Temporary mechanical circulatory support in infarct-related cardiogenic shock: an individual patient data meta-analysis of randomised trials with 6-month follow-up.

BACKGROUND: Percutaneous active mechanical circulatory support (MCS) devices are being increasingly used in the treatment of acute myocardial infarction-related cardiogenic shock (AMICS) despite conflicting evidence regarding their effect on mortality. We aimed to ascertain the effect of early routine active percutaneous MCS versus control treatment on 6-month all-cause mortality in patients with AMICS. METHODS: In this individual patient data meta-analysis, randomised controlled trials of potential interest were identified, without language restriction, by querying the electronic databases MEDLINE via PubMed, Cochrane Central Register of Controlled Trials, and Embase, as well as ClinicalTrials.gov, up to Jan 26, 2024. All randomised trials with 6-month mortality data comparing early routine active MCS (directly in the catheterisation laboratory after randomisation) versus control in patients with AMICS were included. The primary outcome was 6-month all-cause mortality in patients with AMICS treated with early routine active percutaneous MCS versus control, with a focus on device type (loading, such as venoarterial extracorporeal membrane oxygenation [VA-ECMO] vs unloading) and patient selection. Hazard ratios (HRs) of the primary outcome measure were calculated using Cox regression models. This study is registered with PROSPERO, CRD42024504295. FINDINGS: Nine reports of randomised controlled trials (n=1114 patients) were evaluated in detail. Overall, four randomised controlled trials (n=611 patients) compared VA-ECMO with a control treatment and five randomised controlled trials (n=503 patients) compared left ventricular unloading devices with a control treatment. Two randomised controlled trials also included patients who did not have AMICS, who were excluded (55 patients [44 who were treated with VA-ECMO and 11 who were treated with a left ventricular unloading device]). The median patient age was 65 years (IQR 57-73); 845 (79·9%) of 1058 patients with data were male and 213 (20·1%) were female. No significant benefit of early unselected MCS use on 6-month mortality was noted (HR 0·87 [95% CI 0·74-1·03]; p=0·10). No significant differences were observed for left ventricular unloading devices versus control (0·80 [0·62-1·02]; p=0·075), and loading devices also had no effect on mortality (0·93 [0·75-1·17]; p=0·55). Patients with ST-elevation cardiogenic shock without risk of hypoxic brain injury had a reduction in mortality with MCS use (0·77 [0·61-0·97]; p=0·024). Major bleeding (odds ratio 2·64 [95% CI 1·91-3·65]) and vascular complications (4·43 [2·37-8·26]) were more frequent with MCS use than with control. INTERPRETATION: The use of active MCS devices in patients with AMICS did not reduce 6-month mortality (regardless of the device used) and increased major bleeding and vascular complications. However, patients with ST-elevation cardiogenic shock without risk of hypoxic brain injury had a reduction in mortality after MCS use. Therefore, the use of MCS should be restricted to certain patients only. FUNDING: The Heart Center Leipzig at Leipzig University and the Foundation Institut für Herzinfarktforschung.

Mitochondrial Function After Normothermic Regional Perfusion or Direct Procurement Followed by Hypothermic Oxygenated Machine Perfusion in Heart Transplantation After Circulatory Death.

BACKGROUND: Strategies to minimize ischemic damage during heart transplantation (HTX) by donation after circulatory death (DCD) are warranted because the inevitable ischemic injury linked to DCD HTX deteriorates mitochondrial respiratory capacity and ultimately graft quality. This study aimed to examine the myocardial mitochondrial function during DCD HTX with hypothermic oxygenated machine perfusion (HOPE) and compare the effect of normothermic regional perfusion (NRP) with that of direct procurement and perfusion (DPP). METHODS: A porcine DCD HTX model was used with hearts subjected to either DPP (n = 6) or NRP (n = 7) followed by HOPE and orthotopic HTX. Mitochondrial respiratory function was analyzed by high-resolution respirometry in left ventricle biopsies at baseline, after 180 min of HOPE, and after 60 min of reperfusion post-HTX. RESULTS: Mitochondrial oxidative phosphorylation (P = 0.0008), respiratory control ratio (P = 0.04), and coupling efficiency (P = 0.04) declined during DCD HTX. Fatty acid oxidation was preserved after 3 h of HOPE with a modest, statistically nonsignificant decline after reperfusion (P = 0.2). Oxidative phosphorylation was inversely correlated with troponin-T levels (r = -0.70, P = 0.0004). No statistically significant difference in mitochondrial respiratory capacity was observed between participants exposed to NRP and DPP. CONCLUSIONS: Mitochondrial respiratory capacity declined gradually throughout the course of DCD HTX and correlated with the degree of myocardial damage. Following HOPE, the extent of mitochondrial deterioration was comparable between NRP and DPP.

Anthropometric measures and long-term mortality in non-ischaemic heart failure with reduced ejection fraction: Questioning the obesity paradox.

AIMS: Although body mass index (BMI) is the most commonly used anthropometric measure to assess adiposity, alternative indices such as the waist-to-height ratio may better reflect the location and amount of ectopic fat as well as the weight of the skeleton. METHODS AND RESULTS: The prognostic value of several alternative anthropometric measures was compared with that of BMI in 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) enrolled in DANISH. The association between anthropometric measures and all-cause death was adjusted for prognostic variables, including natriuretic peptides. Median follow-up was 9.5 years (25th-75th percentile, 7.9-10.9). Compared to patients with a BMI 18.5-24.9 kg/m2 (n = 363), those with a BMI ≥25 kg/m2 had a higher risk of all-cause and cardiovascular death, although this association was only statistically significant for a BMI ≥35 kg/m2 (n = 91) (all-cause death: hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.28-2.48; cardiovascular death: HR 2.46, 95% CI 1.69-3.58). Compared to a BMI 18.5-24.9 kg/m2, a BMI <18.5 kg/m2 (n = 24) was associated with a numerically, but not a significantly, higher risk of all-cause and cardiovascular death. Greater waist-to-height ratio (as an exemplar of indices not incorporating weight) was also associated with a higher risk of all-cause and cardiovascular death (HR for the highest vs. the lowest quintile: all-cause death: HR 2.11, 95% CI 1.53-2.92; cardiovascular death: HR 2.17, 95% CI 1.49-3.15). CONCLUSION: In patients with non-ischaemic HFrEF, there was a clear association between greater adiposity and higher long-term mortality. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00542945.

Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial.

BACKGROUND: Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. METHODS: In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study. RESULTS: A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73 m2 and 61.0 (52.3-69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p = 0.99). CONCLUSIONS: De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.

Labor Market Participation Among Working-Age Heart Failure Patients With a Cardiac Resynchronization Therapy Device.

PURPOSE: Labor market participation is an important rehabilitation goal for working-age patients living with heart failure (HF). Cardiac resynchronization therapy (CRT) reduces mortality and HF hospitalizations and improves quality of life, but no studies have investigated labor market participation following CRT. We therefore aimed to describe labor market participation in patients with HF before and after CRT implantation. METHODS: This region-wide register-based cohort study comprised patients with HF aged 40 to 63 yr, with ejection fraction ≤35% and QRS duration >130 milliseconds, who received a CRT system from 2000 to 2017 in the Central Denmark Region. Using unambiguous, individual-level linkage in Danish medical and administrative registries, we assessed weekly employment status from 1 yr prior to CRT implantation until 2 to 5 yr of follow-up and conducted stratified analyses by sociodemographic and disease-related risk factors. RESULTS: We identified 546 patients, of whom 42% were in early retirement 1 yr prior to implantation. Active employment decreased from 45% to 19% from 1 yr before until implantation, declining primarily in the last 8 wk before implantation. The proportion of patients in active employment increased in the first 8 wk after CRT implantation and then stabilized, reaching 31% at 1-yr follow-up. We observed lower labor market participation in patients with older age, multimorbidity, lower educational level, and upgrade procedures, but higher in later calendar year. CONCLUSIONS: In working-age patients with HF, labor market participation increased after CRT implantation, despite many patients being retired prior to implantation. We observed differences in active employment related to several sociodemographic and disease-related factors.

Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety. OBJECTIVES: This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy. METHODS: Patients who had received a cardiac allograft at one of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months' treatment. RESULTS: The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: -0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events. CONCLUSIONS: Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211).

Exercise Hemodynamics and Mitochondrial Oxidative Capacity in Disease Stages of Wild-Type Transthyretin Amyloid Cardiomyopathy.

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.

Influence of multimorbidity and socioeconomic position on long-term healthcare utilization and prognosis in patients after cardiac resynchronization therapy implantation.

Aims: We aimed to investigate the influence of socioeconomic position (SEP) and multimorbidity on cross-sectional healthcare utilization and prognosis in patients after cardiac resynchronization therapy (CRT) implantation. Methods and results: We included first-time CRT recipients with left ventricular ejection fraction ≤35% implanted between 2000 and 2017. Data on chronic conditions, use of healthcare services, and demographics were obtained from Danish national administrative and health registries. Healthcare utilization (in- and outpatient hospitalizations, activities in general practice) was compared by multimorbidity categories and SEP by using a negative binomial regression model. The association between SEP, multimorbidity, and prognostic outcomes was analysed using Cox proportional hazards regression. We followed 2007 patients (median age of 70 years), 79% were male, 75% were on early retirement or state pension, 37% were living alone, and 41% had low education level for a median of 5.2 [inter-quartile range: 2.2-7.3) years. In adjusted regression models, a higher number of chronic conditions were associated with increased healthcare utilization. Both cardiovascular and non-cardiovascular hospital contacts were increased. Patients with low SEP had a higher number of chronic conditions, but SEP had limited influence on healthcare utilization. Patients living alone and those with low educational level had a trend towards a higher risk of all-cause mortality [adjusted hazard ratio (aHR): 1.17, 95% confidence interval (CI) 1.03-1.33, and aHR 1.09, 95% CI 0.96-1.24). Conclusion: Multimorbidity increased the use of cross-sectional healthcare services, whereas low SEP had minor influence on the utilizations. Living alone and low educational level showed a trend towards a higher risk of mortality after CRT implantation.

Cost of out-of-hospital cardiac arrest survivors compared with matched control groups.

INTRODUCTION: Societal costs of out-of-hospital cardiac arrest (OHCA) survivors may be extensive due to high health care utilization and sick leave. Knowledge of the costs of OHCA survivors may guide decision-makers to prioritize health resources. AIM: The aims of the study were to evaluate the costs of OHCA survivors from a societal perspective, and to compare these costs to the costs of individuals with non-cardiac arrest myocardial infarction (MI) and individuals with no cardiac disease (non-CD). METHODS: From the Danish OHCA Registers, survivors, with a cardiac arrest between 2005-2018 were identified. Each case was assigned one MI control and one non-CD control, matched on gender and age. Based on register data, costs of healthcare utilization, sick leave, vocational rehabilitation, disability pension and other social benefits one year before event and five years after, were estimated. RESULTS: In total 5,646 OHCA survivors were identified with associated control groups. The mean costs for OHCA survivors during the 6-year period were €119,106 (95%CI: 116,297-121,916), with €83,472 (95%CI: 81,392-85,552) being healthcare costs. Mean costs of OHCA survivors were €49,132 higher than the MI-control group and €100,583 higher than the non-CD control group. CONCLUSIONS: Total costs of OHCA survivors were considerably higher than costs of MI- and non-CD controls. Hospital costs were highest during the first year after event, and work inability during the second to fifth year with sick leave and later disability pension as main burdens.

New York Heart Association functional class and implantable cardioverter-defibrillator in non-ischaemic heart failure with reduced ejection fraction: Extended follow-up of the DANISH trial.

AIMS: Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II-III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long-term effects of primary prevention ICD implantation according to NYHA class in an extended follow-up study of the DANISH trial. METHODS AND RESULTS: The DANISH trial randomized 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all-cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow-up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long-term rate of all-cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20-1.93) and cardiovascular death (HR 1.95 [1.47-2.60]). ICD implantation, compared with usual care, did not reduce the long-term rate of all-cause mortality (all participants: HR 0.89 [95% CI 0.74-1.08]; NYHA class II: HR 0.85 [0.64-1.13]; NYHA class III/IV: HR 0.89 [0.69-1.14]; pinteraction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70-1.09]; NYHA class II: HR 0.78 [0.54-1.12]; NYHA class III/IV: HR 0.89 [0.67-1.19]; pinteraction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40-0.92]; NYHA class II: HR 0.73 [0.40-1.36]; NYHA class III/IV: HR 0.52 [0.29-0.94]; pinteraction = 0.39). CONCLUSIONS: In patients with non-ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00542945.

Employment Status Following Heart Transplantation: Data From the Danish Nationwide Social Service Payment Register During 20 years.

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.

Effect of Implantable Cardioverter-defibrillators in Nonischemic Heart Failure According to Background Medical Therapy: Extended Follow-up of the DANISH Trial.

BACKGROUND: The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH). METHODS AND RESULTS: Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; Pinteraction, 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (Pinteraction, 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (Pinteraction, 0.35). CONCLUSIONS: Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score.

Association between socioeconomic position and discontinuation of pharmacotherapy for heart failure after cardiac resynchronization therapy.

AIMS: Pharmacological therapy remains a cornerstone in heart failure (HF) treatment despite implantation of a cardiac resynchronization therapy (CRT) device. The aim of this study was to investigate the association between 1) drug discontinuation, and 2) long-term adherence to HF pharmacotherapy after CRT implantation and socioeconomic position and multimorbidity. METHODS AND RESULTS: We conducted a registry-based cohort study including all patients who underwent a first-time CRT implantation at Aarhus University Hospital from 2000-2017. HF pharmacotherapy included beta blockers (BBs), renin angiotensin system inhibitors (ACEI/ARB), and mineralocorticoid receptor antagonists (MRAs). Patients were identified using the Danish Pacemaker and ICD Registry, and information about medication and comorbidities was obtained through linkage to the Danish health registries. We identified 2,007 patients of whom 1,880 (94%) were eligible for inclusion. The cumulative incidence of drug discontinuation at 10 years was 6% (95% confidence interval [CI] 5-8%) for BB, 10% (95% CI 9-12%) for ACEI/ARB, and 24% (95% CI 20-27%) for MRAs. Living alone was associated with higher BB discontinuation rates (hazard ratio [HR] 1.83, 95%CI 1.20-2.79), whereas patients with multimorbidity were more likely to discontinue ACEI/ARB- (HR 1.92, 95%CI 1.33-2.80) and MRA therapy (HR 1.51, 95% CI 1.10-2.09). Income- and educational level did not influence drug discontinuation rates, and similar adherence patterns were observed across all strata of socioeconomic position and multimorbidity. CONCLUSION: In patients with CRTs, drug discontinuation rates were low, and adherence to HF pharmacotherapy was comparable regardless of socioeconomic position. Living alone and multimorbidity were associated with discontinuation of specific HF drugs.

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.

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<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Socio-economic position, multimorbidity, and health care utilization among Danish left ventricular assist device patients.

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.

Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model.

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.

Routine screening for HLA Antibodies in Heart Transplant patients-Does it affect clinical decision making?

BACKGROUND: We aimed to assess outcomes in patients with and without donor specific antibodies (DSA) and to evaluate the relationship between DSA presence and graft function, cardiac allograft vasculopathy (CAV), and mortality. METHODS: The study population comprises 193 consecutive long-term heart transplanted (HTx) patients who underwent DSA surveillance between 2016 and 2022. The patients were prospectively screened for CAV through serial coronary angiograms, graft function impairment through serial echocardiograms, and cardiac biomarkers. The patients were followed from the first DSA measurement until death, 5 years follow-up or right censuring on the 30th of June 2023. RESULTS: DSAs were detected in 50 patients using a cut-off at MFI ≥1000 and 45 patients using a cut-off at ≥2000 MFI. The median time since HTx was 9.0 years [3.0-14.4]. DSA positive patients had poorer graft function and higher values of NT-proBNP and troponin T, and more prevalent CAV than DSA negative patients. In total, 25 patients underwent endomyocardial biopsies due to DSA presence while another eight patients underwent endomyocardial biopsies for other reasons. Histological antibody mediated rejection (AMR) signs were seen in three biopsies. During a median follow-up of five years [4.7-5], a total of 41 patients died. Mortality rates did not differ between DSA positive and DSA negative patients (HR 1.2, 95% CI .6-2.4). DSA positive patients were more likely to experience CAV progression than DSA negative patients (HR 2.7, 95% CI 1.5-4.8) CONCLUSIONS: Routine screening reveals DSA in approximately 25% of long-term HTx patients but is rarely related to histopathological AMR signs. DSA presence was associated with poorer graft function and more prevalent and progressive CAV. However, DSA positive patients had similar survival rates to DSA negative patients.

Estimated Glomerular Filtration Rate and Implantable Cardioverter-Defibrillator in Nonischemic Systolic Heart Failure: Extended Follow-Up of DANISH.

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 ≥/<60 mL/min per 1.73 m2) at baseline. In total, 1113 patients had an available estimated glomerular filtration rate measurement at baseline (median estimated glomerular filtration rate 73 mL/min per 1.73 m2), and 316 (28%) had CKD. During a median follow-up of 9.5 years, ICD implantation, compared with usual care, did not reduce the rate of all-cause mortality (no CKD, HR, 0.82 [95% CI, 0.64-1.04]; CKD, HR, 1.02 [95% CI, 0.75-1.38]; Pinteraction=0.31) or cardiovascular death (no CKD, HR, 0.77 [95% CI, 0.58-1.03]; CKD, HR, 1.05 [95% CI, 0.73-1.51]; Pinteraction=0.20), irrespective of baseline CKD status. Similarly, baseline CKD status did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (no CKD, HR, 0.57 [95% CI, 0.32-1.00]; CKD, HR, 0.65 [95% CI, 0.34-1.24]; Pinteraction=0.70). CONCLUSIONS: ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce the rate of sudden cardiovascular death, regardless of baseline kidney function in patients with nonischemic heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

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 < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.