Cardiac electrophysiology studies in mice via the transjugular route: a comprehensive practical guide.

Cardiac arrhythmias are associated with cardiovascular morbidity and mortality. Cardiac electrophysiology studies (EPS) use intracardiac catheter recording and stimulation for profound evaluation of the heart's electrical properties. The main clinical application is investigation and treatment of rhythm disorders. These techniques have been translated to the murine setting to open opportunities for detailed evaluation of the impact of different characteristics (including genetics) and interventions on cardiac electrophysiology and -pathology. Currently, a detailed description of the technique of murine transjugular EPS (which is the standard route of catheter introduction) is lacking. This article provides detailed information on EPS in mice via the transjugular route. This includes catheter placement, stimulation protocols, intracardiac tracing interpretation, artifact reduction, and surface ECG recording. In addition, reference values as obtained in C57BL/6N mice are presented for common electrophysiological parameters. This detailed methodological description aims to increase accessibility and standardization of EPS in mice. Ultimately, also human research and patient care may benefit from translation of the knowledge obtained in preclinical models using this technique.NEW & NOTEWORTHY Electrophysiology studies (EPS) allow in-depth evaluation of cardiac electrophysiology and -pathology. These techniques have been adapted to the murine setting for (translational) studies, mainly focusing on arrhythmogenesis. Despite the frequent application of EPS via the transjugular route, a thorough description of the technique is currently lacking. This article aims to function as a comprehensive guide, also elaborating (for the first time) on nonsurgical aspects such as catheter positioning, tracing artifacts, stimulation protocols, and reference values.

Nuclear cardiac imaging for the diagnosis and management of heart failure: what can be learned from recent guidelines?

The aim of this review is to provide the clinical cardiologist and nuclear medicine specialist a brief overview of the currently accepted clinical use of cardiac nuclear imaging for the diagnosis and management of patients with heart failure based on recent (2012-2015) European Society of Cardiology (ESC) guidelines. We used the most recent ESC guidelines on heart failure, management of stable coronary artery disease, cardiac pacing, myocardial revascularisation, non-cardiac surgery and ventricular arrhythmias and sudden death. Nowadays cardiac nuclear imaging is useful in almost every step in heart failure from diagnostics to treatment. In first diagnosis of heart failure radionuclide imaging can provide information on ventricular function and volumes and nuclear imaging techniques provide accurate and reproducible left ventricular function assessment. In work out of the aetiology of the heart failure CMR, SPECT and PET imaging can demonstrate presence of inducible ischemia and myocardial viability. For prognostic information MIBG might be promising in the future. In treatment planning cardiac nuclear imaging is important to evaluate new angina and to assess accurate left ventricular ejection fraction before cardiac resynchronization therapy. Imaging stress testing is useful in the preoperative evaluation for non-cardiac surgery of heart failure patients. There is until now no recommended place for cardiac nuclear imaging in the follow-up of heart failure patients or prior to the initiation of cardiac rehabilitation.

A systematic literature review on the effects of exercise on human Toll-like receptor expression.

BACKGROUND: Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that are mainly expressed on immune cells. Recognition of various exogenous and endogenous molecular patterns activates the TLR signalling cascade, which orchestrates an inflammatory immune response. Dysfunctional immune responses, including aberrant TLR signalling, are increasingly implicated in the associations between sedentarism, chronic low-grade systemic inflammation and various non-communicable diseases. Conversely, exercise exerts anti-inflammatory effects, which could be conferred through its immunomodulatory properties, potentially affecting TLRs. This study aims to systematically review the effects of exercise on human TLR expression. METHOD: A systematic literature search of Pubmed, Embase, The Cochrane Library and SPORTDiscus for articles addressing the impact of exercise (as isolated intervention) on TLRs in humans was conducted, ending in February 2020. RESULTS: A total of 66 articles were included. The publications were categorised according to exercise modality and duration: acute resistance exercise (4 studies), acute aerobic exercise (26 studies), resistance training program (9 studies), aerobic training program (16 studies), combined (i.e. resistance and aerobic) training program (8 studies) and chronic exercise not otherwise classifiable (9 studies). Five articles investigated more than one of the aforementioned exercise categories. Several trends could be discerned with regard to the TLR response in the different exercise categories. Acute resistance exercise seemed to elicit TLR upregulation, whereas acute aerobic exercise had less activating potential with the majority of responses being neutral or, especially in healthy participants, downregulatory. Chronic resistance and combined exercise programs predominantly resulted in unaltered or decreased TLR levels. In the chronic aerobic exercise category, mixed effects were observed, but the majority of measurements demonstrated unchanged TLR expression. CONCLUSION: Currently published research supports an interplay between exercise and TLR signalling, which seems to depend on the characteristics of the exercise. However, there was large heterogeneity in the study designs and methodologies. Therefore, additional research is required to further corroborate these findings, to define its pathophysiological implications and to elucidate the mechanism(s) linking exercise to TLR signalling.

Sexual counselling in patients with heart failure: Perceptions and current practice by healthcare providers in Flanders.

BACKGROUND: Although heart failure (HF) patients often consider sexual activity as an essential aspect of their quality of life (QoL) and are usually uncertain if it is safe to perform sexual activity, this topic is overall poorly addressed in clinical practice. AIMS: The aim of this study was to explore the perceptions and practices of Flemish caregivers. METHODS: Healthcare providers were recruited through convenience sampling and filled in an adapted version of the UNITE Sexual Counselling Instrument. Several relevant network structures in Flanders were used to distribute the questionnaires-online as well as on paper-to healthcare workers being involved in the care to HF patients. RESULTS: Results of 180 participants indicated that 51.5% of the healthcare providers have never provided sexual counselling in HF patients. Being male, having a masters' degree, having more than 10 years of experience in cardiovascular disease, working in an ambulatory care department and having more positive attitudes were independently associated with a higher provision of sexual counselling in practice. CONCLUSION: Although healthcare providers perceive it as their responsibility to discuss patients' sexual concerns, these issues are not often addressed in daily practice. Increasing knowledge in healthcare providers and specific practical training in providing information on sexual activity in HF patients are recommended. Further studies are needed to investigate how sexual counselling can be provided in agreement with HF patients' expectations and needs.

Incidence of cardiovascular events in patients with stabilized coronary heart disease: the EUROASPIRE IV follow-up study.

The EUROASPIRE surveys (EUROpean Action on Secondary Prevention through Intervention to Reduce Events) demonstrated that most European coronary patients fail to achieve lifestyle, risk factor and therapeutic targets. Here we report on the 2-year incidence of hard cardiovascular (CV) endpoints in the EUROASPIRE IV cohort. EUROASPIRE IV (2012-2013) was a large cross-sectional study undertaken at 78 centres from selected geographical areas in 24 European countries. Patients were interviewed and examined at least 6 months following hospitalization for a coronary event or procedure. Fatal and non-fatal CV events occurring at least 1 year after this baseline screening were registered. The primary outcome in our analyses was the incidence of CV death or non-fatal myocardial infarction, stroke or heart failure. Cox regression models, stratified for country, were fitted to relate baseline characteristics to outcome. Our analyses included 7471 predominantly male patients. Overall, 222 deaths were registered of whom 58% were cardiovascular. The incidence of the primary outcome was 42 per 1000 person-years. Comorbidities were strongly and significantly associated with the primary outcome (multivariately adjusted hazard ratio HR, 95% confidence interval): severe chronic kidney disease (HR 2.36, 1.44-3.85), uncontrolled diabetes (HR 1.89, 1.50-2.38), resting heart rate ≥ 75 bpm (HR 1.74, 1.30-2.32), history of stroke (HR 1.70, 1.27-2.29), peripheral artery disease (HR 1.48, 1.09-2.01), history of heart failure (HR 1.47, 1.08-2.01) and history of acute myocardial infarction (HR 1.27, 1.05-1.53). Low education and feelings of depression were significantly associated with increased risk. Lifestyle factors such as persistent smoking, insufficient physical activity and central obesity were not significantly related to adverse outcome. Blood pressure and LDL-C levels appeared to be unrelated to cardiovascular events irrespective of treatment. In patients with stabilized CHD, comorbid conditions that may reflect the ubiquitous nature of atherosclerosis, dominate lifestyle-related and other modifiable risk factors in terms of prognosis, at least over a 2-year follow-up period.

Lifestyle behaviour and risk factor control in coronary patients: Belgian results from the cross-sectional EUROASPIRE surveys.

OBJECTIVE: The aim of this study was to assess lifestyle behaviour as well as risk factor management across Belgian coronary patients who participated in the cross-sectional European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) surveys. METHODS: Analyses are based on a series of coronary patients by combining data from the Belgian participants in the EUROASPIRE III (328 patients; in 2006-2007) and EUROASPIRE IV (343 patients; in 2012-2013) surveys. Four hospitals located in the Ghent area participated in the surveys. Patients included in the analyses were ≥18 years old and had been hospitalised for a coronary event. Information on cardiovascular risk factors, lifestyle behaviour and medical treatment were obtained. RESULTS: Overall, the proportion of smokers was 11% with 40% persistent smokers. Adequate physical activity levels were reported by 17%, 28% of patients were obese, 47% was central obese and known diabetes was prevalent in 21% of patients. Hypertension was observed in 46% of patients and 20% had a total cholesterol ≥5 mmol/L. About 80% had participated in a cardiac rehabilitation programme and the majority of patients were treated with blood pressure (92%) or lipid-lowering drugs (92%). Anxiety and depressive symptoms were reported by 30% and 24%, respectively. Differences between EUROASPIRE III and IV were limited. CONCLUSIONS: Compared to the overall EUROASPIRE results in Europe, Belgian CHD patients seem to do slightly better. However, tackling obesity, physical inactivity, hypertension and psychosocial distress remains an important challenge in the management of coronary patients.

Effect of renin-angiotensin-aldosterone system blockade in adults with diabetes mellitus and advanced chronic kidney disease not on dialysis: a systematic review and meta-analysis.

The presumed superiority of renin-angiotensin-aldosterone system (RAAS)-blocking agents over other antihypertensive agents in patients with diabetes to delay development of end-stage kidney disease (ESKD) has recently been challenged. In addition, there is ongoing uncertainty whether RAAS-blocking agents reduce mortality and/or delay ESKD in patients with diabetes and chronic kidney disease (CKD) stages 3-5. In this subgroup, there might be an expedited need for renal replacement therapy (RRT) when RAAS-blocking agents are used. We conducted a meta-analysis of randomized controlled trials (RCTs) of at least 6-months duration in adult patients with diabetes who also have non-dialysis CKD stages 3-5. RCTs comparing single RAAS-blocking agents to placebo or alternative antihypertensive agents were included. Outcomes of interest were all-cause mortality, cardiovascular morbidity, progression of renal function, ESKD and adverse events. A total of nine trials (n = 9797 participants with CKD stages 3-5) fit our inclusion criteria. There was no difference between the RAAS group and control group regarding all-cause mortality {relative risk [RR] = 0.97 [95% confidence interval (CI) 0.85-1.10]}, cardiovascular mortality [RR = 1.03 (95% CI 0.75-1.41)] and adverse events [RR = 1.05 (95% CI 0.89-1.25)]. There was a trend for a favourable effect for non-fatal cardiovascular events [RR = 0.90 (95% CI 0.81-1.00)] and a lower risk of the composite endpoint need for RRT/doubling of serum creatinine [RR = 0.81 (95% CI 0.70-0.92)] in the RAAS-blocking agents group versus the control group. We found evidence that in patients with diabetes mellitus and CKD stages 3-5, treatment with RAAS-blocking agents did not result in a clear survival advantage. The effect on renal outcomes did depend on the selected outcome measure. However, we did not find evidence that the use of RAAS-blocking agents expedited the need for RRT in patients with CKD stages 3-5.

Economic and social impact of increased cardiac rehabilitation uptake and cardiac telerehabilitation in Belgium - a cost-benefit analysis.

BACKGROUND: Cardiac rehabilitation for ischaemic heart disease effectively reduces cardiovascular readmission rate and mortality. Current uptake rates however, remain low. This study assesses the social and economic impact of increasing centre-based cardiac rehabilitation uptake and the additional value of cardiac telerehabilitation using cost-benefit analysis (CBA) in Belgium. METHODS: Cost-benefit analysis was conducted to analyse three scenarios: (1) current situation: 20% uptake rate of cardiac rehabilitation; (2) alternative scenario one: 40% uptake rate of cardiac rehabilitation; and (3) alternative scenario two: 20% uptake of cardiac rehabilitation and 20% uptake of both cardiac rehabilitation and telerehabilitation. Impacts considered included cardiac (tele)rehabilitation programme costs, direct inpatient costs, productivity losses and burden of disease. RESULTS: Compared to the current situation, there was a net total monetised benefit of 9.18 M€ and 9.10 M€ for scenarios one and two, respectively. Disability Adjusted Life Years were 12,805-12,980 years lower than the current situation. This resulted in a benefit-cost ratio of 1.52 and 1.43 for scenarios one and two, respectively. CONCLUSIONS: Increased cardiac rehabilitation uptake rates can reduce the burden of disease, and the resulting benefits exceed its costs. This research supports the necessity for greater promotion and routine referral to cardiac rehabilitation to be made standard practice. The implementation of telerehabilitation as an adjunct is to be encouraged, especially for those patients unable to attend centre-based cardiac rehabilitation.

Comorbidities and Psychosocial Characteristics as Determinants of Dropout in Outpatient Cardiac Rehabilitation.

BACKGROUND: Despite the clear benefits of cardiac rehabilitation (CR), a considerable number of patients drop out early. OBJECTIVE: Therefore, we wanted to evaluate dropout in CR with a special focus on comorbidities and psychosocial background. METHODS: Patients who attended CR after acute coronary syndrome, cardiac surgery, or heart failure (N = 489) were prospectively included. Dropout was defined as attending 50% of the training sessions or less (n = 96 [20%]). Demographic and clinical characteristics, exercise parameters, and psychosocial factors were analyzed according to dropout, and those with a trend toward a significant difference (P < .10) were entered in a multivariate logistic model. RESULTS: The presence of a cerebrovascular accident (4.18 [1.39-12.52]) involved a higher risk of dropout, and a comparable trend was seen for the presence of chronic obstructive pulmonary disease (2.55 [0.99-6.54]). Attending the training program only twice per week also implicated a higher risk of an early withdrawal (3.76 [2.23-6.35]). In contrast, patients on ß-blockers were less likely to withdraw prematurely (0.47 [0.22-0.98]). Singles were more likely to drop out (2.89 [1.56-5.35]), as well as those patients who were dependent on others to get to CR (2.01 [1.16-3.47]). Finally, the reporting of severe problems on the anxiety/depression subscale of the EuroQOL-5D questionnaire involved a higher odds for dropout (7.17 [1.46-35.29]). CONCLUSIONS: Neither demographic characteristics nor clinical status or exercise capacity could independently identify patients who were at risk of dropout. The presence of comorbidities and a vulnerable psychosocial background rather seem to play a key role in dropout.

Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology.

BACKGROUND: In order to influence every day clinical practice professional organisations issue management guidelines. Cross-sectional surveys are used to evaluate the implementation of such guidelines. The present survey investigated screening for glucose perturbations in people with coronary artery disease and compared patients with known and newly detected type 2 diabetes with those without diabetes in terms of their life-style and pharmacological risk factor management in relation to contemporary European guidelines. METHODS: A total of 6187 patients (18-80 years) with coronary artery disease and known glycaemic status based on a self reported history of diabetes (previously known diabetes) or the results of an oral glucose tolerance test and HbA1c (no diabetes or newly diagnosed diabetes) were investigated in EUROASPIRE IV including patients in 24 European countries 2012-2013. The patients were interviewed and investigated in order to enable a comparison between their actual risk factor control with that recommended in current European management guidelines and the outcome in previously conducted surveys. RESULTS: A total of 2846 (46%) patients had no diabetes, 1158 (19%) newly diagnosed diabetes and 2183 (35%) previously known diabetes. The combined use of all four cardioprotective drugs in these groups was 53, 55 and 60%, respectively. A blood pressure target of <140/90 mmHg was achieved in 68, 61, 54% and a LDL-cholesterol target of <1.8 mmol/L in 16, 18 and 28%. Patients with newly diagnosed and previously known diabetes reached an HbA1c <7.0% (53 mmol/mol) in 95 and 53% and 11% of those with previously known diabetes had an HbA1c >9.0% (>75 mmol/mol). Of the patients with diabetes 69% reported on low physical activity. The proportion of patients participating in cardiac rehabilitation programmes was low (≈40 %) and only 27% of those with diabetes had attended diabetes schools. Compared with data from previous surveys the use of cardioprotective drugs had increased and more patients were achieving the risk factor treatment targets. CONCLUSIONS: Despite advances in patient management there is further potential to improve both the detection and management of patients with diabetes and coronary artery disease.

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans.

BACKGROUND: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. METHODS: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. RESULTS: Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFß-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. CONCLUSION: In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.

Prevalence, Determinants, and Prognostic Significance of Pulmonary Hypertension in Elderly Patients Admitted with Acute Decompensated Heart Failure: A Report from the BIO-HF Registry.

PURPOSE: Pulmonary hypertension (PHT) is a predictor of mortality and morbidity in patients with chronic heart failure (HF). However, the prevalence, determinants, and prognostic significance of PHT in elderly patients admitted with acute decompensated HF are unclear. METHODS: We prospectively evaluated 401 patients aged ≥ 75 years (mean age 83 ± 5 years, 50% women) with acute HF, who were discharged alive, and whose tricuspid regurgitation (TR) gradient was measured by echocardiography during hospitalization. PHT was defined as a TR gradient ≥ 30 mmHg. The endpoint was all-cause mortality. RESULTS: PHT was found in 280/401 patients (69%), including in 67% of patients with HF with reduced ejection fraction (HFrEF) and 73% of patients with HF with preserved ejection fraction (HFpEF) (P = 0.19). Clinical characteristics and comorbidities were similar between patients with and without PHT. The prevalence of PHT increased with increasing severity of mitral regurgitation (MR) (mild: 65%; moderate: 67%; severe: 85%; P < 0.01). After a mean follow-up of 405 ± 399 days, 118 patients (30%) had died. In a multivariate Cox regression analysis, that included age, sex, serum creatinine, TR gradient, comorbidities, and medications at discharge, age (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.03-1.11, P < 0.001), serum creatinine (HR 1.41, 95% CI 1.15-1.73, P < 0.01), and PHT (HR 1.60, 95% CI 1.03-2.49, P < 0.01) were independent predictors of all-cause mortality. CONCLUSION: In elderly patients admitted with acute HF, PHT is common, mainly associated with the severity of MR and associated with a worse outcome after discharge.

Non-compaction cardiomyopathy: a genetically and clinically heterogeneous disorder.

Left ventricular non-compaction (LVNC) is a rare disease that can occur isolated or in association with other disorders, including congenital heart disease and musculoskeletal disorders. It is characterized by a two-layered myocardium with excessive trabeculation of the left ventricle. Diagnosis is challenging as left ventricular trabeculations can be pathological yet can also be a normal finding in athletes and black people, leading to overdiagnosis. Echocardiography and CMR are important diagnostic tools. LVNC is often complicated by ventricular dysfunction, arrhythmias and thromboembolic events. Based on two cases, we review the pathogenesis, genetic background, clinical features and treatment of LVNC according to the available guidelines.

Participation in cardiac rehabilitation after hospitalisation for heart failure: a report from the BIO-HF registry.

OBJECTIVE: Participation in cardiac rehabilitation (CR) after hospitalisation for heart failure (HF) is estimated to below, but specific data for Belgium are lacking. Therefore, we wanted to evaluate attendance after HF hospitalisation compared to patients after cardiac surgery or acute coronary syndrome (ACS). Moreover, the improvement in exercise capacity was compared with the other patient groups. METHODS AND RESULTS: Patients who were hospitalized for HF (n=428), cardiac surgery (n=358) or ACS (n=467) in a single hospital, were prospectively included between January 2010 and May 2012. After hospitalisation for HF only 9% participated, compared to 29% after ACS and 56% after cardiac surgery. Non-participants in HF were older, more frequently women (P <0.01) and had a better left ventricular ejection fraction (P < 0.05). In addition, they had more frequently atrial fibrillation and problems to walk independently (P <0.01). At the start of the CR, HF patients had a worse clinical status and exercise capacity than patients after cardiac surgery or ACS (all P <0.001). However, exercise training resulted in a significant improvement in each group separately (all P < 0.001) and the relative improvement in exercise capacity in HF was comparable with the other groups. CONCLUSIONS: Only 9% of HF patients participated in CR after hospitalisation. Age, female gender, a relatively well-preserved ventricular function and atrial fibrillation seem to impede attendance to CR. However, HF patients can have as much improvement in exercise capacity as other patient populations, suggesting that more effort is needed to increase participation in CR among HF patients.

Clinical characteristics and short-term outcome of patients admitted with heart failure in Belgium: results from the BIO-HF registry.

AIMS: Hospitalization for acute decompensated heart failure (HF) is associated with poor outcome. As specific data for Belgium are currently not available, the aim of the Belgian BIO-HF registry is to evaluate the clinical characteristics, in-hospital mortality and outcomes after discharge of patients hospitalized for acute HF. METHODS AND RESULTS: This is a prospective observational cohort study conducted in 2 Belgian hospitals. For the current analysis, the first 904 patients who were enrolled between 2008 and 2012 were selected for assessment of clinical characteristics and short-term outcome (all-cause mortality and all-cause mortality+ rehospitalization 3 months after discharge). Mean age of patients was 77 years (51% > or = 80 years), 44% were women and 64% had an eGFR < 60 ml/min/m2. Mean LVEF was 42% with only 40% with LVEF < or = 35%, 20% with LVEF between 36 and 49% and 40% with LVEF 50%. In-hospital mortality was 7.1% with a mortality of 22% in the subgroup of patients with a creatinine > or =2 mg/dl and systolic blood pressure < or = 110 mmHg on admission. Three months after discharge, the all-cause mortality rate was 7.6% and the all-cause mortality or hospitalization for HF 18.3%. Multivariate Cox regression analysis revealed eGFR, COPD, absence of beta blockers and atrial fibrillation at discharge (all P<0.05) as independent predictors of all-cause mortality. CONCLUSIONS: In this Belgian registry of mainly elderly patients admitted with acute HF, a relatively preserved EF and a reduced kidney function were present in the majority of patients. In-hospital and short-term mortality after discharge remain high and are mainly related to the presence of comorbidities such as renal failure and COPD. Comorbidities should be the focus for future efforts to improve the dire outcome of these patients.

Activation of the ergoreceptors in cardiac patients with and without heart failure.

BACKGROUND: The presence of ergoreflex activity and its current relationship to hyperventilation and prognosis in cardiac patients is unclear. Therefore, we evaluated ergoreflex activity in cardiac patients with and without heart failure (CHF) as well as in healthy subjects, and we examined how ergoreceptor activity was related to a mortality risk score in CHF (MAGGIC). METHODS AND RESULTS: Twenty-five healthy subjects and 76 patients were included, among whom were 25 with ischemic heart disease (IHD), 24 with stable CHF, and 27 with unstable CHF. Ergoreflex activity was measured with a dynamic handgrip exercise, followed by post-handgrip regional circulatory occlusion (PH-RCO). Ergoreflex activity contributed significantly to ventilation (median [interquartile range] %V) in unstable CHF (81 [73-91] %V without PH-RCO, 92 [82-107] %V with PH-RCO, and 11 [6-20] difference in %V; P < .001) and was positively correlated with the MAGGIC risk score (Spearman ρ = 0.431; P = .002). No ergoreflex activity was observed in healthy subjects (-4 [-10 to 5] difference in %V), IHD (0 [-8 to 3] Diff in %V) and stable CHF (-3 [-11 to 6] difference in %V). CONCLUSIONS: Ergoreflex activity contributes to hyperventilation, but only in CHF patients with persistent symptoms, and is closely related to the MAGGIC risk score. Ergoreflex activity was not present in patients with IHD or stable CHF, suggesting other reasons for the increased ventilatory drive in those patients.

Gender differences in the management and outcome of atrial fibrillation complicating acute heart failure.

BACKGROUND: Little is known about sex differences in the prevalence, treatment, and outcome of atrial fibrillation complicating acute heart failure. METHODS AND RESULTS: Among 957 patients (429 women, 528 men), included in the BIO-HF registry, 45.2% (n = 194) of the women and 45.1% (n = 238) of the men were admitted with atrial fibrillation. The primary end point was a composite of 1-year all-cause mortality and hospitalization for heart failure. Adjusted 1-year mortality and hospitalization rates were similar between sexes (women 38.5%, men 36.0%; OR for female gender: 1.1, 95% CI 0.65-1.86; P = .71. A significant interaction between female sex and age (P = .002) was observed; with worse prognosis for women <75 years (OR 7.17, 95% CI 1.79-28.66; P = .005) compared with men <75 years. No sex differences in in-hospital treatment, restoration of sinus rhythm (16.5% in women vs 14.2% in men; P = .58), or in-hospital mortality (5.7% in women vs 6.7% in men; P = .69) were observed. CONCLUSIONS: Among patients hospitalized with acute heart failure, no sex differences in the prevalence and management of atrial fibrillation were observed. In-hospital mortality and the composite of 1-year mortality and rehospitalization were not different between sexes, but a significant sex-age interaction was observed, with worse outcome in women <75 years versus men <75 years of age.

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.

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<.001). In male CVB mice, premature mortality occurred between days 8 and 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.

Close Cardiovascular Monitoring during the Early Stages of Treatment for Patients Receiving Immune Checkpoint Inhibitors.

Background: There is an unmet medical need for the early detection of immune checkpoint inhibitor (ICI)-induced cardiovascular (CV) adverse events due to a lack of adequate biomarkers. This study aimed to provide insights on the incidence of troponin elevations and echocardiographic dynamics during ICI treatment in cancer patients and their role as potential biomarkers for submyocardial damage. In addition, it is the first study to compare hs-TnT and hs-TnI in ICI-treated patients and to evaluate their interchangeability in the context of screening. Results: Among 59 patients, the mean patient age was 68 years, and 76% were men. Overall, 25% of patients received combination therapy. Although 10.6% [95% CI: 5.0-22.5] of the patients developed troponin elevations, none experienced a CV event. No significant changes were found in 3D left ventricular (LV) ejection fraction nor in global longitudinal strain f (56 ± 6% vs. 56 ± 6%, p = 0.903 and -17.8% [-18.5; -14.2] vs. -17.0% [-18.8; -15.1], p = 0.663) at 3 months. There were also no significant changes in diastolic function and right ventricular function. In addition, there was poor agreement between hs-TnT and hs-TnI. Methods: Here, we present a preliminary analysis of the first 59 patients included in our ongoing prospective clinical trial (NCT05699915) during the first three months of treatment. All patients underwent electrocardiography and echocardiography along with blood sampling at standardized time intervals. This study aimed to investigate the incidence of elevated hs-TnT levels within the first three months of ICI treatment. Elevations were defined as hs-TnT above the upper limit of normal (ULN) if the baseline value was normal, or 1.5 ≥ times baseline if the baseline value was above the ULN. Conclusions: Hs-TnT elevations occurred in 10.6% of the patients. However, no significant changes were found on 3D echocardiography, nor did any of the patients develop a CV event. There were also no changes found in NT-proBNP. The study is still ongoing, but these preliminary findings do not show a promising role for cardiac troponins nor for echocardiographic dynamics in the prediction of CV events during the early stages of ICI treatment.