Research Spotlight

Lala, A., Chang, H.L., Liu, X., Charles, E.J., Yerokun, B.A., Bowdish, M.E., Thourani, V.H., Mack, M.J., Miller, M.A., O’Gara, P.T., Blackstone, E.H., Moskowitz, A.J., Gelijns, A.C., Mullen, J.C. and Stevenson, L.W. (2021). “Risk for non-home discharge following surgery for ischemic mitral valve disease.” J Thorac Cardiovasc Surg 162(6): 1769-1778.e1767.

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OBJECTIVES: To determine the frequency and risk factors for non-home discharge (NHD) and its association with clinical outcomes and quality of life (QOL) at 1 year following cardiac surgery in patients with ischemic mitral regurgitation (IMR). METHODS: Discharge disposition was evaluated in 552 patients enrolled in trials of severe or moderate IMR. Patient and in-hospital factors associated with NHD were identified using logistic regression. Subsequently, association of NHD with 1-year mortality, serious adverse events (SAEs), and QOL was assessed. RESULTS: NHD was observed in 30% (154/522) with 25% (n = 71/289) in moderate and 36% (n = 83/233) in patients with severe IMR (unadjusted P = .006), a difference not significant after including age (5-year change: adjusted odds ratio [adjOR], 1.52; 95% confidence interval [CI], 1.35-1.72; P < .001), diabetes (adjOR, 1.94; 95% CI, 1.27-2.94; P = .002), and previous heart failure (adjOR, 1.64; 95% CI, 1.06-2.52; P = .03). Odds of NHD were increased for patients with postoperative SAEs (adjOR, 1.85; 95% CI, 1.19-2.86; P = .01) but not based on type of cardiac surgery. Greater rates of death and SAEs were observed in NHD patients at 1 year: adjusted hazard ratio, 4.29 (95% CI, 2.14-8.59; P < .001) and adjusted rate ratio, 1.45 (95% CI, 1.03-2.02; P = .03), respectively. QOL did not differ significantly between groups. CONCLUSIONS: NHD is common following surgery for IMR, influenced by older age, diabetes, previous heart failure, and postoperative SAEs. These patients may be at greater risk of death and subsequent SAEs after discharge. Discussion of NHD with patients may have important implications for decision-making and guiding expectations following cardiac surgery.

Grapsa, J., Blauth, C., Chandrashekhar, Y.S., Prendergast, B., Erb, B., Jr., Mack, M. and Fuster, V. (2021). “Staphylococcus Aureus Infective Endocarditis: JACC Patient Pathways.” J Am Coll Cardiol Nov 13;S0735-1097(21)07811-6. [Epub ahead of print].

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A 19-year-old female patient presented with Staphylococcus aureus infective endocarditis, with suspected subdural brain hemorrhage, disseminated intravascular coagulopathy, and septic renal as well as spleen infarcts. The patient had extensive vegetations on the mitral and tricuspid valves and underwent urgent mitral and tricuspid repair. This paper discusses the clinical case and current evidence regarding the management and treatment of Staphylococcus aureus endocarditis.

Gammie, J.S., Chu, M.W.A., Falk, V., Overbey, J.R., Moskowitz, A.J., Gillinov, M., Mack, M.J., Voisine, P., Krane, M., Yerokun, B., Bowdish, M.E., Conradi, L., Bolling, S.F., Miller, M.A., Taddei-Peters, W.C., Jeffries, N.O., Parides, M.K., Weisel, R., Jessup, M., Rose, E.A., Mullen, J.C., Raymond, S., Moquete, E.G., O’Sullivan, K., Marks, M.E., Iribarne, A., Beyersdorf, F., Borger, M.A., Geirsson, A., Bagiella, E., Hung, J., Gelijns, A.C., O’Gara, P.T. and Ailawadi, G. (2021). “Concomitant Tricuspid Repair in Patients with Degenerative Mitral Regurgitation.” N Engl J Med Nov 13. [Epub ahead of print].

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BACKGROUND: Tricuspid regurgitation is common in patients with severe degenerative mitral regurgitation. However, the evidence base is insufficient to inform a decision about whether to perform tricuspid-valve repair during mitral-valve surgery in patients who have moderate tricuspid regurgitation or less-than-moderate regurgitation with annular dilatation. METHODS: We randomly assigned 401 patients who were undergoing mitral-valve surgery for degenerative mitral regurgitation to receive a procedure with or without tricuspid annuloplasty (TA). The primary 2-year end point was a composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation by two grades from baseline or the presence of severe tricuspid regurgitation, or death. RESULTS: Patients who underwent mitral-valve surgery plus TA had fewer primary-end-point events than those who underwent mitral-valve surgery alone (3.9% vs. 10.2%) (relative risk, 0.37; 95% confidence interval [CI], 0.16 to 0.86; P = 0.02). Two-year mortality was 3.2% in the surgery-plus-TA group and 4.5% in the surgery-alone group (relative risk, 0.69; 95% CI, 0.25 to 1.88). The 2-year prevalence of progression of tricuspid regurgitation was lower in the surgery-plus-TA group than in the surgery-alone group (0.6% vs. 6.1%; relative risk, 0.09; 95% CI, 0.01 to 0.69). The frequencies of major adverse cardiac and cerebrovascular events, functional status, and quality of life were similar in the two groups at 2 years, although the incidence of permanent pacemaker implantation was higher in the surgery-plus-TA group than in the surgery-alone group (14.1% vs. 2.5%; rate ratio, 5.75; 95% CI, 2.27 to 14.60). CONCLUSIONS: Among patients undergoing mitral-valve surgery, those who also received TA had a lower incidence of a primary-end-point event than those who underwent mitral-valve surgery alone at 2 years, a reduction that was driven by less frequent progression to severe tricuspid regurgitation. Tricuspid repair resulted in more frequent permanent pacemaker implantation. Whether reduced progression of tricuspid regurgitation results in long-term clinical benefit can be determined only with longer follow-up. (Funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research; ClinicalTrials.gov number, NCT02675244.).

Madill-Thomsen, K.S., Abouljoud, M., Bhati, C., Ciszek, M., Durlik, M., Feng, S., Foroncewicz, B., Francis, I., Grąt, M., Jurczyk, K., Klintmalm, G., Krasnodębski, M., McCaughan, G., Miquel, R., Montano-Loza, A., Moonka, D., Mucha, K., Myślak, M., Pączek, L., Perkowska-Ptasińska, A., Piecha, G., Reichman, T., Sanchez-Fueyo, A., Tronina, O., Wawrzynowicz-Syczewska, M., Więcek, A., Zieniewicz, K. and Halloran, P.F. (2021). “The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study.” Am J Transplant.

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To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

Kandimalla, R., Xu, J., Link, A., Matsuyama, T., Yamamura, K., Parker, M.I., Uetake, H., Balaguer, F., Borazanci, E., Tsai, S., Evans, D., Meltzer, S.J., Baba, H., Brand, R., Von Hoff, D., Li, W. and Goel, A. (2021). “EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.” Clin Cancer Res 27(22): 6135-6144.

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PURPOSE: DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers. EXPERIMENTAL DESIGN: Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panels RESULTS: We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85-0.95 for most GI cancers. CONCLUSIONS: Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.