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Background MessengerRNA (mRNA) COVID–19 vaccination has been associated with a higher–than–expected occurrence of acute myocarditis. Scarce information is available on mid–term prognosis and changes in cardiac function, volumes, and tissue characterization on cardiac magnetic resonance (CMR). Methods Retrospective, multicenter study including patients with a definite diagnosis of acute myocarditis within 30 days from mRNA COVID–19 vaccination. The diagnosis is based on endomyocardial biopsy (EMB) or autopsy or by the coexistence of positive biomarkers (troponin >99th upper reference limit or elevated creatine kinase myocardial band [CK–MB]) and cardiac MRI findings consistent with AM according to the 2018 updated Lake Louise Criteria. Results 77 patients (median age 25 years [IQR 20–35], 15% female) were included and followed–up for 147 days [IQR 74–215]. Follow–up CMR was available in n=49 patients and showed no changes in biventricular ejection fraction (EF) as compared to CMR at diagnosis (left ventricular EF: 59%[55–65]vs. 60%[57–64], p=0.507, right ventricular EF: 56%[52–62]vs. 57%[52–61], p=0.563, respectively). Late gadolinium enhancement was present in all patients at diagnosis and persisted in only n=39 (79.6%) at follow–up (p=0.001), generally sparing the anterior wall and the septum. N=10 (20.4%) had a persistent edema based on T2–weighted short tau inversion recovery (STIR) sequences, with predominant involvement of inferior or inferior–lateral walls. The proportion of patients with increased T1 and T2 mapping signals significantly decreased at follow–up (n=13 (68%) vs. n=4 (13%),p Conclusions At mid–term follow–up, patients who experienced an acute myocarditis after a mRNA COVID–19 vaccine had preserved biventricular EF. The rate and localization of residual scar or edema on CMR is in line with classic viral myocarditis with a good prognosis. This new piece of information should further reassure patients who experience acute myocarditis after mRNA COVID–19 vaccination.

Background Despite controversial evidence, intra-aortic balloon pump (IABP) is still the most used temporary mechanical support in cardiogenic shock (CS), as a bridge to recovery or to more advanced mechanical support and/or heart transplantation [1]. Indeed, the available evidence, which is mainly restricted to the context of acute coronary syndromes (ACS) and is limited by the variability of CS definitions, shows no benefit in terms of mortality [2]. Randomized controlled trials on IABP in the setting of non-ACS CS are still missing. As a result, European guidelines do not recommend the routine use of IABP, which may be considered in refractory CS [3]. Purpose The aim of our study was to analyse the use of IABP in the context of CS, providing insights into its indications, outcomes, and complications in relation to the aetiology (ACS vs non-ACS) of CS. Methods We retrospectively enrolled all consecutive adult patients receiving IABP for refractory CS at our tertiary referral Hospital between 2009 and 2018, and analysed data focusing on in-hospital outcomes, including death, recovery, heart transplantation, and escalation to more advanced mechanical support such as venoarterial extracorporeal membrane oxygenation (VA-ECMO) or left ventricular assist device (LVAD), and on IABP-related complications. Results 403 patients received IABP, 75.2% (n=303) for ACS CS and 24.8% (n=100) for non-ACS CS. With respect to ACS patients, non-ACS patients were younger (age 59±18.3 vs 73.1±12.6 years old, p0.05]. The incidence of IABP-related overall and major complications (including ischemic stroke, major bleeding, and peripheral or visceral ischemia) was not different with respect to the non-ACS vs ACS aetiology [major complications: 8.0% (n=8) vs 5.0% (n=15), p>0.05]. Conclusions In our experience, in the clinical setting of CS treated with IABP, non-ACS patients show a worse clinical profile and prognosis than ACS patients, and more often require escalation to more advanced mechanical support and/or heart transplantation, while the incidence of IABP-related complications appears similar independently of the aetiology. Funding Acknowledgement Type of funding sources: None.

Background Renal dysfunction is a common complication after heart transplantation (HT). Renal replacement therapy (RRT) after HT has been associated with increased risk of death. Long-term renal dysfunction is associated mainly to immunosuppressive therapy but is also strongly related to post-transplant renal failure. Predictors of early renal dysfunction after HT have not been clearly identified. Purpose We aimed to define predictors of early renal dysfunction after HT. Methods Our consortium includes 10 centers in the US, Canada and Europe. We collected data on all consecutive single-organ HT recipients from 2010 to 2020. The primary outcome was early renal dysfunction (ERD), defined as a composite of need for RRT or creatinine ≥2.5 mg/dL 24 hours after HT. We assessed the incidence of early renal dysfunction and performed univariate and multivariate analyses to identify the recipient and transplant characteristics associated with its development. Results We included 2,764 HT recipients: 282 (10.2%) presented early renal dysfunction and 2482 (89.8%) did not. Recipients who presented postoperative renal dysfunction were more frequently male, Caucasian, with previous sternotomy, higher baseline creatinine, longer ischemic time and worse donor LVEF. They were also more likely to be under RRT, intravenous inotropes or ECMO support and there was more incidence of severe primary graft dysfunction (PGD) (Table 1). Multi-variable logistic regression demonstrated that the strongest predictors for post-transplant renal dysfunction were development of severe PGD (OR 5.26, 2.88–9.62, p Conclusions Early renal dysfunction is a common complication after HT with an incidence around 10% in a large and contemporary cohort. The presence of PGD and need for RRT pre-transplant were the strongest predictors for its development. Interestingly, emergent transplantation or need for MCS were not independently associated with ERD. Further studies are needed to identify patients at high risk of early and late kidney dysfunction that may benefit from combined transplantation. Funding Acknowledgement Type of funding sources: None.

Aims The outcomes of patients presenting with acute myocarditis and life–threatening ventricular arrhythmias (LT–VA) are unclear. The aim of this study was to assess the incidence and predictors of recurrent major arrhythmic events (MAEs) after hospital discharge in this patient population. Methods and Results We retrospectively analysed 156 patients (median age 44 years; 77% male) discharged with a diagnosis of acute myocarditis and LT–VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death or successfully defibrillated ventricular fibrillation, or sustained ventricular tachycardia (sVT) requiring implantable cardioverter–defibrillator therapy or synchronized external cardioversion. Median follow–up was 23months [first to third quartile (Q1–Q3) 7–60]. Fifty–eight (37.2%) patients experienced MAEs after discharge, at a median of 8 months (Q1–Q3 2.5–24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated with MAEs were presentation with sVT [hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.38–6.11]; late gadolinium enhancement involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39–8.53), and absence of positive short–tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40–4.79) at first CMR. Conclusions In this international multicentre study, patients discharged free from HTx or LVAD after an acute myocarditis complicated by LT–VA had a recurrence of MAEs during follow–up of 37.2%, after a median time of 8 months. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmia recurrence.

Background and aims: After heart transplantation, the effects of folate supplementation on total homocysteine plasma levels (THcy) and heart allograft vascular disease (AVD) remain unclear. Methods: Accordingly, we prospectively analyzed 48 heart transplant receipients referred for routine follow-up from July to September 1998 (age 54±11 years, 75% male, 35±27 months from transplant). Among these patients, 17 were treated with folate supplementation for 12 months (Group F), while 31 cross-matched for age, gender, serum creatinine and time from transplant (P>0.3 vs Group F for all) did not assume folate supplementation (Group NF). Routine coronary angiography for AVD detection was routinely obtained in every patient. Results: THcy overall increased during the study period (from 16.6±6.5 to 19.4±7.6 μmol/l, P

Homocysteine represents a risk factor for coronary artery disease determined not only by nutritional habits, but also by the genetic polymorphism of the enzymes involved in its metabolism (i.e. methylenetetrahydrofolate reductase - MTHFR). However, recent prospective studies questioned the initial evidence of a clear epidemiological and pathogenetic link between homocysteine levels and coronary artery disease. Moreover, the relationships between MTHFR polymorphism and coronary artery disease remain unclear. In this paper, the recent literature analyzing the role of homocysteine and MTHFR polymorphism as a risk factor for coronary artery disease has been reviewed.

Hyperhomocysteinemia is a common finding in heart transplant recipients and may represent a risk factor for graft failure. However, the time-course, determinants and effects of medical therapy on total homocysteine plasma levels after heart transplantation remain undetermined. The aim of this study was to prospectively analyze 1) the time-course of total homocysteine in heart transplant recipients; 2) the effects of folate supplements and cyclosporine A on total homocysteine; 3) the relation among renal function, serum vitamin levels, and total homocysteine.Fifty-two heart transplant recipients consecutively evaluated for routine follow-up during 1998 were included in the study (mean age 54 +/- 12 years; 28% female). Among the 52 patients, 10 patients were treated with folate for the entire period of the study (Group F), while 26 patients never received folate (Group NF). The remaining 16 patients who did not take folate on a regular basis were excluded from subgroup analysis. Total homocysteine and creatinine plasma levels were assayed at entry into the study (time 0) and at the end of the study, 12 months later (time 12).Homocysteinemia increased significantly from time 0 to time 12 (p0.001), regardless of creatinine plasma levels (p = 0.03) and folate intake (p0.01). However, total homocysteine levels were lower in Group F compared to Group NF at time 0 and time 12 (p0.02). On multivariate analysis, time of follow-up, serum creatinine and lack of folate intake were positive independent predictors of total homocysteine.Homocysteinemia increased over time in heart transplant recipients, regardless of renal function and folate administration. Lower total homocysteine levels were associated with folate intake, suggesting that folate supplements may play a role in the prevention of vascular allograft disease.

The PTHrP/PTH1R signalling system induces calciotropic and myorelaxant effects on the vascular system and plays critical roles in the development of the cardiovascular system. In animal models, PTHrP exerts important effects on heart rate and contractility, particularly under ischemic conditions, while, in human hearts, the expression of PTHrP by cardiomyocytes remains to be defined in both normal and ischemic conditions. The present study has been conducted on 101 autoptical cases and confirmed on nine explanted hearts in order to analyze the expression of the PTHrP/PTH1R system by ventricular myocardium in respect to morphological aspects of the myocardial ischemic damage, myofiber hypertrophy and disarray, coronarosclerosis, age and sex. Immunohistochemistry showed positive cytoplasmic immunostaining for both PTHrP and PTH1R in ventricular cardiomyocytes. The expression levels of the PTHrP/PTH1R system resulted significantly increased (P = 0.0008 and P < 0.0001, respectively) in association with the myocardial ischemic damage and the presence of cardiomyocyte hypertrophy (P = 0.02 and P = 0.009 respectively). Conversely, increased expression levels of PTHrP alone were observed in myofiber disarray (P = 0.04), whereas PTH1R was augmented in coronarosclerosis (P = 0.004) and age (P = 0.001). Taken together, these results demonstrate that human ventricular cardiomyocytes express PTHrP and PTH1R and suggest that the activation of the PTHrP/PTH1R system could represent an aspect of the embryonic gene program typically reactivated by the myocardium when subjected to ischemia and/or hypertrophy.

Cardiac allograft vasculopathy (CAV) is the major cause limiting long term graft survival after heart transplantation (HT), and is characterized by changes in coronary artery geometry, such as intimal thickening and vessel remodeling. Given the limited strategies available to reduce its impact on outcome, early diagnosis of CAV - for which intravascular ultrasound (IVUS) is the gold standard - is crucial to appropriately modulate therapy and to reduce contributing risk factors. However, a highly reproducible image-analysis method is required to capture the complex mechanisms beyond CAV - related changes in coronary geometry.

Substance abuse cessation is one of the leading factors in determining the eligibility for the heart transplantation waiting list, as noncompliance with this issue may seriously endanger posttransplantation outcomes. Yet, the prevalence of substance-related disorders among candidates for heart transplantation has not been evaluated enough. Eighty three heart transplantation candidates were assessed for prior or current substance-related disorders through the Structured Clinical Interview for mental disorders according to DSM-IV. A prior history of at least one substance-related disorder was found in 64% of patients, with nicotine dependence as the most prevalent diagnosis (61.4% of the sample). Ten subjects were currently smokers, despite heart failure. A prior history of alcohol abuse and caffeine intoxication was found in 9.6% and 2.4% of patients, respectively. Substance abuse or dependence behaviors should be monitored during all the phases of heart transplantation program. Early identification of current substance-related disorders may allow better allocation of organ resources and proper lifestyle modification programs provision. A prior history of substance-related disorders should alert physicians to assess patients for possible relapse, especially after transplantation. The inclusion of a specialist in the assessment and treatment of substance-related disorders in the heart transplantation unit may reduce the risk of unsuccessful outcomes due to noncompliance with an adequate lifestyle.

Purpose Intravascular ultrasound (IVUS) provides unique prognostic information on allograft vasculopathy progression by detecting increase in maximal intimal thickness (MIT) during the first post-heart transplant (HT) year. Later changes in coronary morphology, their prognostic relevance, and risk factors are however unexplored. Methods and Materials We investigated whether changes in coronary morphology assessed in patients receiving serial IVUS at 1 and 5 years after HT predicted fatal and non-fatal cardiovascular (CV) events. We additionally analyzed the impact of metabolic risk factors on changes in IVUS measurements. Results 107 consecutive patients receiving HT between 1999 and 2007 entered the study. During the 11 years of follow-up, incidence of CV death was 8±3% and of CV events was 26±6%. Between year 1 and 5, MIT and intimal volume increased, lumen volume decreased (P Figure ). Among the metabolic parameters, increasing triglycerides and HDL-cholesterol ≤65mg/dl predicted MIT increase ≥ 0.35 mm (P≤0.05). Conclusions This study provides the first suggestive evidence that MIT increase represent a relevant prognostic marker also after the first year after HT. In addition, the finding that clinically relevant MIT is predicted by lipid pattern typical of insulin resistance, provide a strong rationale supporting aggressive therapeutic interventions against metabolic abnormalities mid and long-term after HT.

Purpose Antibody mediated rejection (AMR) is a serious emerging issue in the management of heart transplant (HT) recipients. Although consensus criteria currently define pathological diagnosis of AMR (pAMR), the clinical drawbacks of the pAMR criteria in term of graft function and prognosis, as well as pAMR relationship with donor specific antibodies, (DSA) are unexplored. Methods and Materials In this study we analyze the correlation between pAMR grading, hemodynamic features, DSA detection, and subsequent prognosis in a cohort of consecutive HT recipients with suspected AMR. Results We included 184 patients, with estimated 7-year graft survival of 84±4%, after biopsy. Luminex assay was available in 86 patients, of whom 24 (28%) positive for DSA. pAMR was diagnosed in 72 (39%) recipients (61, pAMR1 and 11 pAMR2). Capillary wedge pressure was higher in patients with pAMR≥1 than in those with pAMR 0 (P=0.03) but we found no difference in hemodynamic data between pAMR 1 and 2. Patients with DSA had a lower cardiac output (P=0.02). However, DSA did not correlate with pAMR grading, but were more often detected in patients with mixed rejection (cellular and AMR), than in those with pAMR alone (P=0.03). Significant angiographic vasculopathy (CAV) accounted for 30% of total deaths, regardless of any rejection grade, and was associated with 12% yearly mortality. pAMR grading per se, on the other hand, was not associated with graft survival, while mixed rejection accounted for a 3.6 times increased risk of graft-related death, in patients without CAV (P=0.04). Conclusions While showing that pathological signs of AMR were associated with a worse hemodynamic profile, with however no differences between pAMR 1 and 2 grades, this study provide suggestive evidence that DSA co-activate both cellular and antibody-mediated graft injury, and that mixed rejection, not AMR alone, drives poor outcome. These data shed new light on the clinical significance of pAMR grading, and brings attention to the adverse consequences of mixed rejection, as opposed to “pure” AMR.

Purpose The RotaFlow (Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany) and Levitronix CentriMag (Levitronix LCC, Waltham, MA) as central or peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) support systems have been investigated as treatment for patients with refractory cardiogenic shock (CS). Methods and Materials Between January 2007 and October 2012, 228 consecutive adult patients were supported on RotaFlow (n=213) or CentriMag (n=15) ECMO, at our institutions (155 men; age 58.3±10.5 years, range: 19-84 years). Indications for support were: failure to wean from cardiopulmonary bypass in the setting of postcardiotomy (n=118) and primary donor graft failure (n=37); post-acute myocardial infarction CS (n=27); acute myocarditis (n=6); and CS on chronic heart failure (n=40). Results A central ECMO setting was established in 102 (44.7%) patients while peripherally in 126 (55.2%). Overall mean support time was 10.9±9.7 days (range: 1-34 days). Eighty-four (36.8%) patients died on ECMO. Overall success rate, in terms of survival on ECMO (n=144), weaning from mechanical support (n=107; 46.9%), bridge to long-term ventricular assist device (n=6; 2.6%) and bridge to heart transplantation (n=31; 13.5%), was 63.1%. Hundred-twenty-two (53.5%) patients were successfully discharged. Stepwise logistic regression identified blood lactate level and CK-MB relative index at 72 h after ECMO initiation, and number of PRBCs transfused on ECMO as significant predictors of mortality on ECMO [p=0.010, odds ratio (OR)=2.94; 95% confidence interval (CI)=1.10–3.14; p=0.010, OR=2.82, 95% CI=1.014 - 3.72; and p=0.011, OR=2.69; 95% CI=1.06–4.16; respectively]. No significant differences were seen by comparing RotaFlow and CentriMag populations in terms of device performance. Conclusions Patients with a poor hemodynamic status may benefit by rapid central and peripheral insertion of ECMO. The blood lactate level, CK-MB relative index and PRBCs transfused should be strictly monitored during ECMO support.