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Objectives: The primary goal of this study was to identify and understand the burden experienced by informal caregivers of patients with HF at the time of hospital discharge. The researchers aimed to guide future education interventions and promote informal caregiver burden screening., Design: The researchers administered the Zarit Burden Interview (ZBI) as a quantitative tool to assess informal caregiver burden. The ZBI is a standardized questionnaire used to measure the extent of burden experienced by informal caregivers. After administering the ZBI, the researchers conducted semi-structured interviews with five informal caregivers of patients with HF. These interviews were guided by probing questions related to ZBI items that were rated with high levels of burden (3 "quite frequently" or 4 "nearly always")., Results: The quantitative data showed that the informal caregivers' burden scores on the ZBI ranged from 4 to 41. Male informal caregivers tended to report lower burden scores. The non-spouse informal caregiver had the highest burden score at 41. The qualitative analysis of the interviews revealed several themes related to informal caregiver burden, including fear, patient expectations, patient dependence on caregivers, social isolation, and stressors associated with medication changes after discharge. Despite the qualitative insights into specific burden-related issues, the quantitative analysis of the ZBI scores showed that, on average, informal caregivers reported little to no burden at the time of acute exacerbation of HF in the patient., Conclusion: The study's findings suggest that while informal caregivers may not report prominent levels of overall burden, they do face specific challenges and stressors, such as social isolation and managing medication changes post-discharge. These findings can inform the development of targeted support and interventions for informal caregivers of patients with HF., Competing Interests: Declaration of competing interest All authors confirm there is zero conflict of interest for this manuscript., (Published by Elsevier Inc.)

Background: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy., Methods: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm 5 and ≥800 dyne·s/cm 5 ). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm 5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed., Findings: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm 5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm 5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm 5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group., Interpretation: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH., Funding: Gossamer Bio., Competing Interests: Declaration of interests ARH reports having received consulting fees from United Therapeutics, Tenax Therapeutics, Merck, and Janssen; having served as an advisory committee member for Gossamer Bio; and having held stock from Tenax Therapeutics. CT, DM, EE, EP, J-MB, LSZ, MC, RA, RFR, and RO report stocks or stock options from Gossamer Bio; and employment at Gossamer Bio. LSZ also reported patents related to seralutinib (assigned to Gossamer Bio or Pulmokine); stocks or stock options from Pulmokine. RFR also reported previous consulting fees from Gossamer Bio. H-AG reports having received consulting fees from Gossamer Bio, Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Bayer AG, Janssen and Actelion, and MSD and Acceleron; participated as an advisory committee member for Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; and as a member of a data and safety monitoring board for Insmed. J-LV reports having received consulting fees from Gossamer Bio, ShouTi, Janssen, Enzyvant, Bayer HealthCare, Merck, Liquidia, Aerami, and Insmed; received payment or honoraria (payment to their institution) for lectures, presentations, or educational events from Janssen, Merck, Novartis, and Boehringer Ingelheim; received payment for expert testimony from Actelion Pharmaceuticals; received either support for attending meetings or travel (payment to their institution) from Merck; participated on a data safety monitoring board (payment to their institution) from Janssen, GSK, and Moderna; membership on steering committees for Gossamer Bio, Insmed, Merck, and United Therapeutics. KMC reports having received grants or contracts (payment made to their institution) for clinical studies overseen by her from Gossamer Bio, Janssen, United Therapeutics, Merck, Acceleron, and Altavant; received consulting fees from Acceleron; received fees for participating on an advisory board for Merck; received fees for work as an advisory committee member for Gossamer Bio; received fees for work as a steering committee member for Janssen; received fees for work on an adjudication committee for Arena and United Therapeutics; and received fees for an editorial role with the American Heart Association. LSH reported having received payment or honoraria for speaker bureau membership from Janssen; participated as an advisory board member for Janssen, MSD, Altavant, and United Therapeutics, and as an advisory committee member for Gossamer Bio; and having stock or stock options at ATXA Therapeutics, iOWNA, and Circular. OS reports having received grants or contracts for research (payment made to their institution) from Janssen, MSD, and AOP Orphan; payment or honoraria for lectures or an educational event from AOP Orphan, Ferrer, Janssen, and MSD; support for attending meetings or travel from MSD and Janssen; and participated on an advisory committee for Gossamer Bio, AOP Orphan, Enzyvant, Ferrer, Janssen, and MSD. PES reports having received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, and AOT; support for either attending meetings or travel from Janssen and MSD; participated in a data safety monitoring board or advisory board for Janssen, MSD, Ferrer, Gossamer Bio, and AOT; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gossamer Bio. RLB reports having received consulting fees from Merck, United Therapeutics, KEROS, Aerovate, Insmed, and Cereno; served as an advisory committee member for Gossamer Bio; served as an advisory board member for Altavant, Merck, Janssen, and Insmed; served on a data safety monitoring board for Janssen; and served on a scientific advisory board for Cereno. RLZ reports having received consulting fees from Johnson & Johnson, United Therapeutics, Bayer, and Alnylam. RNC reports having received consulting fees from Gossamer Bio, Janssen, Bayer, United Therapeutics, and Third Pole; payment or honoraria for lectures from Janssen and Bayer; and participated on an advisory committee for Gossamer Bio, Janssen, and Bayer. RPF reports having royalties or licenses from UpToDate; receiving consulting fees from Janssen and Liquidia; participated on a data safety monitoring board or advisory board from Gossamer Bio (as an advisory committee member); participated on an advisory board for Janssen, Liquidia, Tenax Therapeutics, ShouTi, Insmed, and Merck; and participated on a data safety monitoring board for Aerovate. RTZ reports having received grants or contracts for industry-supported research from United Therapeutics, Janssen, Tenax Therapeutics, and Gossamer Bio; consulting fees from Janssen, Vivus, Morphogen-IX, Merck, and Gossamer Bio; and stock or stock options from Selten. SS reports having received a research grant from United Therapeutics; speaker honoraria (received by his institute) from Janssen and United Therapeutics; served as an advisor to Janssen, Bayer, United Therapeutics, Gossamer Bio, Altavant Sciences, and Merck; served as a steering committee member for Bayer, Keros, and Liquidia Technologies; and served as a data safety monitoring board committee member for the National Institutes of Health K23 grant. VVM reports having received grant support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovie; consulting fees from Aerami, Aerovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex; and participated as an advisory committee member for Gossamer Bio. All authors report receiving medical writing and editorial support for the present manuscript funded by Gossamer Bio., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.

Rationale: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint., Objectives: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension., Methods: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16., Results: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction., Conclusion: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CEM – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, speakers bureau, advisory board), Insmed (research), Bayer (advisory board, steering committee); VF – United Therapeutics Corporation (research), Merck (research), Acceleron (research), Johnson & Johnson (research), Respira (research), Aerovate (research), Cereno (research), Abbott (research); JSS – United Therapeutics Corporation (research, speakers bureau), Bayer (research, speakers bureau); VB – United Therapeutics Corporation (consulting); JK – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, consulting, speakers bureau, advisory board), Acceleron (research), Gossamer (research), Bayer (consulting, speakers bureau, advisory board); RZ – United Therapeutics Corporation (consulting), Bayer (consulting), Janssen (consulting), Johnson & Johnson (consulting); LMG – United Therapeutics Corporation (research, consulting, advisory board), Janssen (research, consulting), Gossamer bio (research, consulting), Merch (research, consulting), Bayer (research, consulting); JH – Acceleron (research), CardiolRx (research), Aaadi Bioscience (research), Astra Zeneca (spouse); JME – United Therapeutics Corporation (research, consulting), Janssen (research), Liquidia (research, consulting), Phase Bio (research), Gossamer Bio (research, consulting), Bayer (research, consulting), Acceleron (research), Altavant (research, consulting), Aerovate (research consulting), Tenax (research), Pharmosa (research), Merck (consulting); AR – United Therapeutics Corporation (consulting), Bayer (consulting), Actelion (consulting); DC, ES, SS, CMT, MB – United Therapeutics Corporation (employee); RJO – United Therapeutics Corporation (research, consulting), Janssen (research, consulting), Merck (research, consulting), Gossamer Bio (research), Insmed (research)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Heart failure is a major health problem with significant economic burden in the United States. Educating heart failure dyads (heart failure patient and informal caregiver) is a relatively new domain and is being proposed by providers, policy makers, and third-party payors. Nurse-led dyad education can improve quality of life and reduce hospital admissions in the heart failure population., Objectives: This integrative literature review focused on evaluating design, delivery content, and outcomes of nurse-led dyadic educational interventions., Methods: PubMed, CINAHL, Cochrane, and Google Scholar databases (1999 -2022) were searched for quantitative and qualitative studies that included these search terms: heart failure, dyads, nonmedical caregivers, caregivers, randomized controlled trials, nurse-led education, education., Results: The search yielded 92 articles. The results included seven randomized controlled trials and one pilot study conducted from 2005 to 2017. Sample sizes ranged from 20 to 155 dyads. Dyads who received education interventions had positive outcomes. Face-to-face coaching provided stronger outcomes. Interventions varied in length from baseline to three months, with post-intervention follow-ups from one to 12 months., Conclusions: A paucity of studies of nurse-led heart failure dyadic educational interventions have been reported in the literature. To advance the science and decrease heart failure readmissions, greater efforts to study and incorporate education and support for heart failure dyads is needed, along with assessment of both patient and caregiver outcomes., Competing Interests: Conflict of Interest Authors do not have a conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Distal pulmonary arterial remodeling and elevated pulmonary vascular resistance are characteristic of pulmonary arterial hypertension (PAH). Current approved vasodilator-specific PAH therapy that includes phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids has demonstrated dramatic enhancement in functional capacity, quality of life, and invasive hemodynamics. However, none of these treatments are curative, underscoring the need to identify new pathophysiologic signaling pathways., Areas Covered: The author provides a comprehensive review on current knowledge and recent development in the understanding of PAH. Furthermore, the author discusses PAH potential genetic causes as well as novel molecular signaling pathways. This article also reviews the currently approved PAH specific therapy based on pivotal clinical trials and ongoing clinical trials using novel compounds that specifically target PAH pathogenesis., Expert Opinion: The discovery of novel signaling pathways - growth factors, tyrosine kinases, BMPs, estrogen, and serotonin - involved in the PAH pathobiology will lead within the next 5 years to the approval of new therapeutic agents targeting these different pathways. If proven beneficial, these new agents may reverse or at least prevent the progression of this devastating and lethal disease.

Introduction: We aimed to assess the impact of digoxin use following left ventricular assist device (LVAD) implantation on clinical outcomes., Methods: Patients implanted with continuous flow LVADs at a single academic medical center and survived to initial hospital discharge were included in the analysis ( n  = 346). Clinical events were captured at a maximum of 2 years of follow up. Digoxin use was defined as 30-day continuous use post-LVAD. Negative binomial regression and Kaplan-Meier method were used to assess the association between digoxin use and clinical outcomes., Results: Mean age of the cohort was 56 years (±13) and 23% (79/346) were female sex. Digoxin was used in 144 patients (41.6%) for a median of 268 days (IQR 154, 616). Digoxin use was associated with a significant reduction in cumulative incidence of gastrointestinal bleeding (GIB) (15% vs 26%, p  = 0.004). After adjusting for age, hypertension, post-operative hemoglobin, RDW, potassium, and GFR, and use of angiotensin receptor/neprilysin inhibitor, there remained a significant 47% reduction in GIB incidence in patients treated with digoxin. There was no significant difference in cumulative incidence in right ventricular failure (RVF) between the two groups. There was no difference in overall 2-year survival between groups., Conclusions: Digoxin use was associated with reduction in GIB events, but not in RVF or mortality. Further studies are needed to confirm these findings and to investigate optimal timing and patient population.

Although pulmonary function testing (PFT) is typically performed for heart transplant evaluation, the prognostic utility of PFTs after transplantation is unknown. We evaluated whether PFT parameters were correlated with outcomes following heart transplantation., Methods: International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry data were utilized. Survival was assessed using Kaplan-Meier method and compared via log-rank test. Cox proportional hazard modeling was used to evaluate univariate and multivariate predictors of survival., Results: Eight hundred two patients pretransplant PFT data were available for evaluation. Forced expiratory volume in 1 s (FEV1) < 50% predicted ( P < 0.0001), and forced vital capacity (FVC) < 50% predicted each had significantly higher mortality ( P  = 0.001) compared with patients with FEV1 or FVC 50%-80% or >80%. FEV1/FVC < 0.7 was not associated with increased mortality. FEV1 and FVC below 50% both predicted longer lengths of stay ( P  = 0.028 for FEV1 and P  = 0.0075 for FVC). After adjusting for male gender, age, body mass index, smoking history, chronic obstructive pulmonary disease, creatinine, albumin, and total bilirubin, FEV1 < 50% (hazard ratio, 4.91; P  < 0.0001; 95% confidence interval, 2.69-8.94) and FVC < 50% (hazard ratio, 2.75; P  = 0.003; 95% confidence interval, 1.4-5.4) both remained independent predictors of mortality., Conclusions: Abnormal pulmonary function (FEV1 or FVC below 50% of predicted) pre-heart transplantation is associated with increased mortality and longer lengths of stay posttransplant., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH., Competing Interests: Dr Zolty is a consultant at Actelion, Bayer, United Therapeutics, and Alnylam. The author report no other conflicts of interest in this work., (© 2021 Zolty.)

Heart Failure (HF) is a major cause of morbidity and mortality in the US. With aging of the US population, the public health burden of HF is enormous. We aimed to develop an ensemble prediction model for 30-day mortality after discharge using machine learning. Using an electronic medical records (EMR) database, all patients with a non-elective HF admission over 10 years (January 2001 - December 2010) within the Montefiore Medical Center (MMC) health system, in the Bronx, New York, were included. We developed an ensemble model for 30-day mortality after discharge and employed discrimination, range of prediction, Brier index and explained variance as metrics in assessing model performance. A total of 7,516 patients were included. The discrimination achieved by the ensemble model was higher 0.83 (95% CI: 0.80 to 0.87) compared to the benchmark model 0.79 (95% CI: 0.75 to 0.84). The ensemble model also exhibited a better range of prediction as well as a favorable profile with respect to the other metrics employed. In conclusion, an ensemble machine learning approach exhibited an improvement in performance compared to the benchmark logistic model in predicting all-cause mortality among HF patients within 30-days of discharge. Machine learning is a promising alternative approach for risk profiling of HF patients, and it enhances individualized patient management., Competing Interests: Conflict of Interest No conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease (COPD) is associated with an increase in the risk of COPD exacerbation, increased hospitalization, and worse survival in this patient population. No specific treatment is available for PH in COPD. However, reported out-of-proportion PH may benefit from a certain type of treatment. This study shows that the use of selexipag in the treatment of out-of-proportion PH in COPD patients was associated with an improvement in functional status evaluated by a six-minute walk test (6MWT) and a mean pulmonary artery pressure at 6 +/- 2 months of treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Abuserewa et al.)

Objectives: The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF)., Background: There are no proven effective treatments for patients with PH-HFpEF., Methods: Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages., Results: Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo., Conclusions: Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603)., Competing Interests: Funding Support and Author Disclosures This study was supported by TENAX Therapeutics. TENAX participated in the execution of the study. Data were collected and analyzed by a clinical research organization. Analysis and interpretation of the data were performed by an independent statistician and the investigators (no role of sponsor). The manuscript was prepared by the investigators. The sponsor was allowed to review the manuscript before submission but had no role in preparing or approval. Dr. Burkhoff has received an institutional research grant from TENAX Therapeutics; and advisory board/consulting from Impulse Dynamics, Corvia Medical, and Axon Therapies. Dr. Borlaug has received research grants from the National Institutes of Health (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX Therapeutics; and advisory board/consulting fees for Aria, Actelion, Boehringer-Ingelheim, Imbria, Janssen, Merck, Novartis, Lilly, Novo Nordisk, Pfizer, and VADovations. Dr. Shah has received research grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), American Heart Association (16SFRN28780016), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Shifamed, TENAX, and United Therapeutics. Dr. Zolty has received research grants from the National Institutes of Health (P01 HL108797, R01 HL134905, R01 LM01), Actelion, TENAX Therapeutics, Gossamer Bio, Lung Biotech, and United Therapeutics; consulting/advisory board for Morphegen-IX, Vivus, Actelion, and Pfizer; and patent holder of FK506 for the treatment of pulmonary hypertension. Dr. Tedford has received institution research funding from TENAX Therapeutics as part of this study; has consulting relationships with Medtronic, Aria CV, Acceleron, Arena Pharmaceuticals, and United Therapeutics; is on the steering committees for Medtronic, Acceleron, and Abbott; on the research advisory board for Abiomed; and does hemodynamic core laboratory work for Actelion and Merck. Dr. Thenappan has received research grants from the Cardiovascular Medical Research and Education Fund, Lillehei Heart Institute High Risk and High Reward Award, United Therapeutics, and TENAX Therapeutics; and consulting/advisory board for United Therapeutics, Actelion, and Altavant Sciences. Dr. Zamanian has consulted for United Therapeutics, Actelion, and Alnylam. Dr. Mazurek has received advisory board honoraria from Actelion Pharmaceuticals and United Therapeutics; has received speaker honoraria from Abbott; and has received research support from Actelion, Complexa, and Corvia. Dr. Rich has consulted for Abbott, Medtronic, Boehringer-Ingelheim, and Novartis. Dr. Simon has received research grants from the National Institutes of Health (R01 AG058659, P01 HL103455), Aadi Biosciences, and Novartis; and has received consulting fees from Actelion, Acceleron, Altavant, United Therapeutics. Dr. Chung has received consulting fees from Abbott, Medtonic, Intershunt, LivaNova, CVRx, and EBR. Dr. Raza has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Majure has received a research grant from TENAX Therapeutics. Dr. Lewis has received research grants from the National Institutes of Health (1R01HL131029, R01HL151841, and AHA GPSGC24800006), Amgen, Applied Therapeutics, AstraZeneca, Corvia, Cytokinetics, and Novartis; and consulting/advisory board for American Reagent, AstraZeneca, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Ironwood, Merck, Novartis, and Pfizer. Dr. Preston has received research grants from Acceleron, Actelion, Complexa, PhaseBio, United Therapeutics, and TENAX Therapeutics; steering committee for Acceleron, Actelion, and United Therapeutics; is on the consulting/advisory board for Actelion, Gilead, Liquidia, and United Therapeutics; and data and safety monitoring board for Pfizer. Dr. Rich has received consulting from TENAX Therapeutics., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

While cytomegalovirus (CMV) reactivation occurs in immunocompetent patients who are critically ill and has been associated with worse outcomes, very few cases of CMV reactivation have been reported following left ventricular assist device (LVAD) implantation. We aimed to evaluate the incidence and risk factors for CMV reactivation following LVAD implantation. Retrospective chart review of patients who had undergone LVAD implantation between July 2004 and December 2018 was performed. Cases with CMV reactivation post-LVAD were randomly matched (1:2) by sex, LVAD type, and implant year with controls utilizing SAS macros. Fisher's exact and paired sample t-tests were performed to evaluate for differences between categorical and continuous variables, respectively. Days to reactivation post-LVAD implantation were calculated in cases, and the corresponding times post-LVAD implantation were determined in control patients for variable comparisons. Survival analysis was performed using the Kaplan-Meier method. Of the 349 patients reviewed, 208 (59.6%) patients were seropositive for CMV before LVAD implantation. Of these 208 patients, eight (3.8%) had CMV reactivation following LVAD implantation. The median time to CMV reactivation following LVAD implantation was 21.5 days (range, 6-177). Six (75%) patients had CMV viremia, and the other two had colitis and pneumonia without viremia. In comparison to controls, patients with CMV had higher creatinine levels (p = 0.039) and higher RDW (p = 0.05) and were more likely to have received steroids within the previous week (p = 0.028) and to have concurrent bacterial infection (p = 0.001). CMV reactivation following LVAD implantation is more frequent than expected. Early testing, diagnosis, and treatment in at-risk patients (i.e., renal failure, steroid use, elevated RDW) might improve clinical outcomes., Competing Interests: The authors have no relevant conflicts of interest to disclose. The authors received no internal or external funding to conduct this study., (Copyright © ASAIO 2020.)

Gastrointestinal bleeding (GIB) is a common cause of morbidity among patients supported by left ventricular assist devices (LVADs). The aim of this study was to identify if pre-LVAD right ventricular (RV) dysfunction is associated with risk of GIB after LVAD implantation. Of 398 patients implanted with LVADs between July 2008 and July 2016, 130 (33%) developed GIB at a median of 2.6 months following LVAD implantation. Arteriovenous malformations (AVMs) were found in 42 (34%) GIB patients. Patients with GIB were older and more likely to have hypertension, diabetes, and ischemic cardiomyopathy. On pre-LVAD echocardiography, GIB patients had increased RV diastolic dimension (4.7 ± 0.8 vs. 4.4 ± 0.9 cm, p = 0.02), a higher rate of greater than mild tricuspid valve (TV) regurgitation (73 [60%] vs. 120 [47%], p = 0.006), and underwent TV repair more often (38 [30%] vs. 43 [16%], p = 0.0006) during LVAD implantation. After multivariable adjustment, preoperative greater than mild RV enlargement (hazard ratio [HR] 2.32, 95% CI 1.12-5.03; p = 0.03), TV regurgitation (HR 1.83, CI 1.02-3.44; p = 0.01), and TV repair (HR 3.76, confidence interval [CI] 1.02-4.44; p = 0.01) remained associated with risk of GIB. This finding was driven by the AVM-GIB subgroup. Preoperative RV enlargement and TV regurgitation are associated with post-LVAD AVM-related GIB., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)

Cardiogenic shock remains one of the most challenging clinical syndromes in modern medicine. Mechanical support is being increasingly used in the management of cardiogenic shock. Intra-aortic balloon pump (IABP) is one of the earliest and most widely used types of mechanical circulatory support. The device acts by external counterpulsation and uses systolic unloading and diastolic augmentation of aortic pressure to improve hemodynamics. Although IABP provides less hemodynamic support when compared with newer mechanical circulatory support devices, it can still be the mechanical support device of choice in appropriate situations because of its relative simplicity of insertion and removal, need for smaller size vascular access and better safety profile. In this review, we discuss the equipment, procedural and technical aspects, hemodynamic effects, indications, evidence, current status and recent advances in the use of IABP in cardiogenic shock.

Background: Exercise performance remains limited in some patients after heart transplantation (HTx). The goal of this study was to assess for association between cardiopulmonary exercise test performance at 1 year after HTx and future development of cardiac allograft vasculopathy (CAV)., Methods: Overall 243 HTx recipients performed cardiopulmonary exercise testing at 1 year after HTx. During the median follow-up period of 31 (interquartile range 19;61) months, 76 (32%) patients were diagnosed with CAV (CAV group)., Results: The CAV group patients had lower exercise capacity (5.2 ± 1.9 versus 6.5 ± 2.2 metabolic equivalents; P = 0.001) and duration (9.6 ± 3.5 versus 11.4 ± 4.8 min; P = 0.008), lower peak oxygen consumption (VO2) (18.4 ± 5.4 versus 21.4 ± 6.1 mL/kg/min; P = 0.0005), lower normalized peak VO2 (63% ± 18% versus 71% ± 19%; P = 0.007), and higher minute ventilation (VE)/carbon dioxide production (VCO2) (34 ± 5 versus 32 ± 5, P = 0.04). On Cox proportional hazards regression analysis, normalized peak VO2 ≤60%, and VE/VCO2 ≥34 were associated with a high hazard for CAV (HR = 1.8 [95% CI 1.10-4.53, P = 0.03] and 2.5 [95% CI 1.01-8.81, P = 0.04], respectively). The subgroup of patients with both normalized peak VO2 ≤60% and VE/VCO2 ≥34 was at highest risk for development of CAV (HR = 5.2, 95% CI 2.27-15.17, P = 0.001)., Conclusions: Normalized peak VO2 ≤60% and VE/VCO2 ≥34 at 1 year after HTx are associated with the development of CAV.

Left ventricular assist device (LVAD) deactivation may be considered in cases of left ventricular recovery, pump thrombosis, infection, and end-of-life palliation. Surgical pump explantation remains the principal method, but percutaneous deactivation presents a safe and effective alternative. We have developed a formal program for percutaneous LVAD deactivation within our advanced heart failure program including patient selection criteria, preprocedure testing, a procedural algorithm, and a postprocedure care plan. Patient selection for percutaneous LVAD deactivation required review by an interdisciplinary heart transplant team including reason for deactivation, cardiac function, surgical risk, and patient preference. All candidates underwent LVAD ramp studies with both transthoracic echocardiography and right heart catheterization assessment. Deactivation was performed under general anesthesia with transesophageal echocardiography guidance. Three Amplatzer Vascular Plug IIs (Abbott, St. Paul, MN) were deployed in the LVAD outflow cannula with the proximal edge of the third plug aligned with the aortic anastomosis of the graft as guided by angiography and 3-dimensional transesophageal echocardiography. In a separate procedure, the LVAD drive line was transected below the skin, which was closed surgically over the driveline stump. Anticoagulation was continued for at least 3 months. Since initiation in January 2017, our program has performed 7 percutaneous LVAD deactivation procedures. All procedures have been successful, 5 of the patients remain medically managed, and 2 have proceeded to heart transplant. Percutaneous LVAD deactivation provides an alternative to surgical explantation. A percutaneous LVAD deactivation program is an important component of an advanced heart failure program., (Copyright © 2020. Published by Elsevier Inc.)

In selected patients with left ventricular assist device-associated infection or malfunction, pump exchange may become necessary after conservative treatment options fail and heart transplantation is not readily available. We examined the survival and complication rate in patients (⩾19 years of age) who underwent HeartMate II to HeartMate II exchange at our institution from 1 January 2010 to 28 February 2018. Clinical outcomes were analyzed and compared for patients who underwent exchange for pump thrombosis (14 patients), breach of driveline integrity (5 patients), and device-associated infection (2 patients). There were no differences in 30-day mortality (p = 0.58), need for temporary renal replacement therapy (p = 0.58), right ventricular mechanical support (p = 0.11), and postoperative stroke (p = 0.80) among groups. Survival at 1 year was 90% ± 7% for the whole cohort and 85% ± 10% for those who underwent exchange for pump thrombosis. In patients exchanged for device thrombosis, freedom from re-thrombosis and survival free from pump re-thrombosis at 1 year were 49% ± 16% and 42% ± 15%, respectively. No association of demographic and clinical variables with the risk of recurrent pump thrombosis after the first exchange was identified. Survival after left ventricular assist device exchange compares well with published results after primary left ventricular assist device implantation. However, recurrence of thrombosis was common among patients who required a left ventricular assist device exchange due to pump thrombosis. In this sub-group, consideration should be given to alternative strategies to improve the outcomes.

Clinical Features: Giant cell myocarditis (GCM) is a rare and a rapidly progressive disorder with fatal outcomes such that patients often require heart transplantation. We present a case of recurrent GCM in a transplanted patient with a history of Crohn disease requiring a novel therapeutic approach., Therapeutic Challenge: After the orthotopic heart transplantation, GCM recurred on aggressive immunosuppression over the months, which included corticosteroids, basiliximab, tacrolimus, antithymocyte globulin, and rituximab. Although combination immunosuppressive therapy containing cyclosporine and 2-4 additional drugs including corticosteroids, azathioprine, mycophenolate mofetil, muromonab, gammaglobulin, or methotrexate have shown to prolong the transplant-free survival by keeping the disease under control, its role in preventing and treating recurrence posttransplantation is unclear., Solution: We added sirolimus, a macrolide antibiotic, with properties of T- and B-lymphocyte proliferation inhibition on the above immunosuppressive treatment postrecurrence of GCM. After sirolimus initiation and continuation, the patient has remained disease free.

Introduction : Pulmonary hypertension (PH) secondary to left-sided heart disease (Group 2 PH) is a frequent complication of heart failure (HF) and is a heterogeneous phenotypic disorder that worsens exercise capacity, increases risk for hospitalization and survival independent of left ventricular ejection fraction (LVEF) or stage of HF. Areas covered : In this review, an update of the current knowledge and some potential challenges about the pathophysiology and treatments of group 2 PH in patients with HF of either preserved or reduced ejection fraction are provided. Also, this review discusses the epidemiology and provides hints for the optimal evaluation and diagnosis of these patients to prevent misclassification of their pulmonary hypertension. Expert opinion : There are many of areas lacking knowledge and understanding in the field of pulmonary hypertension associated to left heart disease (PH-LHD) that should be addressed in the future. Further research should be performed, in terms of pathobiology, and understanding the predisposition (genetic susceptibility and contributing factors) of the different phenotypes of this disorder. More clinical trials targeting new therapeutic options and specific PH therapies are warranted to help this increasing important patient group as the current guidelines recommend to only treat the underlying left-sided heart disease.

Background: The effect of elevated heart rate (HR) on outcomes after heart transplantation (HT) has not been well established. The aim of this study was to assess predictors of elevated HR following HT and its impact on outcomes., Methods and Results: We retrospectively evaluated 394 patients who underwent HT at 2 academic medical centers from 2005 to 2016. Patients were divided into 2 groups based on HR 1 year after HT: HR ≥95 beats/min (n = 162; 41%) and HR <95 beats/min (n = 232; 59%). Median follow-up time was 6.6 (interquartile range [IQR] 2.2-7.5) years. HR ≥95 beats/min 1 year after HT was associated with younger donor age, whereas HR <95 beats/min was associated with heavy donor alcohol use and African-American recipient race. Left ventricular (LV) end-diastolic dimension, mass, and ejection fraction were lower and E/E' higher in the HR ≥95 group at the time of the last follow up. HR ≥95 beats/min at 1 year after HT was independently associated with the development of cardiac allograft vasculopathy and increased mortality., Conclusions: HR ≥95 beats/min 1 year after HT is associated with a reduction in LV size and function, increased incidence of cardiac allograft vasculopathy, and reduced survival. Studies investigating the effect of medical HR reduction on post-HT outcomes are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cardiovascular diseases represent a leading cause of mortality and increased healthcare expenditure worldwide. Heart failure, which simply describes an inability of the heart to meet the body's needs, is the end point for many other cardiovascular conditions. The last three decades have witnessed significant efforts aiming at the discovery of treatments to improve the survival and quality of life of patients with heart failure; many were successful, while others failed. Given that most of the successes in treating heart failure were achieved in patients with reduced left ventricular ejection fraction (HFrEF), we constructed this review to look at the recent evolution of HFrEF pharmacotherapy. We also explore some of the ongoing clinical trials for new drugs, and investigate potential treatment targets and pathways that might play a role in treating HFrEF in the future., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

The aim of this study was to evaluate clinical outcomes after left ventricular assist device (LVAD) implantation in patients with severe pre-LVAD renal dysfunction (RD). The cohort of 165 consecutive patients implanted with HeartMate II LVADs was divided into two groups: 1) baseline glomerular filtration rate (bGFR) ≤ 40 ml/min/1.73 m (n = 30), and 2) GFR > 40 ml/min/1.73 m (n = 135). In both groups, GFR increased significantly at 1 month and then declined, remaining higher than the pre-LVAD level in the bGFR ≤ 40 group and returning back to the pre-LVAD level in the bGFR > 40 group by 1 year post-LVAD follow-up. Post-LVAD dialysis was used in 20% of the bGFR ≤ 40 patients and 7% of the bGFR > 40 patients (p = 0.02). By 3 months, 14% patients had GFR ≤ 40 ml/min/1.73 m. Grade ≥2 tricuspid regurgitation (TR) (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.23-10.28; p = 0.02) and model for end-stage liver disease-XI score ≥ 17 (OR, 4.2; 95% CI, 1.45-12.24; p = 0.01) were risk factors for severe RD at 3 months after LVAD implantation. Eight bGFR ≤ 40 patients underwent heart transplantation. Carefully selected patients with advanced heart dysfunction and bGFR ≤ 40 ml/min/1.73 m can improve kidney function with LVAD support and be able to bridge to isolated heart transplantation. Additional research is needed to refine patient selection for LVAD.

Background: There are currently no data on the efficacy of angiotensin-converting enzyme inhibitors (ACEis) in Hispanic patients with heart failure (HF) and reduced ejection fraction (HFrEF). We aimed to investigate the effect of adding ACEis to beta-blockers on mortality and hospitalization for HF exacerbation in patients with HFrEF stratified by race/ethnicity., Methods and Results: From Montefiore Medical Center's 3 large hospitals, 618 consecutive patients with HFrEF (left ventricular ejection fraction [LVEF] <35%) who were on a beta-blocker were retrospectively identified. Patients were divided into 2 groups based on whether or not they were on an ACEi for 24 consecutive months. Propensity score matching including all baseline characteristics was performed and patients were then categorized into 3 groups: African Americans, Hispanics, and Whites/Caucasians. We evaluated 2-year all-cause mortality and 2-year hospitalization for HF exacerbation. Of 618 patients, 66% were categorized as ACEi and 34% as no-ACEi. Four hundred twenty-seven patients were matched 2:1 between the ACEi and no-ACEi groups. After matching, overall 2-year mortality and hospitalization rates were similar between ACEi and no-ACEi (12.4% vs 17.8%, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.38-1.16; P = .14; and 8.1% vs 9.5%, HR 0.84, 95% CI 0.44-1.60; P = .6; respectively). After stratifying patients based on race/ethnicity, ACEi demonstrated a lower 2-year mortality compared with no-ACEi in Hispanics (9.8% vs 28.4%, HR 0.33, 95% CI 0.13-0.87; P = .018) but not in African Americans (17.0% vs 11.8%, HR 0.94, 95% CI 0.34-2.65; P = .91) or Whites (9.2% vs 10.3%, HR 0.89, 95% CI 0.29-2.74; P = .83). Two-year hospitalization was not different between ACEi and no-ACEi in Hispanics, African Americans, or Whites (all P = NS). In multivariate analysis, ACEi therapy was an independent predictor of lower 2-year mortality (HR 0.33, 95% CI 0.12-0.89; P = .028) in Hispanics only., Conclusions: In this retrospective propensity-matched study of patients with HFrEF who were on a beta-blocker, ACEi therapy was associated with greater mortality reduction in Hispanic patients compared with African Americans and Whites. These findings need to be confirmed in large national studies that include a significant fraction of Hispanic patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: With recent legislation imposing penalties on hospitals for above-average 30-day all-cause readmissions for patients with acute decompensated heart failure (ADHF), there is concern these penalties will more heavily impact hospitals serving socioeconomically vulnerable and underserved populations., Hypothesis: Patients with ADHF and low socioeconomic status have better postdischarge mortality and readmission outcomes when cardiologists are involved in their in-hospital care., Methods: We retrospectively searched the electronic medical record for patients hospitalized for ADHF from 2001 to 2010 in 3 urban hospitals within a large university-based health system. These patients were divided into 2 groups based on whether a cardiologist was involved in their care or not. Measured outcomes were 30- and 60-day postdischarge mortality and readmission rates., Results: Out of the 7516 ADHF patients, 1434 patients were seen by a cardiologist (19%). These patients had lower 60-day mortality (5.4% vs 7.0%; hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.52-0.96, P = 0.034) and lower 30- and 60-day readmission rates (16.7% vs 20.6%; HR: 0.76, 95% CI: 0.66-0.89, P = 0.002, and 26.1% vs 30.2%; HR: 0.81, 95% CI: 0.72-0.92, P = 0.003, respectively). There was no significant difference in the in-hospital mortality between the 2 groups. Compared with other races, whites with systolic HF have marginally lower HF-related readmission rates when treated by cardiologists., Conclusions: In this cohort of ADHF patients from the Bronx, New York, involvement of a cardiologist resulted in improved short-term mortality and readmission outcomes compared with treatment by general internal medicine., (© 2015 Wiley Periodicals, Inc.)

Dosing equivalency of carvedilol and metoprolol remains a debate. Degree of beta 1-blockade is best assessed by blunting of the exercise-induced heart rate. Accordingly, the authors have investigated dosing equivalency by examining baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. Thirty-seven subjects treated with carvedilol (32.9 +/- 3.5 mg; n = 23) or metoprolol succinate (XL) (96.4 +/- 15.9 mg; n = 14) referred for cardiopulmonary exercise testing were studied prospectively. Carvedilol versus metoprolol XL subjects did not differ with respect to baseline heart rate (73 +/- 2 vs 70 +/- 3 bpm), or baseline plasma norepinephrine levels (597.5 +/- 78.3 vs 602.1 +/- 69.6 pg/mL), P = NS. However, despite similar peak exercise norepinephrine levels (2735.8 +/- 320.1 vs 2403.1 +/- 371.6 pg/mL), heart rate at peak exercise was higher in subjects receiving carvedilol (135 +/- 4 bpm) than those receiving metoprolol XL (117 +/- 6 bpm), P = 0.02. Similar norepinephrine release and more complete beta 1-blockade is observed in well-matched subjects with chronic heart failure treated with a mean daily dose of metoprolol XL 96.4 mg compared with carvedilol 32.9 mg.

Background: Peak oxygen consumption (VO(2)) is an important criterion for listing patients for cardiac transplantation. Beta-blockers improve survival without affecting peak VO(2). We questioned the value of peak VO(2) in predicting outcome in patients treated with beta-blockers., Methods and Results: We reviewed the records of 127 patients who had peak VO(2) measured at baseline and were subsequently treated with beta-blockers for at least 3 months. We divided the patients into 2 groups with peak oxygen consumption >14 (VO(2) hi) and < or =14 ml.kg.min (VO(2) lo). VO(2) hi had 109 patients and VO(2) lo had 18 patients. The combined end-point of death or cardiac transplantation was compared between groups. Mean peak VO(2) and left ventricular ejection fraction were lower in VO(2) lo versus VO(2) hi: 12.4+/-1.4 ml.kg.min versus 19.1+/-3.9 ml.kg.min and 17+/-8% versus 21+/-9%, respectively. At 30 months, the percentage of patients who did not reach the combined end-point was 94% in VO(2) lo versus 79% in VO(2) hi (P=.47). In multivariate analysis, only changes in heart rate and LVEF from baseline to follow-up were predictive of survival., Conclusions: Current peak VO(2) cutoff does not predict survival without transplantation of patients who tolerate chronic treatment with beta-blockers.