C.H. Selzman

Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery.

OBJECTIVESnThis 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.nnnBACKGROUNDnThe magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown.nnnMETHODSnEighty 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.nnnRESULTSnAfter 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/m(2), p < 0.01, and 92 vs. 60 ml/m(2), p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m(2), 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.nnnCONCLUSIONSnContinuous-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.

Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation

Non‐invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end‐stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end‐stage heart failure as a result of idiopathic dilated cardiomyopathy (nu2009=u200914) and from normal donors (nu2009=u20095). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1), secondary (D2) and tertiary (D3) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (Pu2009<u20090.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearsons correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were –0.51, 0.59, 0.56 and 0.62 (Pu2009<u20090.05), respectively. The correlation between D1 and collagen content was not significant (ru2009=u20090.46, Pu2009=u20090.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non‐invasive assessment of diffuse fibrosis in failing hearts. Copyright

Association of recipient age and causes of heart transplant mortality: Implications for personalization of post-transplant management-An analysis of the International Society for Heart and Lung Transplantation Registry

BACKGROUNDnSurvival beyond 1 year after heart transplantation has remained without significant improvement for the last 2 decades. A more individualized approach to post-transplant care could result in a reduction of long-term mortality. Although recipient age has been associated with an increased incidence of certain post-transplant morbidities, its effect on cause-specific mortality has not been established.nnnMETHODSnWe analyzed overall and cause-specific mortality of heart transplant recipients registered in the International Society for Heart and Lung Transplantation Registry between 1995 and 2011. Patients were grouped by recipient age: 18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and ≥ 70 years. Multivariable regression models were used to examine the association between recipient age and leading causes of post-transplant mortality. We also compared immunosuppression (IS) use among the different recipient age groups.nnnRESULTSnThere were 52,995 recipients (78% male; median age [5th, 95th percentile]: 54 [27, 66] years). Survival through 10 years after transplant was lower in heart transplant recipients in the 2 more advanced age groups: 49% for 60 to 69 years and 36% for ≥ 70 years (p < 0.01 for pairwise comparisons with remaining groups). The risk of death caused by acute rejection (hazard ratio [HR], 4.11; p < 0.01), cardiac allograft vasculopathy (HR, 2.85; p < 0.01), and graft failure (HR, 2.29; p < 0.01) was highest in the youngest recipients (18-29 years) compared with the reference group (50-59 years). However, the risk of death caused by infection (HR, 2.10; p < 0.01) and malignancy (HR, 2.23; p < 0.01) was highest in older recipients (≥ 70 years). Similarly, the risk of death caused by renal failure was lower in younger recipients than in the reference group (HR, 0.53; p < 0.01 for 18-49 years vs 50-59 years). The use of induction IS was similar among the different recipient age groups, and differences in maintenance IS were not clinically important.nnnCONCLUSIONSnCauses of death in this large cohort of heart transplant recipients varied significantly with recipient age at the time of transplant, with cause-specific mortality profiles suggesting a possible effect of inadequate IS in younger recipients and over-IS in older recipients. Thus, a more personalized approach, possibly including different IS strategies according to recipient age, might result in improved post-transplant survival.

Sheet-like remodeling of the transverse tubular system in human heart failure impairs excitation-contraction coupling and functional recovery by mechanical unloading

Background: Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of patients with chronic heart failure (HF). Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery. Methods: Left ventricular biopsies were obtained from 5 donors and 26 patients with chronic HF undergoing implantation of LVADs. Three-dimensional confocal microscopy and computational image analysis were applied to assess t-system structure, density, and distance of ryanodine receptor clusters to the sarcolemma, including the t-system. Recovery of cardiac function in response to mechanical unloading was assessed by echocardiography during turndown of the LVAD. Results: The majority of HF myocytes showed remarkable t-system remodeling, particularly sheet-like invaginations of the sarcolemma. Circularity of t-system components was decreased in HF versus controls (0.37±0.01 versus 0.46±0.02; P<0.01), and the volume/length ratio was increased in HF (0.36±0.01 versus 0.25±0.02 µm2; P<0.0001). T-system density was reduced in HF, leading to increased ryanodine receptor–sarcolemma distances (0.96±0.05 versus 0.64±0.1 µm; P<0.01). Low ryanodine receptor–sarcolemma distances at the time of LVAD implantation predicted high post-LVAD left ventricular ejection fractions (P<0.01) and ejection fraction increases during unloading (P<0.01). Ejection fraction in patients with pre-LVAD ryanodine receptor–sarcolemma distances >1 µm did not improve after mechanical unloading. In addition, calcium transients were recorded in field-stimulated isolated human cardiomyocytes and analyzed with respect to local t-system density. Calcium release in HF myocytes was restricted to regions proximal to the sarcolemma. Local calcium upstroke was delayed (23.9±4.9 versus 10.3±1.7 milliseconds; P<0.05) and more asynchronous (18.1±1.5 versus 8.9±2.2 milliseconds; P<0.01) in HF cells with low t-system density versus cells with high t-system density. Conclusions: The t-system in end-stage human HF presents a characteristic novel phenotype consisting of sheet-like invaginations of the sarcolemma. Our results suggest that the remodeled t-system impairs excitation-contraction coupling and functional recovery during chronic LVAD unloading. An intact t-system at the time of LVAD implantation may constitute a precondition and predictor for functional cardiac recovery after mechanical unloading.

Stroke Prevention With Carotid Compression in Patients Undergoing Transcatheter Aortic Valve Replacement: a Multi-Center Study

* Corresponding Author: Anwar Tandar, MD Division of Cardiovascular Medicine University of Utah 50 North Medical Drive, SOM, Room 4A100, Salt Lake City, UT 84132, USA Tel. +1 801 585 5559; Fax: +1 801 581 7735; E-Mail: anwar.tandar@hsc.utah.edu Fax +1 203 785 3346 E-Mail: jshd@scienceinternational.org http://structuralheartdisease.org/

Left ventricular perforation after Impella® placement in a patient with cardiogenic shock

Mechanical cardiovascular support devices are now widely used both in the setting of cardiogenic shock as well as during high risk cardiac catheterization procedures. We report a case of a young female patient who presented with presumed myocarditis and rapidly deteriorating decompensated heart failure requiring the implantation of an Impella Circulatory Support System. Upon transfer to our facility it was discovered that during transport, the Impella device had migrated through the left ventricle. She was emergently taken to the operating room where the Impella was surgically removed and biventricular support devices were placed. The patient eventually expired after weeks of treatment in the intensive care unit. We believe this is the first recorded case of an Impella device perforating the left ventricle. Particularly in cases of newly discovered pericardial effusion, change in waveform on the Impella controller placement signal or rapid decompensation, physicians should consider this rare but potentially catastrophic complication associated with mechanical left ventricular support devices.

Worsening of Functional Mitral Regurgitation from Septal Dyssynchrony Induced by Ventricular Pacing in Ebstein's Anomaly Undergoing Percutaneous Mitral Valve Repair

Author(s): Nguyen, Heajung L; Calfon Press, Marcella A; Aboulhosn, Jamil A; Lin, Jeannette P; Benharash, Peyman; Yang, Eric H

Changes in Metabolic Substrate Utilization and Pyruvate Mitochondrial Oxidation Mismatch during Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

s S57 December 2014. Endpoints were incidence of transplantation, waitlist dropout for death or medical worsening, and post-transplant death. Grafts were allocated by simulation to patients according to blood type, morphological and age matching and CRS value, with national sharing. Simulated and historical cumulative incidences of events were compared using a competing risk model for WL events and a Cox model for post transplant death. Results: nCAS significantly decreases the overall mortality from the placement on the waiting list and improves both pre and post transplant patient outcomes. In reducing the transplant access rates gap between High Urgency (HU) and non HU patients, it also provides more equitable dropout risks. Conclusion: A patient-based allocation system including a CRS with objective criteria would correct the excess of positive discrimination for HU patients, providing more equitable results and a very promising alternative to our current CAS. Its combination to a national sharing of all organs would also decrease both WL and post transplant mortality, providing a « just in time » heart allocation for all candidates, improving both efficacy and efficiency.

Magnitude and Time Course of Changes Induced by Continuous-Flow Left Ventricular Assist Device Unloading in Chronic Heart Failure: Insights into Cardiac Recovery

Purpose The magnitude, timeline and sustainability of changes induced by continuous-flow left ventricular assist device (CF-LVAD) unloading on the structure and function of the failing human heart are unknown. Methods and Materials Eighty consecutive patients with chronic heart failure requiring CF-LVAD implantation were prospectively enrolled. Serial echocardiograms (1, 2, 3, 4, 6, 9 and 12 months) were performed after implant to evaluate the longitudinal effects of CF-LVADs on myocardial structure and function. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices that were sustained during LVAD turn-down studies. Results After 6 months of LVAD unloading, 22% of patients had an LVEF of 30-39% and 19% achieved an LVEF≥40% ( Figure ). In those with an LVEF≥40%, LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months and persisted over the 1-year follow-up ( Figure , panel C). LV diastolic function also improved as early as 30 days and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days post-implant (120±39 vs. 82±36xa0ml/m2, p Conclusions CF-LVAD unloading induced in a subset of patients, both ischemic and nonischemics, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression.

QRS and QT Interval Changes and Ventricular Arrhythmias Following Continuous Flow Mechanical Unloading of the Failing Human Heart

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±37xa0ms 128±34xa0ms 120±41xa0ms * QRS 446±62xa0ms 409±77xa0ms 404±78xa0ms * * Pre-LVAD to 4 weeks post LVAD