Research Spotlight

Guo, M. H. and A. R. Gregg (2019). “Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels.” Genet Med Mar 8. [Epub ahead of print].

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PURPOSE: Prenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels. METHOD: We leveraged an exome sequencing database (n = 123,136) to estimate carrier rates across six major ancestries for 415 genes associated with severe recessive conditions. RESULTS: We found that 32.6% (East Asian) to 62.9% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 415 genes. For couples, screening all 415 genes would identify 0.17-2.52% of couples as being at risk for having a child affected by one of these conditions. Screening just the 40 genes with carrier rate >1.0% would identify more than 76% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates >1.0% would include 5 to 28 genes, while a comparable panethnic panel would include 40 genes. CONCLUSION: Our work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.

Grayburn, P. A. and Y. Chandrashekhar (2019). “Imaging Challenges in Tricuspid Regurgitation and Right Ventricular Failure.” JACC Cardiovasc Imaging 12(4): 768-770.

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In clinical practice, it is considerably easier to treat left ventricular (LV) heart failure than right ventricular (RV) heart failure. A number of medical therapies have been shown to improve symptoms and survival in LV failure. In addition, cardiac resynchronization and revascularization in appropriately selected patients may improve LV systolic function. Recently, the use of transcatheter edge-to-edge mitral valve repair has been shown to reduce heart failure hospitalization, mortality, and clinical status in a selected group of patients with persistent severe mitral regurgitation (MR) after optimization of medical therapy. Unfortunately, there are few data demonstrating that treatment of RV failure results in improved symptoms or survival. Diuresis is the mainstay of treatment but is used mainly to palliate symptoms. RV failure may respond to therapies targeted at left-sided heart disease or pulmonary hypertension (PH) in some but not all circumstances. RV failure is less well understood, but current thinking suggests it most often is the result of LV failure, as pulmonary venous congestion is transmitted backward to the RV. An unfavorable septal anatomy and dys-synchrony also influence RV function, possibly to a lesser extent. It can also occur secondary to pulmonary arterial hypertension in the setting of chronic pulmonary disease, congenital heart disease, or various pulmonary vascular diseases. As pulmonary artery systolic pressure (PASP) increases, the RV may respond by dilating with or without concentric hypertrophy, which may protect the RV by mitigating wall stress. RV dilation often causes tricuspid regurgitation (TR) or, conversely, may be caused by TR. There is a complex interplay among RV dilation/dysfunction, PH, and TR, but is less well understood than similar interactions in the left heart. Tricuspid valve disease remains a challenging yet growing need, but a wealth of data are starting to come in to clarify therapeutic needs. This issue of iJACC continues where we left off last month and brings more papers addressing right-sided heart function and various aspects of TR. (Excerpt from text, p. 768; no abstract available.)

Grayburn, P. A. (2019). “The Challenge of Assessing Residual Mitral Regurgitation During MitraClip Procedures: Is 3-Dimensional Vena Contracta Area the Answer?” JACC Cardiovasc Interv 12(6): 592-594.

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Transcatheter mitral valve repair with the MitraClip device has developed into a robust clinical tool for treatment of selected patients with severe mitral regurgitation (MR) in whom mitral valve anatomy is suitable for the device. MitraClip is approved in the United States for patients with primary degenerative MR who are considered prohibitive risk for surgery by an experienced heart team including a surgeon skilled in the art of mitral valve repair. In Europe and other countries, MitraClip is approved for both primary and secondary (functional) MR. Two recent randomized clinical trials showed apparently conflicting results with MitraClip in secondary MR. However, the differences in the 2 trials are likely caused by patient selection, with markedly improved outcomes in the setting of a disproportionately larger severity of MR relative to left ventricular (LV) volumes after optimizing medical therapy for heart failure. Several studies have shown that persistence of moderately severe or severe (3þ or 4þ) MR after the procedure is associated with considerably higher 1-year mortality, such that reduction of MR to moderate or less is paramount. Unfortunately, grading of MR severity in the procedural setting is often difficult and always subjective, partly because of the favorable effects of anesthesia on MR severity, the presence of the Mitra-Clips, and the difficulty balancing the need for further reduction in MR with additional clips versus the risk of iatrogenic mitral stenosis. There is a need for more accurate, precise, and reproducible markers of MR severity. (Excerpt from text, p. 592; no abstract available.)

Fitzgerald, S. T., S. Wang, D. Dai, A. Douglas, R. Kadirvel, M. J. Gounis, J. Chueh, A. S. Puri, K. F. Layton, I. C. Thacker, R. A. Hanel, E. Sauvageau, A. Aghaebrahim, M. A. Almekhlafi, A. M. Demchuk, R. G. Nogueira, V. M. Pereira, P. Kvamme, Y. Kayan, J. E. Delgado Almandoz, A. J. Yoo, D. F. Kallmes, K. M. Doyle and W. Brinjikji (2019). “Platelet-rich clots as identified by Martius Scarlet Blue staining are isodense on NCCT.” J Neurointerv Surg Apr 5. [Epub ahead of print].

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BACKGROUND: Current studies on clot characterization in acute ischemic stroke focus on fibrin and red blood cell composition. Few studies have examined platelet composition in acute ischemic stroke clots. We characterize clot composition using the Martius Scarlet Blue stain and assess associations between platelet density and CT density. MATERIALS AND METHOD: Histopathological analysis of the clots collected as part of the multi-institutional STRIP registry was performed using Martius Scarlet Blue stain and the composition of the clots was quantified using Orbit Image Analysis (www.orbit.bio) machine learning software. Prior to endovascular treatment, each patient underwent non-contrast CT (NCCT) and the CT density of each clot was measured. Correlations between clot components and clinical information were assessed using the chi(2) test. RESULTS: Eighty-five patients were included in the study. The mean platelet density of the clots was 15.7% (2.5-72.5%). There was a significant correlation between platelet-rich clots and the absence of hyperdensity on NCCT, (rho=0.321, p=0.003*, n=85). Similarly, there was a significant inverse correlation between the percentage of platelets and the mean Hounsfield Units on NCCT (rho=-0.243, p=0.025*, n=85). CONCLUSION: Martius Scarlet Blue stain can identify patients who have platelet-rich clots. Platelet-rich clots are isodense on NCCT.

Elmets, C. A., C. L. Leonardi, D. M. R. Davis, J. M. Gelfand, J. Lichten, N. N. Mehta, A. W. Armstrong, C. Connor, K. M. Cordoro, B. E. Elewski, K. B. Gordon, A. B. Gottlieb, D. H. Kaplan, A. Kavanaugh, D. Kivelevitch, M. Kiselica, N. J. Korman, D. Kroshinsky, M. Lebwohl, H. W. Lim, A. S. Paller, S. L. Parra, A. L. Pathy, E. F. Prater, R. Rupani, M. Siegel, B. Stoff, B. E. Strober, E. B. Wong, J. J. Wu, V. Hariharan and A. Menter (2019). “Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities.” J Am Acad Dermatol 80(4): 1073-1113.

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Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations on the basis of available evidence.