Three in One: Three Different Molybdates Trapped in a Thiacalix[4]arene Protected Ag72 Nanocluster for Structural Transformation and Photothermal Conversion.

Polyoxometalates (POMs) represent crucial intermediates in the formation of insoluble metal oxides from soluble metal ions, however, the rapid hydrolysis-condensation kinetics of MoVI or WVI makes the direct characterization of coexisted molecular species in a given medium extremely difficult. Silver nanoclusters have shown versatile capacity to encapsulate diverse POMs, which provides an alternative scene to appreciate landscape of POMs in atomic precision. Here, we report a thiacalix[4]arene protected silver nanocluster (Ag72b) that simultaneously encapsulates three kinds of molybdates (MoO4 2- , Mo6 O22 8- and Mo7 O25 8- ) in situ transformed from classic Lindqvist Mo6 O19 2- , providing more deep understanding on the structural diversity and condensation growth route of POMs in solution. Ag72b is the first silver nanocluster trapping so many kinds of molybdates, which in turn exert collective template effect to aggregate silver atoms into a nanocluster. The post-reaction of Ag72b with AgOAc or PhCOOAg produces a discrete Ag24 nanocluster (Ag24a) or an Ag28 nanocluster based 1D chain structure (Ag28a), respectively. Moreover, the post-synthesized Ag28a can be utilized as potential ignition material for further application. This work not only provides an important model for unlocking dynamic features of POMs at atom-precise level but also pioneers a promising approach to synthesize silver nanoclusters from known to unknown.

Imaging of Left Main Coronary Artery; Untangling the Gordian Knot.

Left Main Coronary Artery (LMCA) disease is considered a standout manifestation of coronary artery disease (CAD), because it is accompanied by the highest mortality. Increased mortality is expected, because LMCA is responsible for supplying up to 80% of total blood flow to the left ventricle in a right-dominant coronary system. Due to the significant progress of biomedical technology, the modern drug-eluting stents have remarkably improved the prognosis of patients with LMCA disease treated invasively. In fact, numerous randomized trials provided similar results in one- and five-year survival of patients treated with percutaneous coronary interventions (PCI) -guided with optimal imaging and coronary artery bypass surgery (CABG). However, interventional treatment requires optimal imaging of the LMCA disease, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The aim of this manuscript is to review the main pathophysiological characteristics, to present the imaging techniques of LMCA, and, last, to discuss the future directions in the depiction of LMCA disease.

Statistical modeling of diabetic neuropathy: Exploring the dynamics of nerve mortality.

Diabetic neuropathy is a disorder characterized by impaired nerve function and reduction of the number of epidermal nerve fibers per epidermal surface. Additionally, as neuropathy related nerve fiber loss and regrowth progresses over time, the two-dimensional spatial arrangement of the nerves becomes more clustered. These observations suggest that with development of neuropathy, the spatial pattern of diminished skin innervation is defined by a thinning process which remains incompletely characterized. We regard samples obtained from healthy controls and subjects suffering from diabetic neuropathy as realisations of planar point processes consisting of nerve entry points and nerve endings, and propose point process models based on spatial thinning to describe the change as neuropathy advances. Initially, the hypothesis that the nerve removal occurs completely at random is tested using independent random thinning of healthy patterns. Then, a dependent parametric thinning model that favors the removal of isolated nerve trees is proposed. Approximate Bayesian computation is used to infer the distribution of the model parameters, and the goodness-of-fit of the models is evaluated using both non-spatial and spatial summary statistics. Our findings suggest that the nerve mortality process changes as neuropathy advances.

Pairwise interaction Markov model for 3D epidermal nerve fibre endings.

In this paper, the spatial arrangement and possible interactions between epidermal nerve fibre endings are investigated and modelled by using confocal microscopy data. We are especially interested in possible differences between patterns from healthy volunteers and patients suffering from mild diabetic neuropathy. The locations of the points, where nerves enter the epidermis, the first branching points and the points where the nerve fibres terminate, are regarded as realizations of spatial point processes. We propose an anisotropic point process model for the locations of the nerve fibre endings in three dimensions, where the points interact in cylindrical regions. First, the locations of end points in R 2 $\mathbb {R}^2$ are modelled as clusters around the branching points and then, the model is extended to three dimensions using a pairwise interaction Markov field model with cylindrical neighbourhood for the z-coordinates conditioned on the planar locations of the points. We fit the model to samples taken from healthy subjects and subjects suffering from diabetic neuropathy. In both groups, after a hardcore radius, there is some attraction between the end points. However, the range and strength of attraction are not the same in the two groups. Performance of the model is evaluated by using a cylindrical version of Ripley's K function due to the anisotropic nature of the data. Our findings suggest that the proposed model is able to capture the 3D spatial structure of the end points.

Spatial modeling of epidermal nerve fiber patterns.

Peripheral neuropathy is a condition associated with poor nerve functionality. Epidermal nerve fiber (ENF) counts per epidermal surface are dramatically reduced and the two-dimensional (2D) spatial structure of ENFs tends to become more clustered as neuropathy progresses. Therefore, studying the spatial structure of ENFs is essential to fully understand the mechanisms that guide those morphological changes. In this article, we compare ENF patterns of healthy controls and subjects suffering from mild diabetic neuropathy by using suction skin blister specimens obtained from the right foot. Previous analysis of these data has focused on the analysis and modeling of the spatial ENF patterns consisting of the points where the nerves enter the epidermis, base points, and the points where the nerve fibers terminate, end points, projected on a 2D plane, regarding the patterns as realizations of spatial point processes. Here, we include the first branching points, the points where the nerve trees branch for the first time, and model the three-dimensional (3D) patterns consisting of these three types of points. To analyze the patterns, spatial summary statistics are used and a new epidermal active territory that measures the volume in the epidermis that is covered by the individual nerve fibers is constructed. We developed a model for both the 2D and the 3D patterns including the branching points. Also, possible competitive behavior between individual nerves is examined. Our results indicate that changes in the ENFs spatial structure can more easily be detected in the later parts of the ENFs.

Origin of radiation tolerance in amorphous Ge2Sb2Te5 phase-change random-access memory material.

The radiation hardness of amorphous Ge2Sb2Te5 phase-change random-access memory material has been elucidated by ab initio molecular-dynamics simulations. Ionizing radiation events have been modeled to investigate their effect on the atomic and electronic structure of the glass. Investigation of the short- and medium-range order highlights a structural recovery of the amorphous network after exposure to the high-energy events modeled in this study. Analysis of the modeled glasses reveals specific structural rearrangements in the local atomic geometry of the glass, as well as an increase in the formation of large shortest-path rings. The electronic structure of the modeled system is not significantly affected by the ionizing radiation events, since negligible differences have been observed before and after irradiation. These results provide a detailed insight into the atomistic structure of amorphous Ge2Sb2Te5 after irradiation and demonstrate the radiation hardness of the glass matrix.

Adenosine stress myocardial perfusion imaging in octogenarians: Safety, tolerability, and long-term prognostic implications of hemodynamic response and SPECT-related variables.

BACKGROUND: Evaluation of tolerability, safety, and prognostic implications of adenosine stress myocardial perfusion imaging (MPI) in octogenarians. METHODS: 370 octogenarians (49% known coronary artery disease) were studied. Hemodynamic response, MPI-related data, and rest-left ventricular ejection fraction (LVEF) based on echocardiography were registered per patient, and prospective follow-up was performed to document all-cause death (ACD), cardiac death (CD), myocardial infarction (MI), and late revascularization. RESULTS: No deaths or MIs were observed during adenosine infusion or the short-term post-infusion period. 86% of patients were able to tolerate a 6-minute infusion. All side effects terminated spontaneously after infusion cessation, except for one case of pulmonary oedema. After 9.3 years, there were 124 ACDs, 62 CDs, 16 MIs, and 35 revascularizations. Differences between survival curves of summed stress score (SSS)-based risk groups were significant for all end points (P < .001). SSS and LVEF were independent predictors of all end points (P ≤ .01) and lung uptake of cardiac end points. ΔHR <10 bpm (OR = 1.78, P = .004) and inability to increase HR by >10 bpm and decrease systolic blood pressure by >10 mmHg (OR = 2, P = .02) during adenosine infusion were independent predictors of ACD and CD, respectively. Hemodynamic response variables, SSS, and lung uptake provided incremental prognostic value over pre-test data for ACD and CD. CONCLUSIONS: In octogenarians, adenosine stress MPI is well tolerated and provides effective long-term risk stratification.

Heart failure study of multipoint pacing effects on ventriculoarterial coupling: Rationale and design of the HUMVEE trial.

Cardiac resynchronization therapy (CRT) is an established therapy for symptomatic heart failure (HF). Unfortunately, many recipients remain nonresponders. Studies have revealed the potential role of multipoint pacing (MPP) in improving response and outcomes. The aim of this study is to compare the effects of MPP against those of standard biventricular pacing (BVP) on (i) ventriculoarterial coupling (VAC) and energy efficiency of the failing heart, (ii) diastolic function, (iii) quality of life, and (iv) NT-proBNP levels and glomerular filtration rate (GFR) during a follow-up of 13 months. HUMVEE is a single-center, prospective, observational, crossover cohort study. Seventy-six patients with BVP indication will be implanted with a system able to deliver both pacing modes. BVP will be activated at implantation and optimized 1 month after. At 6 months postoptimization MPP will be activated and optimized. Optimization will be performed based on stroke volume maximization, as assessed by ultrasound. Laboratory measurements (GFR and NT-proBNP) and echocardiographic studies (VAC calculation, strain rate, diastolic function) will be performed at implantation, 6 months post-BVP optimization and at the end of 13 months of follow-up (6 months post-MPP optimization). Potential reduction in arrhythmogenesis by MPP will also be assessed. MPP is a pacing modality with the potential to improve HF patients' outcomes. The HUMVEE trial will attempt to associate any potential added beneficial effects of MPP over standard BVP with alterations in VAC and energy efficiency of the heart, thus uncovering a novel mechanistic link between MPP and improved outcomes in HF.

Risk stratification for large artery or chronic coronary artery disease-related ischemic stroke in octogenarians undergoing exercise stress myocardial perfusion imaging: A cohort study.

OBJECTIVES: To test, if in octogenarians, treadmill exercise with myocardial perfusion imaging (exercise-MPI) can risk stratify for large artery or chronic CAD-related ischemic stroke (LACCIS). METHODS: Exercise-MPI-related data of 237 octogenarians (55% prior MI or revascularization) without previous stroke were registered and prospective follow-up was performed to document LACCIS. LACCIS was defined as acute onset of neurological symptoms with CT/MRI findings of non-lacunar-type infarcts in the absence of atrial fibrillation or intracardiac embolic sources. RESULTS: After 7.3 years, 10 LACCIS were documented. SSS [HR 1.08 (1.02-1.13 95% CIs), SDS [HR 1.1 (1.04-1.16 95% CIs)], and non-sustained VT or transient AV block during exercise [HR 3.9 (1.7-9.0 95% CIs)] were predictors of LACCIS (P < .01 for all). A SSS threshold of 16 had 81% specificity for identification of future LACCIS and risk groups formed according to this cut-off had significantly different LACCIS-free survival (P = .015). CONCLUSION: Exercise-MPI in octogenarians can provide risk stratification markers for LACCIS.

Modelling the local atomic structure of molybdenum in nuclear waste glasses with ab initio molecular dynamics simulations.

The nature of chemical bonding of molybdenum in high level nuclear waste glasses has been elucidated by ab initio molecular dynamics simulations. Two compositions, (SiO2)57.5-(B2O3)10-(Na2O)15-(CaO)15-(MoO3)2.5 and (SiO2)57.3-(B2O3)20-(Na2O)6.8-(Li2O)13.4-(MoO3)2.5, were considered in order to investigate the effect of ionic and covalent components on the glass structure and the formation of the crystallisation precursors (Na2MoO4 and CaMoO4). The coordination environments of Mo cations and the corresponding bond lengths calculated from our model are in excellent agreement with experimental observations. The analysis of the first coordination shell reveals two different types of molybdenum host matrix bonds in the lithium sodium borosilicate glass. Based on the structural data and the bond valence model, we demonstrate that the Mo cation can be found in a redox state and the molybdate tetrahedron can be connected with the borosilicate network in a way that inhibits the formation of crystalline molybdates. These results significantly extend our understanding of bonding in Mo-containing nuclear waste glasses and demonstrate that tailoring the glass composition to specific heavy metal constituents can facilitate incorporation of heavy metals at high concentrations.

The Role of NT-proBNP Levels in the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction-It Is Not Always a Hide-and-Seek Game.

Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. This has been attributed to the complex pathophysiological mechanisms that accompany individuals with several co-morbidities and symptoms and signs of HFpEF. Natriuretic peptides have been recognized as playing an important role in the diagnosis and monitoring of patients with heart failure with reduced ejection fraction (HFrEF), but their role in HFpEF remains controversial, driven by the different pathophysiological characteristics of these patients. The type of diet consumed has shown various modifying effects on plasma levels of NPs, irrespective of pharmacological treatment.

Exploring the link between blood pressure variability and atrial fibrillation: current insights and future directions.

Atrial fibrillation (AF) is the most common heart rhythm disorder, especially in people over the age of 50, which affects more than 40 million people worldwide. Many studies have highlighted the association between hypertension with the development of AF. Blood pressure variability (BPV) is a dynamic size obtained by recording blood pressure oscillations using specific readings and at specific time intervals. A multitude of internal and external factors shape BPV while at the same time constituting a common pathogenetic pathway with the development of AF. Until recently, BPV has been applied exclusively in preclinical and clinical studies, without significant implications in clinical practice. Indeed, even from the research side, the determination of BPV is limited to patients without AF due to doubts about the accuracy of its measurement methods in patients with AF. In this review, we present the current evidence on common pathogenic pathways between BPV and AF, the reliability of quantification of BPV in patients with AF, the prognostic role of BPV in these patients, and discuss the future clinical implications of BPV in patients with AF.

The Application of Precision Medicine in Structural Heart Diseases: A Step towards the Future.

The personalized applications of 3D printing in interventional cardiology and cardiac surgery represent a transformative paradigm in the management of structural heart diseases. This review underscores the pivotal role of 3D printing in enhancing procedural precision, from preoperative planning to procedural simulation, particularly in valvular heart diseases, such as aortic stenosis and mitral regurgitation. The ability to create patient-specific models contributes significantly to predicting and preventing complications like paravalvular leakage, ensuring optimal device selection, and improving outcomes. Additionally, 3D printing extends its impact beyond valvular diseases to tricuspid regurgitation and non-valvular structural heart conditions. The comprehensive synthesis of the existing literature presented here emphasizes the promising trajectory of individualized approaches facilitated by 3D printing, promising a future where tailored interventions based on precise anatomical considerations become standard practice in cardiovascular care.

Mortality Rates in Patients Undergoing Urgent Versus Elective Transcatheter Aortic Valve Replacement: A Meta-analysis.

Patients with severe aortic stenosis (AoS) often present with acute heart failure and compensation, frequently leading to cardiogenic shock. Transcatheter Aortic Valve Replacement (TAVR) has been recently performed as a bailout treatment in such patients. The aim of our meta-analysis is to compare urgent TAVR with elective procedures. We systematically screened three databases searching for studies comparing urgent vs elective TAVR. Primary endpoint is the 30-days mortality. Secondary endpoints included in-hospital mortality, device success, periprocedural vascular complications, 30-days stroke, 30-days acute kidney injury (AKI), permanent pacemaker implantation (PPM), moderate or severe paravalvular leakage, and 30-days bleeding. Seventeen studies were included, with a total of 84,495 patients. Urgent TAVR was associated with an increased risk for 30-days mortality [Risk Ratio (RR): 2.53, 95% Confidence Intervals (CI): 1.81-3.54)], in-hospital mortality (RR: 2.67, 95% CI: 1.94-3.68), periprocedural vascular complications (RR: 1.91, 95% CI: 1.28-2.85) and AKI (RR: 2.83, 95% CI: 1.93-4.14), compared with elective procedure. No differences were observed in the other secondary endpoints. Urgent TAVR was associated with higher in-hospital and 30-days mortality, possibly driven by the increased incidence of AKI and vascular complications in urgent TAVR. The results highlight the importance of early TAVR in stable AoS patients.

Multipoint left ventricular pacing effects on hemodynamic parameters and functional status: HUMVEE single-arm clinical trial (NCT03189368).

OBJECTIVES: The aim of this study was to assess the capacity of optimized multipoint pacing (MPP) over optimized cardiac resynchronization therapy (CRT), in terms of clinical, functional, and echocardiographic parameters among patients with dyssynchronous heart failure (HF). METHODS: Eighty patients (Caucasian, 77.5% male, 68.4 ± 10.1 years, and 53.8% ischemic cardiomyopathy) sequentially received optimized CRT and optimized MPP over 6- and 12-month periods in a single-arm clinical trial. Clinical, laboratory, and echocardiographic assessment was conducted at baseline and after the completion of each step. RESULTS: Significant additive effects of optimized MPP over optimized CRT were noted with regard to 6-min walking distance (baseline/optCRT/optMPP: 293 ± 120 m vs 367 ± 94 m vs 405 ± 129 m and p < 0.001), NYHA class (2.36 vs 2.19 vs 1.45 and p < 0.001), VTIlvot (14.25 ± 3.2 cm vs 16.2 ± 4 cm vs 17.5 ± 3.4 cm and p < 0.001), stroke volume (48 ± 13.5 ml vs 55 ± 15 ml vs 59 ± 15 ml and p < 0.001), left ventricular ejection fraction (LVEF) (29% ± 7.1% vs 33% ± 7.3% vs 37% ± 7.7% and p < 0.001), maximal left atrial volume (77.2 ± 34.2 ml vs 74.2 ± 39.5 ml vs 67.7 ± 32 ml and p = 0.02), pulmonary artery systolic pressure (35.9 mmHg vs 33.5 mmHg vs 31 mmHg and p < 0.001), and right ventricular strain (-8.3% ± 6.9% vs -8.8% ± 6.6% vs -11.8% ± 6.1% and p = 0.022). With regard to VAC, stroke work (SW), and CP as percentages of maximal, there was a significant difference detected as compared to baseline for both CRT and MPP. Additive effects persisted only if suitable MPP dipoles were present. Exploratory analysis revealed that ischemic cardiomyopathy continued to exhibit significant differences that favor MPP, whereas nonischemic cardiomyopathy had similar findings with regard to total left atrial strain and quality of life. CONCLUSIONS: Optimized MPP showed significant improvements in hemodynamic parameters and ventricular function in patients with HF over optimized CRT. The beneficial effect was more prominent in men and in those with rather reduced LVEF, consistent with findings that suggest a beneficial trend in VAC and CP with more homogeneous depolarization offered by optimized MPP.

Impact of renal sympathetic denervation on cardiac magnetic resonance-derived cardiac indices in hypertensive patients - A meta-analysis.

BACKGROUND: Renal sympathetic denervation (RDN) is a safe device-based option for the treatment of hypertension although current guidelines do not recommend its use in routine clinical practice. In this meta-analysis, we investigated the effects of RDN in cardiac magnetic resonance (CMR)-derived cardiac indices. METHODS: This meta-analysis was performed in accordance with the PRISMA statement. A comprehensive systematic search of MEDLINE database and Cochrane library through to January 2021 was performed. The inclusion criteria were studies that enrolled patients undergoing RDN in whom CMR data were provided for left ventricular end-diastolic volume indexed to body surface area (BSA) (LVEDVI), left ventricular end-systolic volume indexed (LVESVI), left ventricular mass indexed (LVMI), and left ventricular ejection fraction (LVEF) pre and post RDN. A random effects model was used for the analyses. RESULTS: Our search strategy revealed 9 studies that were finally included in the meta-analysis (n=300 patients, mean age: 60 years old, males: 59%). Compared to control group, RDN patients showed significantly lower values in the attained volumes (LVEDVI: -6.70 ml/m2, p=0.01; LVESVI: -3.63 ml/m2, p=0.006). Moreover, RDN group achieved a statistically significant higher attained LVEF (3.49%, p=0.01). A non-significant difference was found in the attained LVMI between RDN and control groups (-2.59 g/m2, p=0.39). Compared to pre-RDN values, RDN reduces significantly the LVMI, the LVEDVI, and the LVESVI while a non-significant change of LVEF was found. CONCLUSIONS: In conclusion, the current study demonstrates the potential beneficial role of RDN in CMR-derived cardiac indices that reflect adverse remodeling. However, large, randomized studies are needed to elucidate the role of RDN in cardiac remodeling in hypertension, heart failure, and other clinical settings.

Comparative Trial of the Effects of Left Ventricular and Biventricular Pacing on Indices of Cardiac Function and Clinical Course of Patients With Heart Failure: Rationale and Design of the READAPT Randomized Trial.

Nonresponse to cardiac resynchronization therapy (CRT) has been related with right ventricular dysfunction. Ventriculoarterial coupling (VAC) assesses energy efficiency of the failing heart and stroke work maximization for a given contractility, for both systemic and pulmonary circulations. Preferential left ventricular pacing (pLVP) can overcome iatrogenic right ventricular dysfunction by achieving left ventricle resynchronization and by allowing for intrinsic activation of the right side, with ramifications extending beyond cardiac output and atrial fibrillation occurrence. In the present article, we detail the design of a single-center randomized clinical trial to evaluate the effects of a pLVP algorithm. More specifically, following randomization of 220 CRT-eligible patients to standard biventricular pacing and pLVP, their clinical course will be followed for 12 months, through echocardiography to study indices of systolic and diastolic function of ventricles, left and right side VAC to evaluate efficiency, and cardiopulmonary exercise test to objectively document improvements in functional status, as well as a self-reported quality of life questionnaire. Device programming will be based on echocardiography-evaluated maximization of stroke volume and subsequent interventricular and atrioventricular delay adjustments delegated to the device. Findings of this trial may provide evidence for alternative programming of the devices, linking pLVP to improved clinical outcomes.

Multipoint left ventricular pacing as an addition to cardiac resynchronization therapy: a bridge to the holy grail?

Cardiac resynchronization therapy (CRT) constitutes a cornerstone to the treatment of advanced dyssynchronous heart failure (DyssHF); moreover it represents one of the few instances that a revolutionary approach was pursued, yielding previously unfathomable benefits to patients out of realistic therapeutic options. However, as is rather extensively established, nonresponse, or even negative response, to CRT continue to plague its course, precluding favourable effects in up to 40% of recipients, for a multitude of reasons. Given the scope of the issue of nonresponse, attempts to negate it by means of altering CRT delivery mode, and, more specifically, by introducing multipoint left ventricular pacing (MPP) have been focused on. Possible reasons for divergent trial results will be presented, as well as potential criteria for predicting whether MPP activation may reap additional benefits as compared to conventional biventricular pacing (BVP). Finally, an alternative framework for approaching CRT in general will be put forward, including advancements which in the (near) future may once more revolutionise heart failure treatment.

Rationale and Design of the ACS-BP Study: Prognostic Value of In-Hospital Blood Pressure and Indices of Atherosclerosis in Acute Coronary Syndromes.

BACKGROUND: High blood pressure (BP) is a leading risk factor for coronary artery disease and other major cardiovascular events. OBJECTIVE: Blood pressure variability (BPV), ambulatory arterial stiffness index (AASI) and ankle- brachial index (ABI) have been proposed as indices that can improve risk stratification for an adverse cardiac outcome. However, their utility in the setting of acute coronary syndromes (ACS) is unclear. METHODS: The ACS-BP study is a single-centre observational cohort study designed to investigate the prognostic role of haemodynamic load and arterial stiffness indices for cardio-renal outcomes in patients with acute myocardial infarction (AMI). All consecutive patients admitted with a diagnosis of acute AMI with or without ST segment elevation were screened for inclusion in the study. The management of AMI will follow current guidelines. RESULTS AND DISCUSSION: Data from baseline clinical and laboratory parameters during their hospitalization were collected. The haemodynamic load of each patient was determined by clinical BP values as well as 24-h ambulatory BP monitoring. The AASI was calculated from the raw 24-h BP data and ABI was measured after the third day of hospitalization using a certified device. Patients were followed-up for 12 months in order to collect data for hard cardiovascular and renal endpoints. CONCLUSION: The study results should clarify the role of these non-invasive tools in secondary risk stratification of such patients.

Predicted Skeletal Muscle Mass and 4-Year Cardiovascular Disease Incidence in Middle-Aged and Elderly Participants of IKARIA Prospective Epidemiological Study: The Mediating Effect of Sex and Cardiometabolic Factors.

The sex-specific effect of skeletal muscle mass (SMM) index (SMI) on 4-year first fatal/non-fatal cardiovascular disease (CVD) event in free-of-disease individuals was examined. In 2009, n = 1411 inhabitants (mean age = 64(12)) from Ikaria were selected. Follow-up was performed in 2013. SMI was created to reflect SMM through appendicular skeletal muscle mass (indirectly calculated through formulas) divided by body mass index (BMI). Fifteen and six tenths percent of participants exhibited CVD (19.8% in men/12% in women, p = 0.002). Significant U-shape trends were observed in participants >65 years old and women irrespective to age confirmed through multi-adjusted Cox regression analysis; in age >65 years, Hazard Ratio (HR)(2nd vs. 1st SMI tertile) = 0.80, 95% Confidence Interval (95%CI) (0.45, 0.96) and in women HR(2nd vs. 1st SMI tertile) = 0.71, 95% CI (0.33, 0.95), while, as for the 3rd SMI tertile, no significant trends were observed. Mediation analysis revealed that mediators of the aforementioned associations in men were the arterial distensibility and total testosterone, while, in women, inflammation, insulin resistance, and arterial distensibility. High SMM accompanied by obesity may not guarantee lower CVD risk. Specific cardiometabolic factors seem to explain this need for balance between lean and fat mass.