Veli K. Topkara

Infectious complications in patients with left ventricular assist device: etiology and outcomes in the continuous-flow era.

BACKGROUND Continuous-flow left ventricular assist devices (LVAD) are increasingly being used in patients with end-stage heart failure and have largely replaced older generation pulsatile devices. While significant rates of infection have been reported in patients with pulsatile device support, incidence and outcomes of this complication for the continuous-flow device patients remain unknown. METHODS Between June 2005 and August 2009, 81 patients were implanted with continuous-flow LVADs at Washington University School of Medicine either as bridge to transplantation or as destination therapy. Outcomes of this study included incidence of postimplantation infection, types of infection, microbiologic profile, and association of postimplantation infections with clinical endpoints. RESULTS Forty-two patients (51.9%) had at least one type of infection on continuous-flow LVAD support with a mean follow-up period of 9.2 ± 9.2 months. Patients who had an infection on LVAD support had a significantly prolonged hospital stay (37.9 ± 32.0 versus 20.7 ± 23.0 days, p = 0.008) and a trend toward increased mortality (33.1% versus 18.7% at 2 years, respectively, log rank p = 0.102) compared with patients who did not. Subgroup analysis revealed that postimplantation sepsis was significantly associated with increased mortality in the continuous-flow LVAD cohort (61.9% versus 18.0% at 2 years, respectively, in septic and nonseptic patients, log rank p = 0.001). The majority of the sepsis cases occurred before hospital discharge, whereas most of the device related infections occurred after discharge. Resistant Staphylococcus and Pseudomonas species were the most common pathogens leading to device- and nondevice-related local infections. Development of driveline or pocket infection had no effect on survival in patients with continuous-flow assist device support (p = 0.193). CONCLUSIONS Even though better clinical outcomes have been achieved with the newer generation continuous-flow devices, infection complications-in particular sepsis-are still a major risk for patients with continuous-flow LVAD implantation. Prevention strategies with aggressive medical and surgical management of infections may increase survival and decrease morbidity among continuous-flow LVAD patients.

Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNAs in Failing Human Heart and Remodeling With Mechanical Circulatory Support

Background— Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). Methods and Results— Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs. Conclusions— The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Role of MicroRNAs in Cardiac Remodeling and Heart Failure

MicroRNAs (miRNAs) are endogenous, short (~22 nucleotide), evolutionarily conserved, non-coding RNAs that regulate gene expression at the post-transcriptional level. Recent evidence suggests that miRNAs are differentially expressed in the failing myocardium and play an important role in progression of heart failure by targeting genes that govern diverse functions in cardiac remodeling process including myocyte hypertrophy, excitation-contraction coupling, increased myocyte loss, and myocardial fibrosis. In addition to their role in adverse cardiac remodeling, miRNAs hold promise as biomarkers of disease progression in heart failure given their presence in circulation and enhanced stability. Further development of miR-based therapeutics may allow for modulation of cardiac and/or systemic levels of specific miRNAs in patients with heart failure . Here, we summarize current knowledge of miRNAs in relation to their role in regulating various aspects of the cardiac remodeling process and discuss their potential use as biomarkers and/or therapeutic targets in heart failure.

An Introduction to Small Non-coding RNAs: miRNA and snoRNA

Research into small non-coding RNAs (ncRNA) has fundamentally transformed our understanding of gene regulatory networks, especially at the post-transcriptional level. Although much is now known about the basic biology of small ncRNAs, our ability to recognize the impact of small ncRNA in disease states is preliminary, and the ability to effectively target them in vivo is very limited. However, given the larger and growing focus on targeting RNAs for disease therapeutics, what we do know about the intrinsic biology of these small RNAs makes them potentially attractive targets for pharmacologic manipulation. With that in mind, this review provides an introduction to the biology of small ncRNA, using microRNA (miRNA) and small nucleolar RNA (snoRNA) as examples.

Left ventricular assist device-related infections: past, present and future

Over the last decade, left ventricular assist device (LVAD) implantation has emerged as an alternative treatment strategy in patients with advanced heart failure irrespective of their transplant eligibility. However, success and applicability of this therapy is largely limited by high complication rates associated with these devices. Although superior outcomes have been achieved with the second-generation continuous-flow LVADs, device-related infections continue to be a prevalent complication in this patient population and contribute significantly to the financial burden of this therapy due to an increased need for hospitalizations and surgical interventions. Patient selection, device design and LVAD-induced immune system dysfunction appear to be major risk factors for the development of device-related infections. Improvements in device design and better patient selection strategies, particularly with respect to identifying individuals with genetic susceptibility to device-related infections, may further reduce this prevalent complication and improve outcomes in patients with advanced heart failure.

Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart

Background—Tumor necrosis factor superfamily ligands provoke a dilated cardiac phenotype signal through a common scaffolding protein termed tumor necrosis factor receptor–associated factor 2 (TRAF2); however, virtually nothing is known about TRAF2 signaling in the adult mammalian heart. Methods and Results—We generated multiple founder lines of mice with cardiac-restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (myosin heavy chain [MHC]-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, left ventricular dilation, and adverse left ventricular remodeling, and a significant decrease in LV+dP/dt and LV−dP/dt when compared with littermate controls (P<0.05 compared with littermate). During the early phases of left ventricular remodeling, there was a significant increase in total matrix metalloproteinase activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total matrix metalloproteinase activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in nuclear factor–&kgr;B activation at 4 to 12 weeks and jun N-terminal kinases activation at 4 weeks in the MHC-TRAF2HC mice. Transciptional profiling revealed that >95% of the hypertrophic/dilated cardiomyopathy–related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained &kgr;B elements in their promoters. Conclusions—These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.

HeartWare and HeartMate II Left Ventricular Assist Devices as Bridge to Transplantation: A Comparative Analysis

BACKGROUND The purpose of this study is to comparatively analyze outcomes of heart transplant patients bridged to transplantation with HeartWare (HW-VAD) versus HeartMate II (HMII-VAD) left ventricular assist devices. METHODS The United Network for Organ Sharing Database was reviewed to identify first-time heart transplant recipients who were bridged to transplantation with either HW-VAD (n=141) or HMII-VAD (n=1824) from January 2009 through July 2012. RESULTS Recipients of HW-VAD had a higher proportion of female patients (27.0% versus 18.9%; p=0.019), a lower body surface area (2.01±0.25 m2 versus 2.06±0.25 m2; p=0.035), and a trend toward a higher peak percentage of panel reactive antibody against human leukocyte class I antigens (40.4%±32.8% versus 33.0%±30.4%; p=0.070). Pretransplantation recipient cardiac index (2.33±0.66 L⋅min(-1)⋅m(-2) versus 2.33±0.68 L⋅min(-1)⋅m(-2)), serum creatinine (1.21±0.43 mg/dL versus 1.26±0.57 mg/dL), and total bilirubin (1.34±3.45 mg/dL versus 1.06±1.84 mg/dL) were comparable between the two groups (p>0.05 for all comparisons). After transplantation, there were no significant differences in freedom from rejection or freedom from cardiac allograft vasculopathy. Posttransplant graft survival rates were similar between the HW-VAD group and the HMII-VAD group at 1, 2, and 3 years (88.4% versus 87.8%, 79.9% versus 83.8%, and 77.4% versus 79.9%, respectively; p=0.843). CONCLUSIONS These findings suggest similar hemodynamic unloading, pretransplant end-organ function, and posttransplant outcomes in patients bridged to transplantation with both the HW-VAD and HMII-VAD.

Dysferlin Mediates the Cytoprotective Effects of TRAF2 Following Myocardial Ischemia Reperfusion Injury

Background We have demonstrated that tumor necrosis factor (TNF) receptor‐associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known. Methods/Results Mice with cardiac‐restricted overexpression of low levels of TRAF2 (MHC‐TRAF2LC) and a dominant negative TRAF2 (MHC‐TRAF2DN) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus. MHC‐TRAF2LC mice were protected against I/R injury as shown by a significant ≈27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ≈38% lower LV developed pressure, a ≈41% greater creatine kinase (CK) release, and ≈52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC‐TRAF2LC and MHC‐TRAF2DN mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ≈39% lower LV developed pressure, a ≈20% greater CK release, and ≈29% greater Evans blue dye uptake after I/R, compared to wild‐type mice, thus phenocopying the response to tissue injury in the MHC‐TRAF2DN mice. Moreover, breeding MHC‐TRAF2LC onto a dysferlin‐null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury. Conclusion The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2‐mediated signaling after I/R injury.

Graft survival after cardiac transplantation for alcohol cardiomyopathy.

Background Alcohol cardiomyopathy (ACM) constitutes up to 40% of patients with non-ischemic dilated cardiomyopathy. Transplant-free survival is worse for patients with ACM versus idiopathic dilated cardiomyopathy (IDCM) with continued exposure. The prognosis for patients with ACM after cardiac transplantation is unknown. Methods We evaluated adults who underwent single-organ, cardiac transplantation from 1994 to 2009 with a diagnosis of ACM (n=134) or IDCM (n=10,243) in the Organ Procurement Transplantation Network registry. Kaplan-Meier curves were generated by cohort for time until graft failure, cardiac allograft vasculopathy, and hospitalization for rejection. A Cox proportional hazards model was created to determine factors associated with each outcome. Results Patients with ACM were more likely to be males (P<0.0001), minorities (P<0.0001), and smokers (P=0.0310) compared with IDCM. Overall graft survival was lower for the ACM cohort (P=0.0001). After multivariate analysis, ACM was not independently associated with graft survival (HR 1.341, 95% CI 0.944–1.906, P=0.1017). Creatinine, total bilirubin, minority ethnicity, graft under-sizing, life support, diabetes, and donor age were independent predictors of graft failure. There were no significant differences between primary cause of death, vasculopathy, or rejection. Conclusions There was no association between ACM and graft survival in this large registry study, but poorer overall survival in the ACM cohort was associated with other recipient characteristics.

Assessment of a new experimental model of isolated right ventricular failure.

To the Editor: In their recent article,Thomaz et al. have described a canine model for isolated right ventricular (RV) heart failure (1). The protocol, as described, calls for multiple epicardial injections of 96% ethanol to a maximum dose of 1 mL/kg body weight; thereby inducing ischemia and coagulative necrosis which in turn leads to transmural myocardial infarction and isolated RV failure as evidenced by reduced RV ejection fraction (RVEF), lower pulmonary artery flow, and preserved left ventricle (LV) function. Even though the model holds promise for use, several points should be considered with regards to the experimental design and its consequences on pathophysiology of the RV failure. From a clinical and hemodynamic standpoint, the proposed model is a better representative of isolated RV failure secondary to acute myocardial infarction as opposed to RV failure due to pressure overload conditions such as pulmonary stenosis, primary pulmonary hypertension, or cor pulmonale, where use of pulmonary artery banding or monocrotaline administration models would be more appropriate (2). Experimental models of myocardial injury in canine are affected by their highly variable coronary anatomy with different levels of collateral flow to the ischemic zone (3). Even though the authors report consistent changes in hemodynamic parameters and echocardiogram indices after induction of injury with reasonable standard error margins, the extent of injury and its variability among the subjects were not assessed. Quantification of infarct size with myocardial imaging techniques or measurement of serum markers of myocardial injury including creatine-kinase, creatine-kinase myocardial band, or troponin would provide valuable information to that effect. Even though authors perform baseline measurements which serve as a control, they did not use a surgical control (sham) arm longitudinally to account for possible RV failure component secondary to perioperative factors such as anesthesia, excessive fluid resuscitation, medications used, or surgical trauma itself. Ethanol injections were carried out epicardially, and the pericardium was left open following the procedure. Intact pericardium has a restrictive effect on the damaged right ventricle and the experimental design does not address this factor (4). Finally, effect on ethanol-induced RV infarction on neurohormonal activation (atrial natriuretic peptide, brain natriuretic peptide, angiotensin, etc.) has not been evaluated. Despite these limitations, the authors introduce a novel isolated RV failure model and contribute to our understanding of the pathophysiology of this disease. This procedure can be an attractive alternative to coronary ligation model given its potential to induce more consistent infarct sizes. Efficacy of the LETTERS TO THE EDITOR 269