Research Spotlight

Posted September 15th 2016

Heart Failure’s Dark Secret: Does Anyone Really Care About Optimal Medical Therapy?

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2016). “Heart failure’s dark secret: Does anyone really care about optimal medical therapy?” Circulation 134(9): 629-631.

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Today, most heart failure physicians focus on devices and transplantation; hospital-based management teams devoted only to achieving optimal medical therapy are scarce. The financial demands on heart failure specialists are enormous. A viable business plan can no longer be based on the misguided hope that payers will reimburse generously for prescriptions of digitalis and diuretics; in contrast, cardiac procedures generate meaningful revenues. A growing advocacy now encourages the use of ventricular assist devices in ambulatory patients on the basis of the dual misconceptions that the hazards are readily managed and that the clinical responses to medical therapy are poor. The biases in favor of performing procedures are so great that a National Institutes of Health–sponsored randomized trial comparing left ventricular assistance and optimal medical therapy in ambulatory patients was closed because of slow recruitment.


Posted September 15th 2016

Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Jenkinson, E. M., M. P. Rodero, P. R. Kasher, C. Uggenti, A. Oojageer, L. C. Goosey, Y. Rose, C. J. Kershaw, J. E. Urquhart, S. G. Williams, S. S. Bhaskar, J. O’Sullivan, G. M. Baerlocher, M. Haubitz, G. Aubert, K. W. Baranano, A. J. Barnicoat, R. Battini, A. Berger, E. M. Blair, J. E. Brunstrom-Hernandez, J. A. Buckard, D. M. Cassiman, R. Caumes, D. M. Cordelli, L. M. De Waele, A. J. Fay, P. Ferreira, N. A. Fletcher, A. E. Fryer, H. Goel, C. A. Hemingway, M. Henneke, I. Hughes, R. J. Jefferson, R. Kumar, L. Lagae, P. G. Landrieu, C. M. Lourenco, T. J. Malpas, S. G. Mehta, I. Metz, S. Naidu, K. Ounap, A. Panzer, P. Prabhakar, G. Quaghebeur, R. Schiffmann, E. H. Sherr, K. R. Sinnathuray, C. Soh, H. S. Stewart, J. Stone, H. Van Esch, C. E. Van Mol, A. Vanderver, E. L. Wakeling, A. Whitney, G. D. Pavitt, S. Griffiths-Jones, G. I. Rice, P. Revy, M. S. van der Knaap, J. H. Livingston, R. T. O’Keefe and Y. J. Crow (2016). “Mutations in snord118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.” Nat Genet: 2016 Aug [Epub ahead of print].

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Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.


Posted September 15th 2016

Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Imaoka, H., Y. Toiyama, H. Fujikawa, J. Hiro, S. Saigusa, K. Tanaka, Y. Inoue, Y. Mohri, T. Mori, T. Kato, S. Toden, A. Goel and M. Kusunoki (2016). “Circulating microrna-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer.” Ann Oncol: 2016 Aug [Epub ahead of print].

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BACKGROUND: Circulating microRNAs (miRNAs) are attracting major interest as potential non-invasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. PATIENTS AND METHODS: Comprehensive miRNA array analysis was carried out using serum samples from patients with colorectal neoplasia and healthy controls. Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma, and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. RESULTS: Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly up-regulated in patients with colorectal adenomas (P < 0.0001) and cancers (P < 0.0001). Serum miR-1290 levels could robustly distinguish adenoma [area under the curve (AUC) = 0.718] and CRC patients (AUC = 0.830) from normal subjects. High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor [hazard ratio (HR) = 4.51; 95% confidence interval (CI) = 1.23-23.69; P = 0.0096] and an independent predictor for tumor recurrence (hazard ratio = 3.92; 95% confidence interval = 1.11-25.14; P = 0.032) in CRC. CONCLUSIONS: Serum miR-1290 is a novel biomarker for early detection, recurrence, and prognosis in CRC.


Posted September 15th 2016

Superior mesenteric artery outcomes after fenestrated endovascular aortic aneurysm repair.

Mirza S. Baig, M.D.

Mirza S. Baig, M.D.

Lala, S., M. Knowles, D. Timaran, M. S. Baig, J. Valentine and C. Timaran (2016). “Superior mesenteric artery outcomes after fenestrated endovascular aortic aneurysm repair.” J Vasc Surg 64(3): 692-697.

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OBJECTIVE: The Zenith (Cook Medical, Bloomington, Ind) fenestrated endovascular graft may be designed with single-wide scallops or large fenestrations to address the superior mesenteric artery (SMA). Misalignment of the SMA with an unstented scallop or a large fenestration is possible. This study assessed SMA outcomes after fenestrated endovascular aortic aneurysm repair (FEVAR). METHODS: During an 18-month period, 47 FEVARs were performed at a single institution. For analysis, patients were grouped according to unstented (n = 23) vs stented (n = 24) SMA scallops/fenestrations. The Institutional Review Board approved this single-institution observational study. Because this was a retrospective review of the data, patient consent was unnecessary for the study. RESULTS: Technical success for FEVAR was 100%. The median follow-up period was 7.7 months (range, 1-16 months). Nine of 21 patients (43%) in the unstented group had some degree of misalignment of the SMA (range, 9%-71%). Among these, four patients (44%) developed complications: three SMA stenoses and one occlusion. The mean peak systolic velocity in patients with and without SMA misalignment was 317.8 cm/s vs 188.4 cm/s (P < .08), respectively. No misalignment occurred in the stented group, and only one of 19 patients (5%) developed an SMA stenosis that required angioplasty. Overall, patients with unstented SMAs had significantly more adverse events directly attributable to SMA misalignment than the stented group (44% vs 5%, respectively; P < .05). CONCLUSIONS: Misalignment of the SMA with the use of unstented unreinforced scallops or fenestrations occurs frequently. Routine stenting of single-wide and large fenestrations, when feasible, may be a safer option for patients undergoing FEVAR.


Posted September 15th 2016

Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice.

Jacqueline O'Leary M.D.

Jacqueline O’Leary M.D.

Levitsky, J., J. G. O’Leary, S. Asrani, P. Sharma, J. Fung, A. Wiseman and C. U. Niemann (2016). “Protecting the kidney in liver transplant recipients: Practice-based recommendations from the american society of transplantation liver and intestine community of practice.” Am J Transplant 16(9): 2532-2544.

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Both acute and chronic kidney disease are common after liver transplantation and result in significant morbidity and mortality. The introduction of the Model for End-stage Liver Disease score has directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver-kidney transplantations performed. Kidney dysfunction in this population is typically multifactorial and related to preexisting conditions, pretransplantation renal injury, perioperative events, and posttransplantation nephrotoxic immunosuppressive therapies. The management of kidney disease after liver transplantation is challenging, as by the time the serum creatinine level is significantly elevated, few interventions affect the course of progression. Also, immunological factors such as antibody-mediated kidney rejection have become of greater interest given the rising liver-kidney transplant population. Therefore, this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestine Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver-kidney transplantation. Key points and practice-based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.