Trial Purpose and Description
AIM 1: To test cardiovascular (CV) stressors targeting endothelial function in previously preeclamptic (PE) women. Activation of the inner-most vascular layer, the endothelium (Fig. 1), primarily promotes vasodilation and in doing so contributes to CV health (10). Endothelial dysfunction interferes with this process and is an important precursor to PE (5;6). To address this Aim, we will test stressors that evoke endothelium-dependent vasodilation: Flow-Mediated Dilation (FMD), a common clinical index of endothelial function, and Post-Exercise Circulatory Occlusion (Fig. 2). These stressors differ in that the former drives vasodilation through shear stress, while the latter is driven by accumulation of exercise metabolites. We hypothesize that vasodilatory responses to both stressors will be reduced or compromised in previously PE women relative to controls.
AIM 2: To test CV stressors targeting Sympathetic Nervous System (SNS) function in previously PE women. Beyond the endothelium lie vascular smooth muscle cells (Fig. 1), which contract to promote vasoconstriction when stimulated by peripheral SNS activity (SNSA). Abnormal elevations in SNSA occurs in PE (7-9), eliciting excessive vasoconstriction (8) which is proposed to be a prime contributor to the sudden onset of severe hypertension in PE (7). To address Aim 2, we will test stressors that acutely increase SNSA: Valsalva¿s Maneuver and a Mental Stress Test (Fig. 2). Valsalva¿s Maneuver is a physiological stimulus acting through the baroreflex loop to stimulate SNSA (11), while Mental Stress evokes a ¿generalized¿ increase in SNSA (12). We hypothesize that SNSA responses to will be exaggerated in previously PE women relative to controls.
AIM 3: To test endothelial-SNS balance during stressors in previously PE women. As described earlier, endothelial and SNS influences often oppose each other. This is a vital clinically relevant consideration because impairment to one regulatory system may mask compromised function in the other, preventing the detection of CV dysfunction if either system is considered in isolation. To address this, we will test two stressors that cause simultaneous activation of the endothelium and SNSA: Static Forearm Exercise and Voluntary Breath-Hold (Fig. 2). In both instances, decreases in circulating oxygen (and other circulating factors) stimulate the endothelium to promote vasodilation, while SNSA increases via the chemoreflex to stimulate increased blood flow and blood redistribution among vascular beds. We hypothesize that both endothelial and SNSA responses to these stressors are impaired in previously PE women compared to controls.
Ages: 18 - 40 years
Gender: Female only
Inclusion: Women will be either 6-24 months post-partum following a PE or n=15 women 6-24 months post-partum following an uncomplicated pregnancy. They will be otherwise healthy and between the ages of 18-40 yrs.
Subjects with the following histories or conditions will be excluded from the study: Gynecologic: a. current or past estrogen-dependent neoplasia, b. unexplained vaginal bleeding, c. history of uterine fibroids, d. current pregnancy, e. known or suspected breast or uterine cancer, f. partial or complete hysterectomy.
Cardiac: a. myocardial infarction, ventricular tachycardia or fibrillation, b. angina, c. valvular disease (mitral insufficiency or stenosis, aortic insufficiency or stenosis), d. congestive heart failure, orthopnea, paroxysmal nocturnal dyspnea, e. current arrhythmias, f. prosthetic valves.
Pulmonary: a. current cigarette smokers, or pipe or cigar smokers, b. chronic obstructive pulmonary disease, c. adult asthma, d. dyspnea on exertion, e. current bronchitis, pneumonia, or tuberculosis, f. lung carcinoma, g. pulmonary embolus, recent (less than 1 year).
Vascular: a. claudications or history of peripheral vascular disease, b. abdominal or thoracic aortic aneurysm, or repair of same, c. cerebral aneurysm, vascular malformations, d. hypertension, systolic or diastolic.
Gastrointestinal: a. GI malignancy, b. hepatitis, current, c. splenomegaly from any cause, d. Cholecystitis, e. current diverticulosis or diverticulitis, inflammatory bowel disease, ulcerative colitis, Crohn¿s disease.
Infectious Disease: any ongoing intercurrent infection.
Hematologic/Oncologic: a. receiving chemotherapy or radiation therapy, b. any metastatic malignancy, c. anemia (hematocrit < 35), d. thrombocytopenia or thrombocytosis, e. neutropenia, f. hematologic malignancy, g. bleeding dyscrasia.
Neurologic: a. history of cerebral vascular accident with any neurologic sequels, b. uncontrolled seizures (e.g., more than 1 seizure/year), c. transient ischemic attacks, d. dementia, e. neurologic conditions producing dyscoordination, peripheral neuropathy, or myopathy.
Endocrine: a. diabetes mellitus, b. any untreated endocrinopathy.
Renal: a. chronic renal diseases, b. any history of renal disease or impairment, c. current urinary tract infection.
Musculoskeletal: a. inflammatory arthritis history (e.g., rheumatoid, psoriatic, Reiters), b. any history of pathologic fractures, including vertebral compression fractures.
Pharmacologic: a. any illegal drug use (self report), b. alcohol use greater than an average of 4 oz/day over 30 days.
Yale University School of Medicine
Dates: 12/01/2016 - 11/30/2018
Last Updated: 02/22/2018
Study HIC#: 2000020048