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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-ɑ-induced release of MPencapsulated miR-126, miR-21, and miR-155 from human aortic endothelial cells (ECs) and their transfer to recipient cells. ECs were treated with TNF-ɑ (100 ng/ml) in the presence or absence of inhibitors that targt different MP production pathways. MPs released in response to TNF-ɑ 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-ɑ 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-ɑ and Rho-associated kinase (ROCK) inhibitor (10 µM) produced MPs with features similar to those produced by TNF-ɑ treatment alone. Our data indicate that TNF-ɑ 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. [ABSTRACT FROM AUTHOR]

Prior reports describing the effects of lanthanum (La3+) on red blood cells (RBC) have focused on the effects of this lanthanide on cell fusion or on membrane characteristics (e.g., ion movement across membrane, membrane protein aggregation); the present study explores its rheological and biophysical effects. Normal human RBC were exposed to La3+ levels up to 200 μM then tested for: (1) cellular deformability using a laser-based ektacytometer and an optical-based rheoscope; (2) membrane viscoelastic behavior via micropipettes; (3) surface charge via micro electrophoresis. La3+ concentrations of 12.5 to 200 μM caused dose-dependent decreases of deformability that were greatest at low stresses: these rheological changes were completely reversible upon removing La3+ from the media either by washing with La3+-free buffer or by suspending La3+-exposed cells in La3+-free media (i.e., viscous dextran solution). Both membrane shear elastic modulus and membrane surface viscosity were increased by 25–30% at 100 or 200 μM. As expected, La3+ decreased RBC electrophoretic mobility (EPM), with EPM inversely but not linearly associated with deformability; changes of EPM were also completely reversible. These results thus indicate novel aspects of RBC cellular and membrane rheological behavior yet raise questions regarding specific mechanisms responsible for La3+-induced alterations. [ABSTRACT FROM AUTHOR]

Cyclic oligomers of glucose, termed cyclodextrins (CDs), can contain 6 (α-CD), 7 (β-CD) or 8 (γ-CD) glucose units and are able to remove cholesterol from platelet membranes and decrease platelet aggregation. The present study was designed to examine the effects of these CDs on RBC aggregation and blood viscosity. Blood from normal adult volunteers was incubated at 37°C with 3.0×10-4 to 1.5 mM levels of the CDs, then processed to obtain platelet-rich plasma, platelet poor plasma and 40% hematocrit blood; measurements included collagen-induced platelet aggregation, RBC aggregation (Myrenne Aggregometer) and blood viscosity at 1–1000 sec-1(Rheolog®). Our results indicate the expected dose-dependent inhibition of platelet aggregation by β-CD, with no significant effects of α-CD or γ-CD. RBC aggregation studies showed no effect of α-CD but highly significant (p<0.01) decreases by both β-CD and γ-CD; at the concentrations studied (1.5×10-3 to 1.5 mM), β-CD had somewhat greater effects. Blood viscosity was not affected by α-CD, but was significantly decreased in a dose-dependent manner by β-CD and, at the highest concentration (1.5 mM), by γ-CD. Interestingly, the effects of β-CD and γ-CD were independent of shear, with these effects not explained by the usual mechanisms. These results suggest the potential hemorheological value of CDs, yet also indicate the need for additional studies. [ABSTRACT FROM AUTHOR]

Although the study of red blood cell (RBC) aggregation continues to be of basic science and clinical interest, aggregation standards for calibration do not exist, and most aggregation studies report data in terms of arbitrary units: quantitative comparisons between studies are thus essentially precluded. However, use of low shear viscometry plus the Casson equation provides a yield shear stress that has defined units and is known to reflect RBC aggregation. Employing human RBC–plasma suspensions exhibiting a wide range of aggregation, the present study examined relations between yield shear stress values and aggregation indices obtained using the Myrenne aggregometer: the latter approach uses a light-transmission technique and provides an “M” index at stasis and an “M1” at very low shear. Our results for normal controls and for angina patients without coronary artery disease indicate highly significant correlations (p<0.001) between the yield stress and both M and M1. Thus, within the range of aggregation studied, these findings lend support to the rheological validity of the Myrenne approach; extension of our findings to intensely aggregating RBC suspensions may require additional validation studies. [ABSTRACT FROM AUTHOR]

The vegetable cheese-like food, natto, is extremely popular in Japan with a history extending back over 1000 years. A fibrinolytic enzyme, termed nattokinase, can be extracted from natto; the enzyme is a subtilisin-like serine protease composed of 275 amino acid residues and has a molecular weight of 27.7 kDa. In vitro and in vivo studies have consistently demonstrated the potent pro-fibrinolytic effect of the enzyme. However, no studies to date have evaluated the effects of nattokinase on various hemorheological parameters and thus we have begun to assess the effects of the enzyme on RBC aggregation and blood viscosity. Blood samples were incubated with nattokinase (final activities of 0, 15.6, 31.3, 62.5 and 125 units/ml) for 30 minutes at 37°C. RBC aggregation was measured using a Myrenne MA-1 aggregometer and blood viscosity assessed over 1–1000 s-1 with a computer controlled scanning capillary rheometer (Rheolog®). Our in vitro results showed a significant, dose-dependent decrease of RBC aggregation and low-shear viscosity, with these beneficial effects evident at concentrations similar to those achieved in previous in vivo animal trials. Our preliminary data thus indicate positive in vitro hemorheological effects of nattokinase, and suggest its potential value as a therapeutic agent and the need for additional studies and clinical trials. [ABSTRACT FROM AUTHOR]

The article provides practical method for computing dextran 500 kDA concentrations in rat plasma through plasma viscosity measurement. The viscosity approach found to be appropriate for any experiments within a living organism that used infusions of dextran solutions to enhance the aggregation of red blood cells.

Development of new drugs is a sophisticated process that requires several, different methods. In our experiments we have applied two rheological models to study experimental and clinically used drugs. The antioxidant properties of several agents were estimated by erythrocyte filtration technique. The known antioxidant compound vitamin E was used to validate our measurements. An experimental cardioprotective agent, H‐2545 provided significant protection against oxidative changes in red blood cell filterability (p<0.001). Although some of the examined, known cardiovascular drugs also showed significant antioxidant effect, they were less efficient than H‐2545 and the scavenger effect of this novel agent exceeded the antioxidant properties of vitamin E. Modification of mexiletine with a pyrroline ring improved significantly its antioxidant capacity suggesting this molecular segment to be responsible for the antioxidant effect. In our second model the antiplatelet effect of experimental poly(ADP‐ribose) polymerase (PARP) inhibitors was evaluated. Two widely used antiplatelet agents: acetyl salicylic acid and eptifibatide served as controls in the validation of the measurements. PARP inhibitors reduced ADP‐induced platelet aggregation in a dose‐dependent manner (p<0.05). However, their hindrance on platelet aggregation waned as the concentration of ADP rose. Regarding the platelets' role in the development of ischemic vascular diseases, the antiaggregating property of PARP inhibitors may exert additional beneficial effects on tissue blood supply under conditions of compromised vascular flow. [ABSTRACT FROM AUTHOR]

The haemodynamic effects veno-arterial extracorporeal membrane oxygenation (VA-ECMO) remain inadequately understood. We investigated invasive left ventricular (LV) haemodynamics in patients who underwent treatment with an intensive care strategy involving extracorporeal cardiopulmonary resuscitation (ECPR). We conducted invasive haemodynamic assessments on 15 patients who underwent ECPR and achieved return of spontaneous circulation. Left ventricular end-diastolic pressure (LVEDP), ejection fraction (LVEF), end-diastolic volume (LVEDV), and stroke work (LVSW) were evaluated using simultaneous invasive left heart catheterization and 3D echocardiography. Paired comparisons between high and low VA-ECMO flow were performed. Invasive haemodynamic studies were performed in 15 patients aged 58 (43,65) years at 3.0 (2.0, 4.0) days after cannulation. Six patients survived the index hospitalization, and 9 expired during the index hospitalization. Among the total cohort, transitioning from the highest VA-ECMO flow (median 4.0 L/min) to the lowest VA-ECMO flow (median 2.0 L/min) led to increases in LVEDV from 85 (68,125) mL to 106 (70,153) mL (p = 0.005) and LVEDP from 14 (8,23) mmHg to 17 (12,30) mmHg (p = 0.001), respectively. Similarly, the LVSW increased from 2051 ± 1525 mL*mmHg at the highest level of VA-ECMO flow to 2627 ± 1559 at the lowest VA-ECMO flow (p = 0.01). High VA-ECMO flow significantly reduced LVEDP, LVEDV, and LVSW compared to low VA-ECMO flow. [ABSTRACT FROM AUTHOR]

A 66-year-old male with recent diagnosis of heart failure with reduced ejection fraction was referred to our institution for management of cardiogenic/vasodilatory shock. During his evaluation, he suffered a sudden cardiac arrest from refractory ventricular tachycardia/fibrillation (VT/VF) despite normal electrolytes and no evidence of prior ventricular arrhythmias. He was placed on rescue peripheral veno-arterial extracorporeal membrane oxygenation support (VA-ECMO) for 4 days and was decannulated without end-organ damage. Continued workup revealed Mayo stage IV immunoglobulin light chain (AL) amyloidosis. Unfortunately, he developed acute cerebellar hemorrhage several days later. Autopsy findings were consistent with AL amyloidosis, with extensive cardiac fibrosis and amyloid deposition in the myocardium and vasculature. While the most common cause of cardiac death in patients with amyloidosis is severe bradycardia and pulseless electrical activity, sustained ventricular arrhythmias have been reported. The use of implantable cardioverter defibrillators (ICD) is highly debated in this population given the lack of survival benefit. Our patient also developed refractory VT/VF arrest, and ICD shocks would not have rescued him while causing significant distress. Emergent VA-ECMO cannulation allowed us to make a diagnosis, yet this intervention cannot be routinely recommended given the limited survival of patients with AL amyloidosis. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiovascular disorders are associated with considerable morbidity and mortality. Whether cardiac conduction disease is caused by genetic defects, procedural perturbations, valvular disease, ischemia, aging, or heart failure, new therapies are warranted. In this issue of the JCI, Goodyer et al. used state-of-the-art technologies to image the cardiac conduction system (CCS) in real time and to deliver targeted therapies to the CCS and its subcomponents. These findings advance the ability to image and treat specific lineages within the adult heart with the potential for broader applications in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The Minnesota Pectoralis Risk Score (MPRS) utilizes computed tomography–quantified thoracic muscle and clinical variables to predict survival after left ventricular assist device (LVAD) implantation. The model has not been prospectively tested in HeartMate 3 recipients. A single-center HeartMate 3 cohort from July 2016 to July 2021 (n = 108) was utilized for this analysis. Cohort subjects with complete covariates for MPRS calculation (pectoralis muscle measures, Black race, creatinine, total bilirubin, body mass index, bridge to transplant status, and presence/absence of contrast) implanted after MPRS development were included. MPRS were calculated on each subject. Receiver operating characteristic curves were generated to test model discrimination at 30-day, 90-day, and 1-year mortality post-LVAD. Next, the performance of the 1-year post-LVAD outcome was compared to the HeartMate 3 survival risk score (HM3RS). The mean age was 58 (15 years), 80% (86/108) were male, and 26% (28/108) were destination therapy. The area under the curve (AUC) for the MPRS model to predict post-LVAD mortality was 0.73 at 30 days, 0.78 at 90 days, and 0.81 at 1 year. The AUC for the HM3RS for the 1-year outcome was 0.693. Each 1-unit point of the MPRS was associated with a significant increase in the hazard rate of death after LVAD (hazard ratio 2.1, 95% confidence interval 1.5-3.0, p < 0.0001). The MPRS had high performance in this prospective validation, particularly with respect to 90-day and 1-year post-LVAD mortality. Such a tool can provide additional information regarding risk stratification to aid informed decision-making. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The impact of heart transplant (HT) waitlist candidate sensitization on waitlist outcomes in the US is unknown. Adult waitlist outcomes in OPTN (October 2018-September 2022) by calculated panel reactive antibody (cPRA) were modeled to identify thresholds of clinical significance. The primary outcome was the rate of HT by cPRA category (low: 0-35, middle: >35-90, high: >90) assessed using multivariable competing risk analysis (compete: waitlist removal for death or clinical deterioration). The secondary outcome was waitlist removal for death or clinical deterioration. The elevated cPRA categories were associated with lower rates of HT. Candidates in the middle (35-90) and high cPRA categories (>90) had an adjusted 24% lower rate (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.80-0.92) and 61% lower rate (HR 0.39 95% CI. 0.33-0.47) of HT than the lowest category, respectively. Waitlist candidates in the high cPRA category listed in the top acuity strata (Statuses 1, 2) had increased rates of delisting for death or deterioration compared to those in the low cPRA category (adjusted HR 2.9, 95% CI 1.5-5.5), however, elevated cPRA (middle, high) was not associated with an increased rate of death and delisting when the cohort was considered as a whole. Elevated cPRA was associated with reduced rates of HT across all waitlist acuity tiers. Among HT waitlist candidates listed at the top acuity strata, the high cPRA category was associated with increased rates of delisting due to death or deterioration. Elevated cPRA may require consideration for critically ill candidates under continuous allocation. [ABSTRACT FROM AUTHOR]

To assess the impact of body mass index (BMI) on survival to hospital discharge of patients presenting with refractory ventricular fibrillation treated with extracorporeal cardiopulmonary resuscitation. We hypothesize that due to limitations in pre-hospital care delivery, people with high BMI have worse survival after prolonged resuscitation and ECPR. This study is a retrospective single-centre study that included patients suffering refractory VT/VF OHCA from December 2015 to October 2021 and had a BMI calculated at hospital admission. We compared the baseline characteristics and survival between patients with obesity (>30 kg/m2) and those without (≤30 kg/m2). Two-hundred eighty-three patients were included in this study, and two-hundred twenty-four required mechanical support with veno-arterial extracorporeal cardiopulmonary membrane oxygenation (VA ECMO). Patients with BMI > 30 (n = 133) had significantly prolonged CPR duration compared to their peers with BMI ≤ 30 kg/m2 (n = 150) and were significantly more likely to require support with VA ECMO (85.7% vs 73.3%, p = 0.015). Survival to hospital discharge was significantly higher in patients with BMI ≤ 30 kg/m2 (48% vs. 29.3%, p < 0.001). BMI was an independent predictor of mortality in a multivariable logistic regression analysis. The four-year mortality rate was low and not significantly different between the two groups (p = 0.32). ECPR yields clinically meaningful long-term survival in patients with BMI > 30 kg/m2. However, the resuscitation time is significantly prolonged, and the overall survival significantly lower compared to patients with BMI ≤ 30 kg/m2. ECPR should, therefore, not be withheld for this population, but faster transport to an ECMO capable centre is mandated to improve survival to hospital discharge. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study explores the evolution of organ donation from patients treated with extracorporeal-cardiopulmonary-resuscitation (ECPR) for refractory out-of-hospital-cardiac-arrest (OHCA) and evaluates the public health benefits of a mature ECPR program. This retrospective, single-center study included OHCA patients (2016–2023) who had mostly initial shockable rhythms and were treated with ECPR. Organ donation rates from non-survivors through these years were analyzed. The public health benefit of ECPR was determined by the ratio of the sum of survivors with Cerebral Performance Category 1–2 and non-survivors who donated at least 1 solid organ, to the total ECPR patients. Temporal trends were analyzed yearly using linear regression. Out of 419 ECPR patients presenting with refractory OHCA over the study period, 116 survived neurologically intact (27.7%). Among non-survivors (n = 303), families of 41 (13.5%) consented to organ donation (median age 51 years, 75.6% male) and organs from 38 patients were harvested, leading to 74 organ transplants to 73 recipients. The transplanted organs included 43 kidneys (58.1%), 27 livers (36.5%), 3 lungs (4%), and 1 heart (1.4%), averaging 2.4 ± 0.9 accepted organs/donor. The number of organ donors and successful transplants correlated positively with the years since the ECPR program's initiation (p trend = 0.009, p trend = 0.01). Overall, 189 patients (116 survivors, 73 organ recipients) benefited from ECPR, achieving organ-failure-free survival. The cumulative public health benefit of ECPR, considering the 116 survivors and 38 donors was 36.8%. The public health benefits of an established ECPR program extend beyond individual ECPR patient survival, forming a new, previously under-recognized source of transplant donors. [ABSTRACT FROM AUTHOR]

Introduction: Cardiogenic shock (CS) is marked by substantial morbidity and mortality. The two major CS etiologies include heart failure (HF) and acute myocardial infarction (AMI). The utilization trends of mechanical circulatory support (MCS) and their clinical outcomes are not well described., Methods: This study compares the rates of MCS utilization, factors associated with utilization, and clinical outcomes in patients who present with HF-CS and AMI-CS, using 2016-2020 National Inpatient Sample data., Results: The study included 329,280 patients, comprising 204,660 cases of AMI-CS and 124,620 of HF-CS. MCS utilization increased over the study period with variable degree among devices, and CS-phenotype. AMI-CS had higher intraaortic balloon pump (32.4 % vs. 8.9 %), extracorporeal membrane oxygenation (2.8 % vs. 2.4 %), and percutaneous ventricular assist device use (14.5 % vs. 8.1 %) compared to HF-CS (p < 0.01). Factors linked to lower MCS use were female sex, age over 60 years, Black race, atrial fibrillation, chronic obstructive lung disease, diabetes mellitus, cirrhosis, previous stroke, or myocardial infarction. After adjusting for various factors, patients with HF-CS vs. AMI-CS had significantly fewer adverse outcomes, including inpatient death, stroke, tracheostomy, mechanical ventilation, and blood transfusion. However, HF-CS had higher odds of acute renal failure requiring dialysis. AMI-CS was associated with shorter hospital stays (8.8 vs. 15.0 days, p < 0.001), lower charges ($251,580 vs. $294,792, p < 0.001), and were less likely to discharge home., Conclusion: Despite the evolving trends in MCS utilization over time, CS patients still face high morbidity and mortality rates. The underlying shock etiology has a substantial impact on outcomes, with AMI cases demonstrating worse complications. This highlights the need for a standardized approach that also takes into consideration etiology, patient-specific factors, care availability, and equitable access., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Babar Basir reports a relationship with AbioMed Inc that includes: consulting or advisory. Babar Basir reports a relationship with Boston Scientific Corporation that includes: consulting or advisory. Babar Basir reports a relationship with Chiesi Pharmaceuticals Inc that includes: consulting or advisory. Babar Basir reports a relationship with ZOLL Medical Corporation that includes: consulting or advisory. Tamas Alexy reports a relationship with Abbott Vascular Inc that includes: speaking and lecture fees. Tamas Alexy reports a relationship with Endotronics that includes: speaking and lecture fees. Tamas Alexy reports a relationship with scPharmaceuticals that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background and Aims: Patients with heart failure with preserved ejection fraction (HFpEF) tend to have low resting and exercise heart rates. Phosphodiesterase-3 (PDE-3) inhibitors improve heart rates, haemodynamics and symptoms in patients with HFpEF. Cilostazol is an oral PDE-3 inhibitor used in peripheral artery disease. This study thought to evaluate the short-term effects of cilostazol on health status, N-terminal brain natriuretic peptide (NT-proBNP) levels and mechanisms of action., Methods: The effect of cilostazol was evaluated in 23 patients with HFpEF in a randomized placebo controlled multiple crossover trial (CLIP-HFpEF). Participants received placebo or cilostazol for 1 week followed by three crossovers to the alternate assignment at weeks 2, 3 and 4. The primary endpoint was the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) overall summary score obtained at the end of each treatment period. NT-proBNP was the secondary endpoint. In an exploratory mechanistic analysis, pulmonary artery (PA) pressures and heart rates were followed amongst the five participants with implanted pressure monitors., Results: Cilostazol improved the KCCQ score by 4.8 points (95% confidence interval, 2.0-7.7, P = 0.003). NT-proBNP levels were 448 (154-1056) pg/mL on placebo and 375 (68-974) pg/mL on cilostazol (P = 0.006). In patients with PA pressure monitors, diastolic pressure was 20.5 (18.7-23.0) mmHg on placebo and 18.0 (17.0-20.0) mmHg on cilostazol, an effect linked to higher heart rates (P < 0.001)., Conclusions: Amongst patients with HFpEF, short-term treatment with cilostazol leads to improvements in health status and NT-proBNP when compared with placebo. These effects are likely conveyed by a heart rate-dependent reduction in cardiac filling pressures., Trial Registration: ClinicalTrials.gov Identifier: NCT05126836., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Monitoring supine pulmonary artery pressures to guide heart failure (HF) management has reduced HF hospitalizations in select patients., Objectives: The purpose of this study was to evaluate the effect of managing seated mean pulmonary artery pressure (mPAP) with the Cordella Pulmonary Artery sensor on outcomes in patients with HF., Methods: Following GUIDE-HF (Hemodynamic-GUIDEd Management of Heart Failure Trial), with U.S. Food and Drug Administration input, PROACTIVE-HF (A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial) was changed from a randomized to a single-arm, open label trial, conducted at 75 centers in the USA and Europe. Eligible patients had chronic HF with NYHA functional class III symptoms, irrespective of the ejection fraction, and recent HF hospitalization and/or elevated natriuretic peptides. The primary effectiveness endpoint at 6 months required the HF hospitalization or all-cause mortality rate to be lower than a performance goal of 0.43 events/patient, established from previous hemodynamic monitoring trials. Primary safety endpoints at 6 months were freedom from device- or system-related complications or pressure sensor failure., Results: Between February 7, 2020, and March 31, 2023, 456 patients were successfully implanted in modified intent-to-treat cohort. The 6-month event rate was 0.15 (95% CI: 0.12-0.20) which was significantly lower than performance goal (0.15 vs 0.43; P < 0.0001). Freedom from device- or system-related complications was 99.2% and freedom from sensor failure was 99.8% through 6 months., Conclusions: Remote management of seated mPAP is safe and results in a low rate of HF hospitalizations and mortality. These results support the use of seated mPAP monitoring and extend the growing body of evidence that pulmonary artery pressure-guided management improves outcomes in heart failure. (Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial [PROACTIVE-HF]; NCT04089059)., Competing Interests: Funding Support and Author Disclosures This work was supported by Endotronix Inc. Drs Miranda, Shah, Macaluso, and Hickey were on the Eligibility Committee of PROACTIVE-HF. Prof Sharif is funded by the Science Foundation Ireland SFI 17/RI/5353. Drs Hiivala, Owens, Sauerland, and Forouzan are employees of Endotronix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart failure remains one of the leading causes of mortality and hospitalizations in the US that not only impacts quality of life but also poses a significant public health burden. The majority of affected patients are admitted with signs and symptoms of congestion. Despite the initial enthusiasm, traditional remote monitoring strategies focusing primarily on weight gain failed to improve clinical outcomes. Implantable pulmonary artery pressure sensors provide earlier and actionable data, but most patients would favor forgoing an invasive procedure in favor of an alternative, non-invasive monitoring platform. Several devices utilizing different combinations of multiparameter monitoring to reliably detect congestion have recently been developed and are undergoing testing in the clinical setting. Combining these sensors with the power of artificial intelligence and machine learning has the potential to revolutionize remote patient monitoring and early congestion detection and to facilitate timely interventions by the care team to prevent hospitalization. This manuscript provides an objective review of novel, noninvasive, multiparameter remote monitoring platforms that may be tailored to individual heart failure phenotypes, aiming to improve quality of life and survival., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The role of hypothermia in post-arrest neuroprotection is controversial. Animal studies suggest potential benefits with lower temperatures, but high-fidelity ECPR models evaluating temperatures below 30 °C are lacking., Objectives: To determine whether rapid cooling to 24 °C initiated upon reperfusion reduces brain injury compared to 34 °C in a swine model of ECPR., Methods: Twenty-four female pigs had electrically induced VF and mechanical CPR for 30 min. Animals were cannulated for VA-ECMO and cooled to either 34 °C for 4 h (n = 8), 24 °C for 1 h with rewarming to 34 °C over 3 h (n = 7), or 24 °C for 4 h without rewarming (n = 9). Cooling was initiated upon VA-ECMO reperfusion by circulating ice water through the oxygenator. Brain temperature and cerebral and systemic hemodynamics were continuously monitored. After four hours on VA-ECMO, brain tissue was obtained for examination., Results: Target brain temperature was achieved within 30 min of reperfusion (p = 0.74). Carotid blood flow was higher in the 24 °C without rewarming group throughout the VA-ECMO period compared to 34 °C and 24 °C with rewarming (p < 0.001). Vasopressin requirement was higher in animals treated with 24 °C without rewarming (p = 0.07). Compared to 34 °C, animals treated with 24 °C with rewarming were less coagulopathic and had less immunohistochemistry-detected neurologic injury. There were no differences in global brain injury score., Conclusions: Despite improvement in carotid blood flow and immunohistochemistry detected neurologic injury, reperfusion at 24 °C with or without rewarming did not reduce early global brain injury compared to 34 °C in a swine model of ECPR., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Extracorporeal cardiopulmonary resuscitation improves outcomes after out-of-hospital cardiac arrest. However, bleeding and thrombosis are common complications. We aimed to describe the incidence and predictors of bleeding and thrombosis and their association with in-hospital mortality., Methods and Results: Consecutive patients presenting with refractory ventricular tachycardia/ventricular fibrillation out-of-hospital cardiac arrest between December 2015 and March 2022 who met the criteria for extracorporeal cardiopulmonary resuscitation initiation at our center were included. Major bleeding was defined by the Extracorporeal Life Support Organization's criteria. Adjusted analyses were done to seek out risk factors for bleeding and thrombosis and evaluate their association with mortality. Major bleeding occurred in 135 of 200 patients (67.5%), with traumatic bleeding from cardiopulmonary resuscitation in 73 (36.5%). Baseline demographics and arrest characteristics were similar between groups. In multivariable analysis, decreasing levels of fibrinogen were independently associated with bleeding (adjusted hazard ratio [aHR], 0.98 per every 10 mg/dL rise [95% CI, 0.96-0.99]). Patients who died had a higher rate of bleeds per day (0.21 versus 0.03, P <0.001) though bleeding was not significantly associated with in-hospital death (aHR, 0.81 [95% CI. 0.55-1.19]). A thrombotic event occurred in 23.5% (47/200) of patients. Venous thromboembolism occurred in 11% (22/200) and arterial thrombi in 15.5% (31/200). Clinical characteristics were comparable between groups. In adjusted analyses, no risk factors for thrombosis were identified. Thrombosis was not associated with in-hospital death (aHR, 0.65 [95% CI, 0.42-1.03])., Conclusions: Bleeding is a frequent complication of extracorporeal cardiopulmonary resuscitation that is associated with decreased fibrinogen levels on admission whereas thrombosis is less common. Neither bleeding nor thrombosis was significantly associated with in-hospital mortality.

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., Competing Interests: Disclosures C. Shenoy has served as a consultant to Lexeo Therapeutics and Medtronic on topics unrelated to the subject matter of this article. The other authors report no conflicts.

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., (2024 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

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., Competing Interests: T.A. is a member of the Abbott Speaker’s Bureau as well as the Speaker’s Bureau for scPharmacuticals. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)