Prevention and Rehabilitation After Heart Transplantation: A Clinical Consensus Statement of the European Association of Preventive Cardiology, Heart Failure Association of the ESC, and the European Cardio Thoracic Transplant Association, a Section of ESOT.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

Chronic kidney disease and orthostatic hypotension in hospitalised older adults.

PURPOSE: Orthostatic hypotension (OH) may predispose older adults to health complications leading to functional impairment. Despite the central role of the kidney in blood pressure control, the contribution of renal function in orthostatic hypotension is poorly investigated. To verify the association between Chronic Kidney Disease (CKD) and OH a population of hospitalised elderly patients with comorbidities was studied. MATERIALS AND METHODS: 174 patients were consecutively admitted to Acute Geriatric Wards. On admission, patients underwent postural systolic (SBP) and diastolic (DBP) blood pressure evaluation by automatic oscillometric device after 10 min rest in lying position, and in standing position at time 0, 1, 3 and 5 min. CKD was assumed for estimated glomerular filtration rate (e-GFR) less than 60 mL/min/1.73 m2. RESULTS: The mean age of the population enrolled was 74.4 ± 7.0. OH was found in 46.0% and CKD in 56.3% of patients, respectively. A lower e-GFR was observed in patients with (56.1 ± 16.7 mL/min/1.73 m2) than in those without OH (61.1 ± 15.9 mL/min/1.73 m2) (p < 0.05). A greater fall in SBP at 0-min (12.8 ± 6.3 vs. 7.7 ± 3.2 mmHg) and at 1-min (8.4 ± 4.5 vs. 5.7 ± 2.8 mmHg) was found in CKD patients in respect to patients without CKD during active standing test (p < 0.05). Similarly, a DBP reduction at 0-min and at 1-min was observed in CKD patients in respect to patients without CKD (p < 0.05). A multivariate logistic regression analysis showed that CKD was associated to OH (OR 2.426; 95%CI 1.192-4.937; p = 0.014). CONCLUSIONS: CKD is associated to OH in hospitalised older adults.

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry.

BACKGROUND: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. METHODS: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. RESULTS: Compared with EU and IR, T2D was associated with increased filling pressures (E/e'ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, - 21% decline in TAPSE/PAPS ratio and - 20% decrease in peak VO2). CONCLUSION: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017.

Role of frailty on cardiac rehabilitation in hospitalized older patients.

BACKGROUND: Cardiovascular diseases are the leading cause of mortality, morbidity, and disability in the world, especially in the older adults. A relevant proportion of patients admitted to Cardiac Rehabilitation (CR) may suffer from frailty, a complex geriatric syndrome with multifactorial aetiology. AIMS: The hypothesis underlying the study is that frailty complicates the management of older patients undergoing CR. The main objective is, therefore, to determine the relationship between frailty and CR outcomes in hospitalized older adults. METHODS: The participants have been recruited among patients aged ≥ 65 years admitted at the hospital for CR. A Comprehensive Geriatric Assessment (CGA)-based Frailty Index (FI) was created following a standard procedure. The outcome was measured as the ratio between 6-min walk test (6MWT) distance at the end of CR and normal predicted values for a healthy adult of same age and gender, according to reference equations. RESULTS: The study population consisted of 559 elderly patients, 387 males (69.2%), with age of 72 (69-76) years. The most frequent diagnosis at admission was ischaemic heart disease (231, 41.5%) and overall 6MWT ratio was 0.62 ± 0.21. At the multivariable regression analysis, gender, diagnosis and FI were significantly and independently associated with 6MWT ratio (p ≤ 0.0001, p ≤ 0.001 and p ≤ 0.0001, respectively), while no significant association emerged for age. CONCLUSION: FI resulted independently correlated to 6MWT ratio in a population of older patients undergoing in-hospital CR programs. Frailty is a multifactorial geriatric syndrome whose assessment is essential for prognostic evaluation of older patients, also in CR clinical setting.

Reliability of fr-AGILE tool to evaluate multidimensional frailty in hospital settings for older adults with COVID-19.

AIMS: The study assesses the reliability of fr-AGILE, a validated rapid tool used for the evaluation of multidimensional frailty in older adults hospitalized with COVID-19. METHODS: Two different staff members independently assessed the presence of frailty in 144 patients aged ≥ 65 years affected by COVID-19 using the fr-AGILE tool. The internal consistency of fr-AGILE was evaluated by examining the item-total correlations and the Kuder-Richardson (KR) formula. The inter-rater reliability was evaluated using linear weighted kappa. RESULTS: Multidimensional frailty severity increases with age and is associated to higher use of non-invasive ventilation (p = 0.025), total severity score on chest tomography (p = 0.001) and in-hospital mortality (p = 0.032). Fr-AGILE showed good internal consistency (KR-20 = 0.742) and excellent inter-rater reliability (weighted kappa = 0.752 and 0.878 for frailty score and frailty degree, respectively). CONCLUSIONS: fr-AGILE tool can quickly identify and quantify multidimensional frailty in hospital settings for older patient affected by COVID-19.

Flow Cytometry Characterization of Pluripotent Transmembrane Glycoproteins on Resident Cervix Uteri Cells in Patients Screened for Cervical Cancer.

The aim of this study was to characterize both by flow cytometry analysis and immunohistochemistry cervix uteri cells of nulliparous women screened for cervical intraepithelial neoplasia (CIN) in comparison to a group without CIN by using mesenchymal stem cell-like and hematopoietic lineage markers. A significant expression for CD29, CD38, HLA-I, and HLA-II was correlated positively to the CIN degree and it was more relevant in patients positive for human papilloma virus (HPV). Thus, identification and detailed characterization of pluripotent resident in uteri cells could be a promising therapeutic target.

Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study.

BACKGROUND AND AIMS: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. METHODS AND RESULTS: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6-14.7 for age ≥85 vs 18-44 y); HR = 4.7; 2.9-7.7 for estimated glomerular filtration rate levels <15 vs ≥ 90 mL/min/1.73 m2; HR = 2.3; 1.5-3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses. CONCLUSIONS: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy.

Validation of "(fr)AGILE": a quick tool to identify multidimensional frailty in the elderly.

BACKGROUND: Several tools have been proposed and validated to operationally define frailty. Recently, the Italian Frailty index (IFi), an Italian modified version of Frailty index, has been validated but its use in clinical practice is limited by long time of administration. Therefore, the aim of this study was to create and validate a quick version of the IFi (AGILE). METHODS: Validation study was performed by administering IFi and AGILE, after a Comprehensive Geriatric Assessment (CGA) in 401 subjects aged 65 or over (77 ± 7 years). AGILE was a 10-items tool created starting from the more predictive items of the four domains of frailty investigated by IFi (mental, physical, socioeconomic and nutritional). AGILE scores were stratified in light, moderate and severe frailty. At 24 months of follow-up, death, disability (taking into account an increase in ADL lost ≥1 from the baseline) and hospitalization were considered. Area under curve (AUC) was evaluated for both IFi and AGILE. RESULTS: Administration time was 9.5 ± 3.8 min for IFi administered after a CGA, and 2.4 ± 1.2 min for AGILE, regardless of CGA (p < 0.001). With increasing degree of frailty, prevalence of mortality increased progressively from 6.5 to 41.8% and from 9.0 to 33.3%, disability from 16.1 to 64.2% and from 22.1 to 59.8% and hospitalization from 17.2 to 58.7% and from 27.0 to 52.2% with AGILE and IFi, respectively (p = NS). Relative Risk for each unit of increase in AGILE was 56, 44 and 24% for mortality, disability and hospitalization, respectively and was lower for IFi (8, 7 and 4% for mortality, disability and hospitalization, respectively). The AUC was higher in AGILE vs. IFi for mortality (0.729 vs. 0.698), disability (0.715 vs. 0.682) and hospitalization (0.645 vs. 0.630). CONCLUSIONS: Our study shows that AGILE is a rapid and effective tool for screening multidimensional frailty, able to predict mortality, disability and hospitalization, especially useful in care settings that require reliable assessment instruments with short administration time.

Type 2 myocardial infarction: is it a geriatric syndrome?

Type 2 myocardial infarctions (T2-MI) is a type of necrosis that results from reduced oxygen supply and/or increased demand secondary to other causes unrelated to acute coronary atherothrombosis. The development and implementation of sensitive and high-sensitivity cardiac necrosis marker and the age-related increase of comorbidity lead to a boost of the frequency of T2-MI. T2-MI is often a complication of a high degree of clinical frailty in older adults, emerging as a "geriatric syndrome". Age-related non-cardiovascular causes may be the triggering factors and are strongly associated with the diagnosis, treatment, and prognosis of T2-MI. To date, there are no guidelines on management of this pathology in advancing age. Patient-centered approach and comprehensive geriatric assessment play a key role in the diagnosis, therapy and prognosis of geriatric patients with T2-MI.

Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors.

Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.

Permanent atrial fibrillation and pulmonary embolism in elderly patients without deep vein thrombosis: is there a relationship?

BACKGROUND AND AIM: Permanent Atrial Fibrillation (pAF) is associated with increased risk of embolic complications. The relationship between pAF and pulmonary embolism (PE) has not been extensively investigated in elderly patients. Here, we aim at verifying whether pAF is associated to an increased risk of PE in a cohort of elderly patients with and without Deep Vein Thrombosis (DVT). METHODS: 235 patients older than 65 years with PE with or without pAF were retrospectively enrolled and stratified by the absence or presence of DVT. The diagnosis of PE was performed by computed tomography angiography (CTA). Right echocardiographic parameters were monitored. The severity of PE was evaluated by CTA quantization (PE score = 1, involvement of main branches of pulmonary artery) and by dimer-D (> 3000 µg/L). RESULTS: DVT was identified only in 51 cases of PE (21.7%). pAF prevalence was higher in PE without than in those with DVT (64.9% vs. 35.1%, p < 0.01). PE severity was more evident in pAF patients without than in those with DVT. Multivariate analysis of the role of pAF on PE severity confirms these results (RR = 3.41 for PE score = 1, and 8.55 for dimer-D > 3000 µg/L). CONCLUSIONS: We conclude that in elderly patients with PE, the prevalence of pFA was doubled, in the absence of DVT, and it is associated with a more severe PE in the absence than in the presence of DVT. Thus, in the absence of DVT, pFA should be considered as cause of PE.

The reverse metabolic syndrome in the elderly: Is it a "catabolic" syndrome?

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure are also found to relate to outcomes in the geriatric population, but in a differing direction. A higher body mass index, hypercholesterolemia and hypertension are not harmful but even permit better survival at advancing age. This phenomenon is called "reverse epidemiology" or "risk factor paradox" and is also detected in a variety of chronic disease states such as chronic heart failure. Accordingly, a low BMI, blood pressure and cholesterol values are associated with a worse prognosis. Several possible causes are hypothesized to explain this elderly paradox, but this phenomenon remains controversial and its underlying reasons are poorly understood. The aim of this review is to recognize the factors behind this intriguing phenomenon and analyse the consequences that it can bring in the management of the cardiovascular therapy in elderly patient. Finally, a new phenotype identified as "catabolic syndrome" has been postulated.

Acute care hospital at different levels of intensity: the role of Geriatrician.

The traditional model of care is based on "disease-centered" management that requires the organization of the hospital in specialized wards, to which the patient is assigned for the main disease. The growing need to optimize economical and human resources and to promote a global approach to the patient has led to the setting up of the intensity of care model. It is a health system based on a "patient-centered" approach, where the hospital is organized in departments dedicated to patients with homogenous needs of care. In Italy, intensity of care model is currently being tested in the hospital organization, where three levels of intensity are proposed: low, medium and high. The purpose of the following review is to describe the role and importance of the Geriatrician in each of these care settings and to highlight the contradiction of a National Health System which promotes the geriatric approach to all types of patients, but does not invest in the formation and integration of the figure of the Geriatrician in clinical practice, condemning it to marginalization or even extinction.

The Italian version of the "frailty index" based on deficits in health: a validation study.

BACKGROUND AND AIM: Several measurements were taken for frailty classification in geriatric population. "Frailty index" is based on "deficits in health," but it is still not available in Italian version. Thus, the aim of the present work was to validate a version of "frailty index" for the Italian geriatric community. METHODS: The validation of Italian frailty index (IFi) is based on a cohort study that enrolled 1077 non-disabled outpatients aged 65 years or older (81.3 ± 6.5 years) in Naples (Italy). IFi has been expressed as a ratio of deficits present/deficits considered after a comprehensive geriatric assessment. IFi was stratified in light, moderate and severe frailty. Mortality, disability (considering an increase in ADL lost ≥1 from the baseline) and hospitalization were considered at 3, 6, 12, 18 and 24 months of follow-up. Area under curve (AUC) was evaluated for both Fried's and IFi frailty index. RESULT: At the end of follow-up, mortality increased from 1.0 to 30.3%, disability from 40.9 to 92.3% and hospitalization from 0.0 to 59.0% (p < 0.001 for trend). Multivariate analysis shows that the relative risk for unit increase in IFi is 1.09 (95% CI = 1.01-1.17, p = 0.013) for mortality, 1.04 (95% CI = 1.01-1.06, p = 0.024) for disability and 1.03 (95% CI = 1.01-1.07, p = 0.041) for hospitalization. AUC is higher in IFi with respect to Fried's frailty index when considering mortality (0.809 vs. 0.658, respectively), disability (0.800 vs. 0.729, respectively) and hospitalization (0.707 vs. 0.646, respectively). CONCLUSIONS: IFi is a valid measure of frailty after the comprehensive geriatric assessment in an Italian cohort of non-institutionalized patients.

Chronic obstructive pulmonary disease and long-term mortality in elderly subjects with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are associated with high rates of mortality in elderly subjects. Concurrent CHF and COPD frequently occur, especially in with advancing age. This study examines long-term mortality in community-dwelling elderly subjects affected by CHF alone, COPD alone, and coexistent CHF and COPD. METHODS: The study evaluated 12-years mortality in 1288 subjects stratified for the presence or absence of CHF or COPD alone, and for coexistence of CHF and COPD. RESULTS: Mortality, at 12 year follow-up, was 46.7% overall, 68.6% in the presence of CHF alone (p < 0.001), 56.9% in the presence of COPD alone (p < 0.01); mortality was 86.2% where CHF and COPD coexisted (p < 0.001) and was significantly higher than in CHF or COPD alone (p < 0.05). Multivariate analysis indicates that CHF (Hazard risk = 1.67, 95% confidence interval 1.15-3.27, p < 0.031) and COPD (Hazard risk = 1.27, 95% confidence interval = 1.08-1.85, p < 0.042) were predictive of long-term mortality. When CHF and COPD simultaneously occurred, the risk dramatically increased up to 3.73 (95% confidence interval = 1.19-6.93, p < 0.001). CONCLUSIONS: Long-term follow-up showed higher mortality among elderly subjects affected by CHF or COPD. Simultaneous presence of CHF and COPD significantly increased the risk of death. Therefore, the presence of COPD in CHF patients should be considered a relevant factor in predicting high risk of mortality.

Prognostic role of lactate on mortality in younger and older patients with cardio-respiratory failure admitted to an acute intensive care unit.

BACKGROUND AND AIM: Acidosis is able to induce negative changes of different organs that increase progressively with aging. At present it is not known whether the levels of lactate may differently influence the prognosis of younger and older patients. Thus, the aim of this study is to evaluate the prognostic value of lactate levels after admission of younger and older patients to an acute intensive care unit. METHODS: Younger (<65 years, n = 118) and older (≥65 years, n = 165) patients admitted to an acute intensive care unit were prospectively enrolled and classified according to diagnosis of acute heart or/and respiratory failure. For each patient, APACHE II score, time of hospitalization and mortality, blood levels of lactate were collected. RESULTS: Both in-hospital mortality and lactate >2.5 mmol/L at the admission was higher in the older than in the younger patients (42.4 vs. 20.3 %, p < 0.01 and 57.8 vs. 31.9 %, p < 0.01, respectively). Lactate level was higher in older than in the younger patients both at admission and after 24 h (3.9 ± 3.4 vs. 2.4 ± 2.2 mmol/L and 2.4 ± 2.0 vs. 1.4 ± 1.3 mmol, p < 0.01, respectively). Accordingly, multivariate analysis shows that lactate was predictive of mortality in younger (OR = 2.65, 95 % CI 1.62-5.24, p = 0.03) and even more in the older (OR = 4.74, 95 % CI 2.10-6.70, p < 0.01) patients. CONCLUSIONS: Lactate concentration increase is associated with increased mortality in younger patients but, even more so, in older patients admitted to an acute intensive care unit. These results confirm the experimental evidence showing acidosis has a greater effect of leading to organ failure and higher mortality with increasing age.

Long-term mortality in frail elderly subjects with osteoarthritis.

OBJECTIVE: Elderly subjects are characterized by a high prevalence of OA and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without OA. METHODS: Mortality was evaluated after a 12-year follow-up in 698 subjects with and 590 subjects without OA recruited in 1992. Clinical frailty was assessed according to the Frailty Staging System and stratified in tertiles. RESULTS: After a 12-year follow-up, mortality was 42.2% in subjects without and 55.8% in subjects with OA (P = 0.256). With increasing frailty, mortality increased by 30.5% (P for trend < 0.001) in subjects without and by 45.6% in subjects with OA (P for trend < 0.001). Multivariate analysis showed that frailty [hazard ratio (HR) = 1.49 for each unit of increase, 95% CI 1.32, 1.94, P < 0.001) but not OA (HR = 1.28, 95% CI 0.987, 1.39, P = 0.412) was predictive of long-term mortality. Moreover, when Cox regression analysis was performed, frailty enhanced the risk of long-term mortality for each unit of increase by 32% (HR = 1.32, 95% CI 1.06, 1.65, P = 0.03) in the absence of OA and by 98% in the presence (HR = 1.98, 95% CI 1.63, 2.95, P < 0.01) of OA. CONCLUSION: Clinical frailty significantly predicts mortality in subjects without OA and even more in those with OA. Thus clinical frailty may be considered a new prognostic factor to identify subjects with OA at high risk of mortality.