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.

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.

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.

L-type Ca(2+) currents overlapping threshold Na(+) currents: could they be responsible for the "slip-mode" phenomenon in cardiac myocytes?

Phosphorylation of Na channels has been suggested to increase their Ca permeability. Termed "slip-mode conductance" (SMC), this hypothesis predicts that Ca influx via protein kinase A (PKA)-modified Na channels can induce sarcoplasmic reticulum (SR) Ca release. We tested this hypothesis by determining if SR Ca release is graded with I(Na) in the presence of activated PKA (with Isoproterenol, ISO). V(m), I(m), and [Ca](i) were measured in feline (n=26) and failing human (n=19) ventricular myocytes. Voltage steps from -70 through -40 mV were used to grade I(Na). Na channel antagonists (tetrodotoxin), L-type Ca channel (I(Ca,L)) antagonists (nifedipine, cadmium, verapamil), and agonists (Bay K 8644, FPL 64176) were used to separate SMC from I(Ca,L). In the absence of ISO, I(Na) was associated with SR Ca release in human but not feline myocytes. After ISO, graded I(Na) was associated with small amounts of SR Ca release in feline myocytes and the magnitude of release increased in human myocytes. I(Na)-related SR Ca release was insensitive to tetrodotoxin (n=10) but was blocked by nifedipine (n=10) and cadmium (n=3). SR Ca release was induced over the same voltage range in the absence of ISO with Bay K 8644 and FPL 64176 (n=9). Positive voltage steps (to 0 mV) to fully activate Na channels (SMC) in the presence of ISO and Verapamil only caused SR Ca release when block of I(Ca,L) was incomplete. We conclude that PKA-mediated increases in I(Ca,L) and SR Ca loading can reproduce many of the experimental features of SMC.

L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices.

Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (I(Ca,L)) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal I(Ca,L) density was not different in the 3 groups but I(Ca,L) was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V(0.5): -7.18+/-1.4 and -7.0+/-0.9 versus 0.46+/-1.1 mV). Both ISO and db-cAMP increased I(Ca,L) in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90+/-15% versus 77+/-19% versus 24+/-12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the I(Ca,L) activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the I(Ca,L) activation was not significantly different between groups. BayK also increased I(Ca,L) more in NF- (81+/-30%) and LVAD- (70+/-15%) than in F- (51+/-8%) HVMs. OA increased I(Ca, L) by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased I(Ca, L) in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal I(Ca,L) density is maintained by increasing in LTCC phosphorylation.

Na(+)-Ca(2+) exchange current and submembrane [Ca(2+)] during the cardiac action potential.

Na(+)-Ca(2+) exchange (NCX) is crucial in the regulation of [Ca(2+)](i) and cardiac contractility, but key details of its dynamic function during the heartbeat are not known. In the present study, we assess how NCX current (I(NCX)) varies during a rabbit ventricular action potential (AP). First, we measured the steady-state voltage and [Ca(2+)](i) dependence of I(NCX) under conditions when [Ca(2+)](i) was heavily buffered. We then used this relationship to infer the submembrane [Ca(2+)](i) ([Ca(2+)](sm)) sensed by NCX during a normal AP and [Ca(2+)](i) transient (when the AP was interrupted to produce an I(NCX) tail current). The [Ca(2+)](i) dependence of I(NCX) at -90 mV allowed us to convert the peak inward I(NCX) tail currents to [Ca(2+)](sm). Peak [Ca(2+)](sm) measured via this technique was >3.2 micromol/L within < 32 ms of the AP upstroke (versus peak [Ca(2+)](i) of 1.1 micromol/L at 81 ms measured with the global Ca(2+) indicator indo-1). The voltage and [Ca(2+)](sm) dependence of I(NCX) allowed us to infer I(NCX) during the normal AP and Ca(2+) transient. The early rise in [Ca(2+)](sm) causes I(NCX) to be inward for the majority of the AP. Thus, little Ca(2+) influx via NCX is expected under physiological conditions, but this can differ among species and in pathophysiological conditions.

Cellular basis of abnormal calcium transients of failing human ventricular myocytes.

Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca2+]i. This study examined the respective roles of the L-type Ca2+ current (ICa), SR Ca2+ uptake, storage and release, Ca2+ transport via the Na+-Ca2+ exchanger (NCX), and Ca2+ buffering in the altered Ca2+ transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control V(m) and measure I(m), respectively, and Fluo-3 was used to measure [Ca2+]i in myocytes from nonfailing (NF) and failing (F) human hearts. Ca2+ transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca2+ uptake rates by the SR and the amount of Ca2+ stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca2+ removal from F myocytes by the NCX, in the density of NCX current as a function of [Ca2+]i, ICa density, or cellular Ca2+ buffering. However, Ca2+ influx during the late portions of the action potential seems able to elevate [Ca2+]i in F but not in NF myocytes. A reduction in the rate of net Ca2+ uptake by the SR slows the decay of the Ca2+ transient and reduces SR Ca2+ stores. This leads to reduced SR Ca2+ release, which induces additional Ca2+ influx during the plateau phase of the action potential, further slowing the decay of the Ca2+ transient. These changes can explain the defective Ca2+ transients of the failing human ventricular myocyte.

Dynamic regulation of sodium/calcium exchange function in human heart failure.

BACKGROUND: Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]i, and [Na]i) and membrane potential (Em), which all change in human heart failure (HF). Therefore, changes in NCX function may contribute to abnormal Ca regulation in human HF. METHODS AND RESULTS: We assessed the cellular bases of differences in NCX function in ventricular myocytes from failing (F) and nonfailing (NF) human hearts. Allosteric activation of NCX by [Ca]i was comparable in F and NF myocytes (K1/2=150+/-31 nmol/L, n=7). The steady-state relation between [Ca]i and NCX current (INCX) was used to infer the local submembrane [Ca]i ([Ca]sm) that is sensed by NCX dynamically during the action potential (AP) and Ca transient (37 degrees C). This involved "tail" INCX measurement during abrupt repolarization of APs and Ca transients, where peak inward INCX indicates [Ca]sm. This allows inference of the direction of Ca transport by the NCX during the AP. In NF myocytes, NCX extrudes Ca for most of the AP. Three factors shift the direction of NCX-mediated Ca transport (to favor more Ca influx) in F versus NF myocytes, as follows: (1) reduced [Ca]sm, (2) prolonged AP duration, and (3) elevated [Na]i. CONCLUSIONS: These results show that Ca entry through NCX may limit systolic dysfunction due to reduced sarcoplasmic reticulum Ca stores in HF but could contribute to slow decay of the [Ca]i transient and to diastolic dysfunction.

Myocyte nitric oxide synthase 2 contributes to blunted beta-adrenergic response in failing human hearts by decreasing Ca2+ transients.

BACKGROUND: Human heart failure (HF) usually exhibits blunted response to beta-adrenergic receptor (AR) stimulation. Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF. METHODS AND RESULTS: Failing human hearts were obtained at transplantation. Contraction and [Ca2+]i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a beta-AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISO+AG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca2+ transient data directly paralleled these results, indicating that altered cellular Ca2+ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca2+ transients. CONCLUSIONS: NOS2 expression strongly limited ISO-induced increases in contraction, twitch Delta[Ca2+]i, and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the beta-AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium.

BACKGROUND: In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium. METHODS AND RESULTS: [Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm2), but [Na+]i and diastolic force were greater in failing (22.1+/-2.6 mmol/L and 15.6+/-3.2 mN/mm2) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm2; P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+]i was higher in failing than in NF myocardium at every stimulation rate. [Na+]i predicted in myocytes from Na+ (pipette)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+]i in failing myocytes. CONCLUSIONS: Na+i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+]i in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca(2+) load and force development. At faster rates, failing myocytes with high [Na+]i cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.

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.

Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes.

UNLABELLED: Prolongation of the Ca2+ transient and action potential (AP) durations are two characteristic changes in myocyte physiology in the failing human heart. The hypothesis of this study is that Ca2+ influx via reverse mode Na+/Ca2+ exchanger (NCX) or via L-type Ca2+ channels directly activates contraction in failing human myocytes while in normal myocytes this Ca2+ is transported into the sarcoplasmic reticulum (SR) to regulate SR Ca2+ stores. METHODS: Myocytes were isolated from failing human (n=6), nonfailing human (n=3) and normal feline hearts (n=9) and whole cell current and voltage clamp techniques were used to evoke and increase the duration of APs (0.5 Hz, 37 degrees C). Cyclopiazonic acid (CPA 10(-6) M), nifedipine (NIF;10(-6) M) and KB-R 7943 (KB-R; 3x10(-6) M) were used to reduce SR Ca2+ uptake, Ca2+ influx via the L-type Ca2+ current and reverse mode NCX, respectively. [Na+)i was changed by dialyzing myocytes with 0, 10 and 20 mM Na(+) pipette solutions. RESULTS: Prolongation of the AP duration caused an immediate prolongation of contraction and Ca2+ transient durations in failing myocytes. The first beat after the prolonged AP was potentiated by 21+/-5 and 27+/-5% in nonfailing human and normal feline myocytes, respectively (P<0.05), but there was no significant effect in failing human myocytes (+5+/-4% vs. steady state). CPA blunted the potentiation of the first beat after AP prolongation in normal feline and nonfailing human myocytes, mimicking the failing phenotype. NIF reduced steady state contraction in feline myocytes but the potentiation of the first beat after AP prolongation was unaltered (21+/-3% vs. base, P<0.05). KB-R reduced basal contractility and abolished the potentiation of the first beat after AP prolongation (2+/-1% vs. steady state). Increasing [Na+]i shortened AP, Ca2+ transient and contraction durations and increased steady state and post AP prolongation contractions. Dialysis with 0 Na+ eliminated these effects. CONCLUSIONS: Ca2+ enters both normal and failing cardiac myocytes during the late portion of the AP plateau via reverse mode NCX. In (normal) myocytes with good SR function, this Ca(2+) influx helps maintain and regulate SR Ca2+ load. In (failing) human myocytes with poor SR function this Ca2+ influx directly contributes to contraction. These studies suggest that the Ca2+ transient of the failing human ventricular myocytes has a higher than normal reliance on Ca2+ influx via the reverse mode of the NCX during the terminal phases of the AP.

Modulation of contractility in failing human myocytes by reverse-mode Na/Ca exchange.

A decrease in the peak systolic [Ca](i) and slow decay of the Ca(i) transient are common features of the end-stage failing human ventricular myocyte and may underlie the contractile abnormalities observed in congestive heart failure. The role of the Na/Ca exchanger has been a great area of interest given the changes observed at the molecular level. Results from these experiments have been inconsistent, however, and therefore cellular-based experiments may be required to characterize the role of the Na/Ca exchanger in failing human myocardium. We review recent data that suggest an increased ability of the Na/Ca exchanger to transport Ca into the cytoplasm in failing human myocytes. We hypothesize that this increased Ca influx can explain the slowed decay and impaired relaxation of failing human ventricular myocytes.

Off-pump technique for Thoratec left ventricular assist device insertion.

We present a case of left ventricular assist device (Thoratec; Thoratec Laboratories Corp, Pleasanton, CA) insertion performed through a left thoracotomy without cardiopulmonary bypass in a patient with severe end-stage congestive heart failure with renal and respiratory dysfunction and a history of multiple cardiac operations.

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.

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.

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.

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.