Single center outcomes after temporary mechanical circulatory assist device prior to Heartmate 3 implantation - a retrospective cohort study.

Objectives. Temporary mechanical circulatory support (TMCS) has become a component in the therapeutic strategy for treatment of cardiogenic shock as a bridge-to-decision. TMCS can facilitate recovery of cardiopulmonary function, end-organ function, and potentially reduce the surgical risk of left ventricular assist device (LVAD) implantation. Despite the improvements of hemodynamics and end-organ function, post-LVAD operative morbidity might be increased in these high-risk patients. The aim of the study was to compare outcomes after Heartmate 3 (HM3) implantation in patients with and without TMCS prior to HM3 implant. Methods. In this retrospective cohort study of all HM3 patients in the period between November 2015 and October 2021, patients with and without prior TMCS were compared. Patients' demographics, baseline clinical characteristics, laboratory tests, intraoperative variables, postoperative outcomes, and adverse events were collected from patient records. Results. The TMCS group showed an improvement in hemodynamics prior to LVAD implantation. Median TMCS duration was 19.5 (14-26) days. However, the TMCS group were more coagulopathic, had more wound infections, neurological complications, and more patients were on dialysis compared with patient without TMCS prior to HM3 implantation. Survival four years after HM3 implantation was 80 and 82% in the TMCS (N = 22) and non-TMCS group (N = 41), respectively. Conclusion. Patients on TMCS had an acceptable short and long-term survival and comparable to patients receiving HM3 without prior TMCS. However, they had a more complicated postoperative course.

GLP-1 increases heart rate by a direct action on the sinus node.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

Short-term outcomes after heart transplantation using donor hearts preserved with ex vivo perfusion.

The standard Conventional Cold Storage (CCS) during heart transplantation procurement is associated with time-dependent ischemic injury to the graft, which is a significant independent risk factor for post-transplant early morbidity and mortality - especially when cold ischemic time exceeds four hours. Since 2018, Rigshospitalet (Copenhagen, Denmark) has been utilising ex vivo perfusion (Organ Care System, OCS) in selected cases. The objective of this study was to compare the short-term clinical outcomes of patients transplanted with OCS compared to CCS. Methods: This retrospective single-centre study was based on consecutive patients undergoing a heart transplant between January 2018 and April 2021. Patients were selected for the OCS group when the cold ischemic time was expected to exceed four hours. The primary outcome measure was six-month event-free survival. Results: In total, 48 patients were included in the study; nine were transplanted with an OCS heart. The two groups had no significant differences in baseline characteristics. Six-month event-free survival was 77.8% [95% CI: 54.9-100%] in the OCS group and 79.5% [95% CI: 67.8-93.2%] in the CCS group (p = 0.91). While the OCS group had a median out-of-body time that was 183 min longer (p < 0.0001), the cold ischemic time was reduced by 51 min (p = 0.007). Conclusion: In a Scandinavian setting, our data confirms that utilising OCS in heart procurement allows for a longer out-of-body time and a reduced cold ischemic time without negatively affecting safety or early post-transplant outcomes.

Three decades of heart transplantation: experience and long-term outcome.

Objectives. Heart transplantation (HTx) has become an established treatment option in patients with end-stage heart failure. The aim of this study was to report on long-term outcome over the past three decades. Design. Consecutive adult patients receiving first-time and isolated HTx from October 3, 1990, to November 2, 2020, at Rigshospitalet, Copenhagen, Denmark, were retrospectively evaluated. Data were obtained from the Scandinavian Transplant Registry and patient medical records. Recipients were grouped by time of transplantation (early era: 1990-1999; mid era: 2000-2009; recent era: 2010-2020). Results. A total of 384 recipients (77% men, median age 50 [IQR: 40-57]) were included. Median number of HTx procedures per year was 12 (10-14). Overall, 22% of patients were bridged to HTx with a mechanical circulatory support device. Median survival for the whole cohort was 13.8 years and improved numerically from the early era (12.6 years) to the mid era (14.9 years). Median survival conditional on survival to 1-year follow-up after HTx was 16.1 years. Survival probability by Kaplan-Meier method improved significantly from the mid to the recent era (log-rank p = .02). Conclusions. Heart transplantation remains an excellent treatment for selected patients with end-stage heart failure and long-term outcome has improved significantly over the past decades.

Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial.

INTRODUCTION: Coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are associated with risk of death, as well as brain, heart and kidney injury. Glucagon-like peptide-1 (GLP-1) analogues are approved for treatment of type 2 diabetes, and GLP-1 analogues have been suggested to have potential organ-protective and anti-inflammatory effects. During cardiopulmonary bypass (CPB), consensus on the optimal fraction of oxygen is lacking. The objective of this study is to determine the efficacy of the GLP-1-analogue exenatide versus placebo and restrictive oxygenation (50% fractional inspired oxygen, FiO2) versus liberal oxygenation (100% FiO2) in patients undergoing open heart surgery. METHODS AND ANALYSIS: A randomised, placebo-controlled, double blind (for the exenatide intervention)/single blind (for the oxygenation strategy), 2×2 factorial designed single-centre trial on adult patients undergoing elective or subacute CABG and/or surgical AVR. Patients will be randomised in a 1:1 and 1:1 ratio to a 6-hour and 15 min infusion of 17.4 µg of exenatide or placebo during CPB and to a FiO2 of 50% or 100% during and after weaning from CPB. Patients will be followed until 12 months after inclusion of the last participant. The primary composite endpoint consists of time to first event of death, renal failure requiring renal replacement therapy, hospitalisation for stroke or heart failure. In addition, the trial will include predefined sub-studies applying more advanced measures of cardiac- and pulmonary dysfunction, renal dysfunction and cerebral dysfunction. The trial is event driven and aims at 323 primary endpoints with a projected inclusion of 1400 patients. ETHICS AND DISSEMINATION: Eligible patients will provide informed, written consent prior to randomisation. The trial is approved by the local ethics committee and is conducted in accordance with Danish legislation and the Declaration of Helsinki. The results will be presented in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02673931.

Variation in Time to Peak Values for Different Lung Function Parameters After Double Lung Transplantation.

BACKGROUND: Establishment of baseline values for forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), or total lung capacity (TLC) is required when diagnosing and phenotyping chronic lung allograft dysfunction after lung transplant. It is generally accepted that the baseline (peak) values of these parameters occur simultaneously, but this assumption has not been substantiated for TLC. METHODS: All lung function measurements in all double lung transplant recipients from a single center in the period from 1992-2014 were included. Time to baseline FEV1 was assessed according to standards from the International Society for Heart and Lung Transplantation, and time to peak FVC, TLC, and diffusion capacity for carbon monoxide were evaluated. RESULTS: A total of 288 double lung transplants surviving more than 3 months after transplant were included. Baseline FEV1 occurred at a median of 0.77 years post transplant and was statistically different from median times to the peak FVC (1.02 years), to peak TLC (1.37 years), and to peak diffusion capacity for carbon monoxide 1.04 years post transplant (all log-rank P < .001). At the time of baseline FEV1, FVC, and TLC were at a mean of 96% and 95% of their peak values, respectively. CONCLUSION: The peak lung function is reached at different time points for different parameters post transplant with FEV1 baseline occurring first. For most patients values of FVC and TLC obtained at time for baseline FEV1 is a good estimate of peak values, but in a small percentage of patients this procedure may jeopardize phenotyping of chronic lung allograft dysfunction based solely on lung function parameters.

[The first 25 years of lung transplantations in Denmark].

Lung transplantation (LTx) has been performed in Denmark since 1992, and chronic obstructive pulmonary disease and interstitial lung diseases are the major indications. All candidates are subject to an intensive evaluation before being accepted for LTx. Follow-up after transplantation is life-long and includes immunosuppressive medication with a high risk of side effects. The median survival in Denmark is 7.0 years. Chronic rejection is common, diagnosed by declining lung function, and it is the most important factor for morbidity and mortality. LTx requires dedicated personnel in an interdisciplinary organisation.

Acute Pulmonary Embolism in a National Danish Cohort: Increasing Incidence and Decreasing Mortality.

This study reports the incidence, clinical profile and mortality for acute pulmonary embolism (PE) patients in the Danish population in four eras from 2004 to 2014. Patients admitted with first-time acute PE from 2004 through 2014 were identified from national patient registries classified according to the International Classification of Diseases, 10th edition, World Health Organization. A total of 30,275 patients from a population of 4,301,673 adult residents aged 18 years or older were diagnosed with first-time acute PE, corresponding to an incidence of 64 (95% confidence interval: 61-66) per 100,000 adult residents per year. Throughout the study period, PE incidence increased from 45 to 83 per 100,000 adult residents. Age at disease onset also increased during the study period, rising from 67.1 to 68.0 (p = 0.002). Cancer was the most frequent concomitant diagnosis, with an incidence of 15.9%. Thoracic computed tomography and referral to specialized cardiac centres increased significantly throughout the study period. The 30- and 90-day mortality rates decreased between 2004 and 2014 from 17 to 11% and from 23 to 18% (p < 0.00), respectively. The 5-year mortality risk was reduced when comparing Era IV (2012-2014) with Era I (2004-2005), with a hazard ratio of 0.93 (p = 0.01). In Denmark, the annual incidence of acute PE has increased during the past decade from 45 to 83 per 100,000 adults with a significant decrease in both short- and long-term mortalities. In recent years, patients were more likely to be investigated with modern diagnostics and referred to cardiac centres for specialized treatment.

Antithrombotic therapy after bioprosthetic aortic valve implantation: Warfarin versus aspirin, a randomized controlled trial.

BACKGROUND: The optimal medical strategy for prevention of thromboembolic events after surgical bioprosthetic aortic valve replacement (BAVR) is still debated. The objective of this study was to compare warfarin therapy (target INR of 2.0 to 3.0) with aspirin 150mg daily as antithrombotic therapy for the first three months after BAVR with or without concomitant coronary artery bypass grafting (CABG). The aim was to evaluate thromboembolic complications, major bleeding complications and death. MATERIALS AND METHODS: Prospective, single-centre, open-label, randomized controlled trial. 370 patients were enrolled, 328 were available for data analysis. RESULTS: At baseline the warfarin and aspirin groups were comparable. Thromboembolic events were comparable between groups 11 (6.6%) vs. 12 (7.5%), p=0.83. Major bleeding events occurred numerically more often in warfarin patients 9 (5.4%) vs. 3 (1.9%), p=0.14. Warfarin was in multivariate analysis significantly associated with major bleeding OR 5.18 (CI 1.06-25.43), p=0.043. 90-day mortality was comparable between groups 8 (4.7%) vs. 6 (3.7%), p=0.79. CONCLUSIONS: Our results suggest that aspirin might be equally effective as warfarin in preventing thromboembolic events after BAVR, but with less major bleedings. Although this is numerically the largest trial testing this hypothesis in a prospective randomized trial, further adequately powered studies are warranted.