Heart transplantation and biomarkers: a review about their usefulness in clinical practice.

Advanced heart failure (AdvHF) can only be treated definitively by heart transplantation (HTx), yet problems such right ventricle dysfunction (RVD), rejection, cardiac allograft vasculopathy (CAV), and primary graft dysfunction (PGD) are linked to a poor prognosis. As a result, numerous biomarkers have been investigated in an effort to identify and prevent certain diseases sooner. We looked at both established biomarkers, such as NT-proBNP, hs-troponins, and pro-inflammatory cytokines, and newer ones, such as extracellular vesicles (EVs), donor specific antibodies (DSA), gene expression profile (GEP), donor-derived cell free DNA (dd-cfDNA), microRNA (miRNA), and soluble suppression of tumorigenicity 2 (sST2). These biomarkers are typically linked to complications from HTX. We also highlight the relationships between each biomarker and one or more problems, as well as their applicability in routine clinical practice.

Left ventricular assist device and transcatheter edge-to-edge mitral valve repair in advanced heart failure: allies or enemies?

The implantation of left ventricular assist devices (LVADs) has been increasing, with good long-term results, in parallel with a growing population with advanced heart failure (HF). However, in some European countries, LVADs are still underused, with one of the main issues being the patient's late referral. On the contrary, the use of transcatheter edge-to-edge mitral valve repair (TEER) has exponentially increased over the past decade, expanding its potential use even in patients on the heart transplantation waiting list. Even though the study populations of the main trials that investigated the prognostic impact of LVAD and TEER are different, in clinical practice a clear distinction might not be so clear. Therefore, patients with refractory HF symptoms and significant mitral regurgitation should be thoroughly evaluated through a multidisciplinary Heart Team meeting with both an advanced HF specialist and interventional cardiologist, to avoid futile procedures and to define the optimal timing for advanced HF therapies, when they are indicated. We analyzed the main available studies and registries on both TEERs and LVADs and we compared their populations and outcomes, to provide the current evidence on the use of LVAD and TEER in the HF population, especially in the light of the recently released 5-year follow-up results, giving some insights on the Italian situation, and finally to stress the importance of a solid HF network between hospitals, aiming for advanced HF patients' timely referral for LVAD or heart transplants.

The role of non-invasive imaging modalities in cardiac allograft vasculopathy: an updated focus on current evidences.

Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse form of vasculopathy affecting almost 50% of patients after 10 years from heart transplant and represents the most common cause of long-term cardiovascular mortality among heart transplant recipients. The gold standard diagnostic technique is still invasive coronary angiography, which however holds potential for complications, especially contrast-related kidney injury and procedure-related vascular lesions. Non-invasive and contrast-sparing imaging techniques have been advocated and investigated over the past decades, in order to identify those that could replace coronary angiography or at least reach comparable accuracy in CAV detection. In addition, they could help the clinician in defining optimal timing for invasive testing. This review attempts to examine the currently available non-invasive imaging techniques that may be used in the follow-up of heart transplant patients, spanning from echocardiography to nuclear imaging, cardiac magnetic resonance and cardiac computed tomography angiography, weighting their advantages and disadvantages.

Clinical, echocardiographic and hemodynamic predictors of right heart failure after LVAD placement.

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implant is associated with increasing morbidity and mortality. The aim of this study was to identify the best predictors of RVF post LVAD-implant among biochemical, haemodynamic and echocardiographic parameters. From 2009 to 2019, 38 patients who underwent LVAD implantation at our centre were prospectively enrolled. Preoperative clinical, laboratory, echocardiographic and haemodynamic parameters were reported. Overall, eight patients (21%) developed RVF over time, which revealed to be strongly related to overall mortality. Pulmonary artery pulsatility index (PAPi) resulted to be the most significant right heart catheterization index in discriminating RVF vs no RVF patients [(1.32 ± 0.26 vs. 3.95 ± 3.39 respectively) p = 0.0036]. Regarding transthoracic echocardiography, RVF was associated with reduced free wall right ventricular longitudinal strain (fw-RVLS) (- 7.9 ± 1.29 vs. - 16.14 ± 5.83) (p < 0.009), which was superior to other echocardiographic determinants of RVF. Among laboratory values, N-terminal pro-brain natriuretic peptide (NT-proBNP) was strongly increased in RVF patients [(10,496.13 pg/ml ± 5272.96 pg/ml vs. 2865, 5 pg/ml ± 2595.61 pg/ml) p = 0.006]. PAPi, NT-proBNP and fwRVLS were the best pre-operative predictors of RVF, a post-LVAD implant complication which was confirmed to have a great impact on survival. In particular, fwRVLS has been proven to be the strongest independent predictor.

Detection of cardiac allograft vasculopathy by multi-layer left ventricular longitudinal strain in heart transplant recipients.

Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse type of coronaropathy that develops in the transplanted human heart, representing a major cause of graft failure and mortality. Nowadays the gold standard for the diagnosis of CAV is coronary angiography (CA). Non-invasive CAV detection, especially in the early stages of the disease, is still challenging. Our study aimed to investigate the role of speckle tracking echocardiography (STE), in particular three-layer STE, in predicting CAV at early stages, and if other traditional echocardiographic, clinical or biochemical parameters could relate to CAV. The study population was composed of a total of 33 heart transplanted patients, divided accordingly to the presence or absence of CAV (12 CAV+ , 22 CAV-). All subjects underwent a complete transthoracic echocardiographic examination on the same day of the CA, and all conventional parameters of myocardial function were obtained, including strain values assessed by STE. Strain values were significantly reduced in presence of CAV, at each myocardial layer but in particular the endocardial-epicardial gradient (- 4.15 ± 1.6 vs - 1.7 ± 0.4% < .0001) that was also highly predictive of CAV (AUC at ROC curve 0.97). Among diastolic parameters, the E wave deceleration time (DT) and the mean E/e' ratio were strongly positively associated with CAV. In our population, left ventricular global longitudinal strain (GLS), layer-specific GLS and the endocardial-epicardial LS gradient, E wave DT and E/e' ratio were the best independent non-invasive predictors of CAV.

Longitudinal Strain Stress-Echo Evaluation of Aged Marginal Donor Hearts: Feasibility in the Adonhers Project.

BACKGROUND: The Adonhers (aged donor heart rescue by stress-echo protocol) Project was created to resolve the current shortage of donor hearts. One of the great limits of stress echo is the operator dependency. Speckle-tracking echocardiography (STE), offering a quantitative objective analysis of myocardial deformation, may help to overcome this limit. This study aimed to verify feasibility of a stress-strain echo analysis in selection of aged donor hearts for heart transplant. METHODS: From February 2014 to October 2015, 22 marginal candidate donors (16 men) ages 58 ± 4 years were initially enrolled. After legal declaration of brain death, all marginal donors underwent bedside echocardiography, with baseline and (when resting echocardiography was normal) dipyridamole (0.84 mg/kg in 6 minutes) stress echo. In all patients, left ventricular (LV) longitudinal myocardial deformation was obtained by STE in the 4-, 2-, and 3-chamber views, obtaining the average global longitudinal strain (GLS). GLS was assessed at baseline and at the peak of stress echo. RESULTS: Baseline echocardiography showed wall motion abnormalities in 9 patients (excluded from donation). Stress echocardiography was performed in the remaining 13 patients. Results were normal in 8, who were uneventfully transplanted in marginal recipients. Stress results were abnormal in 5 (excluded from donation). STE was obtained in all cases (100% feasibility) and ΔGLS was significantly different between normal and pathological stress-echo (+13.2 ± 5.2 versus -6.1% ± 3.1%, P = .0001, respectively). CONCLUSIONS: STE showed an excellent feasibility in analysis of LV myocardial longitudinal strain at baseline and at the peak of stress echo of marginal heart donors. Further experience is needed to confirm STE as a valuable additional mean to better interpret stress echo in marginal donors.

First Evidence of Cardiac Stem Cells From the Left Ventricular Apical Tip in Patients With Left Ventricular Assist Device Implantation.

BACKGROUND: Recent studies have challenged the dogma that the adult heart is a postmitotic organ and raise the possibility of the existence of resident cardiac stem cells (CSCs). Our study aimed to explore if these CSCs are present in the "ventricular tip" obtained during left ventricular assist device (LVAD) implantation from patients with end-stage heart failure (HF) and the relationship with LV dysfunctional area extent. METHODS: Four consecutive patients with ischemic cardiomyopathy and end-stage HF submitted to LVAD implantation were studied. The explanted "ventricular tip" was used as a sample of apical myocardial tissue for the pathological examination. Patients underwent clinical and echocardiographic examination, both standard transthoracic echocardiography (TTE) and speckle tracking echocardiography (STE), before LVAD implantation. RESULTS: All patients presented severe apical dysfunction, with apical akinesis/diskinesis and very low levels of apical longitudinal strain (-3.5 ± 2.9%). Despite this, the presence of CSCs was demonstrated in pathological myocardial samples of "ventricular tip" in all 4 of the patients. It was found to be a mean of 6 c-kit cells in 10 fields magnification 40×. CONCLUSIONS: Cardiac stem cells can be identified in the LV apical segment of patients who have undergone LVAD implantation despite LV apical fibrosis.

Evaluation of Right Ventricular Function in the Management of Patients Referred for Left Ventricular Assist Device Therapy.

BACKGROUND: Speckle tracking echocardiography analysis (STE) has recently allowed an in-depth analysis of right ventricular (RV) performance. The aim of the study was to observe RV function by STE in patients with advanced heart failure before and after left ventricular assist device (LVAD) implantation. METHODS: A transthoracic echocardiogram was performed in 19 patients referred for LVAD implant at baseline and with serial echocardiograms after LVAD implantation (Jarvik 2000). All echocardiographic images were analyzed off line by an independent operator to calculate with STE the RV free wall longitudinal strain (RVLS). RESULTS: All the patients, except 4, showed a progressive increase of RVLS after LVAD implant. However, 4 patients, who presented the lowest RVLS values at baseline, presented a further RV failure in the postoperative. The value of -11% represented the empirical preoperative cutoff able to identify patients at greater risk of postimplant RV failure. CONCLUSIONS: RV myocardial deformation may have important clinical implications for the selection and management of LVAD patients. It can be used to evaluate RV function before LVAD implantation, to drive decisional strategy regarding the management of this type of patients, and after LVAD implant for the follow-up.

Right ventricular longitudinal strain and right ventricular stroke work index in patients with severe heart failure: left ventricular assist device suitability for transplant candidates.

BACKGROUND: Right ventricular (RV) systolic function has a critical role in determining the clinical outcome and the success of using left ventricular assist devices in patients with refractory heart failure. RV deformation analysis by speckle tracking echocardiography (STE) has recently allowed the analysis of RV longitudinal function. Using cardiac catheterization as the reference standard, this study aimed to explore the correlation between RV longitudinal function by STE and RV stroke work index (RVSWI) among patients referred for cardiac transplantation. METHODS: Right heart catheterization and transthoracic echo-Doppler were simultaneously performed in 47 patients referred for cardiac transplant assessment due to refractory heart failure (ejection fraction 25.1 ± 4.5%). Thermodilution RV stroke volume and invasive pulmonary pressures were used to obtain RVSWI. RV longitudinal strain (RVLS) by STE was assessed averaging RV free-wall segments (free-wall RVLS). We also calculated. Tricuspid S' and tricuspid annular plane systolic excursion (TAPSE). RESULTS: No significant correlation was observed for TAPSE on tricuspid S' with RV stroke volume (r = 0.14 and r = 0.06, respectively). A close negative correlation between free-wall RVLS and RVSWI was found (r = -0.82; P < .0001). Furthermore, free-wall RVLS showed the highest diagnostic accuracy (area under the curve of 0.90) with good sensitivity and specificity of 95% and 91%, respectively, to predict depressed RVSWI using a cutoff value less than -11.8%. CONCLUSIONS: Among patients referred for heart transplantation, TAPSE and tricuspid S' did not correlate with invasively obtained RVSWI. RV longitudinal deformation analysis by STE correlated with RVSWI, providing a better estimate of RV systolic performance.

C2 and C0 values for monitoring cyclosporine therapy in stable heart transplant recipients.

INTRODUCTION: We sought to evaluate the behavior of C2 values and their correlation with acute rejection episodes and cyclosporine (CyA) side effects in heart transplant patients whose immunosuppressive therapy, was monitored with C0 trough levels. METHODS: Sixty stable patients who had received heart transplants from 3 months to 60 months prior were randomly observed from September 2001 to June 2004. Four area under the concentration-time curves (AUC) were performed on each patient, a total of 240 AUC curves. RESULTS: Regarding the variability of CyA absorption, two groups of patients were distinguished: group A, "constant absorbers," namely, low variability (<15%) of CyA absorption; group B, "inconstant absorbers" patients with higher (>15%) variability of absorption. Group B patients showed more acute rejection episodes (41%) than group A (19%). CyA side effects were more serious in patients with higher variability of absorption: systemic hypertension, neurological disorders, hyperlipidemia, and gum hyperplasia; Group B patients who developed CyA side effects showed higher maximum and mean C2 levels (P < .05) than group A patients. No differences were found with regard to renal dysfunction between the two groups: all patients showed a mean increase of serum creatinine by at least 50% compared to the baseline value. CONCLUSION: Higher C2 levels were not sufficient to predict acute rejection compared to lower but constants, C2 levels. Patients with inconstant absorption were more often overexposed to CyA than underexposed, developing more side effects than patients with lower variability of absorption. Monitoring CyA therapy with C0 and C2 may prevent over- or underexposure to the drug.

Standardized psychological evaluation pre- and posttransplantation: a new option.

A multicenter study was undertaken involving three teams in Italy to obtain a homogeneous psychological evaluation of patients needing organ transplantations. After a preliminary formulation of a common questionnaire individualizing 22 items, yielding a final score from 0 to 44, 294 forms were analyzed for correlations between variables. The sample responses were related to individual variables as well as by cluster analysis to aggregate typical profiles. Clustering of variables was observed in three areas that showed two variables (no. 6, "ongoing psychotic disturbances" and no. 10 "drugs") to be separate. Area 1 ("psychopathology") highlights psychic disturbances, cognitive disorders, and unhealthy behavioral styles; area 2 ("anxia") correlates anxious symptoms to pretransplant examinations and waiting time; area 3 ("depression") ties personal emotional resources and affective factors. Cluster analysis of the sample identified four groups: Group 1 (16.6%) "at risk;" mean score 25.2 (range 16-31); Group 2 (21.7%) "intermediate-at risk," mean score 32 (range 25-38); Group 3 (29.6%) "intermediate-ideal," mean score 35.3 (range 26-40); and Group 4 (31.9%) "ideal candidate," mean score 40.7 (range 36-44). The two "intermediate" groups were studied for mean values for area 1; namely, a cut-off value of 1.78 constituted a better or worse prognostic factor to assign the patient to either Group 2 or 3. Using a uniform method of psychological evaluation before transplantation reduced single operator subjectivity, obtaining comparable results in different transplant centers and allowing planning interventions for at-risk patients.

Risk factors for smoking abuse after heart transplantation.

Patients (n = 103) were studied before heart transplantation with regard to smoking habits by means of a clinical interview, and 81 were submitted to Minnesota Multiphasic Personality Inventory (MMPI). After a mean time of 50.8 +/- 24.2 months from transplant, they were once again interviewed to ascertain their smoking habits after intervention. Nonsmokers (35 of 103) were still nonabusers. Of the remaining 68 patients who ceased smoking before heart transplant, 12 (17.6%) had returned to tobacco abuse. Dividing these 68 patients into two groups based upon the length of smoking cessation before heart transplant (less than 1 year: short term [ST] more than 1 year: long term [LT]), we noticed that the ST group showed a much greater rate of reabuse (8 of 20, 40%) than the LT group (4 of 48, 8.3%, P =.006). Analyzing six scales of MMPI, we found a statistically different score for self-control ability (scale K) in ST and LT smokers compared to nonsmokers (45.5 and 45.5 vs 51.2, P =.026), and for difficult adaptation (scale Ma) in ST compared both to LT smokers and nonsmokers (ST 57, LT 50.5, NS 47.6; P =.042 LT vs ST, P =.0005 ST vs NS). We concluded that patients who have recently decided to stop smoking and show after MMPI compilation a score of >50 for K and <50 for Ma scale have a higher risk of reabuse and need a greater effort by the transplant team to reinforce their will to stop smoking.

Abdominal aortic aneurysms in heart transplanted patients.

OBJECTIVE: In the AA's opinion, the dilatation of the abdominal aorta is not a contraindication to heart transplantation. METHODS AND MATERIALS: From July 1994 to February 1998, 3 out of 80 heart transplanted patients, required a replacement of their abdominal aorta because of an infrarenal aortic aneurysm. The first patient (62 years old) did not have an aneurysm by time of heart transplantation: his aneurysm (5.1 cm wide) was resected 2 years later. The other two patients (m, 44 years old; m, 60 years old) had a dilatation of 3.1 and 3.5 cm of the abdominal aorta by time of cardiac transplantation: 15 months later, the aneurysms measured 5.8 and 7 cm, respectively, and had been resected. Two resections were performed through a retroperitoneal approach. RESULTS: All 3 patients had uneventful postoperative course. CONCLUSION: Before heart transplantation the aorta must be screened for dilatation or aneurysm, which can be enlarged by operation. Such lesions can be operated on, with low risks, and should not be a contraindication to heart transplantation.

[Pancreatic and duodenal injuries. Considerations on 40 observed cases]. / I traumi del pancreas e del duodeno. Considerazioni su 40 casi osservati.

Traumatic lesions of the pancreas and duodenum are uncommon. The anatomic situation of the viscera makes early diagnosis of such lesions difficult to be achieved; this fact, together with the high incidence of associated lesions, justify the high morbidity and mortality of duodeno-pancreatic traumas. In the present paper we report the two-decades experience (40 traumatic lesions of the pancreas and/or the duodenum) of the Department of Emergency Surgery, University of Milan. The overall mortality (32.5%), even if correlated with the importance of the duodeno-pancreatic lesions, was strictly dependent to the presence of associated injuries which lead to most of the morbidity and mortality.