tailor counseling towards individual needs.

Left Ventricular Assist Device Outflow Graft Compression: Incidence, Clinical Associations and Potential Etiologies.

BACKGROUND: Left ventricular assist devices (LVADs) have revolutionized the treatment of advanced heart failure, but proliferation of device therapy has unmasked potential complications. Reports have emerged of outflow graft narrowing due to extrinsic compression. METHODS AND RESULTS: The records of patients with LVADs that had been implanted at our institution were reviewed. Those who had postimplantation computed tomography angiographies sufficient to analyze the outflow graft lumen were identified, and the studies were analyzed to characterize the outflow graft lumen. We identified 241 patients; 110 (46%) had suitable computed tomography angiographies. Of those, 15 (14%) had evidence of outflow graft lumen narrowing, all in HeartMate devices and all within the portion covered by the bend relief. Of the 15, 3 underwent invasive examination, all without intraluminal thrombus but, rather, with biodebris between the bend relief and the outflow graft. Patients with HeartWare devices had a wide range of biodebris accumulation surrounding the outflow graft but no cases of lumen narrowing. On multivariable analysis, 1) time from device implant to scan, 2) nonischemic cardiomyopathy and 3) age at implant were significantly associated with higher risk of graft narrowing. CONCLUSION: Outflow graft narrowing can be seen in a number of patients with HeartMate LVADs within the portion covered by the bend relief. In the limited number of patients who underwent invasive evaluation, the narrowing was found to arise from extrinsic compression rather than intraluminal thrombus. The clinical significance of this requires further investigation.

HFSA/SAEM/ISHLT Clinical Expert Consensus Document on the Emergency Management of Patients with Ventricular Assist Devices.

Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.

Transthyretin Cardiac Amyloidosis.

PURPOSE OF REVIEW: Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. Transthyretin-derived amyloidosis accounts for 18% of all cases of cardiac amyloidosis. Thus, the study's purpose is to provide a comprehensive review of transthyretin cardiac amyloidosis. RECENT FINDINGS: Wild-type transthyretin (ATTRwt) protein causes cardiac amyloidosis sporadically, with 25 to 36% of the population older than 80 years of age are at risk to develop a slowly progressive, infiltrative amyloid cardiomyopathy secondary to ATTRwt. In contrast, hereditary amyloidosis (ATTRm) is an autosomal dominant inherited disease associated with more than 100 point mutations in the transthyretin gene and has a tendency to affect the heart and nervous system. Up to 4% of African-Americans carry the Val122Ile mutation in the transthyretin gene, the most prevalent cause of hereditary cardiac amyloidosis in the USA. Identifying transthyretin cardiac amyloidosis requires increased awareness of the prevalence, signs and symptoms, and diagnostic tools available for discrimination of this progressive form of cardiomyopathy associated with left ventricular hypertrophy. While there are no FDA-approved medical treatments, investigation is underway on agents to reduce circulating mutated transthyretin.

Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart.

BACKGROUND: Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). METHODS: We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. RESULTS: Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). CONCLUSIONS: Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation.

Pregnancy-related allograft rejection following heart transplant.

Current recommendations do not discourage pregnancy in stable, orthotopic heart transplant (OHT) recipients who are more than 1 year posttransplant, although a highly specialized level of care with a multidisciplinary team is recommended. These patients may incur significant risk to themselves, their allograft, and/or their fetuses. Recognition and treatment of posttransplant complications in pregnancy also may be difficult. Although the risk of recurrent pregnancies in patients with peripartum cardiomyopathy (PPCM) is well defined, the risk of pregnancy after a PPCM patient has undergone OHT is unknown. A case of severe allograft rejection in a woman with a history of PPCM who became pregnant nearly 3 years after OHT is presented and her subsequent management is described. The data available on pregnancy after transplant are based on case reports, registry data, and reviews. The decision to become pregnant should be preceded by an extensive discussion including the patient, her partner, her obstetrician, and the transplant team, reviewing potential risks to her health as well as to her allograft and the fetus. Providers should be clear that many questions pertaining to pregnancy after transplant remain unanswered, and the patient should be comfortable going forward in this situation.

Emergent use of mechanical circulatory support devices: ethical dilemmas.

PURPOSE OF REVIEW: Mechanical Circulatory Support (MCS) devices are 'life-sustaining devices' placed as a bridge to decision, either recovery, transplantation or a lifetime tether with the device. Cardiogenic shock may compromise patient autonomy, or the right for an individual patient to determine his own care. This review addresses an ethical dilemma in the context of complex clinical medical decision-making, during marked uncertainty for outcomes. RECENT FINDINGS: The language in an advanced directive is often imprecise and may not provide clear guidance, especially for emergent decisions related to MCS devices. Despite improving outcomes, application of MCS in critical illness is associated with excessive morbidity and quality of life-limiting adverse outcomes. Several cohort experiences now exist that define deactivation of Left Ventricular Assist Devices (LVADs) in futility as now deemed as morally and ethically appropriate. In contradistinction to euthanasia, deactivation of an LVAD does not introduce new intervention or an additional surgical injury, thereby allowing the patient to die from their original disorder. SUMMARY: Clinicians must maintain the principle of patient autonomy, ensure the viability of an appropriate informed consent process and facilitate surrogate judgment. An interdisciplinary team-based approach is required, and, in some cases, assisted by formal ethics consultations in vexing situations.

Total artificial heart implantation: clinical indications, expected postoperative imaging findings, and recognition of complications.

OBJECTIVE: The purposes of this article are to review the treatment options for late-stage biventricular heart failure, discuss the clinical indications for total artificial heart (TAH) implantation, illustrate the expected imaging findings after uncomplicated TAH implantation, and highlight the radiologic findings of common and uncommon complications associated with TAH implantation through case examples. CONCLUSION: TAH implantation is an effective therapeutic option for the treatment of patients with end-stage biventricular heart failure. The duration of implantation varies depending on a particular patient's medical condition and the eventual availability of a human heart for orthotopic transplantation. TAH recipients often undergo imaging with conventional radiography, CT, or both for the assessment of device-related issues, many of which are life-threatening and require emergency management. As the clinical use of the TAH increases and becomes more commonplace, it is imperative that radiologists interpreting imaging studies recognize both the expected and the unexpected imaging findings that affect patient care.

Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators.

BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

Pathologist Interrater Reliability and Clinical Implications of Elevated Donor-Derived Cell-Free DNA beyond Heart Transplant Rejection.

BACKGROUND: There is significant variability amongst pathologists in the histopathological interpretation of the endomyocardial biopsy (EMB) for acute cellular rejection (ACR) and assessment of variability in the interpretation of antibody-mediated rejection (AMR) has not been reported. In contemporary practice, the strategy of allograft surveillance with donor-derived cell-free DNA (dd-cfDNA) as compared to EMB has not been compared with a focus on long-term clinical outcomes beyond acute rejection (AR). METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter, prospective cohort study that enrolled patients from 2015 to 2020. The center pathologist read was compared to two blinded core cardiac pathologists. ACR and AMR were graded based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. Weighted Cohen's kappa (κ) was used to evaluate interrater reliability between the center and core reads. To assess long-term outcomes, we evaluated a composite of AR, allograft dysfunction, and mortality within 1 year. RESULTS: The study included 94 patients (median age 55 years [IQR 45, 62]), 30% female, 41% Black race) with a total of 429 EMBs and paired dd-cfDNA measures. The concordance rate between center and core pathologists was 77% for ACR (95%CI: 66% - 89%) and 63% for AMR (95%CI: 53% - 74%). 46 patients had an elevation in dd-cfDNA without AR by EMB. The median dd-cfDNA was 0.49% (IQR: 0.35, 1.01) and subsequent AR, allograft dysfunction, or mortality occurred in 59% of these patients at 1 year. In patients with AR by EMB and negative dd-cfDNA (n=5) the composite outcome occurred in 20% of patients at 1 year. At baseline, the positive likelihood ratio (LR+) of dd-cfDNA to detect AR by the center pathologist was 3.74 (95% CI 3.01 - 4.64) and core pathologist was 2.59 (95%CI: 1.95 - 3.45). If the composite outcome was included as a true positive, the LR+ of dd-cfDNA improved to 9.82 (95%CI: 7.04, 13.69) and7.63 (95% CI: 5.61, 10.38) at 1-year, respectively. CONCLUSIONS: Pathologists interrater reliability is limited in both ACR and AMR. The positive LR of dd-cfDNA when compared to traditional histopathology is limited, but when longitudinal clinical outcomes are included to assess diagnostic performance, the LR+ improves significantly. The value of dd-cfDNA extends beyond the diagnosis of AR to include other clinically meaningful outcomes for patients after heart transplant.

Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients.

OBJECTIVES: Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker. RATIONALE AND DESIGN: Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis. PATIENTS: Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both "in vivo" and "in vitro." MAIN RESULTS: In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4±0.38, 1.7±0.41, 2.4±0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2±0.09, 1.4±0.23, 2.2±0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (-18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (-29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain. CONCLUSIONS: Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.