Scalability of cardiovascular intrinsic frequencies: Validations in preclinical models and non-invasive clinical studies.

AIMS: Cardiovascular intrinsic frequencies (IFs) are associated with cardiovascular health and disease, separately capturing the systolic and diastolic information contained in a single (uncalibrated) arterial waveform. Previous clinical investigations related to IF have been restricted to studying chronic conditions, and hence its applicability for acute cardiovascular diseases has not been explored. Studies of cardiovascular complications such as acute myocardial infarction are difficult to perform in humans due to the high-risk and invasive nature of such procedures. Although they can be performed in preclinical (animal) models, the corresponding interpretation of IF measures and how they ultimately translate to humans is unknown. Hence, we studied the scalability of IF across species and sensor platforms. MATERIALS AND METHODS: Scaled values of the two intrinsic frequencies ω1 and ω2 (corresponding to systolic and diastolic dynamics, respectively) were extracted from carotid waveforms acquired either non-invasively (via tonometry, Vivio or iPhone) in humans or invasively in rabbits and rats. KEY FINDINGS: The scaled IF parameters for all species were found to fall within the same physiological ranges carrying similar statistical characteristics, even though body sizes and corresponding heart rates of the species were substantially different. Additionally, results demonstrated that all non-invasive sensor platforms were significantly correlated with each other for scaled IFs, suggesting that such analysis is device-agnostic and can be applied to upcoming wearable technologies. SIGNIFICANCE: Ultimately, our results found that IFs are scalable across species, which is particularly valuable for the training of IF-based artificial intelligence systems using both preclinical and clinical data.

Intrinsic Frequencies of Carotid Pressure Waveforms Predict Heart Failure Events: The Framingham Heart Study.

Intrinsic frequencies (IFs) derived from arterial waveforms are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures is unknown. We hypothesized that IFs are associated with incident CVD risk. Our sample was drawn from the Framingham Heart Study Original, Offspring, and Third Generation Cohorts and included participants free of CVD at baseline (N=4700; mean age 52 years, 55% women). We extracted 2 dominant frequencies directly from a series of carotid pressure waves: the IF of the coupled heart and vascular system during systole (ω1) and the IF of the decoupled vasculature during diastole (ω2). Total frequency variation (Δω) was defined as the difference between ω1 and ω2. We used Cox proportional hazards regression models to relate IFs to incident CVD events during a mean follow-up of 10.6 years. In multivariable models adjusted for CVD risk factors, higher ω1 (hazard ratio [HR], 1.14 [95% CI], 1.03-1.26]; P=0.01) and Δω (HR, 1.16 [95% CI, 1.03-1.30]; P=0.02) but lower ω2 (HR, 0.87 [95% CI, 0.77-0.99]; P=0.03) were associated with higher risk for incident composite CVD events. In similarly adjusted models, higher ω1 (HR, 1.23 [95% CI, 1.07-1.42]; P=0.004) and Δω (HR, 1.26 [95% CI, 1.05-1.50]; P=0.01) but lower ω2 (HR, 0.81 [95% CI, 0.66-0.99]; P=0.04) were associated with higher risk for incident heart failure. IFs were not significantly associated with incident myocardial infarction or stroke. Novel IFs may represent valuable markers of heart failure risk in the community.

A wireless optical handheld device for carotid waveform measurement and its validation in a clinical study.

OBJECTIVE: Here we introduce Vivio, a wireless optical tonometer, and compare its pulse waveform measurement capabilities to the AtCor SphygmoCor. APPROACH: Pulse waveform data from both devices was captured on a heterogeneous cohort of 29 participants (15 males, 14 females), including 16 healthy individuals free from cardiovascular diseases and 13 patients with one or more cardiovascular diseases. These participants were a subgroup of the Huntington Medical Research Institutes (HMRI) iPhone Heart Study. Main r esults: Carotid pulse waveforms captured by Vivio were comparable to those captured using the AtCor SphygmoCor tonometer. The point-by-point root-mean-square error between averaged waveforms captured by either device on the same participant was 6.3% with a standard deviation of 2%. The harmonic content of the pulse waveforms captured by either device was also similar. Data collected by Vivio displayed good to excellent agreement across a wide range of pulse waveform features such as left ventricular ejection time, reflected wave arrival time, the ratio of systolic to diastolic time intervals, and heart rate. A comparison between augmentation index (AI) measured by Vivio and tonometry showed a correlation of 0.82 (p < 0.01). Bland-Altman analysis of this data yielded a bias of -2.5% and limits of agreement spanning -15.1%-10.1%. SIGNIFICANCE: The Vivio has the potential to enhance the availability of noninvasive pulse waveform data, thereby expanding the tools available for the diagnosis and monitoring of cardiovascular disease. When used in combination with advanced waveform analysis methods, Vivio can impact mobile healthcare resulting in improved patient health, quality of life and the overall reduction of healthcare costs.

Proof-of-concept for a non-invasive, portable, and wireless device for cardiovascular monitoring in pediatric patients.

Measurement of cardiac function is vital for the health of pediatric patients with heart disease. Standard tools to measure function including echocardiogram and magnetic residence imaging are time intensive, costly, and have limited accessibility. The Vivio is a novel, non-invasive, handheld device that screens for cardiac dysfunction by analyzing intrinsic frequencies (IF) ω1 and ω2 of carotid artery waveforms. Prior studies demonstrated that left ventricular ejection fraction can be derived from IFs in adults. This study 1) studies whether the Vivio can capture carotid arterial pulse waveform data in children ages 0-19 years old; 2) tests the performance of two sensor head geometries, one larger and smaller than the standard size used in adults, designed for the pediatric population; 3) compares the IFs between pediatric age groups and adults with normal function. The Vivio successfully measured a carotid artery waveform in all children over 5 years old and 28% of children under the age of five. The small head did not accurately measure a waveform in any age group. One-way analysis of variance (ANOVA) demonstrated a difference in the IF ω1 between the adult and pediatric cohorts (F = 7.3, Prob>F = 0.0001). Post host analysis demonstrated a difference between the adult cohort (ω1 = 99 +/- 5 bpm) and the cohorts ages 0-4 (ω1 = 111 +/- 2 bpm; p = 0.0006) and 15-19 years old (ω1 = 105 +/-5 bpm; p = 0.02). One-way ANOVA demonstrated a difference in the IF ω2 between the adult and pediatric cohorts (F = 4.8, Prob>F = 0.003), specifically between the adult (ω2 = 81 +/- 13 bpm) and age 0-4 cohorts (ω2 = 48 +/- 8 bpm; p = 0.002). These results suggest that the Vivio can be used to capture carotid pulse waveform data in pediatric populations and that the data produced can be used to measure intrinsic frequencies.

Accuracy of a Novel Handheld Wireless Platform for Detection of Cardiac Dysfunction in Anthracycline-Exposed Survivors of Childhood Cancer.

Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference).Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland-Altman plots. Linear regression was used to evaluate proportional bias.Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2-44); median anthracycline dose: 225 mg/m2 (25-642)]. Echocardiography overestimated mean EF by 4.9% (P < 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR (t = 3.1, P < 0.001). There was no difference between mean EF derived from Vivio and from CMR (-0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF < 45% (sensitivity 14.3%), Echo EF < 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF < 45% or EF < 50% (sensitivity 85.7%)].Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 24(13); 3119-25. ©2018 AACR.

Experimental Investigation of the Effect of Non-Newtonian Behavior of Blood Flow in the Fontan Circulation.

The Fontan procedure for univentricular heart defects creates a unique circulation where all pulmonary blood flow is passively supplied directly from systemic veins. Computational simulations, aimed at optimizing the surgery, have assumed blood to be a Newtonian fluid without evaluating the potential error introduced by this assumption. We compared flow behavior between a non-Newtonian blood analog (0.04% xanthan gum) and a control Newtonian fluid (45% glycerol) in a simplified model of the Fontan circulation. Particle image velocimetry was used to examine flow behavior at two different cardiac outputs and two caval blood flow distributions. Pressure and flow rates were measured at each inlet and outlet. Velocity, shear strain, and shear stress maps were derived from velocity data. Power loss was calculated from pressure, flow, and velocity data. Power loss was increased in all test conditions with xanthan gum vs. glycerol (mean 10±2.9% vs. 5.6±1.3%, p=0.032). Pulmonary blood flow distribution differed in all conditions, more so at low cardiac output. Caval blood flow mixing patterns and shear stress were also qualitatively different between the solutions in all conditions. We conclude that assuming blood to be a Newtonian fluid introduces considerable error into simulations of the Fontan circulation, where low-shear flow predominates.

Noninvasive iPhone Measurement of Left Ventricular Ejection Fraction Using Intrinsic Frequency Methodology.

OBJECTIVE: The study is based on previously reported mathematical analysis of arterial waveform that extracts hidden oscillations in the waveform that we called intrinsic frequencies. The goal of this clinical study was to compare the accuracy of left ventricular ejection fraction derived from intrinsic frequencies noninvasively versus left ventricular ejection fraction obtained with cardiac MRI, the most accurate method for left ventricular ejection fraction measurement. DESIGN: After informed consent, in one visit, subjects underwent cardiac MRI examination and noninvasive capture of a carotid waveform using an iPhone camera (The waveform is captured using a custom app that constructs the waveform from skin displacement images during the cardiac cycle.). The waveform was analyzed using intrinsic frequency algorithm. SETTING: Outpatient MRI facility. SUBJECTS: Adults able to undergo MRI were referred by local physicians or self-referred in response to local advertisement and included patients with heart failure with reduced ejection fraction diagnosed by a cardiologist. INTERVENTIONS: Standard cardiac MRI sequences were used, with periodic breath holding for image stabilization. To minimize motion artifact, the iPhone camera was held in a cradle over the carotid artery during iPhone measurements. MEASUREMENTS AND MAIN RESULTS: Regardless of neck morphology, carotid waveforms were captured in all subjects, within seconds to minutes. Seventy-two patients were studied, ranging in age from 20 to 92 years old. The main endpoint of analysis was left ventricular ejection fraction; overall, the correlation between ejection fraction-iPhone and ejection fraction-MRI was 0.74 (r = 0.74; p < 0.0001; ejection fraction-MRI = 0.93 × [ejection fraction-iPhone] + 1.9). CONCLUSIONS: 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.

Intrinsic Frequency and the Single Wave Biopsy: Implications for Insulin Resistance.

Insulin resistance is the hallmark of classical type II diabetes. In addition, insulin resistance plays a central role in metabolic syndrome, which astonishingly affects 1 out of 3 adults in North America. The insulin resistance state can precede the manifestation of diabetes and hypertension by years. Insulin resistance is correlated with a low-grade inflammatory condition, thought to be induced by obesity as well as other conditions. Currently, the methods to measure and monitor insulin resistance, such as the homeostatic model assessment and the euglycemic insulin clamp, can be impractical, expensive, and invasive. Abundant evidence exists that relates increased pulse pressure, pulse wave velocity (PWV), and vascular dysfunction with insulin resistance. We introduce a potential method of assessing insulin resistance that relies on a novel signal-processing algorithm, the intrinsic frequency method (IFM). The method requires a single pulse pressure wave, thus the term " wave biopsy."

On the convergence and accuracy of the cardiovascular intrinsic frequency method.

In this paper, we analyse the convergence, accuracy and stability of the intrinsic frequency (IF) method. The IF method is a descendant of the sparse time frequency representation methods. These methods are designed for analysing nonlinear and non-stationary signals. Specifically, the IF method is created to address the cardiovascular system that by nature is a nonlinear and non-stationary dynamical system. The IF method is capable of handling specific nonlinear and non-stationary signals with less mathematical regularity. In previous works, we showed the clinical importance of the IF method. There, we showed that the IF method can be used to evaluate cardiovascular performance. In this article, we will present further details of the mathematical background of the IF method by discussing the convergence and the accuracy of the method with and without noise. It will be shown that the waveform fit extracted from the signal is accurate even in the presence of noise.

Intrinsic frequency for a systems approach to haemodynamic waveform analysis with clinical applications.

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; ω1 and ω2). The IFs are the dominant frequencies of the instantaneous frequency of the coupled heart + 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 (ω1 = ω2). Extracted IFs from clinical data indicate that at young ages the total frequency variation (Δω = ω1 - ω2) is close to zero and that Δω 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.

Controlled partial embedding of carbon nanotubes within flexible transparent layers.

Applications of carbon nanotubes (CNTs) like field emission displays, super-capacitors, and cell growth scaffolds can benefit from controllable embedding of the CNTs in a material such that the CNTs are anchored and protrude a desired length. We demonstrate a simple method for anchoring densely packed, vertically aligned arrays of CNTs into silicone layers using spin-coating, CNT insertion, curing, and growth substrate removal. CNT arrays of 51 and 120 µm in height are anchored into silicone layers of thickness 26 and 36 µm, respectively. Scanning electron microscopy (SEM) and optical microscopy are used to characterize the sample morphology, a 5.5 m s(-1) impinging water jet is used to apply shear stress, and a tensile test shows that the silicone layer detaches from the substrate before the CNTs are ripped from the layer. The CNTs are thus well anchored in the silicone layers. The spin-coating process gives control over layer thickness, and the method should have general applicability to various nanostructures and anchoring materials.