Ary Goldberger

Harvard University | Harvard · Office of Technology Development

We introduce the concept of cardiac neuroautonomic renewability and a method for its quantification. This concept refers to the involuntary nervous system's capacity to improve cardiac control in response to restorative interventions, such as sleep. We used the change in heart rate fragmentation (ΔHRF), before sleep onset compared to after sleep te...

Background: Heart rate fragmentation (HRF), a new non-invasive metric quantifying cardiac neuroautonomic function, is associated with increasing age and cardiovascular disease. Since these are risk factors for cognitive decline and dementia, in the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether disrupted cardiac neuroautonomi...

Physiologic signals have properties across multiple spatial and temporal scales, which can be shown by the complexity-analysis of the coarse-grained physiologic signals by scaling techniques such as the multiscale. Unfortunately, the results obtained from the coarse-grained signals by the multiscale may not fully reflect the properties of the origi...

Heart rate fragmentation (HRF), a marker of abnormal sinoatrial dynamics, was shown to be associated with incident cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA). Here, we test the hypothesis that HRF is also associated with incident atrial fibrillation (AF) in the MESA cohort of participants who underwent in-home polysom...

This perspectives article discusses the use of a novel set of dynamical biomarkers in the assessment of biological versus chronological age. The basis for this development is a recently delineated property of altered sinoatrial pacemaker-neuroautonomic function, termed heart rate fragmentation (HRF). Fragmented rhythms manifest as an increase in th...

Complexity measures are intended to assess the cardiovascular system’s capacity to respond to stressors. We sought to determine if decreased BP complexity is associated with increased estimated risk as obtained from two standard instruments: the Society of Thoracic Surgeons’ (STS) Risk of Mortality and Morbidity Index and the European System for Ca...

Background: A major objective of precision medicine is the elucidation of non-invasive biomarkers of cardiovascular (CV) risk. Recently, we introduced a new dynamical marker of anomalous sino-atrial instability function, termed heart rate fragmentation (HRF), which outperformed traditional and nonlinear heart rate variability metrics in separating...

Background: We recently introduced the concept of heart rate fragmentation along with a set of metrics for its quantification. The term was coined to refer to an increase in the percentage of changes in heart rate acceleration sign, a dynamical marker of a type of anomalous variability. The effort was motivated by the observation that fragmentation...

Ideal for students and as a review for practicing clinicians, Goldberger's Clinical Electrocardiography explains the fundamentals of ECG interpretation and analysis, helping facilitate an understanding of rhythm disorders and the relevant clinical outcomes. The authors take readers through the nuts and bolts of ECG, using Dr. Ary Goldberger's award...

Background: Short-term heart rate variability (HRV) is most commonly attributed to physiologic vagal tone modulation. However, with aging and cardiovascular disease, the emergence of high short-term HRV, consistent with the breakdown of the neuroautonomic-electrophysiologic control system, may confound traditional HRV analysis. An apparent dynamica...

Conventional sleep analysis relies primarily on electroencephalogram (EEG) waveform features assessed in concert with eye movements, respiration and muscle tone. We explore a complementary "complexity domain" approach based on multiscale entropy (MSE) analysis of EEG signals and discuss its relationships to standard sleep analysis and to that based...

Background: Visual non-stress test interpretation lacks the optimal specificity and observer-agreement of an ideal screening tool for intrauterine fetal demise (IUFD) syndrome prevention. Computational methods based on traditional heart rate variability have also been of limited value. Complexity analysis probes properties of the dynamics of physi...

Briefly, the function MsPplots.m (version 1.0) starts with the original time series and employs a coarse-graining procedure to create a set of time series, each of which represents the system’s dynamics on a different time scale. Next, Poincaré (delay) plots are constructed (using the function dscatter.m by Robert Henson) for the original and the c...

Analysis of biomedical time series plays a key role in clinical management and basic investigation. However, most conventional monitors streaming data in real-time show only the most recent values, not referenced to past dynamics. The proposed visualization method (termed “data chromatix”) was developed to address this challenge by bringing memory...

Poincaré delay maps are widely used in the analysis of cardiac interbeat interval (RR) dynamics. To facilitate visualization of the structure of these time series, we introduce multiscale Poincaré (MSP) plots. Starting with the original RR time series, the method employs a coarse-graining procedure to create a family of time series, each of which r...

Electroencephalographic (EEG) signals present a myriad of challenges to analysis, beginning with the detection of artifacts. Prior approaches to noise detection have utilized multiple techniques, including visual methods, independent component analysis and wavelets. However, no single method is broadly accepted, inviting alternative ways to address...

Analysis of biomedical time series plays an essential role in clinical management and basic investigation. However, conventional monitors streaming data in real-time show only the most recent values, not referenced to past dynamics. We describe a chromatic approach to bring the ‘memory’ of the physiologic system’s past behavior into the current dis...

We introduce a generalization of multiscale entropy (MSE) analysis. The method is termed MSE n , where the subscript denotes the moment used to coarse-grain a time series. MSE μ , described previously, uses the mean value (first moment). Here, we focus on [Formula: see text], which uses the second moment, i.e., the variance. [Formula: see text] q...

Diabetes mellitus (DM) is one of the world's most prevalent medical conditions. Contemporary management focuses on lowering mean blood glucose values toward a normal range, but largely ignores the dynamics of glucose fluctuations. We probed analyte time series obtained from continuous glucose monitor (CGM) sensors. We show that the fluctuations in...

We propose that complex (nonlinear) fluctuations of hemodynamic variables including systemic blood pressure parameters) during cardiovascular surgery contain information relevant to risk assessment and intraoperative management. Preliminary analysis of a pilot study supports the feasibility and potential merits of performing a larger, prospective s...

Background The standard continuous glucose monitoring (CGM) output provides multiple graphical and numerical summaries. A useful adjunct would be a visualization tool that facilitates immediate assessment of both long- and short-term variability. Methods We developed an algorithm based on the mathematical method of delay maps to display CGM signal...

Physiologic signals, such as cardiac interbeat intervals, exhibit complex fluctuations. However, capturing important dynamical properties, including nonstationarities may not be feasible from conventional time series graphical representations. We introduce a simple-to-implement visualisation method, termed dynamical density delay mapping ("D3-Map"...

Continuous fetal heart rate (FHR) monitoring remains central to intrapartum care. However, advances in signal analysis are needed to increase its accuracy in diagnosis of fetal hypoxia. To determine whether FHR complexity, an index of multiscale variability, is lower among fetuses born with low (≤7.05) versus higher pH values, and whether this meas...

The physiologic relationship between slow-wave activity (SWA) (0-4Hz) on the electroencephalogram (EEG) and high-frequency (0.1-0.4Hz) cardiopulmonary coupling (CPC) derived from electrocardiogram (ECG) sleep spectrograms is not known. Because high-frequency CPC appears to be a biomarker of stable sleep, we tested the hypothesis that that slow-wave...

We found that heart rate (HR) complexity metrics such as sample entropy (SampEn) identified patients with trauma receiving lifesaving interventions (LSIs). We now aimed (1) to test a multiscale entropy (MSE) index, (2) to compare it to single-scale measures including SampEn, and (3) to assess different parameter values for calculation of SampEn and...

The loss of complexity in physiological systems may be a dynamical biomarker of aging and disease. In this study the effects of combined strength and endurance training compared with those of endurance training or strength training alone on heart rate (HR) complexity and traditional HR variability indices were examined in middle-aged women. 90 prev...

Correlations between the baseline and the change in HR indices at the exercise condition. (DOCX)

Correlations between the baseline and the change in HR indices at the resting condition. (DOCX)

Cerebrogenic ECG abnormalities, especially prominent T wave inversions and prolongation of the QT(U) interval, are well-described. Brady- and tachyarrhythmias, including polymorphic VT, have been also described in the setting of neurologic injury. We report an unusual case of a 22-year-old man who presented with idiopathic acute encephalopathy. His...

Background: Visuomotor abnormalities are common in aging and age-related disease, yet difficult to quantify. This study investigated the effects of healthy aging, sex, and handedness on the performance of a tracing task. Participants (n = 150, aged 21-95 years, 75 females) used a stylus to follow a moving target around a circle on a tablet compute...

An assessment of sleep quality and sleep disordered breathing is determined from the cardiopulmonary coupling between two physiological data series. In an embodiment, an R-R interval series is derived from an electrocardiogram (ECG) signal. The normal beats from the R-R interval series are extracted to produce a normal-to-normal (NN) interval serie...

An assessment of sleep quality and sleep disordered breathing is determined from cardiopulmonary coupling between two physiological data series. An R-R interval series is derived from an electrocardiogram (ECG) signal. The normal beats from the R-R interval series are extracted to produce a normal-to-normal interval series. The amplitude variations...

The Nautilus and the Spiral Curve of Learning “Patho-Phys,” not “Patho-Lists” Saltation: Learning by Leaps and Bounds Sketching: The Art of Learning Medicine Multisourcing Teaching: The Essential Path to Learning and Mastery Mini-Summary

With hospital medicine growing rapidly in both scale and complexity, the learning curve for students is steeper, while experienced physicians are often called upon to act as mentors and caregivers in areas outside their primary fields of expertise. Becoming a Consummate Clinician, an exciting new book in the series Hospital Medicine: Current Concep...

Clinical Use of EBM The Need to Look at Data Critically A New Paradigm? Limitations of RCTs Evidence-Based Medicine and Medical Science: Final Caveats Evidence-Based Medicine: Clinical Inertia and Exit Block Syndromes Mini-Summary

Semantic Bias and the Drugs You Prescribe Semantic Bias and Targeted Therapies Off-Target Effects Semantic Biochemical Bias Homeostasis Revisited Is the Body a Servomechanism Type of Machine? Mini-Summary

What is a Disease? Aging and Disease Primary Disease vs. Inadvertent Injury Internal Stress and Disease: The Caregiver Syndrome External Stress and Disease Defining Disease and Health: Alternative Approaches What is Health? Implications: General and Specific Syndromes within Syndromes A Self-Challenge Mini-Summary

Outliers: Clues or Ruse? Equine Hoofers and Bank Larceny: Time to Retire Two Outmoded Clinical “Pearls”? Etiologies and Applications Mini-Summary

Unexpected Sources of Variability Assessing Observer Variability Computer Interpretations Coping with Observer Variability A Related Caution: Cut-and-Paste Workups Final Note: When Seeing and Believing Diverge

The Hidden History of a History Adverse Effects Mini-Summary

Differential Diagnosis of Chest Discomfort Differential Diagnosis of Right Upper Quadrant Pain “n-Plus”: A Final Note on Crafting Differential Diagnoses Mini-Summary

Half Title Wiley Series Title Copyright Dedication Contents Preface Acknowledgments

Physical Exam and Hypothesis Testing General Appearance Revitalizing the Vital Signs Additional Lapses in Reporting the Vital Signs Under Pressure Finding Hidden Information in Vital Signs-More Advanced Analysis Replacing Semi- Or Pseudoquantitative Measures with More Useful Qualitative Measures Increasing Your Level of Certainty: Internal Confirma...

Defining Medical Errors: Do we Know them When we See Them? The Flip Side Errors that Fly Below the Radar Back to the Index Case Rounding Up Errors Mini-Summary

“Incidental” Findings Classification of Basic Lab Data Presentation of Lab Tests: The Two Major Problems Checking Primary Sources vs. Coping with Work (Over) Flow Pressures Mini-Summary

Evidence-based medicine is an evolutionary process, intended to foster and disseminate the best practice guidelines from an ongoing critical analysis of available data. An underaddressed challenge relates to detecting and correcting delays where the evidence supports, but fails to effect, a timely change in practice. An example pertains to serum di...

The purpose of this opening talk is to describe an example of recent progress in applying fractal concepts to biological systems. We first briefly review several biological systems, and then focus on the fractal features characterized by the long-range correlations found recently in DNA sequences containing non-coding material. We also discuss the...

Dysregulation of autonomic nervous system dynamics is important in the pathophysiology of cardiovascular risk in obstructive sleep apnea (OSA). Heart rate variability (HRV) and impedance cardiography measures can estimate autonomic activity but have not gained traction clinically. The hypothesis of this study was that even in a cohort of patients w...

PhysioNet provides free web access to over 50 collections of recorded physiologic signals and time series, and related open-source software, in support of basic, clinical, and applied research in medicine, physiology, public health, biomedical engineering and computing, and medical instrument design and evaluation. Its three components (PhysioBank,...

Major depression affects multiple physiologic systems. Therefore, analysis of signals that reflect integrated function may be useful in probing dynamical changes in this syndrome. Increasing evidence supports the conceptual framework that complex variability is a marker of healthy, adaptive control mechanisms and that dynamical complexity decreases...

Time irreversibility (asymmetry with respect to time reversal) is an important property of many time series derived from processes in nature. Some time series (e.g., healthy heart rate dynamics) demonstrate even more complex, multiscale irreversibility, such that not only the original but also coarse-grained time series are asymmetric over a wide r...

Abstract Sleep disruption is an important aspect of major depressive disorder but lacks an objective and inexpensive means of assessment. We evaluated the utility of electrocardiogram (ECG)-based cardiopulmonary coupling analysis to quantify physiologic sleep stability in patients with major depression. Relative to controls, unmedicated depressed p...

Studies of the genetics of obstructive sleep apnea may be facilitated by identifying intermediate traits with high heritability that quantify etiological pathways, such as those related to respiratory control. Electrocardiogram (ECG)-based sleep spectrograms, measuring the coupling between respiratory modulation of ECG QRS-wave amplitude and heart...

Balance during quiet stance involves the complex interactions of multiple postural control systems, which may degrade with frailty. The complexity of center of pressure (COP) dynamics, as quantified using multiscale entropy (MSE), during quiet standing is lower in older adults, especially those with falls. We hypothesized that COP dynamics from fra...

The electrocardiogram (ECG)-based sleep spectrogram generates a map of cardiopulmonary coupling based on heart rate variability and respiration derived from QRS amplitude variations. A distinct spectrographic phenotype, designated as narrow-band elevated low frequency coupling (e-LFC(NB)), has been associated with central apneas and periodic breath...

The growing impact of nonlinear science on biology and medicine is fundamentally changing our view of living organisms and disease processes. This book introduces the application to biomedicine of a broad range of interdisciplinary concepts from nonlinear dynamics, such as self-organization, complexity, coherence, stochastic resonance, fractals and...