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ABSTRACT: Background: We observed an outbreak of severe opportunistic infections (OIs) among heart transplant patients coincident with a change from muromonab-CD3 (OKT3) to rabbit anti-thymocyte globulin (Thymoglobulin) for induction immunosuppression. The purpose of this study was to describe the outbreak and, because Thymoglobulin use alone would not be expected to result in such a high rate of OIs, to assess for other risk factors.
Methods: Based on the clustering of cases, the outbreak period was defined as May 2005 to December 2006. The preoutbreak period was defined as January 2003 to April 2005. Clinical and demographic data were collected on all patients who received a transplant during this period, and occurrence of OI was tracked on 14 consecutive patients who received a transplant after resolution of the outbreak.
Results: One hundred two patients underwent heart transplantation during the period studied. Thirteen patients developed severe OIs: 10 during the outbreak period (rate, 10/48 [21%]), 2 before the outbreak (2/50 [4%]), and 1 (1/14 [7%]) in limited follow-up after the outbreak. Opportunistic infections included aspergillosis, nocardiosis, disseminated histoplasmosis, cryptococcal meningitis, mucormycosis, and cytomegalovirus syndrome. In multivariate analysis, patients who received a transplant during the outbreak had a higher risk of OI and were more likely to receive Thymoglobulin than patients who received a transplant before the outbreak. Maintenance prednisone dosing in our patients was higher than in other published series of solid organ transplant recipients treated with Thymoglobulin.
Conclusions: Thymoglobulin induction combined with higher maintenance dosing of prednisone may result in a high rate of serious OIs in heart transplant recipients.
Infectious Disease in Clinical Practice 08/2010; 18(5):318-323.
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ABSTRACT: Few studies have examined the association between procedural volume and clinical outcomes in heart transplantation. This retrospective study was performed on a contemporary cohort of heart transplant recipients to better elucidate the effect of transplant center volume on 1-year mortality.
Data from the Scientific Registry of Transplant Recipients were used to analyze the relationship between transplant center volume and short-term survival. Center volume designation (very low, low, medium, and high) was assigned on the basis of quartiles with approximately equal numbers of patients per group. Survival differences were explored using Cox proportional hazards modeling to adjust for differences in variables between volume groups and to determine variables associated with 1-year mortality.
Between January 1, 1999, and May 31, 2005, 13,230 heart transplantations were performed at 147 transplant centers in the United States. Although most recipient and donor characteristics were similar across quartiles, larger volume centers were more likely to perform transplantations in older candidates and accept organs from older donors with longer cold ischemia times. A statistically significant relationship between transplant center volume and 1-year mortality was observed. Compared with the reference group (very low volume), the hazard ratios for the low, medium, and high-volume quartiles were 0.71, 0.64, and 0.56, respectively (P < .001 for each group compared with the reference).
There was a significant association between transplant center volume and 1-year survival. Patients who undergo cardiac transplantation at very low-volume centers are at higher risk for early mortality than those who undergo transplantation in higher-volume centers.
The Journal of thoracic and cardiovascular surgery 02/2010; 139(4):1064-9. · 3.41 Impact Factor
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ABSTRACT: The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM).
Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM. Proteasome proteolytic activities were markedly reduced in failing and HCM hearts compared with nonfailing hearts (P<0.01). This activity was partially restored after mechanical unloading in failing hearts (P<0.01) and was significantly lower in HCM hearts with pathogenic sarcomere mutations than in those lacking these mutations (P<0.05). There were no changes in the protein content of ubiquitin proteasome system subunits (ie, 11S, 20S, and 19S) or in active-site labeling of the 20S proteolytic subunit beta-5 among groups to explain decreased ubiquitin proteasome system activity in HCM and failing hearts. Examination of protein oxidation revealed that total protein carbonyls, 4-hydroxynonenylated proteins, and oxidative modification to 19S ATPase subunit Rpt 5 were increased in failing compared with nonfailing hearts.
Proteasome activity in HCM and failing human hearts is impaired in the absence of changes in proteasome protein content or availability of proteolytic active sites. These data provide strong evidence that posttranslational modifications to the proteasome may account for defective protein degradation in human cardiomyopathies.
Circulation 02/2010; 121(8):997-1004. · 14.74 Impact Factor
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Stuart D Russell,
Joseph G Rogers,
Carmelo A Milano, David B Dyke,
Francis D Pagani,
Juan M Aranda,
Charles T Klodell,
Andrew J Boyle,
Ranjit John,
Leway Chen,
H Todd Massey,
David J Farrar,
John V Conte
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ABSTRACT: The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail.
We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time. Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37+/-14 to 23+/-10 mg/dL (P<0.0001) and from 1.8+/-0.4 to 1.4+/-0.8 mg/dL (P<0.01), respectively. There were decreases in aspartate transaminase and alanine transaminase in the above-normal groups from 121+/-206 and 171+/-348 to 36+/-19 and 31+/-22 IU (P<0.001), respectively. Total bilirubin for the above-normal group was 2.1+/-0.9 mg/dL at baseline; after an acute increase at week 1, it decreased to 0.9+/-0.5 mg/dL by 6 months (P<0.0001). Both renal and liver values from patients in the normal groups remained normal during support with the left ventricular assist device.
The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period.
Circulation 11/2009; 120(23):2352-7. · 14.74 Impact Factor
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David R Fermin,
Ana Barac,
Sangjin Lee,
Sean P Polster,
Sridhar Hannenhalli,
Tracy L Bergemann,
Suzanne Grindle, David B Dyke,
Francis Pagani,
Leslie W Miller,
Sarah Tan,
Cris Dos Remedios,
Thomas P Cappola,
Kenneth B Margulies,
Jennifer L Hall
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ABSTRACT: We report the first comprehensive analysis of gene expression differences by sex and age in left ventricular samples from 102 patients with dilated cardiomyopathy.
Gene expression data (HG-U133A gene chip, Affymetrix) were analyzed from 30 females and 72 males from 3 separate centers. More than 1800 genes displayed sexual dimorphism in the heart (adjusted P value <0.05). A significant number of these genes were highly represented in gene ontology pathways involved in ion transport and G-protein-coupled receptor signaling. Localization of these genes revealed enrichment on both the sex chromosomes as well as chromosomes 3, 4, and 14. The second goal of this study was to determine the effect of age on gene expression. Within the female cohort, >140 genes were differentially expressed in the <55 years age group compared with the >55 years age group. These genes were highly represented in gene ontology pathways involved in DNA damage. In contrast, zero genes in the male cohort <55 years met statistical significance when compared with the >55 years age group.
Gene expression in dilated cardiomyopathy displayed evidence of sexual dimorphism similar to other somatic tissues and age dimorphism within the female cohort.
Circulation Cardiovascular Genetics 12/2008; 1(2):117-25. · 6.11 Impact Factor
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ABSTRACT: Continuous-flow rotary pumps with axial design are increasingly used for left ventricular assist support. The efficacy of this design compared with pulsatile, volume displacement pumps, with respect to characteristics of left ventricular unloading, and exercise performance remains largely unstudied.
Thirty-four patients undergoing implantation with a pulsatile, volume displacement pump operating in a full-to-empty cycle (HeartMate XVE; Thoratec Inc, Pleasanton, Calif; n=16) or continuous-flow rotary pump with an axial design operating at a fixed rotor speed (HeartMate II; Thoratec Inc; n=18) were evaluated with right heart catheterization and echocardiography preoperatively and at 3 months postoperatively and cardiopulmonary exercise testing 3 months postoperatively. Support with either the XVE or II resulted in significant (P<0.05) increases in cardiac output and reduction in mean pulmonary artery and pulmonary wedge pressures. Exercise capacity at 3 months was similar between groups (% predicted peak VO2-XVE: 46.8+/-10.2 versus II: 49.1+/-13.6). Echocardiography at 3 months demonstrated a significantly (P<0.05) greater reduction in left ventricular end-diastolic volume (-49+/-16% versus -35+/-20%), left ventricular end-systolic volume (-59+/-20 versus -37+/-21%), and percent mitral valve regurgitant volume (-99+/-2% versus -52+/-56%) for the XVE compared with II, respectively.
The HeartMate XVE or II provided equivalent degrees of hemodynamic support and exercise capacity. The XVE was associated with greater left ventricular volume unloading. Characteristics of left ventricular pressure and volume unloading between these pump designs and mode of operation do not influence early exercise performance.
Circulation 09/2007; 116(11 Suppl):I8-15. · 14.74 Impact Factor
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ABSTRACT: Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.
American Journal of Transplantation 02/2004; 4 Suppl 9:38-53. · 6.39 Impact Factor
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Hakan Oral,
Natarajan Sivasubramanian, David B Dyke,
Rajendra H Mehta,
P Michael Grossman,
Kerri Briesmiester,
William P Fay,
Francis D Pagani,
Steven F Bolling,
Douglas L Mann,
Mark R Starling
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ABSTRACT: In an animal model, stretch was shown to induce myocardial tumor necrosis factor-alpha (TNF-alpha) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF-alpha expression and whether there is a relationship between TNF-alpha expression and LV remodeling.
Plasma TNF-alpha and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23+/-12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF-alpha were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF-alpha (3.59+/-1.81 versus 2.03+/-1.02 pg/mL, P<0.005) and its receptor levels were elevated in MR patients. Myocardial TNF-alpha mRNA copies (corrected for beta-actin mRNA expression) in MR patients and donor hearts were 38.96+/-42.74x10(6) and 0.88+/-0.75x10(6), respectively (P=0.01). After MV surgery, there was a decrease in the plasma levels of TNF-alpha (2.79+/-1.14 versus 3.51+/-1.34 pg/mL, P=0.02) and its receptors. There was a correlation between myocardial TNF-alpha expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF-alpha expression and regression in LV end-diastolic (r=-0.76, P=0.007) and end-systolic (r=-0.73, P=0.01) volumes after MV surgery.
TNF-alpha is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF-alpha expression. There is a relationship between TNF-alpha expression and parameters of LV remodeling, suggesting that TNF-alpha may play a role in the pathogenesis of the LV remodeling that occurs in MR.
Circulation 02/2003; 107(6):831-7. · 14.74 Impact Factor
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ABSTRACT: We sought to determine the survival experiences of patients bridged to heart transplantation with either intravenous (IV) inotropes or an implantable left ventricular assist device (LVAD).
Because of the operative risks of LVAD implantation and the reported lower mortality associated with inotropic therapy, bridging to heart transplantation with inotropes is thought to be the preferred treatment option.
Between April 1, 1996, and May 10, 2001, a total of 104 patients were bridged to heart transplantation with either IV inotropes (n = 38) or an implantable LVAD (n = 66; HeartMate). Survival was compared (Kaplan-Meier method) for three periods: survival to transplantation, post-transplantation survival and overall survival (i.e., survival from the onset of bridging to follow-up).
Survival to transplantation was 81 +/- 5% at three months for the LVAD group and 64 +/- 11% for the inotrope group (p = NS). Post-transplantation survival was 95 +/- 4% at three years for the LVAD group (two deaths) and 65 +/- 10% at three years for the inotrope group (nine deaths; p = 0.007). Overall survival was 77 +/- 6% at three years for the LVAD group and 44 +/- 9% at three years for the inotrope group (p = 0.01).
Overall survival for patients who were bridged to heart transplantation with an implantable LVAD was superior to that of patients who were bridged with inotropes. Bridging to transplantation with an implantable LVAD improves utilization of donor hearts.
Journal of the American College of Cardiology 05/2002; 39(8):1247-54. · 14.16 Impact Factor
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ABSTRACT: Pravastatin and simvastatin prolong survival and reduce transplant-related coronary vasculopathy, although low-density lipoprotein (LDL) lowering with these agents is only modest. The objective of this study was to assess the safety of moderate dose atorvastatin and its efficacy when prior treatment with another statin had failed to lower LDL to < 100 mg/dl.
Data from 185 patients were retrospectively evaluated for adverse events, duration of exposure (person-days), and the mean atorvastatin dose exposure. Changes in lipid parameters, and prednisone and cyclosporine doses were determined.
Safety: 48 patients received atorvastatin for 24,240 person-days at a mean dose exposure of 21 +/- 10 mg. Rhabdomyolysis, myositis, myalgias, and hepatotoxicity occurred in 0, 2, 2, and 0 patients, respectively. All events occurred at the 10-mg dose, within the first 3 months, and were rapidly reversible with atorvastatin discontinuation. Efficacy: Thirty-four patients evaluable for efficacy analyses had a pre-atorvastatin LDL of 145 +/- 38 mg/dl on the following statins: pravastatin (n = 30, 40 +/- 0mg), fluvastatin (n = 3, 33 +/- 12 mg), simvastatin (n = 1, 40 mg). After atorvastatin (21 +/- 9 mg/day) for 133 +/- 67 days, LDL was reduced to 97 +/- 24 mg/dl (relative reduction 31 +/- 20%, p < 0.0001). At the end of the observation period (418 +/- 229 days, atorvastatin final dose 24 +/- 14 mg/day), LDL was further decreased to 88 +/- 23 mg (relative reduction 37 +/- 17%, p < 0.0001).
Atorvastatin, when used at moderate doses and with close biochemical and clinical monitoring, appears to be safe and is effective in aggressively lowering LDL in heart transplant recipients when treatment with other statins has failed to achieve LDL goals.
The Journal of Heart and Lung Transplantation 03/2002; 21(2):204-10. · 4.33 Impact Factor
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ABSTRACT: Background. Extracorporeal life support (ECLS) is an effective technique for providing emergent circulatory assistance. However, its use in adult patients is associated with poor survival when myocardial function fails to recover. Due to the prolonged waiting times for heart transplantation, ECLS as a bridge to transplant is associated with poor survival. In addition, ECLS has been reported to be a significant risk factor for death after bridging to an implantable left ventricular assist device (LVAD). After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc) in October 1996, we began using ECLS as a bridge to an implantable LVAD and subsequently transplantation in selected high-risk patients.Methods. From October 1, 1996 to December 1, 1999, 60 adult patients presenting with cardiogenic shock were evaluated for circulatory assistance.Results. Twenty-five patients (group 1) with cardiac arrest or severe hemodynamic instability and multiorgan failure were placed on ECLS. Eight patients survived to LVAD implant, 1 was bridged directly to transplant, and 4 weaned from ECLS. Nine patients in group 1 survived to discharge. Thirty patients (group 2) underwent LVAD implant without ECLS. Twenty-three were bridged to transplant, with 22 surviving to discharge. Five patients (group 3) were placed on extracorporeal ventricular assist with 3 bridged to transplant and all surviving to discharge. One-year actuarial survival from the initiation of circulatory support was 36% (group 1), 73% (group 2), and 60% (group 3). One-year actuarial survival from the time of LVAD implant in group 1, conditional on surviving ECLS, was 75% (p = NS compared with group 2).Conclusions. In selected high-risk patients, LVAD survival after initial ECLS was not different from survival after LVAD support alone. An initial period of resuscitation with ECLS is an effective strategy to salvage patients with cardiac arrest or extreme hemodynamic instability and multiorgan injury.
The Annals of Thoracic Surgery 01/2001; · 3.74 Impact Factor
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ABSTRACT: Predicting end-of-life for left ventricular assist devices is important to determine timing of device removal. A retrospective analysis was performed on 46 patients undergoing implantation of the latest HeartMate XVE from July 1, 2003, through March 31, 2006. Devices were assessed by analysis of motor current waveforms and quantification of the titanium or copper particles within dust localized to the driveline vent filter by optical, polarized light, scanning electron microscopy, and energy dispersive x-ray spectroscopy. Assessments were performed monthly for patients supported > or =330 days or for unexpected device alarms. Thirty-one (67%) patients were supported for <330 days and 15 (33%) were supported for > or =330 days. No malfunctions occurred in patients supported <330 days. For patients supported > or =330 days, five had abnormal current waveforms or copper and titanium dust localized to the vent filter. One underwent urgent transplantation, three underwent device replacement (one death; two ongoing), and one is with ongoing support. Of the remaining 10 patients, seven underwent transplantation; two remain on device; and one died while on left ventricular assist device support. There were no unexpected device failures. Bearing wear of the HeartMate XVE is predictable by analysis of current waveforms or titanium and copper dust within the vent filter.
ASAIO journal (American Society for Artificial Internal Organs: 1992) 53(3):298-303. · 1.39 Impact Factor
