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Background Heart transplantation (HTx) surgically denervates the heart. We examined indices of sinoatrial reinnervation, with emphasis on (1) the occurrence and timing of parasympathetic reinnervation, and (2) the consequences of reinnervation for heart rate (HR) responsiveness and arterial baroreceptor sensitivity. Methods Fifty HTx recipients were prospectively followed for 36 months after surgery. Hemodynamic variables and heart rate variability were continuously recorded at supine rest, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results Suggesting parasympathetic reinnervation: at baseline rest, root of the mean squared differences of successive RR intervals increased from median 3.9(5.9) to 7.1(5.1) ms (p < 0.001); high-frequency power increased from 4.0(12) to 5.7(18.9) ms2 (p = 0.018); and baroreceptor sensitivity increased from 0.04(0.36) to 1.3(2.4) ms/mmHg (p < 0.001). Suggesting sympathetic reinnervation: at baseline rest low-frequency power increased from 0.49(2.5) to 7.5(18.1) ms2 (p < 0.001); and HR responses to sympathetic stimulation during (1) head-up tilt increased from 1.9(4.2) to 9.1(8.2) bpm (p < 0.001), (2) Valsalva increased from 1.6(1.4) to 8.3(10.8) bpm (p < 0.001) and (3) handgrip increased from 0.3(0.6) to 1.9(5.1) bpm (p < 0.001). Signs of sympathetic reinnervation emerged within 6 months, while signs of parasympathetic reinnervation emerged by 24 months. Conclusions Root of the mean squared differences of successive RR intervals, high-frequency and low-frequency variability, HR responsiveness and arterial baroreflex sensitivity all increased after HTx, suggesting functional parasympathetic and sympathetic sinoatrial reinnervation. Accordingly, the pathological regulatory state present in heart transplant recipients, which is responsible for a host of functional and clinical abnormalities, is being partially offset over time by restored autonomic control of the heart in many heart transplant recipients.

Background Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. Methods Fifty HTx recipients were assessed at 2.5, 6 and 12 months after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were carried out at supine rest, 0.2 Hz controlled breathing, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 months. Conclusions Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 months after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 months. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.

Purpose Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation. Methods A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7–12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses. Results During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger. Conclusion Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.

Background: Patency of the coronary arteries is an issue after reports of sudden cardiac death in patients with transposition of the great arteries (TGA) operated with arterial switch (ASO). Recent studies give rise to concern regarding the use of ionising radiation in congenital heart disease, and assessment of the coronary arteries with coronary MR angiography (CMRA) might be an attractive non-invasive, non-ionising imaging alternative in these patients. Theoretically, the use of 3.0T CMRA should improve the visualisation of the coronary arteries. The objective of this study was to assess feasibility of 3.0T CMRA at the coronary artery origins by comparing image quality with non-contrast CMRA in ASO TGA patients to healthy age-matched controls, and by comparing image quality with non-contrast CMRA to contrast enhanced CMRA in the patient group. Material and methods: Twelve patients, 9-15 years (mean 11.9 years, standard deviation 1.5 years), and 12 age-matched controls (mean 12.7 years, standard deviation 1.7 years) were examined with 3D balanced steady-state free precession (SSFP). Nine of twelve patients had Gadolinium-enhanced fast low-angle shot (Gd-FLASH) performed after SSFP. Image quality at the coronary artery origins was evaluated subjectively with a 10 cm figurative visual analogue scale (fVAS) and objectively by signal-to-noise and contrast-to-noise ratio (SNR, CNR). Results: All, but one, coronary artery origins were identified. No significant difference in image quality scores was found between patients and controls with SSFP (mean values 6.5 cm—9.1 cm in patients and 7.0 cm—8.0 cm in controls, p-values > 0.1). With SSFP, intra-observer fVAS mean score was 6.7 cm—8.6 cm and with Gd-FLASH 7.7 cm—8.7 cm. CNR was higher with Gd-FLASH (p < 0.03). Intra-observer agreement index (AI) with SSFP was moderate-to-good (0.43–0.71) and with Gd-FLASH good (0.64–0.79) in all origins. Inter-observer AI was good in the left main stem (LMS) with SSFP (0.65). With Gd-FLASH inter-observer AI was good in LMS (0.78) and moderate (0.5) in the left anterior descending artery, but lacking in the other origins though with a good agreement on Bland-Altman plots. Conclusions: Our findings indicate a better, more reproducible image quality with Gd-FLASH than with non-contrast SSFP CMRA on 3.0T for evaluation of the coronary artery origins in ASO TGA children and adolescents.

We have recently demonstrated that accelerometer-based pump thrombosis and thromboembolic events detection is feasible in vitro. This article focuses on detection of these conditions in vivo. In an open-chest porcine model (n = 7), an accelerometer was attached to the pump casing of an implanted HeartWare HVAD. Pump vibration was analyzed by Fast Fourier Transform of the accelerometer signals, and the spectrogram third harmonic amplitude quantified and compared with pump power. Interventions included injection of thrombi into the left atrium (sized 0.3-0.4 ml, total n = 35) and control interventions; pump speed change, graft obstruction, and saline bolus injections (total n = 47). Graft flow to cardiac output ratio was used to estimate the expected number of thrombi passing through the pump. Sensitivity/specificity was assessed by receiver operating characteristic curve. Graft flow to cardiac output ratio averaged 66%. Twenty-six of 35 (74%) thrombi caused notable accelerometer signal change. Accelerometer third harmonic amplitude was significantly increased in thromboembolic interventions compared with control interventions, 64.5 (interquartile range [IQR]: 18.8-107.1) and 5.45 (IQR: 4.2-6.6), respectively (p0.01). The corresponding difference in pump power was 3 W (IQR: 2.9-3.3) and 2.8 W (IQR: 2.4-2.9), respectively (p0.01). Sensitivity/specificity of the accelerometer and pump power to detect thromboembolic events was 0.74/1.00 (area under the curve [AUC]: 0.956) and 0.40/1.00 (AUC: 0.759), respectively. Persistent high third harmonic amplitude was evident at end of all experiments, and pump thrombosis was confirmed by visual inspection. The findings demonstrate that accelerometer-based detection of thromboembolic events and pump thrombosis is feasible in vivo and that the method is superior to detection based on pump power.

We report 2 continuous flow HeartWareTM left ventricular assist devices successfully used in a patient with advanced heart failure of giant cell myocarditis origin in a biventricular configuration. Despite technical challenges of adapting a left ventricular assist device engineered for systemic pressure to function as a right ventricular assist device, the addition of dynamic banding on the right ventricular assist device outflow graft allowed successful adaptation of afterload. This patient has now been on biventricular configuration support for 9 years, and remains stable to this day.

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and represents approximately 50% of all heart failure (HF) patients. Patients with this complex clinical scenario, characterized by high filling pressures, and reduced cardiac output (CO) associated with progressive multi-organ involvement, have so far not experienced any significant improvement in quality of life or survival with traditional HF treatment. Left ventricular assist devices (LVAD) have offered a new treatment alternative in terminal heart failure patients with reduced ejection fraction (HFrEF), providing a unique combination of significant pressure and volume unloading together with an increase in CO. The small left ventricular cavity in HFpEF patients challenges left-sided pressure unloading, and new anatomical entry points need to be explored for mechanical pressure and volume unloading. Optimized and pressure/volume-adjusted mechanical circulatory support (MCS) devices for HFrEF patients may conceivably be customized for HFpEF anatomy and hemodynamics. We have developed a long-term MCS device for HFpEF patients with atrial unloading in a pulsed algorithm, leading to a significant reduction of filling pressure, maintenance of pulse pressure, and increase in CO demonstrated in animal testing. In this article, we will discuss HFpEF pathology, hemodynamics, and the principles behind our novel MCS device that may improve symptoms and prognosis in HFpEF patients. Data from mock-loop hemolysis studies, acute, and chronic animal studies will be presented.

OBJECTIVES Targeted temperature management (32-36°C) is used for neuroprotection in cardiac arrest survivors. The isolated effects of hypothermia on myocardial function, as used in clinical practice, remain unclear. Based on experimental results, we hypothesized that hypothermia would reversibly impair diastolic function with less tolerance to increased heart rate in patients with uninsulted hearts. DESIGN Prospective clinical study, from June 2015 to May 2018. SETTING Cardiothoracic surgery operation room, Oslo University Hospital. PATIENTS Twenty patients with left ventricular ejection fraction greater than 55%, undergoing ascending aorta graft-replacement connected to cardiopulmonary bypass were included. INTERVENTIONS Left ventricular function was assessed during reduced cardiopulmonary bypass support at 36°C, 32°C prior to graft-replacement, and at 36°C postsurgery. Electrocardiogram, hemodynamic, and echocardiographic recordings were made at spontaneous heart rate and 90 beats per minute at comparable loading conditions. MEASUREMENTS AND MAIN RESULTS Hypothermia decreased spontaneous heart rate, and R-R interval was prolonged (862 ± 170 to 1,156 ± 254 ms, p < 0.001). Although systolic and diastolic fractions of R-R interval were preserved (0.43 ± 0.07 and 0.57 ± 0.07), isovolumic relaxation time increased and diastolic filling time was shortened. Filling pattern changed from early to late filling. Systolic function was preserved with unchanged myocardial strain and stroke volume index, but cardiac index was reduced with maintained mixed venous oxygen saturation. At increased heart rate, systolic fraction exceeded diastolic fraction (0.53 ± 0.05 and 0.47 ± 0.05) with diastolic impairment. Strain and stroke volume index were reduced, the latter to 65% of stroke volume index at spontaneous heart rate. Cardiac index decreased, but mixed venous oxygen saturation was maintained. After rewarming, myocardial function was restored. CONCLUSIONS In patients with normal left ventricular function, hypothermia impaired diastolic function. At increased heart rate, systolic function was subsequently reduced due to impeded filling. Changes in left ventricular function were rapidly reversed after rewarming.

Aim To compare the outcomes in patients with refractory out-of-hospital cardiac arrest (OHCA) fulfilling the criteria for extracorporeal cardiopulmonary resuscitation (ECPR) before and after implementation of an ECPR protocol, whether the patient received ECPR or not. Methods We compared cardiac arrest registry data before (2014–2015) and after (2016–2019) implementation of the ECPR protocol. The ECPR criteria were presumed cardiac origin, witnessed arrest with ventricular fibrillation, bystander CPR, age 18–65, advanced life support (ALS) within 15 min and ALS > 10 min without return of spontaneous circulation (ROSC). The primary outcome was 30-day survival; the secondary outcomes were sustained ROSC, neurological outcome and the proportion of patients transported with ongoing ALS. Results There were 1086 and 3135 patients in the pre- and post-implementation sample; 48 (4%) and 100 (3%) met the ECPR criteria, respectively. Of these, 21 (44%) vs. 37 (37%) were alive after 30 days, p = 0.4, and 30 (63%) vs. 50 (50%) achieved sustained ROSC, p = 0.2. All survivors in the pre-implementation sample had cerebral performance category 1–2 vs. 30 (81%) in the post-implementation sample, p = 0.03. Of the patients fulfilling the ECPR criteria, 7 (15%) and 26 (26%), p = 0.1, were transported with ongoing ALS in the pre- and post-implementation sample, respectively. Conclusions There were no differences in 30-day survival or prehospital ROSC in patients with refractory OHCA before and after initiation of an ECPR protocol.

Background and aim of the study Patients with asymptomatic, severe aortic stenosis are presumed to have a benign prognosis. In this retrospective cohort study, we examined the natural history of contemporary patients advised against aortic valve replacement due to a perceived lack of symptoms. Materials and methods We reviewed the medical records of every patient given the ICD-10-code for aortic stenosis (I35.0) at Oslo University Hospital, Rikshospitalet, between Dec 1st, 2002 and Dec 31st, 2016. Patients who were evaluated by the heart team due to severe aortic stenosis were categorized by treatment strategy. We recorded baseline data, adverse events and survival for the patients characterized as asymptomatic and for 100 age and gender matched patients scheduled for aortic valve replacement. Results Of 2341 patients who were evaluated for aortic valve replacement due to severe aortic stenosis, 114 patients received conservative treatment due to a lack of symptoms. Asymptomatic patients had higher mortality than patients who had aortic valve replacement, log-rank p Conclusions In this retrospective study, asymptomatic patients with severe aortic stenosis who were advised against surgery had significantly higher mortality than patients who had aortic valve replacement.

BACKGROUND While expected need for intensive care after lung transplantation (LTx) does not normally affect organ allocation, it would be useful to estimate whether intensive care capacity is limited. The aim of this study was to assess factors available before LTx to identify predictors of prolonged intensive care unit (ICU) length of stay (LOS) after LTx. METHODS All bilateral LTx recipients excluding re-transplantation and multi-organ transplantation at Oslo University Hospital from 2000 to 2013 were included (n = 277). Predictive factors for ICU LOS were identified using pre- and perioperative variables. RESULTS Univariate analyses showed that recipients with pulmonary arterial hypertension, young age, female gender, low body height, low pretransplant actual total lung capacity (aTLC), and recipients who received an oversized donor lung were at risk for long ICU LOS. Patients with emphysema had lower risk of long ICU LOS. In multivariate analyses, a lower aTLC (p

Background Denervation at heart transplant (HTx) results in attenuated heart rate (HR) control and limited exercise tolerance. Purpose The aim of this study was to assess longitudinal changes in the HR response to exercise in HTx recipients. We compared the results with those of healthy controls. Methods Seventy-four HTx recipients were enrolled in a cardiopulmonary exercise trial. The HR response to maximal exercise was tested at 11 weeks and at 1- and 3-years follow-up post HTx, and compared with the HR response in 50 age and gender matched controls. The HR was measured at rest, at 25-, 50-, 75-, and 100% of VO2peak, and 30 sec, 1, 2, and 4 min after peak exercise on a treadmill or bicycle ergometer. We also assessed the HR reserve and the chronotropic response index (CRI). Results Elleven weeks after HTx, the HR response to exercise was blunted, but improved significantly during follow-up. The change in HR from rest to peak exercise increased by 53% (41 bpm vs 62 bpm; p0.85) in 44% of the HTx recipients at 1 year and in 51% at 3 year after HTx. Conclusion The increase and decrease in HR during exercise are considerably muted in de novo HTx recipients. The HR response improves during the first year after surgery, and thereafter levels off. In contrast the decline in HR after exercise seems to increase with time, which may be related to the effect of exercise. This suggests that partial re-innervation takes place. Whether this response continues to improve in the longer term remains to be determined. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority

Background Barlow's disease provides both diagnostic and therapeutic challenges. The impact of systemic blood-pressure on severity of regurgitation is still unclear. Purpose We hypothesized that mitral annulus behaves passively with enlargement during ventricular systole, and secondly, we tested the hypothesis that severity of regurgitation correlates to systemic blood-pressure (BP) of the patient. Methods Ten patients with Barlow's disease were compared with 10 healthy controls. Brachial blood-pressure was measured according to guidelines. Transthoracic 3D echo was obtained from an apical view (38.6±8.2 frames per second). Data was analyzed using a holographic display. We measured commissure width (CW), septallateral length (SL) and mitral annular surface area throughout the cardiac cycle. Aortic flow ejection time was derived from continuous Doppler across the aortic valve. Timing of aortic valve closure was visually assessed by 3D echo. Onset and end of mitral regurgitation was derived from continuous wave Doppler of transmitral flow. Results Systolic BP in controls and patients were 122±5 and 133±12 mmHg, respectively (p Conclusions We have demonstrated pressure constrained mitral annular dysfunction in Barlow's disease, indicating that systemic blood pressure may modify the severity of regurgitation. The study provides novel insights into mechanisms of mitral regurgitation and potential therapeutic actions in the future. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Grieg Foundation

Background: The paucity of available hearts for transplantation means that more patients remain on durable left ventricular support for longer periods of time. The Registry to Evaluate the HeartWare Left Ventricular Assist System was an investigator-initiated multicenter, prospective, single-arm database established to collect post-Conformité Européene mark clinical information on patients receiving the HeartWare ventricular assist device system as a bridge to transplantation. This registry represents the longest multicenter follow-up of primary left ventricular assist device outcomes. Methods: Data were collected on 254 commercial implants performed between February 2009 and March 2012 from 9 centers in Europe (7) and Australia (2). Patients were followed to device explant, heart transplantation, or death. The outcomes of patients through July/August 2018 were analyzed. Summary statistics were used to describe patient demographics, adverse events, length of support, and outcomes for this extended-term cohort. Results: A total of 122 patients were on support for >2 years, and 34 patients were on support for >5 years. Twenty nine patients are still alive on support (support ranging from 1213 to 3396 days), and 23 of those are on their original HeartWare ventricular assist device system. Kaplan–Meier survival through 7 years was 51%. Through 6 years, freedom from any stroke was 82%, while freedom from severely disabling stroke was 89%. Conclusions: Low rates of heart transplant now require longer periods of left ventricular assist device support in patients. This analysis demonstrates that long-term support using a HeartWare ventricular assist device system offers survival of 51% through 7 years.

Targeted temperature management is part of the standardized treatment for patients in cardiac arrest. Hypothermia decreases cerebral oxygen consumption and induces bradycardia; thus, increasing the heart rate may be considered to maintain cardiac output. We hypothesized that increasing heart rate during hypothermia would impair diastolic function. Human left ventricular trabeculae obtained from explanted hearts of patients with terminal heart failure were stimulated at 0.5 Hz, and contraction-relaxation cycles were recorded. Maximal developed force (Fmax), maximal rate of development of force [(dF/d t)max], time to peak force (TPF), time to 80% relaxation (TR80), and relaxation time (RT = TR80 − TPF) were measured at 37, 33, 31, and 29°C. At these temperatures, stimulation frequency was increased from 0.5 to 1.0 and to 1.5 Hz. At 1.5 Hz, concentration-response curves for the β-adrenergic receptor (β-AR) agonist isoproterenol were performed. Fmax, TPF, and RT increased when temperature was lowered, whereas (dF/d t)max decreased. At all temperatures, increasing stimulation frequency increased Fmax and (dF/d t)max, whereas TPF and RT decreased. At 31 and 29°C, resting tension increased at 1.5 Hz, which was ameliorated by β-AR stimulation. At all temperatures, maximal β-AR stimulation increased Fmax, (dF/d t)max, and maximal systolic force, whereas resting tension decreased progressively with lowering temperature. β-AR stimulation reduced TPF and RT to the same extent at all temperatures, despite the more elongated contraction-relaxation cycle at lower temperatures. Diastolic dysfunction during hypothermia results from an elongation of the contraction-relaxation cycle, which decreases the time for ventricular filling. Hypothermic bradycardia protects the heart from diastolic dysfunction and increasing the heart rate during hypothermia should be avoided. NEW & NOTEWORTHY Decreasing temperature increases the duration of the contraction-relaxation cycle in the human ventricular myocardium, significantly reducing the time for ventricular filling during diastole. During hypothermia, increasing heart rate further reduces the time for ventricular filling and in some situations increases resting tension further impairing diastolic function. Modest β-adrenergic receptor stimulation can ameliorate these potentially detrimental changes during diastole while improving contractile force generation during targeted temperature management.

Background Assessment of qualitative or subjective image quality in radiology is traditionally performed using a fixed-point scale even though reproducibility has proved challenging. Objective Image quality of 3-T coronary magnetic resonance (MR) angiography was evaluated using three scoring methods, hypothesizing that a continuous scoring scale like visual analogue scale would improve the assessment. Materials and methods Adolescents corrected for transposition of the great arteries with arterial switch operation, ages 9–15 years (n=12), and healthy, age-matched controls (n=12), were examined with 3-D steady-state free precession magnetic resonance imaging. Image quality of the coronary artery origin was evaluated by using a fixed-point scale (1–4), visual analogue scale of 10 cm and a visual analogue scale with reference points (figurative visual analogue scale). Satisfactory image quality was set to a fixed-point scale 3=visual analogue scale/figurative visual analogue scale 6.6 cm. Statistical analysis was performed using Cohen kappa coefficient and agreement index. Results The mean interobserver scores for the fixed-point scale, visual analogue scale and figurative visual analogue scale were, respectively, in the left main stem 2.8, 5.7, 7.0; left anterior descending artery 2.8, 4.7, 6.6; circumflex artery 2.5, 4.5, 6.2, and right coronary artery 3.2, 6.3, 7.7. Scoring with a fixed-point scale gave an intraobserver κ of 0.52–0.77 while interobserver κ was lacking. For visual analogue scale and figurative visual analogue scale, intraobserver agreement indices were, respectively, 0.08–0.58 and 0.43–0.71 and interobserver agreement indices were up to 0.5 and 0.65, respectively. Conclusion Qualitative image quality evaluation with coronary 3-D steady-state free precession MR angiography, using a visual analogue scale with reference points, had better reproducibility compared to a fixed-point scale and visual analogue scale. Image quality, being a continuum, may be better determined by this method.

OBJECTIVES A transcatheter heart valve technique can be used in failed mitral valve repairs with annuloplasty rings, deterioriated bioprostheses and in mitral annular calcification, all serving as 'docking stations' for balloon-expandable valves. Specially designed transcatheter mitral valve platforms are used in ongoing studies for native mitral valve regurgitation. We present our single centre experience with transcatheter mitral valve implantation-transapical approach procedures in eleven patients. METHODS Eleven patients were treated between 2011 and 2016. They had severe mitral regurgitation due to either failed repair annuloplasty rings (N = 6), failed bioprostheses (N = 2) or in the native valve (N = 3), all at high risk for open mitral valve surgery. Three different types of transcatheter valves were used: (1) the SAPIEN XT/SAPIEN 3, (2) the Lotus valve and (3) a Tendyne transcatheter mitral valve. Computed tomography reconstruction, echocardiography, 3D printing and bench tests were done in the preoperative evaluation and procedural planning. Transapical approach access was performed via a left minithoracotomy. RESULTS Implantation success was 100% with no left ventricular outflow tract obstruction. Good haemodynamics and improved New York Heart Association class were demonstrated in all patients. One patient died before 30 days due to sepsis. One patient had a valve thrombosis when switching from Coumadin to new oral anticoagulant and had a second valve implanted into the first one as a 'valve-in-valve' procedure. CONCLUSIONS The transapical approach is a safe and straight forward procedure for accessing the mitral valve. 'Transcatheter aortic valve implantation' prostheses may be used in redo surgery due to an already sufficient 'docking station'. These specially designed new prostheses may be beneficial for addressing mitral valve regurgitation, but are still under evaluation. Anticoagulation is mandatory.

Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression. • Wnt5a is elevated in serum and myocardium of HF patients and is associated with measures of progressive HF. • In cardiac fibroblasts, Wnt5a upregulates interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1 through the ERK pathway. • Wnt5a-mediated effects might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.

Purpose Denervation after heart transplantation (HTx) results in attenuated heart rate (HR) control and limited exercise tolerance. The aim of this study was to assess HR response changes to exercise with time in HTx recipients, compared with healthy controls. Methods The HR response to maximal cardiopulmonary exercise was tested in 50 de novo HTx recipients at 11 weeks (range 7-16) after surgery, at 1-year follow-up and in 50 age and gender matched controls. The HR was measured at rest, at 25-, 50-, 75-, and 100% of VO2peak, and 30 sec, 1, 2, and 4 min after peak exercise on a treadmill or bicycle ergometer. We also assessed the HR reserve and the chronotropic response index. Results 11 weeks after HTx, the HR response to exercise was blunted, but improved significantly during follow-up. The change in HR from rest to peak exercise increased by 32% (46 bpm vs 68 bpm; pl p&lt0.001) and normalized in 50% of the HTx recipients at 1 year. Finally, the HR declined more rapidly after exercise at follow-up than at inclusion, however, the decline remained slower than in controls (Figure). Conclusion The increase and decrease in heart rate during exercise are considerably reduced in de novo HTx recipients, but improve during the first year after surgery. Whether this response continues to improve during longer follow-up remains to be determined.

BACKGROUND: Heart transplantation is limited by the scarcity of suitable donors. Patients with advanced biventricular failure may require biventricular support to provide optimal cardiac output and end-organ perfusion. We highlight the outcomes of using the HeartWare HVAD System (HVAD) in a biventricular configuration. METHODS: This retrospective study included patients implanted with HVAD as a biventricular assist device (BiVAD) between 2009 and 2017 at 12 participating centers. When used as a right ventricular assist device (VAD) (RVAD), the HVAD can be attached to the right ventricle (RV) or the right atrium (RA). Kaplan–Meier survival estimates were calculated comparing the 2 RVAD implant locations. Comparisons were also made between the timing of RVAD implantation (primary vs staged) on adverse event (AE) profiles and survival. RESULTS: Among the 93 patients who were implanted with a HVAD BiVAD, Kaplan–Meier survivals at 1-year and 2-year were 56% and 47%, respectively. Survival was independent of the location of the HVAD RVAD implant or whether there was an interval between left VAD and RVAD implantation. The most common AEs were bleeding (35.5%), infection (25.8%), and respiratory failure (20.4%). CONCLUSIONS: This study illustrated similar survival in patients receiving a primary or staged HVAD BiVAD implant at 1 year and 2 years. This study also established that the locations of the RVAD implant (RV or RA) result in similar AE profiles. © 2020 International Society for Heart and Lung Transplantation, Medtronic Abbott Laboratories Medtronic, A.R.S. is a consultant for Medtronic and Transmedics Inc. J.G. and M.O. are consultants for Medtronic and Abbott. C.S.H. is a consultant for Medtronic and has received honoraria from Abbott and Medtronic. D.Z. and J.D.S. are consultants for Medtronic and receive research grant support from Abbott. The remaining authors have no conflicts of interest to disclose., The authors gratefully acknowledge the assistance of Vince Cannon, Alexandra Dedrick, and Kristie Wallace from Medtronic for support in the analysis and preparation of this manuscript. This retrospective study was supported by Medtronic (formerly HeartWare Inc).

Introduction Hypothermia is therapeutically used after cardiac arrest. The moderate hypothermia alters cardiac function, with reduced heart rate (HR), prolonged systolic duration and increased QT interval. The risk of arrhythmia increases with prolonged QT-interval, but clinical studies have not been able to demonstrate an increase of arrhythmic events during moderate hypothermia. The mechanism of this is not thoroughly described, but the concurrent increase in mechanical systolic duration may play a part of the explanation. Purpose QT prolongation and increased electromechanical window (EMW) negativity; the duration of left ventricle mechanical systole relatively to the duration of the electrical systole, are associated with arrhythmia. We hypothesized that moderate hypothermia would increase ECG intervals and systolic duration without an increase in EMW negativity. Methods In an open-chest porcine model (n=10), 2D echocardiography measurements and Doppler recordings were performed with concurrent 3-lead ECG registrations during normothermia (38°C) and moderate hypothermia (33°C) at spontaneous HR. Diastolic and systolic durations were assessed by valve opening to valve closure and Doppler assessed ejection time (ET). Isovolumetric contraction time (IVCT) and EMW, were measured. Systolic function was assessed by ejection fraction (EF), stroke volume (SV) and systolic velocity (s'). Results are presented as means ± SD. Two-sided T-test was used for comparison and P-value Results Moderate hypothermia reduced HR from 91±9 to 82±7 beats/min (p Conclusion Moderate hypothermia increased the QTc-interval but the mechanical systolic duration was even more prolongated. The EMW became positive demonstrating that the mechanical systole outlasted the electrical systole. As less EMW negativity is considered to be protective regarding arrhythmia, these findings may explain why arrhythmia is not frequently occurring during moderate hypothermia. Acknowledgement/Funding None

Background Calcific aortic valve disease is the 2nd most frequent cause of open heart surgery. The valve interstitial cells (VIC) are crucial for calcification. SNF472 (a derivative of phytic acid) is a calcification inhibitor currently in clinical development for the treatment of cardiovascular calcification (Phase 2 CaLIPSO trial, EudraCT 2016–002834–59). SNF472 has been shown to inhibit vascular calcification in several preclinical models. Purpose 1. Establish a new model of calcification in cultured human VIC; 2. Investigate whether SNF472 would inhibit calcification in this model, and 3. Study if SNF472 might inhibit ongoing calcification processes. Methods Healthy and calcified aortic valves were obtained from heart transplant recipients and patients undergoing aortic valve replacement due to calcific valve disease, respectively. VIC were isolated and seeded in basic growth medium, osteogenic differentiation medium (Osteodiff) alone, and with addition of different concentrations of SNF472. The following series of studies were performed: 1. VIC from healthy and calcified valves were cultured for three weeks with Osteodiff; 2. VIC from calcified valves were cultured for 3 weeks in Osteodiff media with 0, 1, 3, 10, 30, or 100 μM SNF472; 3. VIC from calcified valves were cultured for 3 weeks in Osteodiff media in total, but after 1 or 2 weeks 30 or 100 μM SNF472 was added to the cultures (n=8). Calcification was visualized by Alzarin Red staining and quantified by spectrophotometry. Statistics analysis was performed nonparametric One-Way ANOVA (Friedman and Kruskal–Wallis tests) with Dunn's post-test. Results Calcification was found to be 30% stronger in cultures of VIC from calcified valves as compared to cultured VIC from healthy valves (p=0.03). SNF472 successfully inhibited VIC calcification in a dose-dependent manner. SNF472 concentrations of 1, and 3 μM inhibited calcification by 7% (not significant) and 66% (p=0.08) respectively. Concentrations of 10, 30, and 100 μM completely inhibited calcification. 30 and 100 μM of SNF472 added after 1 week reduced ongoing calcification by 84% (p Conclusions VIC from calcified valves have a more pro-calcification phenotype than VIC from healthy valves. SNF472 is able to inhibit the development VIC calcification in vitro. By early intervention SNF472 is also able to stop the progression of ongoing calcification. SNF472 shows to be a promising therapy to treat heart valve calcification. Acknowledgement/Funding EC FP7 (GA 609020), Balearic Islands Government grant (ES01/TCAI/41_2017), FEDER 2014-2020, Laboratoris Sanifit, Palma, Spain; University of Oslo

Background: Organs from older donors are increasingly used in lung transplantation, and studies have demonstrated that this could be safe in selected recipients. However, which recipient groups that have the largest benefit of older organs are unclear. This multicenter study reviews all bilateral lung transplantations (BLTx) from donors 55 years or older stratified by recipient diagnosis and compares outcomes with transplantations from younger donors. Methods: All BLTx recipients (excluding retransplantation) at 5 Scandiatransplant centers between 2000 and 2013 were included (n = 913). Recipients were stratified to diagnosis groups including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and “other.” Intensive care unit (ICU) length of stay (LOS) and survival were assessed. Results: Overall, there was no difference in survival among patients transplanted from donors 55 years or older compared with younger donors. However, in CF recipients, donor age 55 years or older was associated with inferior survival (P = 0.014), and this remained significant in a multivariate model (hazard ratio, 5.0; 95% confidence interval, 1.8–14.1; P = 0.002). There was no significant effect of donor age on survival in recipients with COPD, ILD, or in the “other” group in multivariate models. Utilization of older donors was associated with increased ICU LOS for recipients with CF and ILD, but not in the COPD or “other” group. Conclusions: The BLTx recipients with CF had inferior survival and longer ICU LOS when receiving organs from donors 55 years or older. Recipients with COPD, ILD, or in the “other” group did not have inferior survival in multivariate models.

OBJECTIVES: The purpose of this study was to assess complications and mortality and its predictors, with continuous-flow left ventricular assist devices (CF-LVADs) in the Nordic Countries.DESIGN: This was a retrospective, international, multicenter cohort study.RESULTS: Between 1993 and 2013, 442 surgically implanted long-term mechanical assist devices were used among 8 centers in the Nordic countries. Of those, 238 were CF-LVADs (HVAD or HeartMate II) implanted in patients >18 years with complete data. Postoperative complications and survival were compared and Cox proportion hazard regression analysis was used to identify predictors of mortality. The overall Kaplan-Meier survival rate was 75% at 1 year, 69% at 2 years and 63% at 3 years. A planned strategy of destination therapy had poorer survival compared to a strategy of bridge to transplantation or decision (2-year survival of 41% vs. 76%, p CONCLUSION: Outcome with CF LVAD in the Nordic countries was comparable to other cohorts. Higher age and destination therapy require particularly stringent selection.

Purpose Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR). Methods A total of 50 HTxRs were investigated 7–12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted. Results At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands. Conclusion HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

Objective Current understanding of the prognostic impact of depression on mortality after heart transplantation (HTx) is limited. We examined whether depression after HTx is a predictor of mortality during extended follow-up. Subsequently, we explored whether different symptom dimensions of depression could be identified and whether they were differentially associated with mortality. Methods Survival analyses were performed in a sample of 141 HTx recipients assessed for depression, measured by self-report of depressive symptoms (Beck Depression Inventory – version 1A [BDI-1A]), at median 5.0 years after HTx, and followed thereafter for survival status for up to 18.6 years. We used uni- and multivariate Cox proportional hazard models to examine the association of clinically significant depression (BDI-1A total score ≥10), as well as the cognitive-affective and the somatic subscales of the BDI-1A (resulting from principal component analysis) with mortality. In the multivariate analyses, we adjusted for relevant sociodemographic and clinical variables. Results Clinically significant depression was a significant predictor of mortality (hazard ratio = 2.088; 95% confidence interval = 1.366–3.192; p = .001). Clinically significant depression also was an independent predictor of mortality in the multivariate analysis (hazard ratio = 1.982; 95% confidence interval = 1.220–3.217; p = .006). The somatic subscale, but not the cognitive-affective subscale, was significantly associated with increased mortality in univariate analyses, whereas neither of the two subscales was an independent predictor of mortality in the multivariate analysis. Conclusions Depression measured by self-report after HTx is associated with increased mortality during extended follow-up. Clinical utility and predictive validity of specific depression components require further study. acceptedVersion

Background Chronic thromboembolic pulmonary hypertension (CTEPH) induces right ventricular (RV) adaptive changes but often results in RV failure and death. Balloon pulmonary angioplasty (BPA) is a treatment option in patients in whom pulmonary endarterectomy is contraindicated and in patients with residual pulmonary hypertension after pulmonary endarterectomy. We hypothesized that RV reverse remodeling and improved RV function would occur after BPA in patients with CTEPH. Methods In 26 patients with CTEPH (59 ± 12 years old; 11 men), echocardiography, cardiopulmonary exercise testing, blood samples, and right-sided cardiac catheterization were performed before and after 4 ± 2 BPA procedures. Echocardiography images were analyzed off-line with particular focus on RV function according to current recommendations. Differences from baseline to follow-up were analyzed by paired samples t tests. Results Significant improvements in hemodynamics, peak oxygen consumption, and levels of N-terminal pro-B-type natriuretic peptide were detected after BPA. All measures of RV function improved considerably, including fractional area change (+6%; p = 0.003), tricuspid annular plane systolic excursion (+3 mm; p p = 0.002). RV end-diastolic diameter, area, and free wall thickness decreased significantly, whereas left ventricular diameter and stroke volume increased. Conclusions After BPA, a significant improvement in RV functional parameters could be observed by echocardiography, adding credibility to this form of treatment in patients with CTEPH.

The increasing demand for pulmonary retransplantation (re-LTx) raises ethical issues on the correct allocation of the scarce donor pool. Thus, we performed a thorough review of the current results for re-LTx in the Nordic countries.Seventy-five patients with a median age of 50 years (range, 22 to 64 years) underwent re-LTx from 1992 until June 2013, of which 53 had single re-LTx, 21 had double re-LTx, and 1 patient underwent a heart-lung retransplantation. Primary graft dysfunction (PGD) was the primary indication in 9 cases, bronchiolitis obliterans syndrome (BOS) in 62 cases, and airway complications in 4 cases.Patients who underwent re-LTx in the period 1992 to 1999 (n = 16) had a 1-year survival of 37.5% (95% confidence interval [CI], 19.9 to 70.6), whereas patients who underwent re-LTx in the period 2000 to 2013 (n = 64) had a 1-year survival of 81.0% (95% CI, 71.5 to 91.8). Corresponding 5-year survival was 25.0% (95% CI, 10.7 to 58.4) in the early era group (1992 to 1999) and 57.2% (95% CI, 44.3 to 73.7) in the more recent era group (2000 to 2013; p = 0.0151). Patients with BOS who underwent re-LTx in the period 1992 to 1999 (n = 13) had a 1-year survival of 38.5% (95% CI, 19.3 to 76.5), whereas patients with BOS who underwent re-LTx in the period 2000 to 2013 (n = 49) had a 1-year survival of 85.4% (95% CI, 75.9 to 96.0). Corresponding 5-year survival was 23.1% (95% CI, 8.6 to 62.3) in the early era group (1992 to 1999) and 56.1% (95% CI, 41.9 to 75.2) in the more recent era group (2000 to 2013; p = 0.0199). The cumulative incidence among patients who underwent re-LTx because of BOS and developed BOS again after re-LTX was analyzed. The cumulative incidence curves for time periods 1992 to 1999 and 2000 to 2013 are not statistically different for repeat BOS (p = 0.5087), but they are highly significant for time periods among patients who died (p = 0.02381).Results for re-LTx have improved over time, especially when BOS is the primary indication. The cumulative incidence among patients who underwent re-LTx because of BOS and developed repeat BOS after re-LTX showed equal risk between 1992 to 1999 and 2000 to 2013 in the aspect of developing repeat BOS, but in the later era the patients had a significantly higher chance of surviving.

A 73-year-old woman underwent open mitral valve replacement with the transcatheter Edwards SAPIEN XT valve (Edwards Lifesciences, Corp, Irvine, CA USA) on cardiopulmonary bypass in a native, stenotic mitral valve. Because of left ventricular outflow tract obstruction, the patient died 25 days after implantation. There are previous reports of transcatheter valve implantation in native mitral valve with procedural success. However, in one case report, the patient died 10 days postoperatively.

Background Cognitive impairment is documented early after heart transplantation (HTx), but we lack data on cognitive function beyond the fourth year post-transplant. Against the background of good long-term survival, this knowledge is necessary to improve clinical care throughout the entire post-transplant period. Methods We assessed cognitive function with a neuropsychological test battery in a sample of HTx recipients ≥16 years post-transplant. To improve clinical utility, we also applied adapted consensus criteria for Mild Cognitive Impairment (MCI). Furthermore, we explored sociodemographic and clinical characteristics possibly related to cognitive function. Results Thirty-seven subjects were included 20.3 (±3.8) years after HTx. Mean age was 57.5 (±14.2) years, and 18.9% were women. Up to 38.9% exhibited impaired test performance (ie, performance at least 1.5 standard deviations below the normative mean) on several individual cognitive measures, especially on measures of processing speed, executive functions, memory, and language functions. One subject was diagnosed with dementia, and 30.1% qualified for MCI. Those with MCI had lower hemoglobin than those without. Conclusions A substantial proportion of long-term survivors of HTx might be cognitively impaired. The level of impairment appears comparable to what is defined as MCI in the literature. Modifiable factors related to cognitive impairment might exist.

Aortic valve stenosis due to calcification of the valve leaflets is the most common valve disease in the developed world. It is the third leading cause of cardiovascular disease.1 Risk factors include male gender, smoking, diabetes mellitus, hypertension, high levels of circulating lipids, and metabolic syndrome.2 Calcification was earlier believed to be a passive degenerative process, but it is now recognized as an active disease process driven by the cells native to the aortic valve.3, 4 The only option for treatment is heart surgery with implantation of a valve prosthesis. The heart valve prostheses are either mechanical, requiring life‐long anticoagulation treatment, or based on biological material, which will degenerate and calcify after 10 to 15 years. Implantation of heart valve prostheses has been characterized as “replacing one disease with another.” Understanding the cellular and molecular processes behind valve calcification may possibly lead to nonsurgical treatment. This work was supported by South‐Eastern Norway Regional Health Authority (grant 2013109), the National Association (Norway), the University of Oslo, The Norwegian Research Council, the Government of Russian Federation (grant 074‐U01), and the Russian Foundation of Basic Research (grant 17‐04‐01318).

Introduction: To extend the number of available organs for lung transplantation (LTx), donors with a smoking history are increasingly accepted. Previous studies show conflicting results as to whether this impairs recipient survival. Aims and objectives: The aim was to assess the effects of using lungs from donors with a smoking history for LTx for recipients with cystic fibrosis (CF). Methods: All recipients of bilateral LTx in Norway and Denmark 1990-2013 were included. Donor information and data about recipient survival and lung function was extracted from existing registries. Results: While there was no negative effect of donor smoking status when including all LTx recipients (n=388), we found a negative association between donor smoking status and post-LTx survival in the CF patients (n=86), in whom one-year survival was 82 % vs 90 % and five year survival was 49 % vs 73 % comparing smoking to non-smoking donors (Log-rank p-value 0.005). The negative effects of using organs from smoking donors remained significant when adjusting for donor and recipient age and sex, organ ischemia time and transplant center location in multivariate cox regression analysis. Conclusion: Using donors with a positive smoking history in double lung transplant recipients with cystic fibrosis is associated with inferior survival and decreased lung function.

Introduction: The use of cardiopulmonary bypass is associated with a risk of neurocognitive deficit caused by gaseous microemboli. Flushing the empty bypass circuit with carbon dioxide, which is more soluble than air, may reduce the amount of gaseous microemboli in the priming solution before the initiating of cardiopulmonary bypass. Method: We measured the amount of gaseous microemboli in twenty primed bypass circuits. Ten circuits were flushed with carbon dioxide before being primed and ten circuits were non-flushed. All circuits in both groups were primed with crystalloid priming. An ultrasonic clinical bubble counter was used to count gaseous microemboli in the prime for 20 minutes. Results: The median numbers of gaseous microemboli counts were highest during the first minute in both groups, with a significantly lower median value in the group flushed with carbon dioxide (397.5) versus the non-flushed group (1900). In the 20th minute, the median values of gaseous microemboli were significantly lower (pConclusion: Flushing the bypass circuits with carbon dioxide before priming significantly decreased the number of gaseous microemboli in the priming solution.

We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.

Poststernotomy mediastinitis is a serious complication after open heart surgery. There are currently no specific guidelines with regards to standard treatment. This is a prospective cohort study using a source population of 7842 patients who underwent open heart surgery. Between 1999 and 2010, 83 patients were diagnosed with mediastinitis, of which 24 patients underwent reconstruction with bilateral pectoralis major advancement flap. All surviving patients were seen at follow-up, and postoperative functional level was examined. The closing date was October 1, 2011. Median follow-up time from primary operation was 6.0 (1.6–15.5) years. Median follow-up from postsurgical mediastinitis was26 5.4 (0.4–12.4)years. There was no early mortality, and 22 patients were discharged with complete wound closure and infection control. Quality of life questionnaires revealed significant morbidity with chronic pain and reduced mobility, but despite this, patients were satisfied with their overall health outcome. Mediastinitis remains a serious postoperative complication after open heart surgery accounting for significant morbidity and mortality. Treatment of deep sternal wound infection by pectoralis major flap reconstruction gives excellent wound closure. Follow-up showed that these patients were multimorbid with reduced quality of life as measured. Level of Evidence: Level IV, therapeutic study.

Background The post-market Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE) is an investigator-initiated registry established to collect post–CE Mark Trial clinical data on patients receiving a HeartWare ventricular assist device (HVAD) in the European Union and Australia. Methods The ReVOLVE is a multi-center, prospective, single-arm registry performed at seven centers in Europe and two in Australia. Herein we describe a total of 254 commercial HVAD implants according to labeled indications between February 2009 and November 2012. Summary statistics included patients’ demographics, adverse events, length of support and outcomes. Results Compared with the clinical trial supporting the CE Mark of the HeartWare system, patient selection differed in that patients were older, and there were higher proportions of females and patients with idiopathic cardiomyopathies in the ReVOLVE cohort. Duration of support ranged from 1 to 1,057 days, with a mean of 363 ± 280 days (median 299.5 days). Transplantation was done in 56 patients (22%), explant for recovery was performed in 3 patients (1%), 43 died while on support (17%), and 152 (60%) remain on the device. Success in patients with the HeartWare system was 87% at 6 months, 85% at 1 year, 79% at 2 years and 73% at 3 years. Adverse event rates were low, comparable or improved when compared to the CE Mark Trial. Conclusion Real-world use of the HeartWare system continues to demonstrate excellent clinical outcomes in patients supported with the device.

Purpose Heart Failure with preserved ejection fraction (HFpEF) currently has no treatment options for improving symptoms or survival. We have developed a long-term novel pulsed assist device for treatment of patients with HFpEF. Methods We have developed a small diagonal centrifugal rotary blood pump which utilizes hydrodynamic suspension for magnetically elevated support of a four-blade impeller with partial unloading from the left atrium (LA) to the descending aorta. The pump is adaptive: the physiological needs of the patient are adjusted by both ECG and sensor feedback algorithms. Pulsed power and speed (rpm) maintain pulse pressure at a normal level. The device is designed for minimally invasive Implantation through a 9 × 3 cm thoracotomy. Repeated animal testing (sheeps) is performed. Results Animal studies testing a spectrum of unloading with simultanous hemodynamic and echocardiographic monitoring, have demonstrated adequate pulsed pump unloading between 1.5-3.0 l/min. ECG gated rpm increase in systole avoids LA suction, interference with mitral valve opening and ventricular filling. Blood pressure was maintained at 95-70 mmHg, central venous pressure (CVP) at 10 mmHg and native cardiac output of 3 l/m. Repeated studies with human whole blood without added anticoagulation in a mock loop for 8 hours have demonstrated no hemolysis, no increase in energy consumption or heat, and no clotting inside the pump. Long-term animal studies are planned. Conclusion Partial systolic pulsed unloading of the LA using a novel rotary blood pump demonstrated adequate hemodynamics and maintained normal pulse pressure. This novel pump may become the first possible treatment for patients with HFpEF.

Organs available for solid organ transplantation are mainly procured from brain dead donors. The inflammation associated with brain death may reduce organ quality and increase organ immunogenicity, thus leading to inferior recipient outcome. We hypothesized that the extensive surgical procedure performed during multiorgan procurement enhances the levels of systemic inflammatory biomarkers. We measured the levels of 27 cytokines and the terminal complement complex (TCC) in plasma samples from brain dead organ donors (n = 34) drawn before and at three specific time points during procurement surgery. Baseline levels of G-CSF, interferon-γ, IL-1ra, IL-4, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, macrophage inflammatory protein (MIP)-1β, platelet derived growth factor (PDGF), regulated upon activation T cell expressed and secreted, and tumor necrosis factor-α were significantly elevated in brain dead donors compared with normal individuals (n = 14), but they were not associated with time on ventilator or any other registered clinical variable. Notably, the secretion of G-CSF, IL1-ra, IL-6, IL-8, IL-10, IP-10, MCP-1, MIP-1β, PDGF, and TCC, the latter reflecting ongoing complement activation, increased significantly during surgery. None of the biomarker increases were correlated with operation duration. Multiorgan procurement surgery significantly adds to the inflammatory response revealed by both pro- and anti-inflammatory biomarkers associated with brain death. Future studies should determine whether this is associated with inferior recipient outcome.

Background Studies have shown conflicting results concerning the occurrence of cognitive impairment after successful heart transplantation (HTx). Another unresolved issue is the possible differential impact of immunosuppressants on cognitive function. In this study, we describe cognitive function in a cohort of HTx recipients and subsequently compare cognitive function between subjects on either everolimus- or calcineurin inhibitor (CNI)-based immunosuppression. Methods Cognitive function, covering attention, processing speed, executive functions, memory, and language functions, was assessed with a neuropsychological test battery. Thirty-seven subjects were included (everolimus group: n=20; CNI group: n=17). The extent of cerebrovascular pathology was assessed with magnetic resonance imaging. Results About 40% of subjects had cognitive impairment, defined as performance at least 1.5 standard deviations below normative mean in one or several cognitive domains. Cerebrovascular pathology was present in 33.3%. There were no statistically significant differences between treatment groups across cognitive domains. Conclusions Given the high prevalence of cognitive impairment in the sample, plus the known negative impact of cognitive impairment on clinical outcome, our results indicate that cognitive assessment should be an integrated part of routine clinical follow-up after HTx. However, everolimus- and CNI-based immunosuppressive regimens did not show differential impacts on cognitive function.

The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling. © The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Growing number of patients with terminal heart failure and a shortage of heart donors have increased use of short- and long-term mechanical circulatory support (MCS). Few studies have analyzed survival rates and healthcare costs for heart transplantation (HTx), with or without extracorporeal membrane oxygenation (ECMO) and left ventricular assist device (LVAD).In a retrospective, single-center study, data were analyzed from patients listed for HTx who died on the waiting list (DWL, n = 12), underwent HTx (n = 206), had ECMO as bridge to HTx (ECHTx, n = 15), or received LVAD treatment, either isolated (LVAD, n = 19) or bridging to HTx (LVADHTx, n = 26) during 2005-2012. Survival and hospital costs were assessed.One- and five-year survival rates were 96% and 83% for the LVADHTx group, 92% and 81% for HTx, 70% and 70% for ECHTx, 48% and 36% for LVAD and 0% for the DWL group (overall survival, p 0.001). Total hospital cost at one year was $102,101 ± 202,604 for DWL, $151,685 ± 86,892 for HTx, $292,078 ± 101,915 for ECHTx, $427,337 ± 365,154 for LVAD, and $600,897 ± 198,109 for LVADHTx.The LVADHTx and HTx groups showed excellent one- and five-year survival. The combined group of DWL and HTx patients had similar survival to the combined groups of MCS, but use of LVAD pre-transplant quadrupled the cost.

Background: Vacuum-assisted venous drainage (VAVD) is widely used to enhance venous blood return from patients undergoing cardiopulmonary bypass (CPB). This vacuum can accidentally reach the oxygenator of the heart-lung machine and draw gas bubbles into the blood. This is known as bubble transgression (BT) and may cause air emboli in the arterial blood line. In order to avoid BT and minimize the risk of patient injury, knowledge of oxygenator tolerance to vacuum load is critical. Thus, the main aim of this thesis was to investigate how much vacuum a membrane oxygenator can withstand before BT appears. Methods: We investigated four different adult oxygenators: Quadrox-i, Affinity Fusion, Capiox RX25 and Inspire 6M. They were tested in an in vitro setup where VAVD vacuum was allowed to reach the oxygenator through a non-occlusive roller pump. An ultrasonic clinical bubble counter, Gampt BCC 200, was used to count bubbles on the arterial line when the arterial pump was restarted. Results: We observed a significant increase in bubble count for two of the oxygenators, caused by -30 mmHg of VAVD vacuum in the blood reservoir (Affinity Fusion and Inspire 6M). Massive air ingress was shown in two of the oxygenators, caused by -30 mmHg of VAVD vacuum in the reservoir (Capiox RX25) and -40 mmHg of VAVD vacuum in the reservoir (Affinity Fusion). Conclusion: VAVD vacuum may cause bubble transgression in an oxygenator. This was shown for all the oxygenators in this test. VAVD vacuum may cause visible massive air ingress in an oxygenator. This was shown for two of the oxygenators in this test (Capiox RX25 and Affinity Fusion). An alarm triggering on negative pressure in the oxygenator or a pressure relief valve might improve safety when using VAVD.

OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin (CNI) avoidance (SCHEDULE). The aim of the study was to compare wound complications between EVE and CNI based regimen.MATERIALS AND METHODS: A total of 115 patients (mean age 51±13years, 73% men) were randomized within five days post-HTx to low dose EVE and reduced dose Cyclosporine (CyA) followed by early CyA withdrawal (EVE group; n=56) or standard CyA regimen (CyA group; n=59). All AE/SAEs were prospectively recorded according to the SCHEDULE study protocol, and re-assessed retrospectively by two independent reviewers. Wound complication as primary endpoint was defined as any complication associated with failure of tissue healing. Secondary endpoint was total number of events involving surgical intervention.RESULTS: There were no significant differences between the groups with regards to wound complications (EVE=20, CyA=12)(p=0.08) or total surgical events (EVE=38, CyA=34) (p=0.44). Age>54.5years (median) was an overall risk factor for surgical wound complications regardless of treatment group (p=0.025). There was no difference in the EVE versus CyA group with regards to other surgical events. Majority of events were in 1/3 of the patients.CONCLUSION: De novo initiation of EVE and early CyA withdrawal in HTx patients did not show any significant differences in wound complications or in total surgical events. Majority of complications were seen in a small number of patients.

Heart transplant (HTx) recipients usually have reduced exercise capacity with reported VO(2peak) levels of 50-70% predicted value. Our hypothesis was that high-intensity interval training (HIIT) is an applicable and safe form of exercise in HTx recipients and that it would markedly improve VO(2peak.) Secondarily, we wanted to evaluate central and peripheral mechanisms behind a potential VO(2peak) increase. Forty-eight clinically stable HTx recipients18 years old and 1-8 years after HTx underwent maximal exercise testing on a treadmill and were randomized to either exercise group (a 1-year HIIT-program) or control group (usual care). The mean ± SD age was 51 ± 16 years, 71% were male and time from HTx was 4.1 ± 2.2 years. The mean VO(2peak) difference between groups at follow-up was 3.6 [2.0, 5.2] mL/kg/min (p0.001). The exercise group had 89.0 ± 17.5% of predicted VO(2peak) versus 82.5 ± 20.0 in the control group (p0.001). There were no changes in cardiac function measured by echocardiography. We have demonstrated that a long-term, partly supervised and community-based HIIT-program is an applicable, effective and safe way to improve VO(2peak) , muscular exercise capacity and general health in HTx recipients. The results indicate that HIIT should be more frequently used among stable HTx recipients in the future.

Transcatheter aortic valve implantation (TAVI) offers a new treatment option for patients with severe symptomatic aortic valve stenosis, classified as "inoperable". The purpose of the study was to reveal the association between ascertained hospital costs with the actual patient Diagnosis-Related Group (DRG).We examined 50 consecutive patients who underwent either transapical TAVI, (TAVI-TA) or transfemoral TAVI (TAVI-TF) with the Edwards SAPIEN valve and CoreValve(®) between September 2009 and August 2011.Fourty-nine patients had successful valve deployment. Seven patients died within 30 days of the operation. The mean length of hospital stay for TAVI-TA was 199 hours (range 77-362), and the mean costs for TAVI-TA were 55,690 US$. For TAVI-TF the mean length of hospital stay was 170 hours (range 49-276) and the mean costs were 52,087 US$.There was no significant difference between TAVI-TA and TAVI-TF patient characteristics. There was a significant discrepancy between actual hospital costs and the current Norwegian DRG reimbursement for the TAVI procedure. This discrepancy can be partly explained by excessive costs related to the introduction of a new program with new technology. Costly innovations should be considered in price-setting of reimbursement for novel technology.