Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report.

The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Metabolic Choreography of Energy Substrates During DCD Heart Perfusion.

Background: The number of patients waiting for heart transplant far exceeds the number of hearts available. Donation after circulatory death (DCD) combined with machine perfusion can increase the number of transplantable hearts by as much as 48%. Emerging studies also suggest machine perfusion could enable allograft "reconditioning" to optimize outcomes. However, a detailed understanding of the energetic substrates and metabolic changes during perfusion is lacking. Methods: Metabolites were analyzed using 1-dimensional 1H and 2-dimensional 13C-1H heteronuclear spectrum quantum correlation nuclear magnetic resonance spectroscopy on serial perfusate samples (N = 98) from 32 DCD hearts that were successfully transplanted. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test for significant differences in metabolite resonances during perfusion and network analysis was used to uncover altered metabolic pathways. Results: Metabolite differences were observed comparing baseline perfusate to samples from hearts at time points 1-2, 3-4, and 5-6 h of perfusion and all pairwise combinations. Among the most significant changes observed were a steady decrease in fatty acids and succinate and an increase in amino acids, especially alanine, glutamine, and glycine. This core set of metabolites was also altered in a DCD porcine model perfused with a nonblood-based perfusate. Conclusions: Temporal metabolic changes were identified during ex vivo perfusion of DCD hearts. Fatty acids, which are normally the predominant myocardial energy source, are rapidly depleted, while amino acids such as alanine, glutamine, and glycine increase. We also noted depletion of ketone, ß-hydroxybutyric acid, which is known to have cardioprotective properties. Collectively, these results suggest a shift in energy substrates and provide a basis to design optimal preservation techniques during perfusion.

Mental health, stress, and resilience correlates of heart rate variability among military reservists, guardsmen, and first responders.

The use of heart rate variability (HRV) for monitoring stress has been growing in the behavioral health literature, especially in the areas of posttraumatic stress disorder, stress reactivity, and resilience. Few studies, however, have included general populations under workplace conditions. This study evaluates whether military and other first responders show lower HRV during stress than at baseline and greater post stress rebound, controlling for a myriad of potential confounders. A convenience sample of Reserves, National Guard, veteran, fire, and police personnel provided HRV and self-reported questionnaire responses before, during, and after a cognitive-stressor task with a smart phone application. Timing of HRV application; mental and physical health scores; coping and posttraumatic growth indicators, including being open to new possibilities; and emotional support were predictors of trajectories of the HRV response to stress. Findings from this exploratory study emphasize the strong link between stress and relaxation breathing in both respiratory sinus arrhythmia and low frequency heart rate variability and the need for controlling potential covariates for understanding the relationship between HRV and the stress response and providing a basis for hypothesis driven research.

Non-invasive Vagal Nerve Stimulation Effects on Hyperarousal and Autonomic State in Patients with Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury: Preliminary Evidence.

Posttraumatic stress disorder (PTSD) is a reaction to trauma that results in a chronic perception of threat, precipitating mobilization of the autonomic nervous system, and may be reflected by chronic disinhibition of limbic structures. A common injury preceding PTSD in veterans is mild traumatic brain injury (mTBI). This may be due to the vulnerability of white matter in these networks and such damage may affect treatment response. We evaluated transcutaneous vagal nerve stimulation (tVNS), a non-invasive, low-risk approach that may alter the functions of the limbo-cortical and peripheral networks underlying the hyperarousal component of PTSD and thus improve patient health and well-being. In this single visit pilot study evaluating the impact of tVNS in 22 combat veterans, we used a between-subjects design in people with either PTSD with preceding mTBI or healthy controls. Participants were randomized into stimulation or sham groups and completed a posturally modulated autonomic assessment and emotionally modulated startle paradigm. The primary measures used were respiratory sinus arrhythmia (high-frequency heart rate variability) during a tilt-table procedure derived from an electrocardiogram, and skin conductance changes in response to acoustic startle while viewing emotional images (International Affective Picture System). The stimulation was well tolerated and resulted in improvements in vagal tone and moderation of autonomic response to startle, consistent with modulation of autonomic state and response to stress in this population. Our results suggest that tVNS affects systems underlying emotional dysregulation in this population and, therefore, should be further evaluated and developed as a potential treatment tool for these patients.

Turning subscribers into customers: the future is now.

The launch of Medicare's prescription drug plan marks a major milestone in federal health policy. Nearly 90 percent of Medicare's 43 million beneficiaries now have some form of prescription drug coverage, approximately 6 million of whom had no coverage prior to the introduction of Part D. The enrollment boom presents a tremendous opportunity for health insurers. But the new enrollments also present a challenge, as insurers' ability to build customer loyalty will depend on their success in reorienting themselves to the consumer market where tastes can be even more fickle than in the group business. The good news is that as insurers focus on serving senior customers, there is an even more promising opportunity on the horizon than Medicare Part D: providing products that help consumers-particularly retirees and those nearing retirement-to plan for and manage their out-of-pocket health care spending. The retirement health market beyond Medicare Advantage and Part D could significantly impact many health insurers' bottom line; it's expected to generate $80 billion in revenues and $8-$12 billion in pre-tax profits by 2014.

Reaching out to retirees.

The numbers pertaining to the approaching demographic boom in health-care-related expenditures are eye-popping: Health-related financial products to help retiring baby boomers deal with out-of-pocket costs alone will generate up to 80 billion dollars in revenues and 8-12 billion dollars in pre-tax profits by 2014. But health insurers will have to refocus their efforts if they want to take full advantage of this opportunity. (For more, see "Turning Subscribers Into Customers: The Future Is Now" in the July/August issue, the first in this two-part series.) Two areas are critical: product innovation to provide comprehensive solutions that meet seniors' needs more effectively, and advice-based distribution that creates privileged customer relationships.

Effects of delaying fluid resuscitation on an injury to the systemic arterial vasculature.

OBJECTIVES: To determine the effects of delaying fluid on the rate of hemorrhage and hemodynamic parameters in an injury involving the arterial system. METHODS: Twenty-one adult, anesthetized sheep underwent left anterior thoracotomy and transection of the left internal mammary artery. A chest tube was inserted into the thoracic cavity to provide a continuous measurement of blood loss. The animals were randomly assigned to one of three resuscitation protocols: 1) no fluid resuscitation (NR), 2) standard fluid resuscitation (SR) begun 15 minutes after injury, or 3) delayed fluid resuscitation (DR) begun 30 minutes after injury. All of the animals in the two resuscitation groups received 60 mL/kg of lactated Ringer's solution over 30 minutes. Blood loss and hemodynamic parameters were measured throughout the experiment. RESULTS: Total hemorrhage volume (mean +/- SD) at the end of the experiment was significantly lower (p = 0.006) in the NR group (1,499 +/- 311 mL) than in the SR group (3,435 +/- 721 mL) or the DR group (2,839 +/- 1549 mL). Rate of hemorrhage followed changes in mean arterial pressure in all groups. Hemorrhage spontaneously ceased significantly sooner (p = 0.007) in the NR group (21 +/- 14 minutes) and the DR group (20 +/- 15 minutes) than in the SR group (54 +/- 4 minutes). In the DR group, after initial cessation of hemorrhage, hemorrhage recurred in five of six animals (83%) with initiation of fluid resuscitation. Maximum oxygen (O2) delivery in each group after injury was as follows: 101 +/- 34 mL O2/kg/min at 45 minutes in the DR group, 51 +/- 20 mL O2/kg/min at 30 minutes in the SR group, and 35 +/- 8 mL O2/kg/min at 60 minutes in the NR group. CONCLUSIONS: Rates of hemorrhage from an arterial injury are related to changes in mean arterial pressure. In this animal model, early aggressive fluid resuscitation in penetrating thoracic trauma exacerbates total hemorrhage volume. Despite resumption of hemorrhage from the site of injury, delaying fluid resuscitation results in the best hemodynamic parameters.

Depressive symptoms and access to mental health care in women screened for postpartum depression who lose health insurance coverage after delivery: findings from the Translating Research into Practice for Postpartum Depression (TRIPPD) effectiveness study.

OBJECTIVE: To determine the impact of losing health insurance coverage on perceived need for and access to mental health care in women screened for postpartum depression (PPD) in primary care settings. PATIENTS AND METHODS: The study sample included 2343 women enrolled in a 12-month, multisite, randomized trial that compared clinical outcomes of a comprehensive PPD screening and management program with usual care (March 1, 2006, through August 31, 2010). Screening for PPD occurred at the first postpartum visit (5-12 weeks) using the Edinburgh Postnatal Depression Scale followed by the 9-item Patient Health Questionnaire. Insurance status during the prenatal period, at delivery, and during the first postpartum year and perceived need for and access to mental health care during the first postpartum year were assessed via questionnaires completed by individual patients and participating practices. RESULTS: Rates of uninsured increased from 3.8% during pregnancy and delivery (n=87 of 2317) to 10.8% at the first postpartum visit (n=253 of 2343) and 13.7% at any subsequent visit to the practice after 2 months post partum (n=226 of 1646) (P<.001, both comparisons vs baseline). For patients with data on insurance type during follow-up, insurance loss occurred primarily in Medicaid beneficiaries. Nine-item Patient Health Questionnaire scores and self-reported need for mental health care did not differ significantly between patients who remained insured and those who lost insurance during the first postpartum year. However, of patients who reported the need for mental health care, 61.1% of the uninsured (n=66 of 108) vs 27.1% of the insured (n=49 of 181) reported an inability to obtain mental health care (P<.001). CONCLUSION: Loss of insurance during the first postpartum year did not significantly affect depressive symptoms or perceived need for mental health care but did adversely affect self-reported ability to obtain mental health care.

Multiscale analysis of heart rate variability in non-stationary environments.

Heart rate variability (HRV) is highly non-stationary, even if no perturbing influences can be identified during the recording of the data. The non-stationarity becomes more profound when HRV data are measured in intrinsically non-stationary environments, such as social stress. In general, HRV data measured in such situations are more difficult to analyze than those measured in constant environments. In this paper, we analyze HRV data measured during a social stress test using two multiscale approaches, the adaptive fractal analysis (AFA) and scale-dependent Lyapunov exponent (SDLE), for the purpose of uncovering differences in HRV between chronic fatigue syndrome (CFS) patients and their matched-controls. CFS is a debilitating, heterogeneous illness with no known biomarker. HRV has shown some promise recently as a non-invasive measure of subtle physiological disturbances and trauma that are otherwise difficult to assess. If the HRV in persons with CFS are significantly different from their healthy controls, then certain cardiac irregularities may constitute good candidate biomarkers for CFS. Our multiscale analyses show that there are notable differences in HRV between CFS and their matched controls before a social stress test, but these differences seem to diminish during the test. These analyses illustrate that the two employed multiscale approaches could be useful for the analysis of HRV measured in various environments, both stationary and non-stationary.

Autonomic predictors of recovery following surgery: a comparative study.

Although heart rate and temperature are continuously monitored in patients during recovery following surgery, measures that extract direct manifestations of neural regulation of autonomic circuits from the beat-to-beat heart rate may be more sensitive to outcome. We explore the relationship between features of autonomic regulation and survival in the prairie vole, a small mammal, with features of vagal regulation of the heart similar to humans. Cardiac vagal regulation is manifested in the beat-to-beat heart rate variability (HRV) pattern and can be quantified by extracting measures of the amplitude of periodic oscillations associated with spontaneous breathing. Thus, monitoring beat-to-beat heart rate patterns post-surgery in the prairie vole may provide an opportunity to dynamically assess autonomic adjustments during recovery. Surgeries to implant telemetry devices to monitor body temperature and continuous ECG in prairie voles are routinely performed in our laboratory. Ten of these implanted prairie voles died within 48 h post-surgery. To compare the post-surgery autonomic trajectories with typical surviving prairie voles, the post-surgery data from 17 surviving prairie voles were randomly selected. The data are reported hourly for 27 prairie voles between 6 and 14 h (1h before the demise of the first subject) post-surgery. Receiver operator curves were calculated hourly for each variable to evaluate sensitivity in discriminating survival. The data illustrate that measures of HRV are the most sensitive indicators. These findings provide a foundation for investigating further neural mechanisms of cardiovascular function.

Identification and phylogenetic analysis of 15 MHC class II DRB1 beta1 expressed alleles in a ewe-lamb flock.

Ovar-DRB1 is part of the major histocompatibility complex (MHC) class II of sheep and functions by presenting extracellular-derived peptides to the immune system. Although there are over 100 different Ovar-DRB1 DNA sequences reported in GenBank, only two Ovar-DRB1 mRNA sequences have been reported. As a first step in understanding MHC Class II function as it relates to disease progression in sheep, Ovar-DRB1 transcripts encoding the peptide-binding site or the first domain (beta1) of Ovar-DRB1 in a 32-ewe-lamb flock were identified and characterized by using reverse transcriptase-polymerase chain reaction, cloning, sequencing, and phylogenetic analysis. Fourteen new Ovar-DRB1 beta1 cDNA sequences out of a total of 15 Ovar-DRB1 beta1 cDNA sequences in a ewe-lamb flock of 32 sheep were identified. One Ovar-DRB1 beta1 cDNA sequence was 100% identical to M93432, one of the two Ovar-DRB1 mRNA sequences reported in GenBank. Twelve out of 15 Ovar-DRB1 beta1 cDNA sequences were 100% identical to the corresponding previously reported Ovar-DRB1 genomic DNA sequences, indicating that these Ovar-DRB1 genomic DNA sequences are also transcribed. One of three of the remaining Ovar-DRB1 beta1 cDNA sequences, DRB1*07012, had a synonymous substitution resulting in an identical deduced amino acid sequence to DRB1*0701. Two of the remaining three Ovar-DRB1 beta1 cDNA sequences had nucleotide differences and subsequent deduced amino acid sequence differences when compared to known Ovar-DRB1 beta1 genomic DNA sequences, and therefore, DRB1*0206 and DRB1*0353 represent new Ovar-DRB1 beta1 expressed alleles. Phylogenetic analysis of the 15 Ovar-DRB1 beta1 cDNA sequences revealed that DRB1*0206 had a strong phylogenetic relationship to DRB1*0203, and DRB1*0353 had a strong phylogenetic relationship to DRB1*0303.

Maori spiritual beliefs and attitudes towards organ donation.

Organ transplantation is widely agreed to be beneficial to health. Many transplantations involve donation from the deceased. In Aotearoa/New Zealand, Maori both donate and receive proportionally fewer organs than non-Maori. This paper seeks illumination of this fact in unique Maori spiritual beliefs. These spiritual beliefs are not held by all Maori, and their role in an individual's life may vary, nonetheless they constitute a living tradition. Because cadaveric donation involves removal of organs from the dead person as soon after death as possible, considerations arise about customary rules and observances and the movement between the realm of the living and the dead. This may raise concerns for donors, recipients, and their respective whanau (extended family). In some cases, these concerns may form a consideration against donating posthumously.