Search

BACKGROUND: Heart transplantation in donation after circulatory death (DCD) relies on warm perfusion using either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion. In this study, we explore an alternative: oxygenated hypothermic machine perfusion (HMP) using a novel clinically applicable perfusion system, which is compared to NRP with static cold storage (SCS).METHODS: In a porcine model, a DCD setting was simulated, followed by either (1) NRP and SCS (2) NRP and HMP with the XVIVO Heart preservation system or (3) direct procurement (DPP) and HMP. After preservation, heart transplantation (HTX) was performed. After weaning from cardiopulmonary bypass (CPB), biventricular function was assessed by admittance and Swan-Ganz catheters.RESULTS: Only transplanted hearts in the HMP groups showed significantly increased biventricular contractility (end-systole elastance) 2 hour post-CPB (left ventricle absolute change: NRP HMP: +1.8 ± 0.56, p = 0.047, DPP HMP: +1.5 ± 0.43, p = 0.045 and NRP SCS: +0.97 ± 0.47 mmHg/ml, p = 0.21; right ventricle absolute change: NRP HMP: +0.50 ± 0.12, p = 0.025, DPP HMP: +0.82 ± 0.23, p = 0.039 and NRP SCS: +0.28 ± 0.26, p = 0.52) while receiving significantly less dobutamine to maintain a cardiac output >4l/min compared to SCS. Diastolic function was preserved in all groups. Post-HTX, both HMP groups showed significantly less increments in plasma troponin T compared to SCS.CONCLUSION: In DCD HTX, increased biventricular contractility post-HTX was only observed in hearts preserved with HMP. In addition, the need for inotropic support and signs of myocardial damage were lower in the HMP groups. DCD HTX can be successfully performed using DPP followed by preservation with HMP in a preclinical setting.

BackgroundCardiac resynchronization therapy (CRT) improves symptoms, health-related quality of life and long-term survival in patients with systolic heart failure (HF) and shortens QRS duration. However, up to one third of patients attain no measurable clinical benefit from CRT. An important determinant of clinical response is optimal choice in left ventricular (LV) pacing site. Observational data have shown that achieving an LV lead position at a site of late electrical activation is associated with better clinical and echocardiographic outcomes compared to standard placement, but mapping-guided LV lead placement towards the site of latest electrical activation has never been investigated in a randomized controlled trial (RCT). The purpose of this study was to evaluate the effect of targeted positioning of the LV lead towards the latest electrically activated area. We hypothesize that this strategy is superior to standard LV lead placement.MethodsThe DANISH-CRT trial is a national, double-blinded RCT (ClinicalTrials.gov NCT03280862). A total of 1000 patients referred for a de novo CRT implantation or an upgrade to CRT from right ventricular pacing will be randomized 1:1 to receive conventional LV lead positioning preferably in a non-apical posterolateral branch of the coronary sinus (CS) (control group) or targeted positioning of the LV lead to the CS branch with the latest local electrical LV activation (intervention group). In the intervention group, late activation will be determined using electrical mapping of the CS. The primary endpoint is a composite of death and non-planned HF hospitalization. Patients are followed for a minimum of two years and until 264 primary endpoints occurred. Analyses will be conducted according to the intention-to-treat principle. Enrollment for this trial began in March 2018, and per April 2023, a total of 823 patients have been included. Enrollment is expected to be complete by mid-2024.ConclusionsThe DANISH-CRT trial will clarify whether mapping-guided positioning of the LV lead according to the latest local electrical activation in the CS is beneficial for patients in terms of reducing the composite endpoint of death or non-planned hospitalization for heart failure. Results from this trial are expected to impact future guidelines on CRT. Background: Cardiac resynchronization therapy (CRT) improves symptoms, health-related quality of life and long-term survival in patients with systolic heart failure (HF) and shortens QRS duration. However, up to one third of patients attain no measurable clinical benefit from CRT. An important determinant of clinical response is optimal choice in left ventricular (LV) pacing site. Observational data have shown that achieving an LV lead position at a site of late electrical activation is associated with better clinical and echocardiographic outcomes compared to standard placement, but mapping-guided LV lead placement towards the site of latest electrical activation has never been investigated in a randomized controlled trial (RCT). The purpose of this study was to evaluate the effect of targeted positioning of the LV lead towards the latest electrically activated area. We hypothesize that this strategy is superior to standard LV lead placement. Methods: The DANISH-CRT trial is a national, double-blinded RCT (ClinicalTrials.gov NCT03280862). A total of 1,000 patients referred for a de novo CRT implantation or an upgrade to CRT from right ventricular pacing will be randomized 1:1 to receive conventional LV lead positioning preferably in a nonapical posterolateral branch of the coronary sinus (CS) (control group) or targeted positioning of the LV lead to the CS branch with the latest local electrical LV activation (intervention group). In the intervention group, late activation will be determined using electrical mapping of the CS. The primary endpoint is a composite of death and nonplanned HF hospitalization. Patients are followed for a minimum of 2 years and until 264 primary endpoints occurred. Analyses will be conducted according to the intention-to-treat principle. Enrollment for this trial began in March 2018, and per April 2023, a total of 823 patients have been included. Enrollment is expected to be complete by mid-2024. Conclusions: The DANISH-CRT trial will clarify whether mapping-guided positioning of the LV lead according to the latest local electrical activation in the CS is beneficial for patients in terms of reducing the composite endpoint of death or nonplanned hospitalization for heart failure. Results from this trial are expected to impact future guidelines on CRT. ClinicalTrials.gov identifier: NCT03280862.

Ex vivo lung perfusion (EVLP), is a platform that allows simultaneous testing and treatment of the lungs. However, use of EVLP is costly and requires access to lab animals and accompanying facilities. To increase the use of EVLP for research, we developed a method to perform EVLP using abattoir procured lungs. Furthermore, we were also able to significantly decrease costs.Six pair of lungs were procured from abattoir sheep. The lungs were then flushed and stored in ice for 3 h. A low-flow (20% of cardiac output) approach, a tidal volume of 6 ml/kg bodyweight and total perfusion time of 3 h were chosen. Perfusion fluids and circuits were self-made. Lung biopsies, perfusate collection, respiratory values, circulatory pressures were recorded and hourly blood gas analyses were performed.Mean pOSheep lungs, acquired from an abattoir, can be ex vivo perfused under similar conditions as lab animal lungs with similar results regarding e.g., oxygenation and ATP restoration. Furthermore, costs can be significantly reduced by making use of this abattoir model. By increasing accessibility and lowering costs for experiments using lung perfusion, more results may be achieved in the field of lung diseases.

Background. The hemodynamic effects of aortic arch vessel (AAV) clamping during normothermic regional perfusion (NRP) in donation after circulatory death is unknown. We investigated effects of AAV clamping during NRP compared with no clamping in a porcine model.Methods. In 16 pigs, hemodynamic parameters were recorded including biventricular pressure-volume measurements and invasive blood pressure. Additionally, blood gas parameters and inflammatory cytokines were used to assess the effect of AAV clamping. The animals were centrally cannulated for NRP, and baseline measurements were obtained before hypoxic circulatory arrest was induced by halting mechanical ventilation. During an 8-min asystole period, the animals were randomized to clamp (n = 8) or no-clamp (n = 8) of the AAV before commencement of NRP. During NRP, circulation was supported with norepinephrine (NE) and dobutamine. After 30 min of NRP, animals were weaned and observed for 180 min post-NRP.Results. All hearts were successfully reanimated and weaned from NRP. The nonclamp groups received significantly more NE to maintain a mean arterial pressure >60 mm Hg during and after NRP compared with the clamp group. There were no between group differences in blood pressure or cardiac output. Pressure-volume measurements demonstrated preserved cardiac function‚ including ejection fraction and diastolic and systolic function. No between group differences in inflammatory markers were observed.Conclusions. AAV clamping did not negatively affect donor cardiac function or inflammation after circulatory death and NRP. Significantly less NE was used to support in the clamp group than in the nonclamp group.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (NRP) is a new method for in situ reperfusion and reanimation of potential donor organs in donation after circulatory death by reperfusion of the thoracic and abdominal organs with oxygenated blood. We investigated effects of high oxygenation (HOX) versus low oxygenation (LOX) during NRP on donor heart function in a porcine model.METHODS: Pigs (80 kg) underwent a 15-min anoxic cardiac arrest followed by cardiac reanimation on NRP using a heart-lung bypass machine with subsequent assessment 180 minutes post-NRP. The animals were randomized to HOX (FiO2 1.0) or LOX (FiO2 0.21 increased to 0.40 during NRP). Hemodynamic data were obtained by invasive blood pressure and biventricular pressure-volume measurements. Blood gases, biomarkers of inflammation, and oxidative stress were measured.RESULTS: Eight of 9 animals in the HOX group and 7 of 10 in the LOX group were successfully weaned from NRP. Right ventricular end-systole elastance was significantly improved in the HOX group compared with the LOX group, whereas left ventricular end-systole elastance was preserved at baseline levels. Post-NRP cardiac output, mean arterial, central venous, and pulmonary capillary wedge pressure were all comparable to baseline. Creatinine kinase-MB increased more in the LOX group than the HOX group, whereas proinflammatory cytokines increased more in the HOX group than the LOX group. No difference was found in oxidative stress between groups.CONCLUSIONS: All hearts weaned from NRP showed acceptable hemodynamic function for transplantation. Hearts exposed to LOX showed more myocardial damage and showed poorer contractile performance than hearts reperfused with high oxygen.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival of HTx patients. Mitochondrial dysfunction has been reported in both arteriosclerotic coronary disease and heart failure. However, myocardial mitochondrial function has not been examined in HTx patients with CAV.METHODS: 43 HTx patients (21 patients with CAV and 22 patients without CAV) ≥12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Number and area of mitochondria profiles as well as cristae morphology were assessed by transmission electron microscopy. Echocardiography and coronary angiography were used to measure global longitudinal strain (GLS) and grade CAV.RESULTS: Complex I+II-linked respiration was reduced in patients with CAV compared with patients without CAV (82.7 ± 31.9 pmol O2/(s•mg) vs 116 ± 35.9 pmol O2/(s•mg), p = 0.003). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with left ventricular GLS (r = 0.49, p = 0.002) and negatively associated with elevated biomarkers (Troponin T: r=-0.33, p = 0.04 and NT-proBNP: r = -0.41, p = 0.009). Mitochondrial profile number and area did not differ. However, patients with CAV had a larger proportion of mitochondria with abnormal cristae morphology (p < 0.001).CONCLUSIONS: Myocardial mitochondrial respiration is impaired in patients with CAV and is associated with an abnormal cristae morphology. The mitochondrial dysfunction appears to be associated with reduced myocardial contractile function and elevated biomarkers. These results highlight that mitochondrial targeted treatment in patients with CAV should be assessed in future clinical studies.

BACKGROUND: Survival after heart transplantation has increased due to continuously refined and effective care management. Knowledge is sparse on the influence of multimorbidity and social vulnerability on management. We assessed the long-term influence of multimorbidity and socioeconomic factors on cross-sectional health care service utilization in heart transplant recipients.METHODS: First-time heart transplant recipients, from the Transplant Center at Aarhus University Hospital, were followed from transplant until December 31, 2018. We linked individual-level data from the Scandiatransplant Database to Danish national registers. We followed recipients for 15 years using descriptive statistic.RESULTS: We identified 325 recipients; 79% were male and 60% were between 41 and 60 years of age. The median (IQR) number of chronic conditions at baseline was 1.0 (1.0-2.0). The prevalence of recipients with ≥3 chronic conditions in the follow-up period 0 to 1 year was 10% and 65% within 10 to 15 years. The median use of cross-sectional health care services was higher in recipients with ≥3 chronic conditions compared to CONCLUSIONS: The use of cross-sectional health care services was higher in heart transplant recipients with increased incidence of comorbidities during follow-up intervals. A socioeconomic influence was observed in the utilization of services.

Background: Identification of patients with nonischemic cardiomyopathy who may benefit from prophylactic implantation of a cardioverter-defibrillator. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients who will benefit from prophylactic implantable cardioverter defibrillator (ICD) implantation. Methods: We performed a post hoc analysis of DANISH (Danish ICD Study in Patients With Dilated Cardiomyopathy), in which patients with nonischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤35%, and elevated NT-proBNP (N-terminal probrain natriuretic peptides) were randomized to ICD implantation or control group. Patients were included in the PRD substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00–06:00). PRD was assessed using wavelet analysis according to previously validated methods. The primary end point was all-cause mortality. Cox regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes, cardiac resynchronization therapy, and mean heart rate. We proposed PRD ≥10 deg 2 as an exploratory cut-off value for ICD implantation. Results: A total of 748 of the 1116 patients in DANISH qualified for the PRD substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group ( P =0.40). In Cox regression analysis, PRD was independently associated with mortality (hazard ratio [HR], 1.28 [95% CI, 1.09–1.50] per SD increase; P =0.003). PRD was significantly associated with mortality in the control group (HR, 1.51 [95% CI, 1.25–1.81]; P P =0.71). There was a significant interaction between PRD and the effect of ICD implantation on mortality ( P =0.008), with patients with higher PRD having greater benefit in terms of mortality reduction. ICD implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10 deg 2 (HR, 0.54 [95% CI, 0.34–0.84]; P =0.006; number needed to treat=6), but not in the 468 patients with PRD 2 (HR, 1.17 [95% CI, 0.77–1.78]; P =0.46; P for interaction=0.01). Conclusions: Increased PRD identified patients with nonischemic cardiomyopathy in whom prophylactic ICD implantation led to significant mortality reduction.

Optical Coherence Tomography (OCT) is an intravascular imaging modality enabling detailed evaluation of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). However, its clinical application remains hampered by time-consuming manual quantitative analysis. We aimed to validate a semi-automated quantitative OCT analysis software (Iowa Coronary Wall Analyzer, ICWA-OCT) to improve OCT-analysis in HTx patients. 23 patients underwent OCT evaluation of all three major coronary arteries at 3 months (3M) and 12 months (12M) after HTx. We analyzed OCT recordings using the semiautomatic software and compared results with measurements from a validated manual software. For semi-automated analysis, 31,228 frames from 114 vessels were available. The validation was based on a subset of 4287 matched frames. We applied mixed model statistics to accommodate the multilevel data structure with method as a fixed effect. Lumen (minimum, mean, maximum) and media (mean, maximum) metrics showed no significant differences. Mean and maximum intima area were underestimated by the semi-automated method (β-method mean = − 0.289 mm 2, p < 0.01; β-method max = − 0.695 mm 2, p < 0.01). Bland–Altman analyses showed increasing semi-automatic underestimation of intima measurements with increasing intimal extent. Comparing 3M to 12M progression between methods, mean intimal area showed minor underestimation (β-method mean = − 1.03 mm 2, p = 0.04). Lumen and media metrics showed excellent agreement between the manual and semi-automated method. Intima metrics and progressions from 3M to 12M were slightly underestimated by the semi-automated OCT software with unknown clinical relevance. The semi-automated software has the future potential to provide robust and time-saving evaluation of CAV progression.

ObjectiveTo describe characteristics of patients admitted with refractory cardiac arrest for possible extracorporeal cardiopulmonary resuscitation (ECPR) and gain insight into the reasons for refraining from treatment in some.MethodsNationwide retrospective cohort study involving all tertiary centres providing ECPR in Denmark. Consecutive patients admitted with ongoing chest compression for evaluation for ECPR treatment were enrolled. Presenting characteristics, duration of no-flow and low-flow time, end-tidal carbon dioxide (ETCO2), lactate and pH, and recording of reasons for refraining from ECPR documented by the treating team were recorded. Outcomes were survival to intensive care unit admission and survival to hospital discharge.ResultsOf 579 patients admitted with refractory cardiac arrest for possible ECPR, 221 patients (38%) proceeded to ECPR and 358 patients (62%) were not considered candidates. Median prehospital low-flow time was 70 min (IQR 56 to 85) in ECPR patients and 62 min (48 to 81) in no-ECPR patients, p2. The prevailing combination of contributing factors were non-shockable rhythm, low ETCO2, and metabolic derangement or prehospital low-flow time combined with low ETCO2. Survival to discharge was only achieved in six patients (1.7%) in the no-ECPR group.ConclusionsIn this large nationwide study of patients admitted for possible ECPR, two-thirds of patients were not treated with ECPR. The most frequent reasons to abstain from ECPR were long duration of prehospital low-flow time, metabolic derangement and low ETCO2.

Aims Systematic use of patient-reported outcomes (PROs) have the potential to improve quality of care and reduce costs of health care services. We aimed to describe whether PROs in patients diagnosed with heart disease are directly associated with health care costs. Methods and results A national cross-sectional survey including PROs at discharge from a heart centre with 1-year follow-up using data from national registers. We included patients with either ischaemic heart disease (IHD), arrhythmia, heart failure (HF), or valvular heart disease (VHD). The Hospital Anxiety and Depression Scale, the heart-specific quality of life, the EuroQol five-dimensional questionnaire, and the Edmonton Symptom Assessment Scale were used. The economic analysis was based on direct costs including primary, secondary health care, and medical treatment. Patient-reported outcomes were available from 13 463 eligible patients out of 25.241 [IHD (n = 7179), arrhythmia (n = 4322), HF (n = 987), or VHD (n = 975)]. Mean annual total direct costs in all patients were €23 228 (patients with IHD: €19 479, patients with arrhythmia: €21 076, patients with HF: €34 747, patients with VDH: €48 677). Hospitalizations contributed overall to the highest part of direct costs. For patients discharged with IHD or arrhythmia, symptoms of anxiety or depression, worst heart-specific quality of life or health status, and the highest symptom burden were associated with increased economic expenditure. We found no associations in patients with HF or VHD. Conclusion Patient-reported outcomes at discharge from a heart centre were associated with direct health care costs in patients with IHD and arrhythmia. Registration ClinicalTrials.gov: NCT01926145.

BACKGROUND: After heart transplantation (HTx), invasive coronary angiography is gold standard for surveillance of cardiac allograft vasculopathy (CAV). Non-invasive CAV surveillance is desirable.PURPOSE: We examined left ventricular global longitudinal strain (LVGLS) and non-invasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after heart transplantation (HTx).METHODS: Echocardiographic Doppler coronary flow velocity reserve (CFVR) and left ventricular global longitudinal strain (LVGLS) were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE) including hospitalization due to heart failure, cardiovascular death and significant CAV progression, were recorded.RESULTS: Median follow-up was 3.3 (range 1.7-5.4) years. Patients with low CFVR (CONCLUSIONS: In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx-patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx-patients.

Background: Men and women may respond differently to certain therapies for heart failure with reduced ejection fraction, including implantable cardioverter defibrillators (ICD). In an extended follow-up study of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heart Failure on Mortality), adding 4 years of additional follow-up, we examined the effect of ICD implantation according to sex. Methods: In the DANISH trial, 1116 patients with nonischemic systolic heart failure were randomized to receive an ICD (N=556) or usual clinical care (N=550). The primary outcome was all-cause mortality. Results: Of the 1116 patients randomized in the DANISH trial, 307 (27.5%) were women. During a median follow-up of 9.5 years, women had a lower associated rate of all-cause mortality (hazard ratio [HR], 0.60 [95% CI, 0.47–0.78]) cardiovascular death (HR, 0.62 [95% CI, 0.46–0.84]), nonsudden cardiovascular death (HR, 0.59 [95% CI, 0.42–0.85]), and a numerically lower rate of sudden cardiovascular death (HR, 0.70 [95% CI, 0.40–1.25]), compared with men. Compared with usual clinical care, ICD implantation did not reduce the rate of all-cause mortality, irrespective of sex (men, HR, 0.85 [95% CI, 0.69–1.06]; women, HR, 0.98 [95% CI, 0.64–1.50]; P interaction=0.51). In addition, sex did not modify the effect of ICD implantation on sudden cardiovascular death (men, HR, 0.57 [95% CI, 0.36–0.92]; women, HR, 0.68 [95% CI, 0.26–1.77]; P interaction=0.76). Conclusions: In patients with nonischemic systolic heart failure, ICD implantation did not provide an overall survival benefit, but reduced sudden cardiovascular death, irrespective of sex. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00542945.

BACKGROUND: The incidence of sudden cardiac death (SCD) following heart transplantation (HTx) accounts for approximately 10% of post-HTx deaths. Ischemia, brady- and tachy-arrhythmias caused by rejection and cardiac allograft vasculopathy (CAV) seem related to SCD. Hence, we aimed to investigate the relation between CAV, arrhythmias and silent ischemia in long-term HTx patients. Methods: 49 HTx patients were included. Patients were CAV-classified in accordance with guidelines from the International Society of Heart and Lung Transplantation. Patients were divided into predefined CAV groups (CAV 0, CAV 1, CAV 2 + 3). Incidences of arrhythmia and silent ischemia were detected by 48-h electrocardiogram monitoring and analyzed blinded to CAV-status. Results: Median time since transplantation was 9 years [IQR 4-14]. We observed a higher incidence of non-sustained ventricular tachycardia (NSVT) in CAV 2 + 3 patients than CAV 0 and 1 patients (p = 0.01). Likewise, isolated premature ventricular complexes (PVC) (p =0 .01) and PQ-interval prolongation (p = .01) were more frequent in CAV 2 + 3 patients than CAV 0 and 1 patients. Silent ischemia was only observed among CAV 3 patients (p = 0.04). We saw no significant difference in the incidence of supraventricular tachycardia among CAV groups (p = 0.21). Likewise, no difference in the right bundle branch block was observed (p = 0.68). Conclusion: NSVT was associated with CAV status in long-term HTx patients. Patients with moderate to severe CAV showed higher incidences of PVCs and PQ-interval prolongation than patients with mild or no CAV. Silent ischemia was only seen in patients with severe CAV.

Heart transplantation (HTx) remains the optimal treatment for selected patients with end-stage advanced heart failure. However, survival is limited early by acute rejection and long term by cardiac allograft vasculopathy (CAV). Even though the diagnosis of rejection is based on histology, cardiac imaging provides a pivotal role for early detection and severity assessment of these hazards. The present review focuses on the use and reliability of different invasive and non-invasive imaging modalities to detect and monitor CAV and rejection after HTx. Coronary angiography remains the corner stone in routine CAV surveillance. However, angiograms are invasive and underestimates the CAV severity especially in the early phase. Intravascular ultrasound and optical coherence tomography are invasive methods for intracoronary imaging that detects early CAV lesions not evident by angiograms. Non-invasive imaging can be divided into myocardial perfusion imaging, anatomical/structural imaging and myocardial functional imaging. The different non-invasive imaging modalities all provide clinical and prognostic information and may have a gatekeeper role for invasive monitoring. Acute rejection and CAV are still significant clinical problems after HTx. No imaging modality provides complete information on graft function, coronary anatomy and myocardial perfusion. However, a combination of invasive and non-invasive modalities at different stages following HTx should be considered for optimal personalized surveillance and risk stratification.

This is a case report of a 29-year-old woman who obtained pregnancy two and a half years after a heart transplant due to Danon syndrome. Pregnancy was planned and spontaneous. The fetus did not have Danon syndrome. At the frequent pregnancy visits, maternal echocardiography and fetal ultrasound examinations were reassuring. In gestational week 36+6, high blood pressure and subjective symptoms of severe pre-eclampsia occurred. A healthy boy (3,070 g) was born after an acute caesarean section. Blood pressure normalized rapidly, and the family was discharged on day four after delivery.

UNLABELLED: Advanced heart failure patients often have comorbidities of prognostic importance. However, whether total pretransplantation comorbidity burden predicts mortality in patients treated with heart transplantation (HTx) is unknown. We used population-based hospital and prescription data to examine the ability of the Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI), DANCAMI restricted to noncardiovascular diseases, Charlson Comorbidity Index, and Elixhauser Comorbidity Index to predict 30-d, 1-y, 5-y, and 10-y all-cause and cardiovascular mortality after HTx.METHODS: We identified all adult Danish patients with incident HTx from the Scandiatransplant Database between March 1, 1995, and December 31, 2018 (n = 563). We calculated Harrell's C-Statistics to examine discriminatory performance.RESULTS: The C-Statistic for predicting 1-y all-cause mortality after HTx was 0.58 (95% confidence interval [CI], 0.50-0.65) for a baseline model including age and sex. Adding comorbidity score to the baseline model did not increase the C-Statistics for DANCAMI (0.58; 95% CI, 0.50-0.65), DANCAMI restricted to noncardiovascular diseases (0.57; 95% CI, 0.50-0.64), Charlson Comorbidity Index (0.59; 95% CI, 0.51-0.66), or Elixhauser Comorbidity Index (0.58; 95% CI, 0.51-0.65). The results for 30-d, 5-y, and 10-y all-cause and cardiovascular mortality were consistent.CONCLUSIONS: After accounting for patient age and sex, none of the commonly used comorbidity indices added predictive value to short- or long-term all-cause or cardiovascular mortality after HTx.

Purpose: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-13C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. Methods: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-13C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. Results: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-13C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. Conclusion: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information—in combination with already established MR methods for cardiac investigation—provides a powerful tool to aid the progress of donor heart preservation.

The cognitive function and quality of life after extracorporeal cardiopulmonary resuscitation (ECPR) remain uncertain. In this case report, a 61-year-old male underwent ECPR for refractory out-of-hospital cardiac arrest after 102 minutes of resuscitation. The cause of cardiac arrest was acute myocardial infarction, and occlusion of the left anterior descending artery was treated with balloon angioplasty. Five years later, the patient had preserved psychical and mental health, cognitive function, and good quality of life despite prolonged cardiopulmonary resuscitation.

AimsThe aim of this study was to evaluate left ventricular global longitudinal strain (LVGLS), N-terminal pro brain natriuretic peptide (Nt-ProBNP), and Troponin T as non-invasive markers for acute cellular rejection (ACR) diagnosis and severity assessment after heart transplantation (HTx).MethodsWe retrospectively included all HTx patients transplanted from 2013 to 2019. At each visit, the patients were subjected to endomyocardial biopsy (EMB), measurement of Nt-ProBNP and Troponin T, and protocoled echocardiography with assessment of LVGLS. Sudden drop in graft function (SDGF) was defined as a drop in LVGLS ≥-2% in combination with either an increase in Troponin T ≥20% or Nt-ProBNP ≥30% compared with levels at the latest visit.ResultsWe included 1,436 EMBs from 83 HTx patients. The biopsies were grouped as 0R (n = 857), 1R (n = 538), and ≥2R (n = 41). LVGLS was lower and Troponin T and Nt-ProBNP higher in the 2R group than in the 0R and 1R groups (LVGLS: -12.9 ± 3.8% versus -16.9 ± 3.1% and -16.1 ± 3.3%; Troponin T: 79 [33;230] ng/l versus 27 [13;77] ng/l and 27 [14;68] ng/l; Nt-ProBNP: 4,174 [1,095;9,510] ng/l versus 734 [309;2,210] ng/l and 725 [305;2,082], all p < 0.01). A SDGF was seen at 45 visits of which 19 had ≥2R ACR. EMBs showed ACR in 20 cases without SDGF. Finally, neither was SDGF seen nor did the EMB show rejection in 1,136 cases. Thus, the sensitivity of SDGF for ≥2R ACR detection was 49% (32–65) and specificity 98% (97–99). The positive predictive value (PPV) was 42% (31–55) and the negative predictive value (NPV) 98% (98–99). The diagnostic value improved in a sub-analysis excluding EMBs within 3 months after HTx, clinically interpreted false positive ≥2R ACR cases, and cases with ≥2R ACR who recently (ConclusionsPatients with ≥2R ACR have lower LVGLS and higher Troponin T and Nt-ProBNP than patients without 2R rejection. A non-invasive model combining changes in LVGLS and Troponin T or Nt-ProBNP showed excellent negative predictive value and moderate sensitivity and may be used as a gatekeeper to invasive biopsies after HTx.

According to the World Health Organization, palliative care must be available for everyone with life-threatening diseases. However, in daily practice the primary focus worldwide is on cancer patients. The aim of the article was to generate a national position statement as the first step in implementing palliative care in severe heart disease with focus on advanced heart failure, including tools to identify the need for and timing of palliative care and how palliative care could be organized in Denmark. A task force was formed in the Danish Society of Cardiology Heart Failure Working Group, and the position statement was prepared in collaboration with members from a broad group of specialties, including palliative medicine. Because of major gaps in evidence, the position statement was based on small and low-quality studies and clinical practice statements. This position statement was aligned with the European Society of Cardiology recommendation, focusing on relieving suffering from the early disease stages parallel to standard care and supplementing life-prolonging treatment. The statement delivers practical guidance on clinical aspects and managing symptoms during the three stages of advanced heart disease. Furthermore, the statement describes the importance of communication and topics to be broached, including deactivating implantable cardioverter defibrillators. The statement recommends a targeted effort on organizational strategies using high-quality assessment tools and emphasizes multidisciplinary and intersectoral collaboration. Danish cardiologists supported by allied professionals acknowledge the importance of palliative care in advanced heart disease. This national position statement intended to inform and influence policy and practice and can hopefully inspire other countries to take action toward implementing palliative care in advanced heart disease.

Percutaneous pulmonary angiography may be used for early diagnosis of pulmonary embolism in the hemodynamic unstable patient. Pulmonary embolectomy is an effective treatment option in patients with acute high‐risk pulmonary embolism.

Objectives: Development of right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation remains a leading cause of perioperative morbidity, end-organ dysfunction and mortality. The objective of this study was to investigate whether the etiology of HF (ischemic HF versus non-ischemic HF) affects the risk of RVF within admission for LVAD implantation and during long-term follow-up. Methods: Between January 2011 and June 27, 2018, 3536 patients were prospectively enrolled into EUROMACS registry. Adult patients (>18 years) who received a first time LVAD were included. When excluding patients with congenital, restrictive, hypertrophic, valvular cardiomyopathies, and myocarditis the total population consisted of 2404 patients. Results: The total cohort consists of 2404 patients. Mean age were 55 years and predominantly male sex [2024 (84.2%)]. At the time of LVAD implantation 1355 (56.4%) patients had ischemic HF and 1049 (43.6%) patients had non-ischemic HF. The incidence of RVF was significantly increased in the non-ischemic HF group in the adjusted model (p = .026). The relative risk difference for RVF in patients with non-ischemic HF was in the adjusted model increased by an absolute value of 5.1% (95% CI: 0.61–9.6). In the ischemic HF group 76 patients (13.4%) developed late RVF and 62 patients (14.8%) in the non-ischemic HF group (p = .56). No differences in occurrence of RVF between HF etiology was observed after 2 and 4 years of follow-up, respectively (crude: p = .25, adjusted (sex and age) p = .2 and crude: p = .59, adjusted (sex and age) p = .44). Conclusions: Patients with non-ischemic HF undergoing LVAD had an increased incidence of early RVF compared to patients with ischemic HF in a large European population. During follow-up after discharge 14% patients developed RVF. We recommend HF etiology to be considered in identifying patients who are at risk for postoperative RVF after LVAD implantation.

Aims Left ventricular (LV) myocardial work index (LVMWI) derived from pressure–strain analysis resembles a novel non-invasive method for LV function evaluation. LV global longitudinal strain (LVGLS) has proven beneficial for risk stratification in cardiac amyloidosis (CA) patients. This study aimed to evaluate the potential additive value of LVMWI for outcome prediction in CA patients. Methods and results We enrolled 100 CA patients in the period 2014–19 from Aarhus University Hospital, Denmark and Uppsala University Hospital, Sweden. All patients underwent comprehensive echocardiographic evaluation and were prospectively followed until censuring date on 31 March 2019 or death. During follow-up, we registered major adverse cardiac events (MACE) comprising heart failure requiring hospitalization and all-cause mortality. The median follow-up was 490 (228–895) days. During follow-up, a total of 42% of patients experienced MACE and 29% died. Patients with LVMWI 1043 mmHg% [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2–4.3; P = 0.01]. Furthermore, patients with LVMWI 1039 mmHg% (HR 2.6, 95% CI 1.2–5.5; P Conclusion LV myocardial work may be of prognostic value in CA patients by predicting both MACE and all-cause mortality.

Background: DANISH (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators [ICDs] in Patients With Nonischemic Systolic Heart Failure on Mortality) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with nonischemic systolic heart failure during a median follow-up of 5.6 years, although there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional 4 years of follow-up data from DANISH. Methods: In DANISH, 556 patients with nonischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years). Results: During a median follow-up of 9.5 years (25th–75th percentile, 7.9–10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (hazard ratio [HR] 0.89, [95% CI, 0.74–1.08]; P = 0.24). In patients ≤70 years (n = 829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] versus 158/440 [36%]; HR, 0.78 [95% CI, 0.61–0.99]; P = 0.04), whereas in patients >70 years (n = 287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] versus 68/120 [57%]; HR, 0.92 [95% CI, 0.67–1.28]; P = 0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] versus 164/560 [29%]; HR, 0.87 [95% CI, 0.70–1.09]; P = 0.20; ≤70 years, 87/389 [22%] versus 122/440 [28%]; HR, 0.75 [95% CI, 0.57–0.98]; P = 0.04; >70 years, 60/167 [36%] versus 42/120 [35%]; HR, 0.97 [95% CI, 0.65–1.45]; P = 0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] versus 57/560 [10%]; HR, 0.60 [95% CI, 0.40–0.92]; P = 0.02) and in patients ≤70 years (19/389 [5%] versus 49/440 [11%]; HR, 0.42 [95% CI, 0.24–0.71]; P = 0.0008), but not in patients >70 years (16/167 [10%] versus 8/120 [7%]; HR, 1.34 [95% CI, 0.56–3.19]; P = 0.39). Conclusions: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with nonischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00542945.

Background Extracorporeal cardiopulmonary resuscitation (ECPR) has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). Despite growing interest in and a growing body of literature on ECPR for refractory OHCA, robust evidence on patient eligibility is still lacking. Purpose To describe the survival, neurological outcome, and adherence to the national consensus with respect to use of ECPR for OHCA, and to identify factors associated with outcome. Methods Retrospective, observational cohort study of patients who underwent ECPR for OHCA at four cardiac arrest centres. Binary logistic regression and Kaplan-Meier survival curves were performed to assess association with 30-day mortality. Results A total of 259 patients receiving ECPR for OHCA between July 2011 and December 2020 were included in the study. Thirty-day survival was 26% and a good neurological outcome Cerebral Performance Category (CPC) 1–2 was observed in 94% of patients at discharge. Strict adherence to the national consensus showed a 30-day survival rate of 30%. Adding one or more of the following criteria to the national consensus: signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow 6.8 and lactate 15 mmol/L (RR 1.16, 95% CI 1.16–1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had threefold higher survival rate than patients without signs of life (45% versus 13%, p Conclusion A high survival rate with a good neurological outcome was observed in this population of patients treated with ECPR for OHCA. Signs of life during CPR may aid the decision-making in the selection of appropriate candidates. Stringent patient selection for ECPR may produce higher survival rates but potentially withholds life-saving treatment in a significant proportion of survivors, why optimization of the selection criteria is still necessary. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This work was supported by the Danish Heart Foundation [20-R142-A9498-22178]; and Health Research Foundation of Central Denmark Region [R64-A3178-B1349] Survival and adherence to consensusSigns of life during CPR

Aims: We aim to evaluate changes in invasive haemodynamics, right ventricular (RV) function, and perfusion during the first year after heart transplantation (HTx) and to determine the relation between RV function and myocardial perfusion. Methods and results: Thirty patients were prospectively enrolled at the time of HTx. Right heart catheterization (RHC), comprehensive 2D and 3D echocardiography and cardiac biomarkers were performed at baseline (≤2 weeks after HTx) and at follow-up 1, 3, 6, and 12 months after HTx. At 12 months, HTx patients were subjected to an exercise stress test with assessment of maximal oxygen consumption (VO 2max). RV myocardial perfusion reserve was evaluated by 15O-H 2O positron emission tomography at baseline and at 3 and 12 months after HTx. A group of 43 healthy subjects served as echocardiographic controls and a subgroup comprising 16 healthy controls underwent exercise stress test with simultaneous RHC. At baseline, HTx patients had higher pulmonary artery wedge pressure (PAWP) and right atrial pressure (RAP) and pulmonary vascular resistance (PVR) than healthy controls whereas cardiac index (CI) was reduced (PAWP; 14 mmHg [8;17] vs. 8 mmHg [7;10]; RAP: 7 mmHg [4;11] vs. 5 mmHg [4;6]; PVR: 1.9 wood units [1.3;2.6] vs. 1.1 wood units [1.0;1.4]; CI 2.4 L/min/m 2 [2.2;2.8] vs. 3.3 L/min/m 2 [2.8;.3.6], all P 2max 12 months after HTx (r = 0.75, P

Objectives This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models. Background It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure. Methods The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial. Results Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction Conclusions Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945)

Supplemental Digital Content is available in the text., Background: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. Methods: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. Results: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM (P

Background Mechanical circulatory support (MCS) with either extracorporeal membrane oxygenation or Impella has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). The objective of this study was to describe the gradual implementation, survival and adherence to the national consensus with respect to use of MCS for OHCA in Denmark, and to identify factors associated with outcome. Methods This retrospective, observational cohort study included patients receiving MCS for OHCA at all tertiary cardiac arrest centers (n = 4) in Denmark between July 2011 and December 2020. Logistic regression and Kaplan–Meier survival analysis were used to determine association with outcome. Outcome was presented as survival to hospital discharge with good neurological outcome, 30-day survival and predictors of 30-day mortality. Results A total of 259 patients were included in the study. Thirty-day survival was 26%. Sixty-five (25%) survived to hospital discharge and a good neurological outcome (Glasgow–Pittsburgh Cerebral Performance Categories 1–2) was observed in 94% of these patients. Strict adherence to the national consensus showed a 30-day survival rate of 30% compared with 22% in patients violating one or more criteria. Adding criteria to the national consensus such as signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow 6.8 and lactate 15 mmol/L (RR 1.16, 95% CI 1.16–1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had reduced risk of 30-day mortality (RR 0.63, 95% CI 0.52–0.76). Conclusions A high survival rate with a good neurological outcome was observed in this Danish population of patients treated with MCS for OHCA. Stringent patient selection for MCS may produce higher survival rates but potentially withholds life-saving treatment in a significant proportion of survivors.

Background Extracorporeal cardiopulmonary resuscitation (ECPR) has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). The objective of this study was to to describe the gradual implementation, survival and adherence to the national consensus with respect to use of ECPR for OHCA in Denmark, and to identify factors associated with outcome. Methods This retrospective, observational cohort study included patients receiving ECPR for OHCA at all tertiary cardiac arrest centers (n = 4) in Denmark between July 2011 and December 2020. Logistic regression and Kaplan-Meier survival analysis were used to determine association with outcome. Outcome was presented as survival to hospital discharge with good neurological outcome, 30-day survival and predictors of 30-day survival. Results A total of 259 patients were included in the study. Thirty-day survival was 26% and a good neurological outcome (Glasgow-Pittsburgh Cerebral Performance Categories (CPC) (CPC 1–2)) was observed in 94% of patients at discharge. Strict adherence to the national consensus showed a 30-day survival rate of 30% compared with 22% in patients violating one or more criteria. Adding criteria to the national consensus such as signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow 6.8 and lactate 15 mmol/L (RR 1.16, 95% CI 1.16–1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had a threefold higher survival rate compared to patients without signs of life (45% versus 13%, p

BackgroundVeno-arterial extracorporeal membrane oxygenation (V-A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on pre-defined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning.MethodsAll patients weaned from ECMO between April 2017 and April 2019 at Aarhus University Hospital, Denmark, were consecutively enrolled. Pre-defined haemodynamic, respiratory and echocardiographic criteria were assessed before and during ECMO flow reduction. A weaning attempt was commenced in haemodynamic stable patients and patients remaining stable at minimal flow were weaned from ECMO. Comparisons were made between patients who met the criteria for weaning at first attempt and patients who did not meet these criteria. Patients completing a full weaning attempt with no further need for mechanical support within 24 hours were defined as successfully weaned. ResultsA total of 38 patients were included in the study, of whom 26 (68 %) patients met the criteria for weaning. Among these patients 25 (96%) could be successfully weaned. Successfully weaned patients were younger, had less need for inotropic support and ECMO duration was shorter. Fulfilling the weaning criteria was associated with successful weaning and both favourable 30-day survival and survival to discharge.ConclusionAn integrative weaning approach based on haemodynamic, respiratory and echocardiographic criteria may strengthen the clinical decision process in predicting successful weaning in patients receiving ECMO for refractory cardiac failure.

BACKGROUND: Atrial fibrillation (AF) in heart failure (HF) patients has been associated with a worse outcome. Similarly, excessive supraventricular ectopic activity (ESVEA) has been linked to development of AF, stroke, and death. This study aimed to investigate AF and ESVEA's association with outcomes and effect of prophylactic implantable cardioverter defibrillator (ICD) implantation in nonischemic HF patients.METHODS: A total of 850 patients with nonischemic HF, left ventricle ejection fraction ≤35%, and elevated N-terminal pro-brain natriuretic peptides underwent 24 hours Holter recording. The presence of AF (≥30 seconds) and ESVEA (≥30 supraventricular ectopic complexes (SVEC) per hour or run of SVEC ≥20 beats) were registered. Outcomes were all-cause mortality, cardiovascular death (CVD), and sudden cardiac death (SCD).RESULTS: AF was identified in 188 patients (22%) and ESVEA in 84 patients (10%). After 4 years and 11 months of follow-up, a total of 193 patients (23%) had died. AF was associated with all-cause mortality (hazard ratio [HR] 1.44; confidence interval [CI] 1.04-1.99; P = .03) and CVD (HR 1.59; CI 1.07-2.36; P = .02). ESVEA was associated with all-cause mortality (HR 1.73; CI 1.16-2.57; P = .0073) and CVD (HR 1.76; CI 1.06-2.92; P = .03). Neither AF nor ESVEA was associated with SCD. ICD implantation was not associated with an improved prognosis for neither AF (P value for interaction = .17), nor ESVEA (P value for interaction = .68).CONCLUSIONS: Both AF and ESVEA were associated with worsened prognosis in nonischemic HF. However, ICD implantation was not associated with an improved prognosis for either group.

Background: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro- and macrovascular CAV and major adverse cardiac events in HTx patients. Methods: We evaluated 91 cardiovascular disease-related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro- and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and 15O-H 2O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death. Results: We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p

Background: Impella CP is a left ventricular pump which may serve as a circulatory support during cardiopulmonary resuscitation (CPR) for cardiac arrest (CA). Nevertheless, the survival rate and factors associated with survival in patients undergoing Impella insertion during CPR for CA are unknown. Methods: We performed a retrospective multicenter international registry of patients undergoing Impella insertion during on-going CPR for in- or out-of-hospital CA. We recorded immediate and 30-day survival with and without neurologic impairment using the cerebral performance category score and evaluated the factors associated with survival. Results: Thirty-five patients had an Impella CP implanted during CPR for CA. Refractory ventricular arrhythmias were the most frequent initial rhythm (65.7%). In total, 65.7% of patients immediately survived. At 30 days, 45.7% of patients were still alive. The 30-day survival rate without neurological impairment was 37.1%. In univariate analysis, survival was associated with both an age &lt, 75 years and a time from arrest to CPR &le, 5 min (p = 0.035 and p = 0.008, respectively). Conclusions: In our multicenter registry, Impella CP insertion during ongoing CPR for CA was associated with a 37.1% rate of 30-day survival without neurological impairment. The factors associated with survival were a young age and a time from arrest to CPR &le, 5 min.

Background: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center. Methods: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives ( P Results: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing. Conclusions: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT).METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years.RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark.CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information-in combination with already established MR methods for cardiac investigation-provides a powerful tool to aid the progress of donor heart preservation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients.METHODS: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4 - 8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2 , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-months' treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound.CONCLUSION: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.

Atrial fibrillation (AF) has traditionally been considered an electrical heart disease. However, genetic studies have revealed that the structural architecture of the heart also play a significant role. We evaluated the functional and structural consequences of harboring a titin-truncating variant (TTNtv) in AF patients, using cardiac magnetic resonance (CMR). Seventeen early-onset AF cases carrying a TTNtv, were matched 1:1 with non-AF controls and a replication cohort of early-onset AF cases without TTNtv, and underwent CMR. Cardiac volumes and left atrial late gadolinium enhancement (LA LGE), as a fibrosis proxy, were measured by a blinded operator. Results: AF cases with TTNtv had significantly reduced left ventricular ejection fraction (LVEF) compared with controls (57 ± 4 vs 64 ± 5%, P

Aims Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD. Methods and results A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low ( Conclusion Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation.

OBJECTIVES: This dual-site study evaluated the diagnostic accuracy of the method.BACKGROUND: Pittsburgh compound ([11C]PIB) positron emission tomography (PIB-PET) has shown promise as a specific and noninvasive method for the diagnosis of cardiac amyloidosis (CA).METHODS: The study had 2 parts. In the initial study, 51 subjects were included, 36 patients with known CA and increased wall thickness (15 immunoglobulin light chain [AL] and 21 transthyretin [ATTR] amyloidosis) and 15 control patients (7 were nonamyloid hypertrophic and 8 healthy volunteers). Subjects underwent PIB-PET and echocardiography. Sensitivity and specificity of PIB-PET were established for 2 simple semiquantitative approaches, standardized uptake value ratio (SUVR) and retention index (RI). The second part of the study included 11 amyloidosis patients (5 AL and 6 hereditary ATTR) without increased wall thickness to which the optimal cutoff values of SUVR (>1.09) and RI (>0.037 min-1) were applied prospectively.RESULTS: The diagnostic accuracy of visual inspection of [11C]PIB uptake was 100% in discriminating CA patients with increased wall thickness from controls. Semiquantitative [11C]PIB uptake discriminated CA from controls with a 94% (95% confidence interval [CI]: 80% to 99%) sensitivity for both SUVR and RI and specificity of 93% (95% CI: 66% to 100%) for SUVR and 100% (95% CI: 75% to 100%) for RI. [11C]PIB uptake was significantly higher in AL-CA than in ATTR-CA patients (p < 0.001) and discriminated AL-CA from controls with 100% (95% CI: 88% to 100%) accuracy for both the semiquantitative measures. In the prospective group without increased wall thickness, RI was elevated compared to controls (p = 0.001) and 5 of 11 subjects were evaluated as [11C]PIB PET positive.CONCLUSIONS: In a dual-center setting, [11C]PIB PET was highly accurate in detecting cardiac involvement in the main amyloid subtypes, with 100% accuracy in AL amyloidosis. A proportion of amyloidosis patients without known cardiac involvement were [11C]PIB PET positive, indicating that the method may detect early stages of CA.

BACKGROUND: Long-term survival after heart transplantation (HTx) is compromised by cardiac allograft vasculopathy (CAV) characterized by coronary macro- and microvascular disease. The pathogenesis of CAV is unclear and may involve coronary thrombosis. We investigated whether HTx patients with CAV had higher platelet aggregation and turnover than HTx patients without CAV and healthy controls. Furthermore, we investigated the anti-platelet effect of low-dose aspirin in HTx patients.METHODS: We included 57 patients who had undergone HTx (median 8.3 years from HTx) and 57 healthy controls. Platelet aggregation was measured on-aspirin and off-aspirin using impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA). We evaluated platelet turnover by flow cytometry, CAV burden by coronary angiography and echocardiography, and microvascular function by echocardiographic coronary flow velocity reserve (CFVR).RESULTS: Off-aspirin, HTx patients with CAV (n = 21) had higher ADP-induced platelet aggregation than healthy controls (p < 0.01) and HTx patients without CAV (n = 36) (p < 0.05). Aspirin treatment reduced AA-induced platelet aggregation in both HTx groups, but HTx patients with CAV had higher platelet aggregation on-aspirin than HTx patients without CAV (p < 0.05). Platelet turnover did not differ between HTx patients with CAV and HTx patients without CAV (p > 0.34). HTx patients with lower CFVR values had higher platelet aggregation than HTx patients with higher CFVR values (p < 0.05).CONCLUSIONS: Off-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV and healthy controls. On-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx patients with CAV.

PURPOSE: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality following heart transplantation (HTx). The pathogenesis is multifactorial and involves inflammation, thrombosis, endothelial dysfunction and immunological factors. Non-invasive biomarkers for the diagnosis of CAV have not yet been identified. We aimed to investigate the relation between micro and macrovascular CAV and a wide range of cardiovascular protein biomarkers. METHODS: Using a novel proximity extension assay (Olink® CARDIOVASCULAR III), blood samples from 48 HTx patients (median 9.1 years after HTx) were analyzed for 92 biomarkers reflecting inflammation, immune response, cell adhesion, hemostasis, fibrinolysis, tissue remodeling, and proteolysis. Patients were dichotomized according to micro and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and coronary flow reserve by (15)O-H2O positron emission tomographic imaging. RESULTS: Twenty-seven patients had angiographic CAV. A total of 13 biomarkers differed significantly between groups (Table 1). In particular, N-terminal prohormone brain natriuretic peptide (NT-proBNP), proprotein convertase subtilisin/kexin type 9 (PCSK9), and paraoxonase 3 (PON3) differed consistently between groups. However, after correcting for multiple testing with Bonferroni correction (p

BACKGROUND: Left ventricular pressure-strain-derived myocardial work index (LVMWI) is a novel, noninvasive method for left ventricular (LV) function evaluation in relation to LV pressure dynamics. LV global longitudinal strain (LVGLS) has proven benefit for diagnosis and risk stratification in patients with cardiac amyloidosis (CA), but LVGLS does not adjust for loading conditions. The aim of the present study was to characterize LVMWI at rest and during exercise in patients with CA.METHODS: A total of 155 subjects were retrospectively included. These subjects comprised 100 patients with CA and 55 healthy control subjects. All patients had previously undergone comprehensive two-dimensional echocardiographic examinations at rest. Furthermore, a subgroup 27 patients with CA and 41 control subjects was examined using semisupine exercise stress echocardiography.RESULTS: Patients with CA had significantly lower LVGLS, LVMWI, and LV myocardial work efficiency (LVMWE) than control subjects (P < .0001 for all). The reduction in LV myocardial performance was more pronounced in the basal segments, which led to significant alterations in the average apical-to-basal segmental ratios between patients with CA and control subjects (LVGLS, 2.6 [1.9 to 4.1] vs 1.3 [1.2 to 1.5]; LVMWI, 2.6 [1.7 to 3.8] vs 1.3 [1.1 to 1.5]; LVMWE, 1.1 [1.0 to 1.3] vs 1.0 [1.0 to 1.1]; P < .0001 for all). The average increase in LVMWI from rest to peak exercise was 1,974 mm Hg% (95% CI, 1,699 to 2,250 mm Hg%; P < .0001) in control subjects and 496 mm Hg% (95% CI, 156 to 835 mm Hg%; P < .01) in patients with CA. The absolute numeric LVGLS increase was 5.6% (95% CI, 3.9% to 7.3%; P < .0001) in control subjects and only 1.2% (95% CI, -0.9% to 3.3%; P = .26) in patients with CA (between groups, P < .0001) from rest to peak exercise. The LVMWI increase in patients with CA was mediated by improvement in the apical segments (P < .0001), whereas there was no significant LVMWI alterations in the midventricular or basal segments. LVMWE remained stable during exercise in control subjects (Δ -0.6%; 95% CI, -2.5% to 1.2%; P = .50) but decreased significantly in patients with CA (Δ -2.5%; 95% CI, -4.8% to -0.2%; P < .05).CONCLUSIONS: Patients with CA have significantly reduced magnitude of LVMWI compared with healthy control subjects. With exercise, the differences are even more pronounced. Even though LVMWI increased with exercise, LVMWE decreased, suggesting inefficient myocardial energy exploitation in patients with CA.

Graphical abstract, Highlights • CPFs in relation to the pulmonary valve are very rare. • Physical obstruction of the right coronary ostium by a tumor is a rare finding. • Three-dimensional TEE can demonstrate the pathophysiologic mechanism of a tumor.

Aims Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers. Methods and results A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA-p.Arg471Cys and LMNA-p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild-type protein was only 30:70 in LMNA-p.Arg216Cys carriers with a favourable prognosis while LMNA-p.Arg471Cys and LMNA-p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50. Conclusion The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.

Purpose Cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) affects the epicardial arteries and veins and also the coronary microcirculation. In the absence of proximal epicardial artery stenosis, coronary flow velocity reserve (CFVR) reflects the function of the myocardial microcirculation. We aimed to determine the prognostic value of 1) CFVR and 2) a combination of CFVR and left ventricular global longitudinal strain (LVGLS) in HTx patients. Methods CFVR was evaluated using pulsed wave Doppler echocardiography in 98 HTx patients (median 6.9 years from HTx) examined with coronary angiography. Patients were enrolled from 2013 to 2018 and prospectively followed until June 1st 2020. All-cause mortality and major adverse cardiac events (MACE) including heart failure, significant CAV progression, coronary intervention or cardiovascular death, were recorded. Results Median follow-up was 3.2 [interquartile range 1.9-5.1] years. Patients with low CFVR ( -15.5%), we obtained a strong predictive model for MACE (HR 10.5, 95% CI 4.5-24.5, p Conclusion CFVR strongly predicts MACE and all-cause mortality in HTx-patients. A model combining low CFVR and low LVGLS magnitude was a strong model for MACE and all-cause mortality prediction and could be considered as a non-invasive method for routine CAV surveillance.