TGF-Beta pathway in Kawasaki Disease

Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease
Chisato Shimizu, MD, at al.
Circulation: Cardiovascular Genetics. 2011; 4: 16-25

Background— Transforming growth factor (TGF)-β is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-β signaling might be important in KD susceptibility and disease outcome.

Methods and Results— We investigated genetic variation in 15 genes belonging to the TGF-β pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-β2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-β pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-β2 plasma protein levels changed dynamically over the course of the illness.

Conclusions— These studies suggest that genetic variation in the TGF-β pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.

Bicuspid Aortic Valve: Two developmentally-distinct types!

J Am Coll Cardiol, 2009; 54:2312-2318

Bicuspid Aortic Valves With Different Spatial Orientations of the Leaflets Are Distinct Etiological Entities

Borja Fernández, PhD*,*, Ana C. Durán, PhD*, Teresa Fernández-Gallego, BSc*, M. Carmen Fernández, BSc*, Miguel Such, MD, Josep M. Arqué, MD and Valentín Sans-Coma, PhD*
* Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain Department of Cardiovascular Surgery, University Hospital Virgen de la Victoria, Málaga, Spain Department of Cardiovascular Surgery, University Hospital Carlos Haya, Málaga, Spain

Objectives: The aim of this study was to decide whether bicuspid aortic valves (BAVs) with fused right and noncoronary leaflets (R-N) and BAVs with fused right and left leaflets (R-L) have different etiologies or are the product of a single diathesis.

Background: The BAV is the most common congenital cardiac malformation. The R-N and R-L BAVs are the most frequent BAV subtypes.

Methods: The study was carried out in adult and embryonic hearts of endothelium nitric oxide synthase knock-out mice and inbred Syrian hamsters with a high incidence of R-N and R-L BAVs, respectively. The techniques used were histochemistry, immunohistochemistry, and scanning electron microscopy.

Results: The R-N BAVs result from a defective development of the cardiac outflow tract (OT) endocardial cushions that generates a morphologically anomalous right leaflet. The left leaflet develops normally ("Vertical Orifice" seen in PSSAx echo view). The R-L BAVs are the outcome of an extrafusion of the septal and parietal OT ridges that thereby engenders a sole anterior leaflet. The noncoronary leaflet forms normally ("Horizontal Orifice" seen in PSSAx echo view...more common).

Conclusions: The R-N and R-L BAVs are different etiological entities. The R-N BAVs are the product of a morphogenetic defect that happens before the OT septation and that probably relies on an exacerbated nitric oxide–dependent epithelial-to-mesenchymal transformation. The R-L BAVs result from the anomalous septation of the proximal portion of the OT, likely caused by a distorted behavior of neural crest cells. Care should be taken in further work on BAV genetics because R-N and R-L BAVs might rely on different genotypes. Detailed screening for R-N and R-L BAVs should be performed for a better understanding of the relationships between these BAV morphologic phenotypes and other heart disease.

More postings on this subject

Bicuspid Aortic Valve - Etiology and Associated Lesions

The following letter to the editor highlights other articles that deal with different etiologies for different morphologies of bicuspid aortic valve. Worth reading them all!

J Am Coll Cardiol, 2010; 56:1680, doi:10.1016/j.jacc.2010.03.073 Bicuspid Aortic Valve Morphology

Alexander R. Opotowsky, MD, MPH^_* andMichael J. Landzberg, MD

^_* Children's Hospital Boston, Boston Adult Congenital Heart Service, Department of Cardiology, 300 Longwood Avenue, Boston, Massachusetts 02115 (Email:alexander.opotowsky@childrens.harvard.edu).

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We read with interest and appreciation 3 recent papers in the Journal on the bicuspid aortic valve (BAV).

Fernandez et al. (1) describe distinct developmental patterns for mice and hamsters with right-noncoronary and right-left coronary cusp fusion, respectively. Incredibly, William Osler anticipated, within the limitations of his era, these findings and their significance more than a century ago:

If it turns out to be correct ... that the affected valves are usually those behind ... the coronary arteries ... this would point to some error associated especially with the development of these cusps. It would appear from the observations of Tonge, that two of the segments are formed before the division of the primitive truncus arteriosus is complete, while the third arises laterafter the pulmonary artery and the aorta have divided. It is not at all improbable that we may have here a clew to an explanation of this anomaly, but this is conjectural until we have fullerdetails of the process of the development of the sigmoid valves in mammals (2).

As it becomes increasingly apparent that right-noncoronary and right-left coronary cusp fusion are distinct diseases, research reports on the BAV should make this distinction as Osler suggested: "This point [right-left coronary cusp fusion is the most common BAV morphology], previously overlooked, may prove of interest in the etiology, and should be carefully noted in future observations" (2).

Biner et al. (3) report evidence of a bicuspid aortopathy in first-degree relatives of BAV patients, but did not address the relationship of BAV morphology to aortic properties. We would be interested to know whether BAV morphology in the proband modifies the extent of aortic dilation and stiffness in first-degree relatives.

Tzemos et al. (4) provide data suggesting that the BAV is associated with endothelial dysfunction, at least in the presence of aortic dilation. The authors note that three-fourths of the patients in each BAV group had anteroposterior aortic leaflet orientation (presumably right-left coronary cusp fusion), but no data arepresented on the relationship between BAV morphology and the parameters studied. Does BAV morphology influence the relationship among aortic dilation, aortic stiffness, serum matrix metalloproteinaselevels, and endothelial function?

With deepening understanding of the developmental and physiologic aspects of the BAV and its associated diffuse vasculopathy, we believe that it is vital that data be reported to allow detailed inquiry into potential variation between morphologically and likely clinically and developmentally distinct categories of disease.

References:

1. Fernandez B, Duran AC, Fernandez-Gallego T, et al. Biscupid aortic valves with different spatial orientations of the leaflets are distinct etiological entities J Am Coll Cardiol 2009;54:2312-2318.[Abstract/Free Full Text]

2. Osler W. The Bicuspid Condition of the Aortic Valves. . Transactions of the Association of American Physicians. Philadelphia: Wm. J. Dornan; 1886. pp. 185-192.

3. Biner S, Rafique AM, et al. Aortopathy is prevalent in relatives of bicuspid aortic valve patients J Am Coll Cardiol 2009;53:2288-2295.[Abstract/Free Full Text]

4. Tzemos N, Lyseggen E, Silversides C, et al. Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta J Am Coll Cardiol 2010;55:660-668.[Abstract/Free Full Text]

Also see other posting on this subject

Fernandez et al (ref#1 above)

Left Atrial Appendage Obliteration - Pathology review

J Am Coll Cardiol Intv, 2010; 3:870-877

Left Atrial Appendage Obliteration

Mechanisms of Healing and Intracardiac Integration

Robert S. Schwartz, MD, David R. Holmes, MD, Robert A. Van Tassel, MD, Robert Hauser, MD, Timothy D. Henry, MD, Michael Mooney, MD, Ray Matthews, MD, Shephal Doshi, MD, Russell M. Jones, BS, Renu Virmani, MD

Objectives: The objectives of this study were: 1) to delineate the temporal course of histopathologic healing as the left atrial appendage (LAA) is obliterated by a mechanical device; and 2) to compare this process with other intravascular and intracardiac implanted technologies.

Background: Intracardiac device healing is incompletely understood. We thus studied the histopathology of device-based LAA obliteration.

Methods: Nine dog hearts were examined over time after LAA device placement and results were compared with human hearts with prior LAA obliteration using the same device.

Results: At 3 days in dogs, atrial surfaces were covered by fibrin, which sealed gaps between the LA wall and the device and filled the LA appendage cavity. At 45 days, endothelial cells covered the endocardial surface with underlying smooth muscle cells that sealed the device-LA interface. Regions with prior thrombus were replaced by endocardium surrounding the device membrane. Disorganized thrombus remained in the LAA body and at the periphery near the appendage walls. Mild inflammation was observed as thrombus resorbed. By 90 days, a complete endocardial lining covered the former LAA ostium. Organizing thrombus had become connective tissue, with no residual inflammation. The human necropsy hearts had similar findings. In these 4 hearts (139, 200, 480, and 852 days after implant), the ostial fabric membrane was covered with endocardium. The appendage surface contained organizing thrombus with minimal inflammation. Organizing fibrous tissue was inside the LAA cavity, prominent near the atrial wall. The LAA interior contained organizing thrombus.

Conclusions: This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices.

Figure 1 Composite Images of the LAA and Obliteration

(A) Post-mortem dog heart (no device implanted), showing the exterior view of the left atrial appendage (LAA). (B) Diagrammatic view of the Watchman LAA obliteration method. Metal struts with anchoring hooks secure the device within the body of the appendage cavity. A fabric membrane filter covers the atrial surface of the device, preventing thrombi from escaping into the left atrial chamber. A center hub is used to connect the device to the catheter delivery system. (C) Dog autopsy specimen 28 days after Watchman implant showing a cross-sectional cutaway view of the Watchman device. The fabric membrane is covered with a fine layer of endocardium, and the metal struts are shown holding the device in place. Pectinate muscles internal to the LAA cavity are labeled. (D) Dog autopsy specimen showing a view of the former LAA ostium, now completely obliterated by the endocardium-covered fabric membrane. This view is from the left atrial cavity, where it is clear that thrombi potentially residing the left atrial appendage body could no longer escape into the left atrium and systemic circulation.

There are multiple other images of this device with pathologic specimens from Dog heart and Human heart at different times after implanation. Longest one, after 852 days after implantation.