Considerations for the use of porcine organ donation models in preclinical organ donor intervention research.

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation. Animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury, organ preservation strategies, and future donor-based interventions. Important considerations include cost, public opinion regarding the conduct of animal research, translational value, and relevance of the animal model for clinical practice. We present an overview of two porcine models of organ donation: donation following brain death (DBD) and donation following circulatory death (DCD). The cardiovascular anatomy and physiology of pigs closely resembles those of humans, making this species the most appropriate for pre-clinical research. Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation. It is imperative to minimize animal loss during procedures that are surgically complex. We present our experience with these models and describe in detail the use cases, procedural approach, challenges, alternatives, and limitations of each model.

Does Tracheostomy Improve Outcomes in Those Receiving Venovenous Extracorporeal Membrane Oxygenation?

Patients receiving venovenous extracorporeal membrane oxygenation (VV-ECMO) often require extended periods of ventilation. We examined the role of tracheostomy on outcomes of patients supported with VV-ECMO. We reviewed all patients at our institution who received VV-ECMO between 2013 and 2019. Patients who received a tracheostomy were compared with VV-ECMO-supported patients without tracheostomy. The primary outcome measure was survival to hospital discharge. Secondary outcome measures included length of intensive care unit (ICU) and hospital stay and adverse events related to the tracheostomy procedure. Multivariable analysis was performed to identify predictors of in-hospital mortality. We dichotomized patients receiving tracheostomy into an "early" and "late" group based on median days to tracheostomy following ECMO cannulation and separate analysis was performed. One hundred and fifty patients met inclusion criteria, 32 received a tracheostomy. Survival to discharge was comparable between the groups (53.1% vs. 57.5%, p = 0.658). Predictors of mortality on multivariable analysis included Respiratory ECMO Survival Prediction (RESP) score (odds ratio [OR] = 0.831, p = .015) and blood urea nitrogen (BUN) (OR = 1.026, p = 0.011). Tracheostomy performance was not predictive of mortality (OR = 0.837, p = 0.658). Bleeding requiring intervention occurred in 18.7% of patients following tracheostomy. Early tracheostomy (<7 days from the initiation of VV-ECMO) was associated with shorter ICU (25 vs. 36 days, p = 0.04) and hospital (33 vs. 47, p = 0.017) length of stay compared with late tracheostomy. We conclude that tracheostomy can be performed safely in patients receiving VV-ECMO. Mortality in these patients is predicted by severity of the underlying disease. Performance of tracheostomy does not impact survival. Early tracheostomy may decrease length of stay.

A fast computational model for circulatory dynamics: effects of left ventricle-aorta coupling.

The course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction is affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally efficient, biophysically based mathematical model for the circulatory system is presented. In a four-chamber model of the heart, the LV is represented by a previously described low-order, wall volume-preserving model that includes torsion and base-to-apex and circumferential wall shortening and lengthening, and the other chambers are represented using spherical geometries. Active and passive myocardial mechanics of all four chambers are included. The cardiac model is coupled with a wave propagation model for the aorta and a closed lumped-parameter circulation model. Parameters for the normal heart and aorta are determined by fitting to experimental data. Changes in the timing and magnitude of pulse wave reflections by the aorta are demonstrated with changes in compliance and taper of the aorta as seen in aging (decreased compliance, increased diameter and length), and resulting effects on LV pressure-volume loops and LV fiber stress and sarcomere shortening are predicted. Effects of aging of the aorta combined with reduced LV contractile force (failing heart) are examined. In the failing heart, changes in aortic properties with aging affect stroke volume and sarcomere shortening without appreciable augmentation of aortic pressure, and the reflected pressure wave contributes an increased proportion of aortic pressure.

Enhanced central sympathetic tone induces heart failure with preserved ejection fraction (HFpEF) in rats.

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague-Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20 ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5 µg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708 mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studies.

In a large-volume multidisciplinary setting individual surgeon volume does not impact LVAD outcomes.

BACKGROUND: In complex operations surgeon volume may impact outcomes. We sought to understand if individual surgeon volume affects left ventricular assist device (LVAD) outcomes. METHODS: We reviewed primary LVAD implants at an experienced ventricular assist devices (VAD)/transplant center between 2013 and 2019. Cases were dichotomized into a high-volume group (surgeons averaging 11 or more LVAD cases per year), and a low-volume group (10 or less per year). Propensity score matching was performed. Survival to discharge, 1-year survival, and incidence of major adverse events were compared between the low- and high-volume groups. Predictors of survival were identified with multivariate analysis. RESULTS: There were 315 patients who met inclusion criteria-45 in the low-volume group, 270 in the high-volume group. There was no difference in survival to hospital discharge between the low (91.9%) and high (83.3%) volume matched groups (p = .22). Survival at 1-year was also similar (85.4% vs. 80.6%, p = .55). There was no difference in the incidence of major adverse events between the groups. Predictors of mortality in the first year included: age (hazards ratio [HR]: 1.061, p < .001), prior sternotomy (HR: 1.991, p = .01), increasing international normalized ratio (HR: 4.748, p < .001), increasing AST (HR: 1.001, p < .001), increasing bilirubin (HR: 1.081, p = .01), and preoperative mechanical ventilation (HR: 2.662, p = .005). Individual surgeon volume was not an independent predictor of discharge or 1-year survival. CONCLUSION: There was no difference in survival or adverse events between high and low volume surgeons suggesting that, in an experienced multidisciplinary setting, low-volume VAD surgeons can achieve similar outcomes to their high-volume colleagues.

Combination plate and band fixation for primary closure in bilateral lung transplantation.

BACKGROUND: Sternal complications are common following transverse thoracosternotomy in patients undergoing bilateral lung transplantation. We present a single-institution experience using a next generation rigid fixation system for primary sternal closure following transverse sternotomy for bilateral lung transplantation. METHODS: Retrospective review was performed on all patients who had bilateral sequential lung transplants utilizing a transverse thoracosternotomy from 2016 to 2020. Demographics, baseline characteristics, peri-operative data, and outcomes were collected, reviewed and summarized. Two groups of patients were identified: wire cerclage (Group A), combination plate-and-band rigid fixation (Group B). The primary outcome was sternal complications, which were divided into mechanical and non-mechanical. RESULTS: Twenty-two patients met inclusion criteria. Three patients (13.6%) were in Group A, nineteen patients (86.4%) in Group B. Two patients in each Group A (66.6%) and Group B (10.5%) experienced a sternal complication. Sternal complications included sternal dehiscence (2), sternal malunion (1), and surgical site infection (1). One patient with plate-and-band fixation (5.2%) had a mechanical sternal complication. Three patients required reoperation secondary to sternal complication. CONCLUSIONS: The utilization of a combination plate-and-band rigid fixation system for primary closure is safe and may be an effective method to reduce sternal complications following transverse thoracosternotomy for lung transplantation.

Impaired Exercise Tolerance Early After Heart Transplantation Is Associated With Development of Cardiac Allograft Vasculopathy.

BACKGROUND: Exercise performance remains limited in some patients after heart transplantation (HTx). The goal of this study was to assess for association between cardiopulmonary exercise test performance at 1 year after HTx and future development of cardiac allograft vasculopathy (CAV). METHODS: Overall 243 HTx recipients performed cardiopulmonary exercise testing at 1 year after HTx. During the median follow-up period of 31 (interquartile range 19;61) months, 76 (32%) patients were diagnosed with CAV (CAV group). RESULTS: The CAV group patients had lower exercise capacity (5.2 ± 1.9 versus 6.5 ± 2.2 metabolic equivalents; P = 0.001) and duration (9.6 ± 3.5 versus 11.4 ± 4.8 min; P = 0.008), lower peak oxygen consumption (VO2) (18.4 ± 5.4 versus 21.4 ± 6.1 mL/kg/min; P = 0.0005), lower normalized peak VO2 (63% ± 18% versus 71% ± 19%; P = 0.007), and higher minute ventilation (VE)/carbon dioxide production (VCO2) (34 ± 5 versus 32 ± 5, P = 0.04). On Cox proportional hazards regression analysis, normalized peak VO2 ≤60%, and VE/VCO2 ≥34 were associated with a high hazard for CAV (HR = 1.8 [95% CI 1.10-4.53, P = 0.03] and 2.5 [95% CI 1.01-8.81, P = 0.04], respectively). The subgroup of patients with both normalized peak VO2 ≤60% and VE/VCO2 ≥34 was at highest risk for development of CAV (HR = 5.2, 95% CI 2.27-15.17, P = 0.001). CONCLUSIONS: Normalized peak VO2 ≤60% and VE/VCO2 ≥34 at 1 year after HTx are associated with the development of CAV.

Modeling left ventricular dynamics with characteristic deformation modes.

A computationally efficient method is described for simulating the dynamics of the left ventricle (LV) in three dimensions. LV motion is represented as a combination of a limited number of deformation modes, chosen to represent observed cardiac motions while conserving volume in the LV wall. The contribution of each mode to wall motion is determined by a corresponding time-dependent deformation variable. The principle of virtual work is applied to these deformation variables, yielding a system of ordinary differential equations for LV dynamics, including effects of muscle fiber orientations, active and passive stresses, and surface tractions. Passive stress is governed by a transversely isotropic elastic model. Active stress acts in the fiber direction and incorporates length-tension and force-velocity properties of cardiac muscle. Preload and afterload are represented by lumped vascular models. The variational equations and their numerical solutions are verified by comparison to analytic solutions of the strong form equations. Deformation modes are constructed using Fourier series with an arbitrary number of terms. Greater numbers of deformation modes increase deformable model resolution but at increased computational cost. Simulations of normal LV motion throughout the cardiac cycle are presented using models with 8, 23, or 46 deformation modes. Aggregate quantities that describe LV function vary little as the number of deformation modes is increased. Spatial distributions of stress and strain change as more deformation modes are included, but overall patterns are conserved. This approach yields three-dimensional simulations of the cardiac cycle on a clinically relevant time-scale.

Molecular discoveries and treatment strategies by direct reprogramming in cardiac regeneration.

Cardiac tissue has minimal endogenous regenerative capacity in response to injury. Treatment options are limited following tissue damage after events such as myocardial infarction. Current strategies are aimed primarily at injury prevention, but attention has been increasingly targeted toward the development of regenerative therapies. This review focuses on recent developments in the field of cardiac fibroblast reprogramming into induced cardiomyocytes. Early efforts to produce cardiac regeneration centered around induced pluripotent stem cells, but clinical translation has proved elusive. Currently, techniques are being developed to directly transdifferentiate cardiac fibroblasts into induced cardiomyocytes. Viral vector-driven expression of a combination of transcription factors including Gata4, Mef2c, and Tbx5 induced cardiomyocyte development in mice. Subsequent combinational modifications have extended these results to human cell lines and increased efficacy. The miRNAs including combinations of miR-1, miR-133, miR-208, and miR-499 can improve or independently drive regeneration of cardiomyocytes. Similar results could be obtained by combinations of small molecules with or without transcription factor or miRNA expression. The local tissue environment greatly impacts favorability for reprogramming. Modulation of signaling pathways, especially those mediated by VEGF and TGF-ß, enhance differentiation to cardiomyocytes. Current reprogramming strategies are not ready for clinical application, but recent breakthroughs promise regenerative cardiac therapies in the near future.

Immunopathogenesis and biomarkers of recurrent atrial fibrillation following ablation therapy in patients with preexisting atrial fibrillation.

INTRODUCTION: Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation.

Current Modalities and Mechanisms Underlying Cardioprotection by Ischemic Conditioning.

Ischemic preconditioning is a process which serves to mitigate reperfusion injury. Preconditioning of the heart can be achieved through natural, pharmacological, and mechanical means. Mechanical preconditioning appears to have the greatest chance of good outcomes while methods employing pharmacologic preconditioning have been largely unsuccessful. Remote ischemic preconditioning achieves a cardioprotective effect by applying cycles of ischemia and reperfusion in a distal limb, stimulating the release of a neurohumoral cardioprotective factor incited by stimulation of afferent neurons. The cardioprotective factor stimulates the reperfusion injury salvage kinase (RISK) and survivor activator factor enhancement (SAFE) signaling cascades in cardiomyocytes which promote cell survival by the expression of anti-apoptotic genes and inhibition of the opening of mitochondrial permeability transition pores. Clinical application of ischemic preconditioning involving targets in the RISK and SAFE signaling appears promising in the treatment of acute myocardial infarction; however, clinical trials have yet to demonstrate additional benefit to current therapy.

Depression and anxiety in patients undergoing left ventricular assist device implantation.

BACKGROUND: Depression and anxiety are associated with a worse prognosis in heart failure patients. The aim of this study was to identify the prevalence of depression and anxiety in left ventricular assist device (LVAD) candidates and assess their effect on post-LVAD outcomes. METHODS: Based on the pre-LVAD psychological assessment, the total cohort of 246 patients were divided into 4 groups: 1) no depression or anxiety (NDep&Anx group, n = 138); 2) isolated depression (Dep group, n = 42); 3) isolated anxiety (Anx group, n = 32), and 4) combined depression and anxiety (Dep&Anx group, n = 34). RESULTS: The Dep&Anx group was associated with higher prevalence of female gender (p = 0.03), higher body mass index (p = 0.03), elevated E/E' (p = 0.003), and increased Model For End-Stage Liver Disease (MELD) XI score (p = 0.04) prior to LVAD as compared to the other 3 subgroups. The prevalence of other major psychiatric disorders (p = 0.03) and narcotic dependence (p = 0.004) was higher in the Dep&Anx group. Post-LVAD implantation, heart rate and filling pressures were elevated and readmission rate was higher (p = 0.001) in the Dep&Anx group. There was no difference in survival between the groups (p = 0.40, Log-Rank test). CONCLUSIONS: Pre-existing anxiety and depression was associated with worse HF pre- and post-LVAD implantation and higher readmissions rate after LVAD implantation.

Simulation of Left Ventricular Dynamics Using a Low-Order Mathematical Model.

The eventual goal of this study is to develop methods for estimating dynamic stresses in the left ventricle (LV) that could be used on-line in clinical settings, based on routinely available measurements. Toward this goal, a low-order theoretical model is presented, in which LV shape is represented using a small number of parameters, allowing rapid computational simulations of LV dynamics. The LV is represented as a thick-walled prolate spheroid containing helical muscle fibers with nonlinear passive and time-dependent active contractile properties. The displacement field during the cardiac cycle is described by three time-dependent parameters, using a family of volume-preserving mappings based on prolate spheroidal coordinates. Stress equilibrium is imposed in weak form and the resulting force balance equations are coupled to a lumped-parameter model of the circulation, leading to a system of differential-algebraic equations, whose numerical solution yields predictions of LV pressure and volume, together with spatial distributions of stresses and strains throughout the cardiac cycle. When static loading of the passive LV is assumed, this approach yields displacement and stress fields that closely match results from a standard finite-element approach. When dynamic motion with active contraction is simulated, substantial variations of fiber stress and strain through the myocardium are predicted. This approach allows simulations of LV dynamics that run faster than real time, and could be used to determine patient-specific parameters of LV performance on-line from clinically available measurements, with the eventual goal of real-time, patient-specific analysis of cardiac parameters.

Effect of diltiazem on exercise capacity after heart transplantation.

BACKGROUND: Sinus tachycardia (ST) is common after heart transplantation (HTx). The aim of the study was to evaluate the effect of diltiazem treatment during the first year after HTx on heart rate (HR), cardiac allograft function, and exercise capacity. METHODS: From the total cohort, 25 HTx recipients started diltiazem treatment 4±2 weeks after HTx and continued it for at least 1 year (diltiazem group). Each study case was matched to a control. All patients underwent hemodynamic assessment and cardiopulmonary exercise test (CPET) at 1 year after HTx. RESULTS: HR decreased in the diltiazem group from 99±11 bpm to 94±7 bpm (P=.03) and did not change in the controls (98±11 bpm vs 100±13 bpm, P=.14). The difference between the groups at 1 year after HTx was significant (P=.04). In the diltiazem group left ventricular (LV), stroke volume and ejection fraction increased (48±16 vs 55±17 mL, P=.02, and 60%±10% vs 62%±12% P=.03, respectively) but did not differ from controls. E/E' decreased (10.7±2.7 vs 7.3±1.9, P=.003) while cardiac index was higher (3.5±0.8 vs 3.1±0.5; P=.05) in the diltiazem group at 1-year follow-up. The absolute peak VO2 (21±4 vs 18±6 mL/kg/min; P=.05) and normalized peak VO2 (73%±17% vs 58%±14%; P=.004) were significantly higher in the diltiazem group. CONCLUSIONS: This study showed that diltiazem treatment reduces ST, may improve cardiac allograft function and exercise tolerance during the first year after HTx.

Lower Extremity Revascularization Using Optical Coherence Tomography-Guided Directional Atherectomy: Final Results of the EValuatIon of the PantheriS OptIcal COherence Tomography ImagiNg Atherectomy System for Use in the Peripheral Vasculature (VISION) Study.

PURPOSE: To evaluate the safety and efficacy of a novel optical coherence tomography (OCT)-guided atherectomy catheter in treating patients with symptomatic femoropopliteal disease. METHODS: The VISION trial ( ClinicalTrials.gov identifier NCT01937351) was a single-arm, multicenter, global investigational device exemption study enrolling 158 subjects (mean age 67.2±10.5 years; 87 men) across 20 participating sites. In this cohort, 198 lesions were treated with an average length of 53±40 mm using the Pantheris catheter alone or Pantheris + adjunctive therapy. The primary safety endpoint was the composite of major adverse events (MAEs) through 6 months (objective performance goal 43.2%). Technical success (primary efficacy outcome) was defined as the percent of target lesions with a residual diameter stenosis ≤50% after treatment with the Pantheris device alone (objective performance goal 87.0%). Procedural success was defined as reduction in stenosis to ≤30% after Pantheris ± adjunctive therapy. Tissue specimens retrieved from each treated lesion were histologically analyzed to evaluate the accuracy and precision of OCT image guidance. RESULTS: The primary efficacy outcome was achieved in 192 (97.0%) of the 198 lesions treated with the Pantheris catheter. Across all lesions, mean diameter stenosis was reduced from 78.7%±15.1% at baseline to 30.3%±11.8% after Pantheris alone (p<0.001) and to 22.4%±9.9% after Pantheris ± adjunctive therapy (p<0.001). Of the 198 target lesions, 104 (52.5%) were treated with the Pantheris alone, 84 (42.4%) were treated with Pantheris + adjunctive angioplasty, and 10 (5.1%) with Pantheris + angioplasty + stenting. The composite MAE outcome through 6 months occurred in 25 (16.6%) of 151 subjects. There were no clinically significant perforations, 1 (0.5%) catheter-related dissection, 4 (2%) embolic events, and a 6.4% clinically driven target lesion revascularization rate at 6 months. The 40-lesion chronic total occlusion (CTO) subset (mean lesion length 82±38 mm) achieved a similar significant reduction in stenosis to 35.5%±13.6% after Pantheris alone (p<0.001). Histological analysis of atherectomy specimens confirmed <1% adventitia in 82.1% of the samples, highlighting the precision of OCT guidance. Characterization of the OCT-guided lesions revealed evidence of an underestimation of disease burden when using fluoroscopy. CONCLUSION: OCT-guided atherectomy for femoropopliteal disease is safe and effective. Additionally, the precision afforded by OCT guidance leads to greater removal of plaque during atherectomy while sparing the adventitia.

Sinus tachycardia is associated with impaired exercise tolerance following heart transplantation.

BACKGROUND: Sinus tachycardia often presents in heart transplantation (HTx) recipients, but data on its effect on exercise performance are limited. METHODS: Based on mean heart rate (HR) value 3 months after HTx, 181 patients transplanted from 2006 to 2015 at University of Nebraska Medical Center were divided into two groups: (i) HR<95 beats/min (bpm, n=93); and (ii) HR≥95 bpm (n=88). Cardiopulmonary exercise testing (CPET) was performed 1 year after HTx. RESULTS: Mean HR at 3 months post-HTx was 94±11 bpm and did not change significantly at 1 year post-HTx (96±11 bpm, P=.13). HR≥95 bpm at 3 months was associated with younger donor age (OR 1.1; CI 1.0-1.1, P=.02), female donors (OR -2.4; CI 1.16-5.24 P=.02), and lack of donors' heavy alcohol use (OR -0.43; CI 0.17-0.61; P=.04). HR≥95 bpm at 3 months post-HTx was independently associated with decreased exercise capacity in metabolic equivalent (P=.008), reduced peak VO2 (P=.006), and percent of predicted peak VO2 (P=.002) during CPET. CONCLUSIONS: HR≥95 at 3 months following HTx is associated with reduced exercise tolerance in stable HTx recipients. Medical HR reduction after HTx could improve exercise performance after HTx and merits further investigation.

Targeted myocardial gene expression in failing hearts by RNA sequencing.

BACKGROUND: Myocardial recovery with left ventricular assist device (LVAD) therapy is highly variable and difficult to predict. Next generation ribonucleic acid (RNA) sequencing is an innovative, rapid, and quantitative approach to gene expression profiling in small amounts of tissue. Our primary goal was to identify baseline transcriptional profiles in non-ischemic cardiomyopathies that predict myocardial recovery in response to LVAD therapy. We also sought to verify transcriptional differences between failing and non-failing human hearts. METHODS: RNA was isolated from failing (n = 16) and non-failing (n = 8) human hearts. RNA from each patient was reverse transcribed and quantitatively sequenced on the personal genome machine (PGM) sequencer (Ion torrent) for 95 heart failure candidate genes. Coverage analysis as well as mapping the reads and alignment was done using the Ion Torrent Browser Suite™. Differential expression analyses were conducted by empirical analysis of digital gene expression data in R (edgeR) to identify differential expressed genes between failing and non-failing groups, and between responder and non-responder groups respectively. Targeted cardiac gene messenger RNA (mRNA) expression was analyzed in proportion to the total number of reads. Gene expression profiles from the PGM sequencer were validated by performing RNA sequencing (RNAseq) with the Illumina Hiseq2500 sequencing system. RESULTS: The failing sample population was 75% male with an average age of 50 and a left ventricular ejection fraction (LVEF) of 16%. Myosin light chain kinase (MYLK) and interleukin (IL)-6 genes expression were significantly higher in LVAD responders compared to non-responders. Thirty-six cardiac genes were expressed differentially between failing and non-failing hearts (23 decreased, 13 elevated). MYLK, Beta-1 adrenergic receptor (ADRB1) and myosin heavy chain (MYH)-6 expression were among those significantly decreased in failing hearts compared to non-failing hearts. Natriuretic peptide B (NPPB) and IL-6 were significantly elevated. Targeted gene expression profiles obtained from the Ion torrent PGM sequencer were consistent with those obtained from Illumina HiSeq2500 sequencing system. CONCLUSIONS: Heart failure is associated with a network of transcriptional changes involving contractile proteins, metabolism, adrenergic receptors, protein phosphorylation, and signaling factors. Myocardial MYLK and IL-6 expression are positively correlated with ejection fraction (EF) response to LVAD placement. Targeted RNA sequencing of myocardial gene expression can be utilized to predict responders to LVAD therapy and to better characterize transcriptional changes in human heart failure.

Time-Dependent Regional Myocardial Strains in Patients with Heart Failure with a Preserved Ejection Fraction.

OBJECTIVES: To better understand the etiology of HFpEF in a controlled human population, regional time-varying strains were computed using echocardiography speckle tracking in patients with heart failure with a preserved ejection fraction and normal subjects. METHODS: Eleven normal volunteers and ten patients with echo-graded diastolic dysfunction and symptoms of heart failure were imaged with echocardiography and longitudinal, circumferential, and rotational strains were determined using speckle-tracking. Diastolic strain rate was also determined. Patient demographics and echo-derived flows, volumes, and pressures were recorded. RESULTS: Peak longitudinal and circumferential strain was globally reduced in patients (p < 0.001), when compared to controls. The patients attained peak longitudinal and circumferential strain at a consistently later point in systole than controls. Rotational strains were not different in most LV regions. Early diastolic strain rate was significantly reduced in the patients (p < 0.001). LV mass and wall thickness were significantly increased in the patients; however ejection fraction was preserved and stroke volume was diminished (p < 0.001). CONCLUSIONS: This study shows that patients with HFpEF have reduced early diastolic strain rate and reduced peak strain that is regionally homogeneous and that they also utilize a longer fraction of systole to achieve peak axial strains.

Outcomes in Patients with Severe Preexisting Renal Dysfunction After Continuous-Flow Left Ventricular Assist Device Implantation.

The aim of this study was to evaluate clinical outcomes after left ventricular assist device (LVAD) implantation in patients with severe pre-LVAD renal dysfunction (RD). The cohort of 165 consecutive patients implanted with HeartMate II LVADs was divided into two groups: 1) baseline glomerular filtration rate (bGFR) ≤ 40 ml/min/1.73 m (n = 30), and 2) GFR > 40 ml/min/1.73 m (n = 135). In both groups, GFR increased significantly at 1 month and then declined, remaining higher than the pre-LVAD level in the bGFR ≤ 40 group and returning back to the pre-LVAD level in the bGFR > 40 group by 1 year post-LVAD follow-up. Post-LVAD dialysis was used in 20% of the bGFR ≤ 40 patients and 7% of the bGFR > 40 patients (p = 0.02). By 3 months, 14% patients had GFR ≤ 40 ml/min/1.73 m. Grade ≥2 tricuspid regurgitation (TR) (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.23-10.28; p = 0.02) and model for end-stage liver disease-XI score ≥ 17 (OR, 4.2; 95% CI, 1.45-12.24; p = 0.01) were risk factors for severe RD at 3 months after LVAD implantation. Eight bGFR ≤ 40 patients underwent heart transplantation. Carefully selected patients with advanced heart dysfunction and bGFR ≤ 40 ml/min/1.73 m can improve kidney function with LVAD support and be able to bridge to isolated heart transplantation. Additional research is needed to refine patient selection for LVAD.