Citations

Abstract Advancements in machine learning and computing methods have given new life and great excitement to one of the most essential diagnostic tools to date—the electrocardiogram (ECG). The application of artificial intelligence‐enabled ECG (AI‐ECG) has resulted in the ability to identify electrocardiographic signatures of conventional and unique variables and pathologies, giving way to tremendous clinical potential. However, what these AI‐ECG models are detecting that the human eye is missing remains unclear. In this article, we highlight some of the recent developments in the field and their potential clinical implications, while also attempting to shed light on the physiologic and pathophysiologic features that enable these models to have such high diagnostic yield. © 2022 American Physiological Society. Compr Physiol 12:3417‐3424, 2022.

Abstract Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor‐mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor‐induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article. © 2013 American Physiological Society. Compr Physiol 3:977‐1010, 2013.

Abstract Background: Intra-articular corticosteroid injections (ICSI) have been shown to be an effective symptomatic non-operative treatment for hip osteoarthritis (OA) and other joint-related pain. There has been recent dispute over the true risk of complications from ICSI specifically when injected into the hip. Avascular necrosis (AVN) of the femoral head has been reported to occur in up to 30.5% of patients after undergoing hip ICSI, and up to 50.6% of patients experiencing osteoarthritis progression in as little as 3 months following injection. Purpose: To analyze the current protocol of hip ICSIs performed by two fellowship-trained non-operative sports medicine physicians and assess the rate of femoral head avascular necrosis. We hypothesized that the rate of AVN will be less than what has been recently reported in the literature. Study Design: Retrospective chart review Methods: Patients that underwent at least one intra-articular corticosteroid hip injection by two fellowship trained non-operative sports medicine physicians at this institution were identified using an institutional database. Exclusion criteria included injections with contrast dye used for imaging, injections that administered orthobiologics to the intra-articular, and non-intra-articular injections. Procedure notes were reviewed for anesthetic and steroid type, dosage, and needle size. Each chart was screened for demographic information, post-injection infections, AVN diagnosis, and subsequent hip replacement. 10 patients were identified with an AVN diagnosis. Their MRNs were sent to a board-certified radiologist at the same medical institution. The radiologist was blinded to the patient’s chart and instructed to identify the first radiograph with evidence of AVN. Patients were excluded if the reviewer did not agree with the diagnosis as it appeared in the medical chart or the AVN developed post-traumatically. Results: 449 patients, 530 hips, underwent 1.8 ± 1.4 ICSIs and 16.3% underwent THA at an average of 2.2 ± 2.3 years following their first injection. Of the 530 hips that underwent ICSI, only 1 hip demonstrated findings of AVN on radiographs following the first injection, and this patient had been taking oral prednisone for over 20 years. Conclusions: Intra-articular corticosteroid injections are a relatively safe symptomatic treatment option for hip pain secondary to both OA and non-OA pathology to be considered when other non-operative treatment options have failed. While the use of steroids comes with an inherent risk of osteonecrosis and cartilage damage, these results demonstrate that, when performed properly with ultrasound guidance and sterile technique, the risk of femoral head avascular necrosis is minimal.

Abstract Striated respiratory muscles are necessary for lung ventilation and to maintain the patency of the upper airway. The basic structural and functional properties of respiratory muscles are similar to those of other striated muscles (both skeletal and cardiac). The sarcomere is the fundamental organizational unit of striated muscles and sarcomeric proteins underlie the passive and active mechanical properties of muscle fibers. In this respect, the functional categorization of different fiber types provides a conceptual framework to understand the physiological properties of respiratory muscles. Within the sarcomere, the interaction between the thick and thin filaments at the level of cross‐bridges provides the elementary unit of force generation and contraction. Key to an understanding of the unique functional differences across muscle fiber types are differences in cross‐bridge recruitment and cycling that relate to the expression of different myosin heavy chain isoforms in the thick filament. The active mechanical properties of muscle fibers are characterized by the relationship between myoplasmic Ca 2+ and cross‐bridge recruitment, force generation and sarcomere length (also cross‐bridge recruitment), external load and shortening velocity (cross‐bridge cycling rate), and cross‐bridge cycling rate and ATP consumption. Passive mechanical properties are also important reflecting viscoelastic elements within sarcomeres as well as the extracellular matrix. Conditions that affect respiratory muscle performance may have a range of underlying pathophysiological causes, but their manifestations will depend on their impact on these basic elemental structures. © 2013 American Physiological Society. Compr Physiol 3:1533‐1567, 2013.

Abstract Heart failure is a clinical syndrome characterized by the inability of the cardiovascular system to provide adequate cardiac output at normal filling pressures. This results in a clinical syndrome characterized by dyspnea, edema, and decreased exertional tolerance. Heart failure with preserved ejection fraction (HFpEF) is an increasingly common disease, and the incidence of HFpEF increases with age. There are a variety of factors which contribute to the development of HFpEF, including the presence of hypertension, diabetes, obesity, and other pro‐inflammatory states. These comorbid conditions result in changes at the biochemical and cell signaling level which ultimately lead to a disease with a great deal of phenotypic heterogeneity. In general, the physiologic dysfunction of HFpEF is characterized by vascular stiffness, increased cardiac filling pressures, pulmonary hypertension, and impaired volume management. The normal and abnormal processes associated with aging serve as an accelerant in this process, resulting in the hypothesis that HFpEF represents a form of presbycardia. In this article, we aim to review the processes importance of aging in the development of HFpEF by examining the disease and its causes from the biochemical to physiologic level. © 2022 American Physiological Society. Compr Physiol 12: 3813–3822, 2022.

Abstract Acute kidney injury (AKI) is a syndrome that entails a rapid decline in kidney function with or without injury. The consequences of AKI among acutely ill patients are dire and lead to higher mortality, morbidity, and healthcare cost. To prevent AKI and its short and long‐term repercussions, understanding its pathophysiology is essential. Depending on the baseline kidney histology and function reserves, the number of kidney insults, and the intensity of each insult, the clinical presentation of AKI may differ. While many factors are capable of inducing renal injury, they can be categorized into a few processes. The three primary processes reported in the literature are hemodynamic changes, inflammatory reactions, and nephrotoxicity. The majority of patients with AKI will suffer from more than one during their development and/or progression of AKI. Moreover, the development of one usually leads to the instigation of another. Thus, the interactions and progression between these mechanisms may determine the severity and duration of the AKI. Other factors such as organ crosstalk and how our concurrent therapies interact with these mechanisms complicate the pathophysiology of the progression of the AKI even further. In this narrative review article, we describe these three main pathophysiological processes that lead to the development and progression of AKI. © 2022 American Physiological Society. Compr Physiol 12: 3767–3780, 2022.

Abstract The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre‐ and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short‐term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12: 3731–3766, 2022.

Abstract In this article, we highlight the contributions of passive experiments that address important exercise‐related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical “knockout” animal models among human research participants. Natural experiments are gleaned from data sets that allow population‐based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879‐4907, 2023.

Abstract Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short‐ and long‐term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long‐term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health‐related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age‐matched healthy subjects. Several factors, including alterations in central hemodynamics, HT‐related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high‐intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719‐4765, 2023.