A low voltage activated Ca2+ current found in a subset of human ventricular myocytes.

Low voltage activated (ICa-LVA) calcium currents including Cav1.3 and T-type calcium current (ICa-T) have not been reported in adult human left ventricular myocytes (HLVMs). We tried to examine their existence and possible correlation with etiology and patient characteristics in a big number of human LVMs isolated from explanted terminally failing (F) hearts, failing hearts with left ventricular assist device (F-LVAD) and nonfailing (NF) human hearts. LVA (ICa-LVA) was determined by subtracting L-type Ca2+ current (ICa-L) recorded with the holding potential of -50 mV from total Ca2+ current recorded with the holding potential of -90 mV or -70 mV. ICa- LVA was further tested with its sensitivity to 100 µM CdCl2 and tetrodotoxin. Three HLVMs (3 of 137 FHLVMs) from 2 (N = 30 hearts) failing human hearts, of which one was idiopathic and the other was due to primary pulmonary hypertension, were found with ICa-LVA. ICa-LVA in one FHLVM was not sensitive to 100 µM CdCl2 while ICa-LVA in another two FHLVMs was not sensitive to tetrodotoxin. It peaked at the voltage of -40~-20 mV and had a time-dependent decay faster than ICa-L but slower than sodium current (INa). ICa-LVA was not found in any HLVMs from NF (75 HLVMs from 17 hearts) or F-LVAD hearts (82 HLVMs from 18 hearts) but a statistically significant correlation could not be established. In conclusion, ICa-LVA was detected in some HLVMs of a small portion of human hearts that happened to be nonischemic failing hearts.

Sarcoidosis presenting as massive splenomegaly and severe epistaxis, case report.

Sarcoidosis is a multisystem disorder of unknown etiology. Extrapulmonary sarcoidosis can involve any organ, but isolated spleen involvement is rare. Diagnosis can be challenging as other etiologies may have similar presentations. A 58-year-old African American female presented with life threatening epistaxis, anemia, refractory thrombocytopenia, and massive splenomegaly. Lymphoproliferative, infectious, and autoimmune etiologies were eliminated with laboratory testing and bone marrow biopsy. The patient had multiple splenic artery aneurysms precluding an open diagnostic splenectomy. Partial splenic artery embolization was performed, which normalized the platelet count and resolved the spontaneous bleeding. This allowed diagnostic splenectomy and splenic artery repair to be safely performed. Surgical pathology demonstrated extensive non-caseating granulomas consistent with sarcoidosis. We present this case to demonstrate the omnipotent nature of sarcoidosis and a complex multi-disciplinary approach for successful diagnosis and treatment.

Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.

The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.

Utility of concomitant tricuspid valve procedures for patients undergoing implantation of a continuous-flow left ventricular device.

OBJECTIVE: Patients referred for implantable continuous-flow left ventricular assist devices (cfLVAD) frequently have preoperative right heart failure and tricuspid regurgitation (TR). The objective of this report is to examine early clinical benefits of concomitant tricuspid surgery for these patients. METHODS: Sixty-one of 200 consecutive cfLVAD patients at our institution displayed preimplant right heart dysfunction and significant TR. Thirty-three underwent cfLVAD plus a tricuspid valve procedure (TVP), and 28 had cfLVAD alone. Preimplant characteristics and clinical outcomes were retrospectively studied. As previously described, post-LVAD right ventricular failure was defined as need for right ventricular assist device (RVAD) support or greater than 14 days of intravenous inotropic support. RESULTS: Preimplant characteristics were similar between the 2 groups. Cardiopulmonary bypass time was increased for the group that received concomitant TVPs. The most common TVP consisted of an undersizing ring annuloplasty. The cfLVAD-alone group had greater TR after implant relative to the cfLVAD+TVP group. The cfLVAD-alone group experienced greater postprocedure right ventricular failure relative to cfLVAD+TVP (46.4% vs 18.2%; P < .05). Furthermore, prolonged hospitalization was increased for the cfLVAD-alone group versus the cfLVAD+TVP. Survival was similar between the 2 groups. CONCLUSIONS: Concomitant TVP appears to reduce postprocedure right ventricular failure for patients with significant TR undergoing cfLVAD implantation.

X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.

Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or ß-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.

Clinical impact of concomitant tricuspid valve procedures during left ventricular assist device implantation.

BACKGROUND: Almost 50% of patients referred for implantable left ventricular assist device (LVAD) have significant tricuspid regurgitation (TR). Preoperative TR is associated with negative outcomes but the clinical benefit of concomitant tricuspid valve procedures has not been extensively studied. METHODS: One hundred fifteen patients, undergoing implantable LVADs, were identified as having significant TR by echocardiography prior to their surgical procedure. Patients underwent either LVAD alone (n = 81) versus LVAD plus concomitant tricuspid procedures (n = 34) (29 annuloplasty ring repairs and 5 bioprosthetic replacements.) Preoperative characteristics and hemodynamics, as well as TR severity and clinical outcomes were retrospectively determined from chart and database review and compared for the two groups. RESULTS: Preoperative characteristics and hemodynamics were similar for the two groups. Postoperative TR was markedly reduced for the group undergoing concomitant procedures versus LVAD alone. A temporary right ventricular assist device was required for only one of the 34 cases in which concomitant tricuspid procedures were performed; for patients undergoing LVAD alone, 8 of 81 required right ventricular assist devices. Mean duration of postoperative inotrope utilization was increased for the LVAD alone group versus the group with concomitant tricuspid procedures (10.0 vs 8.0 days, respectively, p = 0.04). The incidence of postoperative renal dysfunction was increased for the LVAD alone group (39%) versus concomitant procedures (21%) (p = 0.05). The LVAD alone group also had a greater mean postimplant length of hospitalization versus the concomitant procedures group (26.0 vs 19.0 days, p = 0.02). Finally, there was a trend toward improved survival for the group with concomitant tricuspid procedures versus LVAD alone. CONCLUSIONS: For patients with significant TR undergoing implantable LVAD procedures, concomitant tricuspid procedures are associated with improved early clinical outcomes.

Impact of tricuspid valve regurgitation in patients treated with implantable left ventricular assist devices.

BACKGROUND: The progression of tricuspid valve regurgitation (TR) and the impact of preoperative TR on postoperative outcomes in patients having left ventricular assist device (LVAD) implantation has not been studied. METHODS: One hundred seventy-six consecutive implantable LVAD procedures were retrospectively reviewed. A total of 137 patients comprised the final study group with complete preimplant characteristics, before and after echocardiogram assessment of TR, and outcomes data. Patients were divided into two groups: insignificant TR (iTR) consisting of those with preimplant TR grades of none, trace, and mild; and significant TR (sTR) consisting of those with moderate and severe TR grades. RESULTS: Relative to patients with iTR, patients with sTR were younger (53.6±12.8 versus 58.4±10.0 years, p=0.02) and more commonly had nonischemic cardiomyopathies (69% versus 38%, p<0.001). The preimplant incidence of iTR and sTR was 51% and 49%. Immediately after the LVAD implant procedure, TR did not significantly change. At late follow-up (156±272 days), 32% had moderate or severe TR. Also, 41% of the original sTR group persisted with moderate or severe TR. Relative to patients with iTR, patients with sTR required longer postimplant intravenous inotropic support (8.5 versus 5.0 days, p=0.02), more commonly required a temporary right ventricular assist device, and had a longer postimplant length of hospital stay (27.0 versus 20.0 days, p=0.03). There was also a trend toward decreased survival for sTR versus iTR (log rank=0.05). CONCLUSIONS: Tricuspid regurgitation is not reduced immediately after LVAD implantation. Significant TR is associated with longer postimplant inotropic support and length of hospital stay.

Reproducibility of left atrial ablation with high-intensity focused ultrasound energy in a calf model.

OBJECTIVE: Achieving transmural tissue ablation might be necessary for successful treatment of atrial fibrillation. The purpose of this study was to evaluate the reproducibility of transmural left atrial ablation using a high-intensity focused ultrasound energy system in a calf model. METHODS: Nine heparinized bovines underwent a beating-heart left atrial ablation with a single application of the high-intensity focused ultrasound device. All animals were acutely killed, and the left atrium was fixed in formalin. Protocolized histological sections (5 µm) were obtained throughout each lesion and prepared with Masson trichrome and hematoxylin and eosin staining. Measurements were performed on a total of 359 slides from the 9 lesions. In addition, fresh left atrial tissues from 18 unused human donor hearts that did not meet the criteria for cardiac transplantation were measured at the site where the high-intensity focused ultrasound device is normally applied. RESULTS: Calf left atrial thickness ranged between 2.5 and 20.1 mm, with a mean of 9.10 mm. High-intensity focused ultrasound ablation consistently produced a 100% transmural lesion in left atrial thickness up to 6 mm. In addition, a transmural lesion was observed in 91% of tissues that were up to 10 mm thick and in 85% that were up to 15 mm thick. Human left atrial thickness ranged between 1.2 to 6 mm, with a mean of 3.7 mm. CONCLUSIONS: Calf left atrial thickness in this study was greater than human left atrial thickness. Human left atrial thickness is generally less than 6 mm, and in this range high-intensity focused ultrasound ablation achieved 100% transmurality. These histological results might correlate with a high success rate of atrial fibrillation ablation by using the high-intensity focused ultrasound system.

Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients.

BACKGROUND: Bleeding is a major cause of morbidity in recipients of continuous-flow left ventricular assist devices (CF-LVAD). A better understanding of the impact of CF-LVAD support on the hemostatic profile is necessary to establish better strategies for anticoagulation therapy and risk assessment for bleeding complications. A prospective multicenter study was conducted to characterize von Willebrand factor (vWF) profiles in patients undergoing CF-LVAD implantation. METHODS: Blood samples were collected before and after CF-LVAD implantation from 37 patients between July 2008 and April 2009 at Duke University and the University of Minnesota. Blood samples were analyzed for vWF, platelet and collagen-binding ability. The presence of high-molecular-weight (HMW) vWF multimers were detected through gel electrophoresis, and deficiency was graded on a scale of 0 (normal) to 3 (severe loss). RESULTS: All 37 patients exhibited significant loss of HMW vWF multimers within 30 days of CF-LVAD implantation. Ten of the 37 patients experienced bleeding complications after CF-LVAD placement. CONCLUSIONS: All CF-LVAD recipients had acquired von Willebrand syndrome after LVAD placement, demonstrated by reduced or absent HMW vWF multimer levels. However, not all recipients had bleeding complications. These findings suggest that loss of HMW vWF multimers alone cannot predict bleeding risk. Further refinement of laboratory techniques and a larger follow-up is required to identify risk factors for bleeding in CF-LVAD recipients.

Impact of left ventricular assist device bridging on posttransplant outcomes.

BACKGROUND: Bridge to heart transplantation with a left ventricular assist device (LVAD) can be a promising therapy for patients who are not effectively stabilized with conservative measures. However, referral for LVAD therapy may be limited secondary to reports of poor outcomes when mechanical circulatory support is required before transplantation. METHODS: A retrospective review was undertaken to evaluate outcomes in United Network of Organ Sharing (UNOS) status 1 heart transplant recipients who were bridged to transplant with an implantable LVAD or with intravenous inotropes only from 1994 to 2007. Preoperative characteristics, posttransplant survival, and postoperative complications were compared between 86 patients with an implantable LVAD and 173 patients bridged with intravenous inotropes only. RESULTS: The patients had similar baseline characteristics and pretransplant hemodynamics. Hemodynamics in the LVAD group, as measured by cardiac index, pulmonary vascular resistance, central venous pressure, and pulmonary capillary wedge pressure, significantly improved during mechanical support. Short-term and long-term posttransplant survival and the incidence of posttransplant infectious complications and rejection episodes during the first year was similar. The incidence of posttransplant renal dysfunction was higher in patients bridged with inotropes. CONCLUSIONS: Patients bridged to transplant with a LVAD represent a subset of UNOS status 1 patients who deteriorated on intravenous inotropic therapy. Bridging to heart transplantation with an implantable LVAD provides comparable outcomes to similar status 1 patients who were stabilized on inotropic infusions only. In contrast with International Society of Heart and Lung Transplantation data, no increase in posttransplant morbidity or mortality occurred in LVAD-bridged patients.

Two-photon laser scanning microscopy of the transverse-axial tubule system in ventricular cardiomyocytes from failing and non-failing human hearts.

Objective. The transverse-axial tubule system (TATS) of cardiomyocytes allows a spatially coordinated conversion of electrical excitation into an intracellular Ca(2+) signal and consequently contraction. Previous reports have indicated alterations of structure and/or volume of the TATS in cardiac hypertrophy and failure, suggesting a contribution to the impairment of excitation contraction coupling. To test whether structural alterations are present in human heart failure, the TATS was visualized in myocytes from failing and non-failing human hearts. Methods and Results. In freshly isolated myocytes, the plasmalemmal membranes were labeled with Di-8-ANEPPS and imaged using two-photon excitation at 780 nm. Optical sections were taken every 300 nm through the cells. After deconvolution, the TATS was determined within the 3D data sets, revealing no significant difference in normalized surface area or volume. To rule out possible inhomogeneity in the arrangement of the TATS, Euclidian distance maps were plotted for every section, allowing to measure the closest distance between any cytosolic and any membrane point. There was a trend towards greater spacing in cells from failing hearts, without statistical significance. Conclusion. Only small changes, but no significant changes in the geometrical dimensions of the TATS were observed in cardiomyocytes from failing compared to non-failing human myocardium.

Reduced effects of BAY K 8644 on L-type Ca2+ current in failing human cardiac myocytes are related to abnormal adrenergic regulation.

Abnormal L-type Ca(2+) channel (LTCC, also named Cav1.2) density and regulation are important contributors to depressed contractility in failing hearts. The LTCC agonist BAY K 8644 (BAY K) has reduced inotropic effects on failing myocardium. We hypothesized that BAY K effects on the LTCC current (I(CaL)) in failing myocytes would be reduced because of increased basal activity. Since support of the failing heart with a left ventricular assist device (LVAD) improves contractility and adrenergic responses, we further hypothesized that BAY K effects on I(CaL) would be restored in LVAD-supported failing hearts. We tested our hypotheses in human ventricular myocytes (HVMs) isolated from nonfailing (NF), failing (F), and LVAD-supported failing hearts. We found that 1) BAY K had smaller effects on I(CaL) in F HVMs compared with NF HVMs; 2) BAY K had diminished effects on I(CaL) in NF HVM pretreated with isoproterenol (Iso) or dibutyryl cyclic AMP (DBcAMP); 3) BAY K effects on I(CaL) in F HVMs pretreated with acetylcholine (ACh) were normalized; 4) Iso had no effect on NF HVMs pretreated with BAY K; 5) BAY K effects on I(CaL) in LVAD HVMs were similar to those in NF HVMs; 6) BAY K effects were reduced in LVAD HVMs pretreated with Iso or DBcAMP; 7) Iso had no effect on I(CaL) in LVAD HVMs pretreated with BAY K. Collectively, these results suggest that the decreased BAY K effects on LTCC in F HVMs are caused by increased basal channel activity, which should contribute to abnormal contractility reserve.

The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function.

Glycoside-induced cardiac inotropy has traditionally been attributed to direct Na(+)-K(+)-ATPase inhibition, causing increased intracellular [Na(+)] and consequent Ca(2+) gain via the Na(+)-Ca(2+) exchanger (NCX). However, recent studies suggested alternative mechanisms of glycoside-induced inotropy: (1) direct activation of sarcoplasmic reticulum Ca(2+) release channels (ryanodine receptors; RyRs); (2) increased Ca(2+) selectivity of Na(+) channels (slip-mode conductance); and (3) other signal transduction pathways. None of these proposed mechanisms requires NCX or an altered [Na(+)] gradient. Here we tested the ability of ouabain (OUA, 3 microm), digoxin (DIG, 20 microm) or acetylstrophanthidin (ACS, 4 microm) to alter Ca(2+) transients in completely Na(+)-free conditions in intact ferret and cat ventricular myocytes. We also tested whether OUA directly activates RyRs in permeabilized cat myocytes (measuring Ca(2+) sparks by confocal microscopy). In intact ferret myocytes (stimulated at 0.2 Hz), DIG and ACS enhanced Ca(2+) transients and cell shortening during twitches, as expected. However, prior depletion of [Na(+)](i) (in Na(+)-free, Ca(2+)-free solution) and in Na(+)-free solution (replaced by Li(+)) the inotropic effects of DIG and ACS were completely prevented. In voltage-clamped cat myocytes, OUA increased Ca(2+) transients by 48 +/- 4% but OUA had no effect in Na(+)-depleted cells (replaced by N-methyl-d-glucamine). In permeabilized cat myocytes, OUA did not change Ca(2+) spark frequency, amplitude or spatial spread (although spark duration was slightly prolonged). We conclude that the acute inotropic effects of DIG, ACS and OUA (and the effects on RyRs) depend on the presence of Na(+) and a functional NCX in ferret and cat myocytes (rather than alternate Na(+)-independent mechanisms).

Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy.

Physiological hemodynamic stress, such as aerobic exercise, is intermittent and requires an increase in Ca2+ -dependent contractility through sympathetic nervous system activation. Pathological hemodynamic stress, such as hypertension, is persistent and requires sustained increases in cardiac function. Over time, this causes left ventricular hypertrophy (LVH)-reduced responsiveness to sympathetic stimulation. In this study, we examined the hypothesis that blunted in vivo adrenergic contractile responsiveness in pressure overload (PO)-induced cardiac hypertrophy is caused by abnormalities in the abundance and/or basal phosphorylation state of Ca2+ regulatory proteins. PO, induced by aortic constriction, caused concentric LVH or dilated LVH. Only animals with dilation exhibited a decrease in baseline left ventricle function [fractional area change (FAC); measured with echocardiography]. All PO animals had a reduced contractile response to adrenergic agonists (increase in FAC with 40 microg.kg(-1).min(-1) dobutamine, control 0.30 +/- 0.04, n = 5 vs. banded 0.10 +/- 0.03, n = 10; P < 0.01). PO animals had reduced phospholamban (PLB) protein abundance (P = 0.07, not significant) and increased PLB phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLB-Thr17, P < 0.05) but not at the protein kinase A-specific site (PLB-Ser16). PLB-Thr17 phosphorylation was inversely correlated with dobutamine-induced increases in contractility in PO animals (r2 = 0.81, P < 0.05). Continuous induction of Ca2+ transients in isolated ventricular myocytes for 24 h increased phosphorylation at PLB-Thr17 and diminished inotropic responsiveness and PLB-Ser16 phosphorylation after exposure to isoproterenol (P < 0.05). These data show that reduced adrenergic responsiveness in feline PO hypertrophy and failure involves increases in basal PLB-Thr17 phosphorylation, suggesting that activation of CaMKII in PO hypertrophy contributes to defective adrenergic reserve in compensated LVH and early heart failure.

Effect of acute unloading via head-up tilt on QTc prolongation in patients with ischemic or non-ischemic cardiomyopathy.

Patients with advanced cardiomyopathy develop prolongations in ventricular myocyte action potential duration that are reflected by prolongations of QT intervals on surface electrocardiograms. Recent studies demonstrate that the placement of a left ventricular (LV) assist device, which induces profound cardiac decompression, acutely increases QT intervals within hours. The goal of this study was to use head-up tilt (HUT) to examine electrocardiographic responses to cardiac unloading in patients with cardiomyopathy. Surface electrocardiograms were analyzed during HUT in 21 patients with cardiomyopathy (ejection fraction <30%) and in 33 age-matched controls. Four to 6 different QT and RR intervals were measured at baseline (supine), at 5 and 25 minutes after HUT. The heart-rate-adjusted QT interval (QTc) was calculated using Bazett's formula. The mean QTc in control patients decreased at 5 minutes (426 +/- 31 vs 418 +/- 28 ms, p < 0.05, vs supine) and was unchanged at 25 minutes (426 +/- 31 vs 423 +/- 25 ms, p = NS, vs supine). However, in patients with cardiomyopathy, there was a significant increase in QTc during HUT (455 +/- 45 vs 473 +/- 42 and 479 +/- 42 ms, p < 0.001, vs supine). The change in heart rate during HUT did not differ between patients with cardiomyopathy and controls. In conclusion, HUT is associated with the immediate prolongation of myocardial repolarization in patients with cardiomyopathy. This response was not seen in age-matched controls. These results suggest that adaptations to chronic cardiac distention may include processes that help accelerate repolarization. Conversely, the prolongation of repolarization after unloading may modulate myocardial relaxation and arrhythmogenic risk.

Prolonged repolarization after ventricular assist device support is associated with arrhythmias in humans with congestive heart failure.

BACKGROUND: Recent observations indicate that the QTc interval often increases in the early postoperative period (<1 week) after mechanical unloading of severely failing hearts with a left ventricular assist device (LVAD). The present study examined whether early changes in ventricular repolarization after LVAD placement are associated with ventricular arrhythmias. METHODS AND RESULTS: An electrocardiogram was obtained within 4 days before LVAD placement, <12 hours after LVAD placement, and weekly thereafter. Patient records were reviewed for documented ventricular tachycardia (VT) or ventricular fibrillation (VF) for 1 week preoperatively and the first 2 weeks postoperatively. Differences in QTc interval between patients with and without VT were evaluated. Ten of 17 patients enrolled (59%) had VT or VF after LVAD placement. Of these, 4 required therapeutic intervention because of clinical instability or symptoms. The change in the QTc (DeltaQTc) between the preoperative and immediate postoperative period was significantly different among patients with VT/VF compared with patients without VT/VF (+23 ms vs. -68 ms, P < .001). CONCLUSION: The early period after initiation of LVAD support of the failing human heart is associated with a relatively high incidence of significant ventricular arrhythmias after LVAD placement. Beyond the impact of myocardial inflammation and wound healing occurring after all LVAD implants, early postoperative increases in the QTc interval after cardiac unloading appear to predispose to ventricular arrhythmias.

Effect of older donor age on risk for mortality after heart transplantation.

BACKGROUND: Despite the increasingly common use of donor hearts at least 50 years of age, controversy still remains regarding long-term outcome. Our goal was to determine if older donor age is associated with an increased risk of mortality and specifically if the use of donor hearts at least 50 years of age reduces survival. METHODS: We retrospectively studied records of all primary heart transplants performed between January 1990 and July 2002. Fifty-six patients who had received donor hearts at least 50 years of age were compared with 611 recipients of donor hearts less than 50 years of age. Clinicopathologic parameters were analyzed for their effect on mortality using the Cox proportional hazard model with calculation of hazard ratios (HR). Cut-point analysis of donor age was used to determine which donor age is associated with the greatest risk of mortality after transplant. RESULTS: Recipients of donor hearts at least 50 years of age were older (58.5 years +/- 7.0 vs 53.2 +/- 11.6; mean +/- standard deviation [SD]; p < 0.0001), suffered more often from ischemic cardiomyopathy (69% vs 50%, p = 0.01), and experienced a longer waiting time (192.2 days +/- 301.0 vs 138.6 +/- 190.8, p < 0.0001). Donor hearts at least 50 years of age (age 54.1 +/- 3.5 years) were more often female (50% vs 34%, p = 0.03), died less often of "head trauma" (9% vs 42%, p < 0.0001), and exhibited fewer cytomegalovirus (CMV) mismatches (29% vs 39%, p = 0.04) than donor hearts less than 50 years of age (age 26.8 +/- 12.3 years). Multivariate predictors of mortality were rejection index (HR 1.90 per unit [rejections/100 survival days], p < 0.0001), donor age (HR 1.16 per 10-year increment, p = 0.002), and recipient age (HR 1.24 per 10-year increment, p = 0.04). Recipients of donor hearts at least 50 years of age had reduced 1-year and 5-year survival ([65.7% vs 81.7%, p < 0.05] and [48.3% vs 68.4%, p < 0.05], respectively), as well as a higher proportion of deaths occurring within 1 month of transplant (41% of total deaths vs 23%, p = 0.06). Cut-point analysis indicated the characteristic of donor age of at least 40 years (categorical variable) to predict mortality with the same degree of fit as age used as a continuous variable. CONCLUSIONS: Although we observed a substantial reduction in survival among patients who were allocated donor hearts at least 50 years of age, this difference was not solely attributable to the categorical variable of donor age 50 in this group. Donor age as a continuous variable, however, was determined to be a notable predictor of survival and use of the donor age cut-point of 40 years (categorical variable) allowed risk stratification with similar accuracy. The use of a donor age cut-point of 40 years may be a useful clinical criterion for graft-related risk assessment.

Altered myocardial Ca2+ cycling after left ventricular assist device support in the failing human heart.

OBJECTIVES: The objective of the present study was to determine whether improved contractility after left ventricular assist device (LVAD) support reflects altered myocyte calcium cycling and changes in calcium-handling proteins. BACKGROUND: Previous reports demonstrate that LVAD support induces sustained unloading of the heart with regression of pathologic hypertrophy and improvements in contractile performance. METHODS: In the human myocardium of subjects with heart failure (HF), with non-failing hearts (NF), and with LVAD-supported failing hearts (HF-LVAD), intracellular calcium ([Ca(2+)](i)) transients were measured in isolated myocytes at 0.5 Hz, and frequency-dependent force generation was measured in multicellular preparations (trabeculae). Abundance of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA), Na(+)/Ca(2+) exchanger (NCX), and phospholamban was assessed by Western analysis. RESULTS: Compared with NF myocytes, HF myocytes exhibited a slowed terminal decay of the Ca(2+) transient (DT(terminal), 376 +/- 18 ms vs. 270 +/- 21 ms, HF vs. NF, p < 0.0008), and HF-LVAD myocytes exhibited a DT(terminal) that was much shorter than that observed in HF myocytes (278 +/- 10 ms, HF vs. HF-LVAD, p < 0.0001). Trabeculae from HF showed a negative force-frequency relationship, compared with a positive relationship in NF, whereas a neutral relationship was observed in HF-LVAD. Although decreased SERCA abundance in HF was not altered by LVAD support, improvements in [Ca(2+)](i) transients and frequency-dependent contractile function were associated with a significant decrease in NCX abundance and activity from HF to HF-LVAD. CONCLUSIONS: Improvement in rate-dependent contractility in LVAD-supported failing human hearts is associated with a faster decay of the myocyte calcium transient. These improvements reflect decreases in NCX abundance and transport capacity without significant changes in SERCA after LVAD support. Our results suggest that reverse remodeling may involve selective, rather than global, normalization of the pathologic patterns associated with the failing heart.

Successful treatment of esophageal cancer with transhiatal esophagectomy after heart transplantation.

A 55-year-old heart transplant recipient with reflux esophagitis presented for routine endoscopic surveillance of an area of Barrett's metaplasia initially seen 3 years previously. Esophagogastroduodenoscopy revealed adenocarcinoma at 33 cm from the incisors. The preoperative clinical stage was T1N0M0 by endoscopic ultrasound. Transhiatal esophagectomy was performed with R0 resection of the cancer, and the patient recovered uneventfully. Pathologic examination confirmed esophageal adenocarcinoma (T1N0M0) in Barrett's mucosa. The patient is doing well, and has no evidence of disease after 18 months.

Use of LeVeen pleuroperitoneal shunt for refractory high-volume chylothorax.

We present a case of intractable high-volume (> 2L/d) chylothorax after transhiatal esophagectomy treated successfully with the simultaneous insertion of both Denver (Denver Biomedical, Golden, CO) and LeVeen (Becton-Dickinson, Rutherford, NJ) pleuroperitoneal shunts. The patient initially had chemoradiotherapy for a T4N1 squamous cell carcinoma of the thoracic esophagus. Re-staging showed a dramatic shrinkage of tumor, and a transhiatal esophagectomy was performed. Sequential bilateral thoracotomies were performed on postoperative days 19 and 26 for attempted control of high-volume chylothorax, but these were unsuccessful. Subsequent pleuroperitoneal shunt insertion was used, which immediately controlled the effusion. A shunt study was performed shortly after hospital discharge, which showed an occluded Denver shunt and a patent LeVeen shunt. The patient succumbed to metastatic carcinoma 18 months after discharge, but no pleural effusion had recurred.