Real-world data of patients affected by advanced heart failure treated with implantable cardioverter defibrillator and left ventricular assist device: Results of a multicenter observational study.

BACKGROUND: Left ventricular assist device (L-VAD) implantation is increasingly used in patients with heart failure (HF) and most patients also have an implantable cardioverter defibrillator (ICD). Limited data are available on the incidence of ICD therapies and complications in this special setting. The aim of this study was to analyze the real-world incidence and predictors of ICD therapies, complications and interactions between ICD and L-VAD. METHODS: We conducted a multicenter retrospective observational study in patients with advanced HF implanted with ICD and a continuous-flow L-VAD, followed-up in five advanced HF centers in Northern Italy. RESULTS: A total of 234 patients (89.7% male, median age 59, 48.3% with ischemic etiology) were enrolled. After a median follow-up of 21 months, 66 patients (28.2%) experienced an appropriate ICD therapy, 22 patients (9.4%) an inappropriate ICD therapy, and 17 patients (7.3%) suffered from an interaction between ICD and L-VAD. The composite outcome of all ICD-related complications was reported in 41 patients (17.5%), and 121 (51.7%) experienced an L-VAD-related complication. At multivariable analysis, an active ventricular tachycardia (VT) zone and a prior ICD generator replacement were independent predictors of ICD therapies and of total ICD-related complications, respectively. CONCLUSIONS: Real-world patients with both L-VAD and ICD experience a high rate of ICD therapies and complications. Our findings suggest the importance of tailoring device programming in order to minimize the incidence of unnecessary ICD therapies, thus sparing the need for ICD generator replacement, a procedure associated to a high risk of complications.

Learning-related feedforward inhibitory connectivity growth required for memory precision.

In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear. Learning of new skills is correlated with formation of new synapses. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes. Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a(-/-) mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as ß-adducin) c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories.

Home-based telesurveillance program in chronic heart failure: effects on clinical status and implications for 1-year prognosis.

BACKGROUND: Studies focusing on the effects of telemanagement programs for chronic heart failure (CHF) on functional status are lacking, and the prognostic value of the clinical response to the programs is unknown. In the Lombardy region of Italy, a home-based telesurveillance program (HTP) including multidisciplinary management and remote telemonitoring for patients with CHF was introduced in 2000 and was formally adopted, as part of the services delivered by the regional healthcare system, in 2006. This article reports the effect of the HTP on the functional status and quality of life and describes the main outcomes observed within 1 year from the end of the program. MATERIALS AND METHODS: Six-month variations of New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), 6-min walking distance (6MWD), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) score were evaluated in 602 CHF patients. Patients showing at least two of the following conditions-NYHA class reduction, increase in LVEF ≥5%, 6MWD >30 m, and a reduction of >24 points of MLHFQ-were defined as "responders." One-year events included unplanned cardiovascular readmissions and mortality. RESULTS: A significant improvement in NYHA class, LVEF, 6MWD, and MLHFQ was observed. Clinical events occurred in 24.1% of non-responders and in 15.9% of responders (p=0.03). An unfavorable response to the program, the presence of an implantable cardioverter defibrillator, and multiple comorbidities were predictors of poor outcome. CONCLUSIONS: The HTP was effective in improving CHF patient functional status, and an unsuccessful response to the intervention seems to be an independent marker of poor prognosis.

Vaccination Recommendations in Solid Organ Transplant Adult Candidates and Recipients.

Prevention of infections is crucial in solid organ transplant (SOT) candidates and recipients. These patients are exposed to an increased infectious risk due to previous organ insufficiency and to pharmacologic immunosuppression. Besides infectious-related morbidity and mortality, this vulnerable group of patients is also exposed to the risk of acute decompensation and organ rejection or failure in the pre- and post-transplant period, respectively, since antimicrobial treatments are less effective than in the immunocompetent patients. Vaccination represents a major preventive measure against specific infectious risks in this population but as responses to vaccines are reduced, especially in the early post-transplant period or after treatment for rejection, an optimal vaccination status should be obtained prior to transplantation whenever possible. This review reports the currently available data on the indications and protocols of vaccination in SOT adult candidates and recipients.

A case series of novel coronavirus infection in heart transplantation from 2 centers in the pandemic area in the North of Italy.

BACKGROUND: Little is known about the coronavirus SARS-CoV-2 disease (COVID-19) in solid organ transplanted patients. We here report a series of heart transplanted patients with COVID-19 from two centers of Italy. METHODS: All heart transplanted patients of Transplant Centers of Bergamo and Torino with a microbiologically confirmed SARS-CoV-2 infection were enrolled. Data collection included clinical presentation, laboratory and radiological findings, treatment and outcome. Follow-up was performed by visit or phone. RESULTS: From February to March 2020 twenty-six heart transplanted patients (age 62±12 years; 77% males; time from transplant 10±10 years; 69% with comorbidities) had a microbiologically confirmed COVID-19. The most frequent symptom was fever, followed by cough. Seventeen patients had a pneumonia, 8 of them severe pneumonia. Seven patients died (27%) and 17 (65%) were hospitalized. Discontinuation of immunosuppression was associated with death (71 vs 21%, p=0.02). Conversely, all patients receiving steroids survived (p<0.001). Patients who received heart transplantation during COVID-19 outbreak survived and no acute graft rejection occurred. Patients who died were older than survivors, had a longer time from transplant and a worse clinical presentation at diagnosis. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. CONCLUSIONS: COVID-19 has a significant impact on long term heart transplanted patients. Conversely, SARS-CoV-2 infection seems to have a limited influence on more recent transplants. Our experience may suggest that heart transplantation programs can be maintained even during the pandemic phase if specific and tailored paths to prevent and to limit virus transmission are provided.

The role of intraoperative transoesophageal echocardiography in the diagnosis and management of a rare multiple fibroelastoma of aortic valve: a case report and review of literature.

Papillary fibroelastoma is the third most common primary tumour of the heart that usually involves the cardiac valves. Multiple papillary fibroelastomas are extremely rare. We report a case with multiple valve papillary fibroelastoma which was identified only by intraoperative transoesophageal echocardiography. The patient complained of atypical chest pains. She was affected by coronary artery disease and had previously had a myocardial infarct. This finding dictated a change in the operative approach. The aortic valve resection was performed in addition to coronary revascularization. If the intraoperative transoesophageal echocardiography was not performed, our patient would have had just coronary artery bypass graft surgery, probably without solving the symptoms. Furthermore, in future she would have undergone another cardiac operation for resection of aortic masses and valve replacement. The intraoperative use of Transoesophageal Echocardiography improves the diagnosis and the management of all cardiac surgical patients.

The unnatural history of failing univentricular hearts: outcomes up to 25 years after heart transplantation.

OBJECTIVES: Heart transplantation (HTx) in children with a univentricular physiology is a challenge. In this study, we aimed to investigate the early and late survival as well as the causes of death of HTx recipients at different stages of univentricular palliation. METHODS: Between January 1987 and September 2015, 40 orthotropic cardiac transplants were performed in 38 children with univentricular hearts at our institution. Outcomes were reviewed using medical records and transplant databases. RESULTS: For the purposes of this analysis, patients were divided into 3 subgroups according to their stage of palliation: Stage 1 (n = 10, 26%), Stage 2 (n = 5, 13%) and Fontan (n = 23, 61%). The median age at HTx was 15.2 years (range 0-38). The median follow-up time after transplantation was 8.7 years (range 0-25.4). Indications for transplant were ventricular dysfunction in 25 (66%) patients, protein losing enteropathy in 10 patients transplanted in Fontan (26%) and refractory arrhythmias in 3 (8%) patients with an atriopulmonary connection. Total mortality was 42% (4.84/100 patient-years), and total early mortality was 21%. Overall survival at 1, 10 and 20 years was 73% (95% confidence interval 56-84%), 58% (95% confidence interval 40-72%) and 49% (95% confidence interval 30-65%), respectively. CONCLUSIONS: HTx is a feasible option for patients with failing univentricular circulation, and although the mortality rate is high, this rate is still comparable to that in patients undergoing HTx for other congenital and non-congenital heart diseases.

Echocardiographic outflow pump ramp test in centrifugal-flow left ventricular assist device.

This study sought to develop a novel echocardiogram outflow ramp test to detect device malfunctions in centrifugal-flow left ventricular assist devices (LVADs). This new ramp pump test is based on the direct analyses of systolic and diastolic ratio (S/D) Doppler velocity in the outflow cannula in the HeartWare LVAD during progressive increases in speed. The results showed that in patients with normal pump function, the Doppler velocity S/D ratio gradually decreased during LVAD speed increases. This test is easily performed and seems promising to detect normal pump function in patients assisted by a centrifugal flow LVAD.

Prognostic impact of late gadolinium enhancement in the risk stratification of heart transplant patients.

AIMS: The aim of the present study was to assess the association of the presence and amount of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) with cardiovascular adverse events in patients with orthotopic heart transplantation (HTx). METHODS AND RESULTS: We enrolled 48 patients (mean age, 54.7 ± 14.6 years; 37 men) at various stages after HTx. All patients underwent standard CMR at 1.5 T, to characterize both cardiac anatomy and LGE. Late gadolinium enhancement was detected in 26 patients (54%). All-cause and cardiovascular mortalities, and a composite of major adverse cardiovascular events (MACE) recurrence were evaluated during the follow-up period for a median of 5.16 years. Ten patients (21%) died and 26 (54%) were readmitted because of MACE. Multivariate Cox analysis identified as independent predictors of MACE a diagnosis of cardiac allograft vasculopathy (CAV) (HR 3.63; 1.5-8.7 95% CI; P = 0.0039), left ventricular end systolic volume index (HR 1.04; 95% CI 1.01-1.079; P = 0.008), LGE mass (HR 1.04; 1.01-1.06 95% CI; P = 0.0007), LGE % of left ventricular mass (HR 1.083; 1.03-1.13 95% CI; P = 0.0002). Independent predictors of all-cause death were CAV (HR 6.33; 95% CI 1.33-30.03; P = 0.0201), LGE mass (HR 1.04; 1.01-1.07 95% CI; P = 0.005), LGE % of left ventricular mass (HR 1.075; 1.02-1.13 95% CI; P = 0.007). Patients with CAV had a risk of MACE by 5 years of 67% (95% CI 0.309-0.851%); the addition of 7.9 LGE % to the risk model increased the predicted risk to 88% (95% CI 0.572-0.967%). CONCLUSIONS: The current study demonstrated that the presence of CAV and the total amount of LGE have a significant independent association with MACE and mortality in HTx patients.

Pathologic correlates of late gadolinium enhancement cardiovascular magnetic resonance in a heart transplant patient.

We report the histopathologic correlates of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) in a patient with heart transplant who died for graft failure a few months after the scan. Extensive late enhancement was present at CMR, and it correlated with extensive fibrosis at histology. To our knowledge, this is the first time the findings on contrast enhancement CMR are compared to the histology of the whole heart in a heart transplantation patient, and the correspondence between LGE and fibrosis, demonstrated in other cardiac pathologies, is confirmed also in this particular setting.

Left ventricular ejection fraction overcrossing 35% after one year of cardiac resynchronization therapy predicts long term survival and freedom from sudden cardiac death: single center observational experience.

BACKGROUND: Reverse remodeling and increased LVEF after CRT correlate with survival and heart failure hospitalizations, but their relationship with the risk of SCD is unclear. We aimed to evaluate whether exceeding a threshold value of 35% for left ventricular ejection fraction (LVEF) 1 year after cardiac resynchronization therapy (CRT) predicts survival and freedom from sudden cardiac death (SCD). METHODS: 330 patients who survived ≥ 6 months after CRT (males 80%, age 62 ± 11 years) were grouped according to 1-year LVEF ≤ 35% (Group 1, n=187, 57%) or >35% (Group 2, n=143, 43%). According to changes vs. baseline (reduction of left end-systolic volume [LVESV] ≥ 10% or increase of LVEF% > 10 units), patients were also classified as echocardiographic (Echo) non-responders (Group A, n=152, 46%) or responders (Group B, n=178, 54%). RESULTS: At baseline, LVESV volume was larger and LVEF was lower in Group 1 vs. Group 2 (p<0.001). After 1 year, echocardiographic improvement was greater in Group 2 vs. Group 1 (p<0.001 for changes in both LVESV and LVEF). Over a median follow-up of 49 months, 47 patients (14%) died, 36 in Group 1 vs. 11 in Group 2 (19% vs. 8%, p=0.004). A significantly higher rate of freedom from all-cause mortality (p=0.002), cardiovascular mortality (p<0.001) and SCD (p<0.001) was observed in Group 2. Multivariate analysis demonstrated that only 1-year LVEF >35% was associated with freedom from SCD/VF. CONCLUSIONS: LVEF >35% after 1 year of CRT characterizes a favorable long-term outcome, with a very low risk for SCD.

Heart transplantation: 25 years' single-centre experience.

OBJECTIVES: Heart transplantation (HTx) is still one of the most effective therapies for end-stage heart disease for patients with no other medical or surgical therapy. We report the results of our 25-year orthotropic HTx single-centre experience. METHODS: From November 1985, 905 orthotopic heart transplants have been performed at our centre. We exclude from the present analysis 13 patients who underwent re-transplantation and 14 pediatric cases (age at HTx <15 years). RESULTS: The present study collected the data of 878 primary adult orthotopic HTx performed at our centre. Mean age at HTx was of 49.6 ±â€Š11.6 years. Mean donor age was 36.9 ±â€Š14.8 years. Hospital mortality was 11.6% (102 patients), early graft failure was the principal cause of death (58 patients) followed by infections (18 cases) and acute rejection (7 patients). Overall actuarial survival was 78.1% at 5 years and 63.8% and 47.5%, respectively, at 10 and 15 years from HTx. Mean survival was 10.74 years; 257 late deaths were reported (33.1%); main causes were neoplasm in 83 patients, and cardiac causes included coronary allograft vasculopathy in 78 patients. Freedom from any infection at 5, 10 and 15 years was 52.2, 44.1 and 40.1%, respectively. Freedom from rejection at 5 years was 36.2%, with 493 patients experiencing at last one episode of rejection, the majority occurring during the first 2 months after transplantation. The long-term survival of HTx recipients is limited in large part by the development of coronary artery vasculopathy and malignancies. In our experience freedom from coronary allograft vasculopathy at 10 years was 66.9%, and 85 patients underwent percutaneous coronary revascularization. In our study population, 44 patients experienced posttransplant lymphoproliferative disorder and 91 patients experienced a solid neoplasm, mean survival free from neoplasm was 12.23 years. CONCLUSION: Over the past four decades the field of HTx has evolved considerably, with improvements in surgical techniques and postoperative patients' care. A careful patient selection and treatment of candidates for transplantation as well as accurate clinical follow-up combined with real multidisciplinary teamwork that involved different heart failure specialists, allowed us to obtain our excellent long-term results.

Association of pre-operative interleukin-6 levels with Interagency Registry for Mechanically Assisted Circulatory Support profiles and intensive care unit stay in left ventricular assist device patients.

BACKGROUND: Inflammatory mechanisms are associated with worse prognosis in end-stage heart failure (ESHF) patients who require left ventricular assist device (LVAD) support. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles describe patient condition at pre-implant and outcome. This study assessed the relationship among inflammation patterns and INTERMACS profiles in LVAD recipients. METHOD: Thirty ESHF patients undergoing LVAD implantation as bridge to transplant were enrolled. Blood and urine samples were collected pre-operatively and serially up to 2 weeks post-operatively for assessment of inflammatory markers (plasma levels of interleukin [IL]-6, IL-8, IL-10, and osteopontin, a cardiac inflammatory-remodeling marker; and the urine neopterin/creatinine ratio, a monocyte activation marker). Multiorgan function was evaluated by the total sequential organ failure assessment (tSOFA) score. Outcomes of interest were early survival, post-LVAD tSOFA score, and intensive care unit (ICU) length of stay. RESULTS: Fifteen patients had INTERMACS profiles 1 or 2 (Group A), and 15 had profiles 3 or 4 (Group B). At pre-implant, only IL-6 levels and the IL-6/IL-10 ratio were higher in Group A vs B. After LVAD implantation, neopterin/creatinine ratio and IL-8 levels increased more in Group A vs B. Osteopontin levels increased significantly only in Group B. The tSOFA score at 2 weeks post-LVAD and ICU duration were related with pre-implant IL-6 levels. CONCLUSIONS: The INTERMACS profiles reflect the severity of the pre-operative inflammatory activation and the post-implant inflammatory response, affecting post-operative tSOFA score and ICU stay. Therefore, inflammation may contribute to poor outcome in patients with severe INTERMACS profile.

The first Caucasian patient with p.Val122Ile mutated-transthyretin cardiac amyloidosis treated with isolated heart transplantation.

Effective treatments for mutated transthyretin (TTR)-related cardiac amyloidosis are limited. Heart transplantation or combined liver-heart transplantation are the most successful options, although results rely on underline mechanism and systemic nature of the disease. In this report, we present the first case of a Caucasian patient with the p.Val122Ile mutated TTR-related cardiac amyloidosis treated with heart transplantation due to this gene mutation frequent in Afro-Americans with a prevalent isolated heart involvement. The choice of isolated heart transplantation instead of combined heart and liver transplantations was based on (1) severe and progressive cardiac disease, (2) evidence of a gene mutation generally associated with isolated cardiac disease and (3) absence of relevant extra-cardiac involvement (with the possible exception of mild peripheral neuropathy). In any case, the very short post-transplant observation period of 10 months does not allow any conclusions on the long-term course of the presented strategy. Finally, it is the first European Caucasian family with the p.Val122Ile TTR mutation that has been described. Till now, very few Caucasian cases of p.Val122Ile mutated TTR-related cardiac amyloidosis have been reported. The patient and some members of his family also had mild peripheral neuropathy suggesting a regional phenotypic heterogeneity of European Caucasian TTR p.Val122Ile.