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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.

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.

Rationale: Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM) are increasingly being used for modeling heart disease and are under development for regeneration of the injured heart. However, incomplete structural and functional maturation of hiPSC-CM, including lack of T-tubules, immature excitation–contraction coupling, and inefficient Ca-induced Ca release remain major limitations. Objective: Thyroid and glucocorticoid hormones are critical for heart maturation. We hypothesized that their addition to standard protocols would promote T-tubule development and mature excitation–contraction coupling of hiPSC-CM when cultured on extracellular matrix with physiological stiffness (Matrigel mattress). Methods and Results: hiPSC-CM were generated using a standard chemical differentiation method supplemented with T3 (triiodothyronine) and/or Dex (dexamethasone) during days 16 to 30 followed by single-cell culture for 5 days on Matrigel mattress. hiPSC-CM treated with T3+Dex, but not with either T3 or Dex alone, developed an extensive T-tubule network. Notably, Matrigel mattress was necessary for T-tubule formation. Compared with adult human ventricular cardiomyocytes, T-tubules in T3+Dex-treated hiPSC-CM were less organized and had more longitudinal elements. Confocal line scans demonstrated spatially and temporally uniform Ca release that is characteristic of excitation–contraction coupling in the heart ventricle. T3+Dex enhanced elementary Ca release measured by Ca sparks and promoted RyR2 (ryanodine receptor) structural organization. Simultaneous measurements of L-type Ca current and intracellular Ca release confirmed enhanced functional coupling between L-type Ca channels and RyR2 in T3+Dex-treated cells. Conclusions: Our results suggest a permissive role of combined thyroid and glucocorticoid hormones during the cardiac differentiation process, which when coupled with further maturation on Matrigel mattress, is sufficient for T-tubule development, enhanced Ca-induced Ca release, and more ventricular-like excitation–contraction coupling. This new hormone maturation method could advance the use of hiPSC-CM for disease modeling and cell-based therapy.

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).

Circulating compounds such as drugs and nutritional components might adhere to the oxygenator fibers and tubing during ECMO support. This study evaluated the amount of nutritional supplements adsorbed to the ECMO circuit under controlled ex vivo conditions. Six identical ECMO circuits were primed with fresh human whole blood and maintained under physiological conditions at 36 °C for 24 h. A dose of nutritional supplement calculated for a 70 kg patient was added. 150 mL volume was drawn from the priming bag for control samples and kept under similar conditions. Blood samples were obtained at predetermined time points and analyzed for concentrations of vitamins, minerals, lipids, and proteins. Data were analyzed using mixed models with robust standard errors. No significant differences were found between the ECMO circuits and the controls for any of the measured variables: cobalamin, folate, vitamin A, glucose, minerals, HDL cholesterol, LDL cholesterol, total cholesterol, triglycerides or total proteins. There was an initial decrease and then an increase in the concentration of cobalamin and folate. Vitamin A concentrations decreased in both groups over time. There was a decrease in concentration of glucose and an increased concentration of lactate dehydrogenase over time in both groups. There were no significant alterations in the concentrations of nutritional supplements in an ex vivo ECMO circuit compared to control samples. The time span of this study was limited, thus, clinical studies over a longer period of time are needed. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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.

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.

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.

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.

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.

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.

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac 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.

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.

A 71-year-old woman with severe congestive heart failure and failed mitral valve repair was referred for surgery. Because of her low ejection fraction, a valve-in-ring procedure was suggested. There was a great difference in the given size for the 34-mm Carpentier-Edwards-Physio-Ring and the biggest available transcatheter valve of 29 mm from Edwards. Therefore, we did a “bench test.” We expanded a 29-mm Edwards SAPIEN-XT aortic valve in a 34-mm Carpentier-Edwards-Physio-Ring. It fitted well and turned out circular with good coaptation of the leaflets. Thereafter, a successful transapical mitral valve-in-ring implantation on cardiopulmonary bypass was performed, and additional leads for cardiac resynchronization was placed.

The absence of an effective, easily implantable right ventricular assist device (RVAD) significantly diminishes long-term treatment options for patients with biventricular heart failure. The implantation of a second rotary left ventricular assist device (LVAD) for right heart support is therefore being considered; however, this approach exhibits technical challenges when adapting current devices to produce the lower pressures required of the pulmonary circulation. Hemodynamic adaptation may be achieved by either reducing the rotational speed of the right pump impeller or reducing the diameter of the right outflow cannula by the placement of a restricting band; however, the optimal value and influence of changes to each parameter are not well understood. Hemodynamics were therefore investigated using different banding diameters of the right outflow cannula (3-6.5 mm) and pump speeds (500-4500 rpm), using two identical rotary blood pumps coupled to a pulsatile mock circulation loop. Reducing the speed of the right pump from 4900 rpm (for left ventricle support) to 3500 rpm, or banding the O10 mm (area 78.5 mm²) right outflow graft to O5.4 mm (22.9 mm²) produced suitable hemodynamics. Pulmonary pressures were most sensitive to banding diameters, especially when RVAD flow exceeded LVAD flow. This occurred between O5.3 and O6.5 mm (22.05-38.5 mm²) and speeds between 3200 and 4400 rpm, with the flow imbalance potentially leading to pulmonary congestion. Total flow was not affected by banding diameters and speeds below this range, and only increased slightly at higher values. Both right outflow banding or right pump speed reduction were found to be effective techniques to allow a rotary LVAD to be used directly for right heart support. However, the observed sensitivity to diameter and speed indicate that challenges may be presented when setting appropriate values for each patient, and control over these parameters is desirable.

Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.

Limited information exists about acute renal failure (ARF) early after heart transplantation (HTx). We correlated pre-, per-, and post-operative patient and donor parameters to the risk of developing ARF. We also analyzed the consequences of ARF on kidney function after HTx, risk of later need for chronic dialysis or kidney transplantation, and mortality. In a retrospective study from 1983 to 2007, 145 (25%) of 585 HTx recipients developed ARF, defined as ≥ 26.4 micromol/L or ≥ 50% increase in serum creatinine from pre-operatively to the seventh day post-HTx and/or the need of early post-operative dialysis. Independent risk factors for ARF were intravenous cyclosporine immediately post-operatively (odds ratio [OR] 2.16, 95% CI 1.34-3.50, p = 0.02), donor age (OR 1.02, 95% CI 1.00-1.04, p = 0.02), and pre-operative cardiac output (OR 1.38, 95% CI 1.12-1.71, p = 0.003). The development of ARF was a predictor for short-term survival (≤ 3 months) ranging from 98% for patients who improved their creatinine after HTx vs. 79% for those in need of dialysis (p < 0.001). However, ARF did not predict subsequent end stage renal disease in need of dialysis or renal transplantation. ARF is a common complication post-HTx. As ARF is associated with short-term survival, post-operative strategies of preserving renal function have the potential of reducing mortality. Of avoidable risk factors, the use of intravenous CsA should be discouraged.

Background The prognostic impact of pulmonary hypertension (PH) before and after heart transplantation (HTx) is debated. We investigated: (i) the significance of pre-operative reversible PH on post-operative survival; (ii) the value of recatheterization while on the waiting list; (iii) the evolution of right heart hemodynamics (RHH) after HTx; and (iv) the prognostic impact of PH at 1 year after HTx. Methods We reviewed the records of 500 HTx recipients transplanted between 1983 and 2007. Pre-operatively, a non-PH group (Group 1, n = 365) fulfilled directly our RHH criteria for HTx, while a PH group (Group 2, n = 135) was accepted after reversibility of PH by acute vasodilatory testing. Recatheterization was performed every third month while on the waiting list and repeatedly after transplantation. Results With a follow-up of 6.8 ± 5.1 years and a 50% survival rate of 12.1 ± 5.4 years, our main findings were as follows: (i) Patients with reversible PH on vasodilatory testing had a survival rate similar to that of patients without PH (11.7 ± 0.8 vs 12.1 ± 0.5 years, p = 0.80). (ii) Pre-operative recatheterization was of limited value as RHH remained stable. Five percent of patients died while on the waiting list and 2 improved clinically and were removed. (iii) Mean pulmonary artery pressure (MAP) was reduced from 28 ± 9 and 40 ± 8 mm Hg pre-operatively to 21 ± 7 and 24 ± 6 mm Hg after 2 weeks and 16 ± 7 and 18 ± 8 mm Hg at 3 years in Groups 1 and 2, respectively. (iv) Recipients with MAP >20 mm Hg at 1 year post-HTx had significantly lower survival than those with MAP ≤20 mm Hg (11.5 ± 0.7 vs 15.6 ± 0.6 years, p Conclusions Elevated pulmonary pressure 1 year after HTx provides significant prognostic information regarding long-term outcome, whereas pre-operative reversible PH in this group does not influence survival.

Background It is well established that the treatment of modifiable risk factors can reduce cardiovascular mortality in the general population. However, there is limited data evaluating the importance of modifiable risk factors for survival following heart transplantation (HTx). Hence, we evaluated the prognostic importance of smoking, obesity, hyperglycemia and hyperlipidemia at 1 year after HTx for all-cause and cardiac mortality. Methods We evaluated 381 patients attending their first annual visit post-HTx. Data regarding modifiable risk factors was collected together with other clinical variables. Median follow-up time was 7.4 years. Results In total, there were 122 (32%) deaths and smoking and elevated total cholesterol were independent risk factors for all-cause mortality (adjusted HR 1.6 [ P = .02] and 1.8 [ P = .003], respectively). A significantly higher incidence of cardiac death was noted amongst smokers and patients with elevated total cholesterol. Elevated body mass index and hemoglobin A 1c did not affect prognosis and elevated total cholesterol was not a risk factor once statin therapy commenced at the time of HTx was instituted as protocol. Conclusions Smoking is a risk factor for all-cause and cardiac mortality, but elevated total cholesterol is a risk factor only in the absence of statin therapy being commenced at the time of HTx.

Background: The secondary metabolites of cyclosporine A (CsA), AM19, AM1c and AM1c9, have been indi- cated to be nephrotoxic. The aim of the present pilot study was to investigate the relationship between acute renal failure and CsA metabolite levels, including relevant pharmacokinetic genotypes, following heart transplantation. Methods: Whole-blood samples were drawn the first posttransplant week in 22 patients (median 54 years, range from 27 to 65). Whole blood concentrations of CsA and its six main metabolites were analyzed with a validated HPLC-MS/MS method, and relevant CYP3A5 and ABCB1 genotypes determined. Renal function was monitored daily during the first posttransplant month and also at months 3, 6 and 12. Results: One patient died early posttransplant. Six patients were in need of dialysis directly after transplantation. Nine pa- tients developed sustained impaired renal function, while six had stable renal function. Sustained renal impairment tended to be associated with high levels of toxic metabolites (P=0.08). Six of the patients with possible ABCB1 TTT-haplotype developed renal impairment (P=0.12). Conclusion: The present study indicates that toxic CsA metabolites seems to be associated with development of impaired renal function and together with ABCB1 genotyping they might be promising biomarkers for optimalization of immuno- suppressive drug treatment in future studies.

Background: Clinical and experimental studies suggest a pathogenic role for inflammation in chronic heart failure (HF). LIGHT is a member of the tumour necrosis factor superfamily involved in innate and adaptive immune responses. Aims: We sought to investigate a potential pathogenic role of LIGHT in chronic HF. Methods: We used various clinical and experimental approaches including studies in post-infarction HF rats and in vitro studies of endothelial cells and peripheral blood mononuclear cells (PBMC). Results: Our main findings were: (i) LIGHT and its receptors (i.e., HVEM and lymphotoxin-β receptor) were regulated during experimental HF, with strong expression in the infarcted area accompanied by up-regulation of HVEM in cardiomyocytes and endothelial cells also in the non-ischaemic part of the left ventricle. (ii) Patients with chronic HF had significantly increased expression of LIGHT on CD3+ T-cells accompanied by increased expression of HVEM on monocytes and within the failing myocardium. (iii) LIGHT induced interleukin (IL)-6 expression in endothelial cells. In HF patients, but not in healthy controls, such an IL-6-inducing effect was also seen in LIGHT activated PBMC. Conclusion: Our findings in both clinical and experimental HF may suggest a role for LIGHT signalling pathways in the progression of chronic HF involving IL-6-related mechanisms.