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Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Recent advances have revealed the medial preoptic area (MPA) as a key site for the regulation of torpor in mice. The MPA is estrogen-sensitive and estrogens also have potent effects on both temperature and metabolism. Here, we demonstrate that estrogen-sensitive neurons in the MPA can coordinate hypothermia and hypometabolism in mice. Selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, whereas selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor in both female and male mice, their effects on thermoregulation and torpor bout initiation exhibit differences across sex. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency. Torpor is a state of reduced metabolism and body temperature that conserves energy when food is scarce. Here the authors show that estrogen-sensitive neurons in the hypothalamus regulate torpor in mice, maintaining torpor in both sexes but initiating torpor and regulating core temperature differentially across sex.

Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100’s nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants.

Posttraumatic stress disorder (PTSD) symptoms develop in approximately 20% of individuals following a sudden, life-threatening cardiac arrhythmia and subsequent implantable cardioverter defibrillator (ICD) implantation. ICD-related PTSD symptoms are not only common but associated with adverse disease outcomes, and yet studies examining psychological treatments for these medically induced symptoms are rare. Written Exposure Therapy (WET) is a brief and efficacious trauma-focused intervention for PTSD, but it has yet to be evaluated in individuals who developed PTSD symptoms following a cardiac event. This paper describes the design and procedures of a multi-method study exploring individuals' ICD-related PTSD symptom manifestations and responses to WET. The study will begin with a qualitative examination of participants' experiences with medically induced PTSD symptoms and their perceptions of WET. Next, we will conduct a single-arm open-label trial to evaluate the feasibility, acceptability, and preliminary efficacy of WET for individuals with ICD-related PTSD symptoms. Adults with elevated ICD-related PTSD symptoms (N = 15) will first complete a semi-structured interview querying participants' experiences with medically induced PTSD symptoms, perceptions of WET, and barriers and facilitators to treatment engagement. They will then complete five weekly sessions of WET. A brief exit interview will be conducted to assess the acceptability of the WET intervention and changes in PTSD symptoms experienced by participants. Primary outcomes of the trial include feasibility (recruitment, retention, adherence) and acceptability (credibility, expectancy, and satisfaction ratings and qualitative interviews). Secondary outcomes include changes in total and fear-related PTSD symptoms, ICD-related fear, and health-related quality of life assessed pre-, during, and post-treatment and at a 1-month follow-up. This study will provide initial evidence of the feasibility, acceptability, and potential utility of WET for ICD-related PTSD symptoms. Results will inform future randomized controlled trials and guide clinical implementation efforts for those with medically induced PTSD.

Purpose of ReviewCardiovascular autonomic dysfunction (AD) among cancer survivors is increasingly being recognized. However, the mechanisms and incidence are poorly understood. In this review, the clinical features, diagnostic modalities, proposed mechanisms, and currently available treatments of cardiovascular AD in cancer survivors are described.Recent FindingsMuch of our current understanding of cardiovascular AD is based on disease states such as diabetes, multisystem atrophy, and Parkinson’s disease. Several non-invasive tests, measurements, and scoring systems have been developed as surrogates for autonomic function, with some even demonstrating associations with all-cause mortality. The mechanism of cardiovascular AD specifically in the cancer population, however, has not been directly studied. The etiology of cardiovascular AD in cancer survivors is likely multifactorial, and proposed mechanisms include direct nerve damage by chemoradiation, the pro-inflammatory state associated with malignancy, and paraneoplastic syndromes. It may also be that cardiovascular AD is an early marker of global cardiomyopathy rather than its own condition. Current pharmacologic options for cardiovascular AD are extrapolated from how it has been treated in other disease processes, and these agents have not been studied in the cancer population or compared head-to-head.SummaryCardiovascular AD in cancer survivors can cause significant debilitation and may be associated with all-cause mortality. Current diagnostic modalities have several limitations, such as standardization and validity. However, given the nonspecific nature of cardiovascular AD, these tools provide an objective marker for diagnosis and tracking treatment response. While the mechanism of cardiovascular AD in cancer survivors has not been directly studied, it may be useful to evoke mechanisms of cardiovascular AD in other disease states such as diabetes, Parkinson’s disease, and multisystem atrophy in addition to identifying unique conditions associated with malignancy like a pro-inflammatory state. Until further studies are performed, management of cardiovascular AD as seen in other disease states may serve as a guide for symptom management in cancer survivors.

The supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans. Dissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components. Nerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average. Human sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart, we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) neuropeptide-Y (NPY) -expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

His Bundle pacing (HBP) restores electrical synchronization in left bundle branch block (LBBB); however, the underlying mechanisms are poorly understood. We examined the relation between native QRS axis in LBBB, a potential indicator of the site of block, and QRS normalization in patients with LBBB. Data from patients (n = 41) undergoing HBP at 3 sites were studied (68 ± 13 years, 13 women). Study criteria included strictly defined complete LBBB and successful implantation of a permanent HBP lead. Preprocedure and postprocedure electrocardiograms were reviewed independently by 2 blinded readers. QRS axis and duration were measured to the nearest 10° and 10 ms, respectively. QRS narrowing or normalization was the primary end point. Of 29 patients meeting study criteria, 9 had frontal plane QRS axes between −60° and −80°, 10 from −40° to 0°, and 10 from +1° to +90°. QRS narrowing occurred in 24 patients (83%, 44 ± 34 ms, p <0.05). Percent QRS narrowing by axis were 26 ± 19%, 29 ± 25%, and 28 ± 23%, respectively. No correlation between prepacing QRS axis and postpacing narrowing was identified (r2 = 0.001, p = 0.9). In patients with or without QRS normalization after HBP, mean QRS duration was 155 ± 21 vs 171 ± 8 ms, respectively, p = 0.014. HBP induces significant QRS narrowing in most patients and normalization in patients with shorter baseline QRS duration. In conclusion, the lack of correlation between native QRS axis and narrowing suggests that proximal His-Purkinje block causes most cases of LBBB, or that additional mechanisms underlie HBP efficacy. Further studies are needed to better understand how to predict those patients in whom HBP will normalize LBBB.

We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations.

Stellate ganglia within the intrathoracic cardiac control system receive and integrate central, peripheral, and cardiopulmonary information to produce postganglionic cardiac sympathetic inputs. Pathological anatomical and structural remodeling occurs within the neurons of the stellate ganglion (SG) in the setting of heart failure (HF). A large proportion of SG neurons function as interneurons whose networking capabilities are largely unknown. Current therapies are limited to targeting sympathetic activity at the cardiac level or surgical interventions such as stellectomy, to treat HF. Future therapies that target the SG will require understanding of their networking capabilities to modify any pathological remodeling. We observe SG networking by examining cofluctuation and specificity of SG networked activity to cardiac cycle phases. We investigate network processing of cardiopulmonary transduction by SG neuronal populations in porcine with chronic pacing-induced HF and control subjects during extended in-vivo extracellular microelectrode recordings. We find that information processing and cardiac control in chronic HF by the SG, relative to controls, exhibits: (i) more frequent, short-lived, high magnitude cofluctuations, (ii) greater variation in neural specificity to cardiac cycles, and (iii) neural network activity and cardiac control linkage that depends on disease state and cofluctuation magnitude.

The growing complexities of clinical medicine and biomedical research have clouded the career path for physician-scientists. In this perspective piece, we address one of the most opaque career stage transitions along the physician-scientist career path, the transition from medical school to research-focused internal medicine residency programs, or physician-scientist training programs (PSTPs). We present the perspectives of medical scientist training program (MSTP) and PSTP directors on critical features of PSTPs that can help trainees proactively align their clinical and scientific training for successful career development. We aim to provide both trainees and MSTP directors with a conceptual framework to better understand and navigate PSTPs. We also offer interview-specific questions to help trainees gather data and make informed decisions in choosing a residency program that best supports their career.