New Paradigm in Sudden Cardiac Death Risk Stratification

New findings promise to have an impact on a range of areas in medicine, including sudden cardiac death (SCD) risk stratification. In this article we learn about PD2i technology, which uses a special algorithm to analyze 15 minutes of ECG data to predict SCD. Tell us about the PD2i technology (including the differences between the PD2i Analyzer, PD2i VS, and PD2i CA). PD2i is a measure of the degrees of freedom of one’s heart rate variability. This analysis can be used for different applications: measuring autonomic activity (PD2i Analyzer), assessing the need for an immediate life-saving intervention in trauma (PD2i Vital Sign, or PD2i VS), and predicting one’s risk of cardiac arrest/sudden cardiac death (PD2i CA). Describe some of the research that has been done so far. Intuitively it is known that the brain influences the heart rate. After all, we know our hearts can begin to race in concert with emotional highs and lows, and there are well known data regarding increased patient mortality in depressed or emotionally stressed patients. However, scientists have taken this understanding a step further. First, in the swine model, Vicor’s director of research and development James Skinner, PhD traced the cardiac innervation back to the brain in normal animals and found that if he stimulated along that tract, even as high up as its origin in the mesial frontal cortex, he could induce ventricular arrhythmias and ventricular fibrillation (VF) in animals with normal hearts. Conversely, if he severed all nerve connections, he could even tie off the left anterior descending artery and cause an acute myocardial infarction — a maneuver that causes VF frequently in pigs — and would never get VF. This suggested to him that while, clearly, VF occurs in the heart, it is initiated by the brain. In fact, recent human clinical data seems to confirm this. The National ICD Registry data has shown that >75% of patients who receive prophylactic ICDs based upon the combined MADIT II/SCD-HeFT criteria, which are in turn based upon having a cardiomyopathy, have never needed the ICD to fire for VT/VF. Conversely, it has been known for some time that almost 80% of people who have had SCD would not have met those implant criteria (i.e., they did not have a cardiomyopathy). All these data point to the fact that having a “bad heart” is neither necessary nor sufficient to produce VF. It is no wonder the situation of SCD risk stratification has recently been described as being in “disarray” by a growing number of cardiologists and electrophysiologists. Existing risk stratification technologies have been hampered by inadequate sensitivity and specificity, difficulty in performing tests, or both. Give us some background information about the creation of the PD2i technology. How did the PD2i come about? There are several known sensory-motor loops that control heart rate, such as temperature, pH, baroreceptor reflex, etc., and Dr. Skinner realized that their behavior, like many things in biology, is governed by a branch of mathematics called nonlinear dynamics (commonly referred to as “chaos theory”). Based upon the great physiologist Walter Canon’s cerebral defense theory and subsequent work looking at the nonlinear mathematics of heart rate variability (HRV), Dr. Skinner postulated that the degree of cooperativity among those sensory-motor loops would be reflected in the degrees of freedom of the HRV signal. It is the brain’s influence on the heart that causes the variations in heart rate in the first place. As we are discovering in many branches of biology and medicine, in healthy organisms there are multiple systems working in opposition and more or less independently (e.g., the sympathetic and parasympathetic nervous systems). If and when these systems begin to coordinate to a high degree, it is a sign that the organism is not doing well — think of it as the brain marshalling the forces to work together to keep the organism alive. Unfortunately, the price we pay for this “hyper-coordination” is a tendency for the brain-heart innervation described above to activate in a way that can lead to VF. Those individuals who have the capability to hyper-coordinate can produce VF while those who cannot, will not. Therefore, Dr. Skinner refined an existing measure of the degrees of freedom of a system, calling it the “point correlation dimension” or PD2i, and showed that it measures the degrees of freedom of a system much more accurately than competing methods. In addition, the results are exceedingly simple to interpret — either the minimum PD2i recorded is below the predetermined cutoff (positive result) or it is not (negative result). What are the benefits of this system? Vicor Technologies has published clinical trial data using PD2i as a predictor of SCD, showing it to be highly accurate, with a sensitivity approaching 100% and a specificity of ~86%. All that is required to conduct the analysis is a recording of 1,000 heart beats in sinus rhythm — approximately 15 minutes of ECG at resting heart rates. The algorithm can use recordings made at rest and is relatively impervious to noise and non-stationarities in the data. This has helped set it apart from other nonlinear measures and seems to account for its unparalleled accuracy. How will this technology affect patient risk stratification for sudden cardiac death? Could this possibly reduce the amount of patients who receive ICDs? We believe PD2i can have a very positive effect on risk stratification for SCD. Our data, thus far, suggest that those patients with a negative result are at a low risk of SCD for now and may not need an ICD (at least for the time being); conversely, those patients who test positive appear to be at significant risk of SCD and may benefit from an ICD. Keep in mind that one can argue that everyone (or at least most) of the 300,000 to 500,000 SCD victims each year should have had an ICD in place to prevent them from dying suddenly. As such, it’s unclear whether the total number of ICD implants will decrease, but PD2i may certainly allow physicians to better target who gets an ICD, ensuring that those who really need one do get one and that those who don’t need one do not. When will the clinical trial for the PD2i CA be complete? What is the next step? We are currently hoping to complete enrollment by early 2010. We are also going to be looking at some large retrospective data sets, which may have an impact even sooner. What are some of the ways in which the PD2i is being used? Vicor was recently contacted by the U.S. Army. They were looking for predictors of severity of injury in combat casualties to assist in the triage process. Just as in the SCD prediction arena, they found that a nonlinear dynamics approach to HRV seemed to offer the best hope, yet they found that the measures they were using did not perform well in real-life conditions of noisy data. Moreover, unlike in SCD prediction, trauma victims need to be assessed rapidly so whatever measure is chosen needs to be able to work on data sets of limited duration. The PD2i was able to accurately identify retrospectively those patients who needed life-saving interventions, using noisy data and as little as 200 heart beats — around 90 seconds of data in a tachycardic, injured patient. Moreover, further studies showed that by continuously calculating PD2i values in a “rolling window fashion,” one can track the progress through treatment, thus potentially providing physicians with a parameter to follow as they initiate treatment. This also opens up the possibility of a new parameter for intra-operative and ICU monitoring. Again, the idea behind all of these applications is the same as with SCD, only on a more acute scale — the sicker the patient is, the more the brain needs to “marshal the forces” of the various compensatory mechanisms to keep him or her alive, and the PD2i can measure that. Is there anything else you’d like to add? Regarding SCD risk stratification, we hope to lead a not-so-quiet revolution in our understanding of the interplay between the brain and the heart, resulting in better tools for physicians to use in treating their patients. About the Author Dr. Weiss is chief medical officer of Vicor Technologies, Inc. Formerly, Dr. Weiss served as medical director of the electrophysiology laboratory of the Boca Raton Community Hospital in Boca Raton and was a partner at Florida Arrhythmia Consultants. He has served as a consultant to Fortune 500 medical device manufacturers such as Medtronic, St. Jude Medical, and Guidant. He also served as a clinical investigator in the two most important clinical trials involving the study of ICDs and SCD: the MADIT II (Multicenter Automatic Defibrillator Implantation Trial) and SCD-HeFT (Sudden Cardiac Death Heart Failure Trial). Dr. Weiss earned his MD (with Distinction in Research) from the Mount Sinai School of Medicine in New York, from which he also received the Nathan A. Setz Award for Research in Cardiovascular and Renal Disease. He holds a BSE, cum laude, in Electrical Engineering and Computer Science from Princeton University.