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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.

We have previously demonstrated that accelerometer-based vibration analysis detects thromboembolism and pump thrombosis in HeartWare Left Ventricular Assist Device (HVAD) using the third harmonic frequency (pump_speedx3). Thromboembolism also affected the amplitude of the nonharmonic frequencies. The aim of this study was to determine whether nonharmonic-amplitude (NHA) analysis can improve the diagnosis of thromboembolic complications. An accelerometer was attached to HVAD in three in vitro and seven in vivo experiments. Control interventions, including load and pump speed alternations (n = 107), were followed by thromboembolic events (n = 60). A sliding fast-Fourier-transform was analyzed, and changes in NHAs were quantified in the acute phase and in a steady state. Receiver operating characteristic curves were constructed with cutoff values of NHA to detect thromboembolic events. Positive predictive values were calculated on the basis of a specificity of 1. In the acute phase, NHA change was 6.5 times higher under thromboembolism than under control interventions (p0.001). Most thromboembolic events lead to concomitant changes in both NHA and third-harmonic amplitude. Combining the two methods improved the PPV by 8.3%. At steady state, signal changes predominantly demonstrated either NHA or third-harmonic changes. Combined signal analysis improved the PPV by 36%. This method enhanced the detection of thromboembolism and pump thrombosis in the HVAD.

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.

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.

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.

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 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.

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.

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.

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: The biocompatibility of cardiopulmonary bypass surfaces has been improved by heparin and polymer surface modifications. The present study compared the effect of two such coatings on the inflammatory reactions after open heart surgery. Methods:Thirty patients undergoing elective heart surgery were randomly assigned to receive one of two types of coated circuits: Bioline (n=15) or phosphorylcholine (Phisio, n=15). The platelet and leukocyte counts, neutrophil activation (myeloperoxidase), complement activation (C3a and TCC), concentrations of lactate dehydrogenase, 27 cytokines (including interleukins, chemokines and growth factors), thrombin-antithrombin complexes, and the endothelial cell marker syndecan-1 were analyzed at five predetermined time points until 24 hrs post operatively. Results: Most measurements were comparable in both groups. However, myeloperoxidase was significantly higher in the Bioline group (p < 0.001). Postoperative lactate dehydrogenase concentrations were significantly higher in the Phisio group (p

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 increasing prevalence of chronic heart failure has stimulated the ongoing development of left ventricular assist devices (LVADs) for both bridge-to-transplant (BTT) and destination therapy (DT). The aim of this prospective, multicenter clinical trial was to determine the efficacy and safety of a third-generation LVAD, the VentrAssist, in a BTT cohort. Methods Patients (n = 33) with end-stage chronic heart failure who required circulatory support as BTT therapy were implanted with a VentrAssist device. The primary outcome was survival until transplant or transplant eligibility with the device in situ at trial end-point (Day 154 after implant). The secondary outcomes were pump flow index and end-organ function. Safety, patient functional status and resource use were also assessed. Results At trial end-point, the success rate was 82% (39.4% transplanted, 42.4% transplant-eligible). The LVAD pump flow index (median ≥2.7 liters/min/m 2 ) was sufficient to maintain an adequate circulation and significantly improve end-organ function. Of the 77 protocol-defined serious adverse events, most occurred within 30 days of implantation. No patients died as a direct result of pump failure or malfunction. After implantation, patient functional status improved, with 70% of patients achieving hospital discharge, and resource use was reduced. Conclusions This trial demonstrated a favorable efficacy and safety profile for use of the VentrAssist LVAD in BTT patients.

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

ALCAPA, anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital disease. We have from 1990 to 2003 operated on seven patients in our clinic. The objective of this study was to describe our experience of treating the condition and to remind other doctors of it as a possible diagnosis.The patients were identified by a retrospective review of our clinical records.Symptoms and signs varied from discomfort and pathologic heart murmur to ventricular fibrillation. All patients were operated on by use of cardiopulmonal bypass. Two died postoperatively within one week, two were reoperated later on because of pulmonary artery stenosis.ALCAPA should be suspected if a young patient with no previous history of heart failure presents with dyspnoe, chest pain or dysrhythmia. ALCAPA must be excluded by coronary angiography in younger patients with mitral insufficiency and no other morphological findings. Patients diagnosed early and operated on have a good prognosis.

Transplant-associated coronary artery disease (TxCAD) appears to be initiated by endothelial cell activation and inflammation involving inflammatory cytokines and chemokines. Osteoprotegerin (OPG) and receptor activator of nuclear Factor-kappaB ligand (RANKL) have been implicated in cardiovascular disease progression and we measured the expression of these mediators in serum and myocardial biopsies taken serially during the first year after heart transplantation (HTx), relating them to the development of TxCAD. Serum OPG as well as myocardial gene expression of RANK and OPG, but not RANKL, were highest early after HTx and declined progressively. Importantly, patients who develop TxCAD or experience episodes of acute rejection showed a lower myocardial RANKL expression throughout the first year after transplantation than patients without these complications. Our findings may suggest an unrecognized role RANKL in maintaining myocardial and/or endothelial integrity and suggest that RANKL should be further investigated as a parameter that may predict development of TxCAD.

Saethre M, Lea T, Borgen MS, Fiane AE, Michaelsen TE, Thorsby E, Haraldsen G, Mollnes TE. Human complement-activating immunoglobulin (Ig)G3 antibodies are essential for porcine endothelial cell activation. Xenotransplantation 2006; 13: 215–223. © Blackwell Munksgaard, 2006 Abstract: Background: Complement-activating naturally occurring anti-porcine endothelial cell antibodies (Abs) are responsible for hyperacute rejection in porcine-to-primate transplantation, whereas the role of complement in acute vascular rejection, characterized by type II endothelial cell activation, is less well understood. We previously demonstrated a correlation between porcine type II endothelial cell activation, as detected by E-selectin expression, and human immunoglobulin (Ig)G3 anti-Galα1-3Gal (Gal) Abs, which was not seen for IgG1, IgG2 or IgG4. The present study was undertaken to investigate whether there is a causal relationship between human anti-porcine IgG3 Abs and porcine endothelial cell activation. Methods: IgG3 was isolated employing a Protein A column to 98.3% purity. Porcine endothelial cells were incubated with isolated human IgG3 or the combination of IgG1, IgG2 and IgG4. E-selectin expression and complement activation were investigated by flow cytometry and Western blotting, respectively. Results: Purified IgG3, in contrast to the other IgG subclasses, induced a substantial increase in E-selectin expression. This activation was accompanied by complement activation as detected by C3 cleavage, and was abolished by heat inactivation or by adding the complement inhibitor FUT-175. Depletion of anti-Gal Abs reduced E-selectin expression by 60%, consistent with the presence of complement-activating anti-porcine non-Gal Abs of the IgG3 subclass. Conclusions: Collectively, these data strengthen the hypothesis that human anti-porcine endothelial cell Abs of the IgG3 subclass are essential for endothelial cell activation in porcine-to-human species grafts and demonstrate such activation to be partly independent of Gal epitopes.

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 (

Background. The possibility that human cytomegalovirus (HCMV) may infect porcine endothelial cells (ECs) was investigated. This may be relevant during xenotransplantation of porcine cells or organs into human recipients. Methods. HCMV was inoculated into low-passage porcine ECs. Replication of virus was detected by development of characteristic cytopathogenic effect. Appearance of immediate early, early, and late antigens was studied by immunocytochemical staining. Infectious virus was detected in human fibroblast cells. Presence of HCMV RNA was studied by Northern Blot and reverse transcriptase polymerase chain reaction. Results. All parameters indicated that a fresh clinical HCMV isolate productively infects porcine ECs. The same cells do not fully support replication of the laboratory strain Ad 169. Conclusion. Our results may indicate the possibility of cross-species infectivity of HCMV to porcine cells.

“When outcomes are consistently good beyond 2 years the devices will be seen not only as a bridge to transplantation but as a feasible alternative to transplantation … .” Editorial Comment: Journal...

Compstatin, a newly described C3-binding peptide, inhibits complement activation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft model. Pig kidneys were perfused with fresh human blood containing either Compstatin (n=6) or a control agent (n=6). Graft survival and activation of complement, leukocytes and platelets both in the fluid-phase and in the tissue were examined. The survival of the Compstatin-perfused kidneys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly and equally activated in both groups during the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but no increase occurred in the Compstatin group during this period. Immunohistochemistry showed less C3 and fibrin deposition and immune electron microscopy showed less terminal SC5b-9 complement complex deposition in the Compstatin group. A significant change in total white cells, neutrophils, myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62L (L-selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significant. There were no differences in platelet counts, thrombospondin, soluble P-selectin or beta-thromboglobulin between the groups. We conclude that Compstatin prolongs graft survival and suggest that it may be a useful agent for attenuating hyperacute rejection by inhibiting C3 and thus terminal complement pathway activation.

s S123 on the wait-list. There was no increased risk of death (OR 1.00, 95% CI 0.791.26; P= 0.96) or deterioration (OR 1.15, 95% CI 0.94-1.40; P= 0.18) for Medicaid patients on the wait-list compared to those with private insurance. Conclusion: Male Medicaid patients who are status 1 are more likely to undergo LVAD placement while awaiting HT. Despite their sicker clinical profile at listing, wait-list outcomes for Medicaid patients are equivalent to those with private insurance.

s S133 OT analysis showed in EVE group (42/93 patients) a lower incidence of MACE (0% vs 15±5.3% p= 0.02), similar mortality (9.2±5.2% vs 11.5±5.0%, p= 0.52) and a promising lower estimated incidence of cancers (at 10 yrs 10±5.6% vs. 39.4±16.1%, p= 0.34). ITT and OT analysis showed a similar GFR one and five years after HTx in both groups. Conclusion: This is a single-center post-hoc analysis of long-term outcomes in patients initially randomized in trials with different endpoints. While confirming major problems in maintaining the assigned EVE therapy in the early post-HTx period, we found suggestive evidence of potential long-term benefits of EVE in reducing MACE and cancers. Although these data are only hypothesis generating, they suggest a delayed introduction of EVE to favor tolerability, aiming to take better advantage of its possible long-term benefits.

Inadequate supplies of human organs for transplantation have evoked an escalating interest in human xenotransplantation. Hyperacute rejection precludes use of discordant organs. We have developed an ex vivo perfusion model in order to evaluate hyperacute rejection in a pig-to-human combination. Pig kidneys (n = 6) perfused with human blood deteriorated rapidly and rejection was seen after 70 (60–87) min (median, 95% confidence interval). Kidneys perfused with pig blood survived 300 (216–360) min, corresponding to the upper time limit of the model. Increases in prostaglandin E2 and 6-keto-prostaglandin F1α indicated endothelial activation. Sequential blood samples revealed a strong progressive inflammatory response with reduced leukocyte and platelet counts, granulocyte activation indicated by increased myeloperoxidase, and complement activation, shown by an increase in C3 activation products and the terminal SC5b-9 complement complex. A significant role for classical pathway activation was indicated by formation of C1rs-C1 inhibitor complexes and activation of C4, whereas factor B was not significantly activated. Biopsies at rejection demonstrated hyperacute rejection with inflammatory changes involving the vessels as well as the nephrons. Where the inflammatory markers could be studied in pig blood, activation was less than in human blood. The present discordant xenotransplant model is a valuable adjunct for evaluation of changes occurring in the human blood perfusate as well as in the pig kidney during hyperacute rejection.

We report experimental use of a new device for transcatheter closure of atrial septal defects. The device was implanted in surgically created atrial septal defects in two pigs. The devices were easy to implant, and the procedures were short. Both devices were implanted correctly in the desired position, and closed the defect completely. No procedural complications nor problems were encountered. The technique is certainly worth trying in the clinical setting. The device appears to be particularly favourable for use in children because it can be implanted through a 7 French sheath.

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 (p0.001). 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.

Naturally occurring anti-Galalpha1-3Gal (anti-Gal) antibodies and complement induce hyperacute rejection (HAR) of porcine organs transplanted to primates. If the hyperacute reaction is prevented, an acute vascular rejection (AVR) occurs within hours to few days. Antibodies are important for the development of AVR, whereas the role of complement is still not clarified. AVR is characterized by protein synthesis-dependent endothelial cell (EC) activation. In the present study we investigated the relation between EC activation as measured by E-selectin expression, and the concentrations of anti-Gal antibodies of IgM, IgG and IgG subclasses in sera from 80 healthy blood donors selected on the basis of sex and age. There was a significant correlation between E-selectin expression and the concentration of IgG3 anti-Gal (r=0.39; P=0.019), which was not seen for the other IgG subclasses or for total IgG anti-Gal. A modest, but significant correlation was found between the concentration of IgM anti-Gal and E-selectin expression (r=0.38; P=0.040), but not between IgM and IgG3 anti-Gal. There was a large interindividual variation in anti-Gal antibodies, 50-fold for IgM and 70-fold for IgG. Females had significantly higher concentrations of IgM anti-Gal than males (P=0.0006), which was explained by a substantial increase in IgM anti-Gal concentration in younger women. The concentration of IgG anti-Gal and the degree of E-selectin expression did not differ between sex or age groups. In conclusion, the close correlation between anti-Gal antibodies of the potent complement activating IgG3 subclass and porcine EC activation, may imply that these antibodies play a role in EC activation characteristic of AVR.

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.

Background The current study was undertaken to examine total hospital costs per patient of a consecutive implantation series of two 3rd generation Left Ventricle Assist Devices (LVAD). Further we analyzed if increased clinical experience would reduce total hospital costs and the gap between costs and the diagnosis related grouped (DRG)-reimbursement. Method Cost data of 20 LVAD implantations (VentrAssist™) from 2005-2009 (period 1) were analyzed together with costs from nine patients using another LVAD (HeartWare™) from 2009-June 2011 (period 2). For each patient, total costs were calculated for three phases - the pre-LVAD implantation phase, the LVAD implantation phase and the post LVAD implant phase. Patient specific costs were obtained prospectively from patient records and included personnel resources, medication, blood products, blood chemistry and microbiology, imaging and procedure costs including operating room costs. Overhead costs were registered retrospectively and allocated to the specific patient by predefined allocation keys. Finally, patient specific costs and overhead costs were aggregated into total hospital costs for each patient. All costs were calculated in 2011-prices. We used regression analyses to analyze cost variations over time and between the different devices. Results The average total hospital cost per patient for the pre-LVAD, LVAD and post-LVAD for period 1 was $ 585, 513 (range 132, 640- 1 247, 299), and the corresponding DRG- reimbursement (2009) was $ 143, 192 . The mean LOS was 54 days (range 12- 127). For period 2 the total hospital cost per patient was $ 413, 185 (range 314, 540- 622, 664) and the corresponding DRG- reimbursement (2010) was $ 136, 963. The mean LOS was 49 days (range 31- 93). The estimates from the regression analysis showed that the total hospital costs, excluding device costs, per patient were falling as the number of treated patients increased. The estimate from the trend variable was -14, 096 US$ (CI -3, 842 to -24, 349, p