The year in cardiovascular medicine 2021: digital health and innovation.

This article presents some of the most important developments in the field of digital medicine that have appeared over the last 12 months and are related to cardiovascular medicine. The article consists of three main sections, as follows: (i) artificial intelligence-enabled cardiovascular diagnostic tools, techniques, and methodologies, (ii) big data and prognostic models for cardiovascular risk protection, and (iii) wearable devices in cardiovascular risk assessment, cardiovascular disease prevention, diagnosis, and management. To conclude the article, the authors present a brief further prospective on this new domain, highlighting existing gaps that are specifically related to artificial intelligence technologies, such as explainability, cost-effectiveness, and, of course, the importance of proper regulatory oversight for each clinical implementation.

Critical appraisal of artificial intelligence-based prediction models for cardiovascular disease.

The medical field has seen a rapid increase in the development of artificial intelligence (AI)-based prediction models. With the introduction of such AI-based prediction model tools and software in cardiovascular patient care, the cardiovascular researcher and healthcare professional are challenged to understand the opportunities as well as the limitations of the AI-based predictions. In this article, we present 12 critical questions for cardiovascular health professionals to ask when confronted with an AI-based prediction model. We aim to support medical professionals to distinguish the AI-based prediction models that can add value to patient care from the AI that does not.

CODE-EHR best practice framework for the use of structured electronic healthcare records in clinical research.

Big data is central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. The covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls. Verification, validation, and data privacy, as well as the social mandate to undertake research are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors and industry. We propose the CODE-EHR Minimum Standards Framework as a means to improve the design of studies, enhance transparency and develop a roadmap towards more robust and effective utilisation of healthcare data for research purposes.

Impact of Sustained Cardiac Tachyarrhythmias Recorded in Coronary Intensive Care Unit on Short- and Long-Term Mortality and Duration of Hospitalization.

BACKGROUND: Studies conducted in coronary intensive care units (CICUs) have demonstrated that tachyarrhythmias are associated with increased mortality after acute coronary syndromes (ACSs). However, the data for tachyarrhythmias occurred in CICUs due to a variety of cardiovascular disorders are limited. METHODS: We conducted a single-center prospective observational study, which included consecutive CICU patients (January 1, 2014 to May 31, 2018). We recorded the ventricular arrhythmias (VAs), supraventricular tachycardias (SVTs), and days of CICU hospitalization. The patients were followed up for 6 months after CICU discharge. RESULTS: A total of 943 patients (age: 66.37 ±15.4 years; 673 males [71.4%]) were included. Patients with tachyarrhythmias had higher in-CICU mortality (8.0% vs 4.1%, P = .029, odds ratio [OR]: 2.04, 95% confidence interval [CI]: 1.08-3.86) and higher 6-month all-cause mortality (12.8% vs 6.1%, P = .002, OR: 2.27, 95% CI: 1.35-3.83) than those who did not develop tachyarrhythmias. Ventricular arrhythmias was significantly associated with higher all-cause mortality than no tachyarrhythmia (15.4% vs 6.1%; P = .001) or SVTs (15.4% vs 7.0%; P = .001). The mean duration of hospitalization for the patients with tachyarrhythmias was 3.89 ± 4.90 days, while for the patients without was 2.79 ± 3.31 days (P < .001). Patients without ACS had higher short- and long-term mortality compared to patients with ACS (9.2% vs 2.9%, P < .001 and 12.9% vs 4.9%, P < .001). CONCLUSIONS: Tachyarrhythmias were associated with prolonged CICU hospitalization, while non-ACS cardiovascular disorders and the occurrence of VAs were associated with increased short- and long-term mortality.

Roadmap for cardiovascular education across the European Society of Cardiology: inspiring better knowledge and skills, now and for the future.

AIMS: The provision of high-quality education allows the European Society of Cardiology (ESC) to achieve its mission of better cardiovascular practice and provides an essential component of translating new evidence to improve outcomes. METHODS AND RESULTS: The 4th ESC Education Conference, held in Sophia Antipolis (December 2016), brought together ESC education leaders, National Directors of Training of 43 ESC countries, and representatives of the ESC Young Community. Integrating national descriptions of education and cardiology training, we discussed innovative pathways to further improve knowledge and skills across different training programmes and health care systems. We developed an ESC roadmap supporting better cardiology training and continued medical education (CME), noting: (i) The ESC provides an excellent framework for unbiased and up-to-date cardiovascular education in close cooperation with its National Societies. (ii) The ESC should support the harmonization of cardiology training, curriculum development, and professional dialogue and mentorship. (iii) ESC congresses are an essential forum to learn and discuss the latest developments in cardiovascular medicine. (iv) The ESC should create a unified, interactive educational platform for cardiology training and continued cardiovascular education combining Webinars, eLearning Courses, Clinical Cases, and other educational programmes, along with ESC Congress content, Practice Guidelines and the next ESC Textbook of Cardiovascular Medicine. (v) ESC-delivered online education should be integrated into National and regional cardiology training and CME programmes. CONCLUSION: These recommendations support the ESC to deliver excellent and comprehensive cardiovascular education for the next generation of specialists. Teamwork between international, national and local partners is essential to achieve this objective.

The long non-coding RNAs MHRT, FENDRR and CARMEN, their expression levels in peripheral blood mononuclear cells in patients with essential hypertension and their relation to heart hypertrophy.

Long non-coding RNAs (lncRNAs) participate in the modulation of cardiac hypertrophy, and they represent potential therapeutic targets in cardiovascular disease. We investigated the expression profiles of selected lncRNAs in peripheral blood mononuclear cells of patients with essential hypertension in relation to left ventricular hypertrophy. We assessed the expression levels of the lncRNAs MHRT, FENDRR and CARMEN using real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly higher MHRT, FENDRR and CARMEN expression levels compared with healthy controls. In addition, we observed significant negative correlations of MHRT (r = -0.323, P = 0.003) and FENDRR (r = -0.380, P = 0.001) and a positive correlation of CARMEN (r = 0.458, P < 0.001) expression levels with left ventricular mass index. Our data reveal that the lncRNAs MHRT, FENDRR and CARMEN show distinct expression profiles in hypertensive patients and they possibly represent candidate therapeutic targets in hypertensive heart disease.

Cardiac resynchronization therapy (CRT) device replacement considerations: upgrade or downgrade? A complex decision in the current clinical setting.

There are limited data about the management of patients presenting for elective generator replacements in the setting of previously implanted cardiac resynchronization therapy (CRT) devices that are nearing end-of-life. The individual patient's clinical status and concomitant morbidities may evolve so that considerations may include not only replacement of the pulse generator, but also potentially changing the type of device [e.g. downgrading CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) or ICD or upgrading of CRT-P to CRT-D]. Moreover, the clinical evidence for CRT-D/CRT-P implantation may change over time, with ongoing research and availability of new trial data. In this review we discuss the ethical, clinical and financial implications related to CRT generator replacements and the need for additional clinical trials to better understand which patients should undergo CRT device downgrading or upgrading at the time of battery depletion.

Alterations in the expression of genes related to contractile function and hypertrophy of the left ventricle in chronically paced patients from the right ventricular apex.

AIM: Long-term right ventricular apical (RVA) pacing may lead to left ventricular (LV) remodelling and heart failure. This study assessed changes in the expression of genes regulating LV contractile function and hypertrophy, after permanent RVA pacing and investigated whether such changes proceed or even predict LV remodelling. METHODS AND RESULTS: We enrolled 52 consecutive patients (age 79.1 ± 7.7 years, 34 males) who underwent pacemaker implantation for bradycardic indications: Group A, 24 individuals with atrioventricular conduction disturbances and group B, 28 patients with sinus node disease. In group A, peripheral blood mRNA levels of gene sarcoplasmic reticulum calcium ATPase decreased at 3, 6, and 12 months' follow-up, while α-myosin heavy chain (MHC) decreased and ß-MHC increased until 6 months follow-up. In this group, 25% of patients demonstrated significant LV remodelling. At 4 years, LV end-systolic diameter increased from 29.67 ± 3.39 mm at baseline to 35.38 ± 4.22 mm, LV end-diastolic diameter increased from 50 ± 4.95 to 56.71 ± 5.52 mm, and ejection fraction declined from 63.04 ± 10.22 to 52.83 ± 10.81%. Early alterations in gene expression were associated with a deterioration in LV function and geometry that became apparent months later. In group B, echocardiographic indexes and mRNA levels of the evaluated genes demonstrated no statistically significant changes. CONCLUSIONS: Permanent RVA pacing in patients with preserved ejection fraction is associated with alterations in the expression of genes regulating LV contractile function and hypertrophy, measured in the peripheral blood. These alterations are traceable at an early stage, before echocardiographic changes are apparent and are associated with LV remodelling that becomes evident in the long term.

Electrophysiological and Electroanatomical Mapping of the Right Atrium in Persistent Atrial Fibrillation: Relation to Collagen Turnover.

BACKGROUND: Atrial fibrillation (AF) is associated with abnormal atrial substrate. We investigated whether patients with persistent lone AF and patients with persistent AF and nonischemic dilated cardiomyopathy (NIDCM) exhibit any differences in electrophysiological and electroanatomical properties of right atrium (RA) and collagen turnover. We also investigated the relationship between mean RA bipolar voltage and collagen turnover. METHODS: Ten patients with a history of persistent lone AF and eight patients with a history of persistent AF and NIDCM were studied. Sinus node recovery times (SNRTs) and effective refractory periods (ERPs) at 600 ms, 500 ms, and 400 ms from the high (HLRA) and low (LLRA) lateral RA, proximal coronary sinus (pCS), and right atrial appendage (RAA) were evaluated, and RA electroanatomic mapping was created. Serum N-terminal propeptide of collagen type I (PINP), cross-linked C-terminal telopeptide of collagen type I (CTx), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinases (TIMP-1) were measured as markers of collagen synthesis and degradation. RESULTS: No differences were found in SNRTs, ERPs from the HLRA, LLRA at 600 ms, pCS and RAA, mean RA bipolar voltage, serum PINP, CTx, MMP-1, and TIMP-1 between the two groups. In persistent lone AF, serum levels of TIMP-1 were related with mean HLRA and HPRA bipolar voltage. CONCLUSIONS: Persistent AF patients with or without NIDCM, demonstrate similar changes in electrophysiological and electroanatomical properties of the RA, as well as similar structural changes. Moreover, serum markers of collagen synthesis are correlated with bipolar voltage in specific regions of RA in persistent lone AF.

Comparison of the antiplatelet effect of clopidogrel hydrogenosulfate and clopidogrel besylate in patients with stable coronary artery disease.

It is well known that patients with poor response to antiplatelet therapy are most likely to have more thrombotic events. Clopidogrel hydrogensulfate (CHS) is a thienopyridine acting as an important antiplatelet agent alone or in combination with acetylsalicylic acid to prevent cardiovascular complications. A different clopidogrel salt, clopidogrel besylate (CB), was recently approved as a generic drug for the same purpose while data about its antiplatelet effect are very scarce. Our study compared the antiplatelet effect of CHS and CB in patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 101) (coronary lesions defined angiographically 30-70 %) were randomized to either CHS (n = 50) or CB (n = 51). After randomization a 600 mg loading dose of the drug was given and monitoring of antiplatelet effect was done 12-14 h later with VerifyNow assay. Antiplatelet response was measured with P2Y12 reaction units (PRU) and % inhibition P2Y12 from baseline (% inhibition P2Y12). Moreover CYP2C19*2, CYP2C19*3 and CYP3Α5 polymorphisms were studied in all patients. Clinical characteristics were similar between the two study groups. No significant difference was observed for baseline platelet reactivity between CHS and CB patients (258 ± 38 vs. 256 ± 38 respectively, p = 0.79). No difference was found for antiplatelet response between the CHS and the CB group, assessed by PRU (195 ± 74 vs. 204 ± 67 respectively, p = 0.51) and by % inhibition P2Y12 (24 ± 25 vs. 24 ± 22 % respectively, p = 0.95). Number of heterozygotes for CYP2C19*2 polymorphism was comparable and their platelet reactivity was similar between the two study groups. Our results indicate that both CB and CHS had an identical antiplatelet effect in patients with stable coronary artery disease. No difference on platelet reactivity of heterozygotes for CYP2C19*2 polymorphism was found between the two study groups.

Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.

AIMS: X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. METHODS AND RESULTS: We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P < 0.001). Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). CONCLUSION: Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov; TRIAL REGISTRATION NUMBER: NCT01674647.

Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion.

BACKGROUND: Anticoagulation before, during, and after cardioversion is effective in reducing stroke risk in patients with atrial fibrillation. OBJECTIVE: The objective of this study is to explore the efficacy and safety of rivaroxaban 20 mg once daily (15 mg if creatinine clearance is 30-49 mL/min) compared with dose-adjusted vitamin K antagonists (VKAs; international normalized ratio 2.0-3.0) in patients scheduled for elective cardioversion. METHODS: This is a prospective, randomized, open-label, parallel group comparison of approximately 1,500 patients from 17 countries with hemodynamically stable nonvalvular atrial fibrillation of >48 hours or unknown duration. Patients will be randomized 2:1 (rivaroxaban:VKA) using 2 cardioversion strategies: the first approach is early cardioversion with the precardioversion anticoagulation goal of 1 to 5 days using rivaroxaban or usual therapy (heparin + VKA). In these patients, transesophageal echocardiography will be encouraged to exclude atrial thrombi. The alternative approach is delayed cardioversion. Rivaroxaban or VKA will be administered for 21 to 56 days before cardioversion. All patients will receive study treatment for 6 weeks postcardioversion. The primary efficacy end point is a composite of all strokes, transient ischemic attacks, noncentral nervous system systemic emboli, myocardial infarctions, and cardiovascular deaths. Each primary end point component will be evaluated separately, and additional composites will be investigated. The principal safety end point is major bleeding. CLINICAL CONTEXT: This will be the first prospective study of a novel oral anticoagulant in the setting of cardioversion. It will provide important information regarding the use of rivaroxaban in the periods preceding and after cardioversion in a broad patient population.

Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies.

Cardiac muscle contraction occurs through an interaction of the myosin head with the actin filaments, a process which is regulated by the troponin complex together with tropomyosin and is Ca(2+) dependent. Mutations in genes encoding sarcomeric proteins are a common cause of familial hypertrophic and dilated cardiomyopathies. The scope of this review is to gather information from studies regarding the in vitro characterisation of six HCM and six DCM mutations on the cardiac TnC gene and to suggest, if possible, how they may lead to dysfunction. Since TnC is the subunit responsible for Ca(2+) binding, mutations in the TnC could possibly have a strong impact on Ca(2+) binding affinities. Furthermore, the interactions of mutant TnCs with their binding partners could be altered. From the characterisation studies available to date, we can conclude that the HCM mutations on TnC increase significantly the Ca(2+) sensitivity of force development or of ATPase activity, producing large pCa shifts in comparison to WT TnC. In contrast, the DCM mutations on TnC have a tendency to decrease the Ca(2+) sensitivity of force development or of ATPase activity in comparison to WT TnC. Furthermore, the DCM mutants of TnC are not responsive to the TnI phosphorylation signal resulting in filaments that preserve their Ca(2+) sensitivity in contrast to WT filaments that experience a decrease in Ca(2+) sensitivity upon TnI phosphorylation.

Sinus rhythm restoration affects collagen turnover in patients with persistent atrial fibrillation.

AIMS: Collagen turnover and atrial fibrosis have been implicated in the generation and perpetuation of atrial fibrillation (AF). We evaluated the importance of serum markers of collagen turnover in predicting the outcome of electrical cardioversion (CV) of persistent AF and the relationship between AF and fibrosis. METHODS AND RESULTS: Serum C-terminal pro-peptide of collagen type-I (CICP) and C-terminal telopeptide of collagen type-I (CITP) were measured in 164 patients with AF before and 2 months after CV. All the patients were successfully cardioverted to sinus rhythm (SR) although in 38 of them AF recurred. Baseline CICP levels were comparable in patients in SR 60 days after CV and in those who experienced a relapse of AF (85.08 ± 16.99 vs. 87.55 ± 10.43 ng/mL, respectively, P = ns). Baseline CITP levels were significantly higher in patients with AF recurrence compared with those who remained in SR (0.48 ± 0.16 vs. 0.32 ± 0.17 ng/mL, respectively, P < 0.0001). In the 126 patients who maintained the SR, CICP levels were significantly lower at the end of the study as compared with the baseline (63.74 ± 15.92 vs. 85.08 ± 16.99 ng/mL P = 0.003), while there was a mild increase in plasma CITP levels (0.36 ± 0.21 vs. 0.32 ± 0.17 ng/mL, respectively, P = 0.03). CONCLUSION: Atrial fibrillation can result in alterations in atrial structure and architecture that make the atrial myocardium more susceptible to the maintenance of the arrhythmia. Sinus rhythm restoration could affect the fibrotic process occurring or exacerbating during AF course.

MicroRNAs in Atrial Fibrillation: Mechanisms, Vascular Implications, and Therapeutic Potential.

Atrial fibrillation (AFib), the most prevalent arrhythmia in clinical practice, presents a growing global health concern, particularly with the aging population, as it is associated with devastating complications and an impaired quality of life. Its pathophysiology is multifactorial, including the pathways of fibrosis, inflammation, and oxidative stress. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as substantial contributors in AFib pathophysiology, by affecting those pathways. In this review, we explore the intricate relationship between miRNAs and the aforementioned aspects of AFib, shedding light on the molecular pathways as well as the potential diagnostic applications. Recent evidence also suggests a possible role of miRNA therapeutics in maintenance of sinus rhythm via the antagonism of miR-1 and miR-328, or the pharmacological upregulation of miR-27b and miR-223-3p. Unraveling the crosstalk between specific miRNA profiles and genetic predispositions may pave the way for personalized therapeutic approaches, setting the tone for precision medicine in atrial fibrillation.

The use of imaging for electrophysiological and devices procedures: a report from the first European Heart Rhythm Association Policy Conference, jointly organized with the European Association of Cardiovascular Imaging (EACVI), the Council of Cardiovascular Imaging and the European Society of Cardiac Radiology.

Implantations of cardiac devices therapies and ablation procedures frequently depend on accurate and reliable imaging modalities for pre-procedural assessments, intra-procedural guidance, detection of complications, and the follow-up of patients. An understanding of echocardiography, cardiovascular magnetic resonance imaging, nuclear cardiology, X-ray computed tomography, positron emission tomography, and vascular ultrasound is indispensable for cardiologists, electrophysiologists as well as radiologists, and it is currently recommended that physicians should be trained in several imaging modalities. There are, however, no current guidelines or recommendations by electrophysiologists, cardiac imaging specialists, and radiologists, on the appropriate use of cardiovascular imaging for selected patient indications, which needs to be addressed. A Policy Conference on the use of imaging in electrophysiology and device management, with representatives from different expert areas of radiology and electrophysiology and commercial developers of imaging and device technologies, was therefore jointly organized by European Heart Rhythm Association (EHRA), the Council of Cardiovascular Imaging and the European Society of Cardiac Radiology (ESCR). The objectives were to assess the state of the level of evidence and a first step towards a consensus document for currently employed imaging techniques to guide future clinical use, to elucidate the issue of reimbursement structures and health economy, and finally to define the need for appropriate educational programmes to ensure clinical competence for electrophysiologists, imaging specialists, and radiologists.