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.

Ex vivo lung perfusion: a procedural guide.

Available donor organs for lung transplantation are scarce. Ex vivo lung perfusion provides a platform to preserve, assess, and recondition donor lungs and can thereby aid in enlarging the donor pool. This video tutorial discusses the indications, preparation, and surgical technique for and the initiation, maintenance and termination of the ex vivo lung perfusion procedure.

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.

Optimization of intra-operative electrophysiological localization of the ligament of Marshall.

Background: The ligament of Marshall (LOM) may play a role in the pathophysiology of several tachyarrhythmias and accurate electrophysiological localization of this structure is crucial for effective ablation therapy. This study therefore quantifies electrophysiological properties of the LOM, and identifies which electrogram (EGM) recording (uni- or bipolar) and processing technologies [local activation time (LAT) and/or voltage mapping] are most suitable for accurate localization of the LOM. Methods: The LOM was electrophysiologically identified in 19 patients (mean age 66 ± 14 years; 12 male) undergoing elective cardiac surgery using intra-operative high-density epicardial mapping, to quantify and visualize EGM features during sinus rhythm. Results: Only a third of LOM potentials that were visualized using unipolar EGMs, were still visible in bipolar activation maps. Unipolar LOM potentials had lower voltages (P50: LOM: 1.51 (0.42-4.29) mV vs. left atrium (LA): 8.34 (1.50-17.91) mV, p < 0.001), less steep slopes (P50: LOM: -0.48 (-1.96 to -0.17) V/s vs. LA: -1.24 (-2.59 to -0.21) V/s, p < 0.001), and prolonged activation duration (LOM: 20 (7.5-30.5) ms vs. LA: 16.5 (6-28) ms, p = 0.008) compared to LA potentials. Likewise, bipolar LOM voltages were also smaller (P50: LOM: 1.54 (0.48-3.28) mV vs. LA: 3.12 (0.50-7.19) mV, p < 0.001). Conclusion: The LOM was most accurately localized in activation and voltage maps by using unipolar EGMs with annotation of primary deflections in case of single potentials and secondary deflections in case of double or fractionated potentials.

Normothermic Ex Situ Heart Perfusion With the Organ Care System for Cardiac Transplantation: A Meta-analysis.

BACKGROUND: Heart transplantation (HTx) is, at present, the most effective therapy for end-stage heart failure patients; however, the number of patients on the waiting list is rising globally, further increasing the gap between demand and supply of donors for HTx. First studies using the Organ Care System (OCS) for normothermic machine perfusion show promising results yet are limited in sample size. This article presents a meta-analysis of heart donation either after brain death (OCS-DBD) or circulatory death (OCS-DCD) on using OCS versus static cold storage used for HTx. METHODS: A systematic literature search was performed for articles discussing the use of normothermic ex situ heart perfusion in adult patients. Thirty-day survival outcomes were pooled, and odds ratios were calculated using random-effects models. Long-term survival was visualized with Kaplan-Meier curves, hazard ratios were calculated and pooled using fixed-effects models, and secondary outcomes were analyzed. RESULTS: A total of 12 studies were included, with 741 patients undergoing HTx, of which 260 with the OCS (173 DBD and 87 DCD). No differences were found between the 3 groups for early and late survival outcomes or for secondary outcomes. CONCLUSIONS: OCS outcomes, for both DBD and DCD hearts, appeared similar as for static cold storage. Therefore, OCS is a safe and effective technique to enlarge the cardiac donor pool in both DBD and DCD, with additional benefits for long-distance transport and surgically complex procedures.