Central pulse pressure and peripheral vascular reactivity in post – preeclamptic patients
What are we measuring?
Brachial artery Brachial systolic blood pressure Brachial diastolic blood pressure
Memory CD4 T cells
100 80
100
*
60 40
60 40
20
20
0
0
central memory
100
80
80
Why are we measuring those things?
~ 4x increased risk of stroke and heart attack
Onset of preeclampsia
Elastic Arteries
60 40
effector memory
Memory CD8 T cells
% CD45RO+
Higher pulse pressure is an indication of stiff arteries.
Healthy Preeclamptic
*
80
100
Index fingers of both hands: VENDYS device tests vascular reactivity (endothelial function)
?
At least >10 Years
Naive CD4 T cells
Naive CD8 T cells
Women who had preeclampsia have a higher risk of stroke and heart attack LONG AFTER delivery Pregnancy
Brachial artery blood pressure measurement with blood pressure cuff SphygmoCor tonometry device measurement generates brachial pulse wave form FDA approved algorithm calculates central pulse wave form from which Central systolic blood pressure Central diastolic blood pressure are calculated
% CD45RO+
Pulse pressure is calculated: Systolic blood pressure – diastolic blood pressure
% CD45RA+
Introduction: Introduction: It is known that post – preeclamptic (PE) women have increased risks for cardiovascular diseases and stroke; however, the etiology is unclear. Central blood pressure is the result of complex pulse wave dynamics in the arterial network. Arterial stiffness is one of the major determinants of the arterial wave dynamics and it is correlated with central (aortic) pulse pressure (cPP) at a given heart rate and peripheral vascular impedance. Increased cPP is clinically important since it is associated with end-organ damage. Here, we studied the changes in central blood pressure and peripheral vascular reactivity in PE patients. Methods: In this study, we compared women who had a healthy pregnancy or preeclampsia (PE) in one of their prior pregnancies. Radial artery waveforms were measured noninvasively using a high-fidelity applanation tonometer with SphygmoCor system (AtCor medical). Waveforms were calibrated using a brachial cuff. A validated and FDA approved transfer function was used to compute central blood pressure and cPP using SphygmoCor software. The VENDYS device (Endothelix Inc.) was used to determine peripheral vascular reactivity. Results: Our study population was between 33 and 46 years of age and the time since delivery of their last child was between 15 and 48 months. cPP was higher in PE patients compared to volunteers. PE patients did not show any differences in their peripheral vascular reactivity as assessed with the VENDYS device. Conclusions: While our PE patients were relatively young and they did not display any frank anatomical changes, central arterial functional abnormalities as marked by elevated cPP were clearly detectable among them. However, the peripheral vascular reactivity was normal in these patients. Our result suggest that noninvasive central hemodynamics assessment might be useful in identifying disease drivers and developing sensitive early diagnostic approaches for PE patients. Correlations with immune disparities are currently investigated.
Delivery
Mechanism: Inflammation (Hypothesis)
% CD45RA+
Abstract
Niema Pahlevan, Ph.D1, 2, 3, and Andrea I. Loewendorf, Ph.D4 1Division of Cardiovascular Medicine, Department of Medicine, University of Southern California, CA 2Department of Aerospace and Mechanical Engineering, University of Southern California, CA 3Advanced Imaging Center, Huntington Medical Research Institutes, Pasadena, CA 4Department of Reproductive and Vascular Immunology, Huntington Medical Research Institutes, Pasadena, CA
[email protected]
60 40
20
20
0
0
Stiff Arteries
central effector memory memory
In our prior study using a different patient group [9], we demonstrated a significant reduction of naïve CD4 T cells and expansion of memory T cells in preeclamptic women at term. In the current study we investigate how far this phenotype persists after the pregnancy. Memory expansion is a normal process that occurs in the immune system but usually takes decades as it is a slow process driven by normal ageing. As far as the community of immunologists is aware, memory formation is an irreversible process. In other words, prior preeclamptic women have an immune system that is phenotypically decades older than their age, most likely permanently so. As the immune system ages, it becomes paradoxically less functional but displays higher baseline inflammation. We postulate that the baseline inflammation in post preeclamptic women is higher than in women who had healthy pregnancies and this baseline inflammation contributes to vascular dysfunction and brain damage.
Epidemiology -
Preeclampsia is more predictive of cardiovascular disease (CVD) than obesity [1]
What is next?
-
A review of 3,598,601 women: preeclampsia was associated with a 3x increased risk of developing chronic hypertension and 2x risk for CVD or CVD-related mortality [2]
-
Study of 1,132,064 women in Taiwan: 13x higher incidence of myocardial infarction, 14.5x higher incidence of stroke in post – PE patients [3]
-
A study in Florida looking at reason for readmission in women with pregnancy related hypertensive disorders within 3 years of index pregnancy. 1,452,926 records, 52% white, 23% African American, 18% Hispanics. African American women had a 4x higher risk of readmission due to cardiovascular problems compared to white or Hispanic women [4]
-
The ‘normal’ pathology of CVD such as atherosclerotic plaques or carotid intima-media thickening is not as common after PE as in CVD generally [5]
-
BUT increased atherosclerotic plaque erosion, possibly a function of endothelial dysfunction, was found [6]
-
Pathologic endothelial activation is observed 10 years after index pregnancy [7]
-
Ten years after PE pregnancy, a trend toward higher arterial pulse wave velocity (PWV, a measure of arterial stiffness) is observed [8]
1) Continue to recruit more volunteers for this study, we now have 8 healthy and 8 prior preeclamptic participants. 2) Follow the participants over time asking them to come back every ~ 3-5 years. Repeat the measurements.
Systole
The majority of current knowledge is based on results from Caucasian populations.
Pregnancy
Systolic/pulse pressure Diastolic flow
The Post – Pregnancy study at HMRI
-
-
The heartbeat produces blood flow and a pressure wave, both of which then meet the vasculature as they exit the heart. The vasculature is not a stiff system of hoses like, for example, garden hoses, but should be elastic and absorb as well as reflect some of the pressure waves. As we age, the arteries stiffen in a normal process but diseases such as hypertension, chronic low – grade inflammation (rheumatoid arthritis, systemic vasculitis, HIV infection, inflammatory bowel disease), and chronic kidney disease can also cause vascular stiffening. One consequence of this is that stiffer arteries in turn will propagate the pressure waves further down the system so more of them will actually reach the organs such as the brain and kidneys where they can cause damage. Picture modified from Kidney International.
The central pulse pressure is elevated in post preeclamptic patients
Performing peripheral blood collection for serum and analysis of the immune cells, brain MRI and MRS, Pulse Wave Analysis, and Heart MRI. Hopefully, we will have a chance to see some of these patients again every ~3-5 years. The power of this study comes from the different types of analysis performed on the same women, not necessarily from the large numbers of patients we will be having.
90 80
200 150 100 50
70
Healthy Preeclamptic
60
in mmHG
Beats per minute
100
40 20
60
pt ic
cl am
Pr
ee
H
ea
lth y
50
Pre- menopausal women ages between 33 to 46 years of age with prior healthy or preeclamptic pregnancies were enrolled in this study. Time since delivery of the last child was between 15 and 48 months. The heart rate and vascular reactivity was assessed using the VENDYS device. The device measures the ability of the peripheral vasculature to comply with increased demand and reports the results in three categories as shown above. Given that endothelial dysfunction is a key component of acute preeclampsia, we are eager to collect data on more women post delivery but at least in this one post – preeclamptic volunteer that we analyzed, the vasculature was able to comply with demand.
0
2nd study visit?
3rd study visit?
Systolic Diastolic Systolic Diastolic Brachial Central
-
The epidemiology indicates a connection between preeclampsia and different vascular – and end organ diseases, our study is designed to understand the biology of those connections. In other words, what do those three arrows in our “Post – Pregnancy study at HMRI” actually stand for? Importantly, we believe that the vascular disease processes at play in preeclamptic women are not unique to preeclampsia or pregnancy. This disease setting exacerbates and accelerates those processes which gives us a chance to study them but understanding them will benefit all of us. The PI of this project, Andrea Loewendorf, is an immunologist and is interested in how the immune system causes endothelial activation and vascular damage as is postulated in hypothesis 1. A role for general “inflammation” is known and assumed but specifics are unclear. These inquiries are approached with the goal of treating acute and long – term effects of preeclampsia. Hypothesis 2, the connection between arterial stiffening and the brain damage observed here is a tempting theory: stiffer vessels propagate the pressure waves and those – together with other factors, possibly inflammation being one of them - cause structural damage. In how far this applies to our patients will have to be further examined; as of right now we have nothing more than a correlation, no causation. Please also see our poster LB-065 Abstract #2432 ”Preeclampsia Causes Lingering Neuronal Damage” which is data from the same patient group.
Literature
Pulse Pressure
Blood pressure
in mmHG
Heart rate
~3-5 years
Our long – term goals
-
MR Spectroscopy Brain Health (Abstract #2432, LB-065)
~3-5 years
Onset of preeclampsia In 3rd trimester
Pulse Wave Velocity Arterial Stiffening Heart Health
Heart rate and vascular reactivity in healthy and preeclamptic patients
1st study visit 15 to 48 months after delivery: damage/activation
Diastolic flow
Recruiting women up to 10 years post healthy or preeclamptic pregnancy Immune System Vascular – and Endothelial Health
Delivery
Systolic/pulse pressure
Diastole
-
0
Brachial
Central
Pre- menopausal women ages between 33 to 46 years of age with prior healthy or preeclamptic pregnancies were enrolled in this study. Time since delivery of the last child was between 15 and 48 months. The blood pressures and pulse pressures were assessed using the SphygmoCor tonometry device.
[1] Heidema WM, Scholten RR, Lotgering FK, Spaanderman ME. History of preeclampsia is more predictive of cardiometabolic and cardiovascular risk factors than obesity. Eur J Obstet Gynecol Reprod Biol. 2015;194:189-93. doi: 10.1016/j.ejogrb.2015.09.010. PubMed PMID: 26433185. [2] Leslie MS, Briggs LA. Preeclampsia and the Risk of Future Vascular Disease and Mortality: A Review. J Midwifery Womens Health. 2016;61(3):315-24. doi: 10.1111/jmwh.12469. PubMed PMID: 27155218. [3] Lin YS, Tang CH, Yang CY, Wu LS, Hung ST, Hwa HL, et al. Effect of pre-eclampsia-eclampsia on major cardiovascular events among peripartum women in Taiwan. Am J Cardiol. 2011;107(2):325-30. doi: 10.1016/j.amjcard.2010.08.073. PubMed PMID: 21211611. [4] Jarvie JL, Metz TD, Davis MB, Ehrig JC, Kao DP. Short-term risk of cardiovascular readmission following a hypertensive disorder of pregnancy. Heart. 2018. doi: 10.1136/heartjnl-2017-312299. PubMed PMID: 29326108 [5] Christensen M, Kronborg CS, Eldrup N, Rossen NB, Knudsen UB. Preeclampsia and cardiovascular disease risk assessment - Do arterial stiffness and atherosclerosis uncover increased risk ten years after delivery? Pregnancy Hypertens. 2016;6(2):110-4. doi: 10.1016/j.preghy.2016.04.001. PubMed PMID: 27155337. [6] Sandvik MK, Leirgul E, Nygard O, Ueland PM, Berg A, Svarstad E, et al. Preeclampsia in healthy women and endothelial dysfunction 10 years later. Am J Obstet Gynecol. 2013;209(6):569 e1- e10. doi: 10.1016/j.ajog.2013.07.024. PubMed PMID: 23899451. [7] Ciftci FC, Ciftci O, Gullu H, Caliskan M, Uckuyu A, Ozcimen EE. Does mild preeclampsia cause arterial stiffness and ventricular remodeling through inflammation? Ginekol Pol. 2014;85(12):900-7. PubMed PMID: 25669058 [8] Nguyen TA, Kahn DA, Loewendorf AI. Maternal-Fetal rejection reactions are unconstrained in preeclamptic women. PLoS One. 2017;12(11):e0188250. doi: 10.1371/journal.pone.0188250. PubMed PMID: 29176779; PubMed Central PMCID: PMCPMC5703473
