1. Cyber-physical modeling of implantable cardiac medical devices
Sol yoon
Ice, Dgist
Feb. 6th. 2012

2. outline Introduction Overview of model-based design
Background knowledge
Integrated Heart Model
Heart Model Validation
Pacemaker Model
Closed-loop case study
Conclusion

3. Introduction

4. The FDA and medical device software
FDA: need for rigorous real-time methodologies to validate and verify medical device software
The use of artificial implantable heart rhythm devices has grown rapidly over the recent decades
However, there is no formal methodology or platform to validate and verify the correct operation of medical device software
Software is reviewed by the FDA only in the incident of a device recall.
Implantable medical devices are a primary example of medical cyber-physical systems
Safety and efficacy of the device and device software must be evaluated within a closed-loop context of the patient

5. Current testing, validation, and verification
The primary approach is unit testing using a playback of prerecorded electrogram and electrocardiogram signals
April 2010, the FDA began the “Infusion Pump Improvement Initiative”
An effective verification methodology is needed for the risk analysis and certification of medical device software
Pacemaker mediated tachycardia (PMT)
A condition where the pacemaker inappropriately drives the heart rate toward the upper rate limit
Can be used for closed-loop system analysis

6. Methodology for closed-loop medical device safety
Developed an integrated functional and formal virtual heart model (VHM)
Clinically relevant
Timed automata based
Developed a pacemaker device model for interactive and clinically relevant test generation
A set of general and patient condition-specific pacemaker software requirement to ensure the safety
Provide a means to test and verify the closed-loop system
The atrial-ventricle synchrony must be enforced

7. Overview of model-based design

8. Previous heart modeling efforts
The model of the heart should capture the electrophysiological (EP) properties of the heart and generate functional signals
Conduction
Timing signal
The heart models have been developed to study the heart functions from the electrical and mechanical aspects.
Signal propagation, distortion, and attenuation
Cardiac output and valve mechanisms
EP: 전기가 생체에 끼치는 작용과 생체에서 발생하는 전기현상을 연구대상으로 하는 생리학을 일컫는다.
현재 정지전위와 흥분전위의 발견 및 이것이 세포막의 나트륨이온의 투과성에 의한 것이라는 결과 등이 발견 또는 연구되고 있다.

9. Requirements for model-based closed-loop V&V
Model fidelity: must cover the functioning heart
Normal sinus rhythm, sinus bradycardia, pacemaker mediated tachycardia, etc.
Simplicity
The heart model currently have hundreds of differential equations or millions of finite elements
Simulation of the models are time consuming and do not interact with medical devices
The VHM presents an abstraction of the timing and electrical conduction
Physical testbed
Enable to operate the heart on VHDL-based FPGA platform for black-box closed-loop testing
합니다.

10. Overview of the vhm approach
Platform provide two interface
A formal signal for medical device software
A functional electrogram for real device implementation
Functional interface (기능호출)를 통하여 들어간 heart model은 종합적인 심전도 시그널 생성에 의하여 closed-loop device validation을 수행할 수 있다.

11. Background knowledge

12. Background knowledge
The heart generates electrical impulses which organize the sequence of muscle contractions during each heart beat
The heart’s electrical timing is fundamental to proper cardiac function
The implantable cardiac pacemaker is a rhythm management device
Such devices have improved the condition of patients with cardiac arrhythmias
심장은 자발적으로 심박 동안 근육수축의 연속을 조직화하여 로 전기 impulse를 생성한다
심장의 electrical timing은 cardiac function의 기본이며
이러한 디바이스는 심장 부정맥을 가지고 있는 환자의 상태를 호전되게 할 수 있다.

13. Cellular-level action potential
The heart tissue can be activated by an external voltage applied to the cell
The upstroke of the action potential is called depolarization, which corresponds primarily to the inward flow of Na+ ions into the cell.
During depolarization, the muscle will contract and the voltage change caused by the depolarization will activate the cells nearby, which causes an activation wave across the heart.
After depolarization, there is a refractory period when ions flow out of the cell.
The voltage is them dropped down to resting potential.
During Effective refractory period, the cell cannot be activated due to the recovery process of the ion channels. So the activation wave will get blocked at the tissue during ERP.
During Relative Refractory period, the ion channels are partially recovered and the cell can be activated. However, the new action potential generated by the depolarization will have different shape,
Thus affecting the refractory periods of the tissue and conduction delay of the activation wave.

14. Electrical conduction system
The tissue at the sinoatrial node (SA) periodically and spontaneously self-depolarizes
The activation signal travels through both atria, causing contraction and pushes blood into the ventricles.
Then the activation is delayed at the atrioventricular (AV) node which allows the ventricles to fill fully
SA node is the primary and natural pacemaker of the heart

15. Cardiac arrhythmias
There are anomalies of the conduction and refractory properties in heart tissue
Bradycardia: failure of impulse generation with anomalies in the SA node and failure of impulse propagation
Tachycardia: impair hemodynamics caused by anomalies in SA node or reentry circuit
Reentry circuit: additional conduction pathways form a conduction loop with the primary conduction pathways

16. Arrhythmia diagnosis and treatment
electrophysiology (EP) testing
Catheters with multiple electrodes on the tip are inserted from the groin into the heart
Can locate timing anomalies, using the spatial information from catheter placement and the temporal information from the timing difference between the pulses
Ablation surgery can treat reentry circuit
Electrocardiography (ECG)
EP (전기 생리학 검사)
Blood vessel (혈관)
Local potential (국소전위)
Ablation: 전극도자자절제술, 전기를 이용하여 심장의 빈맥을 치료하는 수술. 심장의 여러부위에 전기자극을 주어 부정맥을 유발시켜 발생부위를 진단
P wave: 심방의 수축
QRS: depolarization of the 심실 (심실의 탈분극 현상)
T: refractory of the 심실 (심실의 면역기간)

17. Rhythm management devices
Implantable pacemakers have been developed to deliver timely electrical pulses to the heart to treat bradycardia
The pacemaker has two leads inserted into the heart
One in the right atrium
One in the right ventricle
By doing timing analysis of the electrogram (EGM) signals sensed from the two leads
Artificial pacemaker generates electrical pulses when necessary that can maintain ventricular rate
Enforce atrial-ventricular synchronization

18. Heart model

19. A brief overview of extended timed automata
VHM uses a timed-automata semantics, which is similar to the semantic extension used in UPPAAL
The electrical conduction system consists of conduction pathways with different conduction delays and refractory period
The refractory and conduction properties are all timing based, it is natural to model the electrical conduction system as a network of timed automata
Uppaal: validation and verification of real-time systems modeled as networks of timed automata

20. Modeling the electrical conduction system
Node automaton that models the refractory properties of heart tissue
𝑓 𝑡 =1− 𝑡 𝑇𝑟𝑟𝑝 , 𝑡≥1, 𝑡≥𝑇
𝑔 𝑥 = 𝑇 𝑚𝑖𝑛 + (1−(1−𝑥) 3 )∙ 𝑇 𝑚𝑎𝑥 − 𝑇 𝑚𝑖𝑛 , 𝑖=𝐴𝑉 𝑇 𝑚𝑖𝑛 + (1−𝑥) 3 ∙ 𝑇 𝑚𝑎𝑥 − 𝑇 𝑚𝑖𝑛 , 𝑖≠𝐴𝑉
𝑇 𝑚𝑖𝑛 and 𝑇 𝑚𝑎𝑥 are the minimum and maximum values for 𝑇𝑒𝑟𝑝 of the tissue

21. Modeling the electrical conduction system
(b) Path automaton that models the propagation properties of heart tissue
ℎ 𝑐 = 𝑝𝑎𝑡ℎ_𝑙𝑒𝑛/𝑣∙ 1+3𝑐 , 𝑖=𝐴𝑉 𝑝𝑎𝑡ℎ_𝑙𝑒𝑛/𝑣∙ 1+ 3𝑐 2 , 𝑖≠𝐴𝑉
𝑝𝑎𝑡ℎ_𝑙𝑒𝑛 denote the length of the path and vis the conduction velocity

22. Heart model validation

23. Electrophysiology study
Catheter Placement
The typical catheter positions used are high right atrium (HRA)
His bundle electrogram (HBE), which is placed across the valve between atrium and ventricle
Right ventricle apex (RVA), which is placed at the right ventricle apex to monitor electrical activity of the ventricle
Extrastimuli Technique
HRA catheter deliver external pacing signals faster than the intrinsic heart rate
The interval between two consecutive pacing signals is referred to as basic cycle length (BCL)
The interval between the extrastimulus and the last pacing signal of the pacing sequence is referred to as coupling interval
By decreasing the coupling interval gradually, the extrastimulus will reach the RRP of the tissue, causing changes in conduction delays
카테터 (도관)
이른 자극 기술: After the initial pacing sequence, another pacing signal이 배달되고 이것은 extrastimulus라고 한다.
Coupling interval: the length of time between an ectopic beat and the sinus beat preceding it; in an arrhythmia characterized by such beats, the intervals may be constant or inconstant

24. Clinical case study
Key interval values when the coupling interval shortens for a real patient
𝐴 2 , 𝐻 2 , 𝑉 2 are the pulse caused by the extrastimulus
The interval 𝐴 1 − 𝐴 2 is equal to the coupling interval
𝐻 1 − 𝐻 2 , 𝑉 1 − 𝑉 2 indicate conduction delay between the His bundle and the ventricle
Testing result of a real patient using the extrastimuli technique.
A: atrial, H: his bundle, V: ventricular pulses on the HBE electrogram
Caused by extrastimulus
Coupling interval

25. Vhm simulation
VHM is able to generate similar result with extrastimuli technique

26. Pacemaker model

27. Pacemaker model
The artificial pacemaker is designed for patients with bradycardia
Two leads, one in the right atrium and one in the right ventricle, are inserted into the heart
Two leads monitor the local activation of the atria and the ventricles, and generate corresponding sensed event (AS, VS) to its software
The software determines the heart condition by measuring time difference between events and delivers pacing events (AP, VP) to analog circuit
Analog circuit delivers pacing signals to the heart to maintain heart rate and A-V synchrony

28. Ddd pacemaker timing diagram
Five basic timing cycles which diagnose heart condition
Ventricle pace (LRI), ventricle sense (AVI)
Atrial pace (ARP), atrial sense (VRP)
Coordinator between the atrium and ventricle leads (URI)
Each task was assigned a period of 10 ms
* 인체의 혈액순환은 두 심실의 수축으로 인해 일어나는데, 우심실은 우심방에서 정맥혈을 받아 이것을 폐동맥으로 보내고 좌심실은 좌심방에서 동맥혈을 받아 이것을 대 동맥으로 보낸다.

29. Closed-loop case study

30. Endless loop tachycardia (ELT)
The ELT is induced by premature ventricular contraction (PVC), which is due to abnormal self-depolarization of ventricular tissue
건강한 심장에는 atria에서 ventricles까지 즉, SA node to AV node 오직 하나의 conduction path가 있다.
Ddd pacemaker의 ventricle sense (AVI) timer는 atrial lead 와 ventricular lead 사이에 또다른 virtual pathway가 있다.
V-A conduction은 AS(atrial sense) 를 유발하고, pacemaker은 TAVI 후 즉 A-V synchrony funtion 후, VP를 조절한다.

31. conclusion

32. Physical implementation
Can validate the closed-loop electrical interaction between the heart (FPGA) and pacemaker (FireFly node)

33. Conclusion and future work
A primary challenge in life-critical real-time systems is with the design of bug-free medical device software
Using timed automata
designed an integrated functional and formal model of the heart and pacemaker device
A real-time VHM has been developed to model the electrophysiological operation of the human heart