Arrhythmogenic substrate, modulating factors, and triggering factors (the so-called Coumel’s triangle concept) play a primary role in atrial fibrillation (AF) pathophysiology. Several years have elapsed since Coumel and co-workers advanced the concept of the relevance of autonomic nervous system (ANS) influences on atrial cells’ electrophysiological characteristics. The ANS is not only associated with cardiac rhythm regulation but also exerts an important role in the triggering and maintenance of atrial fibrillation. This review aims to describe in detail the autonomic mechanisms involved in the pathophysiology of atrial fibrillation (AF), starting from the hypothesis of an “Autonomic Coumel Triangle” that stems from the condition of the fundamental role played by the ANS in all phases of the pathophysiology of AF. In this article, we provide updated information on the biomolecular mechanisms of the ANS role in Coumel’s triangle, with the molecular pathways of cardiac autonomic neurotransmission, both adrenergic and cholinergic, and the interplay between the ANS and cardiomyocytes’ action potential. The heterogeneity of the clinical spectrum of the ANS and AF, with the ANS playing a relevant role in situations that may promote the initiation and maintenance of AF, is highlighted. We also report on drug, biological, and gene therapy as well as interventional therapy. On the basis of the evidence reviewed, we propose that one should speak of an “Autonomic Coumel’s Triangle” instead of simply “Coumel’s Triangle”.

Reducing levels of low-density lipoprotein cholesterol (LDL-C) below recommended thresholds is a core component of cardiovascular prevention strategies. We hypothesized that the addition of bempedoic acid to patients already on statin–ezetimibe therapy was more effective than titrating the statin dose in reducing LDL-C. The study enrolled 120 patients at high cardiovascular risk and with LDL-C above 70 mg/dL. They were randomly divided into two groups: the bempedoic acid (BA) group, taking bempedoic acid in addition to statin plus ezitimibe, and the statin titration (ST) group, including patients who doubled the dose of statin. At 12 weeks, the BA group presented a more significant decrease in LDL-C compared to the ST group (−22.9% vs. 7.5% p 0.002). The total cholesterol decreased significantly in the BA group compared to ST (−14.8% vs.−4.7%; p 0.013) No significant between-group changes in HDL and triglycerides occurred. At 12 weeks, the number of patients who reached LDL-C lower than 70 mg/dL was 38 (63%) in the BA group versus 22 (37%) in the ST group (between groups, p 0.034). In the BA group, the LDL-lowering effect of bempedoic acid was similar between patients taking atorvastatin and rosuvastatin. No side effects occurred during the follow up period. In conclusion, the addition of bempedoic acid to statin–ezetimibe combined treatment was more effective than doubling the dose of statin in reducing LDL-C levels and increased the number of patients reaching the LDL-C goal.

Background: Isometric exercise effectively reduces blood pressure (BP) but its effects on myocardial work have been poorly studied. For the present study, we compared acute changes in myocardial work during two different isometric exercises, namely, bilateral knee extension and handgrip, in patients with hypertension and underlying ischemic heart disease (IHD). Methods: This was a randomized pilot study in which 48 stable, trained patients with hypertension and IHD were enrolled. Patients were randomly assigned to perform a single session of bilateral knee extension (IKE) or handgrip (IHG) exercises or no exercise (control), with a 1:1:1 ratio. Both exercises were performed at 30% of maximal voluntary contraction and lasted three minutes. Echocardiography and BP measurements were performed at rest, during the exercise, and after ten minutes of recovery. Results: Both exercises were tolerated well, and no side effects occurred. During the exercise, the systolic BP increased significantly in the IKE group compared with the IHG and control groups (ANOVA p < 0.001). Left ventricular global longitudinal strain decreased significantly in the IKE group (−21%) compared with the IHG and control groups (ANOVA p 0.002). The global work index increased significantly in the IKE group (+28%) compared with the IHG and control groups (ANOVA p 0.034). Global constructive work and wasted work increased significantly in the IKE group compared with the IHG and control groups (ANOVA p 0.009 and <0.001, respectively). Global work efficiency decreased significantly in the IKE group (−8%) while remaining unchanged in the IHG and control groups (ANOVA p 0.002). Conclusions: Myocardial work efficiency was impaired during isometric bilateral knee extension but not during handgrip, which evoked a limited hemodynamic response.

Background: Isometric handgrip (IHG) exercise reduces blood pressure (BP) in both normotensive and hypertensive individuals. However, there are few studies specifically addressing its effects in hypertensive patients with ischemic heart disease (IHD). This research aimed to compare acute hemodynamic responses and post-exercise hypotension to single bouts of IHG handgrip performed at two different intensities in patients with IHD. Methods: Fifty-four sedentary patients were enrolled and randomly assigned to one of three groups: (1) high-intensity isometric handgrip performed at 70% of maximal voluntary contraction (MVC) (IHG-70%); (2) low-intensity isometric handgrip performed at 30% of MVC (IHG-30%); (3) control group (no exercise). Heart rate and BP were measured, and transthoracic echocardiography was performed at baseline, during exercise (lasting 3 min), and after 15 min post-exercise. BP was also measured at 30, 45, and 60 min of recovery. Results: No significant changes in systolic BP occurred during the exercise phase between the three study groups. Systolic BP decreased significantly in IHG-70% compared to the control at 30 (−7.7 ± 1.9; p = 0.035) and 45 min (−8.1 ± 2.3; p = 0.021) post-exercise, while there were no significant differences between IHG-70% and IHG-30% at different time-points. There were no significant changes in diastolic BP between the two active groups and between IHG-70 and IHG-30 versus control at different time-points (repeated-measures ANOVA p = 0.257). Global work efficiency was unchanged in IHG-70% (−4%) and IHG-30% (+1%) compared to control (ANOVA p = 0.154). Conclusions: High-intensity and low-intensity isometric handgrip exercises did not cause hemodynamic impairment in IHD. High-intensity exercise was more effective than low-intensity in reducing post-exercise systolic BP.

Background: Isometric exercise effectively reduces blood pressure (BP) but its effects on myocardial work have been poorly studied. In the present study we compared acute changes in myocardial work during two different isometric exercise, bilateral knee extension and handgrip in patients with hypertension and underlying ischemic heart disease (IHD). Methods: 48 stable, trained patients with hypertension and IHD were enrolled. They were randomly assigned to perform a single session of bilateral knee extension (IKE) or handgrip (IHG) or no exercise (control) with a 1:1:1 ratio. Both exercises were performed at 30% of maximal voluntary contraction and lasted three minutes. Echocardiography and BP measurements were performed at rest, during the exercise and after ten minutes of recovery. Results: both exercises were well tolerated, and no side effects occurred. During the exercise: systolic BP increased significantly in the IKE group compared to IHG and control (ANOVA p <0.001). LVGLS decreased significantly in IKE (-21%) compared IHG and control (ANOVA p 0.002). The global work index increased significantly in KE (+28%) compared to HG and control (ANOVA p 0.034). Global constructive work and wasted work increased significantly in the IKE compared to HG and control (ANOVA p 0.009 and <0.001 respectively). Global work efficiency decreased significantly in the IKE group (-8%) while remained unchanged in the IHG and controls (ANOVA p 0.002). Systolic BP increased significantly in the KE group and was unchanged in HG and control. Conclusion: myocardial work efficiency was impaired during isometric bilateral knee extension but not during handgrip. Handgrip evoked a limited hemodynamic response.

Arterial thrombosis emerges from the interplay between plaque disruption, platelet activation, and coagulation pathway amplification on a background of heterogeneous ischemic and bleeding risk. Optimal antithrombotic therapy therefore varies across clinical settings, from acute coronary syndromes (ACS) to chronic coronary syndromes (CCS), ischemic stroke, peripheral artery disease (PAD), and atrial fibrillation (AF) associated with atherosclerotic disease. Contemporary European and North American guidelines endorse an increasingly individualized approach, moving away from rigid “one-size-fits-all” dual antiplatelet therapy (DAPT) duration and intensity and incorporating dual pathway inhibition with low-dose rivaroxaban plus aspirin in selected high-risk CCS and PAD patients. In ischemic stroke, short-course DAPT is confined to minor events and transient ischemic attacks, whereas long-term monotherapy remains standard, and the coexistence of AF typically shifts the balance toward oral anticoagulation. Across all scenarios, antithrombotic benefit must be weighed against bleeding, especially in elderly, frail, or comorbid patients. Evidence gaps remain substantial, particularly in patients with overlapping vascular territories, AF plus atherosclerotic disease, and after ischemic stroke of complex or mixed mechanisms. This narrative review summarizes current evidence and guideline-based strategies in major atherosclerotic settings, proposes a unifying conceptual framework, and highlights key uncertainties and research directions for truly personalized antithrombotic care.