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CLINICAL TRANSLATION WITH HUMAN CARDIAC TISSUE

CardioPRIME® is the AnaBios approach for measuring human cardiomyocyte functionality and sets the industry standard for cardiac-based biomedical research. By leveraging the robust excitation-contraction coupling of mature primary human cardiomyocytes and direct measurements of sarcomeric length, CardioPRIME offers unprecedented insight into cardiomyocyte functionality and provides clinically translatable measurements and biomarkers for proarrhythmia, inotropy, Ca2+ signaling, electrophysiology and cell health. 

INDUSTRY-LEADING PROARRHYTHMIA DETECTION USING HUMAN CARDIOMYOCYTES

As shown in the video below, adult primary cardiomyocytes dissociated from healthy human hearts are placed into optical recording chambers and stimulated at predefined frequencies. Sarcomeric shortening is measured and shown as deflections from baseline.

CardioPRIME harnesses fully functional human cardiomyocytes. The video above illustrates the CardioPRIME platform. Dissociated adult human primary cardiomyocytes are paced via extracellular field stimulation and the resulting sarcomeric shortening is measured. In this example, the cardiomyocyte is paced at 0.5, 1 and 2Hz and the resulting positive frequency-contraction relationship demonstrates the fully functional excitation-contraction process with physiological calcium handling and electromechanical coupling; processes that are often absent or limited in other cardiac models.

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USING CARDIOPRIME FOR PROARRHYTHMIA DETECTION

Proarrhythmia detection with CardioPRIME leverages the tight coupling between electrical events at the membrane and contraction and is illustrated in the figure below. Agents that prolong the action potential and/or cause proarrhythmogenic events such as early afterdepolarizations (EADs) are detected as prolongations and after contractions (AC) in the contractility waveform, respectively.  Using these and other waveform-based biomarkers, Nguyen and colleagues demonstrated an industry-leading predictivity rate of 96% for detecting proarrhythmia (Nguyen et al., 2017).  

Figure 1: Electromechanical Coupling Enables High-Fidelity
Proarrhythmia Detection

Figure 1: Top image, left panel: The action potential drives physical contraction and relaxation. Top panel, middle: Changes in the shape of the action potential, such as drug-induced prolongation, causes subsequent changes in the contractility waveform. Top panel right: Sentinel proarrhythmic triggers such as early-afterdepolarizations (EAD) are reflected in the contractility transient as after-contractions (AC).

Figure 1: Lower image: Real-world example of detecting proarrhythmia as demonstrated by the application of dof. (0.02µM) and AC generation (adapted from Nguyen et al., 2017). 

EARLY INSIGHT INTO POSITIVE & NEGATIVE INOTROPY

Modulating cardiac inotropy is a highly sought-after therapeutic endpoint for heart failure treatment while the appearance of unanticipated inotropic effects in other discovery efforts can halt clinical development. 

As shown in Figure 2 below, CardioPRIME and primary human cardiomyocytes can be used to detect both positive and negative inotropy across multiple mechanisms for both therapeutic drug discovery and safety testing. Vice President of Research & Development Dr. Najah Abi-Gerges and his colleagues recently write a publication for more complete analysis of detecting positive and negative inotropy (Abi-Gerges et al., 2020).  

The ability of CardioPRIME to reliably detect both positive and negative inotropic changes in primary human cardiomyocytes provides early insight into both efficacy and potential toxicities and offers clear translational value that overcomes limitations of stem cell models and avoids costly errors associated with cross-species translation.

Figure 2: Detecting Positive & Negative Inotropy Using Primary
Human Cardiomyocytes

The calcium channel blocker ver. (left), which is known to reduce cardiac contractility through Ca2+ channel block, elicits negative inotropy while milr. (middle) and isop. (right) elicit positive inotropic effects through the phosphodiesterase and b-adrenergic systems, respectively.  

MYOBLAZER: FOR INCREASED THROUGHPUT

MYOBLAZER™ is the proprietary higher throughput platform for CardioPRIME measurements across multiple cells at the same time. As illustrated in Figure 3 and 4 below, MYOBLAZER™ simultaneously visualizes, stimulates and analyzes multiple cardiomyocytes at the same time.  

Simultaneous compound application and data collection reduces experimental time, minimizes time-dependent variability, and increases data robustness which offers a clear advantage over true contractility platforms that rely on measurement of individual cells in a linear fashion.

Figure 3: Increased Throughput with Simultaneous Multi-Cell Recording

MyoBLAZER enables rapid data collection and assessment. Multiple cells are imaged at once in the video in Figure 3 above. In Figure 4 below, regions of interest are defined (left image) and data is simultaneously collected across all denoted cardiomyocytes (right image) 

Figure 4: Regions of Interest & simultaneous data collection
(CLICK IMAGES BELOW TO ENLARGE)
Figure 5: Ex Vivo Human cardiomyocytes ensure clinical translation

In Figure 5 above, cardiomyocytes from two different healthy donors demonstrate decreased sarcomeric shortening (negative inotropy) in response to application of the myosin inhibitor Mavacamten.

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