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.

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.

Case Report: Aortic Valve Replacement After JARVIK 2000 Left Ventricular Assist Device Implantation in Long-Time Survivor With Severe Aortic Valve Regurgitation.

BACKGROUND: There are limited clinical records in the literature regarding aortic valve replacement in left ventricular assist device (L-VAD) patients. Previously we had two cases of severe aortic valve regurgitation in patients with L-VAD support treated with Corvalve prosthesis insertion and Amplatzer closure procedure. Both patients died a few days after the procedure from complications not related to the procedure itself. PATIENT HISTORY: The patient was a male with previous coronary artery bypass graft surgery in 2001 that was complicated with postischemic dilated cardiomyopathy with severe heart failure (ejection fraction [EF], 20%). Cardiac resynchronization therapy was biventricular-pacemaker and cardiac defibrillator implantation in 2009 for recurrent ventricular arrhythmia. L-VAD implantation (Jarvik 2000) with graft apposition in descending thoracic aorta through left thoracotomy access and retro-auricolar cable was performed in October 2013. In 2015 the patient underwent surgical aortic valve replacement with bioprothesis due to progressive worsening of the aortic valve regurgitation. The Jarvik 2000 outflow was occluded with vascular ball occluder inserted via right axillary artery under fluoroscopy before CEC installation. The recovery was without major complications. DISCUSSION: Long-time survivors with Jarvik 2000 are increasing in number and such late complication is expected to become a main future issue. Our previous experience with the interventional approach was delusive. Due to the fatal consequences in similar patients with nonsurgical approaches, we opted for surgical aortic valve replacement. At the moment, the international literature does not describe safe approaches regarding aortic valve replacement in patients with Jarvik 2000 L-VAD. This case shows that surgical valve replacement could be managed with success according to the described specific technique.

First World Report of Internal Power Cable Repair in Left Ventricular Assist Device Jarvik 2000: Case Report.

BACKGROUND: There are limited clinical reports concerning internal power cable fixing in left ventricular assist device (L-VAD) patients. Actually there are no reports in the literature about Jarvik 2000 internal cable repair. We show the first description of a technique for surgical reparation of such a fatal complication. PATIENT HISTORY: The patient was a 62-year-old woman who had L-VAD implantation (Jarvik 2000) with outflow graft apposition in descending thoracic aorta through left thoracotomy access, in 2009. She arrived urgently on January 25, 2014 for Jarvik 2000 dysfunction correlated with head movements. The neck X-rays revealed the rupture of one of the nine power cables located inside the neck and the damaging of two more cables nearby to be ruptured. On the same day she got pump failure due to the final interruption of the remaining two cables, we were obliged to install femoro-femoral extracorporeal membrane oxygenation (ECMO) assistance, to repair the power cables, approaching them through a pacemaker extension cable. The L-VAD outflow was occluded with vascular ball occluder inserted via right axillary artery under fluoroscopy before ECMO installation. At the end the ECMO assistance was interrupted and the Jarvik 2000 was turned back on. The patient was dismissed from the hospital 12 days after the procedure. DISCUSSION: At the moment the international literature is poor regarding this issue. This case provides evidence that in emergency conditions ECMO assistance is mandatory and a hybrid surgical and radiological approach could help to repair the damage in safe conditions.

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.

Severity of aortic stenosis predicts early post-operative normalization of left atrial size and function detected by myocardial strain.

BACKGROUND: Aortic stenosis (AS) causes significant disturbances in left ventricular (LV) and left atrial (LA) function irrespective of the extent of myocardial hypertrophy which associates the increased afterload. We hypothesize that aortic valve replacement (AVR) and removal of LV outflow tract obstruction should result in LA size and function recovery, even partial, and were set to study this in a group of patients with AVR for AS. METHODS: Peak atrial longitudinal strain (PALS) was evaluated in 43 patients with severe isolated AS and normal EF (56.6 ± 3.8%) and no obstructive coronary artery disease candidates for AVR, pre-operatively and then 40 days and 3 months after surgery. Results were compared with those from 34 age- and gender-matched healthy controls. RESULTS: LVEF remained unchanged and LV mass regressed after AVR. Global PALS was reduced pre-operatively and increased 40 days after surgery (p=0.002) and showed only a slight further increase at 3 months follow-up (p<0.0001). Indexed LA volume was increased before surgery, but significantly fell 40 days after surgery (p<0.0001) and showed only a slight further reduction after 3 months (p<0.0001). Trans-aortic mean gradient change after surgery was the only independent predictor of the recovery of LA size and function. CONCLUSIONS: AVR reverses LA abnormalities and regains normal atrial function, a behavior which is directly related to the severity of pre-operative LV outflow tract obstruction. Early identification of LA size enlargement and functional disturbances might contribute to better patient's recruitment for AVR.

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.

Prevalent cardiac phenotype resulting in heart transplantation in a novel LMNA gene duplication.

Mutations in the lamin A/C gene (LMNA) are known to be involved in several diseases such as Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and dilated cardiomyopathies with conduction disease, with considerable phenotype heterogeneity. Here we report on a novel autosomal dominant mutation in LMNA in two direct relatives presenting with different clinical phenotypes, characterized by severe life-threatening limb-girdle muscle involvement and cardiac dysfunction treated with heart transplantation in the proband, and by ventricular tachyarrhythmias with preserved cardiac and skeletal muscle function in her young son. To our knowledge, this is the first report of a duplication in the LMNA gene. The two phenotypes described could reflect different clinical stages of the same disease. We hypothesize that early recognition and initiation of therapeutic manoeuvres in the younger patient may retard the rate of progression of the cardiomyopathy.

NT-proBNP changes, oxidative stress, and energy status of hypertrophic myocardium following ischemia/reperfusion injury.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive functional marker in heart disease, including left ventricular hypertrophy (LVH) secondary to valvular aortic stenosis (AS). We evaluated the association between NT-proBNP changes, oxidative stress, energy status and severity of LVH in patients with AS. Ten patients undergoing aortic valve replacement for AS were studied. Plasma NT-proBNP concentrations were performed by electroluminescence immunoassay 15min after the induction of anesthesia (t0), before aortic cross-clamping (t1), before clamp removal (t2), 15min after myocardial reperfusion (t3), and 24h after surgery (t4). Heart biopsies were obtained and high energy phosphates (ATP, ADP, AMP) were analyzed by capillary electrophoresis (CE). In plasma samples from the coronary sinus, nitrate plus nitrite (NOx) concentrations were also analyzed by CE. Echocardiographic measurements were acquired and correlations between biochemical markers and severity of AS were assessed. NT-proBNP peaked significantly at t4 (p<0.001). A linear correlation between NT-proBNP values measured at t0 and t4 was found (R(2)=0.89; p<0.001). A negative correlation between NT-proBNP production and phosphorylation potential (ATP/ADP ratio) was observed (R(2)=0.62; p<0.01). NOx values positively correlated with NT-proBNP levels (p<0.01). NT-proBNP inversely correlated with aortic valvular area (r=81, p<0.01), positively correlated with mean (r=0.82, p<0.01) and maximum left ventricle-to-aortic gradients (r=0.80, p<0.01), and with left ventricular mass (r=0.69, p<0.01). NT-proBNP is a useful marker of LVH and severity of AS. It may complement echocardiographic evaluation of patients with AS in identifying the optimum time for surgery.

Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial.

We compared efficacy and safety of tacrolimus (Tac)-based vs. cyclosporine (CyA) microemulsion-based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade >/= 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade >/= 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new-onset diabetes mellitus (20.3% vs. 10.5%); post-transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

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.