Heterotopic heart transplantation: the United States experience.

INTRODUCTION: More than 3 decades have passed since the first heterotopic heart transplantation (HHT) was reported. Nowadays, this surgical technique is used rarely, and only in patients who do not qualify for standard orthotopic heart transplantation (OHT). Current indications mainly comprise refractory pulmonary hypertension and a donor-recipient size mismatch (>20%). The objective of this study was to analyze the United States experience with HHT. PATIENTS AND METHODS: The United Network for Organ Sharing (UNOS) database between 1987 and 2007 was analyzed. Patients who underwent heart transplantation were enrolled in this study. Patients with missing transplant dates or history of retransplantation were excluded. RESULTS: A total of 41,379 patients underwent OHT and 178 HHT; 32,361 and 111 patients, respectively, were enrolled. Overall 1-, 5-, and 10-year survival was significantly (P < .001) better in OHT (87.7%, 74.4%, 54.4%) than HHT patients (83.8%, 59%, 35.1%). Survival in patients with transpulmonary gradients (TPG) >15 mmHg was 86.6 %, 73.3%, and 57.4% in the OHT and 93.8%, 64.8%, and 48.6% in the HHT group (P = .35). Pretransplant criteria (HHT versus OHT) with statistically significant differences (P < .05) were as follows (mean + SD): recipient weight, 78.9 + 19.9 versus 74.1 + 23.4 kg; recipient height, 174.9 + 13.9 versus 168 + 25.1 cm; and TPG 12.1 + 7.2 versus 9.6 + 6.3 mmHg. CONCLUSIONS: The results show that HHT remains a feasible option in a highly selected patient population, with overall good results.

Comparison of hemodynamics in the ascending aorta between pulsatile and continuous flow left ventricular assist devices using computational fluid dynamics based on computed tomography images.

This study aims to investigate differences in hemodynamic conditions in the thoracic aorta for pulsatile and continuous-flow left ventricular assist devices (LVADs) using computational fluid dynamics (CFD). Patient-specific models were reconstructed from three patients with continuous-flow LVAD (HeartMate II, Thoratec Corporation) and three patients with biventricular assist devices (Excor, Berlin Heart) where only the aortic part was included in the simulations. CFD simulations were performed with constant inflow for the continuous-flow LVADs and time-varying inflow for the pulsatile devices. Differences in flow patterns, wall shear stress (WSS), and dynamic pressure in the ascending aorta were compared for both cases. Retrograde flow patterns were observed in all cases proximal to the location of the outflow cannula anastomosis site. On average, dynamic pressures derived from the retrograde flow velocities were higher in the continuous-flow group with large variations dependent on the angle of the cannula anastomosis relative to the ascending aorta (continuous group: 0.14 ± 0.2 mm Hg, pulsatile group: 0.013 ± 0.008 mm Hg). Elevated WSS contralaterally to the anastomosis site was observed in three of the six models with higher values for the continuous cases. Lower WSS and reduced pressure in the ascending aorta, both favorable hemodynamic conditions, were found in pulsatile versus continuous-flow LVADs by means of CFD. These findings indicate, along with clinical observations reported by others, the superior performance of pulsatile LVADs.

Integration of the computational fluid dynamics technique with MRI in aortic dissections.

Short-term and long-term prognosis and their determining factors of Type III/Stanford B aortic dissections (TB-AD), which separate the aorta distal at the origin of the subclavian artery into a true lumen and false lumen, have been elusive: One quarter of patients thought to be treated successfully, either by medical or by surgical means, do not survive 3 years. Unfavorable hemodynamic conditions are believed to lead to false lumen pressure increases and complications. A better characterization of TB-AD hemodynamics may therefore impact therapeutic decision making and improve outcome. The large variations in TB-AD morphology and hemodynamics favor a patient-specific approach. Magnetic resonance imaging with its capability to provide high-resolution structural images of the lumen and aortic wall and also to quantify aortic flow and kinetics of an exogenous tracer is a promising clinical modality for developing a deeper understanding of TB-AD hemodynamics in an individual patient. With the information obtained with magnetic resonance imaging, computational fluid dynamics simulations can be performed to augment the image information. Here, an overview of the interplay of magnetic resonance imaging and computational fluid dynamics techniques is given illustrating the synergy of these two approaches toward a comprehensive morphological and hemodynamic characterization of TB-AD.

Influence of LVAD cannula outflow tract location on hemodynamics in the ascending aorta: a patient-specific computational fluid dynamics approach.

To develop a better understanding of the hemodynamic alterations in the ascending aorta, induced by variation of the cannula outflow position of the left ventricular assist device (LVAD) device based on patient-specific geometries, transient computational fluid dynamics (CFD) simulations using the realizable k-ε turbulent model were conducted for two of the most common LVAD outflow geometries. Thoracic aortic flow patterns, pressures, wall shear stresses (WSSs), turbulent dissipation, and energy were quantified in the ascending aorta at the location of the cannula outflow. Streamlines for the lateral geometry showed a large region of disturbed flow surrounding the LVAD outflow with an impingement zone at the contralateral wall exhibiting increased WSSs and pressures. Flow disturbance was reduced for the anterior geometries with clearly reduced pressures and WSSs. Turbulent dissipation was higher for the lateral geometry and turbulent energy was lower. Variation in the position of the cannula outflow clearly affects hemodynamics in the ascending aorta favoring an anterior geometry for a more ordered flow pattern. The new patient-specific approach used in this study for LVAD patients emphasizes the potential use of CFD as a truly translational technique.

Detection of adventitial vasa vasorum and intraplaque neovascularization in carotid atherosclerotic lesions with contrast-enhanced ultrasound and their role in atherosclerosis.

INTRODUCTION: The development of new surrogate markers of atherosclerosis is a crucial goal in the clinical setting, as they may allow physicians to recognize unstable lesions early and identify individuals with vulnerable or unstable lesions who bear an increased risk of future cardio--and cerebrovascular complications. These surrogate markers should be capable of being measured noninvasively using safe and reliable methods. Recently, Nambi et al. demonstrated how the combined measurement of carotid intima media thickness (CIMT) and occurrence of carotid plaques improves the risk prediction of cardiovascular outcomes. These results confirm the value of carotid ultrasound (US) when combined with traditional Framingham risk factors in assessing a patient's risk for atherosclerotic disease. Contrast-enhanced ultrasound (CEUS) is a new imaging approach that is evolving and may become a standard clinical tool for further atherosclerotic risk stratification in the future. The contrast agents used in US imaging are safe, commercially available, and approved for use in echocardiography by the FDA. Thus, CEUS is technically feasible with existing approved commercial equipment and can be performed at the bedside or in an outpatient setting. However, US contrast agents are not yet approved by the FDA for visualization and assessment of the carotid artery and its associated pathologies. The cost effectiveness of CEUS has been shown in the context of gastrointestinal imaging, and CEUS of carotid atherosclerotic lesions is emerging as an approach to complement unenhanced US imaging. By providing the direct visualization of adventitial vasa vasorum (VV) and intraplaque neovascularization, CEUS is capable of depicting two new surrogate markers of atherosclerosis - namely, adventitial VV and intraplaque neovascularization.

Surgical therapy of end-stage heart failure: understanding cell-mediated mechanisms interacting with myocardial damage.

Worldwide, cardiovascular disease results in an estimated 14.3 million deaths per year, giving rise to an increased demand for alternative and advanced treatment. Current approaches include medical management, cardiac transplantation, device therapy, and, most recently, stem cell therapy. Research into cell-based therapies has shown this option to be a promising alternative to the conventional methods. In contrast to early trials, modern approaches now attempt to isolate specific stem cells, as well as increase their numbers by means of amplifying in a culture environment. The method of delivery has also been improved to minimize the risk of micro-infarcts and embolization, which were often observed after the use of coronary catheterization. The latest approach entails direct, surgical, trans-epicardial injection of the stem cell mixture, as well as the use of tissue-engineered meshes consisting of embedded progenitor cells.

Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.

RATIONALE: Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences. OBJECTIVES: To assess whether there is larger-scale genomic instability. METHODS: We performed genome-wide microarray copy number analysis on pulmonary artery endothelial cells and smooth muscle cells isolated from the lungs of patients with PAH. MEASUREMENTS AND MAIN RESULTS: Mosaic chromosomal abnormalities were detected in PAEC cultures from five of nine PAH lungs but not in normal (n = 8) or disease control subjects (n = 5). Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female subjects with mosaic loss of the X chromosome, methylation analysis showed that the active X was deleted. One subject also showed completely skewed X-inactivation in the nondeleted cells, suggesting the pulmonary artery endothelial cell population was clonal before the acquisition of the chromosome abnormality. CONCLUSIONS: Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.

Current status of the MicroMed DeBakey Noon Ventricular Assist Device.

The HeartAttendant programs the controller and sets pump rpm and alarm thresholds. It collects and stores pump parameters when connected to the controller and enables remote monitoring via the Internet. It charges and reconditions the batteries and can provide electrical power from the wall. It eliminates the need for the Clinical Data Acquisition System and the Patient Home Support System. The new controller, in all modes, displays pump flow (L/min), current/amps, power/watts, rpm, and diagnostic and emergency alarms. The HeartAssist 5 is CE-approved in Europe. A new U.S. Food and Drug Administration study of the HeartAssist 5 as a bridge to transplant is being finalized.

Reversal of secondary pulmonary hypertension by axial and pulsatile mechanical circulatory support.

BACKGROUND: Pulmonary hypertension associated with chronic congestive heart failure posses a significant risk of morbidity and death after heart transplantation. Isolated observations suggest that chronic ventricular unloading may lead to normalization of pulmonary pressures and thus render a patient likely to be a heart transplant candidate. METHODS: This study is a retrospective analysis of 9 heart failure patients with secondary pulmonary hypertension (transpulmonary gradient [TPG] > 15 mm/Hg). Two were treated with a pulsatile left ventricular assist device (LVAD) and 7 with an axial-flow LVAD. RESULTS: After LVAD support, mean pulmonary artery pressure decreased from 39 +/- 7 to 31 +/- 5 mm Hg, and the TPG decreased from 19 +/- 3 to 13 +/- 4 mm Hg (p < 0.01). The 1-year Kaplan-Meier survival curve for patients with pre-LVAD TPG > 15 mm Hg vs those with TPG < 15 mm Hg showed no difference in survival (p = 0.6). This finding was supported by analysis of a large multi-institutional cohort obtained from the Organ Procurement and Transplantation Network database, where no differences in survival were found in the same groups. CONCLUSIONS: Pulmonary hypertension that is secondary to congestive heart failure, as defined by a TPG > 15 mm Hg can be reversed by the use of pulsatile and axial-flow LVADs; furthermore, post-transplant survival for patients with secondary pulmonary hypertension treated with an LVAD was no different than for those without pulmonary hypertension who received LVAD support.

Increased expression of stem cell factor and its receptor after left ventricular assist device support: a potential novel target for therapeutic interventions in heart failure.

BACKGROUND: Left ventricular assist devices (LVADs) cause an influx of mast cells into the failing heart, but the underlying mechanism is unknown. This study investigates the potential role of stem cell factor (SCF) and its receptor (c-Kit) in promoting the recruitment of mast cells during heart failure and after LVAD support. METHODS: Myocardial samples were collected from 10 end-stage heart failure patients undergoing LVAD implantation (pre-LVAD) and paired with samples taken at the time of orthotopic heart transplantation (post-LVAD). Biopsies of normal hearts served as controls. We assessed gene expression of SCF and c-Kit. In addition, we stained for SCF, c-Kit, tryptase and chymase, and utilized in situ hybridization to determine the origin of SCF. RESULTS: SCF mRNA and overall mast cell numbers were significantly increased (p < 0.01/p < 0.001) after LVAD support as compared with paired heart failure tissues. c-Kit mRNA was significantly increased post-LVAD compared with normal tissues (p < 0.05). The c-Kit protein was expressed only in cardiac mast cells. SCF mRNA was found in endothelial cells, myocytes and interstitial cells, as confirmed by antibody staining. CONCLUSIONS: LVADs cause an increase of SCF and c-Kit gene expression, which coincides with a surge of mast cells after ventricular unloading. This suggests that SCF functions as an important mediator for the recruitment of mast cells to the mechanically unloaded human heart.

The role of mast cells after solid organ transplantation.

Mast cells are best known as primary responders in allergic reactions, including anaphylaxis and asthma. However, recent studies have shown that mast cells are functionally diverse cells with immunoregulatory properties that influence both the innate and adaptive immunities. Mast cells are capable of producing an array of both proinflammatory and anti-inflammatory mediators, acting as antigen-presenting cells, and expressing a spectrum of costimulatory molecules. Moreover, mast cells seem to confer a certain degree of immune privilege to tissues in concert with T-regulatory cells and are essential players in fibrotic conditions. The following review of the literature serves to further define the role of mast cells in the immunologic reactions affecting transplanted solid organ grafts.

TandemHeart insertion via a femoral arterial GORE-TEX graft conduit in a high-risk patient.

The TandemHeart percutaneous ventricular assist device (pVAD), which provides temporary circulatory support of the left ventricle, can be used in high-risk and hemodynamically unstable patients. The easily inserted TandemHeart provides cardiac support superior to that from the use of intra-aortic balloon pumps. Herein, we discuss TandemHeart implantation via end-to-side femoral arterial grafting in a cardiac patient whose sepsis and multiorgan failure were complicated by coagulopathy and thromboembolism. A 47-year-old woman, on intra-aortic balloon and intravenous inotropic support after an acute myocardial infarction and emergency coronary artery bypass grafting, was transferred to our institution via helicopter. She developed sepsis and multiorgan failure. Her condition was further complicated by coagulopathy and a left-lower-extremity thromboembolism. After 6 weeks of aggressive pharmacologic and intermittent intra-aortic balloon treatment, the patient developed cardiogenic shock and received a TandemHeart pVAD for short-term circulatory support. A GORE-TEX access graft, sewn end-to-side to the femoral artery because of the patient's leg ischemia and very small vessels, served as a conduit for the TandemHeart's femoral arterial inflow cannula. Her difficult circulatory, anatomic, and coagulopathic status stabilized after 2 weeks of TandemHeart support, and she was bridged to the long-term MicroMed DeBakey VAD Child in anticipation of heart transplantation. The case of our patient shows that high-risk patients who have experienced cardiogenic shock with multiorgan failure and coagulopathy can benefit from the TandemHeart pVAD as a bridge to other therapeutic options, even when creative approaches to treatment and to TandemHeart insertion are required.

Mast cell-derived cathepsin g: a possible role in the adverse remodeling of the failing human heart.

BACKGROUND: The role of cardiac mast cells (MCs) in the progression to heart failure has recently become increasingly evident. Cathepsin g is a neutrophil- and mast cell-derived protease, which can convert angiotensin I to angiotensin II and thereby activate the TGF-beta pathway, resulting in myocyte necrosis, hypertrophy, and increased fibrosis. This study focuses on mast cell-derived cathepsin g in the human heart during heart failure and following mechanical unloading by means of heart-assist devices (LVADs). MATERIALS AND METHODS: Myocardial tissue was obtained from 10 patients with end-stage cardiomyopathy at the time of LVAD implantation (pre-LVAD) and following orthotopic heart transplantation (post-LAVD). In addition, biopsies of four normal hearts served as a control group. Paraffin-embedded sections were dual stained for cathepsin g and tryptase, a known marker for mast cells, using standard immunohistochemistry protocols. Total cathepsin g positive mast cells were counted. RESULTS: No cathepsin g positive MCs were found in normal hearts. However, we found evidence for cathepsin g in cardiac MCs in heart failure tissues (pre-LVAD). During heart failure, 46% of total MCs were cathepsin g positive as compared to after mechanical unloading, where only 11% of total MCs were cathepsin g positive (P<0.001). CONCLUSION: Heart failure causes an increase of myocardial MCs. We have provided evidence that cathepsin g positive MCs accumulate during heart failure and their total percentage decreases after ventricular unloading. This coincides with the decrease in myocyte necrosis, hypertrophy, and fibrosis. Thus, cathepsin g may play a role in the progression to heart failure by activating angiotensin II, leading to detrimental effects on the heart.

Decorin-mediated transforming growth factor-beta inhibition ameliorates adverse cardiac remodeling.

BACKGROUND: Implantation of a left ventricular assist device (LVAD) has been shown to induce regression of fibrosis in patients with congestive heart failure (CHF) and improve myocardial function. The mechanism of reverse remodeling after mechanical circulatory support (MCS), however, has not been fully characterized. In this study we examined the anti-fibrotic effects of decorin, an extracellular matrix (ECM) proteoglycan, on the transforming growth factor-beta (TGF-beta) pathway. METHODS: Human myocardial tissue samples were obtained from patients undergoing LVAD implantation and again following subsequent transplantation after a sustained period of MCS. The specimens were examined by utilizing different molecular and histologic techniques, including human cardiac fibroblast in vitro studies. We assessed gene expression, mRNA and protein levels. RESULTS: We found a significant decrease in interstitial fibrosis after MCS, with a decrease in collagen mRNA transcription rates, serving as an indirect measurement of collagen synthesis. Both the mRNA and protein levels of decorin were significantly increased after a period of MCS. Decorin mRNA was up-regulated by 44% after MCS (p < 0.01), which paralleled the increase in interstitial decorin deposition (p < 0.001). In addition, p-SMAD2, a molecular marker downstream of the TGF-beta pathway, was found to be inactivated after MCS (p < 0.02). Moreover, cultured human cardiac fibroblasts exposed to TGF-beta demonstrated decreased collagen production when exogenous decorin was added (p < 0.03). CONCLUSIONS: The decorin molecule is potentially involved in reverse cardiac remodeling, by directly inhibiting the TGF-beta pathway and its pro-fibrotic effects on the failing human heart.

Recurrent device thrombi during mechanical circulatory support with an axial-flow pump is a treatable condition and does not preclude successful long-term support.

The formation of pump thrombus after implantation of axial-flow ventricular assist devices has been described previously. We report a case of recurrent pump thrombus formation in a 63-year-old man who was bridged to heart transplantation with a MicroMed DeBakey ventricular assist device. He was treated with a low, dose-adjusted thrombolytic treatment protocol, and was subsequently successfully bridged to transplantation. Transient pump thrombus formation does not preclude safe long-term support with an axial-flow pump when diagnosed and treated appropriately.

Early mobilization of LVAD recipients who require prolonged mechanical ventilation.

Early mobilization and aggressive physical therapy are essential in patients who receive left ventricular assist devices (LVADs) due to long-term, end-stage heart failure. Some of these patients remain ventilator dependent for quite some time after device implantation. We report our regimen of mobilization with the aid of a portable ventilator, in patients with cardiac cachexia and LVAD implantation. Further, we describe the specific physical therapy interventions used in an LVAD patient who required prolonged mechanical ventilation after device implantation. The patient was critically ill for 5 weeks before the surgery and was ventilator dependent for 48 days postoperatively. There were significant functional gains during the period of prolonged mechanical ventilation. The patient was able to walk up to 600 feet by the time he was weaned from the ventilator and transferred out of the intensive care unit. He underwent successful heart transplantation 6 weeks after being weaned from the ventilator We believe that improving the mobility of LVAD patients who require mechanical ventilation has the potential both to facilitate ventilator weaning and to improve the outcomes of transplantation.