Dyssynchronous heart failure models in canines: New insights into electrocardiographic, echocardiographic and histological features.

BACKGROUND: We investigated the similarities and differences between two experimental approaches using tachy-pacing technology to induce desynchronized heart failure in canines. METHODS: A total of eight dogs were included in the experiment, four were tachy-paced in right ventricle apex (RVAP) and 4 were paced in right atrium after the ablation of left bundle branch to achieve left bundle branch block (RAP+LBBB). Three weeks of follow-up were conducted to observe the changes in cardiac function and myocardial staining was performed at the end of the experiment. RESULTS: Both experimental approaches successfully established heart failure with reduced ejection fraction models, with similar trends in declining cardiac function. The RAP+LBBB group exhibited a prolonged overall ventricular activation time, delayed left ventricular activation, and lesser impact on the right ventricle. The RVAP approach led to a reduction in overall right ventricular compliance and right ventricular enlargement. The RAP+LBBB group exhibited significant reductions in left heart compliance (LVGLS, %: RAP+LBBB -12.60 ± 0.12 to -5.93 ± 1.25; RVAP -13.28 ± 0.62 to -8.05 ± 0.63, p = 0.023; LASct, %: RAP+LBBB -15.75 ± 6.85 to -1.50 ± 1.00; RVAP -15.75 ± 2.87 to -10.05 ± 6.16, p = 0.035). Histological examination revealed more pronounced fibrosis in the left ventricular wall and left atrium in the RAP+LBBB group while the RVAP group showed more prominent fibrosis in the right ventricular myocardium. CONCLUSION: Both approaches establish HFrEF models with comparable trends. The RVAP group shows impaired right ventricular function, while the RAP+LBBB group exhibits more severe decreased compliance and fibrosis in left ventricle.

In-hospital therapies and determinants of treatment strategy selection in patients with atrial fibrillation and left ventricular systolic dysfunction in China: a retrospective study based on the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) project, 2015-2019.

OBJECTIVES: The optimal treatment strategy remains debatable in patients with atrial fibrillation (AF) and heart failure. Our objectives were to summarise in-hospital therapies and determine factors associated with treatment strategy selections. DESIGN: A retrospective study analysing the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) project from 2015 to 2019. SETTING: The CCC-AF project included patients from 151 tertiary and 85 secondary hospitals across 30 provinces in China. PARTICIPANTS: Patients with AF and left ventricular systolic dysfunction (LVSD, defined as left ventricular ejection fraction<50%) were included, with 5560 patients in the study sample. METHODS: Patients were classified by treatment strategies. In-hospital treatments and trends of therapies were analysed. Multiple logistic regression models were used to find determinants of treatment strategies. RESULTS: Rhythm control therapies were used in 16.9% of patients with no significant trends (p trend=0.175). Catheter ablation was used in 5.5% of patients, increasing from 3.3% in 2015 to 6.6% in 2019 (p trend<0.001). Factors negatively associated with rhythm control included increased age (OR 0.973, 95% CI 0.967 to 0.980), valvular AF (OR 0.618, 95% CI 0.419 to 0.911), AF types (persistent: OR 0.546, 95% CI 0.462 to 0.645; long-standing persistent: OR 0.298, 95% CI 0.240 to 0.368), larger left atrial diameters (OR 0.966, 95% CI 0.957 to 0.976) and higher Charlson Comorbidity Index scores (CCI 1-2: OR 0.630, 95% CI 0.529 to 0.750; CCI≥3: OR 0.551, 95% CI 0.390 to 0.778). Higher platelet counts (OR 1.025, 95% CI 1.013 to 1.037) and prior rhythm control attempts (electrical cardioversion: OR 4.483, 95% CI 2.369 to 8.483; catheter ablation: OR 4.957, 95% CI 3.072 to 7.997) were positively associated with rhythm control strategies. CONCLUSION: In China, non-rhythm control strategy remained the dominant choice in patients with AF and LVSD. Age, AF types, prior treatments, left atrial diameters, platelet counts and comorbidities were major determinants of treatment strategies. Guideline-adherent therapies should be further promoted. STUDY REGISTRATION NUMBER: NCT02309398.

Late sodium current in synergism with Ca2+/calmodulin-dependent protein kinase II contributes to ß-adrenergic activation-induced atrial fibrillation.

Atrial fibrillation (AF) is frequently associated with ß-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late INa) and Ca2+/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in ß-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Nav1.5 and phospho-CaMKII protein levels and late INa by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied (p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Nav1.5 and CaMKII, and reversed the increase of late INa (p < 0.05) in a synergistic mode. Overall, late INa in association with the activation of CaMKII potentiates ß-adrenergic stimulation-induced AF and the inhibition of both late INa and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

A novel approach for developing left bundle branch pacing and left bundle branch block in a canine model.

BACKGROUND AND OBJECTIVE: Left bundle branch pacing (LBBP) has shown the benefits in the treatment of dyssynchronous heart failure (HF). The purpose of this study was to develop a novel approach for LBBP and left bundle branch block (LBBB) in a canine model. METHODS: A "triangle-center" method by tricuspid valve annulus angiography for LBBP implantation was performed in 6 canines. A catheter was then applied for retrograde His potential recording and left bundle branch (LBB) ablation simultaneously. The conduction system was stained to verify the "triangle-center" method for LBBP and assess the locations of the LBB ablation site in relation to the left septal fascicle (LSF). RESULTS: The mean LBB potential to ventricular interval and stimulus-peak left ventricular activation time were 11.8 ± 1.2 and 35.7 ± 3.1 ms, respectively. The average intrinsic QRS duration was 44.7 ± 4.7 ms. LBB ablation significantly prolonged the QRS duration (106.3 ± 8.3 ms, p < .001) while LBBP significantly shortened the LBBB-QRS duration to 62.5 ± 5.3 ms (p < .001). After 6 weeks of follow-up, both paced QRS duration (63.0 ± 5.4 ms; p = .203) and LBBB-QRS duration (107.3 ± 7.4 ms; p = .144) were unchanged when comparing to the acute phase, respectively. Anatomical analysis of 6 canine hearts showed that the LBBP lead-tip was all placed in LSF area. CONCLUSION: The new approach for LBBP and LBBB canine model was stable and feasible to simulate the clinical dyssynchrony and resynchronization. It provided a useful tool to investigate the basic mechanisms of underlying physiological pacing benefits.

Predictive value of 10-year atherosclerotic cardiovascular disease risk equations from the China-PAR for new-onset lower extremity peripheral artery disease.

Lower extremity peripheral artery disease (LEPAD) is a common and serious health-threatening disease. The aim of this study was to evaluate the predictive value of 10-year atherosclerotic cardiovascular disease (ASCVD) risk equations from the Prediction for ASCVD Risk in China (China-PAR) project for incident LEPAD after 6.75 ± 0.13 years of follow-up. A total of 3,595 Chinese participants without baseline ASCVD or LEPAD from a community-based cohort were enrolled in our study. The mean (interquartile range) baseline 10-year China-PAR ASCVD risk was 4.35% (2.24-8.44%), and the incidence of new-onset LEPAD during 6.75 ± 0.13 years was 4.23%. In univariable logistic regression analysis, 10-year China-PAR ASCVD risk was significantly associated with LEPAD incidence (odds ratio [OR] for each 1% increase in the risk score = 1.06, 95% confidence interval [CI]: 1.03-1.08, P < 0.001). After adjusting confounders, the relationship remained significant (OR: 1.09, 95% CI: 1.05-1.1. P < 0.001). Participants with the highest risk (≥10%) had significantly increased risk compared to those with the lowest risk (<5%) (OR = 2.65, 95% CI: 1.15-6.07, P = 0.022). Further interaction analyses showed no evidence of heterogeneity according to sex, age, body mass index (BMI), smoking, drinking, hypertension, diabetes mellitus, dyslipidemia, renal function, waist circumference, and family history. In conclusion, 10-year China-PAR ASCVD risk independently predicted the risk of new-onset LEPAD in a Chinese community-based population, indicating the importance of polyvascular diseases (PVDs) and the intrinsic interactions of its components.

Effects on Adherence to a Mobile App-Based Self-management Digital Therapeutics Among Patients With Coronary Heart Disease: Pilot Randomized Controlled Trial.

BACKGROUND: The adherence to secondary prevention treatment in patients with coronary heart disease (CHD) is low. Digital therapeutics (DTx) refers to an emerging branch of medicine that delivers medical interventions directly to patients using evidence-based, clinically evaluated, technology-based software algorithms or apps to facilitate disease management, which may be an efficient tool to optimize adherence. OBJECTIVE: This paper aims to investigate the effect of mobile app-based self-management DTx on long-term use of secondary prevention medications in patients with CHD in China. METHODS: This pilot study was a parallel-designed, open-labeled, single-center, randomized controlled trial. Hospitalized patients with CHD admitted to Peking University First Hospital between April 2016 and June 2017 were randomized before discharge on a 1:1 ratio. The intervention group received regular follow-up combined with DTx, which is a self-management mobile app already installed on an Android 5 (Mi Pad 1, Xiaomi Corporation) tablet. Structured data from the hospital informatics system were integrated automatically, and medication, lifestyle intervention plan, follow-up protocol, and patient education materials were also provided according to the diagnosis. Participants could use DTx for self-management at home. The control group was under conventional hospital-based follow-up care. Patients were followed up for 1 year, and the primary end point was the percentage of all guideline-recommended medications at 12 months. The secondary end points included the percentage adhered to standard secondary prevention medications at 6 months, the control rate of lipid profile, and blood pressure at 6 months and 1 year. RESULTS: Among 300 randomized patients with CHD, 290 (96.7%) were included in the final analysis, including 49.3% (143/290) and 50.7% (147/290) of patients from the intervention and control groups, respectively. Baseline characteristics were similar between the 2 groups. There was a statistically significant improvement in the percentage of all guideline-recommended medications at 12 months in the intervention group compared with the control group (relative risk [RR] 1.34, 95% CI 1.12-1.61; P=.001), and there was no interaction with baseline characteristics. The intervention group had a significantly higher proportion of patients achieving blood pressure under control (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and low-density lipoprotein cholesterol <1.8 mmol/L (RR 1.45, 95% CI 1.22-1.72; P<.001 and RR 1.40, 95% CI 1.11-1.75; P=.004, respectively) at 12 months. Furthermore, on logistic regression, the intervention group had a lower risk of withdrawing from guideline-recommended medications (odds ratio 0.46, 95% CI 0.27-0.78; P=.004). CONCLUSIONS: Among patients with CHD, using a mobile app-based self-management DTx in addition to traditional care resulted in a significant improvement in guideline-recommended medication adherence at 12 months. The results of the trial will be applicable to primary care centers, especially in rural areas with less medical resources. TRIAL REGISTRATION: ClinicalTrials.gov NCT03565978; https://clinicaltrials.gov/ct2/show/NCT03565978.

Cardiogenic shock caused by Takotsubo syndrome complicated with severe anxiety: A case report and literature review.

RATIONALE: Takotsubo syndrome (TTS) is characterized by transient and reversible left ventricular systolic dysfunction, which are often associated with acute physical or emotional stressors. Cancer is one of the comorbidities in TTS, and TTS is even considered as a paraneoplastic syndrome, but its mechanism remains unclear. We report a patient in whom cancer and untreated mental disorders triggered TTS. PATIENT CONCERNS: A 59-year-old man was transferred to the Department of Cardiology because of acute onset of severe chest pain and dyspnea before cystoscopy. He presented with hematuria, had been diagnosed with a high-grade urothelial bladder cancer, and underwent transurethral resection of bladder tumors 4 months previously. He had severe anxiety regarding recurrence and death from cancer, especially after the hematuria recurred. DIAGNOSIS: TTS and severe anxiety. INTERVENTIONS: The results of coronary angiography, a left ventriculogram, echocardiography, and the clinical outcome led to the diagnosis of TTS. The patient was treated with extracorporeal membrane oxygenation support, mechanical ventilation, and drugs for heart failure and anxiety. OUTCOMES: Echocardiography showed normal wall motion on day 6 of symptom onset. Six months after symptom onset, the anxiety score was reduced from 12 to 11, and the patient had no episodes of any discomfort, and no evidence of cancer recurrence was observed. LESSONS: Patients with cancer and TTS have a higher level of stress, and physicians need to pay more attention to early screening and early treatment of mental disorders in these patients. Prompt and effective multidisciplinary treatment, including psychological counseling and antianxiety drugs, can improve the prognosis in such cases.

Dosimetric feasibility of stereotactic ablative radiotherapy in pulmonary vein isolation for atrial fibrillation using intensity-modulated proton therapy.

PURPOSE: To evaluate dosimetric properties of intensity-modulated proton therapy (IMPT) for simulated treatment planning in patients with atrial fibrillation (AF) targeting left atrial-pulmonary vein junction (LA-PVJ), in comparison with volumetric-modulated arc therapy (VMAT) and helical tomotherapy (TOMO). METHODS: Ten thoracic 4D-CT scans with respiratory motion and one with cardiac motion were used for the study. Ten respiratory 4D-CTs were planned with VMAT, TOMO, and IMPT for simulated AF. Targets at the LA-PVJ were defined as wide-area circumferential ablation line. A single fraction of 25 Gy was prescribed to all plans. The interplay effects from cardiac motion were evaluated based on the cardiac 4D-CT scan. Dose-volume histograms (DVHs) of the ITV and normal tissues were compared. Statistical analysis was evaluated via one-way Repeated-Measures ANOVA and Friedman's test with Bonferroni's multiple comparisons test. RESULTS: The median volume of ITV was 8.72cc. All plans had adequate target coverage (V23.75Gy  ≥ 99%). Compared with VMAT and TOMO, IMPT resulted in significantly lower dose of most normal tissues. For VMAT, TOMO, and IMPT plans, Dmean of the whole heart was 5.52 ± 0.90 Gy, 5.89 ± 0.78 Gy, and 3.01 ± 0.57 Gy (P < 0.001), mean dose of pericardium was 4.74 ± 0.76 Gy, 4.98 ± 0.62 Gy, and 2.59 ± 0.44 Gy (P < 0.001), and D0.03cc of left circumflex artery (LCX) was 13.96 ± 5.45 Gy, 14.34 ± 5.91 Gy, and 8.43 ± 7.24 Gy (P < 0.001), respectively. However, no significant advantage for one technique over the others was observed when examining the D0.03cc of esophagus and main bronchi. CONCLUSIONS: IMPT targeting LA-PVJ for patients with AF has high potential to reduce dose to surrounding tissues compared to VMAT or TOMO. Motion mitigation techniques are critical for a particle-therapy approach.

Is the left bundle branch pacing a choice to conquer the right bundle branch block?-A case report.

In patients with preserved ejection fraction or right bundle branch block (RBBB) pattern requiring a high percentage of ventricular pacing, His-bundle pacing (HBP) might be an alternative to biventricular pacing, although the high threshold occasionally occurs. We provided a case of the intrinsic RBBB correction by capturing intra-Hisian left bundle branch (LBB) or distal His-bundle with different output settings. LBB pacing had the advantage of a much lower threshold while remained most synchrony as HBP. LBB pacing might be a promisingly safe and effective procedure for patients with high-grade atrioventricular (AV) block and RBBB pattern.

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study.

INTRODUCTION: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with high affinity and reverses its anticoagulant effect. This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab in healthy Chinese subjects at steady state of dabigatran and explored the effect of idarucizumab on PK and PD of dabigatran. METHODS: Twelve subjects received dabigatran etexilate treatment alone (220 mg twice daily, b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate (220 mg b.i.d., oral) and idarucizumab (2.5 + 2.5 g, intravenous) 2 h after the last administration of dabigatran etexilate. RESULTS: The geometric mean (gMean) values of area under the plasma concentration-time curve (AUC0-∞) and maximum concentration (Cmax) were 44,200 nmol h/L and 30,900 nmol/L, respectively. An amount of 35.3 µmol of idarucizumab, corresponding to 33.8% of the total dose, was excreted by urine over 72 h. The area under the effect (AUECabove,2-12) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT), which indicated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse events reported in this study. No subject tested positive for anti-idarucizumab antibodies. CONCLUSION: Idarucizumab was well tolerated and no subject tested positive for anti-idarucizumab antibodies in this study. PK and PD of idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with those in Japanese and Caucasian subjects. CLINICAL REGISTRATION: ClinicalTrials.gov Identifier No. NCT03086356.

A Pilot Study on Parameter Setting of VisiTag™ Module during Pulmonary Vein Isolation.

OBJECTIVES: To identify optimal predefined criteria (OPC) for filters of the VisiTag™ module in the CARTO 3 system during pulmonary vein isolation (PVI). METHODS: Thirty patients with atrial fibrillation (AF) who experienced PVI first were enrolled. PVI was accomplished by using a Thermocool SmartTouch catheter. Ablation lesions were tagged automatically as soon as predefined criteria of the VisiTag™ module were met. OPC should be that ablation with the setting resulting in the conduction gap (CG) as few as possible, while contiguous encircling ablation line (CEAL) without the tag gap (TG) on the 3D anatomic model as much as possible. RESULTS: When ablation with parameter setting is being catheter movement with a 3 mm distance limit for at least 20 s and force over time (FOT) being off, there were 60 CEAL without TG on the 3D anatomic model. However, 26 CGs were found. After changing FOT setting to be a minimal force of 5 g with 50% stability time, 22 TGs were displayed. Of them, 20 TGs were accompanied by CGs. On reablation at sites of TG with changed parameter setting, 18 CGs were eliminated when 20 TGs disappeared. When reablation with FOT is being a minimal force of 10 g with 50% stability time, 6 remaining CGs were eliminated. However, there was no CEAL. With a mean of follow-up 10.93 months, 2 patients with persistent AF suffered AF recurrence. CONCLUSION: A 3 mm distance limit for at least 20 s and FOT being a minimal force of 5 g with 50% stability time might be OPC for the VisiTag™ module.