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Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation.We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively.A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005).Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l- NG-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.

Objectives Right ventricular failure is the primary reason for mortality in pulmonary hypertension (PH), but little is understood about the energetics of the failing right myocardium. Our aim was to examine mitochondrial function and proteomic signatures in paired remodeled right (RM-RV) and non-remodeled left (NRM-LV) ventricular tissue samples procured during heart-lung transplantation. Methods and Results Contractile dysfunction in RM-RV and preserved contractile function in NRM-LV were determined clinically and by echocardiography. Mitochondria were isolated from fresh paired RV and LV wall specimens of explanted hearts. Respiratory states in response to 4 substrates and an uncoupler were analyzed. Proteomic analysis on the mitochondrial isolates was performed with the use of liquid chromatography–mass spectrometry. The RM-RV mitochondria exhibited higher succinate state 4 levels with lower respiratory control ratio (RCR) compared with state 4 levels for pyruvate-malate (PM) and glutamate-malate (GM). RM-RV mitochondria also exhibited lower state 3 for palmitoyl-carnitine (PC) and state 4 for all complex I substrates compared with NRM-LV. The mean RCR were greater in RM-RVs than in NRM-LVs for PM and GM, which is consistent with tight coupling (low state 4 rates, higher RCRs); however, low RM-RV state 3 rates suggest concurrent substrate-dependent impairment in respiratory capacity. Mitochondrial proteomics revealed greater levels of mitochondrial ADP-ATP translocase and proteins of ATP synthesis, mitochondrial pyruvate and short branched chain acyl-CoA metabolism in RM-RV. Conclusions The mitochondrial respiration and proteomics in RM-RV are different from NRM-LV. These results have important implications in expanding our understanding of RV metabolism and future management of RV failure.

Black bean coats (Phaseolus vulgaris) contain bioactive compounds, including flavonoids and saponins, which have anti-fibrotic effects in which a standardized black bean extract (BBE) has been found to prevent liver fibrosis. Accordingly, the purpose of this study was to test whether BBE prevents remodeling in a murine model of non-ischemic cardiomyopathy. Saponins and flavonols were identified and quantified in BBE. Identification of flavonoids and saponins was confirmed by HPLC-MS-TOF. The cardiomyopathy model was produced by administering angiotensin and oral supplementation of L-NAME. Experimental animals received BBE in their diet at a dose equivalent to 40 mg per kg per day. The cardiomyopathy group (CMP) was characterized by severe maladaptive remodeling, left ventricular (LV) hypertrophy, decreased ejection fraction and increased LV end-diastolic volume. CMP mice treated with BBE had an improvement in ventricular function and reduction in LV mass. In addition, we found 65%, 85% and 83% reductions in interstitial fibrosis, brain natriuretic peptide (BNP) and transforming growth factor (TGFβ) expression, respectively. Consistent with those observations, collagen and TGFβ expression by isolated cardiac fibroblasts was reduced 82% and 70% following administration of BBE. BBE prevents adverse cardiac remodeling by reducing the extent of fibrosis and collagen deposition that occur in cardiomyopathy. These initial studies provide the basis for future research into the therapeutic potential of BBE in heart failure.

Background— Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results— We compared metabolomic, gene transcript, and protein data from 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure tissue: 2.6-fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α ( PGC1A , 1.3-fold) and estrogen-related receptor α ( ERRA , 1.2-fold) and γ ( ERRG , 2.2-fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with left ventricular assist device improved all of these metabolic and transcriptional defects. Conclusions— These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart.

Malfunction of a continuous-flow left ventricular assist device (CF-LVAD) due to device thrombosis is a potentially life-threatening event that currently presents a diagnostic challenge. We aimed to propose a practical echocardiographic assessment to diagnose LVAD malfunction secondary to pump thrombosis.Among 52 patients implanted with a CF-LVAD from a single center who underwent echocardiographic pump speed-change testing, 12 had suspected pump thrombosis as determined by clinical, laboratory, and/or device parameters. Comprehensive echocardiographic evaluation was performed at baseline pump speed and at each 1,000-rpm interval from the low setting of 8,000 rpm to the high setting of 11,000 rpm in 11 of these patients.Receiver operating characteristic curves and stepwise logistic regression analyses showed that the best diagnostic parameters included changes in the LV end-diastolic diameter (0.6 cm), aortic valve opening time (80 msec), and deceleration time of mitral inflow (70 msec) from lowest to highest pump speed. One parameter was predictive of pump malfunction, with 100% sensitivity and 89% specificity, whereas 2 of 3 parameters increased the sensitivity to 100% and specificity to 95%.The 3 echocardiographic variables of measured changes in LV end-diastolic diameter, aortic valve opening time, and deceleration time of mitral inflow between the lowest (8,000 rpm) and highest pump speed settings (11,000 rpm) during echo-guided pump speed-change testing appear highly accurate in diagnosing device malfunction in the setting of pump thrombosis among patients supported with CF-LVAD. Further investigation is warranted to create and validate a prediction score.

Objectives: We sought to compare the effects of interstitial fibrosis and myocardial force generation/relaxation elements on left ventricular (LV) function in patients with end-stage dilated cardio...

Background Predictors of right ventricular failure (RVF) in patients with left ventricular assist devices (LVADs) have not been fully elucidated and are comprised mostly of clinical variables. We evaluated echocardiographic parameters associated with adverse outcomes in this population. Methods Transthoracic echocardiograms (TTEs) before continuous-flow LVAD implantation were analyzed in 109 patients. Twenty-six 2-dimensional and Doppler parameters were assessed for their association with the primary outcome of 30-day RVF, defined as a requirement of an RV assist device or ≥14 consecutive days of inotropic support, and the secondary composite outcome of 30-day death or RVF. Multivariate analysis adjusted for known clinical risk prediction models was performed. Results Overall, 25 (22.9%) and 27 (24.8%) patients reached the primary and secondary end-points, respectively. An increased RV/LV diameter ratio was the only TTE variable independently associated with both the primary (odds ratio [OR] = 5.40; 95% confidence interval [CI] 2.40 to 12.40; p = 0.012) and secondary (OR = 2.70; 95% CI 1.06 to 6.22; p = 0.03) outcomes after multivariate analysis. Scatterplot analysis with regression determined the optimal cut-off value for RV/LV diameter to be 0.75. Based on receiver operating characteristic curves, an increased RV/LV diameter ratio provided an additional predictive value to clinical risk scores. Conclusions A TTE-measured RV/LV diameter ratio of ≥0.75 is independently associated with a higher risk for RVF in patients with continuous-flow LVAD. When used alone, this simple, easily derived, practical echocardiographic measurement has a predictive value equivalent to known clinical risk scores, whereas their combination provides stronger risk prediction for adverse outcomes.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease. Although regional functional heterogeneity in HCM is well-known, cellular and molecular regional heterogeneity in human HCM remain unrecognized. We evaluated the molecular and histological heterogeneity as well as mitochondrial function in HCM and their relation to functional heterogeneity in 16 left ventricular segments from a patient with HCM with normal ejection fraction who underwent heart transplantation for advanced heart failure. The patient was a 61-year-old man who had a long-standing history of HCM with asymmetrical septal hypertrophy and maximum wall thickness of 26 mm. He underwent myectomy because of severe dyspnea and left ventricular outflow tract dynamic obstruction but was in New York Heart Association functional class IV heart failure despite successful surgery. He received an implantable cardioverter-defibrillator because of risk factors for sudden cardiac death. There was no evidence of epicardial coronary artery disease by angiography. The patient underwent cardiac transplantation because of persistent symptoms, …

Background: We have shown previously that the abrogation of acute and chronic rejection of rat cardiac allografts occurs through the down-regulation of RhoA pathway and involves the changes in RhoA kinase (ROCK)-dependent actin cytoskeleton and T cell motility. Here we studied the ability of the Y-27632, a highly selective inhibitor of Rho-associated protein kinase p160ROCK (ROCK1), to abrogate chronic rejection of the allograft and influence T cell infiltration. Methods: Heterotopic cardiac transplants were performed between donor Wistar Furth (WF) and ACI recipient rats. Controls received sub-therapeutic dose of cyclosporine (CsA, 10 mg/kg) for 3 days or 7 days therapeutic dose of cyclosporine. The experimental groups of ACI recipient received one preoperative dose of the Y-27632 inhibitor (2 mg/kg, gavage feed) in conjunction with the sub-therapeutic dose of CsA for 3 days or inhibitor alone for 7 days. The cardiac grafts were harvested at 100 days of post-transplantation for histological and immunohistochemical assessment of chronic rejection, vascular sclerosis, and infiltration by different T cell subtypes. Results: Cardiac allografts from recipients exposed to Y-27632 inhibitor in conjunction with sub-therapeutic dose of CsA showed drastically reduced vascular sclerosis, minimal myocardial total cellular infiltration, and were selectively infiltrated with Foxp3+ T regulatory (Treg) cells. Conclusions: Our novel finding that a single dose of the ROCK1 inhibitor Y-27632 attenuates chronic rejection in rat cardiac model system by promoting development of Treg cells warrants its potential as a novel therapeutic agent specific for the inhibition of chronic rejection.

Congest Heart Fail. 2011;17:140–146. ©2011 Wiley Periodicals, Inc. Left ventricular assist devices (LVADs) induce reverse cardiac remodeling by reducing myocyte size and collagen deposition. On the other hand, cardiac resynchronization therapy (CRT) induces reverse cardiac remodeling by improving electromechanical synchronization. The clinical and structural changes produced by CRT in failing myocardium are known, but whether these changes are accompanied by reverse cellular remodeling is unknown. A total of 12 patients with chronic heart failure (CHF) who underwent CRT and 15 patients who had LVAD therapy as clinically indicated and 8 healthy controls were compared. Demographics, echocardiographic data, and histologic samples from myocardial biopsies were analyzed and compared among groups. The authors found significant increases in myocyte size, myocardial fibrosis, and inflammation in both CHF groups who underwent CRT or LVAD, compared with healthy controls. After CRT or LVAD therapy, a significant decrease in myocyte size and tumor necrosis factor α (TNF-α) expression compared with healthy controls (P

Background Limited information exists on the role of B‐cell‐dependent mechanisms in the progression of heart failure ( HF ). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B‐cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy ( CMP ). Methods and Results CMP protocol involved the use of l ‐ NAME and NaCl in the drinking water and angiotensin‐ II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57 BL /6 background: wild‐type ( WT ) CMP ; severe combined immunodeficiency ( SCID ) CMP (T‐ and B‐cell deficient); CD 22 − CMP (B‐cell depleted); and Nude CMP (T‐cell deficient), with their respective controls. We performed B‐cell depletion and reconstitution protocols. The protective effect of B‐cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD 22 − CMP group compared to WT CMP . Once SCID mice underwent B‐cell reconstitution with isolated CMP B‐cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP ; in addition, in vitro studies demonstrated that activated B‐cells stimulate collagen production by cardiac fibroblasts. Conclusions The absence of B‐cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B‐cells play a contributory role in an angiotensin‐ II ‐induced HF model.

Aims Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. Methods and results In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. Conclusions Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure.

Since the advent of ventricular assist devices with smaller configurations and continuous-flow technology, survival rates for patients with end-stage heart failure have dramatically improved. While the burden of infectious complications is decreased in patients on continuous-flow ventricular assist devices compared to bulkier pulsatile-flow devices, infection remains one of the most common causes of morbidity and mortality. The majority of infections occur at the driveline exit site, beginning with a disruption or trauma to the barrier between the skin and driveline and sometimes spreading deeper. Once infections develop, they can be difficult to eradicate. Depending on the degree of infection, treatment options may include local wound care, antibiotics, or surgical treatment. Preventive strategies and careful surveillance are crucial to improve patient outcomes.

Introduction: Pump thrombosis is a potentially life-threatening event that currently presents a diagnostic challenge. We therefore sought to explore the diagnostic utility and the association of measured cardiac computed tomography (CT) parameters in patients with LVAD malfunction due to pump thrombosis. Methods: From 2009 to 2013, 150 patients underwent placement of Heart Mate II continuous flow pump at our institution. Of these 52 patients, underwent cardiac CT with contrast either as part of a prospective protocol or for suspected malfunction. 14 patients had pump thrombosis per the INTERMACS criteria and the remaining were used as controls. Rigorous linear and area measurements for the inflow and outflow tracts of LVADs were performed. Results: The mean age of the population was 55 ± 11, 36 were male, and 28 had ischemic cardiomyopathy. Results are shown in table 1. For inflow cannula, measurement of axial area shown in figure 1, was significantly higher in the pump thrombosis group compared to the control group 31±16 cm2 vs 20 ± 12 cm2 (p=.02). Although, the difference in the acute angle for the inflow cannula relative to the perpendicular axis between the midpoint of the mitral annulus and tip of inflow cannulas was not significantly different between the two groups, there was a trend towards greater angulation in the pump thrombosis group (60 ± 6 vs 53 ± 15) and there was a positive correlation between both measurements r=0.513, p-value= 0.003. Conclusions: Area in the axial view of the ventricle at the site of the inflow cannula tip may be a surrogate for off axis placement of the cannula. This area may be helpful in predicting pump thrombosis in patients.

Common adverse events in patients supported with Continuous-flow left ventricular assist devices (CF-LVAD) include infections and cerebrovascular accidents (CVA). Some studies have suggested a possible association between blood stream infection (BSI) and CVA.Medical records of patients who received Heartmate II (HMII) CF-LVADs in 2008-2012 at a single center were reviewed. CVA was categorized as either hemorrhagic (HCVA) or ischemic (ICVA). BSI was divided into persistent (pBSI) and nonpersistent (non-pBSI). pBSI was defined as BSI with the same organism on repeated blood culture72 hours from initial blood culture despite antibiotics. Univariate and multivariate analyses were performed to determine predictors. A total of 149 patients had HMII implanted; 76% were male, and the overall mean age was 55.4 ± 13 years. There were a total of 19 (13%) patients who had CVA (7 HCVA and 12 ICVA) at a median of 295 days (range 5-1,096 days) after implantation. There were a total of 28 (19%) patients with pBSI and 17 (11%) patients with non-pBSI. Patients with pBSI had a trend toward greater BMI (31 kg/m(2) vs 27 kg/m(2); P = .09), and longer duration of support (1,019 d vs 371 d; P.001) compared with those with non-pBSI. Persistent BSI was associated with an increased risk of mortality and with all-cause CVA on multivariate analysis (odds ratio [OR] 5.97; P = .003) as well as persistent Pseudomonas aeruginosa infection (OR 4.54; P = .048).Persistent BSI is not uncommon in patients supported by CF-LVAD and is highly associated with all-cause CVA and increased all-cause mortality.

s S95 to compare 1-year survival in patients (pts) receiving a left ventricular assist device (LVAD) as a bridge to transplantation (BTT) or to candidacy (BTC), or HTx from donors ≥ 55 years Methods: Pts receiving a continuous-flow LVAD as BTT/BTC (n= 61) were compared to those undergoing HTx from donors ≥ 55 years (HTx≥ 55y, n= 44 out of 212 adult HTx without prior bridging, 21%) between January 2006 and September 2014. Pts transplanted after LVAD were included in LVAD group only; survival lwas evaluated 1) according to first operation, with pts censored at the time of death or HTx or last follow-up visit, and 2) as overall survival, including postHTx outcome. Results: LVAD and HTx≥ 55y pts differ with respect to gender (Females 9.8 vs 41%, p> 0.005), prior cardiac surgery (11 vs 34%, p= 0.005), hemodynamic (PAPm 38±11 vs 22±8, p> 0.05; PCW 27±8 vs 16±7, p> 0.05). According to first operation, there were 8 deaths in LVAD (13%) and 13 in HTx≥ 55y (32%). Kaplan Meier survival curves estimated a 1-years survival of 87% in LVAD vs 70.5% in HTx≥ 55y pts, (hazard ratio 0.40; 95% confidence interval 0.17-0.97; p= 0.04 for LVAD vs HTx). Early (30 days) mortality was 4.9% in LVAD vs 20.5% in HTx≥ 55y, p0.005) in LVAD than in HTx pts. Nine LVAD pts (14.8%) were transplanted within 1 year, and 7 later; overall survival including post-Htx outcome was 76 % at 1-years. Conclusion: In possible HTx candidates, 1-y survival appears better with LVAD than with HTx from donors≥ 55y, but LVAD complications may require emergency, high risk HTx. Advantages and risks of LVAD or HTx with older donors should be carefully evaluated on an individual basis. Much efforts should be directed to reduce post-LVAD complications, in order to reduce readmissions, and increase the probability of success of subsequent HTx.

In heart failure mitochondrial dysfunction is thought to be responsible for energy depletion and contractile dysfunction. The difficulties in procuring fresh left ventricular (LV) myocardium from humans for assessment of mitochondrial function have resulted in the reliance on surrogate markers of mitochondrial function and limited our understanding of cardiac energetics. We isolated mitochondria from fresh LV wall tissue of patients with heart failure and reduced systolic function undergoing heart transplant or left ventricular assist device placement, and compared their function to mitochondria isolated from the non-failing LV (NFLV) wall tissue with normal systolic function from patients with pulmonary hypertension undergoing heart-lung transplant. We performed detailed mitochondrial functional analyses using 4 substrates: glutamate-malate (GM), pyruvate-malate (PM) palmitoyl carnitine-malate (PC) and succinate. NFLV mitochondria showed preserved respiratory control ratios and electron chain integrity with only few differences for the 4 substrates. In contrast, HF mitochondria had greater respiration with GM, PM and PC substrates and higher electron chain capacity for PM than for PC. Surprisingly, HF mitochondria had greater respiratory control ratios and lower ADP-independent state 4 rates than NFLV mitochondria for GM, PM and PC substrates demonstrating that HF mitochondria are capable of coupled respiration ex vivo. Gene expression studies revealed decreased expression of key genes in pathways for oxidation of both fatty acids and glucose. Our results suggest that mitochondria from the failing LV myocardium are capable of tightly coupled respiration when isolated and supplied with ample substrates. Thus energy starvation in the failing heart may be the result of dysregulation of metabolic pathways, impaired substrate supply or reduced mitochondrial number but not the result of reduced mitochondrial electron transport capacity.

Aims Various reports have raised the possibility of humoral immune responses as contributors for the progression of heart failure. Previous studies, however, have focused on the analysis of serum and documented circulating antibodies against a variety of cardiac proteins. However, there is little evidence on whether anti-cardiac antibodies are deposited in end-stage failing myocardium. Our objective was to determine whether or not there was evidence of deposition of anti-cardiac antibodies and/or activated complement components in end-stage failing human myocardium. Methods and results Myocardial samples were obtained from 100 end-stage heart failure patients and 40 donor control biopsies. Sections were cut and stained using standard fluorescent immunohistochemistry techniques with anti-human immunoglobulin G (IgG), IgG3, and C3c. Gel electrophoresis and protein identification by mass spectrometry were used to confirm the presence of IgG and its antigen. Immunoglobulin G was localized to the sarcolemma in 71% of patients, 48% of those being positive for the subtype IgG3. The proportion of patients with ischaemic heart disease that was positive for IgG was 65% and among those with non-ischaemic aetiologies was 76%. In a subgroup analysis, the presence of IgG and its subunits were confirmed by mass spectrometry and adenosine triphosphate synthase β subunit identified as an antigen. Complement was activated in 31% of all patients. The presence of IgG, IgG3, and C3c was directly correlated with the length of disease ( r = 0.451, P = 0.006). Conclusion Evidence of anti-cardiac antibodies and complement activation was found in a large number of patients with end-stage cardiomyopathy regardless of the aetiology. Adenosine triphosphate synthase appears to be a new prominent antigenic stimulus; but more interestingly, the simultaneous co-existence of activated complement components suggests that this humoral mechanism may participate in disease progression.

We sought to compare the effects of interstitial fibrosis and myocardial force generation/relaxation elements on left ventricular (LV) function in patients with end-stage dilated cardiomyopathy (DCM).Interstitial fibrosis is common in patients with advanced heart failure. However, the extent to which it affects cardiac function remains unclear.Longitudinal, radial, and circumferential strain; strain rate during systole (SRS) and strain rate during early diastole (SRE); LV volume; LV ejection fraction; mean pulmonary capillary wedge pressure (PCWP); and e' were measured in 20 DCM patients. Myocyte diameter, interstitial fibrosis, messenger ribonucleic acid (mRNA) levels of molecules implicated in fibrosis and function (transforming growth factor beta, titin [TTN] N2B and N2BA isoforms, collagen type I, collagen type III, sarcoplasmic reticulum Ca(2+)-ATPase [SERCA2a], phospholamban [PLB], and protein levels of SERCA2a, phosphorylated PLB, and Smad2/3) were correlated with strain from 4 regions per patient (LV apex, midlateral, septum, and right ventricular free wall) as well as LV global function. In another group of 8 DCM patients, we evaluated LV structure and function before and after LV assist device.Significant correlations were present among ejection fraction, e' velocity, PCWP, LV end-diastolic volume/PCWP ratio, strain, SRS, SRE, and mRNA expression of TTN N2B, N2BA, SERCA2a, PLB, and protein levels of SERCA2a and phosphorylated PLB (r = 0.53 to 0.95, p0.05). Weak to no associations were present between strain and interstitial fibrosis and its molecular determinants. In patients with repeat studies, regional strain and SRE best tracked the changes in mRNA expression of TTN isoform N2BA and mRNA and protein expression of SERCA2a.LV systolic and diastolic functions in DCM are primarily associated with myocardial force generation/relaxation elements.

Atrial arrhythmias (AAs) early after lung transplant are frequent and have a significant impact on morbidity and mortality. However, the pathogenesis of AAs after lung transplant remains incompletely understood. In this study we aimed to determine the prevalence of atrial fibrillation (AF) and other AAs, as well as risk factors, clinical outcomes and possible underlying mechanisms associated with AAs after lung transplant.A retrospective analysis was performed on 382 patients who underwent lung transplantation from 2000 to 2010. A 12-lead electrocardiogram (ECG) was obtained and AAs classified as AF and other AAs (atrial flutter [AFL] and supraventricular tachycardia [SVT]). Multivariate logistic regression analysis was performed to determine predictors, and Kaplan-Meier survival curves were constructed.The incidence of AAs was 25%; 17.8% developed AF and 7.6% other AAs (AFL/SVT). The major indication for transplant was idiopathic pulmonary fibrosis (IPF, 35%). Significant predictors of AF were as follows: age; IPF; left atrial enlargement; diastolic dysfunction; and history of coronary artery disease (CAD). Risk factors for other AAs (AFL/SVT) were: age; right ventricle dysfunction; right ventricular enlargement; and elevated right atrial pressure (RAP). One-year mortality was higher in the arrhythmia group (21.5% arrhythmia vs 15.7% no-arrhythmia group; p0.05). In addition, patients treated with anti-arrhythmic medications had higher mortality (p0.05).AAs are common after lung transplantation. Risk factors for developing either AF or other AAs (AFL/SVT) are different. The development of early AAs post-transplant is associated with prolonged post-operative stay and increased mortality. A rate-control strategy should be used as first-line therapy and anti-arrhythmic agents reserved for those patients who do not respond to the initial treatment.

In obesity, reduced cardiac glucose uptake and mitochondrial abnormalities are putative causes of cardiac dysfunction. However, high-fat diet (HFD) does not consistently induce cardiac insulin resistance and mitochondrial damage, and recent studies suggest HFD may be cardioprotective. To determine cardiac responses to HFD, we investigated cardiac function, glucose uptake, and mitochondrial respiration in young (3-month-old) and middle-aged (MA) (12-month-old) male Ldlr−/− mice fed chow or 3 months HFD to induce obesity, systemic insulin resistance, and hyperinsulinemia. In MA Ldlr−/− mice, HFD induced accelerated atherosclerosis and nonalcoholic steatohepatitis, common complications of human obesity. Surprisingly, HFD-fed mice demonstrated increased cardiac glucose uptake, which was most prominent in MA mice, in the absence of cardiac contractile dysfunction or hypertrophy. Moreover, hearts of HFD-fed mice had enhanced mitochondrial oxidation of palmitoyl carnitine, glutamate, and succinate and greater basal insulin signaling compared with those of chow-fed mice, suggesting cardiac insulin sensitivity was maintained, despite systemic insulin resistance. Streptozotocin-induced ablation of insulin production markedly reduced cardiac glucose uptake and mitochondrial dysfunction in HFD-fed, but not in chow-fed, mice. Insulin injection reversed these effects, suggesting that insulin may protect cardiac mitochondria during HFD. These results have implications for cardiac metabolism and preservation of mitochondrial function in obesity.

Objectives: This study evaluated the feasibility, tolerability, and efficacy of a strategy for percutaneous intra-aortic balloon pump (IABP) placement through the left axillary-subclavian artery to provide mechanical circulatory support in patients with end-stage heart failure as a bridge to heart transplantation. Background: The transfemoral approach to IABP placement is associated with major disadvantages, including the risk for infection and limitation of patient mobility in those requiring extended support. Methods: We developed a percutaneous technique for placing IABPs in the left axillary artery that permits upright sitting and ambulation. We performed a retrospective review of data from patients who had undergone left axillary IABP implantation between 2007 and2012. Results: Fifty patients who received a left axillary IABP as a bridge to transplantation were identified, of whom 42 (84%) underwent heart or heart-multiorgan transplantation. Cumulative survival on IABP support was 92%, and post-transplant 90-day survival was 90%. Median duration of support was 18 days. Four of 50 patients (8%) died while on IABP support, and 3 (6%) received greater mechanical circulatory support. Four patients (8%) had clinically significant thromboembolic or bleeding events without long-term sequelae. The most common minor adverse event was IABP malposition, in 22 patients (44%). Prolonged IABP support in the heart-transplantation cohort was associated with significant improvements in mean pulmonary artery pressure and in creatinine and total bilirubin concentrations. Conclusions: Percutaneous insertion of an IABP through the left axillary artery is a feasible and relatively well-tolerated strategy tobridge patients with end-stage heart failure to heart transplantation. This form of mechanical-device treatment permits upright sitting and ambulation in those requiring extended support. © 2013 American College of Cardiology Foundation.

Heart failure readmissions portend worst outcomes in patients with heart failure and impose a heavy burden on the healthcare system. We investigated ST2 (soluble IL33 receptor) as a predictor of heart failure readmissions. We prospectively identified patients that were admitted to our hospital with

Background: Endothelial to Mesenchymal Transition (EndMT) and the reverse phenomenon of mesenchymal to endothelial transitioning (MET) has been shown to contribute to fibrosis in rodent models of heart failure. There are no studies documenting the same in human cardiac tissue. Methods: We performed immunofluorescence dual staining on end stage heart failure myocardial samples obtained from our bio repository. Staining for endothelial and mesenchymal markers were performed with Anti-VE-Cadherin (Santa Cruz Biotechnologies) and anti-Fibroblast specific protein 1 (Dako Antibodies) respectively using standard immunofluoresence techniques. Presence of dual staining on fluorescence microscopy was considered as positive for the presence of EndMT. Vascular density was assessed using a DAB (3-3’ Diaminobenzidine) technique with Anti-CD31 (PECAM, Abcam). Results: Of the end stage heart failure samples, 18 were from left ventricular core during LVAD implant and 5 during a direct transplant as status 1A (axillary intraaortic balloon pump). 10 hearts of patients bridged to transplant with a continuous flow LVAD (Days under support 3436228) were also studied. Mean age was 55y with 82% males and 74% white. 70% of all samples had evidence of EndMT. The number of cells ranged from 1 to 5 per high power field. There was no significant difference between patient characteristics between those with evidence of EndMT versus not, except a higher prevalence of diabetes in the latter group. (Fig 1B) 74% of the end-stage heart failure samples and 60% of the post-VAD samples showed the presence of EndMT cells. Vascular Density was higher in the samples exhibiting EndMT phenomenon. (Figure 1A). Conclusion: We have documented for the first time, the existence of endothelial-mesenchymal transition in human end stage myocardial samples corroborating earlier pioneering studies in rodents. Interestingly the existence of such dual staining cells in end stage hearts (which is highly fibrotic) suggests a possible role of ongoing fibrosis with endothelial to mesenchymal transitioning or potential antifibrotic mechanism though mesenchymal to endothelial transitioning. Further studies of the later process will be warranted to explore potential anti-fibrotic therapeutic implications.

Cardiac amyloidosis is one of the most common of the infiltrative cardiomyopathies and is associated with a poor prognosis. The extent of cardiac involvement with amyloid deposition is an important determinant of treatment options and is the major determinant of outcome in patients with amyloidosis. Several small case series with sequential orthotopic heart transplantation and autologous stem cell transplant have demonstrated an improvement in post-transplant outcome and have revived enthusiasm about heart transplantation for patients with end-stage heart failure due to AL amyloidosis. The purpose of this review is to summarize the evaluation and management of cardiac amyloidosis and to provide our single-center experience with end-stage heart failure due to AL amyloidosis treated with heart transplantation followed by an autologous stem cell transplant.

Background Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection episodes in orthotopic heart transplant (OTH) patients. Follow-up protocols vary widely between transplant centers. At our center, we have implemented a conservative strategy protocol and here we report our outcomes. Methods Patients from 2 cohorts were used for comparison analysis. OHT recipients from 1990 to 1995 comprised the standard strategy group, and those from 2004 to 2009 comprised the conservative strategy group. Survival outcomes and rejection episodes were compared between groups. Results Mean age at OHT was 56 ± 10 years in the standard strategy group and 53 ± 10 years in the conservative strategy group. Both groups were predominantly composed of white men. The etiology of congestive heart failure was ischemic cardiomyopathy in more than 50% of the patients in both groups. From 6 to 12 months after OHT, we found that the number of episodes of rejection/total number of EMBs was 4.9% (8/163) in the standard group vs 2.0% (1/50) in the conservative group. From 12 to 24 months after transplant, the rate was 2.5% (8/320) in the standard group vs 11.9% (5/42) in the conservative group ( p Conclusions Surveillance EMB after 6 months post-OHT in patients receiving contemporary immunosuppression is associated with a low yield of EMB-confirmed rejection in the absence of a clinical indication or echocardiographic findings that support clinical rejection. Most episodes of cellular rejection are mild and do not warrant treatment or a change in immunosuppression. The frequency of EMBs did not correlate with an increased risk of cardiac allograft vasculopathy or death.

Left ventricular assist devices (LVADs) induce reverse cardiac remodeling by reducing myocyte size and collagen deposition. On the other hand, cardiac resynchronization therapy (CRT) induces reverse cardiac remodeling by improving electromechanical synchronization. The clinical and structural changes produced by CRT in failing myocardium are known, but whether these changes are accompanied by reverse cellular remodeling is unknown. A total of 12 patients with chronic heart failure (CHF) who underwent CRT and 15 patients who had LVAD therapy as clinically indicated and 8 healthy controls were compared. Demographics, echocardiographic data, and histologic samples from myocardial biopsies were analyzed and compared among groups. The authors found significant increases in myocyte size, myocardial fibrosis, and inflammation in both CHF groups who underwent CRT or LVAD, compared with healthy controls. After CRT or LVAD therapy, a significant decrease in myocyte size and tumor necrosis factor α (TNF-α) expression compared with healthy controls (P.05) was found. In the CRT group, 6 of 8 patients demonstrated reduction in myocyte size and interstitial fibrosis. In addition, there was a decrease in myocyte size by 13%, total collagen by 27% and TNF-α by 49% in the CRT group vs 28%, 45%, and 45% in the LVAD group. CRT produces cellular reverse remodeling in failing human hearts that are comparable with those produced by LVAD therapy.

Background: Endothelial to Mesenchymal Transition (EndMT) and the reverse phenomenon of mesenchymal to endothelial transitioning (MET) has been shown to contribute to fibrosis in rodent models of heart failure. There are no studies documenting the same in human cardiac tissue. Methods: We performed immunofluorescence dual staining on end stage heart failure myocardial samples obtained from our bio repository. Staining for endothelial and mesenchymal markers were performed with Anti-VE-Cadherin (Santa Cruz Biotechnologies) and anti-Fibroblast specific protein 1 (Dako Antibodies) respectively using standard immunofluoresence techniques. Presence of dual staining on fluorescence microscopy was considered as positive for the presence of EndMT. Vascular density was assessed using a DAB (3-3’ Diaminobenzidine) technique with Anti-CD31 (PECAM, Abcam). Results: Of the end stage heart failure samples, 18 were from left ventricular core during LVAD implant and 5 during a direct transplant as status 1A (axillary intraaortic balloon pump). 10 hearts of patients bridged to transplant with a continuous flow LVAD (Days under support 3436228) were also studied. Mean age was 55y with 82% males and 74% white. 70% of all samples had evidence of EndMT. The number of cells ranged from 1 to 5 per high power field. There was no significant difference between patient characteristics between those with evidence of EndMT versus not, except a higher prevalence of diabetes in the latter group. (Fig 1B) 74% of the end-stage heart failure samples and 60% of the post-VAD samples showed the presence of EndMT cells. Vascular Density was higher in the samples exhibiting EndMT phenomenon. (Figure 1A). Conclusion: We have documented for the first time, the existence of endothelial-mesenchymal transition in human end stage myocardial samples corroborating earlier pioneering studies in rodents. Interestingly the existence of such dual staining cells in end stage hearts (which is highly fibrotic) suggests a possible role of ongoing fibrosis with endothelial to mesenchymal transitioning or potential antifibrotic mechanism though mesenchymal to endothelial transitioning. Further studies of the later process will be warranted to explore potential anti-fibrotic therapeutic implications.

poorly understood. Methods: Data from ASCEND-HF, a randomized clinical trial of patients with acute heart failure (AHF) regardless of left ventricular ejection fraction (LVEF), was used to characterize LFTs at baseline. Logistic regression assessed the association of LFTs and 30-day all-cause mortality and HF rehospitalization; Cox proportional hazards models were used for 180-day all-cause mortality among patients alive at a day 30 landmark. Regression was performed using continuous variables (transformed for linearity assumptions when appropriate) and a dichotomous variable (normal vs. abnormal) for each liver function test. Separate analyses were performed for individual LFT. Abnormal bilirubin was defined as O1.0 mg/dL; for AST and ALT, abnormal values were defined as O35 U/L. Results: Among 4,228 ASCEND-HF patients with LFT data, 42% had abnormal total bilirubin, 22% had abnormal ALT, and 30% had abnormal AST on admission. Patients with abnormal LFTs were younger, had lower body mass index, and lower LVEF compared to those with admission LFTs within the normal range. In multivariable models, higher levels of total bilirubin levels were associated with increased 30-day mortality or HF rehospitalization (HR 1.17 per unit change, 95% CI 1.04, 1.32), and a non-significant trend for 180-day mortality (HR 1.10, 95% CI 0.97, 1.25) (Table 1). Compared with normal baseline LFTs, the presence of an abnormal bilirubin was independently associated with increased 30-day all-cause mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62). After adjustment, there was no association between AST or ALT and either outcome. Conclusions: In this trial of patients with AHF, abnormalities in LFTs were common on presentation. Elevated total bilirubin, but no other liver function test, was independently associated with worse outcomes at 30and 180-days.