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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.)

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.)

Background: Cardiac transplantation in many centers is programmatically limited to patients aged younger than 70 years. We investigated the trends and outcomes for cardiac transplantation in recipients aged 70 years and older in the United States., Methods: De-identified data were provided by United Network of Organ Sharing. Transplant recipients were grouped by age 60-69 years and 70 years and older. Univariate comparisons were performed using Student's t-test or the Pearson chi-square test. Survival was estimated using the Kaplan-Meier technique and compared with the log-rank test. Cox regression was used to determine predictors of death after transplant. Statistical significance was assigned to p < 0.05., Results: Between January 1, 1998, and June 15, 2010, 5,807 sexagenarians and 332 septuagenarians received allografts. The septuagenarian cohort had more men, less diabetes, was less likely to have a ventricular assist device, and more likely to be status II. Donors for septuagenarians were older and died more frequently from intracranial hemorrhage. Median unadjusted survival was 9.8 years for sexagenarians vs 8.5 years for septuagenarians (p = 0.003). There was no difference in the incidence of cerebrovascular accident, length of stay, or pacemaker need between groups. Septuagenarians were less likely to be treated for rejection the first year (p = 0.001). Age was a multivariate predictor of death (hazard ratio, 1.289; 95% confidence interval, 1.039-1.6; p = 0.021)., Conclusions: Selected septuagenarians with advanced heart failure can derive great benefit from cardiac transplantation, although survival is inferior to that of an immediately younger sexagenarian cohort. Most of the mortality risk is seen in the first year after transplantation. A reduced incidence of rejection was observed and warrants further study., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic heart failure (CHF) and chronic kidney disease (CKD) are serious medical conditions with significant morbidity and mortality. Emerging evidence indicates that the function of these two organ systems are affected by each other in a complex interplay. Most patients with CKD suffer frequently from cardiac abnormalities including left ventricular hypertrophy (LVH), left ventricular dilatation (LVD), left ventricular (LV) diastolic and/or systolic dysfunction. Although previously thought that LV systolic dysfunction was an absolute contraindication to renal transplantation, several observational studies have shown this not to be true and that transplantation can lead to significant improvement in LV systolic function. Furthermore, correction of the uremic state by renal transplantation leads to improvement of LVD and possibly regression of LVH. In fact, the reduction of LVH postkidney transplantation was shown to be dependent on adequate renal function and hypertension control. Diabetes mellitus does not seem to be a confounding factor in the improvement of uremic cardiomyopathy with renal transplantation.

Background: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1 alpha (HIF-1 alpha), a transcriptional factor in hypoxic signaling., Methods: Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1 alpha was measured by Western blotting with commercially available antibodies., Results: Heart failure was associated with a decrease in alpha-myosin heavy chain and sarcoplasmic reticulum-Ca(2+) adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1 alpha., Conclusions: Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes.

Background: In chronic heart failure due to a dilated cardiomyopathy phenotype, the molecular bases for contractile dysfunction and chamber remodeling remain largely unidentified., Methods: To investigate the feasibility of measuring global gene expression serially in the intact failing human heart, we performed repeated messenger RNA (mRNA) expression profiling using RNA extracted from endomyocardial biopsy specimens and gene chip methodology in 8 subjects with idiopathic dilated cardiomyopathy. In patients treated with beta-blocking agents or placebo, myocardial gene expression was measured in endomyocardial biopsy material and radionuclide ejection fraction was measured at baseline and after 4 to 12 months of treatment. Gene expression was measured for 12,625 gene sequences by using Affymetrix U95 gene chips and commercially available software. For 6 mRNAs, gene chip results were compared with measurements made by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)., Results: In an unfiltered composite analysis of changes in expression detected in the patients with high-signal intensity chips, 241 genes showed an increase and 331 genes a decrease in mRNA abundance. There was good agreement between changes measured by quantitative RT-PCR and those determined by gene chips. There was less variance between differences in phenotype in patients sampled serially as compared between subjects with similar phenotypes sampled at baseline., Conclusions: Serial gene expression profiling with association to phenotypic change is feasible in the intact human heart and may offer advantages to cross-sectional expression profiling. This study suggests that the intact failing remodeled human heart is in an activated state of gene expression, with a large net reduction in gene expression occurring as phenotypic improvement occurs.

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.