Plant-based red colouration of shell beads 15,000 years ago in Kebara Cave, Mount Carmel (Israel).

Decorating the living space, objects, body and clothes with colour is a widespread human practice. While the habitual use of red mineral pigments (such as iron-oxide, e.g., ochre) by anatomically modern humans started in Africa about 140,000 years ago, the earliest documentation of the use of organic plant or animal-based red pigments is known from only 6,000 years ago. Here, we report the oldest reliable evidence of organic red pigment use 15,000 years ago by the first sedentary hunter-gatherers in the Levant. SEM-EDS and Raman Spectroscopy analyses of 10 red-stained shell beads enabled us to detect and describe the use of a colourant made of Rubiaceae plants roots (Rubia spp., Asperula spp., Gallium spp.) to colour personal adornments from the Early Natufian of Kebara cave, Mount Carmel, Israel. This adds a previously unknown behavioural aspect of Natufian societies, namely a well-established tradition of non-dietary plant processing at the beginning of the sedentary lifestyle. Through a combined multidisciplinary approach, our study broadens the perspectives on the ornamental practices and the chaînes opératoires of pigmenting materials during a crucial period in human history.

Bone aerophones from Eynan-Mallaha (Israel) indicate imitation of raptor calls by the last hunter-gatherers in the Levant.

Direct evidence for Palaeolithic sound-making instruments is relatively rare, with only a few examples recorded from Upper Palaeolithic contexts, particularly in European cultures. However, theoretical considerations suggest that such artefacts have existed elsewhere in the world. Nevertheless, evidence for sound production is tenuous in the prehistoric archaeological record of the Levant, the study of music and its evolution being sparsely explored. Here we report new evidence for Palaeolithic sound-making instruments from the Levant with the discovery of seven aerophones made of perforated bird bones in the Final Natufian site of Eynan-Mallaha, Northern Israel. Through technological, use-wear, taphonomic, experimental and acoustical analyses, we demonstrate that these objects were intentionally manufactured more than 12,000 years ago to produce a range of sounds similar to raptor calls and whose purposes could be at the crossroads of communication, attracting hunting prey and music-making. Although similar aerophones are documented in later archaeological cultures, such artificial bird sounds were yet to be reported from Palaeolithic context. Therefore, the discovery from Eynan-Mallaha contributes new evidence for a distinctive sound-making instrument in the Palaeolithic. Through a combined multidisciplinary approach, our study provides important new data regarding the antiquity and development of the variety of sound-making instruments in the Palaeolithic at large and particularly at the dawn of the Neolithic in the Levant.

The evolution of the CTO-PCI landscape in Belgium and Luxembourg: a four-year appraisal.

BACKGROUND: To chart the evolution of the CTO-PCI landscape in Belgium and Luxembourg, the Belgian Working Group on Chronic Total Occlusions (BWGCTO) was established in 2016. METHODS: Between May 2016 and December 2019, patients undergoing a CTO-PCI treatment were prospectively and consecutively enrolled. Twenty-one centres in Belgium and one in Luxembourg participated. Individual operators had mixed levels of expertise in treating CTO lesions. Demographic, angiographic, procedural parameters and incidence of major adverse cardiac and cerebrovascular events (MACCE) were systematically registered. RESULTS: Over a four-year enrolment period, 1832 procedures were performed in 1733 patients achieving technical success in 1474 cases (80%), with an in-hospital MACCE rate of 2.3%. Fifty-nine (3%) cases were re-attempt procedures of which 41 (69%) were successful. High-volume centres treated more complex lesions (mean J-CTO score: 2.15 ± 1.21) as compared to intermediate (mean J-CTO score: 1.72 ± 1.23; p < 0.001) and low-volume centres (mean J-CTO score: 0.99 ± 1.21; p = 0.002). Despite this, success rates did not differ between centres (p = 0.461). Overall success rates did not differ over time (p = 0.810). High-volume centres progressively tackled more complex CTOs while keeping success rates stable. In all centres, the most applied strategy was antegrade wire escalation (83%). High-volume centres more often successfully applied antegrade dissection and re-entry and retrograde techniques in lesions with higher complexity. CONCLUSION: With variable experience levels, operators treated CTOs with high success and relatively few complications. Although AWE remains the most used technique, it is paramount for operators to be skilled in all contemporary techniques in order to be successful in more complex CTOs.

Angioedema: a rare and sometimes delayed side effect of angiotensin-converting enzyme inhibitors.

The effects of angiotensin converting enzyme (ACE) inhibitors result from the inhibition of the ACE (kininase II) to ultimately influence both the renin-angiotensin system and the degradation of the bradykinin (BK) metabolism. ACE inhibitors block the degradation of BK and substance P by ACE. In addition, an active metabolite of BK (Des-Arg9-BK) is catalysed by kininase I and its degradation is controlled in part by the conversion enzyme. These molecules have been associated with increased plasma extravasation associated with ACE inhibitors. ACE inhibitors are the leading cause of drug-induced Angioedema (AE). Symptoms of AE mainly occur after the first month of treatment by ACE. However, very late onset cases, sometimes after several years of stable therapy, are also described in the literature. It has been observed that patients previously stable under ACE inhibitor will most likely develop AE soon after the addition of another medication, including the combination of aspirin or non-steroid anti-inflammatory drugs with ACE inhibitor which has proved to be the most common cause, accounting for close to 50% of all AE cases related to ACE inhibitors. This side effect of ACE inhibitors, sometimes very late and rare, deserves to be recalled.

Epicardial fat amount is associated with the magnitude of left ventricular remodeling in aortic stenosis.

Both genetic and environmental factors interact to control left ventricular (LV) remodeling in the context of aortic stenosis (AS). Epicardial adipose tissue (EAT) is a specific visceral adipose tissue with paracrine properties in close contact with the myocardium. We sought to assess determinants of EAT amount and its association with the magnitude and pattern of LV remodeling in patients suffering from severe AS. Between January 2014 and September 2017, we prospectively explored consecutive patients referred to our Heart Valve Center for SAVR presenting with severe AS and normal left ventricular ejection fraction (> 50%). Comprehensive transthoracic echocardiography (TTE) including assessment of LV remodeling and EAT amount were performed. 202 patients were included. EAT was significantly larger in elderly, diabetic and obese patients. EAT thickness was correlated positively with indexed LV mass in AS (r2 = 0.21; p < 0.0001) as well as severe LV remodeling pattern. Importantly, this observation persisted after adjustment for other factors associated with LV remodeling (ß ± SE = 1.74 ± 0.34; p < 0.0001). Large amounts of EAT are positively and independently associated with more pronounced and severe LV remodeling in severe AS. Further exploration regarding the impact of functional properties of EAT on LV remodeling is required.

Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue.

BACKGROUND: Epicardial adipose tissue (EAT) thickness and pro-inflammatory status has been shown to be associated with several cardiac diseases, including aortic stenosis (AS). Thus, cardiac visceral fat could represent a potential new target for drugs. In the present study we evaluate the effect of statin therapy on EAT accumulation and inflammation. METHODS: Echocardiographic EAT thickness was assessed in 193 AS patients taking (n.87) and not taking (n.106) statins, undergoing cardiac surgery. To explore the association between statin therapy and EAT inflammation, EAT biopsies were obtained for cytokines immunoassay determination in EAT secretomes. An in vitro study was also conducted and the modulation of EAT and subcutaneous adipose tissue (SCAT) secretomes by atorvastatin was assessed in paired biopsies. RESULTS: Statin therapy was significantly associated with lower EAT thickness (p < 0.0001) and with lower levels of EAT-secreted inflammatory mediators (p < 0.0001). Of note, there was a significant correlation between EAT thickness and its pro-inflammatory status. In vitro, atorvastatin showed a direct anti-inflammatory effect on EAT which was significantly higher compared to the SCAT response to statin incubation (p < 0.0001). CONCLUSIONS: The present study indicates a robust association between statin therapy and reduced EAT accumulation in patients with AS. The present data also suggest a direct relationship between EAT thickness and its inflammatory status, both modulated by statin therapy. The in vitro results support the hypothesis of a direct action of statins on EAT secretory profile. Overall our data suggest EAT as a potential new therapeutic target for statin therapy.

Outcomes of Patients With Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics.

Importance: The natural history and the management of patients with asymptomatic aortic stenosis (AS) have not been fully examined in the current era. Objective: To determine the clinical outcomes of patients with asymptomatic AS using data from the Heart Valve Clinic International Database. Design, Setting, and Participants: This registry was assembled by merging data from prospectively gathered institutional databases from 10 heart valve clinics in Europe, Canada, and the United States. Asymptomatic patients with an aortic valve area of 1.5 cm2 or less and preserved left ventricular ejection fraction (LVEF) greater than 50% at entry were considered for the present analysis. Data were collected from January 2001 to December 2014, and data were analyzed from January 2017 to July 2018. Main Outcomes and Measures: Natural history, need for aortic valve replacement (AVR), and survival of asymptomatic patients with moderate or severe AS at entry followed up in a heart valve clinic. Indications for AVR were based on current guideline recommendations. Results: Of the 1375 patients included in this analysis, 834 (60.7%) were male, and the mean (SD) age was 71 (13) years. A total of 861 patients (62.6%) had severe AS (aortic valve area less than 1.0 cm2). The mean (SD) overall survival during medical management (mean [SD] follow up, 27 [24] months) was 93% (1%), 86% (2%), and 75% (4%) at 2, 4, and 8 years, respectively. A total of 104 patients (7.6%) died under observation, including 57 patients (54.8%) from cardiovascular causes. The crude rate of sudden death was 0.65% over the duration of the study. A total of 542 patients (39.4%) underwent AVR, including 388 patients (71.6%) with severe AS at study entry and 154 (28.4%) with moderate AS at entry who progressed to severe AS. Those with severe AS at entry who underwent AVR did so at a mean (SD) of 14.4 (16.6) months and a median of 8.7 months. The mean (SD) 2-year and 4-year AVR-free survival rates for asymptomatic patients with severe AS at baseline were 54% (2%) and 32% (3%), respectively. In those undergoing AVR, the 30-day postprocedural mortality was 0.9%. In patients with severe AS at entry, peak aortic jet velocity (greater than 5 m/s) and LVEF (less than 60%) were associated with all-cause and cardiovascular mortality without AVR; these factors were also associated with postprocedural mortality in those patients with severe AS at baseline who underwent AVR (surgical AVR in 310 patients; transcatheter AVR in 78 patients). Conclusions and Relevance: In patients with asymptomatic AS followed up in heart valve centers, the risk of sudden death is low, and rates of overall survival are similar to those reported from previous series. Patients with severe AS at baseline and peak aortic jet velocity of 5.0 m/s or greater or LVEF less than 60% have increased risks of all-cause and cardiovascular mortality even after AVR. The potential benefit of early intervention should be considered in these high-risk patients.

Predicting Disease Progression and Mortality in Aortic Stenosis: A Systematic Review of Imaging Biomarkers and Meta-Analysis.

Background: Detecting among patients with aortic stenosis (AS) those who are likely to rapidly progress, yet potentially benefiting from prophylactic aortic valve replacement, is needed for improved patient care. The objective of this study was to evaluate the role of imaging biomarkers in predicting the progression to clinical symptoms and death in patients with AS. Methods: We searched the Pubmed and the International Clinical Trials Registry Platform databases for studies including patients with AS, and investigating imaging techniques, published in any language until Jan 1, 2018. Eligible sets of data include effect of imaging biomarkers relative to: (1) Overall mortality, (2) Cardiac mortality, and (3) Overall events (Symptom onset and Major Adverse Cardiovascular Events). Meta-analysis was used to examine associations between the imaging biomarkers and outcomes of AS using Random Effect models. Results: Eight studies and 1,639 patients were included after systematic review. Four studies investigated aortic valve calcification (AVC) whereas the remaining investigated biomarkers provided by cardiac magnetic resonance (CMR). Four articles investigated the presence of midwall fibrosis on late-gadolinium enhancement imaging, three reported its extent (LGE%) and two, the myocardial extracellular volume (ECV). By decreasing strength of association, there were significant associations between cardiac mortality and LGE% [Relative Risk (RR) = 1.05, 95% Confidence Interval (CI) 1.01-1.10]; overall mortality and AVC (RR = 1.19, 95%CI: 1.05-1.36); overall events and ECV (RR = 1.68, 95%CI: 1.17-2.41); cardiac mortality and midwall fibrosis (RR = 2.88, 95%CI: 1.12-7.39). Conclusion: AVC and myocardial fibrosis imaging biomarkers predict the outcomes in AS, and help understanding AS pathophysiology and setting therapeutic targets.

Coronary chronic total occlusion intervention: utility or futility.

INTRODUCTION: Despite an incidence of about 18-52% of the patients undergoing coronary angiography, chronic total occlusions (CTO) are rarely revascularised by percutaneous angioplasty (PCI). Nevertheless, current evidence suggests that successful CTO angioplasty improves symptoms, quality of life and long-term survival. During the last decade, the improvement of specific tools and techniques for these complex procedures, and the increasing experience of operators, have led to the achievement of success and complication rates almost equivalent to non-CTO angioplasty. Areas covered: This review focuses on the clinical benefits of CTO revascularization and on appropriate patient selection. Expert commentary: Current evidence suggests that successful CTO-PCI improves symptoms, quality of life and long-term survival. During the last years, the improvement of specific techniques for these complex procedures and the increasing experience of operators, have led to the achievement of success and complication rates almost equivalent to non-CTO lesion angioplasty.

[Why to treat a total chronic coronary occlusion?] / Pourquoi traiter une occlusion coronaire totale chronique ?

Despite an incidence of about 15% of the patients undergoing coronary angiography, total chronic occlusions (CTO) are rarely revascularized by percutaneous angioplasty (PCI). Nevertheless, current evidence suggest that successful CTO-PCI improve symptoms, quality of live and long-term survival. During the last years, improvement of specific techniques for these complexes procedures and increasing experience of operators allow actually to obtain success and complications rates almost equivalent to non-CTO lesions angioplasty. This review focus on the clinical benefits of CTO revascularization and on appropriate patient selection.

Bien que présentes chez environ 15% des patients admis pour une coronarographie diagnostique, les occlusions coronaires totales chroniques (CTO) sont très rarement revascularisées par angioplastie percutanée. Pourtant, de nombreux éléments suggèrent que la revascularisation percutanée d'une CTO est associée à une amélioration des symptômes angineux, de la qualité de vie et de la survie à long terme. Ces dernières années, l'amélioration des techniques dédiées à ces procédures complexes et l'expérience croissante des opérateurs ont permis d'obtenir des taux de succès et de complications qui approchent ceux des lésions coronaires non-CTO. Cet article fait le point sur les principaux bénéfices de traiter une CTO et sur la sélection appropriée des patients.

Multimodality imaging for the diagnosis and assessment of aortic stenosis severity.

INTRODUCTION: Aortic stenosis (AS) is the most common cause of valvular heart disease. Imaging plays a major role in the diagnosis and evaluation of AS severity. AREAS COVERED: The present review focuses on new emerging concepts in AS by stressing the substantial value of imaging into the understanding of the complex pathophysiology and management of AS. Expert commentary: Though, standard 2D echocardiography is often diagnostic multi-modality imaging can be required in patients with doubtful results or to refine the evaluation of AS.

Impact of Serial B-Type Natriuretic Peptide Changes for Predicting Outcome in Asymptomatic Patients With Aortic Stenosis.

BACKGROUND: The aim of this study was to determine the impact on the outcome of serial B-type natriuretic peptide (BNP) changes during follow-up in asymptomatic patients with ≥ moderate aortic stenosis (AS) and preserved left ventricular ejection fraction. METHODS: We prospectively screened 69 patients who underwent comprehensive transthoracic echocardiography, BNP level measurement at baseline and after every 6 or 12 months. Annualized BNP changes were calculated as the difference between the last and baseline BNP measurements divided by the duration of follow-up. The primary endpoint was the occurrence of symptoms, aortic valve replacement, or cardiovascular death. RESULTS: During a follow-up of 30 ± 19 months, 43 patients experienced a cardiac event. These patients were significantly older (73 ± 9 vs 65 ± 16 years; P = 0.010), had more often dyslipidemia (79% vs 42%; P = 0.038), more severe AS (peak velocity: 3.9 ± 0.6 vs 3.5 ± 0.6 m/s; P = 0.002), larger indexed left atrial area (10.2 ± 2.5 vs 8.7 ± 1.9 cm(2)/m(2); P = 0.006), and a higher increase in annualized BNP (+90 ± 155 vs +7 ± 49 pg/mL/y; P = 0.010). Patients with higher annualized BNP changes (> 20 pg/mL/y) had a significantly lower cardiac event-free survival (1 year: 63 ± 8% vs 97 ± 3%; 3 years: 31 ± 8% vs 68 ± 8%; P < 0.001). Using the multivariate Cox proportional hazards model, higher annualized BNP changes were significantly associated with increased risk of cardiac events (hazard ratio: 2.73, 95% confidence interval: 1.27-5.86; P = 0.010) after adjustment for age, dyslipidemia, and echocardiographic parameters. CONCLUSIONS: In asymptomatic patients with AS and preserved left ventricular ejection fraction, the use of serial BNP changes may help to anticipate development of class I indication for aortic valve replacement.

Elevated Plasma Soluble ST2 Is Associated with Heart Failure Symptoms and Outcome in Aortic Stenosis.

B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is associated with symptomatic status and outcome in asymptomatic AS is unknown. sST2 and BNP levels were measured in 86 patients (74±13 years; 59 asymptomatic, 69%) with AS (<1.5 cm2) and preserved left ventricular ejection fraction who were followed-up for 26±16 months. Both BNP and sST2 were associated with NYHA class but sST2 (>23 ng/mL, AUC = 0.68, p<0.01) was more accurate to identify asymptomatic patients or those who developed symptoms during follow-up. sST2 was independently related to left atrial index (p<0.0001) and aortic valve area (p = 0.004; model R2 = 0.32). A modest correlation was found with BNP (r = 0.4, p<0.01). During follow-up, 29 asymptomatic patients (34%) developed heart failure symptoms. With multivariable analysis, peak aortic jet velocity (HR = 2.7, p = 0.007) and sST2 level (HR = 1.04, p = 0.03) were independent predictors of cardiovascular events. In AS, sST2 levels could provide complementary information regarding symptomatic status, new onset heart failure symptoms and outcome. It might become a promising biomarker in these patients.

Value of cardiac MRI to evaluate ischemia-related ventricular arrhythmia substrates.

During the course of and after a myocardial ischemia-reperfusion insult, ventricular arrhythmia (VA) may have several single or overlapping potential substrates. Some of these may not be associated with morphological and functional changes, whereas others may have individual susceptibility. Nevertheless, cardiac magnetic resonance currently offers a comprehensive and highly effective toolset for the evaluation of a risk of VA on a patient basis after a myocardial infarction. Indeed, cardiac magnetic resonance has established itself as a reference for the evaluation of the myocardial function and properties, using respectively, cine and tissue characterization imaging to detect and evaluate the extent of acute myocardial injuries, scars and remodeling. This article describes and discusses imaging strategies used to evaluate the substrates for VA in the setting of a myocardial infarction.

Role of multimodality cardiac imaging in the management of patients with hypertrophic cardiomyopathy: an expert consensus of the European Association of Cardiovascular Imaging Endorsed by the Saudi Heart Association.

Taking into account the complexity and limitations of clinical assessment in hypertrophic cardiomyopathy (HCM), imaging techniques play an essential role in the evaluation of patients with this disease. Thus, in HCM patients, imaging provides solutions for most clinical needs, from diagnosis to prognosis and risk stratification, from anatomical and functional assessment to ischaemia detection, from metabolic evaluation to monitoring of treatment modalities, from staging and clinical profiles to follow-up, and from family screening and preclinical diagnosis to differential diagnosis. Accordingly, a multimodality imaging (MMI) approach (including echocardiography, cardiac magnetic resonance, cardiac computed tomography, and cardiac nuclear imaging) is encouraged in the assessment of these patients. The choice of which technique to use should be based on a broad perspective and expert knowledge of what each technique has to offer, including its specific advantages and disadvantages. Experts in different imaging techniques should collaborate and the different methods should be seen as complementary, not as competitors. Each test must be selected in an integrated and rational way in order to provide clear answers to specific clinical questions and problems, trying to avoid redundant and duplicated information, taking into account its availability, benefits, risks, and cost.

The multi-modality cardiac imaging approach to the Athlete's heart: an expert consensus of the European Association of Cardiovascular Imaging.

The term 'athlete's heart' refers to a clinical picture characterized by a slow heart rate and enlargement of the heart. A multi-modality imaging approach to the athlete's heart aims to differentiate physiological changes due to intensive training in the athlete's heart from serious cardiac diseases with similar morphological features. Imaging assessment of the athlete's heart should begin with a thorough echocardiographic examination.Left ventricular (LV) wall thickness by echocardiography can contribute to the distinction between athlete's LV hypertrophy and hypertrophic cardiomyopathy (HCM). LV end-diastolic diameter becomes larger (>55 mm) than the normal limits only in end-stage HCM patients when the LV ejection fraction is <50%. Patients with HCM also show early impairment of LV diastolic function, whereas athletes have normal diastolic function.When echocardiography cannot provide a clear differential diagnosis, cardiac magnetic resonance (CMR) imaging should be performed.With CMR, accurate morphological and functional assessment can be made. Tissue characterization by late gadolinium enhancement may show a distinctive, non-ischaemic pattern in HCM and a variety of other myocardial conditions such as idiopathic dilated cardiomyopathy or myocarditis. The work-up of athletes with suspected coronary artery disease should start with an exercise ECG. In athletes with inconclusive exercise ECG results, exercise stress echocardiography should be considered. Nuclear cardiology techniques, coronary cardiac tomography (CCT) and/or CMR may be performed in selected cases. Owing to radiation exposure and the young age of most athletes, the use of CCT and nuclear cardiology techniques should be restricted to athletes with unclear stress echocardiography or CMR.

Late gadolinium enhancement CMR in primary mitral regurgitation.

AIMS: The appropriate timing for surgery in severe asymptomatic primary mitral regurgitation (MR) remains controversial. It has been shown that late gadolinium enhancement on cardiovascular magnetic resonance (LGE CMR), which may identify myocardial fibrosis, is associated with a worse outcome in various cardiomyopathies. We sought to investigate the prevalence and significance of delayed enhancement in primary MR. METHODS: We prospectively included 41 patients with at least moderate primary MR and without overt signs of left ventricular (LV) dysfunction. Patients with evidence of coronary artery disease, arrhythmias or significant concomitant valvular disease were excluded. All patients were scheduled for transthoracic echocardiography and LGE CMR. RESULTS: A total of 39 patients had interpretable LGE CMR images. Among them, 12 (31%) had late contrast uptake of the LV wall. LGE CMR showed an infarct pattern in three patients, a pattern of mid-wall fibrosis in seven patients and two patients had a combined pattern. Patients with delayed enhancement on CMR had significant higher LV diameters (LV end-systolic diameter 39 ± 4 vs. 34 ± 5 mm, P = 0·002; LV end-diastolic diameter 57 ± 5 vs. 50 ± 5 mm, P = 0·001). There was a trend towards a higher indexed left atrial volume (55 ± 21 vs. 44 ± 13 mL/m², P = 0·06). By contrast, there was no significant association between myocardial contrast uptake and age, LV ejection fraction and MR severity. CONCLUSION: Left ventricular remodelling seems to be associated with the presence of delayed enhancement on CMR in primary MR. Further data are needed to determine whether LGE CMR can predict a less favourable outcome or could improve risk stratification in asymptomatic primary MR.