Left and Right Ventricular Longitudinal Systolic Function Following Aortic Valve Replacement in the PARTNER 2 Trial And Registry.

AIMS: Evaluation of left and right ventricular longitudinal systolic function may enhance risk stratification following aortic valve replacement (AVR). The study objective was to evaluate the changes in left and right ventricular longitudinal systolic function and RV-pulmonary artery (RV-PA) coupling from baseline to 30-days and 1-year after aortic valve replacement (AVR). METHODS AND RESULTS: LV longitudinal strain (LS), tricuspid annulus plane systolic excursion (TAPSE), and RV-PA coupling were evaluated in patients from the PARTNER-2A surgical AVR (SAVR) arm (n=985) and from the PARTNER-2 SAPIEN-3 registry (n=719). TAPSE and RV-PA coupling decreased significantly following SAVR, but remained stable following TAVR. Lower LV LS, TAPSE, or RV-PA coupling at baseline were associated with increased risk of the composite of death, hospitalization, and stroke at 5-years (Adjusted-HRs for LV LS<15%: 1.24 95%CI 1.05-1.45, p=0.001; TAPSE<14mm: 1.44 95%CI 1.21-1.73, p<0.001; RV/PA coupling<0.55mm/mmHg: 1.32 95% CI 1.07-1.63, p=0.011). Reduced TAPSE at baseline was the most powerful predictor of the composite endpoint at 5-years. Patients with LV ejection fraction <50% at baseline had increased risk of the primary endpoint with SAVR (HR: 1.34, 95%CI 1.08-1.68, p=0.009) but not with TAVR (HR: 1.12, 95%CI 0.88-1.42). Lower RV-PA coupling at 30-days showed the strongest association with cardiac mortality. CONCLUSION: SAVR but not TAVR was associated with a marked deterioration in RV longitudinal systolic function and RV-PA coupling. Lower TAPSE and RV-PA coupling at 30-days were associated with inferior clinical outcomes at 5-years. In patients with LVEF<50%, TAVR was associated with superior 5-year outcomes.

Ventricular stroke work and vascular impedance refine the characterization of patients with aortic stenosis.

Aortic stenosis (AS) management is classically guided by symptoms and valvular metrics. However, the natural history of AS is dictated by coupling of the left ventricle, aortic valve, and vascular system. We investigated whether metrics of ventricular and vascular state add to the appreciation of AS state above valve gradient alone. Seventy patients with severe symptomatic AS were prospectively followed from baseline to 30 days after transcatheter aortic valve replacement (TAVR). Quality of life (QOL) was assessed using the Kansas City Cardiomyopathy Questionnaire. Left ventricular stroke work (SWLV) and vascular impedance spectrums were calculated noninvasively using in-house models based on central blood pressure waveforms, along with hemodynamic parameters from echocardiograms. Patients with higher preprocedural SWLV and lower vascular impedance were more likely to experience improved QOL after TAVR. Patients fell into two categories: those who did and those who did not exhibit increase in blood pressure after TAVR. In patients who developed hypertension (19%), vascular impedance increased and SWLV remained unchanged (impedance at zeroth harmonic: Z 0, from 3964.4 to 4851.8 dyne·s/cm3, P = 0.039; characteristic impedance: Z c, from 376.2 to 603.2 dyne·s/cm3, P = 0.033). SWLV dropped only in patients who did not develop new hypertension after TAVR (from 1.58 to 1.26 J; P < 0.001). Reduction in valvular pressure gradient after TAVR did not predict change in SWLV (r = 0.213; P = 0.129). Reduction of SWLV after TAVR may be an important metric in management of AS, rather than relying solely on the elimination of transvalvular pressure gradients.

Rationale and design of the Transcatheter Aortic Valve Replacement to UNload the Left ventricle in patients with ADvanced heart failure (TAVR UNLOAD) trial.

BACKGROUND: Coexistence of moderate aortic stenosis (AS) in patients with heart failure (HF) with reduced ejection fraction is not uncommon. Moderate AS increases afterload, whereas pharmacologic reduction of afterload is a pillar of contemporary HF management. HYPOTHESIS: Unloading the left ventricle by reducing the transaortic gradient with transfemoral transcatheter aortic valve replacement (TAVR) may improve clinical outcomes in patients with moderate AS and HF with reduced ejection fraction. STUDY DESIGN: The TAVR UNLOAD (NCT02661451) is an international, multicenter, randomized, open-label, clinical trial comparing the efficacy and safety of TAVR with the Edwards SAPIEN 3 Transcatheter Heart Valve in addition to optimal heart failure therapy (OHFT) vs OHFT alone in patients with moderate AS (defined by a mean transaortic gradient ≥20 mm Hg and <40 mm Hg, and an aortic valve area >1.0 cm2 and ≤1.5 cm2 at rest or after dobutamine stress echocardiography) and reduced ejection fraction. A total of 600 patients will be randomized in a 1:1 fashion. Clinical follow-up is scheduled at 1, 6, and 12 months, and 2 years after randomization. The primary end point is the hierarchical occurrence of all-cause death, disabling stroke, hospitalizations related to HF, symptomatic aortic valve disease or nondisabling stroke, and the change in the Kansas City Cardiomyopathy Questionnaire at 1 year. Secondary end points capture effects on clinical outcome, biomarkers, echocardiographic parameters, and quality of life. SUMMARY: The TAVR UNLOAD trial aims to test the hypothesis that TAVR on top of OHFT improves clinical outcomes in patients with moderate AS and HF with reduced ejection fraction.

Reduced continuous-flow left ventricular assist device speed does not decrease von Willebrand factor degradation.

BACKGROUND: Nonsurgical bleeding is a frequent complication of continuous-flow left ventricular assist device (LVAD) support. Abnormal von Willebrand factor (vWF) metabolism plays a major role. However, the relationship between LVAD speed and vWF degradation is unknown. Recent evidence has demonstrated that supraphysiologic shear stress from continuous-flow LVADs accelerates vWF degradation and causes an acquired vWF deficiency and bleeding. To manage LVAD-associated bleeding, it has been proposed that reduced LVAD speed may decrease shear stress and thereby reduce pathologic vWF metabolism. However, there are little published data to support this clinical practice. We tested the hypothesis that reduced continuous-flow LVAD speed decreases vWF degradation. METHODS: Whole blood was collected from patients before and after the implantation of a HeartMate II continuous-flow LVAD (n = 10) to quantify in vivo vWF degradation. In parallel, to evaluate the relationship between LVAD rpm and vWF degradation, whole blood was collected from human donors (n = 30). Single-donor units of blood circulated in an ex vivo HeartMate II mock circulatory loop for 12 hours at 11,400, 10,000, or 8600 rpm (n = 10/each rpm group). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblot analysis. Paired Student t tests were performed within each group. ANOVA with Tukey post hoc test was performed across groups. RESULTS: In patients, LVAD support reduced large vWF multimers and significantly (P < .05) increased vWF degradation fragments. The profile of vWF degradation was nearly identical between LVAD patients and blood circulated in the LVAD mock circulatory loop. At 11,400, 10,000, and 8600 rpm, decreased large vWF multimers and significantly increased vWF degradation fragments were noted. vWF degradation fragments were not statistically different across the 3 rpm groups or versus LVAD patients, which suggested that LVAD rpm did not influence vWF degradation. CONCLUSIONS: Reduced LVAD speed (within the clinical operational range) did not significantly decrease vWF degradation in a mock circulatory loop with human blood. During bleeding events, reduced LVAD speed, itself, may not diminish vWF degradation.

Safety of reduced anti-thrombotic strategies in HeartMate II patients: A one-year analysis of the US-TRACE Study.

BACKGROUND: Patients with bleeding complications during left ventricular assist device (LVAD) support often require a reduction in the recommended warfarin plus aspirin regimen. To characterize those who can be safely managed with a reduced anti-thrombotic strategy, the TRACE (STudy of Reduced Anti-Coagulation/Anti-platelEt Therapy in Patients with the HeartMate II LVAS) study was initiated in the United States (U.S.) and Europe. METHODS: The TRACE U.S. arm enrolled HeartMate II (HMII; Thoratec) outpatients on a regimen of reduced anti-thrombotic therapy (RT), defined as vitamin K antagonist (warfarin) only, aspirin only, or no anti-thrombotic agent. The indication for RT, changes in anti-thrombotic therapies, and patient outcomes after RT were documented. Results for patients reaching 12 months or outcome are presented here. RESULTS: Between April 2012 and June 2013, 100 HMII outpatients (85% men) on RT (median age 64.5 [interquartile range, 32, 82] years, 61% with ischemic etiology, 69% destination therapy) were enrolled from 9 U.S. sites. The primary reason for RT initiation was in response to a bleeding event (82%). Pharmacotherapy at RT initiation included warfarin only (38%), aspirin only (28%), or no anti-thrombotic agent (34%). Freedom from ischemic stroke at 1 year was 93.8% ± 2.5%, and freedom from device thrombosis was 92.7% ± 2.7%. Despite RT, a subsequent bleeding event occurred in 52%. CONCLUSIONS: Reducing anti-thrombotic therapies in response to bleeding among HMII patients was achievable but may be associated with a higher risk for device thrombosis. Furthermore, despite an RT strategy, bleeding often will persist in those prone to such events.

Programmed Speed Reduction Enables Aortic Valve Opening and Increased Pulsatility in the LVAD-Assisted Heart.

Aortic valve opening (AVO) during left ventricular assist device (LVAD) support aids in preventing valve fusion, incompetence, and thrombosis. The programmed low speed algorithm (PLSA) allows AVO intermittently by reducing continuous motor speed during a dwell time. AVO and hemodynamics in the LVAD-assisted heart were measured using a HeartMate II (Thoratec Corporation, Pleasanton, CA) LVAD with a PLSA controller in a mock circulatory loop. Left ventricle and aortic pressures, LVAD, and total aortic flow were measured during pre-LVAD, non-PLSA and PLSA combinations of cardiac function, and LVAD speed. The low cardiac setting corresponded to a pre-LVAD cardiac output of 2.8 L/min, stroke volume of 40 ml, and ejection fraction of 22%; the medium setting produced values of 3.5 L/min, 50 ml, and 28%, respectively. Results show that the PLSA controller set at 10 krpm, dropping to 7 krpm for dwell time of 6 s, adequately produced AVO for all tested cardiac functions with only minimal changes in cardiac output. However, AVO frequency was independent of opening area and systolic duration, which both decreased with increasing LVAD support. Furthermore, aortic pulsatility index quadrupled in the aortic root and doubled in the distal aorta during PLSA conditions, providing evidence that AVO and blood mixing are enabled by PLSA control at the appropriate speed.

Preclinical Models for Translational Investigations of Left Ventricular Assist Device-Associated von Willebrand Factor Degradation.

Evidence suggests a major role for von Willebrand factor (vWF) in left ventricular assist device (LVAD)-associated bleeding. However, the mechanisms of vWF degradation during LVAD support are not well understood. We developed: (i) a simple and inexpensive vortexer model; and (ii) a translational LVAD mock circulatory loop to perform preclinical investigations of LVAD-associated vWF degradation. Whole blood was obtained from LVAD patients (n = 8) and normal humans (n = 15). Experimental groups included: (i) blood from continuous-flow LVAD patients (baseline vs. post-LVAD, n = 8); (ii) blood from normal humans (baseline vs. 4 h in vitro laboratory vortexer, ∼ 2400 rpm, shear stress ∼175 dyne/cm(2) , n = 8); and (iii) blood from normal humans (baseline vs. 12 h HeartMate II mock circulatory loop, 10 000 rpm, n = 7). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting. Blood from LVAD patients, blood exposed to in vitro supraphysiologic shear stress, and blood circulated through an LVAD mock circulatory loop demonstrated a similar profile of decreased large vWF multimers and increased vWF degradation fragments. A laboratory vortexer and an LVAD mock circulatory loop reproduced the pathologic degradation of vWF that occurs during LVAD support. Both models are appropriate for preclinical studies of LVAD-associated vWF degradation.

Reduction in driveline infection rates: Results from the HeartMate II Multicenter Driveline Silicone Skin Interface (SSI) Registry.

BACKGROUND: During left ventricular assist device implantation, a surgical tunneling technique to keep the entire driveline (DL) velour portion in the subcutaneous tunnel, resulting in a silicone-skin interface (SSI) at the exit site, has been adopted by many centers. To assess long-term freedom from DL infection associated with this technique, a multicenter SSI registry was initiated. It was hypothesized that the modified tunneling technique is associated with at least 50% reduction in DL infection at 1 year post-implant compared with the velour-to-skin method used in the HeartMate II (HMII) Destination Therapy (DT) trial. METHODS: SSI is a retrospective and prospective registry of patients who have received the HMII device. Results are reported from the retrospective cohort, which consists of 200 patients who were implanted during the period 2009-2012 with the SSI tunneling method and on HMII support for at least 10 months at the time of enrollment. The prevalence and incidence of DL infection after left ventricular assist device implantation in the SSI retrospective cohort were determined and compared with a control group of 201 patients also on HMII support for at least 10 months from the HMII DT clinical trial who were implanted during the period 2007-2009 using the traditional method in which a small section of the velour portion of the DL was externalized. RESULTS: The 1-year and 2-year prevalence rates of DL infection were 9% and 19% in the SSI patient group compared with 23% and 35% in the control group (hazard ratio 0.49, 95% confidence interval 0.33-0.73, p < 0.001). The event-per-patient year was 0.11 and 0.22 for the SSI and control groups, respectively (p < 0.001). Based on a multivariate analysis, age and DL exit side were the only independent variables associated with DL infection. Effects of management changes over the eras were not studied and could have contributed to the findings. CONCLUSIONS: These results suggest that leaving the entire DL velour portion below the skin is associated with 50% reduction in DL infection compared with results from the HMII DT trial.

[Uveal metastasis of thyroid carcinomas. About 3 cases]. / Métastases uvéales des carcinomes thyroïdiens. À propos de 3 cas.

OBJECTIVE: To study the characteristics of ocular metastases of thyroid carcinomas through three observations of patients. RESULTS: Three patients aged respectively 41, 55 and 66 years were followed for thyroid carcinoma. All patients were treated by surgery followed by IRA therapy. They developed ocular metastases after a mean period of 10 years after thyroidectomy. They presented in addition multiple secondary sites such as bone, lungs and cerebrum. The uveal lesion was unilateral and localized at the choroid or iris. The predominant symptomatology was decreased visual acuity. The diagnosis was based on ophthalmoscopic examination and post-IRA therapy scan and was confirmed by anatomopathological study. Treatment options were respectively IRA therapy, sectoral iridectomy and enucleation. Evolution was fatal in 2 cases and towards aggravation for one case. CONCLUSION: Uveal metastases of thyroid cancer are associated with a pejorative prognosis. Ophthalmologic follow-up is necessary when patient presents warning sign mainly with metastatic follicular carcinoma. Conversely, thyroid carcinoma should be considered in the differential diagnosis of a uveal mass of unknown origin.

Clinical features of bone metastasis for differentiated thyroid carcinoma: A study of 21 patients from a Tunisian center.

INTRODUCTION: The differentiated thyroid cancers have a good prognosis unless the presence of metastasis. These distant metastases, especially in bone, are a major cause of impaired quality of life and death requiring intensive management. The aim of our work was to study the patients' data, the disease characteristics and to analyze the therapeutic management of these patients. RESULTS: This study concerned a cohort of 21 patients treated for differentiated thyroid cancer during the period from 1995 to 2011. Eighteen of our patients were aged over 45 years. A majority of them had follicular carcinoma. Bone metastases were often multiple and located at the axial skeleton. They were associated with other types of metastases, especially lung metastasis. A majority of patients received 131I treatment, following surgery or external beam radiotherapy for a palliative purpose. Overall survival was 65% at 5 years and 49% at 10 years. A long-term survival was achieved in 10% of the patients benefiting from a multidisciplinary care adapted to each case. CONCLUSION: Bone metastases often have a pejorative turning in the natural history of differentiated thyroid cancers. The right selection of individuals with better prognosis, for whom more aggressive curative treatment was indicated, requires a better understanding of the features of bone involvement.

Ultrasonic elastography using sector scan imaging and a radial compression.

Elastography is an imaging technique based on strain estimation in soft tissues under quasi-static compression. The stress is usually created by a compression plate, and the target is imaged by an ultrasonic linear array. This configuration is used for breast elastography, and has been investigated both theoretically and experimentally. Phenomena such as strain decay with tissue depth and strain concentrations have been reported. However in some in vivo situations, like prostate or blood vessels imaging, this set-up cannot be used. We propose a device to acquire in vivo elastograms of the prostate. The compression is applied by inflating a balloon that covers a transrectal sector probe. The 1D algorithm used to calculate the radial strain fails if the center of the imaging probe does not correspond to the center of the compressor. Therefore, experimental elastograms are calculated with a 2D algorithm that accounts for tangential displacements of the tissue. In this article, in order to gain a better understanding of the image formation process, the use of ultrasonic sector scans to image the radial compression of a target is investigated. Elastograms of homogeneous phantoms are presented, and compared with simulated images. Both show a strain decay with tissue depth. Then experimental and simulated elastograms of a phantom that contains a hard inclusion are presented, showing that strain concentrations occur as well. A method to compensate for strain decay and therefore to increase the contrast of the strain elastograms is proposed. It is expected that such information will help to interpret and possibly improve the elastograms obtained via radial compression.

Variational method for estimating the effects of continuously varying lenses in HIFU, sonography, and sonography-based cross-correlation methods.

The effects of high intensity focused ultrasound (HIFU)-induced continuously varying thermal gradients on sound ray propagation were modeled theoretically. This modeling was based on Fermat's variational principle of least time for rays propagating in a continuously varying thermal gradient described by a radially symmetric heat equation. Such thermal lenses dynamically affect HIFU beam focusing, and simultaneously create ultrasonic geometric and intensity distortions and artifacts in monitoring devices. Techniques which are based upon ultrasonic cross-correlation methods, such as elastography and two-dimensional temperature estimation, also suffer distortion effects and generate artifacts.

Elastography: Imaging the elastic properties of soft tissues with ultrasound.

Elastography is a method that can ultimately generate several new kinds of images, called elastograms. As such, all the properties of elastograms are different from the familiar properties of sonograms. While sonograms convey information related to the local acoustic backscatter energy from tissue components, elastograms relate to its local strains, Young's moduli or Poisson's ratios. In general, these elasticity parameters are not directly correlated with sonographic parameters, i.e. elastography conveys new information about internal tissue structure and behavior under load that is not otherwise obtainable. In this paper we summarize our work in the field of elastography over the past decade. We present some relevant background material from the field of biomechanics. We then discuss the basic principles and limitations that are involved in the production of elastograms of biological tissues. Results from biological tissues in vitro and in vivo are shown to demonstrate this point. We conclude with some observations regarding the potential of elastography for medical diagnosis.