The influence of endurance exercise training on myocardial fibrosis and arrhythmogenesis in a coxsackievirus B3 myocarditis mouse model.

Nonischaemic myocardial fibrosis is associated with cardiac dysfunction, malignant arrhythmias and sudden cardiac death. In the absence of a specific aetiology, its finding as late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging is often attributed to preceding viral myocarditis. Athletes presenting with ventricular arrhythmias often have nonischaemic LGE. Previous studies have demonstrated an adverse effect of exercise on the course of acute viral myocarditis. In this study, we have investigated, for the first time, the impact of endurance training on longer-term outcomes such as myocardial fibrosis and arrhythmogenicity in a murine coxsackievirus B3 (CVB)-induced myocarditis model. Male C57BL/6J mice (n = 72) were randomly assigned to 8 weeks of forced treadmill running (EEX) or no exercise (SED). Myocarditis was induced 2 weeks later by a single intraperitoneal injection with CVB, versus vehicle in the controls (PBS). In a separate study, mice (n = 30) were subjected to pretraining for 13 weeks (preEEX), without continuation of exercise during myocarditis. Overall, continuation of exercise resulted in a milder clinical course of viral disease, with less weight loss and better preserved running capacity. CVB-EEX and preEEX-CVB mice tended to have a lower mortality rate. At sacrifice (i.e. 6 weeks after inoculation), the majority of virus was cleared from the heart. Histological assessment demonstrated prominent myocardial inflammatory infiltration and cardiomyocyte loss in both CVB groups. Inflammatory lesions in the CVB-EEX group contained higher numbers of pro-inflammatory cells (iNOS-reactive macrophages and CD8+ T lymphocytes) compared to these in CVB-SED. Treadmill running during myocarditis increased interstitial fibrosis [82.4% (CVB-EEX) vs. 56.3% (CVB-SED); P = 0.049]. Additionally, perivascular and/or interstitial fibrosis with extensive distribution was more likely to occur with exercise [64.7% and 64.7% (CVB-EEX) vs. 50% and 31.3% (CVB-SED); P = 0.048]. There was a numerical, but not significant, increase in the number of scars per cross-section (1.9 vs. 1.2; P = 0.195), with similar scar distribution and histological appearance in CVB-EEX and CVB-SED. In vivo electrophysiology studies did not induce sustained monomorphic ventricular tachycardia, only nonsustained (usually polymorphic) runs. Their cumulative beat count and duration paralleled the increased fibrosis between CVB-EEX and CVB-SED, but the difference was not significant (P = 0.084 for each). Interestingly, in mice that were subjected to pretraining only without continuation of exercise during myocarditis, no differences between pretrained and sedentary mice were observed at sacrifice (i.e. 6 weeks after inoculation and training cessation) with regard to myocardial inflammation, fibrosis, and ventricular arrhythmogenicity. In conclusion, endurance exercise during viral myocarditis modulates the inflammatory process with more pro-inflammatory cells and enhances perivascular and interstitial fibrosis development. The impact on ventricular arrhythmogenesis requires further exploration.

Phenotypic spectrum of the first Belgian MYBPC3 founder: a large multi-exon deletion with a varying phenotype.

Background: Variants in the MYBPC3 gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in MYBPC3 (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers. Methods: Probands with HCM caused by a pathogenic deletion of exon 23-26 of MYBPC3 were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding MYBPC3, was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach. Results: We identified 24 probands with HCM harbouring the MYBPC3 exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175-200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; p < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; p = 0.002), arrhythmia (41.7% vs. 12.9%, p = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; p < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; p = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years. Conclusion: A Belgian founder variant, an exon 23-26 deletion in MYBPC3, was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.

The natural history of CVB3 myocarditis in C57BL/6J mice: an extended in-depth characterization.

BACKGROUND AND AIMS: Viral infections are the leading cause of myocarditis. Besides acute cardiac complications, late-stage sequelae such as myocardial fibrosis may develop, importantly impacting the prognosis. Coxsackievirus B3 (CVB)-induced myocarditis in mice is the most commonly used translational model to study viral myocarditis and has provided the majority of our current understanding of the disease pathophysiology. Nevertheless, the late stages of disease, encompassing fibrogenesis and arrhythmogenesis, have been underappreciated in viral myocarditis research to date. The present study investigated the natural history of CVB-induced myocarditis in C57BL/6J mice, expanding the focus beyond the acute phase of disease. In addition, we studied the impact of sex and inoculation dose on the disease course. METHODS AND RESULTS: C57BL/6J mice (12 weeks old; n=154) received a single intraperitoneal injection with CVB to induce viral myocarditis, or vehicle (PBS) as control. Male mice (n=92) were injected with 5 × 105 (regular dose)(RD) or 5 × 106 (high dose)(HD) plaque-forming units of CVB, whereas female mice received the RD only. Animals were sacrificed 1, 2, 4, 8 and 11 weeks after CVB or PBS injection. Virally inoculated mice developed viral disease with a temporary decline in general condition and weight loss, which was less pronounced in female animals (P<0.001). In male CVB mice, premature mortality occurred between days 8-23 after inoculation (RD: 21%, HD: 20%), whereas all female animals survived. Over the course of disease, cardiac inflammation progressively subsided, with faster resolution in female mice. There were no substantial group differences in the composition of the inflammatory cell infiltrates: predominance of cytotoxic T cells at day 7 and 14, and a switch from arginase1-reactive macrophages to iNOS-reactive macrophages from day 7 to 14 were the main findings. There was concomitant development and maturation of different patterns of myocardial fibrosis, with enhanced fibrogenesis in male mice. Virus was almost completely cleared from the heart by day 14. Serum biomarkers of cardiac damage and cardiac expression of remodeling genes were temporarily elevated during the acute phase of disease. Cardiac CTGF gene upregulation was less prolonged in female CVB animals. In vivo electrophysiology studies at weeks 8 and 11 demonstrated that under baseline conditions (i.e. in the absence of proarrhythmogenic drugs), ventricular arrhythmias could only be induced in CVB animals. The cumulative arrhythmia burden throughout the entire stimulation protocol was not significantly different between CVB and control groups. CONCLUSION: CVB inoculation in C57BL/6J mice represents a model of acute self-limiting viral myocarditis, with progression to different patterns of myocardial fibrosis. Sex, but not inoculation dose, seems to modulate the course of disease.

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review.

Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.

Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial.

AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

Safety of Sports for Patients with Subcutaneous Implantable Cardioverter Defibrillator (SPORT S-ICD): study rationale and protocol.

Background: Recent studies suggest that participation in recreational and even competitive sports is generally safe for patients with implantable cardioverter-defibrillators (ICDs). However, these studies included only patients with implanted transvenous ICD (TV-ICD). Nowadays, subcutaneous ICD (S-ICD) is a safe and effective alternative and is increasingly implanted in younger ICD candidates. Data on the safety of sport participation for patients with implanted S-ICD systems is urgently needed. Objectives: The goal of the study is to quantify the risks (or determine the safety) of sports participation for athletes with an S-ICD, which will guide shared decision making for athletes requiring an ICD and/or wishing to return to sports after implantation. Methods: The SPORT S-ICD (Sports for Patients with Subcutaneous Implantable Cardioverter Defibrillator) study is an international, multicenter, prospective, noninterventional, observational study, designed specifically to collect data on the safety of sports participation among patients with implanted S-ICD systems who regularly engage in sports activities. Results: A total of 450 patients will undergo baseline assessment including baseline characteristics, indication for S-ICD implantation, arrhythmic history, S-ICD data and programming, and data regarding sports activities. LATITUDE Home Monitoring information will be regularly transferred to the study coordinator for analysis. Conclusion: The results of the study will aid in shaping clinical decision making, and if the tested hypothesis will be proven, it will allow the safe continuation of sports for patients with an implanted S-ICD.

Impact of recurrent COVID-19 disease waves on acute myocardial infarction epidemics: results from a regional network.

Aims: To assess the impact of COVID-19 related public containment measures during recurrent COVID-19 waves on hospital admission rate for acute myocardial infarction (AMI).Methods and results: Clinical characteristics, reperfusion therapy modalities, COVID-19 status and in-hospital mortality of consecutive AMI patients who were admitted in a regional AMI network were recorded during one year starting in March 2020 and were compared with the year before. The COVID-19 study period encompassed two waves: the first in March-May 2020 and the second in October-December 2020. A total of 1349 AMI patients were hospitalised of which 725 during the pre-COVID period and 624 during the COVID period (incidence rate ratio of 1.16, p = 0,006). The impact was predominantly present in the first wave (32% reduction: n = 204 vs 152) and evanished during the second wave (3% increase (152 vs 156). A similar pattern was observed for ACS with cardiac arrest with a 92% reduction (n = 36 vs 3) during the first wave and no change during the second wave (18 vs 18). After correction for temperature and air quality, COVID-19 epidemic remained associated with a decrease of AMI hospitalisation (p = 0.046). Reperfusion strategy for AMI patients, were comparable between both study periods. The in-hospital mortality between the two periods was comparable (2.6% versus 1.9%), but COVID-19 positive ACS patients (n = 7) had a high mortality rate (14%).Conclusion: COVID-19 related public containment measures resulted during the first wave in a 32% reduction of AMI hospitalisation, but this impact was not visible anymore during the second wave.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Investigating the Cost-Effectiveness of Telemonitoring Patients With Cardiac Implantable Electronic Devices: Systematic Review.

BACKGROUND: Telemonitoring patients with cardiac implantable electronic devices (CIEDs) can improve their care management. However, the results of cost-effectiveness studies are heterogeneous. Therefore, it is still a matter of debate whether telemonitoring is worth the investment. OBJECTIVE: This systematic review aims to investigate the cost-effectiveness of telemonitoring patients with CIEDs, focusing on its key drivers, and the impact of the varying perspectives. METHODS: A systematic review was performed in PubMed, Web of Science, Embase, and EconLit. The search was completed on July 7, 2022. Studies were included if they fulfilled the following criteria: patients had a CIED, comparison with standard care, and inclusion of health economic evaluations (eg, cost-effectiveness analyses and cost-utility analyses). Only complete and peer-reviewed studies were included, and no year limits were applied. The exclusion criteria included studies with partial economic evaluations, systematic reviews or reports, and studies without standard care as a control group. Besides general study characteristics, the following outcome measures were extracted: impact on total cost or income, cost or income drivers, cost or income drivers per patient, cost or income drivers as a percentage of the total cost impact, incremental cost-effectiveness ratios, or cost-utility ratios. Quality was assessed using the Consensus Health Economic Criteria checklist. RESULTS: Overall, 15 cost-effectiveness analyses were included. All studies were performed in Western countries, mainly Europe, and had primarily a male participant population. Of the 15 studies, 3 (20%) calculated the incremental cost-effectiveness ratio, 1 (7%) the cost-utility ratio, and 11 (73%) the health and cost impact of telemonitoring. In total, 73% (11/15) of the studies indicated that telemonitoring of patients with implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy ICDs was cost-effective and cost-saving, both from a health care and patient perspective. Cost-effectiveness results for telemonitoring of patients with pacemakers were inconclusive. The key drivers for cost reduction from a health care perspective were hospitalizations and scheduled in-office visits. Hospitalization costs were reduced by up to US $912 per patient per year. Scheduled in-office visits included up to 61% of the total cost reduction. Key drivers for cost reduction from a patient perspective were loss of income, cost for scheduled in-office visits and transport. Finally, of the 15 studies, 8 (52%) reported improved quality of life, with statistically significance in only 1 (13%) study (P=.03). CONCLUSIONS: From a health care and patient perspective, telemonitoring of patients with an ICD or a cardiac resynchronization therapy ICD is a cost-effective and cost-saving alternative to standard care. Inconclusive results were found for patients with pacemakers. However, telemonitoring can lead to a decrease in providers' income, mainly due to a lack of reimbursement. Introducing appropriate reimbursement could make telemonitoring sustainable for providers while still being cost-effective from a health care payer perspective. TRIAL REGISTRATION: PROSPERO CRD42022322334; https://tinyurl.com/puunapdr.

Low rates of myocardial fibrosis and ventricular arrhythmias in recreational athletes after SARS-CoV-2 infection.

Introduction: High rates of cardiac involvement were reported in the beginning of the coronavirus disease 2019 (COVID-19) pandemic. This led to anxiety in the athletic population. The current study was set up to assess the prevalence of myocardial fibrosis and ventricular arrhythmias in recreational athletes with the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: Consecutive adult recreational athletes (≥18 years old, ≥4 h of mixed type or endurance sports/week) underwent systematic cardiac evaluation after a prior confirmed COVID-19 infection. Evaluation included clinical history, electrocardiogram (ECG), 5-day Holter monitoring, and cardiac magnetic resonance (CMR) imaging with simultaneous measurement of high-sensitive cardiac Troponin I. Data from asymptomatic or mildly symptomatic athletes (Group 1) were compared with those with moderate to severe symptoms (Groups 2-3). Furthermore, a comparison with a historical control group of athletes without COVID-19 (Master@Heart) was made. Results: In total, 35 athletes (18 Group 1, 10 female, 36.9 ± 2.2 years, mean 143 ± 20 days following diagnosis) were evaluated. The baseline characteristics for the Group 1 and Groups 2-3 athletes were similar. None of the athletes showed overt myocarditis on CMR based on the updated Lake Louise criteria for diagnosis of myocarditis. The prevalence of non-ischemic late gadolinium enhancement [1 (6%) Group 1 vs. 2 (12%) Groups 2-3; p = 0.603] or ventricular arrhythmias [1 Group 1 athlete showed non-sustained ventricular tachycardia (vs. 0 in Groups 2-3: p = 1.000)] were not statistically different between the groups. When the male athletes were compared with the Master@Heart athletes, again no differences regarding these criteria were found. Conclusion: In our series of recreational athletes with prior confirmed COVID-19, we found no evidence of ongoing myocarditis, and no more detection of fibrosis or ventricular arrhythmias than in a comparable athletic pre-COVID cohort. This points to a much lower cardiac involvement of COVID-19 in athletes than originally suggested.

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.

Pathophysiology and clinical relevance of atrial myopathy.

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Tumour necrosis factor-alpha serum level is an independent predictor of medium-term all-cause mortality after transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a suitable treatment for patients with severe aortic stenosis and severely increased operative risk. There is need for a better preoperative risk assessment for TAVI candidates. AIM: To determine whether Tumour necrosis factor-alfa (TNFα) is an independent predictor of survival 500 days after TAVI. METHODS: Sixty patients undergoing TAVI were enrolled in the study. TNFα was determined. The CT measured low-density muscle fraction (LDM%) of the psoas muscle was determined. Operative risk assessment by Logistic EuroSCORE, EuroSCORE II, and STS score was performed. Frailty scores (FRAIL scale and Barthel index) were determined. RESULTS: Mean age was 81.01 ± 7.54 years. Twenty-six (43.3%) of the patients were males. In the univariable analyses, FRAIL scale and Barthel index were no predictors of survival after TAVI. In the multivariable analysis, including EuroSCORE II, LDM% and TNFα serum concentration, TNFα serum level was an independent predictor of survival 500 days after TAVI (HR: 3.167; 95%: 1.279-7.842; p = 0.013). The multivariable analysis, including TNFα as a categorical variable, showed that compared to patients in the conjugated first and second TNFα serum level tertile, patients in the third tertile had a hazard ratio (HR) of 10.606 (95%CI: 1.203 - 93.467) (p = 0.033). CONCLUSION: TNFα is an incremental independent predictor of long-term survival after TAVI.

Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years. RESULTS: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (P=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.

Computed tomography measured epicardial adipose tissue and psoas muscle attenuation: new biomarkers to predict major adverse cardiac events and mortality in patients with heart disease and critically ill patients. Part II: Psoas muscle area and density.

Sarcopenia is a syndrome characterised by loss of skeletal muscle mass, loss of muscle quality, and reduced muscle strength, resulting in low performance. Sarcopenia has been associated with increased mortality and complications after medical interventions. In daily clinical practice, sarcopenia is assessed by clinical assessment of muscle strength and performance tests and muscle mass quantification by dual-energy X-ray absorptio-metry (DXA) or bioelectrical impedance analysis (BIA). Assessment of the skeletal muscle quantity and quality obtained by abdominal computed tomography (CT) has gained interest in the medical community, as abdominal CT is performed for various medical reasons, and quantification of the psoas and skeletal muscle can be performed without additional radiation load and dye administration. The definitions of CT-derived skeletal muscle mass quantification are briefly reviewed: psoas muscle area (PMA), skeletal muscle area (SMA), and transverse psoas muscle thickness (TPMT). We explain how CT attenuation coefficient filters are used to determine PMA and SMA, resulting in the psoas muscle index (PMI) and skeletal muscle index (SMI), respectively, after indexation to body habitus. Psoas muscle density (PMD), a biomarker for skeletal muscle quality, can be assessed by measuring the psoas muscle CT attenuation coefficient, expressed in Hounsfield units. The concept of low-density muscle (LDM) is explained. Finally, we review the medical literature on PMI and PMD as predictors of adverse outcomes in patients undergoing trauma or elective major surgery, transplantation, and in patients with cardiovascular and internal disease. PMI and PMD are promising new biomarkers predicting adverse outcomes after medical interventions.

Atrial fibrillation cycle-length (AF-CL) inside the pulmonary veins predicts paroxysmal AF ablation success- the INDUCE-AF study.

BACKGROUND: A novel method to measure atrial fibrillation cycle length (AF-CL) was recently described, based on the average of 10 consecutive signals (FARS10). FARS10 accurately identified pulmonary vein isolation (PVI)-responders among patients with persistent AF. Whether this method is applicable to patients with paroxysmal AF is unknown. OBJECTIVE: The aim of this study is to evaluate the prognostic value of FARS10 measurements in patients with paroxysmal AF. METHODS AND RESULTS: We enrolled paroxysmal AF patients undergoing PVI in a prospective multicenter study. After AF induction with a standardized protocol, the AF-CL was measured using FARS-10 method. The primary endpoint was AF/AT-recurrence. One-hundred and four patients were included (61 ± 14 years, 25% females). After a mean follow-up of 12 ± 4 months, AF/AT recurrence rate was 20%. The fastest PV CL (fPV-CL) was independently associated with the primary endpoint at multivariate analysis (HR 1.02, p < 0.001). Every 10 ms increase in fPV-CL, AF recurrences increased by 20%. The value of 160 ms was found to be the optimal cut-off (specificity 81%, sensitivity 76%). Patients with fPV-CL < 160 ms experienced lower AF recurrences as compared to patients with fPV-CL > 160 ms (8% vs. 32% at 1 year; HR = 0.17, p < 0.001). Progression to persistent AF was observed in 13% of patients with fPV-CL > 160 ms. CONCLUSION: fPV-CL measured with the FARS-10 method accurately predicts PVI success in paroxysmal AF patients undergoing PVI. Patients with slow PV activity (fPV-CL > 160 ms) experience higher AF recurrence rate after PVI and more frequent progression to persistent AF. In 104 patients with paroxysmal atrial fibrillation (AF) undergoing AF ablation, AF was induced at the beginning of the procedure. Pulmonary vein activity was measured using FARS10 measurement (10 consecutive fastest atrial repetitive similar morphology signals). The value of 160 ms was found to be the best cut-off to discriminate outcomes. At 1-year follow-up, patients with fast veins (< 160 ms) experienced significantly fewer AF recurrences as compared to patients with slow veins (> 160 ms). PV activity measured with FARS10 method accurately discriminates pulmonary vein isolation responders, in patients with paroxysmal AF. ABBREVIATIONS: AF atrial fibrillation, AT atrial tachycardia, CL cycle length, FARS10: 10 consecutive fastest atrial repetitive similar morphology signal, fPV fastest pulmonary vein, HR hazard ratio, ms milliseconds.

Dynamic changes of left atrial substrate over time following pulmonary vein isolation: the Progress-AF study.

AIMS: Little is known about dynamic changes of the left atrial (LA) substrate over time in patients with atrial fibrillation (AF). This study aims to evaluate substrate changes following pulmonary vein isolation (PVI). METHODS AND RESULTS: In our prospective observational study, consecutive patients undergoing first PVI-only and redo ablation were included. High-density maps of the two procedures were compared. Progression or regression was diagnosed if a significant concordant decrease or increase in bipolar voltages in ≥2 segments was observed, respectively. In 28 patients (61.2 ± 9.5 years, 39% female, 53.5% persistent AF), 111.013 voltage points from 56 high-density LA maps (1.982 points/patient) were analysed. Comparing the high-density maps of the first and second procedures, in the progression group (17 patients, 61%), there was a decrease in global (-35%, P < 0.001) and all regional voltages. In the regression group (11 patients, 39%), there was an increase in global (+43%, P < 0.001) and regional voltages. Comparing the progression with the regression group, the area of low-voltage zone (LVZ) increased (+3.5 vs. -4.5 cm2, P < 0.001) and LA activation time prolonged (+8.0 vs. -9.1 ms, P = 0.005). Baseline clinical parameters did not predict progression or regression. In patients with substrate progression, pulmonary veins (PVs) were more frequently isolated (P = 0.02) and the AF pattern at recurrence was more frequently persistent (P = 0.005). CONCLUSION: Our study describes bidirectional dynamic properties of the LA substrate with concordant either progressive or regressive changes. Regression occurs with reduced AF burden after the first procedure, while progression is associated with persistent AF recurrence despite durable PV isolation. The dynamic nature of LA substrate poses questions about LVZ-based ablation strategies.

Engagement of atrial fibrillation patients with the AF-EduApp, a new mobile application to support AF management.

Introduction: A multidisciplinary approach is needed for the management of atrial fibrillation (AF) in which the patient has a central role. Smart devices create opportunities to improve AF management. This paper aimed to evaluate the in-house developed AF-EduApp application on its usability, satisfaction, and communication effectiveness with the care team. Methods: During a multicenter, prospective randomized controlled trial, 153 AF patients were included in the AF-EduApp study, with a minimum follow-up of 12 months and a maximum follow-up of 15 months if taking oral anticoagulation (OAC). The AF-EduApp contains six main modules: Questionnaires, Education, Measurement data entry, Medication overview with reminders, Appointments, and Communication with the care team. The App focuses on four main goals: (1) to improve AF knowledge, (2) to increase self-care capabilities, (3) electronic monitoring to improve therapy adherence to OAC, and (4) communication with the care team. Patients unable to use the AF-EduApp were assigned to a no-App control group (n = 41) without intervention comparable to the standard care group (SC, n = 346) of the AF-EduCare study. Results: A total of 152 patients effectively used the App during a mean follow-up of 386.8 ± 108. 1 days (one included patient could not install the application due to an iPhone from the United States). They opened the application on average on 130.1 ± 144.7 days. Of the 109 patients still in follow-up after 12 months (i.e. patients who did not withdraw and on OAC), 90 patients (82.6%) actively used the application at least one day in the next 41 days. The Measurement module was the most used, with a median of used days over the total available days of 6.4%. A total of 75 App patients (49.3%) asked questions, mostly clinical-related questions (e.g. medication use, or actionability on clinical entered parameters). A mean score of 8.1 ± 1.7 about the "perceived quality of follow-up in the past year" was given by the App ITT patients, compared to a score of 7.7 ± 2.0 by the SC group (P = .072). Patients who used the App were more attracted to future follow-up with an application compared to patients who would be capable of using the application of the SC group (31.6% vs. 12.5%; P < .001). Conclusion: This study showed a positive attitude towards using a mobile application, with AF patients using the application one-third of the available days. Patients used the App most for entering measured parameters, and to contact the care team.

Computed tomography measured epicardial adipose tissue and psoas muscle attenuation: new biomarkers to predict major adverse cardiac events (MACE) and mortality in patients with heart disease and critically ill patients. Part I: Epicardial adipose tissue.

Over the last two decades, the potential role of epicardial adipocyte tissue (EAT) as a marker for major adverse cardiovascular events has been extensively studied. Unlike other visceral adipocyte tissues (VAT), EAT is not separated from the adjacent myocardium by a fascial layer and shares the same microcirculation with the myocardium. Adipocytokines, secreted by EAT, interact directly with the myocardium through paracrine and vasocrine pathways. The role of the Randle cycle, linking VAT accumulation to insulin resistance, and the relevance of blood flow and mitochondrial function of VAT, are briefly discussed. The three available imaging modalities for the assessment of EAT are discussed. The advantages of echocardiography, cardiac CT, and cardiac magnetic resonance (CMR) are compared. The last section summarises the current stage of knowledge on EAT as a clinical marker for major adverse cardiovascular events (MACE). The association between EAT volume and coronary artery disease (CAD) has robustly been validated. There is growing evidence that EAT volume is associated with computed tomography coronary angiography (CTCA) assessed high-risk plaque features. The EAT CT attenuation coefficient predicts coronary events. Many studies have established EAT volume as a predictor of atrial fibrillation after cardiac surgery. Moreover, EAT thickness has been independently associated with severe aortic stenosis and mitral annular calcification. Studies have demonstrated that EAT volume is associated with heart failure. Finally, we discuss the potential role of EAT in critically ill patients admitted to the intensive care unit. In conclusion, EAT seems to be a promising new biomarker to predict MACE.

Atrial fibrillation ablation in patients with arrhythmia-induced cardiomyopathy: a prospective multicentre study.

AIMS: This study aims to investigate the clinical and biochemical characteristics of patients with atrial fibrillation (AF) referred for ablation who develop arrhythmia-induced cardiomyopathy (AiCM) as well as their long-term outcomes after catheter ablation (CA). METHODS AND RESULTS: A prospective multicentre study was conducted on consecutive AF patients who underwent CA. AiCM was defined as the development of heart failure in the presence of AF and an improvement of left ventricular fraction by at least 10% at 6 months after ablation. A subgroup of patients underwent peripheral and left atrial blood samples [galectin-3, fatty acid-binding protein 4 (FABP4), and soluble receptor for advanced glycation end products (sRAGE)] at the time of the procedure. Of the 769 patients who underwent AF ablation, 135 (17.56%) met the criteria for AiCM. Independent predictors of AiCM included persistent AF, male gender, left atrial volume, QRS width, active smoking, and chronic kidney disease (CKD). Biomarker analysis revealed that sRAGE, FABP4, and galectin-3 levels were not predictive of AiCM development nor did they differ between groups or predict recurrence. There were no differences in AF recurrence between patients with and without AiCM (30.83% vs. 27.77%; P = 0.392) during a median follow-up of 23.83 months (inter-quartile range 9-36). CONCLUSIONS: In the subset of patients referred for AF ablation, the development of AiCM was associated with persistent AF and CKD. Biomarker analysis was not different between groups nor predicted recurrence. Patients with AiCM benefited from ablation, with a significant improvement in left ventricular ejection fraction and similar AF recurrence rates to those without AiCM.