An ISHLT consensus statement on strategies to prevent and manage hemocompatibility related adverse events in patients with a durable, continuous-flow ventricular assist device.

Life expectancy of patients with a durable, continuous-flow left ventricular assist device (CF-LVAD) continues to increase. Despite significant improvements in the delivery of care for patients with these devices, hemocompatability-related adverse events (HRAEs) are still a concern and contribute to significant morbility and mortality when they occur. As such, dissemination of current best evidence and practices is of critical importance. This ISHLT Consensus Statement is a summative assessment of the current literature on prevention and management of HRAEs through optimal management of oral anticoagulant and antiplatelet medications, parenteral anticoagulant medications, management of patients at high risk for HRAEs and those experiencing thrombotic or bleeding events, and device management outside of antithrombotic medications. This document is intended to assist clinicians caring for patients with a CF-LVAD provide the best care possible with respect to prevention and management of these events.

Warfarin and aspirin versus warfarin alone for prevention of bleeding and thrombotic events in patients with a HeartMate 3™ left ventricular assist device.

BACKGROUND: We conducted a single-center, retrospective comparison of adult patients who received warfarin and ASA or warfarin alone after HeartMate 3 (HM3) LVAD placement. METHODS: The primary outcome was a composite of bleeding and thrombotic events. RESULTS: Of 81 patients, 53 patients received warfarin and ASA, and 28 patients received warfarin alone. A primary outcome event occurred in 22 of 53 patients (41.4%) in the warfarin and ASA group and in 2 of 28 patients (7.1%) in the warfarin alone group (p = 0.0533). The odds of a bleeding event occurring were higher in the warfarin and ASA group (32.1% vs. 7.1%, p = 0.01309). The odds of a thrombotic event occurring were not significantly different between the warfarin and ASA group and the warfarin alone group (9.4% vs. 0%, respectively, p = 0.1582). CONCLUSION: The complete omission of ASA from the antithrombotic regimen of patients with a HM3 LVAD was associated with less bleeding events without an increase in thrombotic events.

Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial.

IMPORTANCE: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. OBJECTIVE: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. DESIGN, SETTING, and PARTICIPANTS: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. Intervention: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. MAIN OUTCOMES AND MEASURES: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. RESULTS: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. CONCLUSIONS AND RELEVANCE: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.

LVAD therapy as a catalyst to heart failure remission and myocardial recovery.

The management of chronic heart failure over the past decade has witnessed tremendous strides in medical optimization and device therapy including the use of left ventricular assist devices (LVAD). What we once thought of as irreversible damage to the myocardium is now demonstrating signs of reverse remodeling and recovery. Myocardial recovery on the structural, molecular, and hemodynamic level is necessary for sufficient recovery to withstand explant and achieve sustained recovery post-LVAD. Guideline-directed medical therapy and unloading have been shown to aid in recovery with the potential to successfully explant the LVAD. This review will summarize medical optimization, assessment for recovery, explant methodologies and outcomes post-recovery with explant of durable LVAD.

The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance.

Noninvasive heart transplant rejection surveillance using gene expression profiling (GEP) to monitor immune activation is widely used among heart transplant programs. With the new development of donor-derived cell-free DNA (dd-cfDNA) assays, more programs are transitioning to a predominantly noninvasive rejection surveillance protocol with a reduced frequency of endomyocardial biopsies. As a result, many practical questions arise that potentially delay implementation of these valuable new tools. The purpose of this review is to provide practical guidance for clinicians transitioning toward a less invasive acute rejection monitoring protocol after heart transplantation, and to answer 10 common questions about the GEP and dd-cfDNA assays. Evidence supporting GEP and dd-cfDNA testing is reviewed, as well as guidance on test interpretation and future directions.

Safety and Efficacy of Early Post-Operative Intravenous Iron Replacement In Patients With HeartMate III Left Ventricular Assist Device.

BACKGROUND: While guidelines suggest intravenous (IV) iron to improve functional status and quality of life (QoL) in patients with NYHA class II-III heart failure (HF), continuous flow left ventricular assist device (CF-LVAD) recipients were not included in early IV iron studies. Our study compared outcomes between patients who did and did not receive IV iron during the index admission following Abbott HeartMate III™ (HM 3) CF-LVAD placement. METHODS: Thirty-three adult patients with a HM3 placed at our institution who received early post-operative IV iron (n = 20) or no IV iron replacement (n = 13) were compared. The co-primary outcomes were mean change in quality of life (by the Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and 6-minute walk distance (6MWD) from baseline to first >90 day clinic follow-up. RESULTS: At first clinic follow-up there was no significant difference between the IV iron and no-IV iron groups in MLHFQ (-27 ± 38 vs -21 ± 41, P = .8822) or 6MWD (360 ± 740 vs 786 ± 722, P = .208). CONCLUSION: Patients receiving IV iron during index admission following HM3 implantation did not experience an improvement in quality of life or functional capacity when compared to those who did not receive IV iron.

Supportive Care and Symptom Management for Patients With Immunoglobulin Light Chain (AL) Amyloidosis.

Immunoglobulin light chain (AL) amyloidosis is a disorder of clonal plasma cells characterized by deposition of amyloid fibrils in a variety of tissues, leading to end-organ injury. Renal or cardiac involvement is most common, though any organ outside the central nervous system can develop amyloid deposition, and symptomatic presentations may consequently vary. The variability and subtlety of initial clinical presentations may contribute to delayed diagnoses, and organ involvement is often quite advanced and symptomatic by the time a diagnosis is established. Additionally, while organ function can improve with plasma-cell-directed therapy, such improvement lags behind hematologic response. Consequently, highly effective supportive care, including symptom management, is essential to improve quality of life and to maximize both tolerance of therapy and likelihood of survival. Considering the systemic nature of the disease, close collaboration between clinicians is essential for effective management.

Special Considerations in the Care of Women With Advanced Heart Failure.

Advanced heart failure (AHF) is associated with increased morbidity and mortality, and greater healthcare utilization. Recognition requires a thorough clinical assessment and appropriate risk stratification. There are persisting inequities in the allocation of AHF therapies. Women are less likely to be referred for evaluation of candidacy for heart transplantation or left ventricular assist device despite facing a higher risk of AHF-related mortality. Sex-specific risk factors influence progression to advanced disease and should be considered when evaluating women for advanced therapies. The purpose of this review is to discuss the role of sex hormones on the pathophysiology of AHF, describe the clinical presentation, diagnostic evaluation and definitive therapies of AHF in women with special attention to pregnancy, lactation, contraception and menopause. Future studies are needed to address areas of equipoise in the care of women with AHF.

Contemporary Trends and Comparison of Racial Differences in Hospitalizations of Adults With Congenital Heart Disease.

As advancements in care improve longevity in patients with congenital heart disease (CHD), it is crucial to further characterize this rapidly growing adult population. It is also essential that equitable care is offered across demographic groups. Hospitalizations for adults with CHD in the National Inpatient Sample were identified to describe trends in overall and cause-specific rates of admission per 1,000 adults with CHD from 2000 to 2018. Primary admission causes were then analyzed and stratified by race. An aggregate rate of left-ventricular assist device placements and heart transplants was calculated for each group and trended over the years. A total of 1,562,001 weighted hospitalizations were identified. Overall, annual rates of hospital admissions increased from 39 per 1,000 adults with CHD in 2000 to 74 per 1,000 in 2018, as did rates of cardiovascular admissions (16 of 1,000 to 34 of 1,000, p <0.001 for both). Transient ischemic attack/stroke (2.5 of 1,000 to 10.7 of 1,000), coronary artery disease (4.1 of 1,000 to 5.6 of 1,000), arrhythmias (2.8 of 1,000 to 4.6 of 1,000), and heart failure (2.8 of 1,000 to 5.0 of 1,000) were the most common cardiovascular primary causes of admission (other than CHD itself), and each significantly increased over time (p <0.001 for each). Mean age at all-cause and primary heart failure hospitalization increased for all races but remained 7 to 9 years younger for Black and Hispanic adults than White adults. In conclusion, hospitalization rates of adults with CHD in the United States increased from 2000 to 2018, largely driven by an increase in adults ≥55 years. Although the age at hospitalization increased overall, Black and Hispanic patients were substantially younger at presentation for advanced heart failure. Anticoagulation guidelines in this population may need revisiting as transient ischemic attack/stroke hospitalizations were frequent.

COVID-19: Understanding Inter-Individual Variability and Implications for Precision Medicine.

Coronavirus disease 2019 (COVID-19) is characterized by heterogeneity in susceptibility to the disease and severity of illness. Understanding inter-individual variation has important implications for not only allocation of resources but also targeting patients for escalation of care, inclusion in clinical trials, and individualized medical therapy including vaccination. In addition to geographic location and social vulnerability, there are clear biological differences such as age, sex, race, presence of comorbidities, underlying genetic variation, and differential immune response that contribute to variability in disease manifestation. These differences may have implications for precision medicine. Specific examples include the observation that androgens regulate the expression of the enzyme transmembrane protease, serine 2 which facilitates severe acute respiratory syndrome coronavirus 2 viral entry into the cell; therefore, androgen deprivation therapy is being explored as a treatment option in males infected with COVID-19. An immunophenotyping study of COVID-19 patients has shown that a subset develop T cytopenia which has prompted a clinical trial that is testing the efficacy of interleukin-7 in these patients. Predicting which COVID-19 patients will develop progressive disease that will require hospitalization has important implications for clinical trials that target outpatients. Enrollment of patients at low risk for progression of disease and hospitalization would likely not result in such therapy demonstrating efficacy. There are efforts to use artificial intelligence to integrate digital data from smartwatch applications or digital monitoring systems and biological data to enable identification of the high risk COVID-19 patient. The ultimate goal of precision medicine using such modern technology is to recognize individual differences to improve health for all.

Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association.

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.

Desensitization for sensitized patients awaiting heart transplant.

PURPOSE OF REVIEW: This review summarizes contemporary desensitization strategies for patients awaiting cardiac transplantation in an era when specific management is still somewhat controversial. RECENT FINDINGS: The number of sensitized patients awaiting heart transplantation is rising. Clinical assessment of antibody levels is mostly focused on human leukocyte antigen (HLA) antibodies. Sensitization to HLA antigens increases the risk of antibody medicated rejection and cardiac allograft vasculopathy after transplant, thus translates to reduced access to compatible donors and increased wait time to transplant. Desensitization therapy is commonly considered in listed patients with cPRA more than 50%, to either decrease the amount of circulating anti-HLA antibodies, reduce the antibody production, or a combination of both. Despite promising results on specific therapies (e.g., plasmapheresis, intravenous immunoglobulin, rituximab, bortezomib), there is a significant gap in knowledge on desensitization therapies in heart transplantation. Most data are from small observational studies and extrapolated from nonheart solid organ transplants. SUMMARY: Management of the sensitized patient awaiting heart transplant is individualized. Desensitization can facilitate negative cross-match and successful transplantation, but is associated with significant cost and potential adverse effects. The long-term outcomes of desensitization therapy remain to be determined, further emphasizing the importance of personalizing the treatment approach to each patient.

NEUROMODULATION OF THE FAILING HEART: LOST IN TRANSLATION?

Sympathovagal imbalance contributes to progressive worsening of HF (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies which supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and baroreceptor activation therapy (BAT) in patients with HF with a reduced ejection fraction (HFrEF). While the phase II studies with BAT remain encouraging, the larger clinical studies with SCS and VNS have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.

Increased Body Mass Index Is Associated with Congestive Heart Failure and Mortality in Adult Fontan Patients.

OBJECTIVE: Obesity affects adults with congenital heart disease (CHD). The effect of an increased body mass index (BMI) with respect to morbidity and mortality has not been evaluated in adults with complex CHD. Our objective was to evaluate the effects of increased BMI on heart failure and mortality in univentricular patients who had undergone Fontan palliation. METHODS: A query of Fontan patients' first appointments at the Washington University Center for Adults with CHD between 2007 and 2014 yielded 79 patients. BMI status as normal (<25 kg/m(2) ), overweight (≥25, <30 kg/m(2) ), and obese (≥30 kg/m(2) ) was established at the patient's first appointment. We analyzed demographics, diuretic requirements, New York Heart Association (NYHA) class, and laboratory values using Student's two-sample t-test and Fisher's exact test. Mortality was assessed via survival curves, and hazard ratios were compiled with proportional hazard modeling. RESULTS: The recent average BMI was significantly greater in patients with NYHA classes II-IV (29.3 ± 9 kg/m(2) ) compared with asymptomatic patients (24.8 ± 5.1 kg/m(2) , P = .006). Additionally, the average BMI of patients with a high diuretic requirement (≥40 mg/day IV furosemide equivalent) was obese, at 32.15 ± 9.1 kg/m(2) , compared with 25.91 ± 7.3 kg/m(2) for those on no or lower doses of diuretics (P = .009). Eighteen of the 79 patients met an endpoint of death, hospice placement, or cardiac transplant by the study conclusion. Kaplan-Meier analysis from time of first appointment until recent follow-up revealed a significant association between time to combined endpoint and BMI class. Cox proportional hazard modeling with age adjustment yielded a hazard ratio of 3.2 (95% CI 1.096-9.379) for obesity upon first presentation to an adult CHD clinic. CONCLUSIONS: In patients with univentricular hearts and Fontan palliation, obesity is associated with symptomatic heart failure and mortality.

Interactions of neuropeptide y, catecholamines, and angiotensin at the vascular neuroeffector junction.

Work from our laboratory has established that angiotensin II (Ang II) produces a greater enhancement of the nerve stimulation (NS)-induced release (overflow) of both norepinephrine (NE) and neuropeptide Y (NPY) and a greater increase in perfusion pressure of the mesenteric arterial bed obtained from the spontaneously hypertensive rat (SHR) compared to age-matched Wistar-Kyoto (WKY) or Sprague-Dawley rats. The enhancement of NS-induced NPY release was blocked by the AT1 receptor antagonist EMD 66684 and the AT2 receptor antagonist PD 123319. Both captopril and EMD 66684 decreased NPY and NE overflow from SHR mesenteric beds, suggesting an endogenous renin-angiotensin system (RAS) is active in the mesenteric artery. We also observed that the recently discovered new arm of the RAS, namely, angiotensin (1-7) (Ang-(1-7)), attenuated the NS-induced increase in NE and NPY release and the accompanied increased perfusion pressure. These inhibitory effects were greater in blood vessels obtained from SHR compared to WKY. We suggest that inhibition of sympathetic neurotransmission contributes to the mechanism(s) by which Ang-(1-7) acts to inhibit the vasoconstrictor effect of Ang II. Administration of the MAS receptor antagonist D-Ala(7)Ang-(1-7) attenuated the decrease in both NE and NPY release due to Ang-(1-7) administration. The AT2 receptor antagonist PD 123391 attenuated the effect of Ang-(1-7) on NE release without affecting the decrease in NPY release. We observed a shift in the balance between Ang II and Ang-(1-7) levels in the SHR with an increase in Ang II and a decrease in Ang-(1-7) in the blood and mesenteric artery. This appears to be due to an increase in angiotensin-converting enzyme (ACE) in the mesenteric artery of the SHR.

Inhibitory effects of angiotensin-(1-7) on the nerve stimulation-induced release of norepinephrine and neuropeptide Y from the mesenteric arterial bed.

Neuropeptide Y (NPY) is a cotransmitter with norepinephrine (NE) and ATP in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin-angiotensin system (RAS), as well as a role for NPY in the development of hypertension in experimental animal models and in humans. Angiotensin II (ANG II) is known to facilitate sympathetic neurotransmission, an effect greater in spontaneously hypertensive rats (SHR) than normotensive Wistar-Kyoto (WKY) rats. A newly discovered product of the RAS is angiotensin-(1-7) [ANG-(1-7)]. There is evidence suggesting that ANG-(1-7) opposes the actions of ANG II, resulting in hypotensive effects. The objective of this study was to investigate the role of ANG-(1-7) on the nerve-stimulated overflow of NE and NPY from the mesenteric arterial bed of SHR and the mechanisms involved in mediating any effects produced. ANG-(1-7) (0.001, 0.01, 0.1 microM) decreased nerve-stimulated NE and NPY overflow, as well as perfusion pressure in preparations obtained from SHR. This effect was greater in preparations of SHR than WKY controls. In addition, ANG-(1-7) decreased NE overflow to a greater extent than NPY overflow. Administration of the Mas receptor antagonist, D-Ala(7) ANG-(1-7), attenuated the decrease in both NE and NPY overflow due to ANG-(1-7) administration. However, the angiotensin type 2 receptor antagonist, PD-123391, attenuated the effect of ANG-(1-7) on NE overflow without affecting the decrease in NPY overflow. Moreover, in the presence of N(G)-nitro-L-arginine methyl ester, ANG-(1-7) decreased NPY overflow, but not NE overflow. ANG-(1-7) decreases the nerve-stimulated overflow of NE and NPY in preparations of SHR, whereas ANG II enhances it. Therefore, ANG-(1-7) may counteract the effects of ANG II by acting on ANG type 2 and Mas receptors.

Nerve stimulation induced overflow of neuropeptide Y and modulation by angiotensin II in spontaneously hypertensive rats.

The sympathetic nervous system and renin-angiotensin system are both thought to contribute to the development and maintenance of hypertension in experimental models such as the spontaneously hypertensive rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and neuropeptide Y (NPY) overflow from perfused mesenteric arterial beds of SHRs at 4-6, 10-12, and 18-20 wk of age, which correspond to prehypertensive, developing hypertensive, and maintained hypertensive stages, respectively, in the SHR. NS also increased PP and NPY overflow from mesenteric beds of Wistar-Kyoto (WKY) normotensive rats. NS-induced increases in PP and NPY were greater in vessels obtained from SHRs of all three ages compared with WKY rats. ANG II produced a greater increase in PP in preparations taken from SHRs than WKY rats. ANG II also resulted in a greater increase in basal NPY overflow from 10- to 12-wk-old and 18- to 20-wk-old SHRs than age-matched WKY rats. ANG II enhanced the NS-induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS-induced NPY overflow by ANG II was blocked by the AT1 receptor antagonist EMD-66684 and the angiotensin type 2 receptor antagonist PD-123319. In contrast, ANG II greatly enhanced norepinephrine overflow in the presence of PD-123319. Both captopril and EMD-66684 decreased neurotransmitter overflow from SHR mesenteric beds; therefore, we conclude that an endogenous renin-angiotensin system is active in this preparation. It is concluded that the ANG II-induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.