Cardiac magnetic resonance in advanced heart failure.

Heart failure (HF) is a chronic and progressive disease that often progresses to an advanced stage where conventional therapy is insufficient to relieve patients' symptoms. Despite the availability of advanced therapies such as mechanical circulatory support or heart transplantation, the complexity of defining advanced HF, which requires multiple parameters and multimodality assessment, often leads to delays in referral to dedicated specialists with the result of a worsening prognosis. In this review, we aim to explore the role of cardiac magnetic resonance (CMR) in advanced HF by showing how CMR is useful at every step in managing these patients: from diagnosis to prognostic stratification, hemodynamic evaluation, follow-up and advanced therapies such as heart transplantation. The technical challenges of scanning advanced HF patients, which often require troubleshooting of intracardiac devices and dedicated scans, will be also discussed.

Aortic regurgitation: A multimodality approach.

Aortic regurgitation (AR) is a common valvular pathology. Multimodality noninvasive cardiovascular imaging is routinely used to assess the mechanism of AR, degree, and its hemodynamic impact on the cardiovascular system. Collecting this information is crucial in establishing the prognosis and in guiding patient management and follow-up. While echocardiography remains the primary test to assess AR, a comprehensive assessment of this valvulopathy can be obtained by combining the information from different techniques. This state-of-the-art review is intended to provide an update ed overview of the applications, strengths, and limits of transthoracic echocardiography, cardiac magnetic resonance, and cardiac computed tomography in patients with AR.

Electromechanical substrate characterization in arrhythmogenic cardiomyopathy using imaging-based patient-specific computer simulations.

AIMS: Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. The aim of this study is to use computer simulations to non-invasively estimate the individual patient's myocardial tissue substrates underlying regional right ventricular (RV) deformation abnormalities in a cohort of AC mutation carriers. METHODS AND RESULTS: In 68 AC mutation carriers and 20 control subjects, regional longitudinal deformation patterns of the RV free wall (RVfw), interventricular septum (IVS), and left ventricular free wall (LVfw) were obtained using speckle-tracking echocardiography. We developed and used a patient-specific parameter estimation protocol based on the multi-scale CircAdapt cardiovascular system model to create virtual AC subjects. Using the individual's deformation data as model input, this protocol automatically estimated regional RVfw and global IVS and LVfw tissue properties. The computational model was able to reproduce clinically measured regional deformation patterns for all subjects, with highly reproducible parameter estimations. Simulations revealed that regional RVfw heterogeneity of both contractile function and compliance were increased in subjects with clinically advanced disease compared to mutation carriers without clinically established disease (17 ± 13% vs. 8 ± 4%, P = 0.01 and 18 ± 11% vs. 10 ± 7%, P < 0.01, respectively). No significant difference in activation delay was found. CONCLUSION: Regional RV deformation abnormalities in AC mutation carriers were related to reduced regional contractile function and tissue compliance. In clinically advanced disease stages, a characteristic apex-to-base heterogeneity of tissue abnormalities was present in the majority of the subjects, with most pronounced disease in the basal region of the RVfw.

Proactive screening for symptoms: A simple method to improve early detection of unrecognized cardiovascular disease in primary care. Results from the Lifelines Cohort Study.

Cardiovascular disease (CVD) often goes unrecognized, despite symptoms frequently being present. Proactive screening for symptoms might improve early recognition and prevent disease progression or acute cardiovascular events. We studied the diagnostic value of symptoms for the detection of unrecognized atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) and developed a corresponding screening questionnaire. We included 100,311 participants (mean age 52 ± 9 years, 58% women) from the population-based Lifelines Cohort Study. For each outcome (unrecognized AF/HF/CAD), we built a multivariable model containing demographics and symptoms. These models were combined into one 'three-disease' diagnostic model and questionnaire for all three outcomes. Results were validated in Lifelines participants with chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM). Unrecognized CVD was identified in 1325 participants (1.3%): AF in 131 (0.1%), HF in 599 (0.6%), and CAD in 687 (0.7%). Added to age, sex, and body mass index, palpitations were independent predictors for unrecognized AF; palpitations, chest pain, dyspnea, exercise intolerance, health-related stress, and self-expected health worsening for unrecognized HF; smoking, chest pain, exercise intolerance, and claudication for unrecognized CAD. Area under the curve for the combined diagnostic model was 0.752 (95% CI 0.737-0.766) in the total population and 0.757 (95% CI 0.734-0.781) in participants with COPD and DM. At the chosen threshold, the questionnaire had low specificity, but high sensitivity. In conclusion, a short questionnaire about demographics and symptoms can improve early detection of CVD and help pre-select people who should or should not undergo further screening for CVD.

Hallucinations after Cardiac Surgery: A Prospective Observational Study.

Background and Objective: Hallucinations after cardiac surgery can be a burden, but their prevalence and phenomenology have not been studied well. Risk factors for postoperative hallucinations, as well as their relation to delirium are unclear. We aimed to study the prevalence and phenomenology of hallucinations after cardiac surgery, and to study the association between hallucinations and delirium in this population. Materials and Methods: We used the Questionnaire for Psychotic Experiences to detect hallucinations in cardiac surgery patients and a control group of cardiology outpatients. We assessed postoperative delirium with validated instruments. Risk factors for postoperative hallucinations and the association between hallucinations and delirium were analysed using logistic regression. Results: We included 201 cardiac surgery patients and 99 cardiology outpatient controls. Forty-four cardiac surgery patients (21.9%) experienced postoperative hallucinations in the first four postoperative days. This was significantly higher compared to cardiology outpatient controls (n = 4, 4.1%, p < 0.001). Visual hallucinations were the most common type of hallucinations in cardiac surgery patients, and less common in outpatient controls. Cardiac surgery patients who experienced hallucinations were more likely to also have delirium (10/44, 22.7%) compared to patients without postoperative hallucinations (16/157, 10.2% p = 0.03). However, the majority of patients with postoperative hallucinations (34/44, 77.3%) did not develop delirium. Conclusion: After cardiac surgery, hallucinations occurred more frequently than in outpatient controls. Hallucinations after cardiac surgery were most often visual in character. Although postoperative hallucinations were associated with delirium, most patients with hallucinations did not develop delirium.

Smoking cessation and risk of recurrent cardiovascular events and mortality after a first manifestation of arterial disease.

AIMS: To quantify the relation between smoking cessation after a first cardiovascular (CV) event and risk of recurrent CV events and mortality. METHODS: Data were available from 4,673 patients aged 61 ± 8.7 years, with a recent (≤1 year) first manifestation of arterial disease participating in the SMART-cohort. Cox models were used to quantify the relation between smoking status and risk of recurrent major atherosclerotic cardiovascular events (MACE including stroke, MI and vascular mortality) and mortality. In addition, survival according to smoking status was plotted, taking competing risk of non-vascular mortality into account. RESULTS: A third of the smokers stopped after their first CV event. During a median of 7.4 (3.7-10.8) years of follow-up, 794 patients died and 692 MACE occurred. Compared to patients who continued to smoke, patients who quit had a lower risk of recurrent MACE (adjusted HR 0.66, 95% CI 0.49-0.88) and all-cause mortality (adjusted HR 0.63, 95% CI 0.48-0.82). Patients who reported smoking cessation on average lived 5 life years longer and recurrent MACE occurred 10 years later. In patients with a first CV event >70 years, cessation of smoking had improved survival which on average was comparable to former or never smokers. CONCLUSIONS: Irrespective of age at first CV event, cessation of smoking after a first CV event is related to a substantial lower risk of recurrent vascular events and all-cause mortality. Since smoking cessation is more effective in reducing CV risk than any pharmaceutical treatment of major risk factors, it should be a key objective for patients with vascular disease.

Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department: A Stepped-Wedge, Cluster Randomized Trial.

BACKGROUND: The HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score is an easy-to-apply instrument to stratify patients with chest pain according to their short-term risk for major adverse cardiac events (MACEs), but its effect on daily practice is unknown. OBJECTIVE: To measure the effect of use of the HEART score on patient outcomes and use of health care resources. DESIGN: Stepped-wedge, cluster randomized trial. (ClinicalTrials.gov: NCT01756846). SETTING: Emergency departments in 9 Dutch hospitals. PATIENTS: Unselected patients with chest pain presenting at emergency departments in 2013 and 2014. INTERVENTION: All hospitals started with usual care. Every 6 weeks, 1 hospital was randomly assigned to switch to "HEART care," during which physicians calculated the HEART score to guide patient management. MEASUREMENTS: For safety, a noninferiority margin of a 3.0% absolute increase in MACEs within 6 weeks was set. Other outcomes included use of health care resources, quality of life, and cost-effectiveness. RESULTS: A total of 3648 patients were included (1827 receiving usual care and 1821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed. LIMITATION: Physicians were hesitant to refrain from admission and diagnostic tests in patients classified as low risk by the HEART score. CONCLUSION: Using the HEART score during initial assessment of patients with chest pain is safe, but the effect on health care resources is limited, possibly due to nonadherence to management recommendations. PRIMARY FUNDING SOURCE: Netherlands Organisation for Health Research and Development.

Cardiac Hepcidin Expression Associates with Injury Independent of Iron.

BACKGROUND: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. METHODS: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. RESULTS: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (ß = 0.734, p < 0.001) and connective tissue growth factor (ß = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. CONCLUSIONS: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

The additional value of three-dimensional transesophageal echocardiography in complex aortic prosthetic heart valve endocarditis.

BACKGROUND: Two-dimensional transthoracic and transesophageal echocardiography (2DTTE and 2DTEE) may fail to detect signs of prosthetic heart valve (PHV) endocarditis due to acoustic shadowing. Three-dimensional (3D) TEE may have additional value; however, data are scarce. This study was performed to investigate the additional value of 3DTEE for the detection of aortic PHV endocarditis and the extent of the disease process. METHODS: Retrospective analysis of complex aortic PHV endocarditis cases that underwent 2DTTE, 2DTEE, and 3DTEE before surgery. Echocardiograms were individually assessed by 2 cardiologists blinded for the outcome. Surgical and pathological inspection served as the reference standard for vegetations and peri-annular extensions (abscesses/mycotic aneurysms). To determine if the proximal coronary arteries were involved in the inflammatory process as well, computed tomography angiography findings were added to reference standard. RESULTS: Fifteen aortic PHV endocarditis cases were identified. According to the reference standard, all 15 cases had peri-annular extensions, 13 of which had a close relationship with the proximal right and/or left coronary artery. In 6 of 15 patients, a vegetation was present. Combined 2DTTE/TEE missed 1/6 vegetations and 1/15 peri-annular extensions. After addition of 3DTEE, all vegetations (6/6) and peri-annular extensions (15/15) were detected, without adding false positives. Compared to 2DTEE, in 3/15 cases, 3DTEE resulted in better delineation of the anatomical relationship of the proximal coronary arteries to the peri-annular extensions. As a result, 3DTEE had an additional value in 5/15 cases. CONCLUSION: In complex aortic, PHV endocarditis 3DTEE may have additional value compared to 2D echocardiography.

Association of mild kidney dysfunction with diastolic dysfunction and heart failure with preserved ejection fraction.

AIMS: We aim to investigate the association between kidney dysfunction and left ventricular diastolic dysfunction parameters and heart failure with preserved ejection fraction (HFpEF) and whether this is sex-specific. METHODS AND RESULTS: We included participants from the HELPFul observational study. Outpatient clinical care data, including echocardiography, and an expert panel judgement on HFpEF was collected. Estimated glomerular filtration rate (eGFR) was calculated by creatinine and cystatin C without race. The association between eGFR with E/e', left ventricular mass index, relative wall thickness, and stage C/D heart failure was tested by multivariable adjusted regression models, stratified by sex, reporting odds ratios and 95% confidence intervals (95% confidence interval). We analysed 880 participants, mean age 62.9 (standard deviation: 9.3) years, 69% female. Four hundred six participants had mild (37.6%) kidney dysfunction (eGFR: 60-89 mL/min/1.73 m2 ) or moderate (8.5%) kidney dysfunction (eGFR: 30-59 mL/min/1.73 m2 ). HFpEF was significantly more prevalent in participants with mild and moderate kidney dysfunction (10.3% and 16.0%, respectively) than participants with normal kidney function (3.4%). A lower kidney function was associated with higher E/e' and higher relative wall thickness values. Participants with moderate kidney dysfunction had a higher likelihood of American College of Cardiology/American Heart Association stage C/D HF (odds ratio: 2.07, 95% confidence interval: 1.23, 3.49) than participants with normal kidney functions. CONCLUSIONS: Both mild and moderate kidney dysfunction are independently associated with left ventricular diastolic dysfunction parameters and HFpEF. This association is independent of sex and strongest for moderate kidney dysfunction. Considering mild-to-moderate kidney dysfunction as risk factor for HFpEF may help identify high-risk groups benefiting most from early intervention.

Identifying plasma proteomic signatures from health to heart failure, across the ejection fraction spectrum.

Circulating proteins may provide insights into the varying biological mechanisms involved in heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). We aimed to identify specific proteomic patterns for HF, by comparing proteomic profiles across the ejection fraction spectrum. We investigated 4210 circulating proteins in 739 patients with normal (Stage A/Healthy) or elevated (Stage B) filling pressures, HFpEF, or ischemic HFrEF (iHFrEF). We found 2122 differentially expressed proteins between iHFrEF-Stage A/Healthy, 1462 between iHFrEF-HFpEF and 52 between HFpEF-Stage A/Healthy. Of these 52 proteins, 50 were also found in iHFrEF vs. Stage A/Healthy, leaving SLITRK6 and NELL2 expressed in lower levels only in HFpEF. Moreover, 108 proteins, linked to regulation of cell fate commitment, differed only between iHFrEF-HFpEF. Proteomics across the HF spectrum reveals overlap in differentially expressed proteins compared to stage A/Healthy. Multiple proteins are unique for distinguishing iHFrEF from HFpEF, supporting the capacity of proteomics to discern between these conditions.

On-screen image-guided lead placement in cardiac resynchronization therapy: Feasibility and outcome in a multicenter setting.

Background: Image guidance to assist left ventricular (LV) lead placement may improve outcome after cardiac resynchronization therapy (CRT), but previous approaches and results varied greatly, and multicenter feasibility is lacking altogether. Objective: We sought to investigate the multicenter feasibility of image guidance for periprocedural assistance of LV lead placement for CRT. Methods: In 30 patients from 3 hospitals, cardiac magnetic resonance imaging was performed within 3 months prior to CRT to identify myocardial scar and late mechanical activation (LMA). LMA was determined using radial strain, plotted over time. Segments without scar but clear LMA were classified as optimal for LV lead placement, according to an accurate 36-segment model of the whole heart. LV leads were navigated using image overlay with periprocedural fluoroscopy. After 6 months, volumetric response and super-response were defined as ≥15% or ≥30% reduction in LV end-systolic volume, respectively. Results: Periprocedural image guidance was successfully performed in all CRT patients (age 66 ± 10 years; 59% men, 62% with nonischemic cardiomyopathy, 69% with left bundle branch block). LV leads were placed as follows: within (14%), adjacent (62%), or remote (24%) from the predefined target. According to the conventional 18-segment model, a remote position occurred only once (3%). On average, 86% of patients demonstrated a volumetric response (mean LV end-systolic volume reduction 36 ± 29%), and 66% of all patients were super-responders. Conclusion: On-screen image guidance for LV lead placement in CRT was feasible in a multicenter setting. Efficacy will be further investigated in the randomized controlled ADVISE (Advanced Image Supported Lead Placement in Cardiac Resynchronization Therapy) trial (NCT05053568).

The Role of Non-Invasive Multimodality Imaging in Chronic Coronary Syndrome: Anatomical and Functional Pathways.

Coronary artery disease (CAD) is one of the major causes of mortality and morbidity worldwide, with a high socioeconomic impact. Currently, various guidelines and recommendations have been published about chronic coronary syndromes (CCS). According to the recent European Society of Cardiology guidelines on chronic coronary syndrome, a multimodal imaging approach is strongly recommended in the evaluation of patients with suspected CAD. Today, in the current practice, non-invasive imaging methods can assess coronary anatomy through coronary computed tomography angiography (CCTA) and/or inducible myocardial ischemia through functional stress testing (stress echocardiography, cardiac magnetic resonance imaging, single photon emission computed tomography-SPECT, or positron emission tomography-PET). However, recent trials (ISCHEMIA and REVIVED) have cast doubt on the previous conception of the management of patients with CCS, and nowadays it is essential to understand the limitations and strengths of each imaging method and, specifically, when to choose a functional approach focused on the ischemia versus a coronary anatomy-based one. Finally, the concept of a pathophysiology-driven treatment of these patients emerged as an important goal of multimodal imaging, integrating 'anatomical' and 'functional' information. The present review aims to provide an overview of non-invasive imaging modalities for the comprehensive management of CCS patients.

Transendocardial cell injection is not superior to intracoronary infusion in a porcine model of ischaemic cardiomyopathy: a study on delivery efficiency.

Stem cell therapy is a new strategy for chronic ischaemic heart disease in patients. However, no consensus exists on the most optimal delivery strategy. This randomized study was designed to assess cell delivery efficiency of three clinically relevant strategies: intracoronary (IC) and transendocardial (TE) using electromechanical mapping guidance (NOGA) compared to surgical delivery in a chronic pig model of ischaemic cardiomyopathy. Twenty-four animals underwent delivery of 10(7) autologous Indium-oxine-labelled bone marrow-derived mesenchymal stem cells (MSC) 4 weeks after infarction and were randomized to one of three groups (n = 8 each group): IC, TE or surgical delivery (reference group). Primary endpoint was defined as percentage (%) of injected dose per organ and assessed by in vivo gamma-emission counting. In addition, troponin and coronary flow were assessed before and after MSC injection. Blinded endpoint analysis showed no significant difference in efficiency after surgical (16 ± 4%), IC (11 ± 1%) and TE (11 ± 3%) (P = 0.52) injections. IC showed less variability in efficiency compared with TE and surgical injection. Overall, TE injection showed less distribution of MSC to visceral organs compared with other modalities. Troponin rise and IC flow did not differ between the percutaneous groups. This randomized study showed no significant difference in cell delivery efficiency to the myocardium in a clinically relevant ischaemic large animal model between IC and TE delivery. In addition, no differences in safety profile were observed. These results are important in view of the choice of percutaneous cell delivery modality in future clinical stem cell trials.

Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response.

TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.

A head-to-head comparison of speckle tracking echocardiography and feature tracking cardiovascular magnetic resonance imaging in right ventricular deformation.

AIMS: Speckle tracking echocardiography (STE) and feature tracking cardiovascular magnetic resonance imaging (FT-CMR) are advanced imaging techniques which are both used for quantification of global and regional myocardial strain. Direct comparisons of STE and FT-CMR regarding right ventricular (RV) strain analysis are limited. We aimed to study clinical performance, correlation and agreement of RV strain by these techniques, using arrhythmogenic right ventricular cardiomyopathy (ARVC) as a model for RV disease. METHODS AND RESULTS: We enrolled 110 subjects, including 34 patients with definite ARVC, 30 preclinical relatives of ARVC patients, and 46 healthy control subjects. Global and regional RV longitudinal peak strain (PS) were measured by STE and FT-CMR. Both modalities showed reduced strain values in ARVC patients compared to ARVC relatives (STE global PS: P < 0.001; FT-CMR global PS: P < 0.001) and reduced strain values in ARVC relatives compared to healthy control subjects (STE global PS: P = 0.042; FT-CMR global PS: P = 0.084). There was a moderate, albeit significant correlation between RV strain values obtained by STE and FT-CMR [global PS r = 0.578 (95% confidence interval 0.427-0.697), P < 0.001]. Agreement between the techniques was weak (limits of agreement for global PS: ±11.8%). Correlation and agreement both deteriorated when regional strain was studied. CONCLUSION: RV STE and FT-CMR show a similar trend within the spectrum of ARVC and have significant correlation, but inter-modality agreement is weak. STE and FT-CMR may therefore both individually have added value for assessment of RV function, but RV PS values obtained by these techniques currently cannot be used interchangeably in clinical practice.

Improving early diagnosis of cardiovascular disease in patients with type 2 diabetes and COPD: protocol of the RED-CVD cluster randomised diagnostic trial.

INTRODUCTION: The early stages of chronic progressive cardiovascular disease (CVD) generally cause non-specific symptoms that patients often do not spontaneously mention to their general practitioner, and are therefore easily missed. A proactive diagnostic strategy has the potential to uncover these frequently missed early stages, creating an opportunity for earlier intervention. This is of particular importance for chronic progressive CVDs with evidence-based therapies known to improve prognosis, such as ischaemic heart disease, atrial fibrillation and heart failure.Patients with type 2 diabetes or chronic obstructive pulmonary disease (COPD) are at particularly high risk of developing CVD. In the current study, we will demonstrate the feasibility and effectiveness of screening these high-risk patients with our early diagnosis strategy, using tools that are readily available in primary care, such as symptom questionnaires (to be filled out by the patients themselves), natriuretic peptide measurement and electrocardiography. METHODS AND ANALYSIS: The Reviving the Early Diagnosis-CVD trial is a multicentre, cluster randomised diagnostic trial performed in primary care practices across the Netherlands. We aim to include 1300 (2×650) patients who participate in a primary care disease management programme for COPD or type 2 diabetes. Practices will be randomised to the intervention arm (performing the early diagnosis strategy during the routine visits that are part of the disease management programmes) or the control arm (care as usual). The main outcome is the number of newly detected cases with CVDs in both arms, and the subsequent therapies they received. Secondary endpoints include quality of life, cost-effectiveness and the added diagnostic value of family and reproductive history questionnaires and three (novel) biomarkers (high-sensitive troponin-I, growth differentiation factor-15 and suppressor of tumourigenicity 2). Finally newly initiated treatments will be compared in both groups. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of the University Medical Center Utrecht, the Netherlands. Results are expected in 2022 and will be disseminated through international peer-reviewed publications. TRIAL REGISTRATION NUMBER: NTR7360.

Heart Size Corrected Electrical Dyssynchrony and Its Impact on Sex-Specific Response to Cardiac Resynchronization Therapy.

BACKGROUND: Women are less likely to receive cardiac resynchronization therapy, yet, they are more responsive to the therapy and respond at shorter QRS duration. The present study hypothesized that a relatively larger left ventricular (LV) electrical dyssynchrony in smaller hearts contributes to the better cardiac resynchronization therapy response in women. For this, the vectorcardiography-derived QRS area is used, since it allows for a more detailed quantification of electrical dyssynchrony compared with conventional electrocardiographic markers. METHODS: Data from a multicenter registry of 725 cardiac resynchronization therapy patients (median follow-up, 4.2 years [interquartile range, 2.7-6.1]) were analyzed. Baseline electrical dyssynchrony was evaluated using the QRS area and the corrected QRS area for heart size using the LV end-diastolic volume (QRSarea/LVEDV). Impact of the QRSarea/LVEDV ratio on the association between sex and LV reverse remodeling (LV end-systolic volume change) and sex and the composite outcome of all-cause mortality, LV assist device implantation, or heart transplantation was assessed. RESULTS: At baseline, women (n=228) displayed larger electrical dyssynchrony than men (QRS area, 132±55 versus 123±58 µVs; P=0.043), which was even more pronounced for the QRSarea/LVEDV ratio (0.76±0.46 versus 0.57±0.34 µVs/mL; P<0.001). After multivariable analyses, female sex was associated with LV end-systolic volume change (ß=0.12; P=0.003) and a lower occurrence of the composite outcome (hazard ratio, 0.59 [0.42-0.85]; P=0.004). A part of the female advantage regarding reverse remodeling was attributed to the larger QRSarea/LVEDV ratio in women (25-fold change in ß from 0.12 to 0.09). The larger QRSarea/LVEDV ratio did not contribute to the better survival observed in women. In both volumetric responders and nonresponders, female sex remained strongly associated with a lower risk of the composite outcome (adjusted hazard ratio, 0.59 [0.36-0.97]; P=0.036; and 0.55 [0.33-0.90]; P=0.018, respectively). CONCLUSIONS: Greater electrical dyssynchrony in smaller hearts contributes, in part, to more reverse remodeling observed in women after cardiac resynchronization therapy, but this does not explain their better long-term outcomes.

Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol.

INTRODUCTION: Rheumatic heart disease (RHD) is a major burden in developing countries and accounts for 80% of all people living with the disease, where it causes most cardiovascular morbidity and mortality in children and young adults. Chronic inflammation and fibrosis of heart valve tissue due to chronic inflammation in RHD will cause calcification and thickening of the impacted heart valves, especially the mitral valve. This fibrogenesis is enhanced by the production of angiotensin II by increased transforming growth factor ß expression and later by the binding of interleukin-33, which is known to have antihypertrophic and antifibrotic effects, to soluble sST2. sST2 binding to this non-natural ligand worsens fibrosis. Therefore, we hypothesise that ACE inhibitors (ACEIs) would improve rheumatic mitral valve stenosis. METHODS AND ANALYSIS: This is a single-centre, double-blind, placebo-controlled, randomised clinical trial with a pre-post test design. Patients with rheumatic mitral stenosis and valve dysfunction will be planned for cardiac valve replacement operation and will be given ramipril 5 mg or placebo for a minimum of 12 weeks before the surgery. The expression of ST2 in the mitral valve is considered to be representative of cardiac fibrosis. Mitral valve tissue will be stained by immunohistochemistry to ST2. Plasma ST2 will be measured by ELISA. This study is conducted in the Department of Cardiology and Vascular Medicine, Universitas Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia, starting on 27 June 2019. ETHICS AND DISSEMINATION: The performance and dissemination of this study were approved by the ethics committee of National Cardiovascular Center Harapan Kita with ethical code LB.02.01/VII/286/KEP.009/2018. TRIAL REGISTRATION NUMBER: NCT03991910.