Background: Resynchronization therapy has become a cornerstone in patients with heart failure (HF). Recent advancements in this field have led to the development of the so-called “left bundle branch area pacing” (LBBAP), a form of pacing where a single ventricular catheter directly addresses the left bundle for a more physiological stimulation. The current literature provides encouraging evidence regarding this topic, but there is still limited data for the older population, particularly those aged ≥75 years. This review aims to clarify how LBBAP has been explored in this cohort and if its application could be safe and effective even in the most advanced stages of life. Methods: A search of articles from PubMed was conducted. Patients were considered older if above 75 years of age. Data regarding Italian statistics were obtained from national registries. Results: The current literature supports the safety and effectiveness of LBBAP in older patients across different indications, with outcomes comparable to those reported in younger patients and a suggested cost-effectiveness. Conversely, data regarding patients affected by cardiac amyloidosis are still inconclusive. Conclusions: LBBAP represents a valuable resource for patients of all ages, but frailty is a major issue in the older population that needs to be addressed. The potential integration of this technology with defibrillator capabilities will enable an even more extensive application in the near future.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass, strength, and function, represents a growing public health challenge in aging populations. Emerging mechanistic evidence suggests that ketogenic diets (KDs) and elevated circulating β-hydroxybutyrate (βOHB) levels may offer selective and context-dependent nutritional strategies to support muscle health during aging. This review summarizes current evidence on the effects of ketogenic diets and ketone body metabolism on muscle mass and function, with a focus on underlying molecular mechanisms and clinical relevance in older adults. βOHB acts not only as an alternative energy substrate but also as a signaling molecule, notably through histone deacetylase inhibition and modulation of inflammatory pathways. Nutritional ketosis in humans typically results in circulating βOHB concentrations of approximately 0.5-3.0 mM, which may be sufficient to engage some of these signaling pathways, although the extent of these effects in human tissues remains incompletely defined. Preclinical studies indicate that long-term ketogenic diets preserve muscle mass, strength, and mitochondrial function in aging models. Limited clinical evidence, largely derived from populations with sarcopenic obesity or metabolic comorbidities, suggests that protein-adequate ketogenic diets, when implemented as an adjunct to physical exercise, may help preserve fat-free mass and improve functional outcomes, while exogenous ketones show potential to augment post-exercise anabolic signaling. Overall, the integration of mechanistic and preliminary clinical data provides a supplementary and exploratory framework suggesting that ketogenic diets may represent a promising adjunctive strategy for sarcopenia prevention, although well-designed long-term randomized controlled trials are required to define their efficacy, safety, and optimal clinical application.

Currently the mechanisms that lead an atherosclerotic plaque to become unstable and those that trigger the coagulative/thrombotic processes leading to acute coronary syndrome have yet to be clarified. It has been suggested a possible role of microRNAs in the physiopathology of the atherosclerotic process related to acute and chronic ischemic cardiomyopathy. However, no data exists on the correlation between microRNAs expression in coronary (upstream and downstream of the coronary lesion) and arterial (at the aortic root level) blood from patients with acute coronary syndromes (ACS) and chronic coronary syndromes (CCS) before and after angioplasty. The study's primary objective is to assess miRnome analysis in coronary and arterial blood sampling in ACS and CCS patients before and after angioplasty. The secondary objective is to analyze interleukin-6 and soluble ST2 levels in the peripheral plasma samples before and after angioplasty. Ten patients with ACS and ten patients with CCS will be enrolled. Coronary stenosis treated with angioplasty will be located in the proximal segments of the three main vessels: the anterior interventricular artery, the circumflex artery, and the right coronary artery. The angioplasty procedure will be performed according to standard clinical practice. Before and after angioplasty, blood samples upstream and downstream of the coronary lesion will be taken, arterial sampling at the aortic root level will be performed, and peripheral venous blood will be collected. The expression of serum microRNAs will be analyzed by Next-generation sequencing. Quantitative analysis of pro- and anti-inflammatory molecules such as interleukin-6 and the soluble form of the soluble ST2 will be performed on various blood samples. This study is registered in ClinicalTrials.Gov on October 30, 2023 (ID NCT06103357).

Blood bacterial DNA (BB-DNA) has been identified as a novel biomarker for metabolic dysfunction, yet its relationship with epigenetic features in type 2 diabetes mellitus (DM2) patients remains largely unexplored. This study investigated the relationship between BB-DNA and epigenetic, inflammatory, and aging-related markers in 285 elderly both with and without DM2. BB-DNA levels were higher in DM2 patients than in non-diabetic subjects, with the highest levels in those with severe renal impairment. BB-DNA showed a positive association with plasma IL-1β, linking bacterial DNA to systemic inflammation. Epigenetic analysis revealed a negative correlation between BB-DNA and DNA methylation-based leukocyte telomere length, suggesting accelerated aging in DM2. Additionally, BB-DNA was positively associated with DNAm-based biological age estimators, particularly DNAmPhenoAge and DNAmAge Skin Blood Clock. BB-DNA also correlated with DNAmVEGFA and DNAmCystatin C, key markers of diabetic nephropathy and vascular dysfunction. Furthermore, BB-DNA levels were associated with hypomethylation of genes involved in inflammation (e.g., IL1β, TNFα, IFNγ), cellular senescence (p16, p21, TP53), and metabolic regulation (e.g., IGF1, SREBF1, ABCG1, PDK4). These associations suggest that increased BB-DNA may reflect and potentially promote a pro-inflammatory and pro-senescent epigenetic profile in DM2. Importantly, many of these associations remained significant after adjusting for diabetes status, supporting BB-DNA as a robust biomarker across clinical subgroups. These findings provide new insights into the relationship between BB-DNA, inflammation, and epigenetic aging in DM2, highlighting BB-DNA as a potential biomarker for disease progression and complications, particularly in relation to renal dysfunction and systemic inflammation.

Aging is accompanied by chronic low-grade inflammation ("inflammaging"), which contributes to increased morbidity and mortality in older adults. This study evaluated the prognostic value of circulating inflammatory biomarkers, i.e. interleukin-6 (IL-6), interleukin-10 (IL-10), and CXCL9, and their integration with frailty for long-term risk stratification. We analyzed 1,009 patients (median age, 84 years) hospitalized in acute care wards of three Italian geriatric hospitals as part of the ReportAGE cohort. Frailty was assessed using a deficit accumulation–based Frailty Index (FI), and serum cytokines were measured by immunoassay. Cytokine-specific risk categories were combined into a composite I3 score (range, 3–9). Cox proportional hazards models adjusted for age, sex, comorbidity burden, polypharmacy, and laboratory variables were used to assess associations with 10-year mortality. In a subset of 237 patients, DNA methylation–based estimates of cytokine levels were also analyzed. Higher I3 scores were independently associated with increased mortality (hazard ratio [HR] 2.42, 95

Left ventricular hypertrabeculation is one of the most debated conditions in modern cardiology. Many studies have tried to characterise this disease by addressing the various clinical risks and diagnostic tools, but its very nosological existence is currently being challenged. The latest ESC guidelines on cardiomyopathies state that it should be addressed as a morphologic trait rather than an intrinsic disease of the cardiac muscle. Despite the huge number of diagnostic criteria and possible phenocopies, no specific consensus identifies a specific flowchart regarding the management of patients with suspected hypertrabeculation. This review aims to provide a clinical approach for patients with a phenotypical appearance of excessive trabeculation.

BACKGROUND AND AIMS:Chest radiography (CXR) is the gold standard tool for early mechanical complications' detection after cardiac implantable electronic devices (CIED) procedures, along with CIED electrical parameters control for the diagnosis of early catheter dislodgement. However, the detection of thoracic complications using CXR is limited, and it requires radiation exposure. Thoracic ultrasound (TUS) is a more versatile and quicker alternative for the diagnosis of thoracic pathologies, although its use in cardiac electrophysiology is not yet validated. Aim of this study was to compare the diagnostic power of CXR and TUS in the diagnosis of non-infective early complications of CIED implantation. METHODS:A total of 397 patients who underwent CIED implantation were prospectively enrolled from 1 November 2021, to 30 September 2022. Following surgery, all patients underwent CXR and TUS at the patient's bed and the electrical parameters were tested before discharge. RESULTS:21 patients experienced mechanical complications (5.3%), of which the most common were pneumothorax (3.3%) and pericardial effusion (2%). TUS demonstrated non-inferior accuracy in diagnosing early mechanical complications, with increased sensitivity when compared to CXR. When associated with device interrogation, TUS was at least as accurate as CXR and device control in diagnosing lead dislodgment. CONCLUSIONS:TUS has a non-inferior diagnostic power compared to the CXR to detect early mechanical complications of CIED implantation, avoiding x-ray exposure. Our results suggest that TUS could be employed as a primary technique in association with standard electrical control to diagnose postoperative complications.

Cardiovascular diseases (CVDs) persist as the primary cause of death worldwide, accounting for roughly 17.9 million fatalities each year. The prevalence of obesity, metabolic syndrome, and type 2 diabetes (key risk factors for CVD) continues to escalate at an alarming rate, necessitating novel therapeutic strategies to address this global health crisis. Nutritional ketosis, induced through ketogenic diets, modified fasting, intermittent fasting, and medium-chain triglyceride (MCT) oil consumption, has garnered attention for its potential cardioprotective effects. Ketosis is a metabolic state in which the body, due to a significantly reduced intake of carbohydrates, shifts its primary energy source from glucose to ketone bodies, i.e., beta-hydroxybutyrate (BHB), acetoacetate, and acetone, which are produced in the liver from fatty acids. This review examines the mechanisms by which ketone bodies, particularly BHB, mitigate cardiovascular risk. We focus mainly on the anti-inflammatory and antioxidative properties of BHB and summarize recent evidence to highlight the clinical relevance of ketosis in cardiometabolic health.

Atrial fibrillation (AF) has been associated with higher morbidity and mortality rates, especially in older patients. Subclinical atrial fibrillation (SCAF) is defined as the presence of atrial high-rate episodes (AHREs) > 190 bpm for 10 consecutive beats > 6 min and <24 h, as detected by cardiac implanted electronic devices (CIEDs). The selection of eligible patients for anticoagulation therapy among elderly individuals with AHREs detected through CIEDs remains a contentious issue. The meta-analysis of ARTESiA and NOAH-AFNET 6 clinical trials revealed that taking Edoxaban or Apixaban as oral anticoagulation therapy can reduce the risk of stroke by approximately 32% while increasing the risk of major bleeding by approximately 62%. However, it is still unclear which are, among patients with SCAF, those who can take the highest net clinical benefit from anticoagulant therapy. The present review summarizes the current evidence on this intriguing issue and suggests strategies to try to better stratify the risk of stroke and systemic embolism in patients with AHREs. We propose incorporating some parameters including chronic kidney disease (CKD), obesity, enlarged left atrial volume, the efficacy in blood pressure management, and frailty into the traditional CHA2DS2-VASc score. Future trials will be needed to verify the clinical usefulness of the proposed prognostic score mainly in the view of a personalized therapeutic approach in patients with SCAF.

Background Few studies explored the effect of the combination of glucose sodium-cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on the incidence of cardiovascular events in patients with type 2 diabetes (T2D) and acute myocardial infarction (AMI). Methods We recruited patients with T2D and AMI undergoing percutaneous coronary intervention, treated with either SGLT-2i or GLP-1RA for at least 3 months before hospitalization. Subjects with HbA1c < 7% at admission were considered in good glycemic control and maintained the same glucose-lowering regimen, while those with poor glycemic control (HbA1c ≥ 7%), at admission or during follow-up, were prescribed either a SGLT-2i or a GLP-1RA to obtain a SGLT-2i/GLP-1RA combination therapy. The primary outcome was the incidence of major adverse cardiovascular events (MACE) defined as cardiovascular death, re-acute coronary syndrome, and heart failure related to AMI during a 2-year follow-up. After 3 months, the myocardial salvage index (MSI) was assessed by single-photon emission computed tomography. Findings Of the 537 subjects screened, 443 completed the follow-up. Of these, 99 were treated with SGLT-2i, 130 with GLP-1RA, and 214 with their combination. The incidence of MACE was lower in the combination therapy group compared with both SGLT-2i and GLP-1RA treated patients, as assessed by multivariable Cox regression analysis adjusted for cardiovascular risk factors (HR = 0.154, 95% CI 0.038–0.622, P = 0.009 vs GLP-1RA and HR = 0.170, 95% CI 0.046–0.633, P = 0.008 vs SGLT-2i). The MSI and the proportion of patients with MSI > 50% was higher in the SGLT-2i/GLP-1RA group compared with both SGLT-2i and GLP-1RA groups. Interpretation The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2D and AMI compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event. Trial registraition ClinicalTrials.gov ID: NCT06017544.

Elevation of cardiac damage biomarkers is associated with adverse clinical outcomes and increased mortality in COVID-19 patients. This study assessed the association of admission serum levels of sST2 and H-FABP with in hospital mortality in 191 geriatric patients (median age 86 yrs., IQR 82-91 yrs.) with COVID-19 and available measures of hs-cTnT and NT-proBNP at admission. Cox proportional hazards models were utilized to predict in hospital mortality, considering clinical/biochemical confounders as covariates. A composite cardiac score was calculated to improve predictive accuracy. Patients deceased during their hospital stay (26%) exhibited higher levels of all biomarkers, which demonstrated good discrimination for in-hospital mortality. Addition of sST2 and H-FABP significantly improved the discriminatory power of hs-cTnT and NT-proBNP. The composite cardiac score (AUC=0.866) further enhanced the predictive accuracy. Crude and adjusted Cox regressions models revealed that both sST2 and H-FABP were independently associated with in-hospital mortality (HR for sST2 >129 ng/mL, 4.32 [1.48-12.59]; HR for H-FABP >= 18 ng/mL, 7.70 [2.12-28.01]). The composite cardiac score also independently correlated with in-hospital mortality (HR for 1-unit increase, 1.47 [1.14-1.90]). In older patients with COVID-19, sST2 and H-FABP demonstrated prognostic value, improving the predictive accuracy of the routinely assessed biomarkers hs-cTnT and NT-proBNP.

MultiMorbidity (MM), defined as the co-occurrence of two or more chronic conditions, is associated with poorer health outcomes, such as recurrent hospital readmission and mortality. As a group of conditions, cardiovascular disease (CVD) exemplifies several challenges of MM, and the identification of prognostic minimally invasive biomarkers to stratify mortality risk in patients affected by cardiovascular MM is a huge challenge. Circulating miRNAs associated to inflammaging and endothelial dysfunction, such as miR-17, miR-21-5p, and miR-126-3p, are expected to have prognostic relevance. We analyzed a composite profile of circulating biomarkers, including miR-17, miR-21-5p, and miR-126-3p, and routine laboratory biomarkers in a sample of 246 hospitalized geriatric patients selected for cardiovascular MM from the Report-AGE INRCA database and BioGER INRCA biobank, to evaluate the association with all-cause mortality during 31 days and 12 and 24 months follow-up. Circulating levels of miR-17, miR-126-3p, and some blood parameters, including neutrophil to lymphocyte ratio (NLR) and eGFR, were significantly associated with mortality in these patients. Overall, our results suggest that in a cohort of geriatric hospitalized patients affected by cardiovascular MM, lower circulating miR-17 and miR-126-3p levels could contribute to identify patients at higher risk of short- and medium-term mortality.

Abstract Background The Neutrophil-to-lymphocyte ratio (NLR) is a marker of poor prognosis in hospitalized older patients with different diseases, but there is still no consensus on the optimal cut-off value to identify older patients at high-risk of in-hospital mortality. Therefore, in this study we aimed at both validating NLR as a predictor of death in older hospitalized patients and assess whether the presence of specific acute diseases can modify its predictive value. Methods This prospective cohort study included 5034 hospitalizations of older patients admitted to acute care units in the context of the ReportAge study. NLR measured at admission was considered as the exposure variable, while in-hospital mortality was the outcome of the study. ROC curves with Youden’s method and restricted cubic splines were used to identify the optimal NLR cut-off of increased risk. Cox proportional hazard models, stratified analyses, and Kaplan–Meier survival curves were used to analyse the association between NLR and in-hospital mortality. Results Both continuous and categorical NLR value (cut-off ≥ 7.95) predicted mortality in bivariate and multivariate prognostic models with a good predictive accuracy. The magnitude of this association was even higher in patients without sepsis, congestive heart failure, and pneumonia, and those with higher eGFR, albumin, and hemoglobin (p < 0.001). A negative multiplicative interaction was found between NLR and eGFR < 45 (p = 0.001). Conclusions NLR at admission is a readily available and cost-effective biomarker that could improve identification of geriatric patients at high risk of death during hospital stay independent of admitting diagnosis, kidney function and hemoglobin levels.

Background Coronavirus disease COVID-19 is a heterogeneous condition caused by SARS-CoV-2 infection. Generally, it is characterized by interstitial pneumonia that can lead to impaired gas-exchange, acute respiratory failure, and death, although a complex disorder of multi-organ dysfunction has also been described. The pathogenesis is complex, and a variable combination of factors has been described in critically ill patients. COVID-19 is a particular risk for older persons, particularly those with frailty and comorbidities. Blood bacterial DNA has been reported in both physiological and pathological conditions and has been associated with some haematological and laboratory parameters but, to date, no study has characterized it in hospitalized old COVID-19 patients The present study aimed to establish an association between blood bacterial DNA (BB-DNA) and clinical severity in old COVID-19 patients. Results BB-DNA levels were determined, by quantitative real-time PCRs targeting the 16S rRNA gene, in 149 hospitalized older patients (age range 65–99 years) with COVID-19. Clinical data, including symptoms and signs of infection, frailty status, and comorbidities, were assessed. BB-DNA was increased in deceased patients compared to discharged ones, and Cox regression analysis confirmed an association between BB-DNA and in-hospital mortality. Furthermore, BB-DNA was positively associated with the neutrophil count and negatively associated with plasma IFN-alpha. Additionally, BB-DNA was associated with diabetes. Conclusions The association of BB-DNA with mortality, immune-inflammatory parameters and diabetes in hospitalized COVID-19 patients suggests its potential role as a biomarker of unfavourable outcomes of the disease, thus it could be proposed as a novel prognostic marker in the assessment of acute COVID-19 disease.

Herpesviridae reactivation such as cytomegalovirus (CMV) has been described in severe COVID-19 (COronaVIrusDisease-2019). This study aimed to understand if CMV reactivation in older COVID-19 patients is associated with increased inflammation and in-hospital mortality. In an observational single-center cohort study, 156 geriatric COVID-19 patients were screened for CMV reactivation by RT-PCR. Participants underwent a comprehensive clinical investigation that included medical history, functional evaluation, laboratory tests and cytokine assays (TNF-α, IFN-α, IL-6, IL-10) at hospital admission. In 19 (12.2%) of 156 COVID-19 patients, CMV reactivation was detected. Multivariate Cox regression models showed that in-hospital mortality significantly increased among CMV positive patients younger than 87 years (HR: 9.94, 95% CI: 1.66–59.50). Other factors associated with in-hospital mortality were C-reactive protein (HR: 1.17, 95% CI: 1.05–1.30), neutrophil count (HR: 1.20, 95% CI: 1.01–1.42) and clinical frailty scale (HR:1.54, 95% CI: 1.04–2.28). In patients older than 87 years, neutrophil count (HR: 1.13, 95% CI: 1.05–1.21) and age (HR: 1.15, 95% CI: 1.01–1.31) were independently associated with in-hospital mortality. CMV reactivation was also correlated with increased IFN-α and TNF-α serum levels, but not with IL-6 and IL-10 serum changes. In conclusion, CMV reactivation was an independent risk factor for in-hospital mortality in COVID-19 patients younger than 87 years old, but not in nonagenarians.

Abstract Background and Aims The choice of the vascular access for cardiac pacing devices (CIED) implant may impact on patients outcome. Recent studies and consensus documents encourage the use of an extra-thoracic access to prevent adverse events. In this large, multicenter, retrospective study we report the impact of leads access on post-procedural outcome. Methods Consecutive patients receiving a CIED from 2008 to 2019 in 4 high-volume Italian hospitals were enrolled. Short- and long-term complications (i.e. pneumothorax, cardiac tamponade, pocket decubitus, pocket hematoma, lead dislodgement, lead failure) were collected and their relationship with the type of vascular access (extra- vs intra-thoracic, i.e. cephalic vein/extra-thoracic axillary vein vs subclavian vein puncture) was analyzed. Primary endpoint was the occurrence of at least one complication during follow-up. Results A total of 4,443 patients were enrolled; 3,374 (75.9%) received a pacemaker (PM) and 1,069 (24.1%) an implantable cardioverter defibrillator (ICD). Mean follow-up was 1,630±1,010 days. At least one complication occurred in 7.6% of patients. At multivariate Cox regression analysis, adjusted for baseline confounders, the presence of structural heart disease (HR 1.59, 95%CI 1.21-2.10; p=0.001), anticoagulant therapy at implantation [HR 1.31, 95%CI 1.0004-1.71; p=0.05) and female gender (HR 0.78, 95%CI 0.63-0.98; p=0.03) were associated with the primary outcome measure. Extra-thoracic access did not reduce the risk of complications compared to intra-thoracic access (HR 0.97, 95%CI 0.76-1.25 p=0.81). The use of both accesses in the same patient conferred a significant increase in the risk of complications (HR vs single approach:1.95, 95%CI 1.41-2.69; p <0.001). Conclusions The choice of a different vascular access (intra- vs extra-thoracic) does not impact on post-procedural complications in patients receiving CIED. In particular, the intra-thoracic subclavian vein puncture by experienced operators is not related to a poorer outcome. The need for both types of access in the same patient (i.e. increased procedure complexity) increases the risk of post-procedural complications.Graphical abstract