Contrast Echocardiography in Heart Failure: Update 2023.

PURPOSE OF REVIEW: The application of ultrasound-enhancing agents (contrast agents) has improved the accuracy and reproducibility of echocardiography. The review focuses on the currently approved and evolving indications for contrast echocardiography in patients with heart failure, specifically examining clinical studies conducted after the publication of the guidelines in 2017 and 2018. RECENT FINDINGS: The current ASE/EACVI recommendations for contrast echocardiography are based on its accuracy and reproducibility in comparison to non-enhanced echocardiography or other imaging modalities like cardiac MRI. However, tissue characterization remains limited with contrast echocardiography. During the last few years, several studies have demonstrated the clinical impact of using contrast agents on the management of patients with heart failure. There is growing evidence on the benefit of using contrast echocardiography in critically ill patients where echocardiography without contrast agents is often suboptimal and other imaging methods are less feasible. There is no risk of worsening renal function after the administration of ultrasound-enhancing agents, and these agents can be administered even in patients with end-stage renal disease. Contrast echocardiography has become a valuable tool for first-line imaging of patients with heart failure across the spectrum of patients with chronic heart failure to critically ill patients.

Increased Virtual Visits to Physicians During the COVID-19 Pandemic and Estimated Impact on Physician Compensation: The Case of Lung and Colorectal Cancers, Chronic Obstructive Pulmonary Diseases, and Heart Failure in Alberta, Canada.

Introduction: The COVID-19 pandemic started in Alberta in March 2020 and significantly increased telehealth service use and provision reducing the risk of virus transmission. We examined the change in the number and proportion of virtual visits by physician specialty and condition (chronic obstructive pulmonary diseases [COPD], heart failure [HF], colorectal and lung cancers), as well as associated changes in physician compensation. Methods: A population-based design was used to analyze all processed physician claims comparing the number and proportion of virtual visits and associated physician billings relative to in-person between pre- (2019/2020) and intra-pandemic (2020/2021). Physician compensations were the claim amounts paid by the health insurance. Results: Pre-pandemic (intra-), there were 8,981 (8,897) lung cancer, 9,245 (9,029) colorectal, 37,558 (36,292) HF, and 68,270 (52,308) COPD patients. Each patient had totally 2.3-4.7 (of which 0.4-0.6% were virtual) general practitioner (GP) visits and 0.9-2.3 (0.2-0.7% were virtual) specialist visits per year pre-pandemic. The average number and proportion of per-patient virtual visits to GPs and specialists grew significantly pre- to intra-pandemic by 2,138-4,567%, and 2,201-7,104%, respectively. Given the lower fees of virtual compared with in-person visits, the reduction in physician compensation associated with the increased use of virtual care was estimated at $3.85 million, with $2.44 million attributed to specialist and $1.41 million to GP. Discussion: Utilization of telehealth increased significantly, while the physician billings per patient and physician compensation declined early in the pandemic in Alberta for the four chronic diseases considered. This study forms the basis for future study in understanding the impact of virtual care, now part of the fabric of health care delivery, on quality of care and patient safety, overall health service utilization (such as diagnostic imaging and other investigations), as well as economic impacts to patients, health care systems, and society.

A Systems-Level Evaluation Framework for Virtual Care.

The virtual care landscape is significantly changing, largely due to an increased demand initiated by the COVID-19 pandemic and the evolution of technology. Complex questions about how to best leverage virtual care and its impact remain unanswered. Our team developed a systems-level evaluation framework to inform virtual care service design and evaluation to take a more comprehensive approach to planning and implementing virtual care. We designed the framework for application in Alberta Health Services (AHS) by engaging virtual care users (patients, families and healthcare providers), implementation staff and decision makers across the organization. Here we report our design process and key lessons learned. The framework received endorsement by AHS senior leadership for application across the system. Our next step is to test the framework. By sharing our design process and experiences, we aim to help inform other national and international jurisdictions plan virtual care evaluations within their context.

Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells.

IL-6 affects tissue protective/reparative and inflammatory properties of vascular endothelial cells (ECs). This cytokine can signal to cells through classic and trans-signaling mechanisms, which are differentiated based on the expression of IL-6 receptor (IL-6R) on the surface of target cells. The biological effects of these IL-6-signaling mechanisms are distinct and have implications for vascular pathologies. We have directly compared IL-6 classic and trans-signaling in ECs. Human ECs expressed IL-6R in culture and in situ in coronary arteries from heart transplants. Stimulation of human ECs with IL-6, to model classic signaling, triggered the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and ERK1/2 signaling pathways, whereas stimulation with IL-6 + sIL-6R, to model trans-signaling, triggered activation of STAT3, PI3K-Akt, and ERK1/2 pathways. IL-6 classic signaling reduced persistent injury of ECs in an allograft model of vascular rejection and inhibited cell death induced by growth factor withdrawal. When inflammatory effects were examined, IL-6 classic signaling did not induce ICAM or CCL2 expression but was sufficient to induce secretion of CXCL8 and support transmigration of neutrophil-like cells. IL-6 trans-signaling induced all inflammatory effects studied. Our findings show that IL-6 classic and trans-signaling have overlapping but distinct properties in controlling EC survival and inflammatory activation. This has implications for understanding the effects of IL-6 receptor-blocking therapies as well as for vascular responses in inflammatory and immune conditions.

Variability of left ventricular volume and ejection fraction measurements using contrast echocardiography: The influence of the left ventricular length measurements in a large cohort of patients during monitoring cardiotoxic effects of chemotherapy.

OBJECTIVE: To investigate the influence of length difference in left ventricular (LV) long axis between the apical four-chamber and two-chamber views on measurements of LV volumes and ejection fraction (EF). METHODS: Seven hundred consecutive cancer patients underwent contrast echocardiography from July 2010 to May 2014. All patients received the echocardiographic contrast agent Definity. Recordings of apical views were analyzed by a sonographer and then by a cardiologist. The end-diastolic and end-systolic LV volumes (EDV and ESV), and LV lengths as well as EF, were measured using the biplane Simpson's method. Inter-observer variability was assessed using relative mean error (RME) and Bland-Altman analysis. RESULTS: Six hundred ninety-two patients had contrast echocardiograms with complete endocardial definition. The LV length difference of the long axis measured by the cardiologist was ≤1 mm in 284 studies (41%), 2 mm in 146 studies (21%), 3 mm in 103 studies (15%), and ≥4 mm in 159 studies (23%). The limits of agreement (LOA) and RME increase with the increasing length difference. Compared to the groups with length difference <4 mm, the RME of the measurements of indexed EDV, indexed ESV, and EF was significantly greater in the group with length difference ≥4 mm (P < .05). CONCLUSION: These results highlight the need for reviewing the LV long axis length measurements in order to provide reproducible LV volumes and EF measurements and may be used as benchmarks for quality control. A length difference of ≤3 mm can be achieved in most of our patients and is associated with an excellent inter-observer agreement.

Bim regulates alloimmune-mediated vascular injury through effects on T-cell activation and death.

OBJECTIVE: Bim is a proapoptotic Bcl-2 protein known to downregulate immune responses and to also be required for antigen-induced T-cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T-cell responses in a model of vascular rejection. APPROACH AND RESULTS: Bim was required for proliferation of CD4 and CD8 T cells, and for interleukin-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T-cell activation, whereas a complete elimination of Bim was required to prevent CD4 T-cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim(+/-), but not Bim(-/-), graft recipients. T-cell proliferation in response to allograft arteries was significantly reduced in both Bim(+/-) and Bim(-/-) mice, but cell death was attenuated only in Bim(-/-) animals. CONCLUSIONS: Bim controls both T-cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries.

Positive feedback regulation of human inducible nitric-oxide synthase expression by Ras protein S-nitrosylation.

The production of nitric oxide (NO) by inducible NO synthase (iNOS) regulates many aspects of physiology and pathology. The expression of iNOS needs to be tightly regulated to balance the broad ranging properties of NO. We have investigated the feedback regulation of cytokine-induced iNOS expression by NO in human cells. The pharmacological inhibition of iNOS activity reduced iNOS protein levels in response to cytokine stimulation in a human epithelial cell line (A549 cells) as well as in primary human astrocytes and bronchial epithelial cells. The addition of exogenous NO using a NO donor prevented the reduction in iNOS levels caused by blockade of iNOS activity. Examination of signaling pathways affected by iNOS indicated that NO S-nitrosylated Ras. Transfection of cells with a S-nitrosylation-resistant Ras mutant reduced iNOS protein levels, indicating a role for this Ras modification in the amplification of iNOS levels. Further, the induction of iNOS protein levels correlated with the late activation of the phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) pathways, and inhibition of these signaling molecules reduced iNOS levels. Altogether, our findings reveal a previously unknown regulatory pathway that amplifies iNOS expression in human cells.

Induction of endothelial nitric oxide synthase expression by IL-17 in human vascular endothelial cells: implications for vascular remodeling in transplant vasculopathy.

IL-17 is a signature cytokine of Th17 cells, a recently described subset of effector CD4 T cells implicated in the development of several pathologies. We have examined the role of IL-17 in regulating endothelial NO synthase (eNOS) expression in human vascular endothelial cells (ECs) because of the key role of eNOS in determining the pathological outcome of immune-mediated vascular diseases. In cultured ECs, IL-17 increased expression of eNOS, eNOS phosphorylation at Ser(1177), and NO production. The induction of eNOS expression by IL-17 was prevented by the pharmacological inhibition of NF-κB, MEK, and JNK, as well as by small interfering RNA-mediated gene silencing of these signaling pathways. The expression of IL-17 was then examined by immunohistochemistry in human arteries affected by transplant vasculopathy (TV), a vascular condition that is a leading reflection of chronic heart transplant rejection. IL-17 was expressed by infiltrating leukocytes in the intima of arteries with TV, and the majority of IL-17-positive cells were T cells. The number of IL-17-positive cells was not correlated with the intima/media ratio, but was negatively correlated with the amount of luminal occlusion. There was also a significant positive correlation between the number of IL-17-positive cells and the density of eNOS-expressing luminal ECs in arteries with TV. Altogether, these findings show that IL-17 induces the expression of eNOS in human ECs and that this may facilitate outward expansion of arteries afflicted with TV.

Left ventricular ejection fraction and volumes: it depends on the imaging method.

BACKGROUND AND METHODS: In order to provide guidance for using measurements of left ventricular (LV) volume and ejection fraction (LVEF) from different echocardiographic methods a PubMed review was performed on studies that reported reference values in normal populations for two-dimensional (2D ECHO) and three-dimensional (3D ECHO) echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR). In addition all studies (2 multicenter, 16 single center) were reviewed, which included at least 30 patients, and the results compared of noncontrast and contrast 2D ECHO, and 3D ECHO with those of CMR. RESULTS: The lower limits for normal LVEF and the normal ranges for end-diastolic (EDV) and end-systolic (ESV) volumes were different in each method. Only minor differences in LVEF were found in studies comparing CMR and 2D contrast echocardiography or noncontrast 3D echocardiography. However, EDV and ESV measured with all echocardiographic methods were smaller and showed greater variability than those derived from CMR. Regarding agreement with CMR and reproducibility, all studies showed superiority of contrast 2D ECHO over noncontrast 2D ECHO and 3D ECHO over 2D ECHO. No final judgment can be made about the comparison between contrast 2D ECHO and noncontrast or contrast 3D ECHO. CONCLUSION: Contrast 2D ECHO and noncontrast 3D ECHO show good reproducibility and good agreement with CMR measurements of LVEF. The agreement of volumes is worse. Further studies are required to assess the clinical value of contrast 3D ECHO as noncontrast 3D ECHO is only reliable in patients with good acoustic windows.

Granzyme B in aging and age-related pathologies.

Aging is a major risk factor for pathologies that manifest later in life. Much attention is devoted towards elucidating how prolonged environmental exposures and inflammation promote biological (accelerated) tissue aging. Granzymes, a family of serine proteases, are increasingly recognized for their emerging roles in biological aging and disease. Widely recognized as intracellular mediators of cell death, granzymes, particularly granzyme B (GzmB), also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and impaired healing. Consequently, this has prompted the field to reconsider how GzmB regulation, accumulation, and proteolysis impact health and disease with age. While GzmB is observed in numerous age-related conditions, the current review focuses on mechanistic studies where proof-of-concept has been forwarded.