Nuclear Osteopontin Is a Marker of Advanced Heart Failure and Cardiac Allograft Vasculopathy: Evidence From Transplant and Retransplant Hearts

Abstract

Background Heart transplant is the gold standard therapy for patients with advanced heart failure. Over 5,500 heart transplants are performed every year worldwide. Cardiac allograft vasculopathy (CAV) is a common complication post-heart transplant which reduces survival and often necessitates heart retransplantation. Post-transplant follow-up requires serial coronary angiography and endomyocardial biopsy (EMB) for CAV and allograft rejection screening, respectively; both of which are invasive procedures. This study aims to determine whether osteopontin (OPN) protein, a fibrosis marker often present in chronic heart disease, represents a novel biomarker for CAV. Methods Expression of OPN was analyzed in cardiac tissue obtained from patients undergoing heart retransplantation using immunofluorescence imaging ( n = 20). Tissues from native explanted hearts and three serial follow-up EMB samples of transplanted hearts were also analyzed in five of these patients. Results Fifteen out of 20 patients undergoing retransplantation had CAV. 13/15 patients with CAV expressed nuclear OPN. 5/5 patients with multiple tissue samples expressed nuclear OPN in both 1 st and 2 nd explanted hearts, while 0/5 expressed nuclear OPN in any of the follow-up EMBs. 4/5 of these patients had an initial diagnosis of dilated cardiomyopathy (DCM). Conclusion Nuclear localization of OPN in cardiomyocytes of patients with CAV was evident at the time of cardiac retransplant as well as in patients with DCM at the time of the 1 st transplant. The results implicate nuclear OPN as a novel biomarker for severe CAV and DCM.

Osteopontin and Transplantation: Where Are We Now?

“…Elevated OPN level on day 0 and 7th after KTx was associated with the lower probability of rejection-free survival and was an independent predictor of AR Alchi et al ( 2005 ) Yes OPN expression in kidney biopsies of patients with AR was high and correlated with elevated interstitial monocytes infiltration, and inflammation Rouschop et al ( 2006 ) Yes/No Renal OPN and CD44 expression was higher in KTx patients with AR than in non-rejecting group and correlated with the degree of interstitial inflammation. Soluble CD44 plasma concentration was higher in rejecting than in non-rejecting patients; however, soluble OPN plasma level was similar in both groups Mansour et al ( 2021 ) No Elevated urine OPN level and OPN expression in kidney donors was associated with lower risk of delayed graft function and graft failure HTx Schipper et al ( 2011 ) Yes OPN plasma level was higher in patients with heart failure than in healthy controls and decreased after HTx Irion et al ( 2020 ) Yes OPN expression in cardiac tissue of patients with CAV who received retransplantation was high LTx Cabiati et al ( 2017 ) Yes OPN plasma level and OPN expression in liver tissue of patients with HCV-positive HCC undergoing LTx was higher than in healthy controls and correlated with thrombin, 7 s-collagen and Notch-1. A significant reduction of OPN plasma levels was observed at 6 months after LTx Sieghart et al ( 2011 ) Yes OPN expression in HCC patients undergoing LTx was high.…”

“…In addition, it has been found that OPN plasma concentration after HTx decreased significantly to levels observed in the control group. In another study Irion et al ( 2020 ) analyzed the expression of nuclear OPN in cardiac tissue from 20 heart transplant patients receiving retransplantation. Moreover, the number of cells (including cardiomyocytes and non-cardiomyocytes) with nuclear OPN has been evaluated.…”

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

“…To investigate the expression of SGLT-2 in paraffin-embedded renal (or cardiac) sections, immunofluorescence imaging was performed on kidneys from all groups as previously described [ 78 ]. Sections from kidneys were incubated for 45 min at 70 degrees, dewaxed with xylene washes and hydrated by graded ethanol washes of 100% (twice for 3 min), 95%, 80% and 70% followed by water immersion (twice for 4 min).…”

Noninvasive methods to reduce cardiac complications postheart transplant

“…Aside from advances in imaging, there has been a concurrent search for biomarkers associated with CAV for early detection and as potential treatment targets. These include osteopontin, a pro-inflammatory cytokine that correlates with severe CAV [39]; endothelin-1, a vasoconstrictor peptide associated with accelerated CAV development [40]; and various microRNAs [41][42][43], among others [44][45][46][47][48]. These markers still require prospective validation to assess their utility in CAV detection, as well as continued evaluation as possible treatment targets.…”