Wayne State University

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Lockette Lab

Research

  • Cardiovascular Consequences of Traumatic Brain Injury

    We found that traumatic brain injury (TBI) assaults the entire cardiovascular system with acute, marked in-creases in blood pressure, heart rate, toxic reactive oxygen species (ROS), and impaired blood flow regulation in the brain. These profound and often unpredictable consequences of TBI dramatically compromise our ability to effectively treat patients during the critical post-TBI phase of treatment. Equally disturbing is the possibility that these immediate and catastrophic cardiovascular responses to TBI could have long term, detrimental ef-fects on TBI survivors which are not understood. The urgency of this research is particularly acute for our mili-tary personnel who frequently sustain both impact- and blast-induced head injuries. Our overarching challenge is two-fold and inextricably linked: (1) To understand the consequences and best treatment of the immediate cardiovascular challenges induced by TBI; and (2) To understand the linkage of immediate cardiovascular im-pact and its long-term, life-altering effects. This is a collaborative project among experienced investigators from the Wayne State University School of Medicine, the University of Vermont, the University of Texas, and the Uni-formed Services University for the Health Sciences. We propose the unifying hypothesis that increased cardio-vascular reactivity and diminished cerebrovascular responsiveness after TBI results from an immediate, dra-matic and pathological activation of the sympathetic nervous system which leads to a surge of catecholamines and the attendant generation of destructive reactive oxygen species (ROS). Furthermore, we contend that this flood of ROS leaves a lasting pathological imprint on cardiac and vascular smooth muscle and endothelial cells to negatively alter normally well controlled, homeostatic responses of the systemic cardiovascular system and cerebral blood flow regulation. A corollary is that alteration in cerebral blood flow regulation, which is exquisitely designed to maintain constant blood flow (autoregulation) and to deliver blood on demand (functional hypere-mia), through a process called neurovascular coupling, would impact the entire body and its health. Using vali-dated animal models of both impact- and our unique and innovative open field model of blast-induced TBI, we will elucidate the basis of long-term increased cardiovascular reactivity following TBI. Central to our program is the elucidation of the underlying mechanisms of the cerebrovascular dysfunction following TBl which exhibits many similarities to small vessel disease of brain, a major cause of stroke and dementia. We will quantify cardiac function two days (acutely) and sixty days (chronic, long term) following TBI with assessments of: (1) blood pressure; (2) cardiac diastolic relaxation time assessed by magnetic resonance imaging; (3) left ventricular ejection fraction volumes measured by Doppler echocardiography; (4) stiffness of conduit blood vessels as-sessed with measurements of pulse wave velocity; (5) vascular myogenic tone and endothelial-dependent vas-odilation in perfused resistance vessels; and (6) endothelial and vascular smooth muscle cell rigidity measured with atomic force microscopy. Neurovascular coupling will be assessed ex vivo by measuring brain parenchy-mal arteriole vasodilation in response to neuronal stimulation and in vivo as blood flow in response to sensory stimulation. Key in translating our rodent findings to humans, we will explore the basis of elevated sympathetic nervous system activity and its impact on a greater blood pressure responses and diminished endothelial-dependent vasodilation and cerebral autoregulation at rest, and in response to stress, in men and women with a history of TBI when compared to humans without a history of TBI.

  • The "Male Warrior Triad"

    In 1993, the American College of Sports Medicine first held a symposium on the "female athlete triad." While moderate exercise is beneficial for women of all ages, "excessive" exercise training in some women could lead to abnormally low body fat, amenorrhea (irregular periods) from low estrogen, and osteoporosis (thinning bones). These female athletes were prone to musculoskeletal injuries and other unhealthy sequelae such as athlete "burnout." It was not until 2016 that published reports first appeared about a subset of male athletes who excessively train and could similarly experience adverse health issues that parallel those outcomes from the female athlete triad of low body fat, increased stress hormones (i.e. the "fight or flight" hormones) with hy- pogonadism (low testosterone), low bone mineral density, and burnout. The investigators hope to determine whether a similar syndrome, the "male warrior triad," exists in some men who train at the highest intensity level over prolonged periods of time. The principal investigator hypothesizes that, in some pre-disposed male athletes, as in special operations personnel, exhaustive training increases the stress hormones adrenaline and cortisol and reduces an athlete's testosterone levels. These hormonal changes lead to increased risk of musculoskeletal injury, hindered recovery from training, heightened sensitivity to pain, and diminished feelings of well-being, and greater propensity for analgesic misuse. This work is mission essential because understanding training-induced trends in stress hormones and testosterone may help to identify those athletes at greater risk of musculoskeletal injury, increased pain sensitivity and analgesic use, and athlete burnout, i.e. depression and anxiety. We shall follow male, collegiate level athletes over the course of their competitive season in both an observational study and a longitudinal study to test the hypothesis that training-induced increases in stress hormones, and reductions in testosterone concentrations, will correlate with an increased propensity for musculoskeletal injury, increased pain sensitivity, increased analgesic use, and burnout (i.e. a decrement in mood--depression and anxiety).

  • COVID and Blood Pressure

    Active duty military Service members with pathologic elevations in blood pressure are medically disqualified from deployment because it hinders operational readiness. However, chronic hypertension does not develop overnight, and like the civilian population, there are many Service members with "pre-hypertension," i.e. elevated blood pressures that are not high enough, yet, to warrant drug treatment. Men and women with hypertension are more likely to have worse outcomes with COVID-19 infection. The pathology and clinical manifestations of patients with COVID-19 infection are similar to those observed in individuals who have experienced high altitude pulmonary edema (HAPE) or swimming-induced pulmonary edema (SIPE). Also similar is the finding that high blood pressure predisposes individuals to both severe COVID-19 infection and the development of HAPE or SIPE. The investigators hope to prove that the similar pre-disposition to severe respiratory distress with HAPE, SIPE, and severe COVID-19 infection are due to a common link: abnormal ventilatory responses to hypoxemia (low blood oxygen) related to having higher blood pressures within the normal range. To achieve that goal, the investigators will first assess ventilatory (breathing) responses to hypoxia (low oxygen) and hypercapnia (high carbon dioxide) in healthy, fit men and women with a wide range of resting blood pressures and whose demographics match the population of U.S. military Service members. It is anticipated that individuals with higher blood pressures, when compared to subjects with lower blood pressures, will have diminished ventilatory responses to hypoxia and hypercapnia. If true, modification of blood pressure through more attentive lifestyle modifications, e.g. reduced dietary salt intake, could reduce the clinical severity of COVID-19 infection, and also, reduce the severity of HAPE and SIPE in Service members who must operate in mountainous terrain or diving underwater. Although it is known that over time, chronic hypoxia and hypercapnia can raise blood pressure, there have been no studies to determine if higher blood pressure is associated with diminished ventilatory responses that can lead to hypoxemia, i.e. low oxygen levels in the blood.

  • Funny Channels and Post-Traumatic Stress Disorder (PTSD)

    There are no uniformly successful drug treatments for post-traumatic stress disorder (PTSD); most psychotropic medications have minimal therapeutic efficacy, and among those that do, it is likely because their side effects of excessive sedation and somnolence are more welcome to the military Service member than the anxiety, hypervigilance, hyperalgesia, and nightmares often found in PTSD. We propose the novel hypothesis that stress-induced changes in the expression of newly identified "funny channels" in the brain contribute to the pathogenesis of PTSD, and targeted, pharmacological manipulation of these channels could reduce the development or progression of the symptoms of PTS. Our hypothesis is based on four observations: (1) Post-traumatic stress increases the activation of the sympathetic nervous system, and the pharmacologic agents that inhibit this autonomic pathway, namely propranolol, prazosin, and clonidine offer the most promise thus far for the treatment of PTSD. (2) Regular, strenuous exercise often relieves anxiety and sleep disturbances, and endurance athletes such as runners often describe a positive, addictive "high" that comes as a pleasant feeling of euphoria, anxiolysis, and analgesia during exertion and that remains in between workout bouts. (3) Regular exertional exercise induces a chronic reduction in heart rates, at rest and in response to stress, and it is due to exercise-induced down-regulation of the autonomic nervous system, and also, cardiac cyclic nucleotide gated hyperpolarization channel (HCN4, Ih, "funny channel"). (4) Neuronal "funnel channels" have been reported to mediate anxiolysis and analgesia. It would be of low risk, but high payout, to determine whether or not cortical HCN channels are similarly affected by stress or exercise as are cardiac funny channels. The transcription and expression of genes encoding the cortical funny channel following stress or exercise have not been assessed, and until now, it has not been suggested that neuronal funny channels could be manipulated to mimic the effect of exercise to reduce the manifestations of PTSD. There are already FDA-approved drugs that specifically inhibit the cardiac funny channel Ih, but the indications are limited to reduce heart rate in patients with congestive heart failure and angina pectoris. Although many patients have received no direct cardiac benefit from these medications in placebo controlled clinical trials, there has been uniform reporting that the quality of life of these patients is significantly improved. This is no small finding, yet, no one has investigated the mechanism responsible for these patients' consistent reports of subjective improvement. We posit that like exercise, or pharmacological antagonism of the Ih will reduce central neuronal hyperexcitability and diminish PTSD-related anxiety, nightmares, and reduce the hyperalgesia of PTSD.

  • Zinc Supplementation and Cardiovascular Morbidity in Diabetes Mellitus

    Oral zinc supplementation in patients with diabetes mellitus undeniably improves glycemic control. How-ever, there is reluctance to recommend zinc supplements to these patients because there is no evidence that the zinc-dependent improvement in glycemic control offers protections from the cardiovascular morbidities associated with diabetes mellitus, especially myocardial infarction and thrombotic stroke. We propose a ran-domized, double blind, cross over study to test the hypothesis that oral zinc supplementation will block the enhanced cardiovascular, cerebrovascular, and platelet reactivity that lead to myocardial infarction and stroke in subjects with diabetes mellitus. Specifically, the PI expects to show that when compared to placebo, four months of daily, oral zinc supplementation will enhance flow mediated vasodilation while also diminishing stress-induced increases in blood pressure, cerebrovascular reactivity, and platelet aggregation. These assessments will be made in men and women non-invasively, and non-pharmacologically, using validated state-of-the-art techniques. We will also determine whether zinc-induced improvements in cardiovascular phenotypes is accompanied by systemic reductions in inflammation and oxidative stress.