Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Left ventricular hemodynamics with veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: There is considerable debate about the hemodynamic effects of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). AIMS: To evaluate the changes in left ventricular (LV) function, volumes, and work in patients treated with VA-ECMO using invasive LV catheterization and three-dimensional echocardiographic volumes. METHODS: Patients on VA-ECMO underwent invasive hemodynamic evaluation due to concerns regarding candidacy for decannulation. Hemodynamic parameters were reported as means±standard deviations or medians (interquartile ranges) after evaluating for normality. Paired comparisons were done to evaluate hemodynamics at the baseline (highest) and lowest tolerated levels of VA-ECMO support. RESULTS: Twenty patients aged 52.3 ± 15.8 years were included. All patients received VA-ECMO for refractory cardiogenic shock (5/20 SCAI stage D, 15/20 SCAI stage E). At 3.0 (2.0, 4.0) days after VA-ECMO cannulation, the baseline LV ejection fraction was 20% (15%, 27%). The baseline and lowest VA-ECMO flows were 4.0 ± 0.6 and 1.5 ± 0.6 L/min, respectively. Compared to the lowest flow, full VA-ECMO support reduced LV end-diastolic volume [109 ± 81 versus 134 ± 93 mL, p = 0.001], LV end-diastolic pressure (14 ± 9 vs. 19 ± 9 mmHg, p < 0.001), LV stroke work (1858 ± 1413 vs. 2550 ± 1486 mL*mmHg, p = 0.002), and LV pressure-volume area (PVA) (4507 ± 1910 vs. 5193 ± 2388, p = 0.03) respectively. Mean arterial pressure was stable at the highest and lowest flows (80 ± 16 vs. 75 ± 14, respectively; p = 0.08) but arterial elastance was higher at the highest VA-ECMO flow (4.9 ± 2.2 vs lowest flow 2.7 ± 1.6; p < 0.001). CONCLUSIONS: High flow VA-ECMO support significantly reduced LV end-diastolic pressure, end-diastolic volume, stroke work, and PVA compared to minimal support. The Ea was higher and MAP was stable or minimally elevated on high flow.

Pharmacotherapy in the heart transplant recipient: A primer for nurse clinicians and pharmacists.

Heart transplantation (HT) is the definitive treatment for eligible patients with end-stage heart disease. A major complication of HT is allograft rejection which can lead to graft dysfunction and death. The guiding principle of chronic immunosuppression therapy is to prevent rejection of the transplanted organ while avoiding oversuppression of the immune system, which can cause opportunistic infections and malignancy. The purpose of this review is to describe immunosuppressive management of the HT recipient-including agent-specific pharmacology and pharmacokinetics, outcomes data, adverse effects, clinical considerations, and recent guideline updates. We will also provide recommendations for medical prophylaxis of immunosuppressed patients based on the most recent clinical guidelines. Additionally, we highlight the importance of medical therapy adherence and the effect of social determinants of health on the long-term management of HT. HT recipients are a complex and high-risk population. The objective of this review is to describe basic pharmacotherapy in HT and implications for nurses and pharmacists.

A novel opportunity to improve heart failure care: focusing on subcutaneous furosemide.

The prevalence of heart failure (HF) continues to rise in developed nations. Symptomatic congestion is the most common reason for patients to seek medical attention, and management often requires intravenous (IV) diuretic administration in the hospital setting. Typically, the number of admissions increases as the disease progresses, not only impacting patient survival and quality of life but also driving up healthcare expenditures. pH-neutral furosemide delivered subcutaneously using a proprietary, single-use infusor system (Furoscix) has a tremendous potential to transition in-hospital decongestive therapy to the outpatient setting or to the patient's home. This review is aimed at providing an overview of the pharmacodynamic and pharmacokinetic profile of the novel pH-neutral furosemide in addition to the most recent clinical trials demonstrating its benefit when used in the home setting. Given the newest data and approval by the Food and Drug Administration in the US, it has the potential to revolutionize the care of patients with decompensated HF. Undoubtedly, it will lead to improved quality of life as well as significantly reduced healthcare costs related to hospital admissions.

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.

Designing a patient-specific search of transplant program performance and outcomes: Feedback from heart transplant candidates and recipients.

BACKGROUND: The Scientific Registry of Transplant Recipients provides transplant program-specific information, but it is unclear what patients and stakeholders need to know. Acceptance criteria for the candidate waitlist and donor organs vary by program and region, but there is no means to search for programs by the clinical profiles of recipients and donors. METHODS: We examined variability in program-specific characteristics that could influence access to transplantation. We also conducted three interviews and three focus groups with heart transplant candidates and recipients. Participants evaluated prototypes of a patient-specific search tool and its capacity to identify programs tailored to specific patient needs. Patient experiences and feedback influenced the development of tools. RESULTS: The distribution of recipient and donor characteristics influenced access to transplantation, as age and body mass index varied across programs (all with p < .01). Several themes emerged related to decision-making and the perceived usability of the patient-specific search. Perceptions of the prototypes varied, but were positive overall and support making the patient-specific search publicly available. Participants revealed barriers to evaluating transplant programs and suggest that patient-specific search results may optimize the process. CONCLUSIONS: The patient-specific tool (http://transplantcentersearch.org/) is valued by heart transplant patients and is important to maximizing access to transplant.

PROVIDE-HF primary results: Patient-Reported Outcomes inVestigation following Initiation of Drug therapy with Entresto (sacubitril/valsartan) in heart failure.

BACKGROUND: In PARADIGM-HF, sacubitril/valsartan improved quality of life (QOL) versus enalapril in heart failure with reduced ejection fraction (HFrEF), yet limited data are available regarding QOL changes after sacubitril/valsartan initiation in routine practice. METHODS: PROVIDE-HF was a prospective study within a national research network (Patient-Centered Outcomes Research Network) of HFrEF outpatients recently initiated on sacubitril/valsartan versus controls with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change. The primary end point was mean Kansas City Cardiomyopathy Questionnaire (KCCQ) change through 12 weeks. Other end points included responder analyses: ≥5-point and ≥20-point KCCQ increase. Adjusted QOL change was estimated after propensity score weighting. RESULTS: Overall, 270 patients had both baseline and 12-week KCCQ data (151 sacubitril/valsartan; 119 control). The groups had similar demographics and HF details: median EF 28% and N-terminal pro-brain natriuretic peptide 1083 pg/mL. Sacubitril/valsartan patients had larger improvements in KCCQ (mean difference +4.76; P = .027) and were more likely to have a ≥5-point and ≥20-point response (all P < .05). Adjusted comparisons demonstrated similar numerical improvements in the change in KCCQ (+4.55; 95% CI -0.89 to 9.99; P = .101) and likelihood of ≥5-point increase (odds ratio 1.55; 95% CI: 0.84-2.86; P = .16); ≥20-point increase remained statistically significant (odds ratio 3.79; 95% CI 1.47-9.73; P = .006). CONCLUSIONS: In this prospective HFrEF study of sacubitril/valsartan initiation compared with recent angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation/dose change, the between-group difference in the primary end point, mean KCCQ change at 12 weeks was not statistically significant following adjustment, but sacubitril/valsartan initiation was associated with early improvements in QOL and a higher likelihood of ≥20-point improvement in KCCQ at 12 weeks. These data add additional real-world evidence related to patient-reported outcomes following the initiation of sacubitril/valsartan in routine clinical practice.

Nonsustained ventricular tachycardia in heart failure with preserved ejection fraction.

BACKGROUND: Ventricular tachycardia (VT) is a common arrhythmia in heart failure with reduced ejection fraction but its incidence, predictors, and significance have not been determined in heart failure with preserved ejection fraction (HFpEF). METHODS: We performed a retrospective review of arrhythmias in two cohorts of patients with an HFpEF diagnosis. Patients in cohort 1 (n = 40) underwent routine arrhythmia surveillance with a 14-day ambulatory electrocardiogram (ECG) monitor. Patients in cohort 2 (n = 85) had cardiac pacemakers and underwent routine device interrogations. RESULTS: In cohort 1, 13 patients (32.5%) had one or more episodes of nonsustained VT (NSVT) on ambulatory ECG. In cohort 2, 38 patients (44.7%) had NSVT on cardiac pacemaker interrogations. During a median (interquartile range) follow-up of 3.0 (1.6 to 5.1) years, 15 (12%) patients died (20% of patients with NSVT versus 6.8% of those without NSVT; P = .03). In logistic regression analysis, NSVT was associated with a 3.4-fold higher odds of death (95% confidence interval 1.08 to 10.53; P = .04) in HFpEF. CONCLUSIONS: In conclusion, patients with HFpEF have a relatively high, and possibly underappreciated, burden of NSVT, which confers a higher risk of mortality. The frequent episodes of NSVT in these patients may provide insight into the mechanism of sudden cardiac death in HFpEF.

Update on COVID-19 Myocarditis.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gained worldwide attention at the end of 2019 when it was identified to cause severe respiratory distress syndrome. While it primarily affects the respiratory system, we now have evidence that it affects multiple organ systems in the human body. Cardiac manifestations may include myocarditis, life threatening arrhythmias, acute coronary syndrome, systolic heart failure, and cardiogenic shock. Myocarditis is increasingly recognized as a complication of Coronavirus-19 (COVID-19) and may result from direct viral injury or from exaggerated host immune response. The diagnosis is established similar to other etiologies, and is based on detailed history, clinical exam, laboratory findings and non-invasive imaging studies. When available, cardiac MRI is the preferred imaging modality. Endomyocardial biopsy may be performed if the diagnosis remains uncertain. Current management is mainly supportive with the potential addition of interventions recommended for severe COVID-19 disease, such as remdesivir, steroids, and convalescent plasma. In the setting of cardiogenic shock and refractory, life-threatening arrhythmias that persist despite medical therapy, advanced mechanical circulatory support devices should be considered. Ultimately, early recognition and aggressive intervention are key factors in reducing morbidity and mortality. Our management strategy is expected to evolve further as we learn more about COVID-19 disease and the associated cardiac complications.

TNF-α alters the release and transfer of microparticle-encapsulated miRNAs from endothelial cells.

MicroRNAs (miRNAs) encapsulated within microparticles (MPs) are likely to have a role in cell-to-cell signaling in a variety of diseases, including atherosclerosis. However, little is known about the mechanisms by which different cell types release and transfer miRNAs. Here, we examined TNF-α-induced release of MP-encapsulated miR-126, miR-21, and miR-155 from human aortic endothelial cells (ECs) and their transfer to recipient cells. ECs were treated with TNF-α (100 ng/ml) in the presence or absence of inhibitors that target different MP production pathways. MPs released in response to TNF-α were characterized by: 1) 70-80% decrease in miRNA/MP levels for miR-126 and -21 but a significant increase in pre-miR-155 and miR-155 (P < 0.05), 2) 50% reduction in uptake by recipient cells (P < 0.05), and 3) diminished ability to transfer miRNA to recipient cells. Cotreatment of donor ECs with TNF-α and caspase inhibitor (Q-VD-OPH, 10 µM) produced MPs that had: 1) 1.5- to 2-fold increase in miRNA/MP loading, 2) enhanced uptake by recipient cells (2-fold), and 3) increased ability to transfer miR-155. Cotreatment of ECs with TNF-α and Rho-associated kinase (ROCK) inhibitor (10 µM) produced MPs with features similar to those produced by TNF-α treatment alone. Our data indicate that TNF-α induced the production of distinct MP populations: ROCK-dependent, miRNA-rich MPs that effectively transferred their cargo and were antiapoptotic, and caspase-dependent, miRNA-poor MPs that were proapoptotic. These data provide insight into the relationship between MP production and extracellular release of miRNA, as well as the potential of encapsulated miRNA for cell-to-cell communication.

Right Ventricular Function on Cardiovascular Magnetic Resonance Imaging and Long-Term Outcomes in Stable Heart Transplant Recipients.

BACKGROUND: In heart transplant recipients, right ventricular (RV) dysfunction may occur for a variety of reasons. Whether RV dysfunction in the stable phase after heart transplantation is associated with long-term adverse outcomes is unknown. We aimed to determine the long-term prognostic significance of RV dysfunction identified on cardiovascular magnetic resonance imaging (CMR) at least 1 year after heart transplantation. METHODS: In consecutive heart transplant recipients who underwent CMR for surveillance, we assessed 2 CMR measures of RV function: RV ejection fraction and RV global longitudinal strain (RVGLS). We investigated associations between RV dysfunction and a composite end point of death or major adverse cardiac events, including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS: A total of 257 heart transplant recipients (median age, 59 years; 75% men) who had CMR at a median of 4.3 years after heart transplantation were included. Over a median follow-up of 4.4 years after the CMR, 108 recipients experienced death or major adverse cardiac events. In a multivariable Cox regression analysis adjusted for age, time since transplantation, indication for transplantation, cardiac allograft vasculopathy, history of rejection, and CMR covariates, RV ejection fraction was not associated with the composite end point, but RVGLS was independently associated with the composite end point with a hazard ratio of 1.08 per 1% worsening in RVGLS ([95% CI, 1.00-1.17]; P=0.046). RVGLS provided incremental prognostic value over other variables in multivariable analyses. The association was replicated in subgroups of recipients with normal RV ejection fraction and recipients with late gadolinium enhancement imaging. A similar association was seen with a composite end point of cardiovascular death or major adverse cardiac events. CONCLUSIONS: CMR feature tracking-derived RVGLS assessed at least 1 year after heart transplantation was independently associated with the long-term risk of death or major adverse cardiac events. Future studies should investigate its role in guiding clinical decision-making in heart transplant recipients.

Survival After Simultaneous Heart-kidney Transplant in Recipients With a Durable LVAD and Chronic Kidney Disease: Effect of the 2018 Heart Allocation Policy Change.

BACKGROUND: Heart transplantation remains the most definitive therapy for qualified candidates with end-stage heart failure. Concomitant kidney disease is common in this population prompting an increase in simultaneous heart-kidney (SHK) transplantation in recent years. The goal of our study was to explore the effects of the 2018 heart allocation policy (HAP) change on candidate listing characteristics and compare survival rates at 1 y in patients that were supported with a left ventricular assist device (LVAD) pretransplant and underwent SHK or heart alone transplant (HAT). METHODS: We used data from the Scientific Registry of Transplant Recipients and identified all adults who underwent primary SHK or HAT between January 2010 and March 2022. Recipients supported with a durable LVAD and estimated glomerular filtration rate <60 mL/min/1.73 m 2 were selected (n = 309 SHK; 217 pre- and 92 post-HAP and n = 3,324 HAT; 2738 pre- and 586 post-HAP). RESULTS: Difference in survival at 1 y did not reach statistical significance. Comparing the 1-y survival of SHK and HAT recipients who were bridged with LVAD pre-HAP, we found no significant difference ( P = 0.694). Adjusting for the same covariates in a multivariable model did not affect the results (SHK versus HAT hazard ratio 0.84 [0.51, 1.37]; P = 0.48). In contrast, SHK recipients supported with an LVAD who were listed and transplanted post-HAP change had significantly lower 1-y survival, when compared with HAT ( P = 0.037). CONCLUSIONS: Our findings suggest that the HAP change had a potentially negative impact on the survival of select patients undergoing SHK transplant. Further research is warranted in this area.