4D flow MRI quantification of mitral and tricuspid regurgitation: Reproducibility and consistency relative to conventional MRI.

BACKGROUND: In patients with mitral or tricuspid valve regurgitation, evaluation of regurgitant severity is essential for determining the need for surgery. While transthoracic echocardiography is widely accessible, it has limited reproducibility for grading inlet valve regurgitation. Multiplanar cardiac MRI is the quantitative standard but requires specialized local expertise, and is thus not widely available. Volumetric 4D flow MRI has potential for quantitatively grading the severity of inlet valve regurgitation in adult patients. PURPOSE: To evaluate the accuracy and reproducibility of volumetric 4D flow MRI for quantification of inlet valvular regurgitation compared to conventional multiplanar MRI, which may simplify and improve accessibility of cardiac MRI. STUDY TYPE: This retrospective, HIPAA-compliant imaging-based comparison study was conducted at a single institution. SUBJECTS: Twenty-one patients who underwent concurrent multiplanar and 4D flow cardiac MRI between April 2015 and January 2017. FIELD STRENGTH/SEQUENCES: 3T; steady-state free-precession (SSFP), 2D phase contrast (2D-PC), and postcontrast 4D flow. ASSESSMENT: We evaluated the intertechnique (4D flow vs. 2D-PC), intermethod (direct vs. indirect measurement), interobserver and intraobserver reproducibility of measurements of regurgitant flow volume (RFV), fraction (RF), and volume (RVol). STATISTICAL TESTS: Statistical analysis included Pearson correlation, Bland-Altman statistics, and intraclass correlation coefficients. RESULTS: There was high concordance between 4D flow and multiplanar MRI, whether using direct or indirect methods of quantifying regurgitation (r = 0.813-0.985). Direct interrogation of the regurgitant jet with 4D flow showed high intraobserver consistency (r = 0.976-0.999) and interobserver consistency (r = 0.861-0.992), and correlated well with traditional indirect measurements obtained as the difference between stroke volume and forward outlet valve flow. DATA CONCLUSION: 4D flow MRI provides highly reproducible measurements of mitral and tricuspid regurgitant volume, and may be used in place of conventional multiplanar MRI. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1147-1158.

Why Did COAPT Win While MITRA-FR Failed? Defining the Appropriate Patient Population for MitraClip.

In 2018, the world of functional mitral regurgitation changed with the presentation of two trials - Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT). The trials, which seemed to point in two different directions, raised significant questions for the field. This article looks at the differences in effective regurgitant area, guideline-directed medical therapy, patient selection, technical clues and other reasons why the trials had similar aims but very different findings.

Percutaneous tricuspid valve replacement: orthotopic and heterotopic valves.

The tricuspid valve has long been described as the "forgotten valve", leaving tricuspid valve disease relatively neglected. However, the number of people in the United States affected by severe tricuspid regurgitation is growing. Isolated surgery for severe tricuspid regurgitation in the setting of right ventricular heart failure carries a high mortality risk, and therefore, attention to corrective therapies has increased. Because of the different etiologies for tricuspid regurgitation, multiple percutaneous transcatheter options for tricuspid valve repair for severe regurgitation are being studied and have been developed, including annuloplasty systems, leaflet and coaptation devices, vena caval (heterotopic) valve implantations, and tricuspid valve (orthotopic) replacement. In this paper, we review the heterotopic and orthotopic tricuspid valve transcatheter options for severe tricuspid regurgitation.

Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity.

To achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, gene-modified murine bone marrow-derived dendritic cells (DC) was used in a murine lung cancer model. To attract mature host DC and activated T cells at the tumor site, the DC were transduced with an adenoviral vector expressing secondary lymphoid tissue chemokine (CCL21/SLC). Sixty percent of the mice treated with 10(6) DC-AdCCL21 intratumorally (7-10 ng/ml/10(6) cells/24 h of CCL21) at weekly intervals for 3 weeks showed complete tumor eradication, whereas only 25% of mice had complete resolution of tumors when mice were treated with fibroblasts expressing CCL21. In contrast only 12% of the mice treated with unmodified or control vector modified DC (DC-AdCV) showed complete tumor eradication. DC-AdCCL21 administration led to increases in the CD4(+), CD8(+), and CD3(+)CXCR3(+) T cells, as well as DC expressing CD11c(+) DEC205(+). CD4(+)CD25(+) T-regulatory cells infiltrating the tumors were markedly reduced after DC-AdCCL21 therapy. The tumor site cellular infiltrates were accompanied by the enhanced elaboration of granulocyte macrophage colony-stimulating factor, IFN-gamma, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor beta and prostaglandin E(2). DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-gamma, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-gamma significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.

Tumor cyclooxygenase 2-dependent suppression of dendritic cell function.

Dendritic cells (DCs) serve as professional antigen-presenting cells and are pivotal in the host immune response to tumor antigens. To define the pathways limiting DC function in the tumor microenvironment, we assessed the impact of tumor cyclooxygenase (COX)-2 expression on DC activities. Bone marrow-derived DCs were cultured in either tumor supernatant (TSN) or TSN from COX-2-inhibited tumors. After culture, DCs were pulsed with tumor-specific peptides, and their ability to generate antitumor immune responses was assessed following injection into established murine lung cancer. In vitro, DC phenotype, alloreactivity, antigen processing and presentation, and interleukin (IL)-10 and IL-12 secretion were evaluated. DCs cultured in TSN failed to generate antitumor immune responses and caused immunosuppressive effects that correlated with enhanced tumor growth. However, genetic or pharmacological inhibition of tumor COX-2 expression restored DC function and effective antitumor immune responses. Functional analyses indicated that TSN causes a decrement in DC capacity to (a) process and present antigens, (b) induce alloreactivity, and (c) secrete IL-12. Whereas TSN DCs showed a significant reduction in cell surface expression of CD11c, DEC-205, MHC class I antigen, MHC class II antigen, CD80, and CD86 as well as a reduction in the transporter-associated proteins, transporter associated with antigen processing 1 and 2, the changes in phenotype and function were not evident when DCs were cultured in supernatant from COX-2-inhibited tumors. We conclude that inhibition of tumor COX-2 expression or activity can prevent tumor-induced suppression of DC activities.

Interleukin-7 gene-modified dendritic cells reduce pulmonary tumor burden in spontaneous murine bronchoalveolar cell carcinoma.

The antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing interleukin (IL)-7 (DC-AdIL-7) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. These transgenic mice (CC-10 TAg), expressing the SV40 large T antigen under the Clara cell promoter, develop bilateral multifocal pulmonary adenocarcinomas and die at 4 months as a result of progressive pulmonary tumor burden. Injection of DC-AdIL-7 in the axillary lymph node region (ALNR) weekly for 3 weeks led to a marked reduction in tumor burden with extensive lymphocytic infiltration of the tumors and enhanced survival. The antitumor responses were accompanied by the enhanced elaboration of interferon (IFN)-gamma and IL-12 as well as an increase in the antiangiogenic chemokines, IFN-gamma-inducible protein 10 (IP-10/CXCL10) and monokine induced by IFN-gamma (MIG/CXCL9). In contrast, production of the immunosuppressive mediators IL-10, transforming growth factor (TGF)-beta, prostaglandin E(2) (PGE(2)), and the proangiogenic modulator vascular endothelial growth factor (VEGF) decreased in response to DC-AdIL-7 treatment. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of DC-AdIL-7 in regulation of tumor immunity and its use in lung cancer genetic immunotherapy.

Systematic review of interventions to repair ascending aortic pseudoaneurysms.

BACKGROUND: The safety and efficacy of endovascular therapies for ascending aortic pseudoaneurysms (AAPs) are still controversial. METHODS: We report an endovascular correction of an AAP in a high-risk surgical patient and present the results of a literature review focusing on AAP treatment strategies. A multilingual search of AAP therapy was performed with limiting dates of January 1980 to May 2014. The studies were classified by intervention. RESULTS: A 79-year-old male with a 9 × 10 × 7 cm AAP in the anterior mediastinum was considered too high risk for surgery. An endovascular closure with a 12 mm Amplatzer septal occluder device (St. Jude Medical) was performed, and computed tomography angiography at 3-month follow-up exhibited a thrombosed AAP with minimal residual shunt. In our literature search, we identified 355 cases of AAPs, mostly case reports (91.5%) and a few patient series (8.5%). Surgical correction accounted for 73.8% of the cases, 5% of the patients were conservatively treated or considered too critically ill for any intervention, and 21.2% were treated with endovascular techniques. The most commonly reported endovascular techniques were stent grafts (9.8%) and septal occluder devices (9.8%). CONCLUSION: Although endovascular closure of AAPs with off-label devices is a reliable option for controlling the expansion and symptoms in high-risk surgical patients, solid data on survival are lacking. Efforts to promote discussion within the heart team to expand the application of endovascular techniques can provide groundbreaking evidence to support the use of endovascular techniques as guideline therapy when facing these complicated cases.

Endovascular stent-graft repair of ascending aortic dissection with a commercially available thoracic endograft.

We describe the endovascular treatment of a type A thoracic aortic dissection (TAAD) in a patient deemed unfit for surgical repair with a commercially available thoracic endograft. A patient with a symptomatic acute TAAD, multiple medical comorbidities, and ascending thoracic aortic and arch dilation underwent successful endovascular repair with the use of a commercially available stent graft, resulting in complete resolution of his symptoms despite slight but persistent perigraft false lumen perfusion. Although surgical repair remains the gold standard, endografting has promise and may have a positive impact on the current treatment algorithm for TAAD. Advances must occur in graft manufacturing, and further data will be required before wider application is appropriate.

Percutaneous left ventricular support for high-risk PCI and cardiogenic shock: who gets what?

BACKGROUND: Temporary use of a percutaneous left ventricular assist device (PLVAD) may be beneficial in patients undergoing high-risk percutaneous coronary intervention (PCI) and those with cardiogenic shock (CS). METHODS: Seventy-four consecutive patients undergoing high-risk PCI and those with CS receiving intraaortic balloon pump (IABP), TandemHeart (TH), or Impella device (IMP) were enrolled. Patient undergoing high-risk PCI (n=57) and those treated for CS (n=17) were analyzed as separate cohorts. Patients undergoing IABP-assisted PCI were compared to those undergoing PLVAD (TH and IMP)-assisted PCI. The primary end point was in-hospital major adverse cardiovascular events, and the secondary end point was in-hospital vascular complications. RESULTS: For the high-risk PCI cohort (n=57), 22 received PLVAD and 35 received IABP. Patients receiving IABP were younger and less likely to have a prior myocardial infarction (MI) and less likely to be on dialysis compared to those receiving PLVAD support. Patients receiving PLVAD support had a higher baseline Syntax score, had a higher prevalence of unprotected left main disease, underwent treatment of more coronary lesions, received more coronary stents, and more likely received drug-eluting stents compared to those receiving IABP support. The primary and secondary end points were similar between both groups. For the CS cohort (n=17), 4 received PLVAD and 13 received IABP. Patients receiving PLVAD support were more likely to have a prior MI, had a lower ejection fraction, underwent treatment of more coronary lesions, and received more coronary stents compared to those receiving IABP support. The primary and secondary end points were similar between both groups. CONCLUSIONS: IABP compared with PLVAD use for high-risk PCI and CS is associated with significantly different baseline patient, clinical, procedural, and angiographic characteristics. In-hospital clinical outcome was similar between both groups in both the high-risk PCI and the CS cohorts. When physicians have access to each of these devices, short-term clinical outcome appears to be similar.

IL-10 mediates sigma 1 receptor-dependent suppression of antitumor immunity.

Sigma receptors are unique endoplasmic reticulum proteins that mediate signaling for a variety of drugs. We determined the effect of sigma(1) receptor agonists on immune responses in a syngeneic lung cancer model. Sigma(1) receptor agonists, including cocaine, up-regulated splenocyte IL-10 mRNA and protein production in vitro in a sigma receptor-dependent, pertussis toxin-sensitive manner. In vivo, sigma(1) receptor agonists promoted tumor growth and induced IL-10 at the tumor site. Increased tumor growth was prevented by administration of specific Abs to IL-10 or by administration of specific sigma(1) receptor antagonists. We report that sigma(1) receptor ligands, including cocaine, augment tumor growth through an IL-10 dependent mechanism.

EBV-induced molecule 1 ligand chemokine (ELC/CCL19) promotes IFN-gamma-dependent antitumor responses in a lung cancer model.

The antitumor efficacy of EBV-induced molecule 1 ligand CC chemokine (ELC/CCL19) was evaluated in a murine lung cancer model. The ability of ELC/CCL19 to chemoattract both dendritic cells and T lymphocytes formed the rationale for this study. Compared with diluent-treated tumor-bearing mice, intratumoral injection of recombinant ELC/CCL19 led to significant systemic reduction in tumor volumes (p < 0.01). ELC/CCL19-treated mice exhibited an increased influx of CD4 and CD8 T cell subsets as well as dendritic cells at the tumor sites. These cell infiltrates were accompanied by increases in IFN-gamma, MIG/CXCL9, IP-10/CXCL10, GM-CSF, and IL-12 but a concomitant decrease in the immunosuppressive molecules PGE(2) and TGFbeta. Transfer of T lymphocytes from ELC/CCL19 treated tumor-bearing mice conferred the antitumor therapeutic efficacy of ELC/CCL19 to naive mice. ELC/CCL19 treated tumor-bearing mice showed enhanced frequency of tumor specific T lymphocytes secreting IFN-gamma. In vivo depletion of IFN-gamma, MIG/CXCL9, or IP-10/CXCL10 significantly reduced the antitumor efficacy of ELC/CCL19. These findings provide a strong rationale for further evaluation of ELC/CCL19 in tumor immunity and its use in cancer immunotherapy.