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.

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.

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.

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.

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.

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.

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.

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.

Comparison of left ventricular and biventricular pacing: Rationale and clinical implications.

Cardiac resynchronization therapy constitutes a cornerstone in advanced heart failure treatment, when there is evidence of dyssynchrony, especially by electrocardiography. However, it is plagued both by persistently high (~30%) rates of nonresponse and by deterioration of right ventricular function, owing to iatrogenic dyssynchrony in the context of persistent apical pacing to ensure delivery of biventricular pacing. Left ventricular pacing has long been considered an alternative to standard biventricular pacing and can be achieved as easily as inserting a single pacing electrode in the coronary sinus. Although monoventricular left ventricular pacing has been proven to yield comparable results with the standard biventricular modality, it is the advent of preferential left ventricular pacing, combining both the powerful resynchronization potential of multipolar coronary sinus and right-sided electrodes acting in concert and the ability to preserve intrinsic, physiological right ventricular activation. In this review, we aim to present the underlying principles and modes for delivering left ventricular pacing, as well as to highlight advantages of preferential over monoventricular configuration. Finally, current clinical evidence, following implementation of automated algorithms, regarding performance of left ventricular as compared with biventricular pacing will be discussed. It is expected that the field of preferential left ventricular pacing will grow significantly over the following years, and its combination with other advanced pacing modalities may promote clinical status and prognosis of patients with advanced dyssynchronous heart failure.

Hypertension and patients with acute coronary syndrome: Putting blood pressure levels into perspective.

Arterial hypertension is a well-established cardiovascular risk factor, and blood pressure (BP) control has largely improved the prognosis of hypertensive patients. A number of studies have assessed the role of BP levels in the prognosis of patients with acute coronary syndromes. Pathophysiologic links of hypertension to acute myocardial infarction (MI) include endothelial dysfunction, autonomic nervous system dysregulation, impaired vasoreactivity, and a genetic substrate. A history of hypertension is highly prevalent among patients presenting with MI, and some, but not all, studies have associated it with a worse prognosis. Some data support that low levels of admission and in-hospital BP may indicate an increased risk for subsequent events. Risk scores used in patients with MI have, therefore, included BP levels and a history of hypertension in their variables. Of note, good long-term BP control, ideally initiated prior to discharge, should be pursued in order to improve secondary prevention.

Revealing the intrinsic nature of the mid-gap defects in amorphous Ge2Sb2Te5.

Understanding the relation between the time-dependent resistance drift in the amorphous state of phase-change materials and the localised states in the band gap of the glass is crucial for the development of memory devices with increased storage density. Here a machine-learned interatomic potential is utilised to generate an ensemble of glass models of the prototypical phase-change alloy, Ge2Sb2Te5, to obtain reliable statistics. Hybrid density-functional theory is used to identify and characterise the geometric and electronic structures of the mid-gap states. 5-coordinated Ge atoms are the local defective bonding environments mainly responsible for these electronic states. The structural motif for the localisation of the mid-gap states is a crystalline-like atomic environment within the amorphous network. An extra electron is trapped spontaneously by these mid-gap states, creating deep traps in the band gap. The results provide significant insights that can help to rationalise the design of multi-level-storage memory devices.

Cardiac Resynchronisation Therapy and Cellular Bioenergetics: Effects Beyond Chamber Mechanics.

Cardiac resynchronisation therapy is a cornerstone in the treatment of advanced dyssynchronous heart failure. However, despite its widespread clinical application, precise mechanisms through which it exerts its beneficial effects remain elusive. Several studies have pointed to a metabolic component suggesting that, both in concert with alterations in chamber mechanics and independently of them, resynchronisation reverses detrimental changes to cellular metabolism, increasing energy efficiency and metabolic reserve. These actions could partially account for the existence of responders that improve functionally but not echocardiographically. This article will attempt to summarise key components of cardiomyocyte metabolism in health and heart failure, with a focus on the dyssynchronous variant. Both chamber mechanics-related and -unrelated pathways of resynchronisation effects on bioenergetics - stemming from the ultramicroscopic level - and a possible common underlying mechanism relating mechanosensing to metabolism through the cytoskeleton will be presented. Improved insights regarding the cellular and molecular effects of resynchronisation on bioenergetics will promote our understanding of non-response, optimal device programming and lead to better patient care.

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.

Screening for Latent Tuberculosis Infection in Patients with Autoimmune Diseases Before Initiating TNF-α Inhibitors Therapy.

INTRODUCTION: QFT-GIT is more sensitive than TST in patients under immunosuppressive therapy, but TST detects more cases of LTBI. TST remains an inexpensive test worldwide, which does not need laboratory equipment. MATERIAL AND METHODS: Overall, 457 patients having autoimmune diseases were referred. Of those referred, 158 patients were screened with QFT-GIT and TST. No patient in the present study was known to be HIV positive, or had a history of tuberculosis contact the last year. Additionally, neither of the two methods distinguish latent from active TB, and neither one is better at recognizing patients with autoimmune diseases who could avail from preventive chemoprophylaxis. RESULTS: QFT-GIT is more sensitive than TST in patients under immunosuppressive therapy, but TST detects more cases of LTBI. TST remains an inexpensive test worldwide, which does not need laboratory equipment. CONCLUSION: Since the literature for the economic evaluation of LTBI screening has not clearly defined which test is ultimately more cost-effective, low income countries like Greece should continue using TST as the primary method for diagnosis of LTBI.

Modeling the Phase-Change Memory Material, Ge2Sb2Te5, with a Machine-Learned Interatomic Potential.

The phase-change material, Ge2Sb2Te5, is the canonical material ingredient for next-generation storage-class memory devices used in novel computing architectures, but fundamental questions remain regarding its atomic structure and physicochemical properties. Here, we introduce a machine-learning (ML)-based interatomic potential that enables large-scale atomistic simulations of liquid, amorphous, and crystalline Ge2Sb2Te5 with an unprecedented combination of speed and density functional theory (DFT) level of accuracy. Two applications exemplify the usefulness of such an ML-driven approach: we generate a 7200-atom structural model, hitherto inaccessible with DFT simulations, that affords new insight into the medium-range structural order and we create an ensemble of uncorrelated, smaller structures, for studies of their chemical bonding with statistical significance. Our work opens the way for new atomistic insights into the fascinating and chemically complex class of phase-change materials that are used in real nonvolatile memory devices.