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Abstract Aims Increasing numbers of patients with advanced heart failure and significant comorbidity and social barriers are considered for left ventricular assist devices (LVADs). We sought to examine health care utilization post‐LVAD implantation, including the influence of individual‐level socio‐economic position and multimorbidity. Methods and results We conducted a Danish nationwide cohort study linking individual‐level data from clinical LVAD databases, the Scandiatransplant Database, and Danish national medical and administrative registries. Socio‐economic position included cohabitation status, educational level, and employment status. Multimorbidity was defined as two or more chronic conditions from at least two chronic disease groups. Health care utilization (hospital activity, general practice activity, and redeemed medical prescriptions) within 2 years post‐discharge after LVAD implantation was evaluated using descriptive statistics at 0.5 year intervals. We identified 119 patients discharged alive with first‐time LVAD implanted between 2006 and 2018. The median age of the patients was 56.1 years, and 88.2% were male. Patients were followed until heart transplantation, LVAD explantation, death, 31 December 2018, or for 2 years. The median follow‐up was 0.8 years. The highest median use of health care services was observed 0–0.5 years post‐LVAD discharge compared with the subsequent follow‐up intervals: 0.5–1, 1–1.5, and 1.5–2 years, respectively. The median (interquartile range) number of hospitalizations was 10 (7–14), bed days 14 (9–28), outpatient visits 8 (5–12), telephone contacts with a general practitioner 4 (2–8), and total redeemed medical prescriptions 26 (19–37) within 0–0.5 years post‐LVAD discharge compared with the median utilization within the consecutive follow‐up periods [e.g. within 0.5–1 year: hospitalizations 5 (3–8), bed days 8 (4–14), outpatient visits 5 (3–8), telephone contacts 2 (0–5), and redeemed medical prescriptions 24 (18–30)]. The median use of health care services was stable from 0.5 years onwards. The median number of hospitalizations and bed days was slightly higher in patients living alone with a low educational level or low employment status within 0–0.5 years post‐LVAD implantation. Finally, the median number of in‐hospital days and redeemed prescriptions was higher among patients with pre‐existing multimorbidity. Conclusions Among patients who underwent LVAD implantation, health care utilization was high in the early post‐LVAD discharge phase and was influenced by socio‐economic position. Multimorbidity influenced the number of in‐hospital days and redeemed prescriptions during the 2 year follow‐up.

Background The Danish National Patient Registry (DNPR) is a valuable resource for population-based research, but the validity of routine registration of advanced heart failure (HF) treatments within the registry is unknown. We, therefore, investigated the validity of HF, advanced HF treatments, and HF readmissions in the DNPR. Methods We randomly sampled patients registered at a Danish University Hospital during 2017-2021 from the DNPR. We identified 200 patients with first-time HF, 390 patients with one of eight advanced HF treatments, and 133 patients with HF admission after implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy (CRT). Compared with medical record reviews, we calculated positive predictive values (PPVs) with 95 confidence intervals (CIs). Results The PPV for first-time HF was 81 (95 CI: 74-86). For advanced HF treatments, the PPV was 97 (95 CI: 91-99) for ICD, 96 (95 CI: 86-100) for CRT-pacemaker, 88 (95 CI: 76-95) for CRT-defibrillator, 100 (95 CI: 83-100) for left ventricular assist device, 43 (95 CI: 18-71) for intra-aortic balloon pump, 38 (95 CI: 25-35) for impella, 100 (95 CI: 93-100) for cardiopulmonary support, and 100 (95 CI: 94-100) for heart transplantation. The PPV for HF admission after ICD was 25 (95 CI: 16-37) and 18 (95 CI: 9.2-30) after CRT. Conclusions The PPV of routine registrations in the DNPR was moderate for first-time HF, high for most advanced HF treatments, and low for HF admissions after ICD or CRT. Thus, the DNPR is a valuable data source for population-based research on first-time HF and many advanced HF treatments.

Abstract Background Lactate is traditionally recognized as a by-product of anaerobic metabolism. However, lactate is a preferred oxidative substrate for stressed myocardium. Exogenous lactate infusion increases cardiac output (CO). The exact mechanism underlying this mechanism has yet to be elucidated. The aim of this study was to investigate the cardiovascular mechanisms underlying the acute haemodynamic effects of exogenous lactate infusion in an experimental model of human-sized pigs. Methods In this randomised, blinded crossover study in eight 60-kg-pigs, the pigs received infusions with one molar sodium lactate and a control infusion of tonicity matched hypertonic saline in random order. We measured CO and pulmonary pressures using a pulmonary artery catheter. A pressure–volume admittance catheter in the left ventricle was used to measure contractility, afterload, preload and work-related parameters. Results Lactate infusion increased circulating lactate levels by 9.9 mmol/L (95% confidence interval (CI) 9.1 to 11.0) and CO by 2.0 L/min (95% CI 1.2 to 2.7). Afterload decreased as arterial elastance fell by -1.0 mmHg/ml (95% CI -2.0 to -0.1) and systemic vascular resistance decreased by -548 dynes/s/cm5 (95% CI -261 to -835). Mixed venous saturation increased by 11 percentage points (95% CI 6 to 16), whereas ejection fraction increased by 16.0 percentage points (95% CI 1.1 to 32.0) and heart rate by 21 bpm (95% CI 8 to 33). No significant changes in contractility nor preload were observed. Conclusion Lactate infusion increased cardiac output by increasing heart rate and lowering afterload. No differences were observed in left ventricular contractility or preload. Lactate holds potential as a treatment in situations with lowered CO and should be investigated in future clinical studies. Graphical Abstract

Background: Long-term survival after heart transplantation (HTx) is limited by cardiac allograft vasculopathy (CAV). The pathogenesis of CAV is poorly understood, and treatment has not yet been well-established. In this exploratory study, we aimed to identify novel immune and nonimmune biomarkers correlated to CAV development, and biomarkers predicting CAV-related events. Methods: Using a proteomic panel, 92 cardiovascular disease-related proteins were evaluated in 26 de novo HTx patients at 3 and 12 months post-transplantation. Intima-area changes were assessed using optical coherence tomography. Major adverse cardiac events (MACE) included significant CAV progression, heart failure, and cardiovascular death. Results: The median follow-up was 6.8 years. We found changes in 4 inflammatory biomarkers: matrix metalloproteinase 3 (MMP-3) and matrix metalloproteinase 2 (MMP-2) were significantly increased after 3 months in the group of patients with the highest intima proliferation, and after 12 months in patients experiencing MACE, respectively. Monocyte chemotactic protein 1 (MCP-1) was increased after 12 months in patients experiencing MACE. Platelet-derived growth factor subunit A (PDGF-A) was significantly increased after 3 months in the group of patients with highest intima proliferation. Conclusions: We identified 4 biomarkers that may be associated with CAV development which differed significantly between groups of intima proliferation and MACE; MMP-2, MMP-3, MCP-1, and PDGF-A. Further studies are needed to examine whether our findings offer the basis to seek new markers of graft vasculopathy or treatment options.

Background Wild‐type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance, hemodynamics, and mitochondrial function in disease stages of ATTRwt has not previously been studied but may provide new insights into the pathophysiology and clinical performance of the patients. Methods and Results The study investigated 47 patients diagnosed with ATTRwt at Aarhus University Hospital, Denmark. Patients were stratified according to the disease stages of the National Amyloidosis Centre (NAC) as NAC I with low levels of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) (NAC I‐L, n=14), NAC I with high levels NT‐proBNP (NAC I‐H, n=20), and NAC II‐III (n=13). Exercise testing with simultaneous right heart catheterization was performed in all patients. Endomyocardial biopsies were collected from the patients and the mitochondrial oxidative phosphorylation capacity was assessed. All NAC disease groups, even in the NAC I‐L group, a significant abnormal increase in biventricular filling pressures were noted during exercise while the filling pressures was normal or near normal at rest. The inotropic response to exercise was reduced with diminished increase in cardiac output which was significantly more pronounced in the NAC I‐H (Diff. ‐2.4, 95% CI (−4.2: −0.7), P=0.00) and the NAC II‐III group (Diff: −3.1 L/min, 95% CI (−5.2: −1.1), P=0.00) compared with the NAC I‐L group. The pulmonary artery wedge pressure to cardiac output ratio at peak exercise was significantly different between NAC I‐L and NAC II‐III (Diff: 1.6 mm Hg*min/L, 95% CI (0.01:3.3, P=0.04)). Patients with ATTRwt had a reduced oxidative phosphorylation capacity which correlated to left ventricular mass but not to cardiac output capacity. Conclusions An abnormal restrictive left ventricle and right ventricle response to exercise was demonstrated, even present in patients with early‐stage ATTRwt. In more advanced disease stages a progressive impairment of the pressure‐flow relationship was noted. The myocyte energetics is deranged but not associated to the contractile reserve or restrictive filling characteristics in ATTRwt.

Abstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer’s acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P

Background The ketone body 3‐hydroxybutyrate (3‐OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3‐OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D‐3‐OHB and L‐3‐OHB, remain undetermined. Methods and Results Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3‐hour infusions of either D/L‐3‐OHB (racemic mixture), 100% L‐3‐OHB, 100% D‐3‐OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure‐volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high‐resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D‐[11C]3‐OHB and L‐[11C]3‐OHB positron emission tomography. All three 3‐OHB infusions increased 3‐OHB levels (P

Most studies on vocational rehabilitation after heart transplantation (HTX) are based on self-reported data. Danish registries include weekly longitudinal information on all public transfer payments. We intended to describe 20-year trends in employment status for the Danish heart-transplant recipients, and examine the influence of multimorbidity and socioeconomic position (SEP). Linking registry and Scandiatransplant data (1994–2018), we conducted a study in recipients of working age (19–63 years). The cohort contained 492 recipients (79% males) and the median (IQR) age was 52 years (43–57 years). Five years after HTX, 30% of the survived recipients participated on the labor market; 9% were in a flexible job with reduced health-related working capacity. Moreover, 60% were retired and 10% eligible for labor market participation were unemployed. Recipients with multimorbidity had a higher age and a lower prevalence of employment. Five years after HTX, characteristics of recipients with labor market participation were: living alone (27%) versus cohabitation (73%); low (36%) versus medium-high (64%) educational level; low (13%) or medium-high (87%) income group. Heart-transplant recipients with multimorbidity have a higher age and a lower prevalence of employment. Socioeconomically disadvantaged recipients had a lower prevalence of labor market participation, despite being younger compared with the socioeconomically advantaged.

Background: Cardiac allograft vasculopathy (CAV) is a prevailing complication following heart transplantation. We aimed to investigate if CAV causes equal vascular remodeling in the major coronary arteries using quantitative optical coherence tomography (OCT) and to explore the prognostic potential of OCT-derived measurements from each coronary artery. Methods: Sixty-four heart transplanted patients had a combined total of 114 full 3-vessel OCTs and coronary angiographies performed between 2013 and 2019. OCT pullbacks were categorized by angiographic CAV classification. Registration of disease progression was censored on July 1, 2022. Results: OCT recordings were classified as follows: no significant CAV, n = 73; mild CAV, n = 18; moderate CAV, n = 13; and severe CAV, n = 10. From intercoronary comparison of severe CAV, we found significant differences by both average lumen/intima ratio (p

Background Patients with heart failure and chronic kidney disease (CKD) may have an increased risk of death from causes competing with arrhythmic death, which could have implications for the efficacy of implantable cardioverter‐defibrillators (ICDs). We examined the long‐term effects of primary prophylactic ICD implantation, compared with usual care, according to baseline CKD status in an extended follow‐up study of DANISH (Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality). Methods and Results In the DANISH trial, 1116 patients with nonischemic heart failure with reduced ejection fraction were randomized to receive an ICD (N=556) or usual care (N=550). Outcomes were analyzed according to CKD status (estimated glomerular filtration rate ≥/