Cardiac ischemia and reperfusion in mice: a comprehensive hemodynamic, electrocardiographic and electrophysiological characterization.

Malignant ventricular arrhythmias (VA) after acute myocardial infarction remain a major threat. Aim of this study was to characterize the electrophysiological and autonomic sequelae of cardiac ischemia and reperfusion (I/R) in mice during the first week post incident. Left ventricular function was serially assessed using transthoracic echocardiography. VA were quantified by telemetric electrocardiogram (ECG) recordings and electrophysiological studies on the 2nd and 7th day after I/R. Cardiac autonomic function was evaluated by heart rate variability (HRV) and heart rate turbulence (HRT). Infarct size was quantified by planimetric measures. I/R caused significant myocardial scarring and diminished left ventricular ejection fraction. The ECG intervals QRS, QT, QTc, and JTc were prolonged in I/R mice. Both spontaneous VA scored higher and the inducibility of VA was raised in I/R mice. An analysis of HRV and HRT indicated a relative reduction in parasympathetic activity and disturbed baroreflex sensitivity up to 7 days after I/R. In summary, during the first week after I/R, the murine heart reflects essential features of the human heart after myocardial infarction, including a greater vulnerability for VA and a decreased parasympathetic tone accompanied by decelerated depolarization and repolarization parameters.

Prevalence and prognostic impact of dynamic atrial functional mitral regurgitation assessed by isometric handgrip exercise.

AIMS: In atrial functional mitral regurgitation (aFMR), a considerable proportion of patients displays a discrepancy between symptoms and echocardiographic findings at rest. Exercise testing plays a substantial role in assessing the haemodynamic relevance of mitral regurgitation (MR) and is recommended by current guidelines. Here, we aimed to assess the prevalence, extent, and prognostic impact of exercise-induced changes in patients with aFMR. METHODS AND RESULTS: Patients with at least mild MR who underwent handgrip exercise echocardiography at the University Hospital Duesseldorf between January 2019 and September 2021 were enrolled. Patients were followed-up for one year to assess clinical outcomes. Eighty patients with aFMR were included (median age: 80 (77-83) years; 53.8% female). The median N-terminal pro brain natriuretic petide level was 1756 (1034-3340) ng/l. At rest, half of the patients (53.8%) had mild MR, 20 patients (25.0%) had moderate MR, and 17 patients (21.2%) had severe MR. In approximately every fifth patient (17.5%) with non-severe MR at rest, the MR became severe during exercise. Handgrip exercise led to a re-classification of MR severity in 28 patients (35.0%). At one-year follow-up, adverse events occurred more often in patients with severe MR at rest (76.5%) and exercise-induced dynamic severe MR (66.7%) than in those with non-severe MR (28.6%) (p < 0.001). CONCLUSIONS: Handgrip exercise during echocardiography revealed exercise-induced changes in aFMR in every third patient. These data may have implications for therapeutic decision-making in symptomatic patients with non-severe aFMR at rest.

Aging impairs the neurovascular interface in the heart.

Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased Sema3a expression or endothelial Sema3a overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed Sema3a expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.

Clinical Impact of Circulating Galectin-3 on Ventricular Arrhythmias and Heart Failure Hospitalization Independent of Prior Ventricular Arrhythmic Events in Patients with Implantable Cardioverter-defibrillators.

Objective For risk stratification of sudden cardiac death in patients with structural heart disease, more precise predictors in addition to left ventricular ejection fraction (LVEF) are clinically needed. The present study assessed the utility of galectin-3 as an independent indicator for the prognosis of heart failure patients with implantable cardioverter-defibrillators (ICD). Methods The study population consisted of 91 consecutive patients who underwent a routine ICD checkup in our ICD outpatient clinic. Circulating galectin-3 was assessed using a commercially available enzyme-linked immunosorbent assay kit. The enrolled patients were prospectively followed. The primary endpoint was defined as the occurrence of appropriate ICD therapy (AIT), and the secondary endpoint was defined as the occurrence of unplanned overnight hospitalization due to decompensated heart failure (dHF). Results During a mean follow-up of 472±107 days, AIT occurred in 18 patients (20%). Unplanned hospitalizations due to dHF were noted in 12 patients (13%). A receiver-operative characteristics analysis demonstrated a sensitivity of 83% and specificity of 68% for AIT occurrences with a galectin-3 cut-off value of 13.1 ng/mL (area under the curve =0.82). A Kaplan-Meier analysis demonstrated that patients with galectin-3 >13.1 ng/mL had significantly higher incidences of AIT as compared to those with lower galectin-3 (log-rank, p<0.001). This significance was also observed in both subgroup analyses with ischemic and non-ischemic etiology. Cox regression demonstrated that higher galectin-3 was an independent predictor of AIT and dHF, even after adjusting for previous arrhythmic events. Conclusion The circulating galectin-3 level can be used as a clinical indicator of subsequent occurrence of ventricular arrhythmic events and decompensated heart failure, regardless of a history of ventricular arrhythmias.

Performance of a convolutional neural network derived from an ECG database in recognizing myocardial infarction.

Artificial intelligence (AI) is developing rapidly in the medical technology field, particularly in image analysis. ECG-diagnosis is an image analysis in the sense that cardiologists assess the waveforms presented in a 2-dimensional image. We hypothesized that an AI using a convolutional neural network (CNN) may also recognize ECG images and patterns accurately. We used the PTB ECG database consisting of 289 ECGs including 148 myocardial infarction (MI) cases to develop a CNN to recognize MI in ECG. Our CNN model, equipped with 6-layer architecture, was trained with training-set ECGs. After that, our CNN and 10 physicians are tested with test-set ECGs and compared their MI recognition capability in metrics F1 (harmonic mean of precision and recall) and accuracy. The F1 and accuracy by our CNN were significantly higher (83 ± 4%, 81 ± 4%) as compared to physicians (70 ± 7%, 67 ± 7%, P < 0.0001, respectively). Furthermore, elimination of Goldberger-leads or ECG image compression up to quarter resolution did not significantly decrease the recognition capability. Deep learning with a simple CNN for image analysis may achieve a comparable capability to physicians in recognizing MI on ECG. Further investigation is warranted for the use of AI in ECG image assessment.

A modified approach for programmed electrical stimulation in mice: Inducibility of ventricular arrhythmias.

BACKGROUND: Electrophysiological studies in mice, the prevailing model organism in the field of basic cardiovascular research, are impeded by the low yield of programmed electrical stimulation (PES). OBJECTIVE: To investigate a modified approach for ventricular arrhythmia (VA) induction and a novel scoring system in mice. METHOD: A systematic review of literature on current methods for PES in mice searching the PubMed database revealed that VA inducibility was low and ranged widely (4.6 ± 10.7%). Based on this literature review, a modified PES protocol with 3 to 10 extrastimuli was developed and tested in comparison to the conventional PES protocol using up to 3 extrastimuli in anesthetized wildtype mice (C57BL/6J, n = 12). Induced VA, classified according to the Lambeth Convention, were assessed by established arrhythmia scores as well as a novel arrhythmia score based on VA duration. RESULTS: PES with the modified approach raised both the occurrence and the duration of VA compared to conventional PES (0% vs 50%; novel VA score p = 0.0002). Particularly, coupling of >6 extrastimuli raised the induction of VA. Predominantly, premature ventricular complexes (n = 6) and ventricular tachycardia <1s (n = 4) were observed. Repeated PES after adrenergic stimulation using isoprenaline resulted in enhanced induction of ventricular tachycardia <1s in both protocols. CONCLUSION: Our findings suggest that the presented approach of modified PES enables effective induction and quantification of VA in wildtype mice and may well be suited to document and evaluate detailed VA characteristics in mice.

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.