Therapeutic Drug Monitoring of Micophenolate Mofetil in Cardiac Transplant Patients by Limited Sampling Strategy: An Update

In the last few years, much progress in avoiding acute and chronic rejection in transplanted patients has been made by introducing new and more effective drugs with different formulations and combinations, and fewer side effects. Standardized protocols have been proposed for different organs, but individualized therapy based on immunosuppressive therapy blood monitoring is necessary because of pharmacological interaction, new generic drug introductions, and different absorptions and biodistributions. In specific mycophenolate mofetil dosing through mycophenolic acid (MPA), therapeutic drug monitoring has demonstrated minimal risk of organ transplant rejection. Even if the MPA area under the 12 h concentration–time curve is more accurate than MPA levels, it appears to be resource consuming and clinically impractical because of the need for numerous blood samples. Limited sampling strategy (LLS) has been proposed to overcome this problem. In heart-transplanted patients, MPA LSS is useful in guiding clinical management and dosing. The purpose of this chapter is to describe the state of the art of MPA LSS employment in heart transplantation and to perform an update of the scientific literature

Cardiac Cell Senescence and Redox Signaling

Aging is characterized by a progressive loss of the ability of the organism to cope with stressors and to repair tissue damage. As a result, chronic diseases, including cardiovascular disease, increase their prevalence with aging, underlining the existence of common mechanisms that lead to frailty and age-related diseases. In this frame, the progressive decline of the homeostatic and reparative function of primitive cells has been hypothesized to play a major role in the evolution of cardiac pathology to heart failure. Although initially it was believed that reactive oxygen species (ROS) were produced in an unregulated manner as a byproduct of cellular metabolism, causing macromolecular damage and aging, accumulating evidence indicate the major role played by redox signaling in physiology. Aim of this review is to critically revise evidence linking ROS to cell senescence and aging and to provide evidence of the primary role played by redox signaling, with a particular emphasis on the multifunctional protein APE1/Ref in stem cell biology. Finally, we will discuss evidence supporting the role of redox signaling in cardiovascular cells

ECMO as Bridge to Heart Transplantation

Extracorporeal membrane oxygenation (ECMO) is increasingly employed to support patients affected by refractory cardiogenic shock. When patients cannot be weaned from ECMO because of severe heart dysfunction, heart transplantation (HTx) or implantation of a durable mechanical circulatory support should be considered. Traditionally, the use of ECMO as a direct bridge to HTx was burdened by high mortality. However, during these last years, the widespread employment of ECMO increased centers’ experience in the management of this device, and new allocation policies provided the highest priority level for ECMO HTx candidates. Therefore, these factors could have mitigated the negative outcomes previously reported. The aim of this chapter is to describe the role of ECMO as a direct bridge to HTx, analyzing results of this strategy, and how to determine candidacy and risk stratification among the severely ill population of patients supported by this mechanical circulatory support

Limited Sampling Strategies to Monitoring Mycophenolic Acid Exposure in a Heterogeneous Population of Heart Transplant Recipients: A Pilot Study

Mycophenolate mofetil (MMF) represents a cornerstone in heart transplant (HTx) treatment. The area under the 12-hour concentration-time curve (AUC0-12h) of mycophenolic acid (MPA) -MMF’s active drug- is associated with treatment outcome. Nonetheless, therapeutic drug monitoring (TDM) of MPA AUC0-12h is impractical to assess in clinical practice and Limited Sampling Strategies (LSSs) represent a consolidated tool to estimate AUC0-12h. Two LSSs were previously generated in a selected cohort of HTx recipients treated with MMF and cyclosporine (CsA). This pilot study aimed to test these LSSs in a cohort of non-selected HTx recipients treated with MMF combined with CsA or tacrolimus (TAC). Complete PK profile was performed in 40 adults HTx recipients. MPA-AUC0-12h was estimated by two algorithms, LSS3 and LSS4, based on 3 and 4 time-points. The evaluation was made through linear regression and Bland-Altman analyses. Both LSS3 and LSS4 tended to underestimate the value of MPA-AUC0-12h (mean percentage prediction error, MPE%: −6.0%; and −4.8%, respectively). Nonetheless, high correlations (r: 0.92 and 0.94, respectively) and goodness of fit of linear regression models (R2: 0.84 and 0.88, respectively) emerged for both LSSs. A study with a wider and more homogenous sample size should be performed to support these results

Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Background: The clinical outcome of patients affected by dilated cardiomyopathy (DCM) is heterogeneous, since its pathophysiology is only partially understood. Interleukin 1 beta levels could predict the mortality and necessity of cardiac transplantation of DCM patients. Objective: To investigate mechanisms triggering sterile inflammation in dilated cardiomyopathy (DCM). Methods: Hearts explanted from 62 DCM patients were compared with 30 controls, employing immunohistochemistry, cellular and molecular biology, as well as metabolomics studies. Results: Although misfolded protein accumulation and aggresome formation characterize DCM hearts, aggresomes failed to trigger the autophagy lysosomal pathway (ALP), with consequent accumulation of both p62(SQSTM1) and dysfunctional mitochondria. In line, DCM hearts are characterized by accumulation of lipoperoxidation products and activation of both redox responsive pathways and inflammasome. Consistently with the fact that mTOR signaling may impair ALP, we observed, an increase in DCM activation, together with a reduction in the nuclear localization of Transcription Factor EB -TFEB- (a master regulator of lysosomal biogenesis). These alterations were coupled with metabolomic alterations, including accumulation of branched chain amino acids (BCAAs), known mTOR activators. Consistently, reduced levels of PP2Cm, a phosphatase that regulates the key catabolic step of BCAAs, coupled with increased levels of miR-22, a regulator of PP2Cm levels that triggers senescence, characterize DCM hearts. The same molecular defects were present in clinically relevant cells isolated from DCM hearts, but they could be reverted by downregulating miR-22. Conclusion: We identified, in human DCM, a complex series of events whose key players are miR-22, PP2Cm, BCAA, mTOR, and ALP, linking loss of proteostasis with inflammasome activation. These potential therapeutic targets deserve to be further investigated

Prognostic role of endocarditis in isolated tricuspid valve surgery. A propensity-weighted study

Objectives The role of the underlying etiology in isolated tricuspid valve surgery has not been investigated extensively in current literature. Aim of this study was to analyse outcomes of patients undergoing surgery due to endocarditis compared to other pathologies. Methods The SURTRI study is a multicenter study enrolling adult patients who underwent isolated tricuspid valve surgery (n = 406, 55 ± 16 y.o.; 56% female) at 13 international sites. Propensity weighted analysis was performed to compare groups (IE group n = 107 vs Not-IE group n = 299). Results No difference was found regarding the 30-day mortality (Group IE: 2.8% vs Group Not-IE = 6.8%; OR = 0.45) and major adverse events. Weighted cumulative incidence of cardiac death was significantly higher for patients with endocarditis (p = 0.01). The composite endpoint of cardiac death and reoperation at 6 years was reduced in the Group IE (63.2 ± 6.8% vs 78.9 ± 3.1%; p = 0.022). Repair strategy resulted in an increased late survival even in IE cases. Conclusions Data from SURTRI study report acceptable 30-day results but significantly reduced late survival in the setting of endocarditis of the tricuspid valve. Multi-disciplinary approach, repair strategy and earlier treatment may improve outcomes. © 2022 The Author

A standardized approach to treat complex aortic valve endocarditis: a case series

Background Surgical treatment of complicated aortic valve endocarditis often is challenging, even for experienced surgeons. We aim at demonstrating a standardized surgical approach by stentless bioprostheses for the treatment of aortic valve endocarditis complicated by paravalvular abscess formation. MethodsSixteen patients presenting with aortic valve endocarditis (4 native and 12 prosthetic valves) and paravalvular abscess formation at various localizations and to different extents were treated by a standardized approach using stentless bioprostheses. The procedure consisted of thorough debridement, root replacement with reimplantation of the coronary arteries and correction of accompanying pathologies (aortoventricular and aortomitral dehiscence, septum derangements, Gerbode defect, total atrioventricular conduction block, mitral and tricuspid valve involvement).ResultsAll highly complex patients included (14 males and 2 females; median age 63 years [range 31–77]) could be successfully treated with stentless bioprostheses as aortic root replacement. Radical surgical debridement of infected tissue with anatomical recontruction was feasible. Although predicted operative mortality was high (median logarithmic EuroSCORE I of 40.7 [range 12.8–68.3]), in-hospital and 30-day mortality rates were favorable (18.8 and 12.5% respectively). ConclusionsRepair of active aortic valve endocarditis complicated by paravalvular abscess formation and destruction of the left ventricular outflow tract with stentless bioprosthesis is a valuable option for both native and prosthetic valves. It presents a standardized approach with a high success rate for complete debridement, is readily available, and yields comparable clinical outcomes to the historical gold standard, repair by homografts. Additionally, use of one type of prosthesis reduces logistical issues and purchasing costs

The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy

Aims The ageing heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene–environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischaemia, atherosclerosis, and diabetes models. Here, we asked whether the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous ageing. Methods and results Immunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage. Conclusions We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart’s ageing. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people