Frail hypertensive older adults with prediabetes and chronic kidney disease: insights on organ damage and cognitive performance - preliminary results from the CARYATID study.

BACKGROUND: Hypertension and chronic kidney disease (CKD) pose significant public health challenges, sharing intertwined pathophysiological mechanisms. Prediabetes is recognized as a precursor to diabetes and is often accompanied by cardiovascular comorbidities such as hypertension, elevating the risk of pre-frailty and frailty. Albuminuria is a hallmark of organ damage in hypertension amplifying the risk of pre-frailty, frailty, and cognitive decline in older adults. We explored the association between albuminuria and cognitive impairment in frail older adults with prediabetes and CKD, assessing cognitive levels based on estimated glomerular filtration rate (eGFR). METHODS: We conducted a study involving consecutive frail older patients with hypertension recruited from March 2021 to March 2023 at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, followed up after three months. Inclusion criteria comprised age over 65 years, prior diagnosis of hypertension without secondary causes, prediabetes, frailty status, Montreal Cognitive Assessment (MoCA) score < 26, and CKD with eGFR > 15 ml/min. RESULTS: 237 patients completed the study. We examined the association between albuminuria and MoCA Score, revealing a significant inverse correlation (r: 0.8846; p < 0.0001). Subsequently, we compared MoCA Score based on eGFR, observing a significant difference (p < 0.0001). These findings were further supported by a multivariable regression analysis, with albuminuria as the dependent variable. CONCLUSIONS: Our study represents the pioneering effort to establish a significant correlation between albuminuria and eGFR with cognitive function in frail hypertensive older adults afflicted with prediabetes and CKD.

Quantitative ultrasound (QUS) in the evaluation of liver steatosis: data reliability in different respiratory phases and body positions.

Liver steatosis is the most common chronic liver disease and affects 10-24% of the general population. As the grade of disease can range from fat infiltration to steatohepatitis and cirrhosis, an early diagnosis is needed to set the most appropriate therapy. Innovative noninvasive radiological techniques have been developed through MRI and US. MRI-PDFF is the reference standard, but it is not so widely diffused due to its cost. For this reason, ultrasound tools have been validated to study liver parenchyma. The qualitative assessment of the brightness of liver parenchyma has now been supported by quantitative values of attenuation and scattering to make the analysis objective and reproducible. We aim to demonstrate the reliability of quantitative ultrasound in assessing liver fat and to confirm the inter-operator reliability in different respiratory phases. We enrolled 45 patients examined during normal breathing at rest, peak inspiration, peak expiration, and semi-sitting position. The highest inter-operator agreement in both attenuation and scattering parameters was achieved at peak inspiration and peak expiration, followed by semi-sitting position. In conclusion, this technology also allows to monitor uncompliant patients, as it grants high reliability and reproducibility in different body position and respiratory phases.

Cardiac sympathetic innervation and mortality risk scores in patients with heart failure.

INTRODUCTION: In the risk stratification and selection of patients with heart failure (HF) eligible for implantable cardioverter-defibrillator (ICD) therapy, 123 I-meta-IodineBenzylGuanidine (123 I-mIBG) scintigraphy has emerged as an effective non-invasive method to assess cardiac adrenergic innervation. Similarly, clinical risk scores have been proposed to identify patients with HF at risk of all-cause mortality, for whom the net clinical benefit of device implantation would presumably be lower. Nevertheless, the association between the two classes of tools, one suggestive of arrhythmic risk, the other of all-cause mortality, needs further investigation. OBJECTIVE: To test the relationship between the risk scores for predicting mortality and cardiac sympathetic innervation, assessed through myocardial 123 I-mIBG imaging, in a population of patients with HF. METHODS: In HF patients undergoing 123 I-mIBG scintigraphy, eight risk stratification models were assessed: AAACC, FADES, MADIT, MADIT-ICD non-arrhythmic mortality score, PACE, Parkash, SHOCKED and Sjoblom. Cardiac adrenergic impairment was assessed by late heart-to-mediastinum ratio (H/M) <1.6. RESULTS: Among 269 patients suffering from HF, late H/M showed significant negative correlation with all the predicting models, although generally weak, ranging from -0.15 (p = .013) for PACE to -0.32 (p < .001) for FADES. The scores showed poor discrimination for cardiac innervation, with areas under the curve (AUC) ranging from 0.546 for Parkash to 0.621 for FADES. CONCLUSION: A weak association emerged among mortality risk scores and cardiac innervation, suggesting to integrate in clinical practice tools indicative of both arrhythmic and general mortality risks, when evaluating patients affected by HF eligible for device implantation.

Current challenges and perspectives in lung cancer care during COVID-19 waves.

PURPOSE OF REVIEW: In the era of the SARS-Cov2 pandemic, the multidisciplinary care of patients with lung cancer is the main challenge for clinicians. The depiction of complex networking between SARS-CoV2 and cancer cells is crucial to understanding the downstream signalling pathways leading to more severe clinical behaviour of COVID-19 among lung cancer patients. RECENT FINDINGS: The immunosuppressive status caused by both blunted immune response and active anticancer treatments (e.g. radiotherapy, chemotherapy) affects also the response to vaccines. Furthermore, the COVID-19 pandemic has significantly influenced early detection, therapeutic management, and clinical research for patients with lung cancer. SUMMARY: SARS-CoV-2 infection does undoubtedly represent a challenge for care of patients with lung cancer. Since symptoms of infection may overlap with underlying condition, diagnosis must be reached and treatment should start as soon as possible. Although any cancer treatment should be procrastinated as long as infection is not cured, every choice must be pondered on individual basis, according to clinical conditions. Underdiagnosis should be avoided, and both surgical and medical treatment must be tailored to each patient. Therapeutic scenario standardization represents a major challenge for clinicians and researchers.

Role of Endothelial Progenitor Cells in Frailty.

Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are important mechanisms in the pathophysiology of frailty. Endothelial progenitor cells (EPCs) are considered important contributors of the endothelium homeostasis and turn-over. In the elderly, EPCs are impaired in terms of function, number and survival. In addition, the modification of EPCs' level and function has been widely demonstrated in atherosclerosis, hypertension and diabetes mellitus, which are the most common age-related diseases. The purpose of this review is to illustrate the role of EPCs in frailty. Initially, we describe the endothelial dysfunction in frailty, the response of EPCs to the endothelial dysfunction associated with frailty and, finally, interventions which may restore the EPCs expression and function in frail people.

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.

Transient Receptor Potential (TRP) Channels in Tumor Vascularization.

Tumor diseases are unfortunately quick spreading, even though numerous studies are under way to improve early diagnosis and targeted treatments that take into account both the different characteristics associated with the various tumor types and the conditions of individual patients. In recent years, studies have focused on the role of ion channels in tumor development, as these proteins are involved in several cellular processes relevant to neoplastic transformation. Among all ion channels, many studies have focused on the superfamily of Transient Receptor Potential (TRP) channels, which are non-selective cation channels mediating extracellular Ca2+ influx. In this review, we examined the role of different endothelial TRP channel isoforms in tumor vessel formation, a process that is essential in tumor growth and metastasis.

Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences.

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage and repair, together with the preservation of endothelial integrity, is of crucial importance for the homeostasis of endothelium. Endothelial Progenitor Cells (EPCs) represent a heterogenous cell population, characterized by the ability to differentiate into mature endothelial cells (ECs), which contribute to vascular homeostasis, neovascularization and endothelial repair. A modification of the number and function of EPCs has been described in numerous chronic inflammatory and auto-immune conditions; however, reports that focus on the number and functions of EPCs in RA are characterized by conflicting results, and discrepancies exist among different studies. In the present review, the authors describe EPCs' role and response to RA-related endothelial modification, with the aim of illustrating current evidence regarding the level of EPCs and their function in this disease, to summarize EPCs' role as a biomarker in cardiovascular comorbidities related to RA, and finally, to discuss the modulation of EPCs secondary to RA therapy.

Systemic lupus erythematosus, endothelial progenitor cells and intracellular Ca2+ signaling: A novel approach for an old disease.

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease featured by an increased cardiovascular risk that may lead to premature patient's death. It has been demonstrated that SLE patients suffer from early onset endothelial dysfunction which is due to the impairment of endogenous vascular repair mechanisms. Vascular integrity and homeostasis are maintained by endothelial progenitor cells (EPCs), which are mobilized in response to endothelial injury to replace damaged endothelial cells. Two main EPCs subpopulations exist in peripheral blood: endothelial colony forming cells (ECFCs), which represent truly endothelial precursors and can physically engraft within neovessels, and myeloid angiogenic cells (MACs), which sustain angiogenesis in a paracrine manner. Emerging evidence indicates that ECFCs/MACs are down-regulated and display compromised angiogenic activity in SLE, thereby contributing to the pathogenesis of this disease. Intracellular calcium (Ca2+) signaling plays a crucial role in maintaining vascular integrity by stimulating migration, proliferation and tube formation in both ECFCs and MACs. Herein, we illustrate the evidences that support the role played by EPCs dysfunction in SLE. Subsequently, we discuss about the hypothesis that the Ca2+ handling machinery is compromised in SLE-derived ECFCs and MACs, thereby resulting in their reduced pro-angiogenic activity. Finally, we speculate about the proposal to exploit intracellular Ca2+ signaling to improve ECFCs' reparative phenotype and suggest this strategy as a new approach to treat SLE patients.

Impact of body mass index on cardiac adrenergic derangement in heart failure patients: a 123I-mIBG imaging study.

PURPOSE: To assess the impact of body mass index (BMI) on cardiac adrenergic derangement, measured by iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging in heart failure (HF) patients. Overweight and obesity represent relevant health issues, and augmented sympathetic tone has been described in patients with increased BMI. An extensive literature supports that HF-dependent cardiac denervation, measured through mIBG parameters, is an independent predictor of cardiovascular outcomes and mortality. However, the influence of BMI on cardiac mIBG uptake has not been largely investigated. METHODS: We prospectively enrolled patients with systolic HF, collecting demographic, clinical, echocardiographic data, and mIBG imaging parameters. In order to detect the factors associated with mIBG parameters, a model building strategy, based on the Multivariable Fractional Polynomial algorithm, has been employed. RESULTS: We studied 249 patients with systolic HF, mean age of 66.4 ± 10.6 years, and mean left ventricular ejection fraction (LVEF) of 30.7% ± 6.4, undergoing cardiac 123I-mIBG imaging to assess HF severity and prognosis. Seventy-eight patients (31.3%) presented a BMI ≥ 30 kg/m2 and obese patients showed a significant reduction in early heart to mediastinum (H/M) ratio (1.66 ± 0.19 vs. 1.75 ± 0.26; p = 0.008) and a trend to reduction in washout rate (33.6 ± 18.3 vs. 38.1 ± 20.1; p = 0.092) compared with patients with BMI < 30 kg/m2. Multiple regression analysis revealed that BMI, age, and LVEF were significantly correlated with early and late H/M ratios. CONCLUSIONS: Results of the present study indicate that BMI, together with LVEF and age, is independently correlated with cardiac mIBG uptake in HF patients.

Correction to: COVID-19 and the elderly patients: insights into pathogenesis and clinical decision-making.

In the published article, the title was published incorrectly as COVID-19.

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making.

The elderly may represent a specific cluster of high-risk patients for developing COVID-19 with rapidly progressive clinical deterioration. Indeed, in older individuals, immunosenescence and comorbid disorders are more likely to promote viral-induced cytokine storm resulting in life-threatening respiratory failure and multisystemic involvement. Early diagnosis and individualized therapeutic management should be developed for elderly subjects based on personal medical history and polypharmacotherapy. Our review examines the pathogenesis and clinical implications of ageing in COVID-19 patients; finally, we discuss the evidence and controversies in the management in the long-stay residential care homes and aspects of end-of-life care for elderly patients with COVID-19.

Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity.

Diabetes mellitus (DM) and heart failure (HF) are frequent comorbidities among elderly patients. HF, a leading cause of mortality and morbidity worldwide, is characterized by sympathetic nervous system hyperactivity. The prevalence of diabetes mellitus (DM) is rapidly growing and the risk of developing HF is higher among DM patients. DM is responsible for several macro- and micro-angiopathies that contribute to the development of coronary artery disease (CAD), peripheral artery disease, retinopathy, neuropathy and diabetic nephropathy (DN) as well. Independently of CAD, chronic kidney disease (CKD) and DM increase the risk of HF. Individuals with diabetic nephropathy are likely to present a distinct pathological condition, defined as diabetic cardiomyopathy, even in the absence of hypertension or CAD, whose pathogenesis is only partially known. However, several hypotheses have been proposed to explain the mechanism of diabetic cardiomyopathy: increased oxidative stress, altered substrate metabolism, mitochondrial dysfunction, activation of renin-angiotensin-aldosterone system (RAAS), insulin resistance, and autonomic dysfunction. In this review, we will focus on the involvement of sympathetic system hyperactivity in the diabetic nephropathy.

Indexes of Angiogenic Activation in Myocardial Samples of Patients with Advanced Chronic Heart Failure.

Background and objectives: Ischemic and idiopathic heart failure are characterized by reactive cardiac fibrosis and impaired vasculogenesis involving pro-angiogenic factors such as angiogenin, angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2), as demonstrated in experimental models of heart failure. However, differences in the molecular pathways between these cardiomyopathies are still unclear. In this short communication, we evaluate and compare the expression of pro-angiogenic molecules in the heart tissue of patients with advanced chronic heart failure (CHF) of ischemic vs. nonischemic etiology. Materials and Methods: We obtained heart tissue at transplantation from left ventricular walls of 16 explanted native hearts affected by either ischemic (ICM) or nonischemic dilated cardiomyopathy (NIDCM). Tissue samples were examined using immunohistochemistry for angiogenic molecules. Results: We found immunopositivity (I-pos) for angiopoietin-1 mainly in the cardiomyocytes, while we observed I-pos for Ang-2 and Tie-2 receptor mainly in endothelial cells. Expression of Procollagen-I (PICP), angiogenin, Ang-1, and Tie-2 receptor was similar in ICM and NIDCM. In contrast, endothelial immunopositivity for Ang-2 was higher in ICM samples than NIDCM (p = 0.03). Conclusions: In our series of CHF heart samples, distribution of Ang-1 and angiogenin was higher in cardiomyocytes while that of Ang-2 was higher in endothelial cells; moreover, Ang-2 expression was higher in ICS than NIDCM. Despite the small series examined, these findings suggest different patterns of angiogenic stimulation in ICM and NIDCM, or at least a more altered endothelial integrity in ICD. Our data may contribute to a better understanding of the angiogenesis signaling pathways in CHF. Further studies should investigate differences in the biochemical processes leading to heart failure.

Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure.

RATIONALE: Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional ß-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients. OBJECTIVE: The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients. METHODS AND RESULTS: We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality. CONCLUSIONS: Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF.

Imaging and Molecular Mechanisms of Alzheimer's Disease: A Review.

Alzheimer's disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer's, as they provide an in vivo window to the pathological processes occurring in Alzheimer's brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer's disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer's research and clinical practice.

Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure.

PURPOSE: Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac 123I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by 123I-mIBG scintigraphy, in patients with HF. METHODS AND RESULTS: We studied 180 HF patients (age = 66.1 ± 10.5 years [yrs]), left ventricular ejection fraction (LVEF = 30.6 ± 6.3 %) undergoing cardiac 123I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75 years (age = 77.7 ± 4.0 year), 67 patients aged 62-72 years (age = 67.9 ± 3.2 years) and 60 patients aged ≤61 year (age = 53.9 ± 5.6 years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p < 0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age. CONCLUSIONS: Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by 123I-mIBG imaging. This finding suggests that cardiac 123I-mIBG uptake in patients with HF might be affected by patient age.

Impact of diabetes mellitus on lymphocyte GRK2 protein levels in patients with heart failure.

BACKGROUND: Diabetes mellitus (DM) is associated with impaired prognosis in patients with heart failure (HF), but pathogenic mechanisms are unclear. In the failing heart, elevated ß-adrenergic receptor (ß-AR) activation by catecholamines causes G-protein-coupled receptor kinase-2 (GRK2) upregulation which is responsible for ß-AR signalling dysfunction. Importantly, GRK2 expression, measured in peripheral lymphocytes of HF patients, correlates with levels of this kinase in the failing myocardium reflecting the loss of hemodynamic function. Moreover, HF-related GRK2 protein overexpression promotes insulin resistance by interfering with insulin signalling. The aim of this study was to assess lymphocyte GRK2 protein levels in HF patients with and without DM. METHODS AND MATERIALS: Patients with a diagnosis of HF were enrolled in the study. All subjects underwent a complete clinical examination (including NYHA functional class assessment and echocardiography) and blood draw for serum N-terminal pro-brain natriuretic peptide (NT-proBNP), lymphocyte GRK2 and plasma norepinephrine (NE) levels. Demographic data including age, sex, medications, cardiovascular risk factors and presence of comorbidities were also collected. RESULTS: Two hundred and sixty-eight patients with HF (left ventricular ejection fraction [LVEF] 30.6 ± 7.6%) with and without DM were enrolled. No differences between the two groups were found in terms of demography, HF aetiology, LVEF, NYHA class, NE and NT-proBNP. GRK2 was significantly higher in patients with DM compared to non-DM. At multivariate linear regression analysis, LVEF, NE, NT-proBNP and diabetes came out to be independent predictors of GRK2 levels in the overall study population. CONCLUSION: In HF patients, DM is associated with significantly more elevated lymphocyte GRK2 protein levels, likely reflecting more compromised cardiac ß-AR signalling/function, despite similar hemodynamic status and neuro-hormonal activation compared to patients without DM. These findings contribute to explain the negative prognostic impact of DM in patients with HF.

Frailty and Parkinson's disease: the role of diabetes mellitus.

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with a progressive loss of dopaminergic neurons, clinically characterized by motor and non-motor signs. Frailty is a clinical condition of increased vulnerability and negative health outcomes due to the loss of multiple physiological reserves. Chronic hyperglycemia and insulin resistance, which characterize diabetes mellitus (DM), have been reported to alter dopaminergic activity, increase the risk of PD, and influence the development of frailty. Even though diabetes may facilitate the development of frailty in patients with PD, this relationship is not established and a revision of the current knowledge is necessary. Furthermore, the synergy between DM, PD, and frailty may drive clinical complexity, worse outcomes, and under-representation of these populations in the research. In this review, we aimed to discuss the role of diabetes in the development of frailty among patients with PD. We summarized the clinical characteristics and outcomes of patients with concomitant DM, PD, and frailty. Finally, interventions to prevent frailty in this population are discussed.