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Traditionally focused on obstructive atherosclerosis, contemporary research indicates that up to 70% of patients undergoing coronary angiography for angina and ischemic symptoms do not exhibit significant stenoses. Nonobstructive coronary artery disease (CAD) has emerged as a prevalent phenotype among these patients. This review emphasizes the emerging understanding that nonobstructive coronary artery disease, encompassing conditions such as ANOCA (Angina with No Obstructive Coronary Artery Disease), INOCA (Ischemia with No Obstructive Coronary Artery Disease), and MINOCA (Myocardial Infarction with No Obstructive Coronary Arteries), represents the most prevalent phenotype in cardiac patients. It delves into the complex pathophysiology underlying these conditions, focusing on microvascular dysfunction and coronary vasoreactivity, which contribute to myocardial ischemia despite the absence of significant coronary obstructions. Additionally, the review critically examines the limitations of current treatments which primarily target obstructive lesions and underscores the necessity for tailored therapies that address the specific microvascular and immunoinflammatory pathways involved in nonobstructive CAD. The main focus of this review is to advocate for a shift in diagnostic and therapeutic strategies to better identify and manage this widely prevalent yet under-recognized subset of CAD. [ABSTRACT FROM AUTHOR]

One mechanism to regulate pathological vascular calcification (VC) is its active inhibition. Loss or inactivation of endogenic inhibitors is a major inductor of VC. Such inhibitors are proteins rich in gamma-glutamyl residues (Gla-proteins), whose function strongly depends on vitamin K. The current narrative review is focused on discussing the role of extrahepatic vitamin K-dependent Gla-proteins (osteocalcin, OC; matrix Gla-protein, MGP; Gla-rich protein, GRP) in cardio-vascular pathology. Gla-proteins possess several functionally active forms whose role in the pathogenesis of VC is still unclear. It is assumed that low circulating non-phosphorylated MGP is an indicator of active calcification and could be a novel biomarker of prevalent VC. High circulating completely inactive MGP is proposed as a novel risk factor for cardio-vascular events, disease progression, mortality, and vitamin K deficiency. The ratio between uncarboxylated (ucOC) and carboxylated (cOC) OC is considered as an indicator of vitamin K status indirectly reflecting arterial calcium. Despite the evidence that OC is an important energy metabolic regulator, its role on global cardio-vascular risk remains unclear. GRP acts as a molecular mediator between inflammation and calcification and may emerge as a novel biomarker playing a key role in these processes. Gla-proteins benefit clinical practice as inhibitors of VC, modifiable by dietary factors. [ABSTRACT FROM AUTHOR]

Bioprinting is a promising alternative method to generate skin substitutes because it can replicate the structural organization of the skin into biomimetic layers in vitro. In this study, six primary human skin cell types were used to bioprint a trilayer skin construct consisting of epidermis, dermis, and hypodermis. Transplantation of the bioprinted skin with human cells onto full-thickness wounds of nu/nu mice promoted rapid vascularization and formation of epidermal rete ridges analogous to the native human epidermis, with a normal-looking extracellular matrix. Cell-specific staining confirmed the integration of the implanted cells into the regenerated skin. Using a similar approach, a 5 centimeter–by–5 centimeter bioprinted autologous porcine skin graft was transplanted onto full-thickness wounds in a porcine excisional wound model. The bioprinted skin graft improved epithelialization, reduced skin contraction, and supported normal collagen organization with reduced fibrosis. Differential gene expression demonstrated pro-remodeling protease activity in wounds transplanted with bioprinted autologous skin grafts. These results demonstrate that bioprinted skin can support skin regeneration to allow for nonfibrotic wound healing and suggest that the skin bioprinting technology may be applicable for human clinical use. Editor's summary: Full-thickness skin wounds are often treated with autologous skin grafting, but this option is limited by the volume of skin that can be harvested. Another treatment option consists of dermal skin substitutes, but results are frequently suboptimal. Here, Jorgensen and colleagues incorporated six human skin cell types into a multilayered skin construct through extrusion bioprinting. In vitro, this construct maintained a three-layer structure and matured appropriately. In mice, the construct accelerated wound healing and promoted neovascularization and extracellular matrix remodeling to reduce fibrosis and scar formation. In pigs, grafting with an autologous porcine bioprinted skin contruct led to increased epithelialization and reduced wound contraction, suggesting that bioprinted skin might be an alternative to treat human full-thickness wounds. —Melissa Norton [ABSTRACT FROM AUTHOR]

Background: Catheter ablation (CA) remains challenging due to suboptimal success rates in persistent atrial fibrillation (AF). Existing mapping technologies cannot reliably distinguish sources in this patient population. Recently, the novel electrographic flow (EGF) mapping system was developed using a modified Horn‐Schunk optical flow algorithm to detect and quantify patterns of electrical wavefront propagation in the atria. Objectives: To test the hypothesis that targeted source ablation based on EGF mapping is superior to empiric AF ablation. Methods: We included all consecutive patients undergoing EGF guided ablation for persistent AF. All patients underwent pulmonary vein isolation (PVI) and were treated with the same EAM system (CARTO). The outcome of PVI+EGF guided CA was compared with data of PVI‐only procedures (PVI‐only group) and PVI plus additional empiric adjunctive linear and substrate ablations (PVI+LINES group). 12‐months outcome as freedom from AF and atrial tachycardia/flutter (AT/AFL), procedural safety and efficiency characterized by procedure duration, fluoroscopy use, radiofrequency applications and duration, were analyzed. Both intention‐to‐treat and per protocol analysis were conducted. Results: A total number of 70 patients (39 in PVI+EGF, 16 in PVI‐only and 15 patients in PVI+LINES group) were enrolled. Intention‐to‐treat analysis showed fewer AF recurrences in PVI+EGF as compared with the PVI‐only or PVI+LINES groups at 12 months (25.6% vs. 62.5% vs. 53.3%, p =.02). There were no differences in AT/AFL recurrence (17.9% vs. 37.5% vs. 20.0%, p =.37). Procedure times were longer in PVI+EGF group (p <.01), and there were no differences in fluoroscopy use (p =.67). Conclusion: Our data suggest that patients treated with EGF‐guided CA developed fewer AF recurrences. Although the procedure times are longer, it seems to be safe and offers a more targeted, patient‐specific ablation strategy beyond PVI than adjunctive empiric lines and substrate ablation in this complex group of patients. [ABSTRACT FROM AUTHOR]

In this paper, the feasibility of myocardial recovery is analyzed through a literature review. First, the phenomena of remodeling and reverse remodeling are analyzed, approached through the physics of elastic bodies, and the terms myocardial depression and myocardial recovery are defined. Continuing, potential biochemical, molecular, and imaging markers of myocardial recovery are reviewed. Then, the work focuses on therapeutic techniques that can facilitate the reverse remodeling of the myocardium. Left ventricular assist device (LVAD) systems are one of the main ways to promote cardiac recovery. The changes that take place in cardiac hypertrophy, extracellular matrix, cell populations and their structural elements, β-receptors, energetics, and several biological processes, are reviewed. The attempt to wean the patients who experienced cardiac recovery from cardiac assist device systems is also discussed. The characteristics of the patients who will benefit from LVAD are presented and the heterogeneity of the studies performed in terms of patient populations included, diagnostic tests performed, and their results are addressed. The experience with cardiac resynchronization therapy (CRT) as another way to promote reverse remodeling is also reviewed. Myocardial recovery is a phenomenon that presents with a continuous spectrum of phenotypes. There is a need for algorithms to screen suitable patients who may benefit and identify specific ways to enhance this phenomenon in order to help combat the heart failure epidemic. [ABSTRACT FROM AUTHOR]

Treatment of atrial fibrillation (AF) remains challenging despite significant progress in understanding its underlying mechanisms. The first detailed, quantitative theory of functional re-entry, the 'leading circle' model, was developed more than 40 years ago. Subsequently, in decades of study, an alternative paradigm based on spiral waves has long been postulated to drive AF. The rotor as a 'spiral wave generator' is a curved 'vortex' formed by spin motion in the two-dimensional plane, identified using advanced mapping methods in experimental and clinical AF. However, it is challenging to achieve complementary results between experimental results and clinical studies due to the limitation in research methods and the complexity of the rotor mechanism. Here, we review knowledge garnered over decades on generation, electrophysiological properties, and three-dimensional (3D) structure diversity of the rotor mechanism and make a comparison among recent clinical approaches to identify rotors. Although initial studies of rotor ablation at many independent centres have achieved promising results, some inconclusive outcomes exist in others. We propose that the clinical rotor identification might be substantially influenced by (i) non-identical surface activation patterns, which resulted from a diverse 3D form of scroll wave, and (ii) inadequate resolution of mapping techniques. With rapidly advancing theoretical and technological developments, future work is required to resolve clinically relevant limitations in current basic and clinical research methodology, translate from one to the other, and resolve available mapping techniques. [ABSTRACT FROM AUTHOR]

Myocardial ischemic injury and its resolution are the key determinants of morbidity or mortality in heart failure. The cause and duration of ischemia in patients vary. Numerous experimental models and methods have been developed to define genetic, metabolic, molecular, cellular, and pathophysiological mechanisms, in addition to defining structural and functional deterioration of cardiovascular performance. The rapid rise of big data, such as single-cell analysis techniques with bioinformatics, machine learning, and neural networking, brings a new level of sophistication to our understanding of myocardial ischemia. This mini-review explores the multifaceted nature of ischemic injury in the myocardium. We highlight recent state-of-the-art findings and strategies to show new directions of high-impact approach to understanding myocardial tissue remodeling. This next age of heart and circulatory physiology research will be more comprehensive and collaborative to uncover the origin, progression, and manifestation of heart failure while strengthening novel treatment strategies. [ABSTRACT FROM AUTHOR]

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Aim: In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI.Methods: Patients undergoing PCI for stable angina (SA) or non-ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the procedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR >32 or CFR <2 or RRR <2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI.Results: A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs-troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p=0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p=0.03 & 4.25 vs 2.75, p < 0.01). Neutrophil count was lower after PCI in the colchicine arm (p=0.02), and hsCRP post-PCI remained low in both treatment arms (1.0 mg/L vs 1.7 mg/L, p=0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs-troponin-I change (46 ng/L vs 152 ng/L, p=0.01).Conclusion: In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation. [ABSTRACT FROM AUTHOR]

Background: Octogenarians and beyond have often been neglected in the populational study of disease despite being at the highest point of non-modifiable disease risk burden and the fastest-growing age group for the past decade. This study examined the characteristics and in-hospital management of octogenarian patients with acute coronary syndrome (ACS) in a multi-ethnic, middle-income country in South East Asia.Method: This retrospective study utilised the Malaysian National Cardiovascular Disease- ACS (NCVD-ACS) registry. Consecutive patient data of those ≥80 years old admitted with ACS at 24 participating hospitals from 2008 to 2017 (n = 3162) were identified. Demographics, in-hospital intervention, and evidence-based pharmacotherapies over the 10-years were examined and compared across groups of interests using the Chi-square test. Multivariate logistic regression was used to calculate the adjusted odds ratio of receiving individual therapies according to patients' characteristics.Results: Octogenarians made up 3.8% of patients with ACS in the NCVD-ACS registry (mean age = 84, SD ± 3.6) from 2008 until 2017. The largest ethnic group was Chinese (44%). Most octogenarians (95%) have multiple cardiovascular risk factors, with hypertension (82%) being the main. Non-ST-elevation myocardial infarction (NSTEMI) predominated (38%, p < 0.001). Within the 10-year, there were positive increments in cardiovascular intervention and pharmacotherapies. Only 10% of octogenarians with ACS underwent percutaneous coronary intervention (PCI), the majority being STEMI patients (17.5%; p < 0.05). More than 80% were prescribed aspirin (91.3%) either alone or combined, dual antiplatelet therapy (DAPT) (83.3%), anticoagulants (89.7%) and statins (89.6%), while less being prescribed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (47.6%) and beta-blockers (43.0%). Men were more likely to receive PCI than women (adjusted Odds Ratio (aOR): 0.698; 95% CI: 0.490-0.993). NSTEMI (aOR = 0.402, 95% CI: 0.278-0.583) and unstable angina (UA) (aOR = 0.229, 95% CI: 0.143-0.366) were less likely to receive PCI but more likely given anticoagulants (NSTEMI, aOR = 1.543, 95% CI: 1.111-2.142; UA, aOR = 1.610, 95% CI: 1.120-2.314) than STEMI. The presence of cardiovascular risk factors and comorbidities influences management.Conclusion: Octogenarians with ACS in this country were mainly treated with cardiovascular pharmacotherapies. As the number of octogenarians with ACS will continue to increase, the country needs to embrace the increasing use of PCI in this group of patients. [ABSTRACT FROM AUTHOR]

Background: Vitamin K is associated with reduced cardiovascular disease risk such as heart failure, possibly by carboxylation of matrix-gla protein (MGP), a potent inhibitor of vascular calcification. The relationship of vitamin K intake or status with cardiac structure and function is largely unknown. Therefore this study aims to investigate the prospective association of vitamin K status and intake with echocardiographic measures. Methods: This study included 427 participants from the Hoorn Study, a population-based cohort. Vitamin K status was assessed at baseline by plasma desphospho-uncarboxylated MGP (dp-ucMGP) with higher concentrations reflecting lower vitamin K status. Vitamin K intake was assessed at baseline with a validated food-frequency questionnaire. Echocardiography was performed at baseline and after a mean follow-up time of 7.6, SD=±0.7 years. We used linear regression for the association of vitamin K status and intake with left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI), adjusted for potential confounders. Results: The mean age was 66.8, SD=±6.1 years (51% were male). A high vitamin K status was prospectively associated with decreased LVMI (change from baseline to follow-up: -5.0, 95% CI: -10.5;0.4 g/m2.7) for the highest quartile compared to the lowest in women (P-interaction sex=0.07). No association was found in men. Vitamin K status was not associated with LVEF or LAVI. Vitamin K intake was not associated with any of the echocardiographic measures. Conclusions: This study showed a high vitamin K status being associated with decreased LVMI only in women, while intakes of vitamin K were not associated with any cardiac structure or function measures. These results extend previous findings for a role of vitamin K status to decrease heart failure risk. [ABSTRACT FROM AUTHOR]

Background: Infective endocarditis (IE) is diagnosed in 7-8% of streptococcal bloodstream infections (BSIs), yet it is unclear when to perform transthoracic (TTE) and transoesophageal echocardiography (TOE) according to different streptococcal species. The aim of this sub-study was to propose a flowchart for the use of echocardiography in streptococcal BSIs.Methods: In a population-based setup, we investigated all patients admitted with streptococcal BSIs and crosslinked data with nationwide registries to identify comorbidities and concomitant hospitalization with IE. Streptococcal species were divided in four groups based on the crude risk of being diagnosed with IE (low-risk < 3%, moderate-risk 3-10%, high-risk 10-30% and very high-risk > 30%). Based on number of positive blood culture (BC) bottles and IE risk factors (prosthetic valve, previous IE, native valve disease, and cardiac device), we further stratified cases according to probability of concomitant IE diagnosis to create a flowchart suggesting TTE plus TOE (IE > 10%), TTE (IE 3-10%), or "wait & see" (IE < 3%).Results: We included 6393 cases with streptococcal BSIs (mean age 68.1 years [SD 16.2], 52.8% men). BSIs with low-risk streptococci (S. pneumoniae, S. pyogenes, S. intermedius) are not initially recommended echocardiography, unless they have ≥3 positive BC bottles and an IE risk factor. Moderate-risk streptococci (S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae, S. salivarius, S. thermophilus) are guided to "wait & see" strategy if they neither have a risk factor nor ≥3 positive BC bottles, while a TTE is recommended if they have either ≥3 positive BC bottles or a risk factor. Further, a TTE and TOE are recommended if they present with both. High-risk streptococci (S. mitis/oralis, S. parasanguinis, G. adiacens) are directed to a TTE if they neither have a risk factor nor ≥3 positive BC bottles, but to TTE and TOE if they have either ≥3 positive BC bottles or a risk factor. Very high-risk streptococci (S. gordonii, S. gallolyticus, S. mutans, S. sanguinis) are guided directly to TTE and TOE due to a high baseline IE prevalence.Conclusion: In addition to the clinical picture, this flowchart based on streptococcal species, number of positive blood culture bottles, and risk factors, can help guide the use of echocardiography in streptococcal bloodstream infections. Since echocardiography results are not available the findings should be confirmed prospectively with the use of systematic echocardiography. [ABSTRACT FROM AUTHOR]

Coronary microvascular dysfunction (CMD) has emerged as an important therapeutic target in the contemporary management of ischemic heart disease. However, due to a lack of a reliable traditional "gold standard" test for CMD, optimal treatment remains undefined. The index of microcirculatory resistance (IMR) is an intra-coronary wire-based technique that provides a more reliable and quantitative assessment of CMD and has been increasingly used as a preferred endpoint for evaluating CMD treatment strategies in recent studies. IMR can help diagnose CMD in angina patients with non-obstructive epicardial coronary disease, predict peri-procedural myocardial infarction in stable patients undergoing coronary stenting, and predict long-term prognosis after acute myocardial infarction. Studies of IMR in the setting of non-ST-elevation acute coronary syndromes are still lacking. This review critically appraises the current published literature evaluating targeted therapies for CMD using IMR as the assessment tool and provides insights into evidence gaps in this important field. [ABSTRACT FROM AUTHOR]

Introduction: Literature supports the existence of drivers as maintainers of atrial fibrillation (AF). Whether ultrahigh density (UHD) contact mapping may detect them is unknown. Methods: We sequentially mapped the left atrial (LA) activation during spontaneous persistent AF and performed circumferential pulmonary vein isolation (CPVI), followed by remapping and ablation of potential drivers (rotational and focal propagation sites) with Rhythmia™ in 90 patients. The time reference was an LA appendage (LAA) electrogram (EGM). Regions with uniform color were defined as "organized." Only patients (51) with no previous ablation were considered for acute results and follow‐up reporting. Results: LA maps (175 ± 28 ml, 43578 ± 18013 EGM) were acquired in 23 ± 7 min. In all post‐CPVI maps potential drivers (7.3 ± 3.2/patient) were visualized: 85% with rotational propagation and continuous low voltage in the center; the remaining with focal propagation and an organized EGM at the site of earliest activation. The RF delivery time for extra‐PV driver ablation was 12.2 ± 7.9 min. There was a progressive increase of AF organization: the LAA cycle length prolonged, the number of potential drivers decreased, and the organized LA surface in AF increased from 14 ± 6% to 28 ± 16% (p =.0007). Termination of AF without cardioversion was obtained in 67%. AF recurrence rate at 15 ± 7.3 months was 17.6% after the first procedure. Conclusions: Sequential UHD contact activation mapping of persistent AF allows visualization of potential drivers. A sequential strategy of CPVI followed by ablation of potential drivers with limited RF time resulted in an increasing organization of AF and good acute and long‐term results. [ABSTRACT FROM AUTHOR]

Generalized synchronization is an emergent functional relationship between the states of the interacting dynamical systems. To analyze the stability of a generalized synchronization state, the auxiliary system technique is a seminal approach that is broadly used nowadays. However, a few controversies have recently arisen concerning the applicability of this method. In this study, we systematically analyze the applicability of the auxiliary system approach for various coupling configurations. We analytically derive the auxiliary system approach for a drive--response coupling configuration from the definition of the generalized synchronization state. Numerically, we show that this technique is not always applicable for two bidirectionally coupled systems. Finally, we analytically derive the inapplicability of this approach for the network of coupled oscillators and also numerically verify it with an appropriate example. [ABSTRACT FROM AUTHOR]

The path toward the synchronization of an ensemble of dynamical units goes through a series of transitions determined by the dynamics and the structure of the connections network. In some systems on the verge of complete synchronization, intermittent synchronization, a time-dependent state where full synchronization alternates with non-synchronized periods, has been observed. This phenomenon has been recently considered to have functional relevance in neuronal ensembles and other networked biological systems close to criticality. We characterize the intermittent state as a function of the network topology to show that the different structures can encourage or inhibit the appearance of early signs of intermittency. In particular, we study the local intermittency and show how the nodes incorporate to intermittency in hierarchical order, which can provide information about the node topological role even when the structure is unknown. [ABSTRACT FROM AUTHOR]

Aims: Immunomodulation in heart failure (HF) has been studied in several randomized controlled trials (RCTs) with variable effects on cardiac structure, function, and outcomes. We sought to determine the effect of immunomodulation on left ventricular ejection fraction (LVEF), LV end‐diastolic dimension (LVEDD), and all‐cause mortality in patients with HF with reduced ejection fraction (HFrEF) through meta‐analyses and trial sequential analyses (TSAs) of RCTs. Methods and results: PubMed, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov were systematically reviewed to identify RCTs that studied the effects of immunomodulation in patients with HFrEF. The primary endpoint in this analysis was change in LVEF. Secondary outcomes were changes in LVEDD and all‐cause mortality. TSA was used to quantify the statistical reliability of data in the cumulative meta‐analyses. Nineteen RCTs with 1341 HFrEF subjects were eligible for analyses. The aetiology of HF, specific immunomodulation strategy, and treatment duration were variable across trials. Immunomodulation led to a greater improvement in LVEF [mean difference: +5.7% 95% confidence interval (CI): 3.0–8.5%, P < 0.001] and reduction in LVEDD (mean difference: −3.7 mm, 95% CI: −7.0 to −0.4 mm, P = 0.028) than no immunomodulation in meta‐analyses and TSAs. We observed a non‐significant decrease in all‐cause mortality among those on immumomodulation (risk ratio: 0.7, 95% CI: 0.4–1.3, P = 0.234), but the Z‐curve for cumulative treatment effect of immunomodulation in the TSA did not cross the boundary of futility. Conclusions: Immunomodulation led to improved cardiac structure and function in patients with HFrEF. While these benefits did not translate into a significant improvement in mortality, our analysis suggests that larger studies of targeted immunomodulation are needed to understand the true benefits. [ABSTRACT FROM AUTHOR]

Purpose: No previous study has evaluated the relationship between vitamin K and frailty. Thus, we assessed the relationship between vitamin K status and frailty over 13 years in the Longitudinal Aging Study Amsterdam (LASA). Methods: Prospective cohort study with 644 community-dwelling adults ≥ 55 years from the LASA cohort. In 2002–2003, plasma desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) was measured as marker of vitamin K status through a sandwich ELISA. Frailty was measured at baseline and in four follow-up examinations with the LASA Frailty Index (LASA-FI), which was used as both a continuous and a dichotomous measure (FI ≥ 0.25), as indicator of the degree of frailty and frailty risk, respectively. Statistical analyses were performed with multivariable generalized estimating equations using the lowest dp-ucMGP tertile, reflecting a high vitamin K status, as reference. Results: The mean (SD) age was 59.9 (2.9) years, and 54% were female. Compared with the lowest tertile, the medium and highest dp-ucMGP tertile were associated with a higher degree of frailty [1.40, 95% confidence interval (0.01–2.81) and 1.62, (0.18–3.06), respectively. P trend: 0.03]. Additionally, the medium and highest dp-ucMGP tertile had a higher odds ratio of frailty [1.75 (1.11–2.77) and 1.63 (1.04–2.57), respectively]. The degree of frailty increased over time, but the differences by dp-ucMGP tertiles existed since baseline and remained stable during follow-up. Conclusions: Baseline plasma low vitamin K status was associated with a greater degree of frailty and frailty risk in this cohort of older adults, which highlights the importance of ensuring an optimal nutritional status of this vitamin to prevent frailty in later life. [ABSTRACT FROM AUTHOR]

Synchronization of network-coupled dynamical units is important to a variety of natural and engineered processes including circadian rhythms, cardiac function, neural processing, and power grids. Despite this ubiquity, it remains poorly understood how complex network structures and heterogeneous local dynamics combine to either promote or inhibit synchronization. Moreover, for most real-world applications it is impossible to obtain the exact specifications of the system, and there is a lack of theory for how uncertainty affects synchronization. We address this open problem by studying the synchrony alignment function (SAF), which is an objective measure for the synchronization properties of a network of heterogeneous oscillators with given natural frequencies. We extend the SAF framework to analyze network-coupled oscillators with heterogeneous natural frequencies that are drawn as a multivariate random vector. Using probability theory for quadratic forms, we obtain expressions for the expectation and variance of the SAF for given network structures. We conclude with numerical experiments that illustrate how the incorporation of uncertainty yields a more robust theoretical framework for enhancing synchronization, and we provide new perspectives for why synchronization is generically promoted by network properties including degree-frequency correlations, link directedness, and link weight delocalization. [ABSTRACT FROM AUTHOR]

Aims: Galectin‐3 (Gal‐3) is implicated in the pathogenesis of heart failure and is also influenced by ageing. This study aims to determine the extent to which Gal‐3 levels estimate odds of myocardial dysfunction in ageing cohorts, 'upstream' prior to clinical disease. Methods and results: Four hundred seventy‐five asymptomatic subjects underwent simultaneous assessments of cardiovascular structure and function, with measurements of circulating Gal‐3. Myocardial dysfunction was defined as impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s) <0.84) (mean E/A ratio 0.84 in the cohort). Of 475 subjects (mean age 68 ± 12 years, 231 women), 222 (47%) had myocardial dysfunction. Subjects with myocardial dysfunction were older (mean age 73 ± 5 vs. 64 ± 14 years, P < 0.0001), and more had hypertension (59 vs. 40%, P < 0.0001), dyslipidaemia (54 vs. 39%, P = 0.001), diabetes mellitus (25 vs. 14%, P = 0.002), higher body mass index (BMI) (24 vs. 23 kg/m2, P = 0.002), and higher heart rate (76 vs. 71 b.p.m., P = 0.0001). Participants with impaired myocardial relaxation had lower peak velocity flow in early diastole E (0.6 ± 0.1 vs. 0.8 ± 0.2 m/s, P < 0.0001), higher peak velocity flow in late diastole by atrial contraction A (0.9 ± 0.1 vs. 0.7 ± 0.2 m/s, P < 0.0001), and higher mitral valve flow deceleration time (224.7 ± 43.2 vs. 204.8 ± 33.1 m/s, P < 0.0001). Participants with impaired myocardial relaxation had higher Gal‐3 levels (17.2 ± 6.2 vs. 15.5 ± 4.1, P = 0.0004) but similar B‐type natriuretic peptide (37 ± 4 vs. 34 ± 29, P = 0.37) and high‐sensitivity troponin I (21 ± 72 vs. 11 ± 41, P = 0.061) levels and urine microalbumin‐to‐creatinine ratio (4.6 ± 8.1 vs. 4.2 ± 10.8, P = 0.75) compared with those without impaired myocardial relaxation. After multivariable adjustments, Gal‐3 [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.00–1.10, P = 0.039], age (OR 2.60, 95% CI 1.64–4.11, P < 0.0001), BMI (OR 2.16, 95% CI 1.44–3.23, P < 0.0001), and heart rate (OR 1.04, 95% CI 1.02–1.06, P < 0.0001) were associated with impaired myocardial relaxation. Adjusted ORs (95% CI) for myocardial dysfunction were 1.0 (ref), 1.62 (0.92–2.85), 1.92 (1.08–3.41), and 2.01 (1.11–3.66) across consecutive quartiles of Gal‐3 after adjustment for age, BMI, risk factors, and heart rate. Conclusions: Among asymptomatic community‐dwelling elderly adults, the highest quartile of Gal‐3 was associated with two‐fold increased odds of myocardial dysfunction compared with the lowest quartile of Gal‐3. Gal‐3 may have a role as an 'upstream' biomarker in estimating odds of myocardial ageing prior to clinical disease. [ABSTRACT FROM AUTHOR]

Identifying effective pharmacological treatments for heart failure (HF) patients remains critically important. Given that the development of drugs de novo is expensive and time consuming, drug repositioning has become an increasingly important branch. In the present study, we propose a two-step drug repositioning pipeline and investigate the novel therapeutic effects of existing drugs approved by the US Food and Drug Administration to discover potential therapeutic drugs for HF. In the first step, we compared the gene expression pattern of HF patients with drug-induced gene expression profiles to obtain preliminary candidates. In the second step, we performed a systems biology approach based on the known protein–protein interaction information and targets of drugs to narrow down preliminary candidates to obtain final candidates. Drug set enrichment analysis and literature search were applied to assess the performance of our repositioning approach. We also constructed a mode of action network for each candidate and performed pathway analysis for each candidate using genes contained in their mode of action network to uncover pathways that potentially reflect the mechanisms of candidates' therapeutic efficacy to HF. We discovered numerous preliminary candidates, some of which are used in clinical practice and supported by the literature. The final candidates contained nearly all of the preliminary candidates supported by previous studies. Drug set enrichment analysis and literature search support the validity of our repositioning approach. The mode of action network for each candidate not only displayed the underlying mechanisms of drug efficacy but also uncovered potential biomarkers and therapeutic targets for HF. Our two-step drug repositioning approach is efficient to find candidates with potential therapeutic efficiency to HF supported by the literature and might be of particular use in the discovery of novel effective pharmacological therapies for HF. [ABSTRACT FROM AUTHOR]

Aims The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. Methods and results Peripheral venous NPY levels were significantly higher in patients with STEMI (n  = 45) compared to acute coronary syndromes/stable angina (n  = 48) or with normal coronary arteries (NC, n  = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated (r  = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304 (1 μM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y1 receptors. Conclusion High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y1 receptor, and antagonists may be a useful PPCI adjunct therapy. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) presents a growing clinical and public health burden for which better rhythm control therapies are needed. Focal impulse and rotor mapping (FIRM), currently marketed as a part of the Topera Rotor Mapping system (Abbott Laboratories, Austin, TX, USA), represents a potentially transformational approach to guide the invasive treatment of AF. However, many years after its initial marketing clearance, the clinical utility of this technology remains uncertain. In this article, we review the scientific rationale for this novel approach to AF ablation, evaluate the current clinical evidence for FIRM‐guided ablation, and characterize its premarket regulatory assessment. Lessons for clinicians considering adoption of newly marketed mapping systems are presented. [ABSTRACT FROM AUTHOR]

The article focuses on issues about wide-ranging conversations about racism, patriotism, and policing in the U.S. which were not limited to adults as high school students in the country joined the conversation, as did their elementary counterparts. Information about the study of the novel "All American Boys" is presented.

Aims: Neuroendocrine activation is associated with poor outcome in heart failure (HF). The neuropeptide gastrin‐releasing peptide (GRP), derived from the precursor proGRP1‐125 (proGRP), has recently been implicated in inflammation and wound repair. We investigated the predictive value of proGRP on clinical outcomes in HF patients with reduced ejection fraction. Methods and results: The association between plasma proGRP (time‐resolved immunofluorometric assay) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anaemia, enrolled in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED‐HF) trial. Median proGRP levels in the RED‐HF cohort were markedly increased [95 ng/L (25th, 75th percentile, 69–129 ng/L)] with 64% patients above the 80 ng/L reference limit. Baseline proGRP correlated with estimated glomerular filtration rate (r = 0.52), N terminal pro brain natriuretic peptide (r = 0.33), troponin T (r = 0.34), and haemoglobin (r = 0.16) (all P < 0.001). The incidence outcome increased with increasing tertiles of baseline proGRP (primary endpoint third tertile vs. the lowest tertile; hazard ratio 1.91; 95% confidence interval 1.60–2.28, P < 0.001). However, these associations were markedly attenuated and non‐significant in adjusted models. No interaction between baseline proGRP and the effect of darbepoetin alfa treatment was detected. Moreover, no significant association between changes in proGRP during 6 month follow‐up and outcome was observed. Conclusions: Pro‐gastrin‐releasing peptide is increased in patients with HF with reduced ejection fraction and anaemia, in particular in patients with poor renal function. However, proGRP adds little as a prognostic marker on top of conventional HF risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Atrial fibrillation and heart failure are increasing in prevalence, and frequently coexist. Despite the desire to restore sinus rhythm in heart failure patients, large studies comparing rate control to pharmacologic rhythm control have failed to show superiority of either approach. This may in part be due to the inefficacy and higher risk of adverse effects with antiarrhythmic drugs in HF patients. As such, catheter ablation for atrial fibrillation in patients with heart failure with reduced ejection fraction has been increasingly explored as a treatment modality. We review the contemporary evidence regarding patient selection, efficacy, safety, and impact of catheter ablation on outcomes in patients with atrial fibrillation and heart failure with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: Rotor mapping and ablation have gained favour over the recent years as an emerging ablation strategy targeting drivers of atrial fibrillation (AF). Their efficacy, however, has been a topic of great debate with variable outcomes across centres. The aim of this study was to systematically review the recent medical literature to determine the medium-term outcomes of rotor ablation in patients with paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PeAF).Methods and results: A systematic search of the contemporary scientific literature (PubMed and EMBASE) was performed in August 2017. Only studies assessing arrhythmia-free survival from rotor ablation of AF were included. We used the random-effects model to assess the primary outcome of pooled medium-term single-procedure AF-free survival for both PAF and PeAF. Success rates from multiple procedures and complication rates were also examined. We included 11 observational studies (4 PAF and 10 PeAF) with a total of 556 patients (166 PAF and 390 PeAF). Pooled single-procedure freedom from AF was 37.8% [95% confidence interval 5.6-86.3%] at a mean follow-up period of 13.8 ± 1.8 months for PAF and 59.2% (95% CI 41.4-74.9%) at a mean follow-up period of 12.9 ± 6 months for PeAF. There was a marked heterogeneity between studies (I2 = 93.8% for PAF and 88.3% for PeAF). The mean complication rate of rotor ablation among the reported studies was 3.4%.Conclusion: The wide variability in success rate between different centres performing rotor ablations suggests that the optimal ablation strategy, particularly targeting rotors, is unclear. Results from randomized studies are necessary before this technique can be considered as an established clinical tool. [ABSTRACT FROM AUTHOR]

We investigate the dynamics of large, globally-coupled systems of Kuramoto oscillators with heterogeneous interaction delays. For the case of exponentially distributed time delays we derive the full stability diagram that describes the bifurcations in the system. Of particular interest is the onset of hysteresis where both the incoherent and partially synchronized states are stable for a range of coupling strengths — this occurs at a codimension-two point at the intersection between a Hopf bifurcation and saddle node bifurcation of cycles. By studying this codimension-two point we find the full set of characteristic time delays and natural frequencies where bistability exists and identify the critical time delay and critical natural frequency below which bistability does not exist. Finally, we examine the dynamics of the more general system where time delays are drawn from a Gamma distribution, finding that more homogeneous time delay distributions tend to both promote the onset of synchronization and inhibit the presence of hysteresis. [ABSTRACT FROM AUTHOR]

Introduction Targeting localized drivers (electrical rotors or focal impulses) during catheter ablation for atrial fibrillation (AF) has been proposed as a strategy to improve procedural success. However, the strength and quality of the evidence to support this approach is unclear. Methods and results Clinical studies reporting efficacy or safety outcomes of driver-guided ablation for AF were identified in Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Pubmed, and conference abstracts from major scientific meetings. Random-effects meta-analysis of efficacy outcomes from controlled studies was performed. Thirty-one reports from 30 studies were included: two randomized controlled trials, five nonrandomized controlled studies, and 23 uncontrolled studies. In controlled studies, driver-guided ablation has been associated with higher rates of acute AF termination (RR 2.08, 95% CI 1.43-3.05; P < 0.001) and increased freedom from AF/atrial tachycardia (AT) at ≥1 year (RR 1.34, 95% CI 1.05-1.70; P = 0.02). Similar rates of procedural complications have been reported between ablation strategies. Overall, current data on driver-guided ablation are predominantly from nonrandomized studies with considerable heterogeneity in mapping and ablation strategies used and in clinical outcomes reported. Conclusion Pooled data on the efficacy of AF driver-guided catheter ablation suggest increased freedom from AF/AT relative to conventional strategies. However, most studies are nonrandomized and of moderate quality. Though promising data exist, there remains no conclusive evidence for the efficacy of AF driver ablation. Robust data from randomized trials are needed. [ABSTRACT FROM AUTHOR]

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and,where appropriate and/or necessary, the patient's caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. [ABSTRACT FROM AUTHOR]

Aims: Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia- reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI). Methods and results: In a two-centre, double-blind, placebo-controlled trial, 117 patients with NSTEMI were randomized at a median of 2 days after symptom onset to receive placebo (n = 59) or tocilizumab (n = 58), administered as a single dose prior to coronary angiography. High sensitivity (hs) C-reactive protein and hsTnT were measured at seven consecutive timepoints between Days 1 and 3. The area under the curve (AUC) for high-sensitivity C-reactive protein was the primary endpoint. The median A U C for high-sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group (4.2 vs. 2.0 mg/L/h, P < 0.001). Also, the median A U C for hsTnT during hospitalization was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h, P = 0.007). The differences between the two treatment groups were observed mainly in (i) patients included ≤ 2 days from symptom onset and (ii) patients treated with percutaneous coronary intervention (PCI). No safety issues in the tocilizumab group were detected during 6 months of follow-up. Conclusion: Tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release in NSTEMI patients. [ABSTRACT FROM AUTHOR]

Background: In a previous human intervention study, we observed an improved vitamin K status after 8 weeks of intake of a yogurt that was fortified with vitamin K2 (as menaquinone-7, MK-7) and enriched with vitamins C and D3, magnesium and polyunsaturated fatty acids. It was hypothesized that the added nutrients contributed to this improvement. Here we report on a study in which we compared the fasting plasma concentrations of MK-7 from (a) yogurt enriched with MK-7, vitamins D3 and C, magnesium, n-3 poly unsaturated fatty acids (n-3 PUFA) and fish oil (yogurt Kplus), (b) yogurt fortified with MK-7 only (yogurt K) and (c) soft gel capsules containing only MK-7.Subjects/methods: For 42 days, healthy men and postmenopausal women between 45 and 65 years of age daily consumed either yogurt K, yogurt Kplus or capsules. Circulating MK-7, 25-hydroxy vitamin D (25(OH)D) and markers for vitamin K status (uncarboxylated osteocalcin (ucOC) and desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP)) were assessed. Plasma MK-7 was also measured during the washout period of 2 weeks. MK-7 and dp-ucMGP were measured in citrated plasma, and 25(OH)D3 and ucOC were measured in the serum.Results: The increase in plasma MK-7 with the yogurt Kplus product was more pronounced than the increase in MK-7 with the capsules. Circulating dp-ucMGP and ucOC were significantly lowered after consumption of the yogurt products and the MK-7 capsules, reflecting vitamin K status improvement. No significant differences in fasting plasma concentrations of various biomarkers between the yogurts were found.Conclusions: Dairy matrix and nutrient composition may affect MK-7 delivery and improvement of vitamin K status. Yogurt fortified with MK-7 is a suitable matrix to improve the nutritional status of the fat-soluble vitamins. [ABSTRACT FROM AUTHOR]

Chronotherapy involves the administration of medication in coordination with the body's circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects. The aim of this study is to investigate the "time of administration" recommendations on chronotherapy for commonly-prescribed medicines in Australia. This study also aimed to explore the quality of information on the timing of administration presented in drug information sources, such as consumer medicine information (CMI) and approved product information (PI). Databases were searched for original research studies reporting on the impact of "time of administration" of the 30 most commonly-prescribed medicines in Australia for 2014. Further, time of administration recommendations from drug information sources were compared to the evidence from chronotherapy trials. Our search revealed 27 research studies, matching the inclusion and exclusion criteria. In 56% (n = 15) of the research studies, the therapeutic effect of the medicine varied with the time of administration, i.e., supported chronotherapy. For some medicines (e.g., simvastatin), circadian-based optimal administration time was evident in the information sources. Overall, dedicated studies on the timing of administration of medicines are sparse, and more studies are required. As it stands, information provision to consumers and health professionals about the optimal "time" to take medications lags behind emerging evidence. [ABSTRACT FROM AUTHOR]

Since natriuretic peptides were successfully integrated into the clinical practice of heart failure ( HF), the possibility of using new biomarkers to advance the management of affected patients has been explored. While a huge number of candidate HF biomarkers have been described recently, very few have made the difficult translation from initial promise to clinical application. These markers mirror the complex pathophysiology of heart failure at various levels: cell loss (troponin), fibrosis ( ST2 and galectin-3), infection (procalcitonin), and renal disease (several renal markers). In this review, we examine the best emerging candidates for clinical assessment and management of patients with HF. [ABSTRACT FROM AUTHOR]

The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures. [ABSTRACT FROM AUTHOR]

Aims Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction ( HFpEF). The aim of this study was to determine the association between galectin-3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to assess the association between galectin-3 and clinical outcomes. Methods and results Aldo- DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II-III, LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2 ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline, and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline galectin-3 was 12.1 ng/ mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2 ( P = 0.021), 6 min walk distance ( P = 0.002), and Short Form 36 ( SF-36) physical functioning ( P = 0.001), and directly correlated with NYHA class ( P = 0.007). Baseline NT-proBNP correlated with E/e' velocity ratio ( P ≤ 0.001), left atrial volume index ( P < 0.001), and LV mass index ( P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with all-cause death or hospitalization independent of treatment arm [hazard ratio ( HR) 3.319, 95% confidence interval ( CI) 1.214-9.07, P = 0.019] and NT-proBNP ( HR 3.127, 95% CI 1.144-8.549, P = 0.026). Spironolactone did not influence galectin-3 levels. Conclusion Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP. [ABSTRACT FROM AUTHOR]

Aims We sought to test the hypothesis that plasma galectin 3 (Gal-3) is positively associated with the risk of heart failure (HF) in male subjects. Methods and results While Gal-3 has been reported as prognostic factor in HF patients, limited data are available on the role of Gal-3 in the development of HF. We used a prospective nested-case control study (n = 462 cases and 462 controls) within the Physicians' Health Study for current analyses. For each case of HF, we randomly selected one control among subjects that were alive and free of HF at the time of index case occurrence and matched on age, race, and time of blood collection. Gal-3 was measured using ELISA and we used conditional logistic regression to compute adjusted odds ratios. Mean age at baseline was 58.3 y and median log-Gal-3 was 1.50 (IQR: 1.20-1.73) ng/ml. Cubic splines suggested a non-linear relation between Gal-3 and HF. Odds ratios (95% CI) for HF were 1.0 (ref), 0.89 (0.58-1.38), 1.08 (0.71-1.67), and 1.57 (1.03-2.39) across consecutive quartiles of Gal-3 after adjustment for body mass index, diabetes, atrial fibrillation, hypertension, C-reactive protein, alcohol, smoking, and exercise. The Gal-3-HF relation was seen for HF with and without antecedent coronary heart disease. Conclusions Our data are consistent with a positive non-linear association between Gal-3 and HF risk in male subjects. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy to the thorax increases the risk of radiation-induced heart disease. We and others have shown that local irradiation to the murine heart results in inflammatory and fibrotic responses and decreased microvascular density. In the present study we tested whether thalidomide is able to inhibit radiation-induced heart disease. Methods: Single doses of 16 Gy or 0 Gy (sham treatment) were delivered to the hearts of mice. At 16 weeks after irradiation the mice were allocated to receive a thalidomide-containing chow (100 mg/kg body weight/day) or control chow until the end of the experiment. At 40 weeks after irradiation, functional imaging was performed and the hearts were examined for histological damage. Results: Irradiation led to an increase in epicardial thickness and infiltrating inflammatory cells in the epicardium as well as an increase in interstitial collagen content. The microvasculature had a decreased alkaline phosphatase activity and reduced pericyte coverage. Thalidomide had no protective role in any of these processes. There were no differences in heart function measured between the treatment groups. Conclusions: Although others have shown protective effects of thalidomide in disease models involving inflammation, fibrosis and blood vessel maturation, thalidomide was not able to reduce radiation-induced heart damage. [ABSTRACT FROM AUTHOR]

Galectin-3 is a carbohydrate-binding protein involved in inflammatory and fibrotic processes in various tissues. In the heart, galectin-3 activation has been associated with progression of cardiac fibrosis leading to cardiac remodeling and heart failure development. Clinical studies have shown that galectin-3 is a valuable prognostic marker in cardiovascular disease recognizing patients at risk. Most published results are from cohorts with chronic heart failure patients, but also in patients with acute heart failure, acute cardiac syndromes, as well as in cohorts from the general population. Galectin-3 levels were prognostic when looking at various endpoints, most prominently mortality, new onset heart failure and other cardiovascular endpoints. This review on galectin-3 provides an overview of the biological function of the marker and important findings from animal model studies and summarizes the key results of published analyses of clinical cohorts. The potential future role of galectin-3 is discussed. [ABSTRACT FROM AUTHOR]

The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term 'inflammation'. Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-α led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective. [ABSTRACT FROM AUTHOR]

Background Chronotherapy involves altering the timing of medication administration to improve the overall control of a disease and to minimise treatment side-effects, and is an emerging concept in the field of therapeutics. Aim The aim of this review is to conduct an in-depth analysis of the recent literature in order to identify and evaluate the evidence base for drug chronotherapy. Method A literature search was conducted in three databases (Medline, Embase, International Pharmaceutical Abstracts) using the search terms 'Chronotherapy', 'Chronopharmacology', 'Chronopharmacokinetics', 'Chronopharmacodynamics', 'Chronoefficacy', 'Chronoformulation', 'Morning and Evening', 'Morning and Bedtime' and their combinations. The selection criteria for the inclusion of articles in the review included currency (years 2008-Aug 2011), publication in English language, studies done in Humans and non-review articles that pertained to 'drug' therapy. Results Our search revealed a total of 192 journal articles, of which 41 articles were selected for review. The specific hypothesis for the effectiveness of chronotherapy that was tested in these 41 studies was chronoeffectiveness (n = 34), followed by chronopharmacokinetics (n = 5), chronomodulation (n = 3) and chronopharmacodynamics (n = 2). The findings from two-thirds (n = 27) of the reviewed studies, support the notion of chronotherapy. Conclusion The review presents the scope of chronotherapy in drug utilization. We believe that the knowledge of chronotherapy is growing and the current research for chronotherapy is promisingly in the conceptualization or early experimental phase. Going forward, chronotherapy studies should also explore genetic, gender and age related differences. Preliminary screening of new drugs for chronotherapeutic potential may be a way of enhancing quality use of medicines. [ABSTRACT FROM AUTHOR]

Objectives. The predictive value of preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) was evaluated in patients with acute coronary syndrome undergoing coronary artery bypass grafting (CABG). Design. As a substudy to a clinical trial 383 patients with acute coronary syndrome undergoing CABG were studied. 17 patients had a concomitant procedure. NT-proBNP was measured immediately preoperatively and evaluated with regard to in-hospital mortality, and severe circulatory failure postoperatively according to prespecified criteria. Follow-up was 3.2 ± 0.9 years. Results. In patients with isolated CABG, receiver operating characteristics (ROC) analysis showed an area under the curve (AUC) of 0.82 for in-hospital mortality and 0.87 for severe circulatory failure respectively with a best cut-off for preoperative NT-proBNP of 1028 ng/L. This cut-off level independently predicted severe circulatory failure. Patients with NT-proBNP < 1028 ng/L had significantly better long-term survival (p = 0.004). Preoperative NT-proBNP was higher in patients with concomitant procedure than isolated CABG (2146 ± 1858 v 887 ± 1635 ng/L; p = 0.0005). In patients with concomitant procedure ROC analysis showed an AUC of 0.93 for severe circulatory failure with a best cut-off for preoperative NT-proBNP of 3145 ng/L. Conclusions. Preoperative NT-proBNP predicted in-hospital mortality, severe circulatory failure postoperatively and long-term survival in patients undergoing surgery for acute coronary syndrome but a higher threshold was found in patients having concomitant procedures. [ABSTRACT FROM AUTHOR]

Galectin-3, a structurally unique beta-galactoside-binding lectin, through the specific protein-protein and protein-carbohydrate interactions participates in numerous biological processes, such as cell proliferation and apoptosis, adhesion and activation. Its expression and secretion by until now an unknown mechanism are modulated by diverse molecules and are dependent on different physiological and pathophysiological conditions. By autocrine and paracrine actions, galectin-3 modulates many immune reactions and affects various immune cells, particularly those of monocyte-macrophage lineage. This is why galectin-3 has recently become an attractive therapeutic target. However, molecular mechanisms of its actions as well as regulatory mechanism of its expression and activation are still largely unknown. In this study, we show that lipopolysaccharide (LPS) provokes upregulation of galectin-3 expression on both gene and protein level in monocyte-like THP-1 cells, which can be inhibited by dexamethasone, but not with non-steroidal anti-inflammatory drugs aspirin and indomethacin. Resting and LPS-challenged monocyte-like THP-1 cells do not have detectable amount of surface-bound galectin-3, but are able to bind exogenously added galectin-3 with the same capacity. Although galectin-3 is generally considered to be a pro-inflammatory molecule, here we show that the exogenously added galectin-3 does not affect interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α production in resting and LPS-activated monocyte-like THP-1 cells nor influences its own gene expression level in those cells. [ABSTRACT FROM AUTHOR]

It has been proposed that exercise capacity during whole body exercise in post-infarction congestive heart failure (CHF) patients is limited by skeletal muscle function. We therefore investigated the balance between cardiopulmonary and muscular metabolic capacity. CHF patients ( n=8) and healthy subjects (HS, n=12) were included. Patients with coronary artery disease (CAD, n=8) were included as a control for medication. All subjects performed a stepwise incremental load test during bicycling (∼24 kg muscle mass), two-legged knee extensor (2-KE) exercise (∼4 kg muscle mass) and one-legged knee extensor (1-KE) exercise (∼2 kg muscle mass). Peak power and peak pulmonary oxygen uptake (VO2peak) increased and muscle-specific VO2peak decreased with an increasing muscle mass involved in the exercise. Peak power and VO2peak were lower for CHF patients than HS, with values for CAD patients falling between CHF patients and HS. During bicycling, all groups utilized 24-29% of the muscle-specific VO2peak as measured during 1-KE exercise, with no difference between the groups. Hence, the muscle metabolic reserve capacity during whole body exercise is not different between CHF patients and HS, indicating that appropriately medicated and stable post-infarction CHF patients are not more limited by intrinsic skeletal muscle properties during whole body exercise than HS. [ABSTRACT FROM AUTHOR]