The reductionist approach has dominated the fields of biology and medicine for nearly a century. Here, we present a systems science approach to the analysis of physiological waveforms in the context of a specific case, cardiovascular physiology. Our goal in this study is to introduce a methodology that allows for novel insight into cardiovascular physiology and to show proof of concept for a new index for the evaluation of the cardiovascular system through pressure wave analysis. This methodology uses a modified version of sparse time-frequency representation (STFR) to extract two dominant frequencies we refer to as intrinsic frequencies (IFs; v 1 and v 2 ). The IFs are the dominant frequencies of the instantaneous frequency of the coupled heart þ aorta system before the closure of the aortic valve and the decoupled aorta after valve closure. In this study, we extract the IFs from a series of aortic pressure waves obtained from both clinical data and a computational model. Our results demonstrate that at the heart rate at which the left ventricular pulsatile workload is minimized the two IFs are equal (v 1 ¼ v 2 ). Extracted IFs from clinical data indicate that at young ages the total frequency variation (Dv ¼ v 1 2 v 2 ) is close to zero and that Dv increases with age or disease (e.g. heart failure and hypertension). While the focus of this paper is the cardiovascular system, this approach can easily be extended to other physiological systems or any biological signal.

Analysis of carotid waveforms using intrinsic frequency methods can be used to document left ventricular ejection fraction with accuracy comparable with that of MRI. The measurements require no training to perform or interpret, no calibration, and can be repeated at the bedside to generate almost continuous analysis of left ventricular ejection fraction without arterial cannulation.

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In this article, we offer an artificial intelligence method to estimate the carotid-femoral Pulse Wave Velocity (PWV) non-invasively from one uncalibrated carotid waveform measured by tonometry and few routine clinical variables. Since the signal processing inputs to this machine learning algorithm are sensor agnostic, the presented method can accompany any medical instrument that provides a calibrated or uncalibrated carotid pressure waveform. Our results show that, for an unseen hold back test set population in the age range of 20 to 69, our model can estimate PWV with a Root-Mean-Square Error (RMSE) of 1.12 m/sec compared to the reference method. The results convey the fact that this model is a reliable surrogate of PWV. Our study also showed that estimated PWV was significantly associated with an increased risk of CVDs.Cardiovascular diseases (CVDs) and stroke are among the major causes of death in the United States and the total cost related to them was more than $316 billion in 2011-2012 1,2 . New cardiovascular monitoring methods are urgently needed in order to limit the growing burden of CVDs. Arterial stiffening is one of the risk factors for CVDs 3,4 , which can be assessed non-invasively by calculating the carotid to femoral PWV 5 . This parameter is a gold standard of arterial stiffness, the rate at which pressure waves move down the aortic vessel 6 . Increased arterial stiffness is related to an increased risk of cardiovascular events; therefore, it has become an independent marker for CVDs 6,7 . Because of its clinical significance, there has been a surge in addressing arterial stiffness and PWV 8 . Arterial stiffness and its surrogates such as PWV have been suggested as one of the risk factors along with other biomarkers such as high cholesterol, diabetes, and left ventricular hypertrophy when cardiovascular risk is being evaluated 8 . Past studies have shown a strong correlation between PWV and the presence of CVDs 9-14 .Although carotid-femoral PWV measurement is non-invasive, this process is intrusive as it requires the waveform collection from inguinal region. Obtaining accurate carotid-femoral PWV measurements often requires a well-trained staff within a clinical setting 15 . The need of the medical community is an easy-to-use and non-intrusive method to measure carotid-femoral PWV with acceptable accuracy and precision; see ref. 16 .At the same time, recent advances in the field of artificial intelligence have opened up new areas and methods in creating novel modeling and predictive methods for clinical use 17 . The model and analysis in this paper are in accord to this path of introducing artificial intelligence to the field of medical sciences.In this study, a novel, easy-to-use, and non-invasive approach to estimate carotid-femoral PWV, from a single carotid waveform measurement, is explored. This method is based on the newly developed Intrinsic Frequency (IF) algorithm 18,19 . IF method solely needs one uncalibrated trace of a carotid, or aortic, pressure waveform. Our method takes an un...