A pooled analysis of posttransplant survival following combined heart-liver transplantation.

Because no single center has accumulated a large experience with this complex operation, the effectiveness of combined orthotopic heart transplantation (OHT) and orthotopic liver transplantation (OLT) in achieving long-term survival has been unknown. Cases of OHT-OLT were pooled from a U.S. transplant recipient registry and from previously published literature. Aggregate data from these sources was used for survival analysis. Thirty-six patients having undergone OHT-OLT were listed in the national registry; the one- and five-year patient survival rates of these patients were 88% and 78%, respectively. Many patients remain alive at 8+ years after transplantation. An analysis of the pooled results of previously-published cases estimated a one-year patient survival rate of 84%. In selected disease processes, OHT-OLT can correct underlying metabolic deficiencies. While rarely indicated, OHT-OLT is a successful treatment for patients with end-stage heart and liver disease, with survival comparable to that seen after isolated orthotopic heart or orthotopic liver transplantation.

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.

Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

Placement of a left ventricular assist device in a patient with dextrocardia.

Dextrocardia most commonly presents in the setting of situs inversus, but it may occur as an isolated anomaly with normal position of the abdominal organs. Herein we present a 54-year-old man with ischemic cardiomyopathy and dextrocardia with normal position of the abdominal organs who presented with an exacerbation of congestive heart failure requiring inotropic support as well as mechanical ventilation. An implantable, wearable left ventricular assist device was placed in this patient to allow for ambulation and eventual discharge home. The patient survived 4 months before he developed pneumonia and expired.

Technique for repair of fractures and separations involving the cartilaginous portions of the anterior chest wall.

Internal fixation of the ribs has been shown in numerous studies to decrease complications following traumatic rib fractures. Anterior injuries to the chest wall causing cartilaginous fractures, although rare, can cause significant disability and can lead to a variety of complications and, therefore, pose a unique clinical problem. Here, we report the surgical technique used for four patients with internal fixation of injuries to the cartilaginous portions of the chest wall treated at our center. All patients had excellent clinical outcomes and reported improvement in symptoms, with no associated complications. Patients who have injuries to the anterior portions of the chest wall should be considered for internal fixation of the chest wall when the injuries are severe and can lead to clinical disability.

Angiotensin Inhibition Is Associated with Preservation of T-Cell and Monocyte Function and Decreases Multiple Organ Failure in Obese Trauma Patients.

BACKGROUND: Obese patients are more prone to post-injury multiple organ failure (MOF). Obesity pathophysiology includes an adipose-tissue-derived, renin-angiotensin-aldosterone system affecting inflammatory responses via leukocyte angiotensin receptors. We hypothesized that obese patients receiving pre-injury angiotensin-converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB) therapy would have decreased MOF and differences in immune cell frequencies. STUDY DESIGN: We analyzed the Inflammation and the Host Response to Injury trauma-related database. Patients receiving pre-injury ACE or ARB were stratified as obese (BMI >30 kg/m(2)) or nonobese (BMI <30 kg/m(2)). Groups were age, sex, and Injury Severity Score matched against patients not receiving this therapy. Primary end points were Marshall Multiple Organ Dysfunction Score, Denver-2 Postinjury MOF Score, leukocyte markers on T cells, and monocytes measured by flow cytometry. RESULTS: We evaluated 1,932 patients. One hundred and ten were receiving pre-injury ACE/ARB; 94 patients had data available to calculate BMI. Obese patients receiving ACE/ARB showed maximum Marshall (5.83 ± 2.87) and Denver-2 (2.45 ± 2.32) scores similar to nonobese patients receiving or not receiving ACE/ARB, and obese patients not receiving ACE/ARB had significantly higher Marshall (6.49 ± 2.57; p = 0.009) and Denver-2 (3.33 ± 2.21; p = 0.006) scores. Leukocyte analysis suggested improved T-cell function and monocyte maturation in obese patients on ACE/ARB. CONCLUSIONS: Obese patients receiving preinjury ACE/ARB therapy demonstrate post-injury MOF scores similar to nonobese patients; obese patients not receiving these medications have greater post-injury MOF. Leukocyte analysis demonstrates improved immune regulation. Modulation of the renin-angiotensin-aldosterone system pathway might represent a novel therapeutic target in severely injured obese patients.

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.

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.

Impact of left ventricular assist device (LVAD)-mediated humoral sensitization on post-transplant outcomes.

BACKGROUND: Humoral sensitization, defined as a panel-reactive antibody (PRA) screen of >10%, places heart transplant recipients at a greater risk of acute rejection and mortality. Previous studies have suggested an increased sensitization in left ventricular assist device (LVAD) recipients, although neither the impact of device selection nor the clinical importance of elevated PRA in these patients has been completely described. METHODS: Using the registry of the International Society for Heart and Lung Transplantation (ISHLT), we compared PRA levels in 7,686 heart transplant recipients to determine the impact of LVAD therapy on humoral sensitization, acute rejection and mortality. To determine the impact of device selection on sensitization, we compared data from the ISHLT registry as well as from our own institution. RESULTS: Elevated PRA levels were found in 16.6% of LVAD recipients, compared with 7.6% of non-LVAD controls (p < 0.0001). Sensitization differed by device type, being present in 21.9% of Thoratec recipients, 14.4% of HeartMate recipients, and 15.5% of Novacor recipients (p = 0.01). Despite these findings, LVAD use had no impact on rejection rates. LVAD use was associated with a small increase (4.4% and 4.3%, respectively) in 1- and 2-year mortality. CONCLUSIONS: These findings support the concept that mechanical circulatory support increases the rate of humoral sensitization. However, these differences in sensitization do not translate to substantial differences in the clinical outcomes of rejection and mortality.

Organ-specific regulation of pro-inflammatory molecules in heart, lung, and kidney following brain death.

BACKGROUND: Nonspecific inflammatory events following brain death may increase the intensity of the immunological host response. The present study investigated the course of pro-inflammatory molecules in heart, lung, kidney, and plasma after brain death induction. MATERIALS AND METHODS: Brain death was induced in five pigs by inflation of an intracranial Foley catheter and five pigs were sham-operated as controls. Each experiment was terminated 6 h after brain death/sham operation and the organs were harvested. We measured the mRNA and protein levels for TNF-alpha, IL-1beta, and IL-6 in heart, lung, kidney, and plasma. Additionally, the mRNA expression for IL-6R, ICAM-1, MCP-1, and TGF-beta was determined in each organ. RESULTS: After 6 h, the plasma cytokine levels were higher in the brain-dead animals than in the sham-operated. In heart, lung, and kidney there was an increase in IL-6 and IL-1beta following brain death, while TNF-alpha was up-regulated in lung only (P < 0.05). MCP-1 and TGF-beta were significantly higher in heart and lung and IL-6R increased in heart after brain death (P < 0.05). CONCLUSIONS: Brain death was associated with non-uniform cytokine expression patterns in the investigated organs. These expression patterns may cause variable pro-inflammatory priming resulting in different degrees of damage and explain the organ-specific variation in outcomes after transplantations.

Interaction between isolated human myocardial mast cells and cultured fibroblasts.

INTRODUCTION: Previously, we reported an increase in interstitial collagen and total mast-cell numbers in heart failure versus normal myocardium. A secondary increase, primarily in chymase-negative mast cells, occurred following LVAD support compared to matched pre-LVAD tissue samples and was associated with a decrease in interstitial collagen and bFGF. To further elucidate the changes in interstitial collagen, we investigated the direct interaction between mast cells, isolated from failing myocardium with or without previous LVAD support, and human fibroblasts in a coculture model. Additionally, the expression of HSP-47, the pro-collagen-specific chaperone protein, was determined in the particular myocardium. MATERIALS AND METHODS: Myocardial tissue was obtained from 10 patients with end-stage dilated cardiomyopathy (DCM) at the time of transplantation. Five patients were transplanted following LVAD support, five patients without previous LVAD support. Mast cells were isolated according to a standard protocol, including collagenase digestion and cell separation. The isolated mast cells were co-cultured with human fibroblasts for 12 h, with or without stimulation of degranulation, and protein synthesis was measured by [(3)H]-proline incorporation. HSP-47 immunostaining was performed in the different myocardial samples and the positive cells were quantified. RESULTS: Stimulated mast cells isolated from DCM tissue (without previous LVAD support) caused a 92% increase in [(3)H]-proline incorporation and consequently in protein production in fibroblasts compared to mast-cell free culture (P < 0.01), while conversely stimulated mast cells isolated from LVAD supported myocardium decreased the [(3)H]-proline incorporation by 63% (P < 0.01) below baseline. Nonstimulated mast cells did not significantly alter the protein production over baseline. There was also a significant increase in the number of HSP-47-positive cells in DCM myocardium compared to normal (P < 0.01) and there was a shift toward normal after LVAD support (P < 0.01). CONCLUSION: We demonstrate that fibroblast protein production in vitro is significantly altered by mast cells and that the direction of change is dependent on whether myocardium was supported by LVAD. We suggest that under long-term LVAD support there is a phenotypic alteration in myocardial mast cells, which leads to a change in concentration and/or composition of mediators, capable of re-remodeling the myocardial matrix.