Survival and Neurologic Outcomes From Pharmacologic Peptide Administration During Cardiopulmonary Resuscitation of Pulseless Electrical Activity.

BACKGROUND: Outcomes from cardiopulmonary resuscitation (CPR) following sudden cardiac arrest are suboptimal. Postresuscitation targeted temperature management has been shown to have benefit in subjects with sudden cardiac arrest due to ventricular fibrillation, but there are few data for outcomes from sudden cardiac arrest due to pulseless electrical activity. In addition, intra-CPR cooling is more effective than postresuscitation cooling. Physical cooling is associated with increased protein kinase B activity. Therefore, our group developed a novel peptide, TAT-PHLPP9c, which regulates protein kinase B. We hypothesized that when given during CPR, TAT-PHLPP9c would improve survival and neurologic outcomes following pulseless electrical activity arrest. METHODS AND RESULTS: In 24 female pigs, pulseless electrical activity was induced by inflating balloon catheters in the right coronary and left anterior descending arteries for ≈7 minutes. Advanced life support was initiated. In 12 control animals, epinephrine was given after 1 and 3 minutes. In 12 peptide-treated animals, 7.5 mg/kg TAT-PHLPP9c was also administered at 1 and 3 minutes of CPR. The balloons were removed after 2 minutes of support. Animals were recovered and neurologically scored 24 hours after return of spontaneous circulation. Return of spontaneous circulation was more common in the peptide group, but this difference was not significant (8/12 control versus 12/12 peptide; P=0.093), while fully intact neurologic survival was significantly more common in the peptide group (0/12 control versus 11/12 peptide; P<0.00001). TAT-PHLPP9c significantly increased myocardial nicotinamide adenine dinucleotide levels. CONCLUSIONS: TAT-PHLPP9c resulted in improved survival with full neurologic function after sudden cardiac arrest in a swine model of pulseless electrical activity, and the peptide shows potential as an intra-CPR pharmacologic agent.

Comparison Between a Single-Lead ECG Garment Device and a Holter Monitor: A Signal Quality Assessment.

Wearable electronics are increasingly common and useful as health monitoring devices, many of which feature the ability to record a single-lead electrocardiogram (ECG). However, recording the ECG commonly requires the user to touch the device to complete the lead circuit, which prevents continuous data acquisition. An alternative approach to enable continuous monitoring without user initiation is to embed the leads in a garment. This study assessed ECG data obtained from the YouCare device (a novel sensorized garment) via comparison with a conventional Holter monitor. A cohort of thirty patients (age range: 20-82 years; 16 females and 14 males) were enrolled and monitored for twenty-four hours with both the YouCare device and a Holter monitor. ECG data from both devices were qualitatively assessed by a panel of three expert cardiologists and quantitatively analyzed using specialized software. Patients also responded to a survey about the comfort of the YouCare device as compared to the Holter monitor. The YouCare device was assessed to have 70% of its ECG signals as "Good", 12% as "Acceptable", and 18% as "Not Readable". The R-wave, independently recorded by the YouCare device and Holter monitor, were synchronized within measurement error during 99.4% of cardiac cycles. In addition, patients found the YouCare device more comfortable than the Holter monitor (comfortable 22 vs. 5 and uncomfortable 1 vs. 18, respectively). Therefore, the quality of ECG data collected from the garment-based device was comparable to a Holter monitor when the signal was sufficiently acquired, and the garment was also comfortable.

Electrocardiogram Monitoring Wearable Devices and Artificial-Intelligence-Enabled Diagnostic Capabilities: A Review.

Worldwide, population aging and unhealthy lifestyles have increased the incidence of high-risk health conditions such as cardiovascular diseases, sleep apnea, and other conditions. Recently, to facilitate early identification and diagnosis, efforts have been made in the research and development of new wearable devices to make them smaller, more comfortable, more accurate, and increasingly compatible with artificial intelligence technologies. These efforts can pave the way to the longer and continuous health monitoring of different biosignals, including the real-time detection of diseases, thus providing more timely and accurate predictions of health events that can drastically improve the healthcare management of patients. Most recent reviews focus on a specific category of disease, the use of artificial intelligence in 12-lead electrocardiograms, or on wearable technology. However, we present recent advances in the use of electrocardiogram signals acquired with wearable devices or from publicly available databases and the analysis of such signals with artificial intelligence methods to detect and predict diseases. As expected, most of the available research focuses on heart diseases, sleep apnea, and other emerging areas, such as mental stress. From a methodological point of view, although traditional statistical methods and machine learning are still widely used, we observe an increasing use of more advanced deep learning methods, specifically architectures that can handle the complexity of biosignal data. These deep learning methods typically include convolutional and recurrent neural networks. Moreover, when proposing new artificial intelligence methods, we observe that the prevalent choice is to use publicly available databases rather than collecting new data.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Algorithm for Mobile Platform-Based Real-Time QRS Detection.

Recent advancements in smart, wearable technologies have allowed the detection of various medical conditions. In particular, continuous collection and real-time analysis of electrocardiogram data have enabled the early identification of pathologic cardiac rhythms. Various algorithms to assess cardiac rhythms have been developed, but these utilize excessive computational power. Therefore, adoption to mobile platforms requires more computationally efficient algorithms that do not sacrifice correctness. This study presents a modified QRS detection algorithm, the AccYouRate Modified Pan-Tompkins (AMPT), which is a simplified version of the well-established Pan-Tompkins algorithm. Using archived ECG data from a variety of publicly available datasets, relative to the Pan-Tompkins, the AMPT algorithm demonstrated improved computational efficiency by 5-20×, while also universally enhancing correctness, both of which favor translation to a mobile platform for continuous, real-time QRS detection.

Implantable Defibrillator System Shock Function, Mortality, and Cause of Death After Magnetic Resonance Imaging.

BACKGROUND: Studies have shown that magnetic resonance imaging (MRI) does not have clinically important effects on the device parameters of non-MRI-conditional implantable cardioverter-defibrillators (ICDs). However, data on non-MRI-conditional ICD detection and treatment of arrhythmias after MRI are limited. OBJECTIVE: To examine if non-MRI-conditional ICDs have preserved shock function of arrhythmias after MRI. DESIGN: Prospective cohort study. (ClinicalTrials.gov: NCT01130896). SETTING: 1 center in the United States. PATIENTS: 629 patients with non-MRI-conditional ICDs enrolled consecutively between February 2003 and January 2015. INTERVENTIONS: 813 total MRI examinations at a magnetic field strength of 1.5 Tesla using a prespecified safety protocol. MEASUREMENTS: Implantable cardioverter-defibrillator interrogations were collected after MRI. Clinical outcomes included arrhythmia detection and treatment, generator or lead exchanges, adverse events, and death. RESULTS: During a median follow-up of 2.2 years from MRI to latest available ICD interrogation before generator or lead exchange in 536 patients, 4177 arrhythmia episodes were detected, and 97 patients received ICD shocks. Sixty-one patients (10% of total) had 130 spontaneous ventricular tachycardia or fibrillation events terminated by ICD shocks. A total of 210 patients (33% of total) are known to have died (median, 1.7 years from MRI to death); 3 had cardiac arrhythmia deaths where shocks were indicated without direct evidence of device dysfunction. LIMITATIONS: Data were acquired at a single center and may not be generalizable to other clinical settings and MRI facilities. Implantable cardioverter-defibrillator interrogations were not available for a subset of patients; adjudication of cause of death relied solely on death certificate data in a subset. CONCLUSION: Non-MRI-conditional ICDs appropriately treated detected tachyarrhythmias after MRI. No serious adverse effects on device function were reported after MRI. PRIMARY FUNDING SOURCE: Johns Hopkins University and National Institutes of Health.

Ankle-Brachial Index and Energy Production in People Without Peripheral Artery Disease: The BLSA.

Background Lower ankle-brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross-sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown. Method and Results We analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow-up (mean follow-up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant (kPCr) from phosphorus-31 magnetic resonance spectroscopy. Greater kPCr indicated higher mitochondrial oxidative capacity. Although kPCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change (Change) of left and right ABI and kPCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline kPCr, both left and right baseline ABI, and ABI change in both legs, (kPCr)Change was directly associated with ipsilateral (left) (ABI)Change (standardized [STD]-ß=0.14; P=0.0168) but not with contralateral (right) (ABI)Change (P=0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD-ß=0.18; P=0.0051). (kPCr)Change was steeper in White race participants (STD-ß=0.16; P=0.0122) and body mass index (STD-ß=0.13; P=0.0479). There was no significant association with current smoking status (P=0.63), fasting glucose (P=0.28), heart rate (P=0.67), mean blood pressure (P=0.78), and low-density lipoprotein (P=0.75), high-density lipoprotein (P=0.82), or triglycerides (P=0.15). Conclusions In people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.

Reduced motion external defibrillation: Reduced subject motion with equivalent defibrillation efficiency validated in swine.

BACKGROUND: External defibrillators are used for arrhythmia cardioversion and for defibrillating during cardiac arrest. During defibrillation, short-duration biphasic pulses cause intense motion due to rapid chest-wall muscle contraction. A reduced motion external defibrillator (RMD) was constructed by integrating a commercial defibrillator with a Tetanizing-waveform generator. A long-duration, low-amplitude, tetanizing waveform slowly stimulated the chest musculature before the biphasic pulse, reducing muscle contraction during the shock. OBJECTIVE: The purpose of this study was to evaluate RMD defibrillation in swine for subject motion during defibrillation pulses and for defibrillation effectiveness. RMD defibrillation can reduce the duration of arrhythmia ablation therapy or simplify cardioversion procedures. METHODS: The tetanizing unit delivered a triangular 1-kHz pulse of 0.25- to 2.0-second duration and 10- to 100-V peak amplitude, subsequently triggering the conventional defibrillator to output standard 1- to 200-J energy biphasic pulses at the next R wave. Forward limb motion was evaluated by measuring peak acceleration and limb work during RMD (tetanizing + biphasic) or biphasic pulse-only waveforms at 10-3-second sampling rate. Seven swine were arrested electrically and subsequently defibrillated. Biphasic pulse-only and RMD defibrillations were repeated 25-35 times per swine, varying tetanizing parameters and biphasic pulse energy. Defibrillation thresholds (DFTs) were established by measuring the minimum energy required to restore sinus rhythm with biphasic pulse-only or RMD defibrillations. RESULTS: Two forward-limb acceleration peaks occurred during both the tetanizing waveform and biphasic pulse, indicating rapid and slower nociceptic (pain sensation) nerve fiber activation. Optimal RMD tetanizing parameters (25-35 V, 0.25- to 0.75-second duration), relative to biphasic pulse-only defibrillations, resulted in 74% ± 10% smaller peak accelerations and 85% ± 10% reduced limb work. DFT energies were identical when comparing RMD to biphasic pulse-only defibrillations. CONCLUSION: Relative to conventional defibrillations, RMD defibrillations maintain rhythm restoration efficiency with drastically reduced subject motion.

Closed cranial window rodent model for investigating hemodynamic response to elevated intracranial pressure.

Background: Elevated intracranial pressure (ICP) occurs in several physiological and pathological conditions, yet long-term sequellae are not common, which implies that blood flow is preserved above ischemic thresholds. Methods: This pilot study sought to confirm this hypothesis using a closed cranial window model in a rat in which ICP was elevated to 120 mmHg for 12 min, and superficial cortical perfusion was measured by laser Doppler flowmetry and laser speckle flowmetry. Results: Following a transient increase, cortical blood flow decreased to between 25% and 75% of baseline. These levels correspond to disrupted metabolism and decreased protein synthesis but did not exceed thresholds for electrical signaling or membrane integrity. This may partially explain how some episodes of elevated ICP remain benign. Conclusion: The closed cranial window model provides a platform for prospective study of physiologic responses to artificially elevated ICP during neurosurgery to promote hemostasis.

Sex Differences in Longitudinal Determinants of Carotid Intima Medial Thickening With Aging in a Community-Dwelling Population: The Baltimore Longitudinal Study on Aging.

Background Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age-associated hemodynamic alterations in men and in women are not fully explored. Methods and Results We analyzed repeated measures of IMT, blood pressure, and carotid-femoral pulse wave velocity over a 20-year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease. Linear mixed-effects models were used to calculate the individual rates of change (Change) of IMT, pulse pressure, mean arterial pressure, and pulse wave velocity, among other covariates. Multivariate regression analysis was used to examine the association of IMTChange with baseline and rates of change of hemodynamic parameters and cardiovascular risk factors. IMT increased at accelerating rates from 0.02 mm/decade at age 50 years to 0.05 mm/decade at age 80 years greater rates in men than in women. IMTChange was positively associated with baseline low-density lipoprotein, low-density lipoproteinChange, and baseline systolic blood pressure and systolic blood pressureChange, but inversely with baseline diastolic blood pressure and diastolic blood pressureChange. When blood pressure was expressed as pulse pressure and MAP, IMTChange was positively associated with baseline pulse pressure and pulse pressureChange and inversely with baseline mean arterial pressure and mean arterial pressureChange. In sex-specific analysis, these associations were observed in women, but not in men. Conclusions In summary, our analyses showed that IMT increases at accelerating rates with aging. Age-associated changes in IMT were modulated by concurrent changes of low-density lipoprotein in both sexes, and of pulsatile and mean blood pressure in women but not men.

CPR and ECMO: The Next Frontier.

Cardiopulmonary resuscitation (CPR) is a first-line therapy for sudden cardiac arrest, while extracorporeal membrane oxygenation (ECMO) has traditionally been used as a means of countering circulatory failure. However, new advances dictate that CPR and ECMO could be complementary for support after cardiac arrest. This review details the emerging science, technology, and clinical application that are enabling the new paradigm of these iconic circulatory support modalities in the setting of cardiac arrest.

Subclinical Longitudinal Change in Ankle-Brachial Index With Aging in a Community-Dwelling Population Is Associated With Central Arterial Stiffening.

Background Aging is associated with a modest decline in ankle-brachial index (ABI); however, the underpinnings of this decline are not fully understood. The greater systolic ankle than brachial blood pressure, a normal ABI implies, is partially attributed to lower central than peripheral arterial stiffness. Hence, we examined the hypothesis that the age-associated decline in ABI is associated with central arterial stiffening with aging, assessed by pulse wave velocity. Methods and Results We analyzed longitudinal data from 974 participants aged 27 to 95 years from the Baltimore Longitudinal Study of Aging who were free of clinically significant cardiovascular disease. Participants had an average of 4 visits with a 6.8-year average follow-up time. Linear mixed-effects models showed that the average ABI decline beyond the age of 70 years was 0.03 per decade. In multiple regression analysis, the ABI rate of change was inversely associated with initial age (standardized ß=-0.0711, P=0.0282), independent of peripheral disease factors and baseline ABI. After adjustment, the pulse wave velocity rate of change was inversely associated with ABI rate of change (standardized ß=-0.0993, P=0.0040), rendering the association of the latter with initial age nonsignificant (standardized ß=-0.0265, P=0.5418). Conclusions A modest longitudinal decline in ABI beyond the age of 70 years was shown to be independent of traditional risk factors for peripheral arterial disease but was accounted for by an increase in pulse wave velocity. A modest decline in ABI with aging might be a manifestation of changes in central hemodynamics and not necessarily attributable to peripheral flow-limiting factors.

The design, development, and evaluation of a prototypic, prosthetic venous valve.

BACKGROUND: Chronic venous insufficiency is a serious disease for which there is no clearly successful surgical treatment. Availability of a proven prosthetic vein valve could provide such an option by reducing venous reflux while permitting normal antegrade flow. METHODS: A new prosthetic vein valve design has been developed which mimics the function of a natural valve by ensuring complete closure of the leaflets with minimal obstruction for antegrade flow. A 2:1 mock-up of the device was tested to evaluate its ability to prevent regurgitation and several key modifications were made. A subsequently re-designed 1:1 prototype was then built in 4 slightly different size configurations and then each tested under physiologic conditions of pulsatile flow in both supine and standing positions. RESULTS: Each of the configurations showed acceptable amounts of antegrade resistance and effective orifice area and showed low values of regurgitation and % reflux with two of the prototype configurations (flange lengths of 2.5 mm and 3.75 mm) having corresponding values of <2.5 mmHg-min/L, >97%, 11 mL, and 36%, respectively. These values are particularly striking when compared to the corresponding regurgitation and % reflux values of 60 mL and 205%, respectively, when no device is present. CONCLUSION: The results of this study show that this prototype vein valve design is capable of providing significant relief of reflux under realistic conditions without inducing any increase in antegrade flow resistance and warrants further testing with in vivo models.

Physiologically-based testing system for the mechanical characterization of prosthetic vein valves.

Due to the relatively limited amount of work done to date on developing prosthetic vein (as opposed to cardiac) valves, advances in this topic require progress in three distinct areas: 1) improved device design, 2) relevant device testing conditions, and, 3) appropriate parameters for evaluation of results. It is the purpose of this paper to address two of these issues (#2 and #3) by: 1) performing a study of normal volunteers to quantify the anatomy and hemodynamic features of healthy venous valves, 2) construction of a 2-step, in vitro testing procedure, which simulates both physiologic and postural conditions seen in the lower extremity venous system, and, 3) defining several modified and new parameters which quantify dynamic valve characteristics.