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Outcomes of Patients Receiving Temporary Circulatory Support Prior to Durable LVAD P. Shah ,1 F.D. Pagani,2 S.S. Desai,3 N.A. Burton,4 S. Maltais,5 N.A. Haglund,6 S.M. Dunlay,7 K.D. Aaronson,8 J.M. Stulak,9 M. Davis,5 C. Salerno,10 J.A. Cowger.11 1Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, VA; 2Cardiac Surgery, University of Michigan, Ann Arbor, MI; 3Heart Failure and Transplantation, Inova Fairfax Hospital, Falls Church, VA; 4Cardiac Surgery, Inova Fairfax Hospital, Falls Church, VA; 5Cardiac Surgery, Vanderbilt University, Nashville, TN; 6Heart Failure and Transplantation, Vanderbilt University, Nashville, TN; 7Heart Failure and Transplantation, Mayo Clinic, Rochester, MN; 8Heart Failure and Transplantation, University of Michigan, Ann Arbor, MI; 9Cardiac Surgery, Mayo Clinic, Rochester, MN; 10Cardiac Surgery, St. Vincent Heart Center of Indiana, Carmel, IN; 11Heart Failure and Transplant, St. Vincent Heart Center of Indiana, Carmel, IN.

We appreciate the interest that Dr. Marullo and colleagues have taken in our study [(1)][1]. Previous data on left ventricular assist device (LVAD)-induced myocardial recovery have suggested that the patient's age and duration of heart failure history may be associated with successful recovery [(2,3

ObjectivesThis study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function.BackgroundThe magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown.MethodsEighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies.ResultsAfter 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m2, p < 0.01, and 92 vs. 60 ml/m2, p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m2, p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading.ConclusionsContinuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression.

Purpose The effect of continuous flow left ventricular assist devices (CF-LVAD) on the arrhythmogenicity of the failing heart is a controversial issue. We sought to investigate the association of CF-LVAD unloading on the electrical properties of the failing heart including the incidence of sustained ventricular tachycardia (VT)/ ventricular fibrillation (VF). Methods and Materials The records of 80 CF-LVAD patients from the UTAH Cardiac Transplant Program implanted between 2008 and 2011 were retrospectively reviewed. 12-lead ECGs and ICD interrogations were reviewed. We examined 12 lead ECGs for QRS and QT intervals before, 4 and 12 weeks after CF-LVAD implant. ICD recording episodes of VT and VF were checked before and after LVAD implantation. Results The average age was 55±15 years (75% males) and 53% had non-ischemic cardiomyopathy. The QRS duration was found to be decreased at 4 weeks following CF-LVAD implant and this decrease was sustained at 12 weeks (Table). The QT interval also decreased at 4 and 12 weeks (Table). QRS and QT changes were observed in patients with both paced (n=43; 68.3%) and normal ventricular activation. Twenty eight patients had a history of sustained VT/VF pre CF-LVAD. Twenty one patients had VT/VF episodes following CF-LVAD implant; 8 patients presented with de novo arrhythmias. The majority of ventricular arrhythmias were monomorphic VTs (66.7%); 4 (50%) occurred in the first 4 weeks, while 4 (50%) occurred 4-12 weeks following CF-LVAD. Conclusions Chronic CF-LVAD unloading is associated with shortening of QRS and QT intervals. Ventricular arrhythmias occurred de novo following surgery despite those changes. Further studies are needed to understand the effect of unloading on the ventricular arrhythmogenic milieu and substrate. 4 Weeks post 12 weeks post Pre-LVAD LVAD LVAD P value QT 155±37 ms 128±34 ms 120±41 ms * QRS 446±62 ms 409±77 ms 404±78 ms * * Pre-LVAD to 4 weeks post LVAD

Purpose MicroRNAs (miRNAs,) are small non-coding molecules that negatively regulate gene transcription.MiRNAs show unique patterns of expression both in the myocardium and blood of chronic heart failure (HF) patients.A subset of HF patients experience myocardial functional improvement following mechanical unloading induced by left ventricular assist device (LVAD).The aim of this study was to determine whether functional improvement is associated with measurable changes in circulating miRNAs. Methods and Materials LVAD- induced myocardial functional response was defined as a relative increase in left ventricular (LV) ejection fraction >50% and a relative decrease in LV end- systolic volumes >25% (LVAD Responders).Peripheral blood samples were collected after continuous flow LVAD unloading from two patients’ groups: LVAD Responders (n=7) and LVAD- Non Responders (n=11).Profiling of 14 circulating miRNAs previously shown to be abnormally expressed in HF (miRNAs -15b,-208;-499;-205;-133a;-133b;-145;-21;-29a;-9;-195,-23a,-200b) was performed in serum samples and normalized to the level of miR 16 that was used as an endogenous control. Results Average duration LVAD support was 157± 87 days. MiRNAs- 15b and- 133b were present at significantly higher levels in serum of LVAD Non -Responders compared to LVAD Responders (15.78 fold, p Conclusions Functional myocardial response to LVAD unloading was associated with lower circulating levels of miRs -15b and – 133b, which may increase expression of their correspondingly regulated genes.The full biological significance of this finding and the contribution of these specific miRNAs to HF recovery as well as the potential use of these molecules to predict myocardial improvement in LVAD recipients warrants further investigation.

Purpose Cardiomyocyte hypertrophy, myocardial fibrosis and decreased microvascular density are key structural characteristics of myocardial remodeling and heart failure (HF). We sought to examine whether these structural remodeling features have a uniform pattern across the left ventricle (LV). Methods and Materials We studied 50 patients with end-stage HF and focused our analysis on the patients with non ischemic cardiomyopathy to minimize any regional differences related with coronary artery disease– induced ischemia and scar formation. Tissue from the apical and basal LV myocardium was obtained at the time of heart transplant. CD34 immunohistochemistry along with Masson’s Trichrome and Periodic Acid Schiff histochemical stains were performed for evaluation of microvascular density, myocardial fibrosis and cardiomyocyte hypertrophy, respectively. Analysis was performed on full thickness epicardium to endocardium sections with the use of state-of-the-art whole field digital microscopy. Results We found no significant differences in myocardial fibrosis, microvascular density and cardiomyocyte cross section area between LV apex and base (Table). [ figure 1 ] Conclusions We did not observe significant differences in key structural remodeling features between the apical and the basal LV myocardium in patients with advanced non ischemic cardiomyopathy. This regional structural uniformity across the LV suggests that the tissue obtained from the apex at the time of left ventricular assist device implantation and explantation could be informative of the global LV myocardial structural state and as such can advance our understanding of mechanical unloading-induced changes on the failing human heart.

Purpose Survival beyond one year after heart transplantation has remained without improvement for the last two decades. A more individualized approach to post-transplant care could result in reduction of long-term mortality. While recipient age has been associated with an increased incidence of certain post-transplant morbidities, its impact on causes-specific mortality has not been well described. Methods and Materials We examined ISHLT Registry data of patients transplanted between 1995 and 2011. We evaluated post-transplant survival and leading causes of death in 6 groups, selected based on recipient age: 18-29, 30-39, 40-49, 50-59, 60-69 and >70 years. Results The study included 52,995 patients. Ten-year survival was lower in heart transplant recipients in the two more advanced age groups – 49% for 60-69 years and 36% for >70 years, p Figure , panel A-B) and cardiac allograft vasculopathy was highest in younger recipients, while the cumulative incidence of deaths related to infection, malignancy ( Figure , panel C-D) and renal failure was highest in older recipients. Conclusions this large cohort of heart transplant recipients, specific causes of death varied significantly with recipient age. Our data suggest that more personalized strategies, possibly including different immunosuppression strategies based on recipient age, might result in improved post-transplant survival. This hypothesis should be tested prospectively.

Purpose We previously showed significant improvements of microvascular density (MVD) on the failing human heart after pulsatile flow left ventricular assist devices (PF-LVAD). However, controversy exists on whether continuous flow devices (CF-LVAD) have deleterious effects on endothelium, myocardial microvasculature and coronary artery function. Methods and Materials 32 paired left ventricular specimens before and after CF-LVAD, and 15 normal hearts not allocated for transplant were analyzed. State-of-the-art whole field digital microscopy was used for complete endo-to-epicardium microvascular evaluation after immunhistochemical stain for endothelial cell marker CD34. mRNA microarray analysis of known vascular mediators was evaluated. Bradykinin (BK) and sodium nitroprusside (SNP) evoked vasorelaxation was assessed ex vivo in precontracted coronary arteries (~250 μm i.d.) to assess endothelium-dependent and –independent vasorelaxation using isometric tension procedures. Results [figure 1] Maximal BK (10 -6 M; ~70%) and SNP (10 -4 M; ~90%) –evoked vasorelaxation was similar before and after CF –VAD, indicating that endothelial and vascular smooth muscle function was not harmed by exposure to continuous flow. A trend of improvement in MVD ~8% increase (p=0.08, figure 1A) was seen after CF-VAD.Microarray analysis suggested a TIE-1 mediated mechanism for this modest MVD increase (p=0.07, Figure1B), compared to other angiogenic factors (VEGF, c-Kit, Flt-3, TIE-2; p=NS). Conclusions CF-LVAD did not adversely remodel the coronary vasculature to an extent influencing arterial function. Future studies may help elucidate the role of various degrees of pulsatility on the TIE-1 mediated improvement of MVD during mechanical unloading.

Purpose Advances in ex-vivo organ perfusion may soon allow for extension of the time between organ procurement and heart transplant. However, presently the necessity for short allograft ischemic time in heart transplantation makes human leukocyte antigen (HLA) matching between donors and recipients impractical. Our aim was to investigate whether HLA mismatch is correlated with antibody mediated rejection (AMR) in heart transplantation. Methods and Materials The records of patients transplanted at the UTAH Cardiac Transplant Program between 1992 and 2011 were reviewed. HLA-mismatch at major antigen class I loci HLA-A and HLA-B, and class II loci HLA-DR and HLA-DQ, were analyzed using the Cox proportional hazards regression model. AMR was defined with the occurrence of ≥ 3 AMR episodes. Results Four hundred and fifty one patients met our inclusion criteria, 77% were male and the age was 45±19 years. HLA-DR and DQ have significant association with the incidence of AMR within the first year and at any time ( table ). There was no significant difference in the incidence of antibody mediated rejection (AMR) in patients with HLA class I mismatch. Conclusions HLA-DR and HLA-DQ mismatch appear to be associated with increased incidence of AMR after heart transplant. Prospective HLA class II antigens matching may result in reduced incidence of AMR and better outcome in heart transplantation. [ Figure 1 ]

holic, 436 viral, 808 other). The FDCM cohort was younger (p 0.0001) with less DM (p 0.0001) & renal dysfunction (p 0.0001). It was also associated with higher PRA (p 0.0001) & VAD use (p 0.012). FDCM dx increased by era (Table 1). Survival (3, 5 & 10y) was: FDCM (91, 84, 64%) & non-FDCM (88, 80, 55%) (Figure 1, log rank p 0.0004). FDCM unadjusted HR for all-cause mortality was 0.72 (CI 0.60-0.86, p 0.0002). Multivariate analysis yielded a HR of 0.75 (CI 0.62-0.90, p 0.0001). Conclusions: FDCM post-HT survival was significantly better & was associated with younger age & improved renal function, increased VAD use & higher PRA. Further study is needed as this may reflect selection bias as FDCM percentage is likely underestimated.

Transesophageal echocardiogram (TEE) is considered the gold standard modality in detecting left atrial appendage (LAA) thrombi in patients with atrial fibrillation (AF). However, this is a semi-invasive procedure with potential life-threatening complications. Cardiac computed tomography (CCT) has