Mitral regurgitation in heart failure with preserved ejection fraction: The interplay of valve, ventricle, and atrium.

Mitral regurgitation (MR) is highly prevalent among patients with heart failure and preserved ejection fraction (HFpEF). Despite this combination being closely associated with unfavourable outcomes, it remains relatively understudied. This is partly due to the inherent heterogeneity of patients with HFpEF. To address this gap, dissecting HFpEF into mechanism-based phenotypes may offer a promising avenue for advancing our comprehension of these complex intertwined conditions. This review employs the validated CircAdapt model to explore the haemodynamic implications of moderate to severe MR across a well-defined spectrum of myocardial disease, characterized by impaired relaxation and reduced myocardial compliance. Both heart failure and mitral valve disease share overlapping symptomatology, primarily attributed to elevated pulmonary pressures. The intricate mechanisms contributing to these elevated pressures are multifaceted, potentially influenced by diastolic dysfunction, left atrial myopathy, and MR. Accurate evaluation of the haemodynamic and clinical impact of MR necessitates a comprehensive approach, taking into account the characteristics of both the left atrium and left ventricle, as well as their intricate interactions, which may currently be underemphasized in diagnostic practice. This holistic assessment is imperative for enhancing our understanding and refining therapeutic strategies within this patient cohort.

Non-invasive imaging in acute decompensated heart failure with preserved ejection fraction.

Non-invasive imaging plays an increasingly important role in emergency medicine, given the trend towards smaller, portable ultrasound devices, the integration of ultrasound imaging across diverse medical disciplines, and the growing evidence supporting its clinical benefits for the patient. Heart failure with preserved ejection fraction (HFpEF) provides a compelling illustration of the impactful role that imaging plays in distinguishing diverse clinical presentations of heart failure with numerous associated comorbidities, including pulmonary, renal, or hepatic diseases. While a preserved left ventricular ejection fraction might misguide the clinician away from diagnosing cardiac disease, there are several clues provided by cardiac, vascular, and lung ultrasonography, as well as other imaging modalities, to rapidly identify (decompensated) HFpEF. Congestion remains the primary reason why patients with heart failure (irrespective of ejection fraction) seek emergency care. Furthermore, comprehensive phenotyping is becoming increasingly important, considering the development of targeted treatments for conditions exhibiting HFpEF physiology, such as cardiac amyloidosis. Timely recognition in such cases has lasting implications for long-term outcomes.

Mitral Valve Surgery for Mitral Regurgitation Results in Reduced Left Ventricular Ejection Fraction in Barlow's Disease as Compared with Fibro-Elastic Deficiency.

Surgical correction of severe mitral regurgitation (MR) can reverse left ventricular (LV) remodeling in patients with mitral valve prolapse (MVP). However, whether this process is similar to the case in Barlow's Disease (BD) and Fibro-elastic Deficiency (FED) is currently unknown. The aim of this study is to evaluate post-operative LV reverse remodeling and function in patients with BD versus FED. In this study, 100 MVP patients (BD = 37 and FED = 63) with severe MR who underwent mitral valve surgery at three Belgian centers were retrospectively included. Transthoracic echocardiography was used to assess MR severity, LV volumes and function before surgery and 6 months thereafter. Baseline MR severity, LV ejection fraction (LVEF), indexed LV end-diastolic (LVEDVi) and end-systolic volumes (LVESVi) were not different between the groups. After a median follow-up of 278 days, there was a similar decrease in LVEDVi, but a trend towards a smaller decrease in LVESVi in BD compared to FED (-3.0 ± 11.2 mL/m2 vs. -5.3 ± 9.0 mL/m2; p = 0.154). This resulted in a significantly larger decrease in LVEF in BD (-8.3 ± 9.6%) versus FED (-3.9 ± 6.9%) after adjusting for baseline LVEF (p < 0.001) and type of surgical intervention (p = 0.01). These findings suggest that LV (reverse) remodeling in BD could be affected by other mechanisms beyond volume overload, potentially involving concomitant cardiomyopathy.

mPAP/CO Slope and Oxygen Uptake Add Prognostic Value in Aortic Stenosis.

BACKGROUND: Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L-1·min-1. A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown. METHODS: In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm2 underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141). RESULTS: One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; P=0.036), indexed left atrial volume (OR per SD, 2.15; P=0.001), E/e' at rest (OR per SD, 1.61; P=0.012), mPAP/CO slope (OR per SD, 2.01; P=0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; P=0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; P=0.219). Peak Vo2 (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area (P<0.001). These results were confirmed in the validation cohort. CONCLUSIONS: In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo2 were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo2 and mPAP/CO slope cumulatively improved risk stratification.

Evolution of the use of intraosseous vascular access in prehospital advanced cardiopulmonary resuscitation: The IOVA-CPR study.

INTRODUCTION: Obtaining vascular access is crucial in critically ill patients. The EZ-IO® device is easy to use and has a high insertion success rate. Therefore, the use of intraosseous vascular access (IOVA) has gradually increased. AIM: We aim to determine how IOVA was integrated into management of vascular access during out-of-hospital cardiac arrest (OHCA) resuscitation. METHODS: Analysing the data from the OHCA French registry for events occurring between 1 January 2013 and 15 March 2021, we studied: demography, circumstances of occurrence and management including vascular access, delays and evolution. The primary outcome was the rate of IOVA implantation. RESULTS: Among the 7156 OHCA included in the registry, we analysed the 3964 (55%) who received cardiopulmonary resuscitation. The vascular access was peripheral in 3122 (79%) cases, intraosseous in 775 (20%) cases and central in 12 (<1%) cases. The use of IOVA has increased linearly (R2 = 0.61) during the 33 successive trimesters studied representing 7% of all vascular access in 2013 and 33% in 2021 (p = 0.001). It was significantly more frequent in traumatic cardiac arrest: 12% versus 5%; p < 0.0001. The first epinephrine bolus occurred significantly later in the IOVA group, at 6 (4-10) versus 5 (3-8) min; p < 0.0001. Survival rate in the IOVA group was significantly lower, at 1% versus 7%; p < 0.0001. CONCLUSION: The insertion rate of IOVA significantly increased over the studied period, to reach 30% of all vascular access in the management OHCA patients. The place of the intraosseous route in the strategy of venous access during the management of prehospital cardiac arrest has yet to be determined.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

AIMS: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. METHODS AND RESULTS: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. CONCLUSION: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Smartphone-based atrial fibrillation screening in the general population: feasibility and impact on medical treatment.

Aims: The aim of this study is to determine the feasibility, detection rate, and therapeutic implications of large-scale smartphone-based screening for atrial fibrillation (AF). Methods and results: Subjects from the general population in Belgium were recruited through a media campaign to perform AF screening during 8 consecutive days with a smartphone application. The application analyses photoplethysmography traces with artificial intelligence and offline validation of suspected signals to detect AF. The impact of AF screening on medical therapy was measured through questionnaires. Atrial fibrillation was detected in the screened population (n = 60.629) in 791 subjects (1.3%). From this group, 55% responded to the questionnaire. Clinical AF [AF confirmed on a surface electrocardiogram (ECG)] was newly diagnosed in 60 individuals and triggered the initiation of anti-thrombotic therapy in 45%, adjustment of rate or rhythm controlling strategies in 62%, and risk factor management in 17%. In subjects diagnosed with known AF before screening, a positive screening result led to these therapy adjustments in 9%, 39%, and 11%, respectively. In all subjects with clinical AF and an indication for oral anti-coagulation (OAC), OAC uptake increased from 56% to 74% with AF screening. Subjects with clinical AF were older with more co-morbidities compared with subclinical AF (no surface ECG confirmation of AF) (P < 0.001). In subjects with subclinical AF (n = 202), therapy adjustments were performed in only 7%. Conclusion: Smartphone-based AF screening is feasible at large scale. Screening increased OAC uptake and impacted therapy of both new and previously diagnosed clinical AF but failed to impact risk factor management in subjects with subclinical AF.

Utility of Left and Right Ventricular Strain in Arrhythmogenic Right Ventricular Cardiomyopathy: A Prospective Multicenter Registry.

BACKGROUND: Imaging evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains challenging. Myocardial strain assessment by echocardiography is an increasingly utilized technique for detecting subclinical left ventricular (LV) and right ventricular (RV) dysfunction. We aimed to evaluate the diagnostic and prognostic utility of LV and RV strain in ARVC. METHODS: Patients with suspected ARVC (n = 109) from a multicenter registry were clinically phenotyped using the 2010 ARVC Revised Task Force Criteria and underwent baseline strain echocardiography. Diagnostic performance of LV and RV strain was evaluated using the area under the receiver operating characteristic curve analysis against the 2010 ARVC Revised Task Force Criteria, and the prognostic value was assessed using the Kaplan-Meier analysis. RESULTS: Mean age was 45.3±14.7 years, and 48% of patients were female. Estimation of RV strain was feasible in 99/109 (91%), and LV strain was feasible in 85/109 (78%) patients. ARVC prevalence by 2010 ARVC Revised Task Force Criteria is 91/109 (83%) and 83/99 (84%) in those with RV strain measurements. RV global longitudinal strain and RV free wall strain had diagnostic area under the receiver operating characteristic curve of 0.76 and 0.77, respectively (both P<0.001; difference NS). Abnormal RV global longitudinal strain phenotype (RV global longitudinal strain > -17.9%) and RV free wall strain phenotype (RV free wall strain > -21.2%) were identified in 41/69 (59%) and 56/69 (81%) of subjects, respectively, who were not identified by conventional echocardiographic criteria but still met the overall 2010 ARVC Revised Task Force Criteria for ARVC. LV global longitudinal strain did not add diagnostic value but was prognostic for composite end points of death, heart transplantation, or ventricular arrhythmia (log-rank P=0.04). CONCLUSIONS: In a prospective, multicenter registry of ARVC, RV strain assessment added diagnostic value to current echocardiographic criteria by identifying patients who are missed by current echocardiographic criteria yet still fulfill the diagnosis of ARVC. LV strain, by contrast, did not add incremental diagnostic value but was prognostic for identification of high-risk patients.

Aptamers Targeting the PD-1/PD-L1 Axis: A Perspective.

Aptamers have emerged in recent years as alternatives to antibodies or small molecules to interfere with the immune check points by blocking the PD-1/PD-L1 interactions and represent an interesting perspective for immuno-oncology. Aptamers are RNA or DNA nucleotides able to bind to a target with high affinity, with the target ranging from small molecules to proteins and up to cells. Aptamers are identified by the SELEX method that can be modified for specific purposes. The range of applications of aptamers covers therapy as well as new alternative assay technologies similar to ELISA. Aptamers' limited plasma stability can be managed using delivery strategies. The goal of this Perspective is to give an overview of the current development of aptamers targeting the most studied immune checkpoint modulators, PD-1 and PD-L1, and analogous strategies with aptamers for other immuno-related targets.

Convergent micro-wave assisted synthesis of quinazolinone and its precursor using the bio-sourced solvent pinane.

A general microwave synthesis of 4-oxo-3,4-dihydroquinazolin-2-yl propanoic acids and their diamide precursors from the corresponding substituted benzamide and succinic anhydride is described, using pinane as a sustainable solvent that favors the cyclization step. The conditions are some of the most simple and cost effective reported.

Reduced Left Atrial Appendage Flow Is Associated With Future Atrial Fibrillation After Cryptogenic Stroke.

BACKGROUND: Hemostasis within the left atrial appendage (LAA) is a common cause of stroke, especially in patients with atrial fibrillation (AF). Although LAA flow provides insights into LAA function, its potential for predicting AF has yet to be established. The aim of this study was to explore whether LAA peak flow velocities early after cryptogenic stroke are associated with future AF on prolonged rhythm monitoring. METHODS: A total of 110 patients with cryptogenic stroke were consecutively enrolled and underwent LAA pulsed-wave Doppler flow assessment using transesophageal echocardiography within the early poststroke period. Velocity measurements were analyzed offline by an investigator blinded to the results. Prolonged rhythm monitoring was conducted on all participants via 7-day Holter and implantable cardiac monitoring devices, with follow-up conducted over a period of 1.5 years to determine the incidence of AF. The end point of AF was defined as irregular supraventricular rhythm with variable RR interval and no detectable P waves lasting ≥30 sec during rhythm monitoring. RESULTS: During a median follow-up period of 539 days (interquartile range, 169-857 days), 42 patients (38%) developed AF, with a median time to AF diagnosis of 94 days (interquartile range, 51-487 days). Both LAA filling velocity and LAA emptying velocity (LAAev) were lower in patients with AF (44.3 ± 14.2 and 50.7 ± 13.3 cm/s, respectively) compared with patients without AF (59.8 ± 14.0 and 76.8 ± 17.3 cm/sec, respectively; P < .001 for both). LAAev was most strongly associated with future AF, with an area under the receiver operating characteristic curve of 0.88 and an optimal cutoff value of 55 cm/sec. Age and mitral regurgitation were independent determinants of reduced LAAev. CONCLUSIONS: Impaired LAA peak flow velocities (LAAev < 55 cm/sec) in patients with cryptogenic stroke are associated with future AF. This may facilitate the selection of appropriate candidates for prolonged rhythm monitoring to improve its diagnostic accuracy and implementation.

Inside PD-1/PD-L1,2 with their inhibitors.

This review summarizes current knowledge in the development of immune checkpoint inhibitors, including antibodies and small molecules.

Arrythmia-Mediated Valvular Heart Disease.

The aging population is rising at record pace worldwide. Along with it, a steep increase in the prevalence of atrial fibrillation and heart failure with preserved ejection fraction is to be expected. Similarly, both atrial functional mitral and tricuspid regurgitation (AFMR and AFTR) are increasingly observed in daily clinical practice. This article summarizes all current evidence regarding the epidemiology, prognosis, pathophysiology, and therapeutic options. Specific attention is addressed to discern AFMR and AFTR from their ventricular counterparts, given their different pathophysiology and therapeutic needs.

Three-dimensional transoesophageal echocardiography: how to use and when to use-a clinical consensus statement from the European Association of Cardiovascular Imaging of the European Society of Cardiology.

Three-dimensional transoesophageal echocardiography (3D TOE) has been rapidly developed in the last 15 years. Currently, 3D TOE is particularly useful as an additional imaging modality for the cardiac echocardiographers in the echo-lab, for cardiac interventionalists as a tool to guide complex catheter-based procedures cardiac, for surgeons to plan surgical strategies, and for cardiac anaesthesiologists and/or cardiologists, to assess intra-operative results. The authors of this document believe that acquiring 3D data set should become a 'standard part' of the TOE examination. This document provides (i) a basic understanding of the physic of 3D TOE technology which enables the echocardiographer to obtain new skills necessary to acquire, manipulate, and interpret 3D data sets, (ii) a description of valvular pathologies, and (iii) a description of non-valvular pathologies in which 3D TOE has shown to be a diagnostic tool particularly valuable. This document has a new format: instead of figures randomly positioned through the text, it has been organized in tables which include figures. We believe that this arrangement makes easier the lecture by clinical cardiologists and practising echocardiographers.

Abnormal Mechanics Relate to Myocardial Fibrosis and Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

BACKGROUND: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. METHODS: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). RESULTS: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis (P<0.001). An abnormal strain pattern with distinct peaks pre-end-systole and post-end-systole in inferior-lateral wall was frequent in patients with fibrosis (81 versus 26%, P<0.001) but absent in patients without MVP with basal inferior-lateral wall fibrosis (n=20). During median follow-up of 1008 days, 36 of 87 patients with MVP with >6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. CONCLUSIONS: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

Digit preference and biased conclusions in cardiac arrest studies.

BACKGROUND: In cardiac arrest (CA), time is directly predictive of patients' prognosis. The increase in mortality resulting from delayed cardiopulmonary resuscitation has been quantified minute by minute. Times reported in CA management studies could reflect a timestamping bias referred to as "digit preference". This phenomenon leads to a preference for certain numerical values (such as 2, 5, or 10) over others (such as 13). Our objective was to investigate whether or not digit preference phenomenon could be observed in reported times of the day related to CA management, as noted in a national registry. METHODS: We analyzed data from the French National Electronic Registry of Cardiac Arrests. We analyzed twelve times-of-the-day corresponding to each of the main steps of CA management reported by the emergency physicians who managed the patients in prehospital settings. We postulated that if CA occurred at random times throughout the day, then we could expect to see events related to CA management occurring at a similar rate each minute of each hour of the day, at a fraction of 1/60. We compared the fraction of times reported as multiples of 15 (0, 15, 30, and 45 - on the hour, quarters, half hour) with the expected fraction of 4/60 (i.e. 4 × 1/60). MAIN RESULTS: A total of 47,211 times-of-the-day in relation to 6131 CA were analyzed. The most overrepresented numbers were: 0, with 3737 occurrences (8% vs 2% expected, p < 0.0001) and 30, with 2807 occurrences (6% vs 2% expected, p < 0.0001). Times-of-the-day as multiples of 15 were overrepresented (22% vs 7% expected, p < 0.0001). CONCLUSION: Prospectively collected times were considerably influenced by digit preference phenomenon. Studies that are not based on automatic time recordings and that have not evaluated and considered this bias should be interpretated with caution.

Sex Differences in Extensive Mitral Annular Calcification With Associated Mitral Valve Dysfunction.

Mitral annular calcification (MAC)-related mitral valve (MV) dysfunction is an increasingly recognized entity, which confers a high burden of morbidity and mortality. Although more common among women, there is a paucity of data regarding how the phenotype of MAC and the associated adverse clinical implications may differ between women and men. A total of 3,524 patients with extensive MAC and significant MAC-related MV dysfunction (i.e., transmitral gradient ≥3 mm Hg) were retrospectively analyzed from a large institutional database, with the goal of defining gender differences in clinical and echocardiographic characteristics and the prognostic importance of MAC-related MV dysfunction. We stratified patients into low- (3 to 5 mm Hg), moderate- (5 to 10 mm Hg), and high- (≥10 mm Hg) gradient groups and analyzed the gender differences in phenotype and outcome. The primary outcome was all-cause mortality, assessed using adjusted Cox regression models. Women represented the majority (67%) of subjects, were older (79.3 ± 10.4 vs 75.5 ± 10.9 years, p <0.001) and had a lower burden of cardiovascular co-morbidities than men. Women had higher transmitral gradients (5.7 ± 2.7 vs 5.3 ± 2.6 mm Hg, p <0.001), more concentric hypertrophy (49% vs 33%), and more mitral regurgitation. The median survival was 3.4 years (95% confidence interval 3.0 to 3.6) among women and 3.0 years (95% confidence interval 2.6 to 4.5) among men. The adjusted survival was worse among men, and the prognostic impact of the transmitral gradient did not differ overall by gender. In conclusion, we describe important gender differences among patients with MAC-related MV dysfunction and show worse adjusted survival among men; although, the adverse prognostic impact of the transmitral gradient was similar between men and women.