Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study.

BACKGROUND: Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. METHODS: We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. RESULTS: A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17-66) ng/mL and a median peak concentration of 207 (134-293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%-65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2-2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. CONCLUSIONS: In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF.

Stabilization of Rapidly Progressive Cardiac Allograft Vasculopathy Using mTOR Inhibition After Heart Transplantation.

BACKGROUND: Inhibition of the mammalian target of rapamycin (mTor) pathway after heart transplantation has been associated with reduced progression of coronary allograft vasculopathy (CAV). The application of low-dose mTOR inhibition in the setting of modern immunosuppression, including tacrolimus, remains an area of limited exploration. METHODS: This retrospective study included patients who received heart transplantation between January 2009 and January 2019 and had baseline, 1-year and 2-3-year coronary angiography with intravascular ultrasound (IVUS). Intimal thickness in 5 segments along the left anterior descending artery was compared across imaging time points in patients who were transitioned to low-dose mTOR inhibitor (sirolimus) vs standard treatment with mycophenolate on a background of tacrolimus. Long-term adverse cardiovascular outcomes (revascularization, severe CAV, retransplant, and cardiovascular death) were also assessed. RESULTS: Among 216 patients (mean age 51.5 ± 11.9 years, 77.8% men, 80.1% white), 81 individuals (37.5%) were switched to mTOR inhibition. mTOR inhibition was associated with a reduction in intimal thickness by 0.05 mm (95% CI 0.02-0.07; P < 0.001). This reduction was driven by patients who met the criteria for rapidly progressive CAV 1-year post-transplant (0.12 mm; P = 0.016 for interaction). After a median follow-up of 8.6 (IQR 6.6-11) years, 40 patients had major adverse cardiovascular outcomes. The use of mTOR inhibitors was not significantly associated with cardiovascular outcomes (P = 0.669). CONCLUSION: Transitioning patients after heart transplantation to an immunosuppression regimen composed of low-dose mTOR inhibition and tacrolimus was associated with a lack of progression of CAV, particularly in those with rapidly progressive CAV at 1 year, but not with long-term cardiovascular outcomes.

The Promise and Risks of mHealth in Heart Failure Care.

Mobile health (mHealth) is an emerging approach to health care. It involves wearable, connected technologies that facilitate patient-symptom or physiological monitoring, support clinical feedback to patients and physicians, and promote patients' education and self-care. Evolving algorithms may involve artificial intelligence and can assist in data aggregation and health care teams' interpretations. Ultimately, the goal is not merely to collect data; rather, it is to increase actionability. mHealth technology holds particular promise for patients with heart failure, especially those with frequently changing clinical status. mHealth, ideally, can identify care opportunities, anticipate clinical courses and augment providers' capacity to implement, titrate and monitor interventions safely, including evidence-based therapies. Although there have been marked advancements in the past decade, uncertainties remain for mHealth, including questions regarding optimal indications and acceptable payment models. In regard to mHealth capability, a better understanding is needed of the incremental benefit of mHealth data over usual care, the accuracy of specific mHealth data points in making clinical care decisions, and the efficiency and precision of algorithms used to dictate actions. Importantly, emerging regulations in the wake of COVID-19, and now the end of the federal public health emergency, offer both opportunity and risks to the broader adoption of mHealth-enabled services. In this review, we explore the current state of mHealth in heart failure, with particular attention to the opportunities and challenges this technology creates for patients, health care providers and other stakeholders.

Organ Donation and Transplantation among Non-US Citizens: Opportunities to Improve Global Equity in Heart Transplantation.

BACKGROUND: Non-US citizens/non-US residents (NCNR) are a unique and growing population. Patterns of heart donation and heart transplantation (HT) within this subgroup have not been described fully. The purpose of this study was to evaluate the use of organs from NCNR donors and the characteristics and outcomes of NCNR HT recipients. METHODS: All adult donors whose hearts were recovered for HT and all primary adult HT recipients from 2013 to 2020 were identified using the United Network for Organ Sharing. Donors and recipients were categorized as citizens, residents, or NCNR. NCNR were further categorized by reason for travel to the United States. Outcomes included mortality, infection, and rejection at 1-year after transplantation. RESULTS: NCNR accounted for 0.4% (n = 77) of heart donors. Most NCNR donors identified as Hispanic (61%), were predominately recovered from the South and Southwest United States, and were less likely to express written documentation to be a donor compared with citizens and residents. NCNR accounted for 0.7% (n = 147) of all HT recipients. The majority identified as non-Hispanic White individuals (57.1%). Compared with citizens and residents, NCNR recipients seemed to be sicker, as evidenced by higher intra-aortic balloon pump use before HT and higher priority United Network for Organ Sharing status. Of NCNR recipients, 63% traveled to the United States for HT, predominately from Kuwait (29.9%) and Saudi Arabia (20%). At 1-year after transplant, there were no differences in mortality, infection, or rejection between the groups. CONCLUSIONS: A growing subgroup of NCNR travel from countries with low HT rates to the United States for HT. This finding highlights the need for strategies to improve equitable access to HT domestically and abroad.

Association Between Change in Ambulatory Pulmonary Artery Pressures and Natriuretic Peptides in Patients with Heart Failure: Results From the EMBRACE-HF Trial.

BACKGROUND: Remote monitoring of pulmonary artery (PA) pressures and serial N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements guide heart failure (HF) treatment, but their association has yet to be described. METHODS AND RESULTS: In the Empagliflozin Evaluation by Measuring the Impact on Hemodynamics in Patients with Heart Failure (EMBRACE-HF) trial, patients with HF and a remote PA pressure monitoring device were randomized to empagliflozin vs placebo. PA diastolic pressures (PADP) and NT-proBNP levels were obtained at baseline and 6 and 12 weeks. We used linear mixed models to examine the association between change in PADP and change in NT-proBNP, adjusting for baseline covariates. Of 62 patients, the mean patient age was 66.2 years, and 63% were male. The mean baseline PADP was 21.8 ± 6.4 mm Hg, and the mean NT-proBNP was 1844.6 ± 2767.7 pg/mL. The mean change between baseline and averaged 6- and 12-week PADP was -0.4 ± 3.1 mm Hg, and the mean change between baseline and averaged 6- and 12-week NT-proBNP was -81.5 ± 878.6 pg/mL. In adjusted analyses, every 2-mm Hg decrease in PADP was associated with an NT-proBNP reduction of 108.9 pg/mL (95% confidence interval -4.3 to 222.0, P = .06). CONCLUSIONS: We observed that short-term decreases in ambulatory PADP seem to be associated with decreases in NT-proBNP. This finding may provide additional clinical context when tailoring treatment for patients with HF.

Translating Pressure Into Practice: Operational Characteristics of Ambulatory Hemodynamic Monitoring Program in the United States.

BACKGROUND: Ambulatory hemodynamic monitoring (AHM) using an implantable pulmonary artery pressure sensor (CardioMEMS) is effective in improving outcomes for patients with heart failure. The operations of AHM programs are crucial to clinical efficacy of AHM yet have not been described. METHODS AND RESULTS: An anonymous, voluntary, web-based survey was developed and emailed to clinicians at AHM centers in the United States. Survey questions were related to program volume, staffing, monitoring practices, and patient selection criteria. Fifty-four respondents (40%) completed the survey. Respondents were 44% (n = 24) advanced HF cardiologists and 30% (n = 16) advanced nurse practitioners. Most respondents practice at a center that implants left ventricular assist devices (70%) or performs heart transplantation (54%). Advanced practice providers provide day-to-day monitoring and management in most programs (78%), and use of protocol-driven care is limited (28%). Perceived patient nonadherence and inadequate insurance coverage are cited as the primary barriers to AHM. CONCLUSIONS: Despite broad US Food and Drug Administration approval for patients with symptoms and at increased risk for worsening heart failure, the adoption of pulmonary artery pressure monitoring is concentrated at advanced heart failure centers, and modest numbers of patients are implanted at most centers. Understanding and addressing the barriers to referral of eligible patients and to broader adoption in community heart failure programs is needed to maximize the clinical benefits of AHM.

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.

Orthostatic variation of pulmonary artery pressure in ambulatory heart failure patients.

AIM: To study effect of change in position (supine and standing) on pulmonary artery pressure (PAP) in ambulatory heart failure (HF) patients. METHODS: Seventeen patients with CardioMEMS® sensor and stable heart failure were consented and included in this single center study. Supine and standing measurements were obtained with at least 5 min interval between the two positions. These measurements included PAP readings utilizing the manufacturer handheld interrogator obtaining 10 s data in addition to the systemic blood pressure and heart rate recordings. RESULTS: Mean supine and standing readings and their difference (Δ) were as follows respectively: Systolic PAP were 33.4 (± 11.19), 23.6 (± 10) and Δ was 9.9 mmHg (p = 0.0001), diastolic PAP were 14.2 (± 5.6), 7.9 (± 5.7) and Δ was 6.3 mmHg (p = 0.0001) and mean PAP were 21.8 (± 7.8), 14 (± 7.2) and Δ was 7.4 mmHg (p = 0.0001) while the systemic blood pressure did not vary significantly. CONCLUSION: There is orthostatic variation of PAP in ambulatory HF patients demonstrating a mean decline with standing in diastolic PAP by 6.3 mmHg, systolic PAP by 9.9 mmHg and mean PAP by 7.4 mmHg in absence of significant orthostatic variation in systemic blood pressure or heart rate. These findings have significant clinical implications and inform that PAP in each patient should always be measured in the same position. Since initial readings at the time of implant were taken in supine position, it may be best to use supine position or to obtain a baseline standing PAP reading if standing PAP is planned on being used.

Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.

BACKGROUND: Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II-IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. METHODS: The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II-IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT03387813. FINDINGS: Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74-1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66-1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80-1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70-1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61-0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. INTERPRETATION: Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. FUNDING: Abbott.

Electromagnetic interference from left ventricular assist devices detected in patients with implantable cardioverter-defibrillators.

INTRODUCTION: Electromagnetic interference (EMI) from left ventricular assist devices (LVADs) can cause implantable cardioverter-defibrillator (ICD) oversensing. We sought to assess the frequency of inappropriate shocks/oversensing due to LVAD-related EMI and prospectively compare integrated (IB) versus dedicated bipolar (DB) sensing in patients with LVADs. METHODS: Single-center study in LVAD patients with Medtronic or Abbott ICDs between September 2017 and March 2020. We excluded patients that were pacemaker dependent. Measurements were obtained of IB and DB sensing and noise to calculate a signal-to-noise ratio (SNR). Device checks were reviewed to assess appropriate and inappropriate sensing events. RESULTS: Forty patients (age 52 ± 14 years, 75% men, 38% ischemic cardiomyopathy) were included with the median time between LVAD implantation and enrollment of 6.7 months (2.3, 11.4 months). LVAD subtypes included: HeartWare (n = 22, 55%), Heartmate II (n = 10, 25%), and Heartmate III (n = 8, 20%). Over a follow-up duration of 21.6 ± 12.9 months after LVAD implantation, 5% of patients (n = 2) had oversensing of EMI from the LVAD (both with HeartWare LVADs and Abbott ICDs) at 4 days and 10.8 months after LVAD implantation. Both patients underwent adjustment of ventricular sensing with resolution of oversensing and no further events over 5 and 15 months of further follow-up. The SNR was similar between IB and DB sensing (50 [29-67] and 57 [41-69], p = 0.89). CONCLUSION: ICD oversensing of EMI from LVADs is infrequent and can be managed with reprogramming the sensitivity. There was no significant difference in the R-wave SNR with IB versus DB ICD leads.

Outcomes in Patients With Chronic Kidney Disease and End-stage Renal Disease and Durable Left Ventricular Assist Device: Insights From the United States Renal Data System Database.

BACKGROUND: There is paucity of data regarding durable left ventricular assist device (LVAD) outcomes in patients with chronic kidney disease (CKD) stages 3-5 and CKD stage 5 on dialysis (end-stage renal disease [ESRD]). METHODS AND RESULTS: We conducted a retrospective study of Medicare beneficiaries with ESRD and a 5% sample of patients with CKD with an LVAD (2006-2018) to determine 1-year outcomes using the United States Renal Data System database. The LVAD implantation, comorbidities, and outcomes were identified using appropriate International Classification of Diseases, 9th and 10th edition codes. We identified 496 patients with CKD and 95 patients with ESRD who underwent LVAD implantation. The patients with ESRD were younger (59 years vs 66 years; P < .001), had more Blacks (40% vs 24.6%, P = .009), compared with the CKD group. The 1-year mortality (49.5% vs 30.9%, P < .001) and index mortality (27.4% vs 16.7%, P = .014) rates were higher for patients with ESRD. A subgroup analysis showed significantly higher mortality in ESRD vs CKD 3 (49.5% vs 30.2%, adjusted P = .009), but no significant difference in mortality between stage 3 vs 4/5 (30.2% vs 30.8%, adjusted P = .941). There was no significant difference in secondary outcomes (bleeding, stroke, and sepsis/infection) during follow-up between the 2 groups. CONCLUSIONS: Patients with ESRD undergoing LVAD implantation had significantly higher index and 1-year mortality rates compared with patients with CKD.

Emerging Implantable-Device Technology for Patients at the Intersection of Electrophysiology and Heart Failure Interdisciplinary Care.

Cardiac implantable electronic devices, including implantable cardioverter-defibrillators and therapy, are part of guideline-indicated treatment for a subset of patients with heart failure with reduced ejection fraction. Current technological advancements in cardiac implantable electronic devices have allowed the detection of specific physiological parameters that are used to forecast clinical decompensation through algorithmic, multiparameter remote monitoring. Other recent emerging technologies, including cardiac contractility modulation and baroreflex activation therapy, may provide symptomatic or physiological benefits in patients without indications for cardiac resynchronization. Our goal in this state-of-the-art review is to describe the new commercially available technologies, their purported mechanisms of action, and the evidence surrounding their clinical roles, limitations and future directions. Finally, we underline the need for standardized workflow and close interdisciplinary management of this population to ensure the delivery of high-quality care.

Sex Differences in Heart Failure.

Heart failure (HF) continues to be a major contributor of morbidity and mortality for men and women alike, yet how the predisposition for, course and management of HF differ between men and women remains underexplored. Sex differences in traditional risk factors as well as sex-specific risk factors influence the prevalence and manifestation of HF in unique ways. The pathophysiology of HF differs between men and women and may explain sex-specific differences in clinical presentation and diagnosis. This in turn, contributes to variation in response to both pharmacologic and device/surgical therapy. This review examines sex-specific differences in HF spanning prevalence, risk factors, pathophysiology, presentation, and therapies with a specific focus on highlighting gaps in knowledge with calls to action for future research efforts.

Palliative Inotropes in Advanced Heart Failure: Comparing Outcomes Between Milrinone and Dobutamine.

BACKGROUND: We sought to describe and compare outcomes among advanced patients with heart failure (not candidates for orthotopic heart transplant/left ventricular assist device) on long-term milrinone or dobutamine, which are not well-studied in the contemporary era. METHODS AND RESULTS: We included adults with refractory stage D heart failure who were not candidates for orthotopic heart transplant or left ventricular assist device and discharged on palliative dobutamine or milrinone. The primary outcome was 1-year survival. A 6-month predictor of survival analysis was conducted. A total of 248 patients (133 on milrinone, 115 on dobutamine) were included. There were no differences in baseline comorbidities between milrinone and dobutamine cohorts, except for the prevalence of chronic kidney disease, which was higher in the dobutamine group. On discharge, the proportion of patients on beta-blockers and mineralocorticoid antagonists was higher in milrinone group. Overall, the 1-year mortality rate was 70%. The dobutamine cohort had a significantly higher 1-year mortality rate (84% vs 58%, P <0.001). The type of inotrope did not predict survival at 6 months when adjusted for discharge medications and comorbidities. Beta-blockers and angiotensin-converting enzyme/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor continued at discharge predicted survival at 6 months. CONCLUSIONS: The 1-year mortality from palliative inotropes remains high. Compared with dobutamine, use of milrinone was associated with improved survival owing to better optimization of guideline-directed medical therapy, primarily beta-blocker therapy.

Outcomes in Patients With LVADs Undergoing Simultaneous Heart-Kidney Transplantation.

BACKGROUND: Multiple studies have shown better outcomes for simultaneous heart-kidney transplant (sHKT) than for isolated orthotopic heart transplant (iOHT) in recipients with chronic kidney disease (CKD). However, outcomes in patients supported by durable left ventricular assist devices (LVADs) have not been well studied. METHODS: Patients with durable LVADs and stage 3 or higher CKD (eGFR < 60 mL/min/1.73 m2) undergoing iOHT or sHKT between 2008 and 2020 were identified from the United Network for Organ Sharing registry. A Kaplan-Meier survival analysis with associated log-rank test was conducted to compare post-transplant survival rates. Multivariable modeling was used to identify risk-adjusted predictors of 1 year post-transplant mortality. RESULTS: We identified 4375 patients; 366 underwent sHKT, and 4009 underwent iOHT. The frequency of sHKT increased during the study period. The 1-year post-transplant survival rate was worse in patients after sHKT than in patients after iOHT (80.3% vs 88.3%; P < 0.001) and persisted up to 5 years post-transplant (P = 0.001). sHKT recipients were more likely to require dialysis after transplantation and had longer hospital lengths of stay (P < 0.001). Multivariable analysis showed that sHKT remained an independent risk factor for mortality at 1 year (OR 1.58; P = 0.002). CONCLUSIONS: sHKT is becoming more common in patients with durable LVADs. Compared with iOHT, patients with sHKTs have worse short- and long-term survival rates and are more likely to require post-transplant dialysis.

Ambulatory factors influencing pulmonary artery pressure waveforms and implications for clinical practice.

CardioMEMS, a remote pulmonary artery pressure monitoring system, provides waveform patterns for the ambulatory heart failure patient. These waveforms provide significant insights into patient volume and clinical management. We aim to provide a foundation for understanding the determinants of waveform characteristics and provide practical examples illustrating how to interpret and integrate common scenario waveforms into clinical decision-making. A total of three groups of relevant scenarios were included namely (a) location and activity at time of waveform transmission, (b) impact of contemporary interventions, and (c) arrhythmias. We illustrate that waveform analysis can be individualized to each patient's care strategy in the appropriate clinical context to help guide clinical decision-making.

UBA6 and NDFIP1 regulate the degradation of ferroportin.

Hepcidin regulates iron homeostasis by controlling the level of ferroportin, the only membrane channel that facilitates export of iron from within cells. Binding of hepcidin to ferroportin induces the ubiquitination of ferroportin at multiple lysine residues and subsequently causes the internalization and degradation of the ligand-channel complex within lysosomes. The objective of this study was to identify components of the ubiquitin system that are involved in ferroportin degradation. A HepG2 cell line, which inducibly expresses ferroportingreen fluorescent protein (FPN-GFP), was established to test the ability of small interfering (siRNA) directed against components of the ubiquitin system to prevent BMP6- and exogenous hepcidin-induced ferroportin degradation. Of the 88 siRNA directed against components of the ubiquitin pathway that were tested, siRNA-mediated depletion of the alternative E1 enzyme UBA6 as well as the adaptor protein NDFIP1 prevented BMP6- and hepcidin-induced degradation of ferroportin in vitro. A third component of the ubiquitin pathway, ARIH1, indirectly inhibited ferroportin degradation by impairing BMP6-mediated induction of hepcidin. In mice, the AAV-mediated silencing of Ndfip1 in the murine liver increased the level of hepatic ferroportin and increased circulating iron. The results suggest that the E1 enzyme UBA6 and the adaptor protein NDFIP1 are involved in iron homeostasis by regulating the degradation of ferroportin. These specific components of the ubiquitin system may be promising targets for the treatment of iron-related diseases, including iron overload and anemia of inflammation.

Impact of ultra-conservative ICD programming in patients with LVADs: Avoiding potentially unnecessary tachy-therapies.

BACKGROUND: Patients with left ventricular assist devices (LVAD) often tolerate ventricular arrhythmias (VA). We aim to assess the frequency and outcomes of ICD therapies averted by ultraconservative ICD programming (UCP) in LVAD patients. METHODS: This single center, retrospective cohort study included patients with LVADs and ICDs implanted from 2015 to 2019 that had UCP. The aim for UCP was to maximally delay VA treatments and maximize anti-tachycardia pacing (ATP) prior to ICD shocks. VA events were reviewed after UCP and evaluated under prior conservative programming to assess for potentially averted events (that would have resulted in either ATP or defibrillation with prior programming). RESULTS: Fifty patients were included in the study with follow-up of median 16 ± 10.2 months after UCP. The median time from LVAD implantation to reprogramming was 7 days (IQR 5-9 days). Fourteen patients (28%) had potentially averted VA events that would have been treated with their prior ICD programming (82 total events, median two events per patient, IQR 1-10 events). Treated VA events occurred in 15 patients (30%). Eleven of the 14 patients with potentially averted VAs had treated events as well. Only one patient reported definitive symptoms of self-limited "dizziness" during a potentially averted event that did not result in hospitalization. No patients died of complications from or needed emergent care/hospitalization due a potentially averted VA. CONCLUSIONS: UCP in LVAD patients likely prevented unnecessary VA treatments in many patients with minimal reported symptoms during these potentially averted events. Prospective studies are necessary to confirm these findings.

Prognostic Role of Cardiopulmonary Exercise Testing in Wild-Type Transthyretin Amyloid Cardiomyopathy Patients Treated With Tafamidis.

BACKGROUND: The prognostic value of cardiopulmonary exercise testing (CPET) in patients with wild-type transthyretin cardiac amyloidosis treated with tafamidis is unknown. METHODS AND RESULTS: This retrospective study included patients with wtATTR who underwent baseline cardiopulmonary exercise testing and were treated with tafamidis from August 31, 2018, until March 31, 2020. Univariate logistic and multivariate cox-regression models were used to predict the occurrence of the primary outcome (composite of mortality, heart transplant, and palliative inotrope initiation). A total of 33 patients were included (median age 82 years, interquartile range [IQR] 79-84 years), 84% were Caucasians and 79% were males). Majority of patients had New York Heart Association functional class III disease at baseline (67%). The baseline median peak oxygen consumption (VO2) and peak circulatory power (CP) were 11.35 mL/kg/min (IQR 8.5-14.2 mL/kg/min) and 1485.8 mm Hg/mL/min (IQR 988-2184 mm Hg/mL/min), respectively, the median ventilatory efficiency was 35.7 (IQR 31-41.2). After 1 year of follow-up, 11 patients experienced a primary end point. Upon multivariate analysis, the low peak VO2 (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.79, P = .007], peak CP (HR 0.98, 95% CI 0.98-0.99, P = .02), peak oxygen pulse (HR 0.62, 95% CI 0.39-0.97, P = .03), and exercise duration of less than 5.5 minutes (HR 5.82, 95% CI 1.29-26.2, P = .02) were significantly associated with the primary outcome. CONCLUSIONS: Tafamidis-treated patients with wtATTR who had baseline low peak VO2, peak CP, peak O2 pulse, and exercise duration of less than 5.5 minutes had worse outcomes.

Venoarterial Extracorporeal Membrane Oxygenation in Cardiogenic Shock: Lifeline of Modern Day CICU.

Cardiogenic shock (CS) portends an extremely high mortality of nearly 50% during index hospitalization. Prompt diagnoses of CS, its underlying etiology, and efficient implementation of treatment modalities, including mechanical circulatory support (MCS), are critical especially in light of such high predicted mortality. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides the most comprehensive cardiopulmonary support in critically ill patients and hence has seen a steady increase in its utilization over the past decade. Hence, a good understanding of VA-ECMO, its role in treatment of CS, especially when compared with other temporary MCS devices, and its complications are vital for any critical care cardiologist. Our review of VA-ECMO aims to provide the same.