Biomechanical response of ultrathin slices of hypertrophic cardiomyopathy tissue to myosin modulator mavacamten.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder of the heart, but effective treatment options remain limited. Mavacamten, a direct myosin modulator, has been presented as novel pharmacological therapy for HCM. The aim of this study was to analyze the biomechanical response of HCM tissue to Mavacamten using living myocardial slices (LMS). LMS (n = 58) from patients with HCM (n = 10) were cultured under electromechanical stimulation, and Verapamil and Mavacamten were administered on consecutive days to evaluate their effects on cardiac biomechanics. Mavacamten and Verapamil reduced contractile force and dF/dt and increased time-to-relaxation in a similar manner. Yet, the time-to-peak of the cardiac contraction was prolonged after administration of Mavacamten (221.0 ms (208.8 - 236.3) vs. 237.7 (221.0 - 254.7), p = 0.004). In addition, Mavacamten prolonged the functional refractory period (FRP) (330 ms (304 - 351) vs. 355 ms (313 - 370), p = 0.023) and better preserved twitch force with increasing stimulation frequencies, compared to Verapamil. As such, Mavacamten reduced (hyper-)contractility and prolonged contraction duration of HCM LMS, suggesting a reduction in cardiac wall stress. Also, Mavacamten might protect against the development of ventricular tachyarrhythmias due to prolongation of the FRP, and improve toleration of tachycardia due to better preservation of twitch force at tachycardiac stimulation frequencies.

Insights Into the Effects of Low-Level Vagus Nerve Stimulation on Atrial Electrophysiology: Towards Patient-Tailored Cardiac Neuromodulation.

BACKGROUND: Low-level vagus nerve stimulation through the tragus (tLLVNS) is increasingly acknowledged as a therapeutic strategy to prevent and treat atrial fibrillation. However, a lack in understanding of the exact antiarrhythmic properties of tLLVNS has hampered clinical implementation. OBJECTIVES: In this study, the authors aimed to study the effects of tLLVNS on atrial electrophysiology by performing intraoperative epicardial mapping during acute and chronic tLLVNS. METHODS: Epicardial mapping of the superior right atrium was performed before and after arterial graft harvesting in patients undergoing coronary artery bypass grafting without a history of atrial fibrillation. The time needed for arterial graft harvesting was used to perform chronic tLLVNS. Electrophysiological properties were compared before and during chronic tLLVNS. RESULTS: A total of 10 patients (median age 74 years [IQR: 69-78 years]) underwent tLLVNS for a duration of 56 minutes (IQR: 43-73 minutes). During acute and chronic tLLVNS, a shift of the sinoatrial node exit site toward a more cranial direction was observed in 5 (50%) patients. Unipolar potential voltage increased significantly during acute and chronic tLLVNS (3.9 mV [IQR: 3.1-4.8 mV] vs 4.7 mV [IQR: 4.0-5.3 mV] vs 5.2 mV [IQR: 4.8-7.0 mV]; P = 0.027, P = 0.02, respectively). Total activation time, slope of unipolar potentials, amount of fractionation, low-voltage areas and conduction velocity did not differ significantly between baseline measurements and tLLVNS. Two patients showed consistent "improvement" of all electrophysiological properties during tLLVNS, while 1 patient appeared to have no beneficial effect. CONCLUSIONS: We demonstrated that tLLVNS resulted in a significant increase in unipolar potential voltage. In addition, we observed the following in selective patients: 1) reduction in total activation time; 2) steeper slope of unipolar potentials; 3) decrease in the amount of fractionation; and 4) change in sinoatrial node exit sites.

Biomimetic cultivation of atrial tissue slices as novel platform for in-vitro atrial arrhythmia studies.

Living myocardial slices (LMS) are beating sections of intact human myocardium that maintain 3D microarchitecture and multicellularity, thereby overcoming most limitations of conventional myocardial cell cultures. We introduce a novel method to produce LMS from human atria and apply pacing modalities to bridge the gap between in-vitro and in-vivo atrial arrhythmia studies. Human atrial biopsies from 15 patients undergoing cardiac surgery were dissected to tissue blocks of ~ 1 cm2 and cut to 300 µm thin LMS with a precision-cutting vibratome. LMS were placed in a biomimetic cultivation chamber, filled with standard cell culture medium, under diastolic preload (1 mN) and continuous electrical stimulation (1000 ms cycle length (CL)), resulting in 68 beating LMS. Atrial LMS refractory period was determined at 192 ± 26 ms. Fixed rate pacing with a CL of 333 ms was applied as atrial tachyarrhythmia (AT) model. This novel state-of-the-art platform for AT research can be used to investigate arrhythmia mechanisms and test novel therapies.

Acute Biomechanical Effects of Empagliflozin on Living Isolated Human Heart Failure Myocardium.

PURPOSE: Multiple randomized controlled trials have presented SGLT2 inhibitors (SGLT2i) as novel pharmacological therapy for patients with heart failure, resulting in reductions in hospitalization for heart failure and mortality. Given the absence of SGLT2 receptors in the heart, mechanisms of direct cardioprotective effects of SGLT2i are complex and remain to be investigated. In this study, we evaluated the direct biomechanical effects of SGLT2i empagliflozin on isolated myocardium from end-stage heart failure patients. METHODS: Ventricular tissue biopsies obtained from 7 patients undergoing heart transplantation or ventricular assist device implantation surgery were cut into 27 living myocardial slices (LMS) and mounted in custom-made cultivation chambers with mechanical preload and electrical stimulation, resulting in cardiac contractions. These 300 µm thick LMS were subjected to 10 µM empagliflozin and with continuous recording of biomechanical parameters. RESULTS: Empagliflozin did not affect the maximum contraction force of the slices, however, increased total contraction duration by 13% (p = 0.002) which was determined by prolonged time to peak and time to relaxation (p = 0.009 and p = 0.003, respectively). CONCLUSION: The addition of empagliflozin to LMS from end-stage heart failure patients cultured in a biomimetic system improves contraction and relaxation kinetics by increasing total contraction duration without diminishing maximum force production. Therefore, we present convincing evidence that SGLT2i can directly act on the myocardium in absence of systemic influences from other organ systems.