Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients. METHODS: Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates. RESULTS: At the time of PJP-related hospitalization, patients' mean age was 49 ± standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases. CONCLUSIONS: We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.

The Exercise aNd hEArt transplant (ENEA) trial - a registry-based randomized controlled trial evaluating the safety and efficacy of cardiac telerehabilitation after heart transplant.

BACKGROUND: Heart transplant (HTx) is gold-standard therapy for patients with end-stage heart failure. Cardiac rehabilitation (CR) is a multidisciplinary intervention shown to improve cardiovascular prognosis and quality of life. The aim in this randomized controlled trial is to explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, biomarkers of rehabilitation outcomes will be identified, as data that will enable treatment to be tailored to patient phenotype. METHODS: Patients after HTx will be recruited at IRCCS S. Maria Nascente - Fondazione Don Gnocchi, Milan, Italy (n = 40). Consenting participants will be randomly allocated to either of two groups (1:1): an intervention group who will receive on-site CR followed by 12 weeks of telerehabilitation, or a control group who will receive on-site CR followed by standard homecare and exercise programme. Recruitment began on 20th May 2023 and is expected to continue until 20th May 2025. Socio-demographic characteristics, lifestyle, health status, cardiovascular events, cognitive function, anxiety and depression symptoms, and quality of life will be assessed, as well as exercise capacity and muscular endurance. Participants will be evaluated before the intervention, post-CR and after 6 months. In addition, analysis of circulating extracellular vesicles using Surface Plasmon Resonance imaging (SPRi), based on a rehabilomic approach, will be applied to both groups pre- and post-CR. CONCLUSION: This study will explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, a rehabilomic approach will be used to investigate biomolecular phenotypization in HTx patients. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT05824364.

Estimation of Right Atrial Pressure by Ultrasound-Assessed Jugular Vein Distensibility in Patients With Heart Failure.

BACKGROUND: Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population. METHODS: We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup. RESULTS: A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64-0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73-0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg; P<0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank P=0.034). CONCLUSIONS: Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03874312.

Immune checkpoint inhibitor-associated myocarditis: from pathophysiology to rechallenge of therapy - a narrative review.

Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.

Intravenous continuous home inotropic therapy in advanced heart failure: Insights from an observational retrospective study.

INTRODUCTION: Intravenous inotropic support represents an important therapeutic option in advanced heart failure (HF) as bridge to heart transplantation, bridge to mechanical circulatory support, bridge to candidacy or as palliative therapy. Nevertheless, evidence regarding risks and benefits of its use is lacking. METHODS: we conducted a retrospective single center study, analysing the effect of inotropic therapies in an outpatient cohort, evaluating the burden of hospitalizations, the improvement in quality of life, the incidence of adverse events and the evolution of organ damage. RESULTS: twenty-seven patients with advanced HF were treated in our Day Hospital service from 2014 to 2021. Nine patients were treated as bridge to heart transplant while eighteen as palliation. Comparing data regarding the year before and after the beginning of inotropic infusion, we observed a reduction of hospitalization (46 vs 25, p<0,001), an improvement of natriuretic peptides, renal and hepatic function since the first month (p<0,001) and a better quality of life in 53% of the population treated. Two hospitalizations for arrhythmias and seven hospitalizations for catheter-related complications were registered. CONCLUSIONS: in a selected population of advanced HF patients, continuous home inotropic infusion were able to reduce hospitalizations, improving end organ damage and quality of life. We provide a practical guidance on starting and maintaining home inotropic infusion while monitoring a challenging group of patients.

Haemodynamic effects of sacubitril/valsartan in advanced heart failure.

AIMS: The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, has been shown to be effective in treatment of patients with heart failure (HF), but limited data are available in patients with advanced disease. This retrospective observational study assessed the effects of ARNI treatment in patients with advanced HF. METHODS AND RESULTS: We reviewed medical records of all advanced HF patients evaluated at our centre for unconventional therapies from September 2016 to January 2019. We studied 44 patients who started ARNI therapy and who had a haemodynamic assessment before beginning ARNI and after 6 ± 2 months. The primary endpoint was variation in pulmonary pressures and filling pressures at 6 months after starting ARNI therapy. Mean patient age was 51.6 ± 7.4 years; 84% were male. At 6 ± 2 months after starting ARNI, there was significant reduction of systolic pulmonary artery pressure [32 mmHg, interquartile range (IQR) 27-45 vs. 25 mmHg, IQR 22.3-36.5; P < 0.0001] and mean pulmonary artery pressure (20 mmHg, IQR 15.3-29.8 vs. 17 mmHg, IQR 13-24.8; P = 0.046). Five of 22 patients (23%) were deferred from the heart transplant list because of improvement, whereas four were listed de novo. After 23 ± 9 months, three patients were treated with a left ventricular assist device implantation, whereas six patients underwent heart transplantation (one in emergency conditions for refractory ventricular tachycardia). CONCLUSIONS: Sacubitril/valsartan is effective in reducing filling pressures and pulmonary pressures in patients with advanced HF. The absence of adverse events during follow-up suggests that sacubitril/valsartan is safe and well-tolerated in this cohort of patients.

Endothelial Dysfunction in Patients with Advanced Heart Failure Treated with Levosimendan Periodic Infusion Compared with Optimal Medical Therapy: A Pilot Study.

Endothelial dysfunction (ED) is frequently found in patients with heart failure (HF). Among several pharmacological agents reported to improve endothelial function, levosimendan seems to be a promising one, even though, to date, only two previously published studies have evaluated its effects on ED in these patients. The aim of our pilot study was to further investigate the role of periodic levosimendan infusion on endothelial function in patients affected by advanced HF. In this cross-sectional study, three different groups were enrolled: 20 patients with advanced HF treated with periodic levosimendan (LEVO), 20 patients with HF on optimal medical therapy (OMT), and 20 healthy subjects (control group). ED was evaluated through flow-mediated dilation (FMD) at the level of the brachial artery. The three groups presented similar ages with significant differences in gender distribution, systolic blood pressure, and chronic kidney disease (eGFR < 30 mL/min). In HF patients, ischaemic aetiology was more prevalent in the LEVO group than in the OMT group (60 vs. 40%, p < 0.001). The New York Heart Association (NYHA) functional class was worse in the LEVO group, as well as in NT-proBNP (5636.7 ± 6164.6 ng/dL and 1243.7 ± 1487.2 ng/dL, in the LEVO and OMT groups, respectively, p = 0.005). The FMD was significantly higher in the healthy control group compared to that of the OMT group (15.7 ± 6.4 vs. 9.1 ± 6.0%, p = 0.007) while it showed an intermediate value in LEVO patients (12.4 ± 7.1%) (ANOVA p = 0.010). In conclusion, levosimendan therapy seems to ameliorate endothelial dysfunction related to heart failure. Longitudinal studies in patients on periodic therapy are needed in order to confirm the long-term effects of levosimendan on ED.

[ANMCO Position paper: Cardiovascular disease in women - prevention, diagnosis, treatment and organization of care]. / Position paper ANMCO: Malattie cardiovascolari nella donna ­ prevenzione, diagnosi, terapia e organizzazione delle cure.

Cardiovascular diseases are still the main cause of death among women despite the improvements in treatment and prognosis achieved in the last 30 years of research. The determinant factors and causes have not been completely identified but the role of "gender" is now recognized. It is well known that women tend to develop cardiovascular disease at an older age than men, and have a high probability of manifesting atypical symptoms not often recognized. Other factors may also co-exist in women, which may favor the onset of specific cardiac diseases such as those with a sex-specific etiology (differential effects of estrogens, pregnancy pathologies, etc.) and those with a different gender expression of specific and prevalent risk factors, inflammatory and autoimmune diseases and cancer. Whether the gender differences observed in cardiovascular outcomes are influenced by real biological differences remains a matter of debate.This ANMCO position paper aims at providing the state of the research on this topic, with particular attention to the diagnostic aspects and to care organization.

Long-term administration of intravenous inotropes in advanced heart failure.

BACKGROUND: Patients in heart transplantation (HTx) waiting list for advanced heart failure (HF) are susceptible to acute deterioration refractory to standard HF medical therapies. Limited data are available on long-term in-hospital continuous intravenous (IV) inotropic therapy as bridge to definite therapies. METHODS AND RESULTS: We reviewed medical records of all heart transplant recipients treated in the pre-HTx phase with in-hospital continuous IV inotropes at our institution between 2012 and 2018. We analysed data before the beginning of continuous IV therapy and at the moment of HTx. We report data of 24 patients (mean age of 43.5 ± 15.7 years) treated with IV inotropes as bridge to HTx (median follow-up of 28 months after HTx). The main length of IV inotropic therapy was 84 ± 66 days (min 22; max 264 days). At the beginning, the most frequently used inotrope was dopamine (median dosage of 3 mcg/kg/min, interquartile range 2.5-3.75), alone (n = 11, 46%) or in combination with other inotropes (n = 13, 54%). In 18 patients, the class of inotropes was changed during the hospitalization. We registered a progressive improvement of perfusion markers and neuro-hormonal activation. CONCLUSION: In-hospital continuous parenteral inotropic therapy may serve as a temporary pharmacological bridge to HTx in patients with advanced HF that are actively listed to HTx with good reply in terms of prognosis and perfusion markers.

COVID-19 in Heart Transplant Recipients: A Multicenter Analysis of the Northern Italian Outbreak.

OBJECTIVES: The aim of this study was to assess the clinical course and outcomes of all heart transplant recipients affected by coronavirus disease-2019 (COVID-19) who were followed at the leading heart transplant centers of Northern Italy. BACKGROUND: The worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Heart transplant patients represent a unique cohort of chronically immunosuppressed subjects in which SARS-CoV-2 may stimulate an unpredictable clinical course of infection. METHODS: Since February 2020, we enrolled all 47 cases (79% male) in a first cohort of patients, with a mean age of 61.8 ± 14.5 years, who tested positive for SARS-CoV-2, out of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at 7 heart transplant centers in Northern Italy. RESULTS: To date, 38 patients required hospitalization while 9 remained self-home quarantined and 14 died. Compared to the general population, prevalence (18 vs. 7 cases per 1,000) and related case fatality rate (29.7% vs. 15.4%) in heart transplant recipients were doubled. Univariable analysis showed older age (p = 0.002), diabetes mellitus (p = 0.040), extracardiac arteriopathy (p = 0.040), previous PCI (p = 0.040), CAV score (p = 0.039), lower GFR (p = 0.004), and higher NYHA functional classes (p = 0.023) were all significantly associated with in-hospital mortality. During the follow-up two patients died and a third patient has prolonged viral-shedding alternating positive and negative swabs. Since July 1st, 2020, we had 6 new patients who tested positive for SARS-CoV-2, 5 patients asymptomatic were self-quarantined, while 1 is still hospitalized for pneumonia. A standard therapy was maintained for all, except for the hospitalized patient. CONCLUSIONS: The prevalence and mortality of SARS-CoV-2 should spur clinicians to immediately refer heart transplant recipients suspected as having SARS-CoV2 infection to centers specializing in the care of this vulnerable population.

A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature.

BACKGROUND: Pregnancy after heart transplantation (HTx) may expose the recipient to hemodynamic and immunologic risks and the newborn to toxic effects of immunosuppressive therapy. Adequate preconception counseling is crucial to identify optimal timing and to modify immunosuppressive therapy to minimize risks for both the mother and the fetus. METHODS: We describe our experience with 12 pregnancies occurred in 11 women who had undergone HTx at our center. RESULTS: Pregnancies ran without severe complications or rejections, and none of the babies have shown major defects at birth. However, as reported in the literature, weight at birth rated in lower range in most of the newborns, probably due to in utero cyclosporine exposure. Up to now, none of the babies showed clinical signs of heart disease, although more than half of the mothers had an inherited or familial cardiomyopathy. CONCLUSIONS: Despite potential mother and fetal complications, successful pregnancy and delivery are possible after HTx, provided that optimum timing, close monitoring, and therapy adjustments are guaranteed. Becoming a mother appears to be an important achievement for young women after HTx, even when there is a risk to transmit an inheritable heart disease.

Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients: Results of the Prospective Randomized Study EVERHEART.

BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization. METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint. RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02). CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.

[Cardiac involvement in Churg-Strauss syndrome]. / Il coinvolgimento cardiaco nella sindrome di Churg-Strauss.

Churg-Strauss syndrome, recently renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a rare form of systemic vasculitis, characterized by disseminated necrotizing vasculitis with extravascular granulomas occurring among patients with asthma and tissue eosinophilia. EGPA is classified as a small and medium-sized vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) and the hypereosinophilic syndrome. Typical clinical features include asthma, sinusitis, transient pulmonary infiltrates and neuropathy. Blood eosinophils are often >1500/µl or more than 10% on the differential leukocyte count. Blood eosinophils should always be tested in unexplained cardiac disorders, and may normalize even after low doses of corticosteroids. ANCA are positive in 40-60% of cases, mainly anti-myeloperoxidase. Heart involvement occurs in approximately 15-60% of EGPA patients, especially those who are ANCA negative. Any cardiac structure can be involved, and patients present with myocarditis, heart failure, pericarditis, arrhythmia, coronary arteritis, valvulopathy, intracavitary cardiac thrombosis. Although cardiovascular involvement is usually an early manifestation, it can also occur later in the course of the disease. A significant proportion of patients with cardiac involvement is asymptomatic. In the absence of symptoms and major ECG abnormalities, cardiac involvement may be detected in nearly 40% of the patients. All patients with EGPA should be studied not only with a detailed history of cardiac symptoms and ECG, but also with echocardiography; if abnormalities are detected, a cardiac magnetic resonance study should be performed. Coronary angiography and endomyocardial biopsy should be reserved to selected cases. Heart involvement carries a poor prognosis and causes 50% of the deaths of these patients. It is often insidious and underestimated. Optimal therapy is therefore important and based on high-dose corticosteroids plus immunosuppressive agents, particularly cyclophosphamide in case of myocardial inflammation. Thus, early diagnosis of cardiac involvement and subsequent therapy may prevent progression of cardiac disease. At present, the role of troponin and brain natriuretic peptide in monitoring and therapy remains unclear. Orthotopic heart transplantation is feasible in case of severe disease, even if the experience is limited in -EGPA, and optimal post-transplantation immunosuppressive strategy has yet to be defined.

Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

BACKGROUND: Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once. METHODS: We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association. RESULTS: Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths. CONCLUSIONS: The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified.

Blood glutathione as a marker of cardiac allograft vasculopathy in heart transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx). Between immunologic and non-immunologic factors, reactive oxygen species generation has been proposed as pathogenetic mechanism. This study was aimed at evaluating redox status in HTx recipients and verifying whether it could be independently associated with CAV. METHODS: Fifty-five consecutive male HTx recipients, median [interquartile range] age 60 yr [50, 64], underwent angiography 67 months [21, 97] after HTx to assess CAV, defined as significant stenosis in >or=1 epicardial vessel or any distal vessel attenuation. All patients underwent blood sampling 89 months [67, 119] after HTx for biochemical (glucose, creatinine, total and LDL cholesterol, and cyclosporin levels) and redox evaluation [plasma reduced and total homocysteine, cysteine, cysteinylglycine, glutathione, blood reduced glutathione (GSH(bl)) and vitamin E]. Univariate Odds Ratios (OR) with 95% confidence interval (95% CI, highest vs. lowest quartile) were estimated on the basis of a logistic regression analysis between clinical, conventional biochemical and redox data. Only the significant variables at univariate entered into multivariate analysis. RESULTS: CAV was documented in 15 (27%) patients. Univariate analysis showed that time from HTx to angiography (OR 3.97, 95% CI 1.15-14, p = 0.03) and GSH(bl) (OR 0.31, 95% CI: 0.14-0.70, p = 0.005) were significantly associated with CAV. However, multivariate analysis revealed GSH(bl) as the only independent predictor of CAV (OR 0.31, 95% CI: 0.13-0.74, p = 0.008). CONCLUSIONS: In HTx recipients reduced levels of GSH(bl) are independently associated with CAV. Given its potent intracellular scavenger properties, GSH(bl) may serve as a marker of antioxidant defence consumption, favouring CAV development.