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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

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

Aims Transplant-associated coronary artery disease (TxCAD) is a major cause of post-transplant graft failure. The aim of this study was to investigate a possible role of mannose-binding lectin (MBL) deficiency and complement activation in TxCAD. Methods and results In a prospective study of heart transplant recipients ( n =38) with a follow-up of 5.3±1.3 years (range: 0.9–6.6), angiographically verified TxCAD ( n =6) was correlated to plasma MBL, complement activation, and endothelial activation (soluble E-selectin). MBL deficiency (

Severe aortic insufficiency developed in a 56-year-old woman 4 years after cardiac transplantation. Aortic valve replacement was performed with insertion of a 23 mm Carbo Medics mechanical prosthesis. The patient recovered completely and is, 5 months after valvular replacement, in New York Heart Association functional class I.