Transitioning to Palliative Care in an Italian Cardiac Intensive Care Unit Network.

BACKGROUND: Recent data indicate that end-of-life management for patients affected by acute decompensated heart failure in cardiac intensive care units is aggressive, with late or no engagement of palliative care teams. OBJECTIVE: To assess current palliative care and end-of-life practices in a contemporary Italian multicenter registry of patients with cardiogenic shock due to acute decompensated heart failure. METHODS: A survey-based approach was used to collect data on palliative care and end-of-life management practices. The AltShock-2 registry enrolled patients with cardiogenic shock from 12 participating centers. A subset of 153 patients with cardiogenic shock due to acute decompensated heart failure enrolled between March 2020 and March 2023 was analyzed, with a focus on early engagement of palliative care teams and deactivation of implantable cardioverter-defibrillators (ICDs). RESULTS: "Do not resuscitate" orders were documented in patient records in only 5 of 12 centers (42%). Palliative care teams were engaged for 21 of 153 enrolled patients (13.7%). Among the 51 patients with ICDs, 6 of 17 patients who died (35%) had defibrillator deactivation. Of the 17 patients who died, 13 died in the hospital and 4 died within 6 months after discharge; 1 patient had ICD deactivation supported by palliative care services at home. CONCLUSIONS: Therapy-limiting practices, including ICD deactivation, are not routine in the Italian centers participating in this study. The results emphasize the importance of integrating palliative care as a simultaneous process with intensive care to address the unmet needs of these patients and their families.

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083).

[Ten questions on cardiac magnetic resonance in patients with heart failure: from etiological diagnosis to prognostic stratification]. / Dieci quesiti in tema di risonanza magnetica cardiaca nel paziente con scompenso cardiaco: dalla diagnosi eziologica alla stratificazione prognostica.

Cardiac magnetic resonance (CMR) imaging has progressively become part of the imaging methods recommended in patients with heart failure. CMR represents the gold standard for assessing volumes, function, biventricular kinetics and providing tissue characterization through scans with and without contrast medium. In patients with heart failure with reduced ejection fraction (HFrEF) and ischemic dilated cardiomyopathy, CMR allows to search for viability, accurately estimate volumes and ejection fraction. It can assess scar extent for predicting response to cardiac resynchronization therapy and for establishing an indication for implanting a defibrillator in borderline cases. In patients with HFrEF and non-ischemic dilated cardiomyopathy, CMR helps to identify specific etiological subgroups and to estimate the arrhythmic risk beyond ejection fraction. In patients with heart failure with preserved ejection fraction, CMR offers the possibility of diagnosing specific phenotypes, including sarcomeric hypertrophic cardiomyopathy, amyloidosis or Fabry disease, and adds prognostic information. Both clinical and scientific interest in this imaging method is constantly expanding; the clinicians dealing with heart failure cannot fail to know the technique, the indications and all the potential that CMR can offer.

Temporal trends in characteristics, treatment, and outcomes of heart failure in octogenarians over two decades.

INTRODUCTION AND OBJECTIVES: Octogenarians represent the most rapidly expanding population segment in Europe. The prevalence of heart failure (HF) in this group exceeds 10%. We assessed changes in clinical characteristics, therapy, and 1-year outcomes over 2 decades in chronic HF outpatients aged ≥ 80 years enrolled in a nationwide cardiology registry. METHODS: We included 2520 octogenarians with baseline echocardiographic ejection fraction measurements and available 1-year follow-up, who were recruited at 138 HF outpatient clinics (21% of national hospitals with cardiology units), across 3 enrolment periods (1999-2005, 2006-2011, 2012-2018). RESULTS: At recruitment, over the 3 study periods, there was an increase in age, body mass index, ejection fraction, the prevalence of obesity, diabetes, dyslipidemia, pre-existing hypertension, and atrial fibrillation history. The proportion of patients with preserved ejection fraction rose from 19.4% to 32.7% (P for trend <.0001). Markers of advanced disease became less prevalent. Prescription of beta-blockers and mineralocorticoid receptor antagonists increased over time. During the 1-year follow-up, 308 patients died (12.2%) and 360 (14.3%) were admitted for cardiovascular causes; overall, 591 (23.5%) met the combined primary endpoint of all-cause mortality or cardiovascular hospitalization. On adjusted multivariable analysis, enrolment in 2006 to 2011 (HR, 0.70; 95%CI, 0.55-0.90; P=.004) and 2012 to 2018 (HR, 0.61; 95%CI, 0.47-0.79; P=.0002) carried a lower risk of the primary outcome than recruitment in 1999 to 2005. CONCLUSIONS: Among octogenarians, over 2 decades, risk factor prevalence increased, management strategies improved, and survival remained stable, but the proportion hospitalized for cardiovascular causes declined. Despite increasing clinical complexity, in cardiology settings the burden of hospitalizations in the oldest old with chronic HF is declining.

[ANMCO Position paper: Care pathway for advanced heart failure patients candidate for heart transplantation/ventricular assist device]. / Position paper ANMCO: Percorso assistenziale del paziente con insufficienza cardiaca avanzata candidabile a trapianto/assistenza ventricolare meccanica.

Heart failure is a complex clinical syndrome with a severe prognosis, despite therapeutic progress. The management of the advanced stages of the syndrome is particularly complex in patients who are referred to palliative care as well as in those who are candidates for cardiac replacement therapy. For the latter group, a prompt recognition of the transition to the advanced stage as well as an early referral to the centers for cardiac replacement therapy are essential elements to ensure that patients follow the most appropriate diagnostic-therapeutic pathway. The aim of this document is to focus on the main diagnostic and therapeutic aspects related to the advanced stages of heart failure and, in particular, on the management of patients who are candidates for cardiac replacement therapy.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Prevalence Of familial hypercholeSTerolaemia (FH) in Italian Patients with coronary artERy disease: The POSTER study.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a powerful risk factor for cardiovascular (CV) events. High levels of low-density lipoprotein cholesterol (LDL-C) since birth are linked to the early onset of atherosclerotic disease. A genetic mutation determining FH is present in about one subject out of 250; FH should be more represented among subjects with a documented diagnosis of coronary artery disease (CAD). The POSTER Study evaluated the prevalence of FH in Italian patients with a recent CAD event. METHODS: Eighty-two cardiology centres enrolled patients with a documented CAD event; CV risk profile, drug therapy and biochemical parameters were collected. Dutch Lipid Clinic Network (DLCN) criteria were used to define patients with a potential FH diagnosis (score ≥6); these patients underwent molecular testing for genetic diagnosis of FH. RESULTS: Overall, 5415 patients were enrolled and the main index events were myocardial infarction with ST-elevation, non ST-elevation acute coronary syndrome (ACS), or a recent coronary revascularization (34.8%, 37.2%, and 28% respectively). Mean age was 66 ± 11 years, men were 78%; about 40% were already treated with statins, proportion that increased after the acute event (96.5%). Based on the DLCN score, the prevalence of potential FH was 5.1%, 0.9% of them had a diagnosis of definite FH (score >8). These patients were younger than patients with a score <6 (56 ± 10 vs 66 ± 11, p < 0.001), and LDL-C levels were in most of them (~87%) >190 mg/dL. FH was genetically confirmed in 42 subjects (15.9%); genetic diagnosis was defined as not conclusive for FH in 63 patients (23.9%). Finally, in 159 subjects (60.2%) no pathogenic mutations in the tested genes were identified, defining them as negative for monogenic familial hypercholesterolemia. CONCLUSIONS: Results underscore a relatively high prevalence of potential FH in patients with a recent CAD event. Therefore, an early identification of these subjects may help improve the management of their high CV risk and, by cascade screening, identify possible FH relatives.

Renal effects of Sacubitril/Valsartan in heart failure with reduced ejection fraction: a real life 1-year follow-up study.

Real-life data confirming the favourable renal outcome in patients with heart failure (HF) treated with Sacubitril/Valsartan, previously found in several trials (RCTs), are still scant. We evaluated the renal effects of Sacubitril/Valsartan in a real-life sample of HF patients. Observational analysis of 54 consecutive outpatients affected by HF with reduced ejection fraction (HFrEF) and clinical indication for Sacubitril/Valsartan. Patients were evaluated at baseline (T0) and after six (T6) and twelve (T12) months after initiating Sacubitril/Valsartan and compared with a group of 30 historical controls. Mean age: 65.5 ± 11.7 years. Older patients: 29 (53.7%). Mean baseline estimated glomerular filtration rate (eGFR): 59.4 ± 19.2 ml/min/1.73 m2. Patients with chronic kidney disease (CKD), defined by an eGFR < 60 ml/min/1.73 m2, were 29 (53.7%). Sacubitril/Valsartan was less titrated in both older patients and patients with CKD. There were no changes in diuretics during follow-up. Systolic blood pressure (BP) decreased during follow-up (p = 0.014), while left ventricular ejection fraction (LVEF) slighly increased (p < 0.001). Renal function improved after 12 months compared to historical controls (p for interaction < 0.001) and a greater benefit was found in subjects aged < 65 years (p for interaction = 0.002) and patients with CKD (p for interaction = 0.009). A statistically (p = 0.009), but not clinically significant increase in serum potassium was also found, regardless of age and CKD. This is the first study focused on the renal effects of Sacubitril/Valsartan in HFrEF patients followed for 12 months in a real-life clinical context. The improved eGFR, despite lower BP, represents an important confirmation outside the peculiar world of RCTs.

[Primary cardiac lymphoma in an immunocompetent young adult: outcome with chemotherapy]. / Linfoma primitivo cardiaco in un giovane adulto immunocompetente: outcome positivo a medio termine con trattamento chemioterapico.

Primitive cardiac lymphoma (PCL) is a rare disease accounting for only 1-2% of primary cardiac tumors. Diffuse large B cell lymphoma is the most common type and shows a rapid progression with poor prognosis. The clinical presentation of PCL is nonspecific, and echocardiographic study is essential to the initial work-up. Magnetic resonance imaging and computed tomography scan are the methods of choice for the assessment of tumor extension. The definitive diagnosis is histopathology examination. Chemotherapy and radiotherapy represent the best treatment and should be started promptly after PCL diagnosis. We here report a case of PCL in a 59-year-old man complicated by pulmonary microembolism, atrial fibrillation and signs of right outflow tract obstruction.

Safety and efficacy of non-continuous echocardiography-guided pericardiocentesis: a single-center study of 478 patients.

BACKGROUND: There are limited contemporary data on the safety and efficacy of echocardiography-guided pericardiocentesis in Italy. The aim of the study was to evaluate safety and efficacy of pericardiocentesis, performed with non-continuous echocardiography monitoring. All the procedures performed at Department of Cardiovascular Disease, Ospedali Riuniti Ancona, from January 2001 to June 2013, were retrospectively analyzed to determine risks connected to the procedure and its success rate. Epidemiological data, procedure indications and etiology of the effusions were also recorded. METHODS: In the study period, 478 pericardiocentesis were performed for cardiac tamponade (N.=161), to remove large amount of fluid (N.=215) or for diagnostic purposes (N.=102). Echocardiographic evaluation, performed just before the procedure, was used to define the site of entry, to measure the distance from the skin to the fluid, and to establish how to direct the needle. RESULTS: We observed an extremely low rate of complications (<1%), without any death. The procedure was fully successful in 98% of cases and achieved only partial fluid removal in the remained 10 patients. The etiology of the effusion was malignancy or post cardiothoracic surgery in almost 60% of cases. Over the years there was an increase of pericardiocentesis performed after a cardiothoracic surgery (P=0.002); There was a significant reduction of the average amount of drained fluid in the years 2010-2013 vs. the period 2001-2009. CONCLUSIONS: Echocardiography-guided pericardiocentesis is an effective and safe procedure, with a low rate of complications.

Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease.

BACKGROUND & AIMS: Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been described, of which A 2A potentially inhibits inflammation. The aim of this study was to investigate the role of A 2A in mucosal inflammation by administering a selective A 2A agonist (ATL-146e) to experimental models of inflammatory bowel disease. METHODS: The anti-inflammatory effects of ATL-146e were studied in the acute and chronic rabbit formalin-immune complex models of colitis and the SAMP1/YitFc mouse model of spontaneous ileitis. RESULTS: ATL-146e significantly reduced the acute inflammatory index and tissue necrosis compared with vehicle ( P < .01) in the acute model of rabbit immune colitis. In the chronic rabbit immune colitis model, ATL-146e significantly suppressed inflammatory cell infiltration into the colonic mucosa ( P < .05) and prevented mortality. The administration of ATL-146e significantly decreased the chronic inflammatory index ( P < .01) and villus distortion index ( P < .01) in the ileum of SAMP1/YitFc mice, and ameliorated adoptively transferred ileitis in severe combined immunodeficient mice injected with CD4 + T cells from SAMP1/Yit mice ( P < .05). Tumor necrosis factor, interferon gamma, and interleukin 4 concentrations were significantly suppressed by ATL-146e treatment in supernatants from cultures of mesenteric lymph node cells of SAMP1/YitFc mice ( P < .05 vs vehicle-treated mice). CONCLUSIONS: A 2A adenosine receptor activation by ATL-146e significantly reduced inflammation in the intestinal mucosa. This effect was associated with decreased leukocyte infiltration and inhibition of proinflammatory cytokines. Activation of A 2A by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.

Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation.

BACKGROUND & AIMS: Strict T H 1 polarization is believed to underlie the pathogenesis of intestinal inflammation in Crohn's disease. In the present study we tested the hypothesis that TH2 cytokines also may participate in disease development in SAMP1/YitFc mice that spontaneously develop terminal ileitis with perianal manifestations. METHODS: Cytokine messenger RNA (mRNA) expression was studied by real-time polymerase chain reaction (PCR). Lamina propria mononuclear cells (LPMCs) were purified and stimulated cytokine secretion was analyzed. Blockade of interferon (IFN)-gamma or interleukin (IL)-4 was performed by using specific neutralizing monoclonal antibodies (MAbs). CD4+/IL-4-secreting lymphocytes were purified from SAMP1/YitFc mesenteric lymph nodes (MLNs) and their ability to induce ileitis was tested after transfer to SCID recipients. RESULTS: Initiation of ileitis in SAMP1/YitFc mice was T H 1-mediated because up-regulation of IFN-gamma and tumor necrosis factor (TNF) preceded the histologic injury, whereas IFN-gamma neutralization prevented the development of chronic inflammation (P <.005) by interfering with the expansion of lymphocytes. In contrast, the establishment of chronic ileitis coincided with significant increases in IL-5 (35x) and IL-13 (29x) mRNA expression (P <.005), as well as in T H 2 cytokine secretion by lamina propria lymphocytes (P <.05 vs. AKR controls). IL-4 blockade diminished IFN-gamma mRNA expression and significantly ameliorated the severity of established ileitis (P <.05) by decreasing the histologic indices for villous distortion and active inflammation. In addition, IL-4 augmented the in vitro IFN-gamma secretion by lymphocytes, whereas IL-4-secreting CD4+ lymphocytes were sufficient for adoptively transferring ileitis to SCID recipients. CONCLUSIONS: Our results indicate that both TH1 and TH2 pathways mediate Crohn's-like ileitis and suggest that combined TH1/TH2 manipulation may offer a therapeutic advantage for the treatment of Crohn's disease.

Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease.

TL1A is a novel TNF-like factor that acts as a costimulator of IFN-gamma secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn's disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4(+) and CD8(+) lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-gamma production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.

TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis.

Tumor necrosis factor alpha (TNF-alpha) is an important mediator of programmed cell death, and TNF-alpha blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-alpha therapy in CD remains poorly understood. SAMP1/YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-alpha therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-alpha antibodies in human CD, a single injection of a chimeric anti-murine TNF-alpha antibody into SAMP1/YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-alpha-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-alpha reduced membrane bound FAS/CD95 expression in IEC from SAMP1/YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-alpha therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.

Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn's disease.

Resident intestinal bacteria likely play an important role in the pathogenesis of Crohn's disease through their interaction with the gut immune system. SAMP1/YitFc mice spontaneously develop chronic, discontinuous, transmural ileitis with many features similar to Crohn's disease. The aim of this study was to determine the effects and elucidate the mechanisms of action of antibiotic treatment in the SAMP1/YitFc mouse model of ileitis. Mice were treated orally with ciprofloxacin and metronidazole before the development of ileitis (prevention protocol) or after ileitis was fully established (treatment protocol). Terminal ilea were harvested for histological scoring, and lamina propria and mesenteric lymph node cells were isolated for analysis of activation markers and cytokine production. Antibiotic therapy significantly decreased the severity of ileitis both in the prevention (40% reduction, p < 0.05) and the treatment (25% reduction, p < 0.01) protocols, compared with untreated, control mice. These effects were associated with a decreased percentage of CD4(+)/CD45RB(high) lymphocytes in mesenteric lymph nodes of antibiotic-treated mice, as well as decreased production of IFN-gamma (prevention: 0.53 +/- 0.21 vs 1.84 +/- 0.04 ng/ml, p < 0.05; treatment: 8.4 +/- 0.4 vs 12.4 +/- 0.7 ng/ml, p < 0.005) and TNF (prevention: 61.5 +/- 13 vs 134 +/- 19 pg/ml, p < 0.01; treatment: 333.5 +/- 11 vs 496 +/- 20 pg/ml, p < 0.001). The number of activated lamina propria lymphocytes was also reduced after antibiotic treatment. In conclusion, antibiotic therapy significantly ameliorates the severity of ileitis in SAMP1/YitFc mice by a mechanism involving down-regulation of activated gut lymphocytes and inhibition of intestinal Th1 cytokine production.