An Electromechanical Model-Based Study on the Dosage Effects of Ranolazine in Treating Failing HCM Cardiomyocyte

Cardiovascular System Medicine
Electromechanical characteristics Cardiomyocyte Hypertrophic cardiomyopathy Heart failure Ranolazine Computational model

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease, affecting approximately 1 in 500 people globally. The primary characteristic of HCM is asymmetric hypertrophy of the myocardium. In its early stages, it may manifest as hyperdynamic contraction of the left ventricle (LV). However, as the disease progresses, patients may develop complications such as left ventricular outflow tract obstruction, myocardial bridging, and arrhythmias, ultimately leading to cardiac dysfunction and heart failure (HF). Particularly in younger patients, the risk of HCM progressing to heart failure is high, with approximately 42%-52% of patients developing HF before the age of 60. Therefore, finding effective treatments is crucial for improving the quality of life and prognosis of HCM patients.

Ranolazine is a drug commonly used to treat angina and arrhythmias. In recent years, it has also been found to have therapeutic potential for HCM and HF patients. Studies have shown that Ranolazine, by inhibiting the late sodium current (INaL) in cardiomyocytes, can alleviate electrophysiological abnormalities and arrhythmias, thereby improving cardiac function. However, research on the electromechanical response of HCM failing cardiomyocytes to Ranolazine and its dosage effects remains insufficient. In particular, the optimal dosage of Ranolazine for patients with varying degrees of heart failure has not been clearly defined. To address this, researchers systematically investigated the electromechanical characteristics and dosage effects of Ranolazine on HCM failing cardiomyocytes using computational models.

Source of the Study

The study was conducted by Taiwei Liu, Mi Zhou, and Fuyou Liang, affiliated with the School of Ocean and Civil Engineering at Shanghai Jiao Tong University, Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, and the State Key Laboratory of Ocean Engineering at Shanghai Jiao Tong University, respectively. The research paper was published on January 16, 2025, in the journal Cellular and Molecular Bioengineering, titled “An Electromechanical Model-Based Study on the Dosage Effects of Ranolazine in Treating Failing HCM Cardiomyocyte.”

Research Process

1. Construction of the Computational Model

The research team developed a model for HCM failing cardiomyocytes based on existing electromechanical models of left ventricular cardiomyocytes. The model includes four sub-models, each describing the electrophysiological activities, ion and molecule transport, excitation-contraction coupling, and passive mechanical properties of cardiomyocytes. Each sub-model is described using ordinary differential equations (ODEs) or partial differential equations (PDEs).

  • Electrophysiology Sub-model: Describes the transmembrane ion currents of cardiomyocytes, particularly abnormal currents associated with HCM heart failure, such as INaL and L-type calcium current (ICaL).
  • Ion Transport Sub-model: Simulates the transmembrane transport of ions such as sodium, potassium, and chloride, ensuring intracellular ion homeostasis.
  • Excitation-Contraction Coupling Sub-model: Links electrical signals to the contractile force of cardiomyocytes through a cross-bridge (XB) dynamics model.
  • Passive Mechanical Properties Sub-model: Describes the visco-hyperelastic mechanical behavior of cardiomyocytes, using the Quasi-Linear Viscoelastic (QLV) model and the Holzapfel-Gasser-Ogden (HGO) model for simulation.

2. Calibration of Model Parameters

The research team calibrated the model parameters based on literature data to simulate heart failure states of varying severity and changes in ion channels following Ranolazine treatment. Key parameters included the conductance of INaL (gNaL), the intensity of the sodium-calcium exchange current (INCX), and parameters related to intracellular calcium handling.

3. Numerical Simulation and Data Analysis

The research team conducted extensive numerical simulations to model the electromechanical behavior of HCM failing cardiomyocytes under different doses of Ranolazine. Each simulation included 1000 cardiac cycles of isosarcometric twitch simulation and 10 cardiac cycles of isometric twitch simulation. By analyzing variables such as action potential (AP), intracellular calcium transient (CaT), total Cauchy stress (TCS), and twitch stretch (TS), the therapeutic effects of Ranolazine were evaluated.

Key Findings

1. Improvement of Electrophysiological Abnormalities by Ranolazine

The study found that Ranolazine significantly improved electrophysiological abnormalities in HCM failing cardiomyocytes by inhibiting INaL. Specific manifestations included: - Prolonged Action Potential: The AP of HCM failing cardiomyocytes was significantly prolonged, accompanied by early after-depolarizations (EADs). After Ranolazine treatment, EADs disappeared, and the AP waveform normalized. - Reduction in Calcium Overload: Ranolazine reduced diastolic intracellular calcium overload, improving the diastolic function of cardiomyocytes.

2. Dosage Effects of Ranolazine

The study also found that the therapeutic effects of Ranolazine were dose-dependent. In HCM cardiomyocytes with moderate heart failure, the effective dose threshold of Ranolazine was 8 μM. When the dose was below 8 μM, improvements in electromechanical variables were not significant. However, increasing the dose beyond 8 μM did not substantially enhance the therapeutic effects.

3. Impact of Heart Failure Severity on Dosage Effects

The study further explored the dosage effects of Ranolazine under different severities of heart failure. The results showed: - Mild Heart Failure: The effective dose threshold was 2 μM. - Severe Heart Failure: The effective dose threshold increased to 9 μM.

This indicates that the effective dose threshold of Ranolazine is closely related to the severity of heart failure.

Conclusion

The study systematically investigated the electromechanical characteristics and dosage effects of Ranolazine on HCM failing cardiomyocytes using computational models. The findings revealed that Ranolazine, by inhibiting INaL, significantly improved electrophysiological abnormalities and diastolic function in HCM failing cardiomyocytes. Additionally, the therapeutic effects of Ranolazine were dose-dependent, with the effective dose threshold varying with the severity of heart failure. These findings provide a theoretical basis for understanding the therapeutic mechanisms of Ranolazine and offer important references for personalized clinical treatment.

Highlights of the Study

  1. Innovative Methodology: The research team developed a computational model incorporating electromechanical coupling, enabling more realistic simulation of cardiomyocyte physiology.
  2. Systematic Study of Dosage Effects: This is the first study to systematically investigate the dosage effects of Ranolazine under varying severities of heart failure using computational models.
  3. Clinical Significance: The study provides theoretical support for personalized treatment of HCM heart failure patients, aiding in the optimization of Ranolazine’s clinical use.

Research Value

This study not only deepens the understanding of Ranolazine’s therapeutic mechanisms but also provides important dosage references for clinical treatment. In the future, with the accumulation of more experimental data, the precision and applicability of the model will be further enhanced, offering more accurate guidance for the treatment of HCM heart failure patients.