AIMS:Intermediate high-risk pulmonary embolism (PE) is associated with increased risk of haemodynamic deterioration and death, but balancing the risk of thrombolytics or catheter-based treatment and efficacy has been challenging. This trial compared the additional efficacy of catheter-based ultrasound low-dose thrombolysis (USAT) over intravenous low-dose thrombolysis or heparin alone. METHODS AND RESULTS:In an investigator-initiated randomized clinical multicentre trial, we randomized 210 adult patients with acute, intermediate high-risk PE admitted to emergency departments in two regions of Denmark. Patients were allocated 1:1:1 to one of three treatment strata: low-dose thrombolysis (20 mg alteplase administered over 6 h) by USAT, by intravenous administration, or heparin alone. The efficacy of the interventions was assessed by comparing the refined Modified Miller Score, rmMS, (0-40 points, higher score indicating higher thrombus burden) from CT angiographies performed at baseline and 48-96 h post-randomization. Two comparisons were investigated: the reduction of rmMS with low-dose thrombolysis (USAT or intravenously) compared to heparin alone and the reduction of rmMS with low-dose thrombolysis administered by USAT compared to the intravenous route. The safety endpoint included the risk of bleeding.We included 210 patients with acute PE, 49% were female, the mean age was 70 (IQR 62-76), and the mean body mass index was 30 (26-34). Compared to heparin alone, low-dose thrombolysis reduced the rmMS by 3.6 points (95% CI 2.2-5.0, P < 0.001), but the reduction in rmMS was not different in the ultrasound-assisted thrombolysis (USAT) vs. the intravenous route, mean difference -0.1 (95% CI: -1.9-1.7), P = 0.88. Bleeding complications were numerically more frequent with low-dose thrombolysis, albeit not statistically significant. No differences in other outcomes were observed. CONCLUSION:Low-dose thrombolysis reduced thrombus burden more than heparin alone in patients with acute intermediate high-risk PE. However, USAT did not show greater thrombus reduction than intravenous thrombolysis. The rate of death and risk of bleeding complications were increased with low-dose thrombolysis. TRIAL REGISTRATION:clinicaltrials.gov, NCT04088292.

Microaxial flow pump treatment improves survival in selected patients with infarct-related cardiogenic shock; however, treatment carries substantial risks, and benefit may vary by patient subgroup. Systolic blood pressure (SBP) has been proposed as a modifier of the survival benefit. To investigate whether SBP at randomization modifies the survival benefit of microaxial flow pump treatment in ST-segment elevation myocardial infarction–related cardiogenic shock. This was a post hoc analysis of the Danish-German (DanGer) Shock open-label randomized clinical trial among adult patients with ST-segment elevation myocardial infarction complicated by cardiogenic shock, conducted between 2013 and 2023 at 14 tertiary invasive cardiac centers in Denmark, Germany, and the United Kingdom. Data analysis was performed from January 7 to April 7, 2024. Microaxial flow pump therapy plus standard care vs standard care alone. All-cause mortality at 180 days according to randomization SBP. Of 355 patients included in the DanGer Shock trial, 351 patients had available SBP at randomization (median [IQR] age, 69 [59-76] years; 277 [79%] male). In a dichotomized regression analysis, microaxial flow pump treatment significantly reduced mortality for SBPs lower than 82 mm Hg compared with standard care alone (odds ratio [OR], 0.34; 95% CI, 0.18-0.63; P < .001). This was not evident for higher pressures (OR, 0.96; 95% CI, 0.53-1.70; P = .90; P for interaction = .02). Kaplan-Meier survival analysis and spline regression analysis supported these findings ( P for interaction = .02; P for nonlinearity = .01). Randomization SBP was associated with the survival benefit of microaxial flow pump treatment, with the most hypotensive patients deriving the largest survival benefit. Early SBP may help identify patients most likely to gain a net benefit from microaxial flow pump treatment. Findings are hypothesis generating. ClinicalTrials.gov Identifier: NCT01633502

BACKGROUND:Maintaining adequate oxygen delivery during cardiopulmonary bypass (CPB)-assisted cardiac surgery is crucial, but hyperoxia has been suggested to cause organ injury. We compared the effects of restrictive vs liberal oxygenation during CPB and weaning from CPB on clinical outcomes in cardiac surgery. METHODS:We conducted a single-centre, patient- and assessor-blinded randomised trial on adults undergoing CPB-assisted coronary artery bypass grafting, aortic valve replacement, or both. Participants were randomly assigned (1:1) to restrictive (Fio2=50%) or liberal (Fio2=100%) oxygen therapy during and for the first hour after weaning from CPB. The primary composite outcome was the time to death, stroke, renal failure requiring dialysis, or new-onset or worsening heart failure during follow-up. RESULTS:Among 1389 participants (mean age, 67 yr [range, 29-85 yr]; 17% female), randomisation to receive Fio2 50% resulted in median Pao2 levels of 19-23 kPa during CPB, compared with >60 kPa in participants receiving Fio2 100%. During a median follow-up period of 5.9 yr (interquartile range, 2.5-8.3), 167/695 (24%) participants in the restrictive oxygenation group and 168/694 (24%) participants in the liberal oxygenation group met the primary endpoint (hazard ratio, 1.01 [95% confidence interval, 0.8-1.3]; P=0.92). There was no difference in adverse event rates between restrictive and liberal oxygen therapy. CONCLUSIONS:Among patients undergoing elective or urgent CPB-assisted coronary artery bypass grafting, aortic valve replacement, or both, no significant differences were observed in mortality, dialysis-dependent renal failure, stroke, or new-onset or worsening heart failure between a restrictive oxygenation strategy (Fio2 50%) and a liberal oxygenation strategy (Fio2 100%) during CPB and the subsequent weaning period. CLINICAL TRIAL REGISTRATION:NCT02673931.

BACKGROUND:GLP-1 (glucagon-like peptide-1) agonists have been proven beneficial in reducing the risk of and injury associated with several cardiovascular diseases. The efficacy in cardiopulmonary bypass-assisted cardiac surgery is unknown. This trial aimed to investigate the efficacy of an infusion of the GLP-1 agonist exenatide during and after open-heart surgery in reducing the risk of death and major organ failure. METHODS:Randomized, double-blinded, 2-by-2 factorial design, single-center clinical trial, also including liberal (FiO2 of 100%) or restrictive (FiO2 of 50%) oxygenation during and after bypass. The present article presents the results of the exenatide intervention. We included adult patients undergoing elective cardiopulmonary bypass-assisted coronary artery bypass grafting or aortic valve replacement. Patients were predominantly low risk. The intervention was an infusion of 17.4 µg of exenatide or placebo during cardiopulmonary bypass and the first hour after weaning thereof. The main outcome was time to a composite end point consisting of death, stroke, renal failure requiring dialysis, or new/worsening heart failure during follow-up. Secondary end points included occurrence of prespecified adverse events. RESULTS:A total of 1389 patients were included in the analyses. Within a follow-up period of a median of 5.9 years (min-max; 2.5-8.3 years), 170 (24%) patients in the exenatide group and 165 (24%) patients experienced a primary end point. We found no difference in time to the first event between patients randomized to FiO2 50% versus FiO2 100% (hazard ratio, 1.0 [95% CI, 0.83-1.3]; P=0.80). We found no significant difference in rates of adverse events between the 2 groups. CONCLUSIONS:Exenatide during cardiopulmonary bypass and weaning thereof did not significantly reduce the incidence of death, stroke, renal failure, or new/worsening heart failure in patients undergoing coronary artery bypass grafting and aortic valve replacement. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02673931.

AbstractAimsSocioeconomic deprivation is a risk marker for worse prognosis in patients with heart failure (HF), and a potential barrier to referral for advanced HF evaluation. The relationship between socioeconomic status (SES) and invasive haemodynamics in patients undergoing evaluation for advanced HF therapies is unknown.MethodsWe combined a consecutive clinical registry of patients evaluated for advanced HF with patient‐level data on SES (household income, education, workforce status, cohabitant status and distance from home to tertiary HF centre) derived from nationwide registries. Using this information, the cohort was divided into groups of low‐, medium‐ and high degree of socioeconomic deprivation. The associations between SES and invasive haemodynamics were explored with multiple linear regression adjusted for age and sex.ResultsA total of 631 patients were included. The median age was 53 years, and 23% were women. Patients in the highest income quartile versus the lowest (Q4 vs. Q1) were older (median age 57 vs. 50 years) and more often male (83% vs. 67%), both P < 0.001. Increasing household income (per 100 000 Danish kroner,1 EUR = 7.4 DKK) was associated with lower pulmonary capillary wedge pressure (PCWP) [−0.18 mmHg, 95% confidence interval (CI) −0.36 to −0.01, P = 0.036] but not significantly associated with central venous pressure (CVP) (−0.07 mmHg, 95% CI −0.21 to 0.06, P = 0.27), cardiac index (−0.004 L/min/m2, 95% CI −0.02 to 0.01, P = 0.60), or pulmonary vascular resistance (PVR) (−0.003 Wood units, 95% CI −0.37 to 0.16, P = 0.84). Comparing the most deprived with the least deprived group, adjusted mean PVR was higher (0.35 Wood units, 95% CI 0.02 to 0.68, P = 0.04), but PCWP (0.66 mmHg, 95% CI −1.49 to 2.82, P = 0.55), CVP (−0.26 mmHg, 95% CI −1.76 to 1.24, P = 0.73) and cardiac index (−0.03 L/min/m2, 95% CI −0.22 to 0.17, P = 0.78) were similar.ConclusionsMost haemodynamic measurements were similar across layers of SES. Nevertheless, there were some indications of worse haemodynamics in patients with lower household income or a high accumulated burden of socioeconomic deprivation. Particular attention may be warranted in socioeconomically deprived patients to ensure timely referral for advanced HF evaluation.

Objectives: The aim was to investigate the advanced hemodynamic effects of the two MAP-targets during intensive care on systemic hemodynamics in comatose patients after cardiac arrest. Design: Secondary analysis of a randomized controlled trial. Setting: Primary vasopressor used was per protocol norepinephrine. Hemodynamic monitoring was done with pulmonary artery catheters (PAC) and measurements were made on predefined time points. The primary endpoint of this substudy was the difference in cardiac index within 48 h from a repeated measurements-mixed model. Secondary endpoints included systemic vascular resistance index (SVRI), heart rate, and stroke volume index. Patients: Comatose survivors after out-of-hospital cardiac arrest. Interventions: The "Blood pressure and oxygenations targets after out-of-hospital cardiac arrest (BOX)"-trial was a randomized, controlled, double-blinded, multicenter-study comparing targeted mean arterial pressure (MAP) of 63 mmHg (MAP63) vs 77 mmHg (MAP77). Measurements and main results: Among 789 randomized patients, 730 (93%) patients were included in the hemodynamic substudy. From PAC-insertion (median 1 hours after ICU-admission) and the next 48 hours, the MAP77-group received significantly higher doses of norepinephrine (mean difference 0.09 mu g/kg/min, 95% confidence interval (CI) 0.07-0.11, p(group) < 0.0001). Cardiac index was significantly increased (0.20 L/min/m(2) (CI 0.12-0.28), p(group) < 0.0001) as was SVRI with an overall difference of (43 dynes m(2)/s/cm5 (CI 7-79); p(group) = 0.02). Heart rate was increased in the MAP77-group (4 beats/minute; CI 2-6, p(group) < 0.003), but stroke volume index was not (p(group )= 0.10). Conclusions: Targeted MAP at 77 mmHg compared to 63 mmHg resulted in a higher dose of norepinephrine, increased cardiac index and SVRI. Heart rate was also increased, but stroke volume index was not affected by a higher blood pressure target.

AbstractImportanceGlucagon-like peptide-1 (GLP-1) agonists have been proven beneficial in reducing risk of and injury associated with several cardiovascular diseases. The efficacy in cardiopulmonary bypass (CPB)-assisted cardiac surgery is unknown.ObjectiveThis trial aimed to investigate the efficacy of an infusion of the GLP-1 antagonist Exenatide during and after open heart surgery in reducing risk of death and major organ failure.DesignRandomized, double-blinded, 2-by-2 factorial design, clinical trial, also including liberal (FiO2 of 100%) or restrictive (FiO2 of 50%) oxygenation during and after bypass. The present paper presents the results of the Exenatide intervention.SettingSingle site, tertiary heart center.ParticipantsAdult patients undergoing elective cardiopulmonary bypass-assisted coronary artery bypass grafting and/or aortic valve replacement.InterventionInfusion of 17.4 µg og Exenatide or placebo during cardiopulmonary bypass and the first hour after weaning thereofMain outcomesThe main outcome was time to a composite endpoint consisting of death, stroke, renal failure requiring dialysis, or new/worsening heart failure during follow-up. Secondary endpoints included occurrence of prespecified adverse events.ResultsA total of 1389 patients were included in the analyses. Within a follow-up period of median of 5.9 years (min – max; 2.5 – 8.3 years), 170 patients (24%) in the Exenatide group and 165 patients (24%) experienced a primary endpoint. We found no difference in time to first event between patients randomized to FiO250% versus FiO2100% (HR 1.0 [95%CI 0.83 – 1.3],p= 0.80). We found no significant difference in rates of adverse events between the two groups.Conclusions and RelevanceExenatide during cardiopulmonary bypass and weaning thereof did not significantly reduce the incidence of death, stroke, renal failure, or new/worsening heart failure in patients undergoing coronary artery bypass grafting and/or aortic valve replacement.Trial registrationDanish Medicines Agency: Protocol no. HJE-PHARMA-001, EudraCT no. 2015-003050-41, 2ndof October 2015Local Ethics Committee “Videnskabsetisk komité C, Region Hovedstaden”: No. H-15010562www.clinicaltrials.gov: ID no. NCT0267393Key PointsQuestionIs a single dose of Exenatide effectively reducing risk of death or major organ injury in patients undergoing cardiopulmonary bypass (CPB)-assisted cardiac surgery?Findings1400 patients undergoing coronary artery bypass grafting and/or aortic valve replacement were randomized to 17,4 µg of Exenatide or placebo during CPB and the first hour after weaning. The hazard ratio (95%CI) for time to the first occurring composite endpoint consisting of death, stroke, renal failure requiring dialysis, and new/worsening heart failure was 1.0 (0.83 – 1.3).MeaningExenatide infusion during CPB-assisted cardiac surgery does not improve outcomes.

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.) In a randomized trial involving patients with STEMI and cardiogenic shock, mortality at 6 months was lower with mechanical circulatory support with a microaxial flow pump than with standard care alone.

BACKGROUND:Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking. METHODS:We randomly assigned comatose patients who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months. RESULTS:A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS:Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Background: β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. Methods: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III–IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week’s treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. Results: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07–0.75] L/min/BSA; P =0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (−1.6 [CI, −0.4 to −2.8] Wood units; P =0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. Conclusions: Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: 2016-002367-34.

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.

Background: Factors determining referral for advanced heart failure (HF) evaluation are poorly studied. We studied the influence of socioeconomic aspects on the referral process in Denmark, which has a taxpayer-funded national health care system. Methods: We identified all patients aged 18 to 75 years with a first diagnosis of HF during 2010 to 2018. Hospitalized patients had to be discharged alive and were then followed for the outcome of undergoing a right heart catheterization (RHC) used as a surrogate marker of advanced HF work-up. Results: Of 36 637 newly diagnosed patients with HF, 680 (1.9%) underwent RHC during the follow-up period (median time to RHC of 280 days [interquartile range, 73-914]). Factors associated with a higher likelihood of RHC included the highest versus lowest household income quartile (HR, 1.56 [95% CI, 1.19-2.06]; P=0.001), being diagnosed with HF at a tertiary versus nontertiary hospital (HR, 1.68 [95% CI, 1.37-2.05]; P<0.001) and during a hospitalization versus outpatient visit (HR, 1.67 [95% CI, 1.42-1.95]; P<0.001). Level of education, occupational status, and distance to tertiary hospital were not independently associated with RHC. Older age, cancer, and a psychiatric diagnosis were independently associated with a decreased probability of RHC. Conclusions: Higher household income, HF diagnosis during hospitalization, and first admission at a tertiary hospital were associated with increased likelihood of subsequent referral for RHC independent of other demographic and clinical variables. Greater attention may be required to ensure timely referral for advanced HF therapies in lower income groups.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by high propensity to life-threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to ARVC reside in the PKP2 gene, which encodes the PKP2 protein (plakophilin-2). Methods: We describe a comprehensive characterization of the ARVC molecular landscape as determined by high-resolution mass spectrometry, RNA sequencing, and transmission electron microscopy of right ventricular biopsy samples obtained from patients with ARVC with PKP2 mutations and left ventricular ejection fraction >45%. Samples from healthy relatives served as controls. The observations led to experimental work using multiple imaging and biochemical techniques in mice with a cardiac-specific deletion of Pkp2 studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Results: Samples from patients with ARVC present a loss of nuclear envelope integrity, molecular signatures indicative of increased DNA damage, and a deficit in transcripts coding for proteins in the electron transport chain. Mice with a cardiac-specific deletion of Pkp2 also present a loss of nuclear envelope integrity, which leads to DNA damage and subsequent excess oxidant production (O-2(.-) and H2O2), the latter increased further under mechanical stress (isoproterenol or exercise). Increased oxidant production and DNA damage is recapitulated in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Furthermore, PKP2-deficient cells release H2O2 into the extracellular environment, causing DNA damage and increased oxidant production in neighboring myocytes in a paracrine manner. Treatment with honokiol increases SIRT3 (mitochondrial nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-3) activity, reduces oxidant levels and DNA damage in vitro and in vivo, reduces collagen abundance in the right ventricular free wall, and has a protective effect on right ventricular function. Conclusions: Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of ARVC. We show transcriptional downregulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease (before loss of left ventricular ejection fraction <45%), which associates with increased oxidant production (O-2(.-) and H2O2). We propose therapies that limit oxidant formation as a possible intervention to restrict DNA damage in ARVC.

Diastolic dysfunction (DD) in heart failure is associated with increased myocardial cytosolic calcium and calcium-efflux through the sodium-calcium exchanger depends on the sodium gradient. Beta-3-adrenoceptor (beta 3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, beta 3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction, New York Heart Association II-III, and left ventricular ejection fraction <40% to receive the beta 3-AR agonist mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended heart failure therapy. We performed echocardiography and cardiac computed tomography and measured N-terminal probrain natriuretic peptide at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59 +/- 11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between the groups by echocardiography (E/e ' placebo: 13 +/- 7 to 13 +/- 5, P = 0.21 vs. mirabegron: 12 +/- 6 to 13 +/- 8, P = 0.74, between-group follow-up difference 0.2 [95% CI, -3 to 4], P = 0.89) or cardiac computed tomography (left atrial volume index: between-group follow-up difference 9 mL/m(2 )[95% CI, -3 to 19], P = 0.15). DD gradings did not change within or between the groups following 2 algorithms (P = 0.72, P = 0.75). N-terminal probrain natriuretic peptide remained unchanged in both the groups (P = 0.74, P = 0.64). In patients with HF with reduced ejection fraction, no changes were identified in diastolic measurements, gradings or biomarker after beta 3-AR stimulation compared with placebo. The findings add to the previous literature questioning the role of impaired Na+-Ca2+-mediated calcium export as a major culprit in DD. NCT01876433.

Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2 according to the principle of Fick (VO2 = cardiac output*arteriovenous oxygen content difference). DO2 was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2 was 169 ± 59 mL O2 per minute in TTM33 and 217 ± 53 mL O2 per minute in TTM36 (p < 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2 minute (95% confidence interval [CI]: 31-74, pgroup < 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2 between the groups. DO2 was overall 277 mL O2 per minute (95% CI: 175-379, pgroup < 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: -0.1 to 5, pgroup = 0.09]). VO2 during the first 36 hours after OHCA correlated significantly with temperature, and VO2 was 19 mL O2 per minute lower per degree reduction in temperature (95% CI: 15-22), p < 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2 and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2 fell by 19 mL O2 per minute.

Background: Somatostatin inhibits intestinal motility and hormonal secretion and is a potent arterial vasoconstrictor of the splanchnic blood flow. It is unknown if somatostatin concentrations are associated with central hemodynamic measurements in patients with advanced heart failure (HF). Methods: A prospective study of HF patients with a left ventricular ejection fraction (LVEF) <45% referred to right heart catheterization (RHC) for evaluation for heart transplantation (HTX) or left ventricular assist device (LVAD). Results: Fifty-three patients were included with mean LVEF 18 ± 8% and majority in NYHA-class III–IV (79%). Median plasma somatostatin concentration was 18 pmol/L. In univariable regression analysis, log(somatostatin) was associated with increased central venous pressure (CVP; r2 = 0.14, p = 0.003) and a reduced cardiac index (CI; r2 = 0.15, p = 0.004). When adjusted for selected clinical variables (age, gender, LVEF, eGFR and BMI), log(somatostatin) remained a significant predictor of CVP (p = 0.044). Increased somatostatin concentrations predicted mortality in multivariable models (hazard ratio: 5.2 [1.2–22.2], p = 0.026) but not the combined endpoint of death, LVAD implantation or HTX. Conclusions: Somatostatin concentrations were associated with CVP and CI in patients with HF. The pathophysiological mechanism may be related to congestion and/or hypoperfusion of the intestine. Somatostatin was an independent predictor of mortality in advanced HF.

Acute heart failure is a common and severe condition in Danish emergency hospitals. Hypertensive pulmonary oedema, cardiogenic shock and congestive heart failure are the most common phenotypes. The aim of this review is to summarise the most recent international guidelines for acute triage and treatment of acute heart failure. Afterload is reduced with nitrates, congestion is treated with intravenous loop-diuretics, and in selected patients, cardiac output could be increased by inotropic drugs or mechanical support devices.

BACKGROUND:Noninvasive screening for cardiac allograft vasculopathy (CAV) instead of invasive coronary angiography (ICA) within the first 3 to 5 years after heart transplantation (HTx) is controversial. We evaluated a strategy of intravascular ultrasound (IVUS)-guided conversion to early noninvasive screening post-HTx.METHODS:A single-center study of 103 consecutive HTx recipients from 2008 to 2018 undergoing ICA at 1 year post-HTx. Of 88 patients with normal 1-year ICA, sixty-six patients underwent IVUS examination for risk stratification by maximal intimal thickness (MIT) into (i) low-risk group (MIT < 0.5 mm) (n = 41, 62%) followed noninvasively versus (ii) high-risk group (MIT ≥ 0.5 mm) (n = 25, 38%) followed with yearly ICA. Both groups underwent ICA at year 5 post-HTx. We evaluated a combined endpoint of angiographic CAV and death at 5-year follow-up post-HTx.RESULTS:Median (IQR) age was 51 (33-60) years, and 62% were male. Follow-up was 1443 (1125-1456) days. Survival free from angiographic CAV (Kaplan-Meier) differed significantly between groups (log-rank p < .0001). A subgroup of 27 patients completed ICA at year 5, and the proportion of angiographic CAV was significantly lower in low-risk patients (p < .0001).CONCLUSION:IVUS-guided selection for early noninvasive CAV screening appears to be safe and holds promise as a novel strategy for early risk stratification and CAV surveillance post-HTx.

Objective. To examine how liver function (LF) relates to invasive hemodynamics cross-sectionally and longitudinally, in advanced heart failure (AHF) patients treated with maximally tolerated medical HF therapy. Design. A retrospective study of 309 consecutive AHF patients with a left ventricular ejection fraction < 45% treated with maximally tolerated medical HF therapy who were referred for AHF therapies. All patients underwent right heart catheterization (RHC) using Swan-Ganz catheters. Cardiac output was measured using thermodilution. Measurements of pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), cardiac index (CI) and mean arterial pressure (MAP) were obtained. RHC and evaluation of LF were repeated (median (IQR) = 186.5 (150-208) days) in 33 patients. Results. Mean (SD) age was 50 (+/- 13) years, and 239 (77%) were men. Only 22 (7%) were treated with inotropes, and none were receiving mechanical circulatory support. Median (IQR) plasma alanine transaminase (ALT) was 32 (22-53) U/l, alkaline phosphatase (ALP) 82 (63-122) U/l, bilirubin 14 (9-22) mu mol/l, albumin 39 (35-43) g/l, lactate dehydrogenase 212 (175-275) U/l, and the prothrombin time/International Normalized Ratio (PT/INR) 1.1 (1.0-1.3). In multivariate analyses significant associations between LF tests and hemodynamics were seen for CVP: ALP (beta = 0.031, p = .0002), bilirubin (beta = 0.027, p = .004), and INR (beta = 0.013, p = .002). PCWP (beta = 0.020, p = .002) and CI (beta = -0.17, p = .005) were also associated with bilirubin. Over time, changes in bilirubin correlated positively with changes in CVP (beta = 1.496, p = .005). Conclusion. In optimally treated AHF patients, CVP was associated with both markers of biliary excretion and liver synthesis function, whereas changes in CVP were associated with changes in markers of biliary excretion. Decongestion may improve measures of LF in AHF.