LEFT VENTRICULAR DYSFUNCTION IN PREECLAMPTIC PATIENTS
A Dissertation submitted to
THE TAMILNADU DR M.G.R MEDICAL UNIVERSITY CHENNAI
In partial fulfillment of the regulations for the award of the degree of M.D.(OBSTETRICS AND GYNAECOLOGY) – BRANCH - II
REGISTER NUMBER: 221816208
THANJAVUR MEDICAL COLLEGE THANJAVUR - 613004
THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI, TAMILNADU
May 2021
CERTIFICATE FROM INSTITUTION
This is to certify that the dissertation titled “LEFT VENTRICULAR DYSFUNCTION IN PREECLAMPTIC PATIENTS” is a bonafide work done by Dr.B.RAJAPRIYA , Post graduate student, Department of Obstetrics and Gynaecolgy at Thanjavur Medical College, Thanjavur -04, during the period January 2019 to April 2020 in partial fulfillment of rules and regulations of the Tamilnadu Dr. M.G.R Medical University, for the award of M.D. degree Branch II(Obstetrics and Gynaecology) examination to be held in May 2021.
Prof. Dr.S.MARUTHU THURAI M.S.,M.Ch.,( Vascular) The Dean,
Thanjavur Medical college,
Thanjavur-613004.
CERTIFICATE
This is to certify that the dissertation titled “LEFT VENTRICULAR DYSFUNCTION IN PREECLAMPTIC PATIENTS” is a bonafide work done by Dr.B.RAJAPRIYA , Post graduate student, Department of Obstetrics and Gynaecolgy , Thanjavur Medical College, Thanjavur , under my guidance and supervision in partial fulfillment of rules and regulations of the Tamilnadu Dr.
M.G.R Medical University, for the award of M.D. degree Branch II(Obstetrics and Gynaecology) examination to be held in May 2021.The period of study was from January 2019 to April 2020.
Prof .Dr.R.RAJARAJESWARI MD.,DGO.,DNB, Guide and Head of the Department,
Department of Obstetrics and Gynaecology, Thanjavur Medical College,
Thanjavur.
CERTIFICATE FOR ANTI PLAGIARISM
This is to certify that this dissertation work titled “LEFT VENTRICULAR DYSFUNCTION IN PREECLAMPSIA” of the candidate Dr.B.RAJAPRIYA with Registration Number 221816208 for the award of MD degree in the branch of Obstetrics & Gynaecology. I personally verified the urkund.com website for the purpose of plagiarism check. I found that uploaded thesis file contains from introduction to conclusion pages and result shows 10 percentage of plagiarism in the dissertation.
Prof . Dr.R.RAJARAJESWARI MD.,DGO.,DNB, Guide and Head of the Department ,
Department of Obstetrics and Gynaecology, Thanjavur Medical college ,
Thanjavur.
DECLARATION
I solemnly declare that the dissertation titled “LEFT VENTRICULAR DYSFUNCTION IN PREECLAMPTIC
PATIENTS” was done by me at Department of Obstetrics and Gynaecology, Thanjavur Medical College, Thanjavur, during the year 2018 – 2021 under the guidance and
supervision of Prof. Dr.RAJARAJESWARI, MD.,DGO.,DNB., This dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical University,Chennai in partial fulfillment of the University regulations for the award of M.D.BRANCH II ( Obstetrics and Gynaecology).
Place: Thanjavur -04
Date Dr. B.Rajapriya,
MD Post Graduate Student,
Dept of Obstetrics and Gynaecology, Thanjavur Medical College.
ACKNOWLEDGEMENT
I gratefully acknowledge and sincerely thank Prof.
Dr.S.MARUTHUTHURAI MS.,MCH.,(Vascular),The Dean, Thanjavur Medical College and hospital, Thanjavur for permitting me to conduct the study and use facilities of the institution for my study.
I wish to express my respect and sincere gratitude to my beloved teacher and Head of the Department, Prof. Dr. R.RAJARAJESWARI, MD.,DGO.,DNB., Department of obstetrics and Gynaecology, Thanjavur Medical College, Thanjavur for her valuable guidance and encouragement during the study and also throughout my course period.
I Sincerely thank our. Dr.S.UDAYA ARUNA MD.,DGO and Dr. J. PRABHA MD.,OG for their constant support and guidance throughout the study.
I am bound my ties of gratitude to Assistant Professor Dr.THENDRAL.MD.,OG.,for her valuable guidance in conducting this study.
I am greatly indebted to Prof. Dr SENTHIL KUMAR
MD.,D.M.,(CARDIOLOGY) Head of the Department, Department of
Cardiology, Thanjavur Medical College, Thanjavur, for giving me permission to do this study.
My sincere thanks to Dr.GOMATHI ,M.D.,D.M,(CARDIOLOGY) , Assistant professor, Department of Cardiology, Thanjavur Medical College, Thanjavur for her guidance which helped me to carry out the study successfully.
I wish to express my thanks to Dr.L.MAGESHWARAN M.D., Assisstant Professor and Academic Officer incharge, Department of Pharmacology, Thanjavur Medical College,Thanjavur for his support and guidance during his study.
I Wish to express my sincere thanks to all the Assistant Professors of Obstetrics and Gynaecology Department for their support during the study.
I thank the Secretary and the Chairman of Institution Ethical Committee, Thanjavur Medical College, Thanjavur.
I would be failing in my duty, if don’t place my sincere thanks to those patients who were the subjects of my study. Above all I thank God Almighty for immense blessings.
CONTENTS
S. NO TITLE PAGE NO
1. INTRODUCTION 1
2. AIMS AND OBJECTIVES 3
3. REVIEW OF LITERATURE 4
4. STUDY METHODOLOGY 54
5. RESULTS AND ANALYSIS 59
6. DISCUSSION 83
7. CONCLUSION 90
8. ANNEUXURES
BIBLOGRAPHY
PROFORMA
MASTER CHART
ABBREVIATIONS
SBP systolic blood pressure
DBP diastolic blood pressure
NO nitric oxide
AT angiotensin
PGI2 prostacyclin I2
TX thromboxane
ET endothelins
sFlt soluble fms - like tyrosine kinase
VEGF vascular endothelial growth factor
PIGF placental growth factor
sEng endoglin
TGF transforming growth factor
EF ejection fraction
FS fractional shortening
LV left ventricle
ANP atrial natriuretic peptide
BNP brain natriuretic peptide
DT deceleration time
IVRT isovolumetric relaxation time
CO cardiac output
EDV end diastolic volume
ESV end systolic volume
LVEDD left ventricular end diastolic dimension
LVESD left ventricular end systolic dimension
PWD pulsed – wave doppler
CWD continuous wave doppler
CDI color doppler imaging
LA left atrium
SV stroke volume
ECG electrocardiogram
1
INTRODUCTION
Preeclampsia is a pregnancy specific disorder which constitutes hypertension after 20 weeks of gestation associated with proteinuria. Preeclampsia is a multisystem disorder of unknown etiology. Hypertensive disorders represent the most common medical complication of pregnancy affecting 7 % to 15%
pregnant women of all gestations. According to systematic review of World Health Organisation (WHO), hypertensive disorder remains a leading cause of direct maternal mortality. Hypertension along with haemorrhage and infection forms the deadly triad that contributes to mortality and morbidity during pregnancy and childbirth.
In developing countries, it ranks second to anaemia as a cause of maternal mortality and morbidity. Cardiac failure with pulmonary edema may occur with normal heart in hypertensive patients. It is emphasized that particularly preeclamptic pregnant women develop pulmonary edema more often than non pregnant women. Preeclampsia is a recognized predisposing factor for diastolic dysfunction, systolic dysfunction, ischemic heart disease and idiopathic cardiomyopathy.
Pregnancy is characterized by various important hemodynamic changes.
During pregnancy plasma volume increases by 50%. The increase in total red cell volume is about 25%. The resting pulse rate increases by about 10 beats per minute. Cardiac output increases by about 40% in order to achieve increase in uterine blood flow and hence placental perfusion. The arterial blood pressure
2
reaches a nadir in mid-pregnancy and rises thereafter. The decrease in blood pressure is due to reduction in systemic vascular resistance that occurs in pregnancy. These changes are physiological in normal pregnancies. But these changes are altered in patients with preeclampsia.
Preeclampsia is associated higher prevalence of asymptomatic global left ventricular dysfunction and myocardial injury than uneventful pregnancy. Hence this prospective study was undertaken to evaluate cardiovascular hemodynamic changes between preeclamptic women and normotensive pregnant women.
3
AIM AND OBJECTIVES OF THE STUDY
To study the left ventricular systolic and diastolic function in women with preeclampsia by transthoracic echocardiography and to compare these features with normotensive pregnant women, belonging to third trimester.
4
REVIEW OF LITERATURE HISTORICAL PROSPECTIVE
Preeclampsia was called as toxemia of pregnancy, based on the mistaken belief that the condition was caused by toxins. The word “eclampsia” is from the Greek word “eklampsis” meaning lightning. The first known description of the condition was by Hippocrates in the 5th century BC.
CLASSIFICATION OF HYPERTENSIVE DISORDERS OF PREGNANCY This clinical classification is adopted by the International Society for Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders during pregnancy can be classified into four well defined groups1.
They are
1.Gestational hypertension
2.Preeclampsia and eclampsia syndrome 3.Chronic hypertension
4.Preeclampsia superimposed chronic hypertension
NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAMME (2000) classifies hypertensive disorders of pregnancy into five types.
5
They are :
1. Gestational hypertension. This is the most common type of hypertensive disorder of pregnancy. This is also known as pregnancy induced hypertension (PIH).
2. Preeclampsia 3. Eclampsia
4. Chronic hypertension
5. Chronic hypertension with superimposed preeclampsia GESTATIONAL HYPERTENSION :
It is defined as new onset hypertension with systolic blood pressure of 140mmHg or more or diastolic blood pressure of 90mmHg or more or both on two occasions at least 4 hours apart which develops after 20 weeks of gestation , during labour or in the first 24 hours of postpartum, without proteinuria or any other severe systemic features of preeclampsia in a previously normotensive nonproteinuric women and the blood pressure resolves within 12weeks of postpartum. Almost half of these women will develop preeclampsia syndrome subsequently. Gestational hypertension is reclassified as transient hypertension by some if there is no evidence of preeclampsia and blood pressure returns to normal within 12 weeks of postpartum.
6
As per National Institute for Health and Clinical Excellence (NICE) 2010 guidelines, hypertension is further classified based on the severity into mild, moderate and severe hypertension for the purpose of management.
MILD HYPERTENSION: systolic blood pressure of 140 – 149 mmHg, diastolic blood pressure 90-99mmHg.
MODERATE HYPERTENSION: systolic blood pressure of 150-159 mmHg, diastolic blood pressure of 100-109 mmHg.
SEVERE HYPERTENSION: systolic blood pressure ≥160mmHg, diastolic blood pressure ≥ 110mmHg.
PREECLAMPSIA:
Preeclampsia is a pregnancy specific syndrome that is associated with new onset hypertension, which occurs mostly after 20 weeks of gestation and frequently near term. In this, hypertension is associated with proteinuria greater than 0.3g/L in a 24 hour urine collection, dipstick reading of 2+ by qualitative urine examination or protein creatinine ratio of 0.3 or more after 20 weeks of gestation2.
As per new ACOG Practice Bulletin, although hypertension and proteinuria are the classical criteria for diagnosis of preeclampsia, the presence of any one of the following severe features in women with gestational hypertension without proteinuria should also be classified as preeclampsia3.
These following features are included in the diagnostic criteria for preeclampsia since they increase the risk of mortality and morbidity and require surveillance.
7
Thrombocytopenia (platelet count less than 1,00,000×109/L)
Severe persistent epigastric pain or right upper quadrant pain that is not accounted by any alternative diagnosis
Renal insufficiency with serum creatinine concentration > 1.1mg/d L or doubling of the baseline without any prior renal disease
Impaired liver function as indicated by elevated serum transaminase levels to twice the upper limit of normal concentration
Pulmonary edema
New onset headache unresponsive to acetaminophen or with visual disturbances, convulsions
ECLAMPSIA:
Convulsions occurring in a patient with preeclampsia are called as eclampsia. It is characterized by new onset of focal or multifocal tonic – clonic convulsions or coma that occur in pregnancy or postpartum. This is unrelated to other cerebral conditions such as epilepsy, cerebral ischaemia and infarction/
haemorrhage or drug use. It is the most severe form of preeclampsia. Eclampsia occurs in 1.9%-3% of cases of preeclampsia. These convulsions are caused by excessive release of excitatory neurotransmitters like glutamate; massive depolarization of neurons and bursts of action potentials. Clinical and experimental evidence suggests that extended seizures will produce significant brain injury and brain dysfunction.
8
HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome:
Severe form of preeclampsia is characterized by
Hemolysis
1.peripheral blood smear with abnormal findings like fragmented red cells, spherocytosis and reticulocytosis
2.serum bilirubin more than or equal to 1.2mg/d l)
Elevated liver enzymes twice the upper limit of normal (Aspartate aminotransferase and/or alanine aminotransferase >70U/L, Lactate dehydrogenase >600U/L)
Thrombocytopenia (platelet count < 100,000/mm3)
DIAGNOSTIC CRITERIA FOR HELLP SYNDROME:
Sibai proposed criteria for ‘complete’ or ‘true’ HELLP syndrome (Tennessee classification system 2004):
1.Intravascular hemolysis diagnosed by abnormal peripheral blood smear 2.Increased serum bilirubin≥20.5µmol/l or ≥1.2mg/100ml
3.Elevated LDH levels(>600units/l) 4.Platelet count <1,00,000/microlitre 5.Serum AST(SGOT)levels >70IU/l
Mississippi Triple class system further classifies this HELLP syndrome base on platelet count. They are:
Class I – with platelet count <50× 106/l
9
Class II – with platelet count 50×106/l to 100×106/l Class III- 100×106/l to 150×106/l
CHRONIC HYPERTENSION:
Hypertension present before 20th week of gestation or that is diagnosed preconception. Elevation of blood pressure that persists after 12weeks postpartum is also retrospectively diagnosed as chronic hypertension4.
1. Essential hypertension is diagnosed when there is no underlying cause for hypertension.
2. Secondary hypertension that occurs due to renovascular disease, renal parenchymal disease, endocrine disorders or coarctation of aorta.
PREECLAMPSIA SUPERIMPOSED ON CHRONIC HYPERTENSION:
This is diagnosed when one or more features of preeclampsia (e.g.
proteinuria, elevated liver enzymes, thrombocytopenia) develop for the first time during pregnancy after 20 weeks in a women with preexisting chronic hypertension5.
Preeclampsia can be classified as mild or severe.
Indicators of severity:
1. Severe hypertension systolic blood pressure≥160mmHg or diastolic blood pressure of ≥110mmHg or both on two occasions atleast 4 to 6 hours apart.
10
2. Elevated serum creatinine level ( >1.1mg/dL or double the baseline value) 3. Oliguria < 500ml urine output in 24 hours
4. Pulmonary edema
5. Microangiopathic hemolysis
6. Thrombocytopenia (Platelets <100,000/mm3) 7. Elevated ALT and AST
8. Pain in the epigastrium or right upper quadrant.
9.vomitting
10. Headache, visual disturbances.
12. Intrauterine growth restriction
Incidence:
It occurs in 8 to 10 % of pregnancies. It varies according to geographical location. In nulliparous population the incidence is 3 to 10% and in multiparas it mis 1.4 to 4%6. (worldwide studies reviewed by Staff and coworkers (2015). Our hospital incidence is 6 to 7%.
11
PREDISPOSING FACTORS:
AGE:
Young and nulliparous women are vulnerable to develop preeclampsia and older women are at increased risk for chronic hypertension with superimposed preeclampsia.6
PARITY:
Most commonly occurs in nulliparous women and its occurrence is less common in subsequent pregnancies8.
SOCIAL STATUS:
Preeclampsia is frequently seen in low socioeconomic status group of population.9
RACE:
Incidence of preeclampsia is more (11%) in African-American women and in addition black women have greater morbidity.9
GENETIC PREDISPOSITION:
Genetic and familial factors have strong influence in occurrence of preeclampsia mostly due to Mendelian recessive trait.10
12
TWIN PREGNANCY:
When compared to singleton pregnancy, twin pregnancies have increased incidence of preeclampsia.11
HYDATIFORM MOLE:
In hydatiform mole, they are exposed to superabundance of chorionic villi and so there is increased incidence of preeclampsia.12
ENVIRONMENTAL FACTORS:
People living in high attitude in cold weather have higher arterial blood pressure and they have increased risk for preeclampsia.13
OBESITY:
There is increased incidence of preeclampsia in obesity and they also have increased tendency to develop essential hypertension.14
SMOKING:
Smoking carries reduced risk for hypertension during pregnancy. The protective role of smoking is likely explained by the biological effects of carbon monoxide that is produced during smoking. This carbon monoxide inhibits the production of placental antiangiogenic proteins and it also inhibits placental apoptosis.15
13
DISEASES COMPLICATING PREGNANCY:
Preeclampsia and diabetes:
Risk of developing preeclampsia is increased two to four fold among women with type 1 or type 2 diabetes.16
Women with preexisting renal disease have increased risk to develop chronic hypertension and chronic hypertension with superimposed preeclampsia.
Approximately one third of women with Anti Phospholipid Syndrome (APLA) will develop preeclampsia. In addition to this, this syndrome is associated with other adverse pregnancy outcomes like early pregnancy loss, fetal death and intrauterine growth restriction.17
ETIOLOGY:
The exact nature of the primary event causing preeclampsia is not known.
The currently considered important mechanisms proposed to explain preeclampsia include
1. Placental implantation with abnormal trophoblastic invasion of uterine vessels
2. Immunological maladaptive tolerance between maternal and fetal tissues.
3. Maternal maladaptation to normal cardiovascular or inflammatory changes of pregnancy.
4. Genetic factors include inherited predisposing genes and epigenetic influences.
14
1.Abnormal trophoblastic invasion:
Abnormal trophoblastic invasion of the spiral arteries, inappropriate endothelial cell activation and dysfunction and exaggerated inflammatory response are the key features in etiopathogenesis of preeclampsia. Redman and coworkers(2015) given the concept of “two – stage disorder” theory of preeclampsia.
Primary stage involves abnormal placentation .in normal pregnancy the wall of the spiral arteries is invaded by endovascular trophoblastic cells.
This migration transforms the small, musculoelastic spiral arteries into large tortuous channels that carry a large amount of blood to the intervillous space and are resistant to effects of vasomotor agents. In preeclampsia, the trophoblastic invasion occurs only some of the spiral arteries and does not progress into the myometrial portion of the arteries.
The secondary stage is maternal systemic syndrome associated with an exaggerated endothelial cell activation and a generalized hyperinflammatory state.
15
The central part in etiopathology of preeclampsia is placental ischaemia, that leads to the release of soluble factors and micro or nanovesicles into the maternal circulation which is responsible for the clinical signs of preeclampsia like hypertension and proteinuria. These factors were referred as “toxins,” hence the name “toxemia of pregnancy. The cause for placental ischemia is thought to be inadequate remodeling of the spiral arteries that brings maternal blood into the intervillous space of placenta. The mechanism responsible for this remodeling involves migration of trophoblasts from the anchoring villi of the placenta into the decidua and superficial myometrium and also the lumen and wall of the spiral arteries.18
Susan Fisher’s laboratory gave major contributions for understanding the mechanisms responsible for normal and abnormal invasion of trophoblasts and
16
they discovered that cytotrophoblasts adopt an endothelial adhesive phenotype within the lumen of the spiral arteries and this process is defective in preeclampsia.
A paper published by the Fisher identifies two major pathologic processes implicated in the pathophysiology of preeclampsia: defective trophoblast invasion and an antiangiogenic state.19
2. Immunological factors:
Mainly preeclampsia occurs in first pregnancy. This is explained by the invoking immune mechanisms linked to the fact that genetically foreign fetus challenges the maternal immune system. The hypothesis is that maternal immune system ‘learns’ to accommodate the fetus. This adaptation may be relatively defective in a first pregnancy but less common in subsequent pregnancies. In addition to this, there may be partner specificity, which strengthens the argument that preeclampsia results from the relative failure of maternal tolerance to paternal alloantigens.
A longer preconception duration from coitus reduces the risk of pre‐
eclampsia by promoting maternal tolerance to paternally derived antigens.
Pregnancy itself enhances this tolerance which is slowly lost after delivery.
Whether a change of partner increases the risk of pre‐eclampsia depends on the coital interval with the new partner, not the duration of time since the last pregnancy.
Loss of maternal immune tolerance to paternally derived placental and fetal antigens is another cited theory for preeclampsia (Erlebacher, 2013). Redman and
17
colleagues (2015a) reviewed the possible role immune maladaptation in preeclampsia. In women destined to be preeclamptic, the extravillous trophoblasts early in pregnancy express reduced amounts of immunosuppressive non classic human leukocyte antigen G. 20
3. Endothelial cell activation:
The ischemic placenta in this preeclampsia releases certain factors such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines like TNF-α ( Tumour necrosis factor α) and Interleukin 6 which cause maternal endothelial dysfunction characterized by elevated circulating endothelin (ET-1), reactive oxygen species (ROS), and increased vascular sensitivity to angiotensinII.20
This endothelial cell activation may result from extreme activated state of leucocytes in maternal circulation. Cytokines like tumour necrosis factor α and the interleukins also contribute to systemic oxidative stress. This leads to formation of self propagating lipid peroxides that in turn generate toxic radicals that injure systemic vascular endothelial cells.
4.Genetic factors:
Preeclampsia appears to be multifactorial, polygenic disorder. From the epidemiological point of view, many studies have given the fact that preeclampsia is a disease with strong familial predisposition and this also varies with socioeconomic, racial and geographic features.
18
It has been reported that preeclampsia syndrome is 5 times more common in women with first-degree relatives with PE while those with second-degree relatives have double the risk. It is believed that paternal genes also play an important role in the development of PE. This is evidenced by the fact that risk of preeclampsia is increased in women with pregnancies of men who have previously been involved in pregnancies complicated with PE. This has specific importance since genomic imprinting results from the involvement of paternal genes in the control of invasion and placental growth, whereas maternal genes inhibit it and they are responsible for the adaptive immune response of pregnancy.
A large genetic association study of preeclampsia was published by Goddard et al. by evaluating 775SNPs in 190 genes in more than 350 PE mother and offspring pairs and 600 control pairs. They detected six genes which are related to preeclampsia with significative maternal-fetal genotype interaction. They areIGF1, IGF2R, IL4R, CSF1, GNB3 and THBS4. These findings and others suggest that preeclampsia has a multifactorial polygenic inheritance with a genetic component in the development of this disease.21
19
PATHOGENESIS:
1.VASOSPASM
The maternal vascular endothelium appears to be the important target area of factors triggered during preeclampsia. Both endothelium-derived relaxing and contractile factors play an important role in the regulation of arterial compliance, vascular resistance and also in regulation of blood pressure. Whenever there are abnormalities in the production or action of these factors, the vasculature is predisposed to vasospasm, leukocyte adherence, oxidative stress and vascular endothelial inflammation. Once the immune cells adhere to the activated vascular endothelium a cascade of cellular interactions occur causing widening of junction
20
between cells and allowing immune cell infiltration into the vascular wall thereby invading local tissues. As a result of this, the endothelium becomes leaky and allowing extravasation of fluid, which is recognized clinically as edema. The markers of endothelial dysfunction may serve as predictors of the syndrome in women who develop preeclampsia since many of the markers are often elevated weeks prior to onset of clinical manifestations. Such markers include Endothelin- 1, soluble vascular adhesion molecule and interleukin-8, endothelial leukocyte adhesion molecule-1(ELAM).22
Thus in preeclampsia, systemic endothelial activation causes vasospasm that increases resistance and produce hypertension. Decrease in synthesis of nitric oxide (NO) and increase in endothelin by the vascular endothelium also accounts for increased resistance in preeclampsia. Endothelial injury causes interstitial leakage through which blood constituents, including activated platelets and fibrinogen get deposited in the subendothelium. Because of this maldistribution and interstitial leakage, there will be ischemia in surrounding tissues that leads to necrosis, hemorrhage and also contribute other end organ dysfunction of preeclampsia.
2. Endothelial cell activation:
While various factors including genetic, behavioral, immunological and environmental influences have been implicated in the pathogenesis of preeclampsia, the main focus of the most recent obstetric literature is to highlight the studies that link endothelial cell dysfunction and hypertension in preeclampsia.
21
The pathophysiology underlying preeclampsia was proposed by Roberts and colleagues to occur in two stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome.
Endothelial dysfunction manifests as enhanced formation of factors such as endothelin, reactive oxygen species (ROS) and increased vascular sensitivity to angiotensin II. In addition, preeclampsia is also associated with decreased formation of vasodilators like nitric oxide and prostacyclin. These alterations in vascular function not only leads to hypertension but also multi-organ dysfunction and it may progress to eclampsia or HELLP syndrome.
Endothelial cell injury forms the main mechanism behind preeclampsia pathogenesis. In response to placental ischemia, placental protein factors are secreted to maternal circulation that provoke activation and dysfunction of vascular endothelium. Normal intact endothelium has anticoagulant properties.
By releasing nitric oxide, intact endothelium blunt the response of vascular smooth muscle to vasopressors.
Any injury or activation of endothelium secrete less nitric oxide and may secrete substances which promote coagulation and increased sensitivity to vasopressors. Increased circulating levels of fibronectin factor VII antigen and thrombomodulin all are markers of endothelial dysfunction reported in preeclampsia.
22
3. Enhanced pressor responses
Normal pregnant women are refractory to vasopressors like angiotensin II.
However women with preeclampsia have increased vascular reactivity to infused norepinephrine and angiotensin II. This increased vascular reactivity to vasopressors in women with early preeclampsia has been identified by Raab and coworkers on 1956 and Talledo and associates in 1968 using either norepinephrine or angiotensin II.
In 1973, Gant et al described the enhanced blood pressure response to angiotensin II (AT II) clearly precedes the onset of preeclampsia. But mechanisms underlying this increased vascular reactivity remained inconclusive. Increased blood pressure in preeclampsia is not due to elevated levels of angiotensin II because AT II levels are not elevated, nor the levels of other vasoconstrictive hormones, such as epinephrine or norepinephrine.
It was reported that significant neutrophil infiltration into systemic vasculature of women with preeclampsia was associated with marked systemic vascular inflammation. These neutrophils release reactive oxygen species (ROS) that may enhance vascular reactivity by the RhoA kinase pathway. When RhoA kinase is activated, it phosphorylates the myosin phosphatase target subunit 1 (MYPT1), which inhibits the myosin light chain phosphatase (MLCP), so myosin light chains remain phosphorylated, and this inturn enhances calcium sensitization.
It was studied that ROS have been shown to activate this pathway in rat aorta and
23
rat pulmonary arteries and ROS are found to be mediators of angiotensin II signaling .23
Nitric oxide, a potent vasodilator synthesized by endothelial cells from L- arginine, inhibits platelet aggregation and adhesion to vascular endothelial surfaces. Because endothelial cell damage plays an important role in the pathogenesis of preeclampsia, it is very important to determine whether nitric oxide production is decreased in patients with preeclampsia. Circulating levels of nitrite are found to be decreased in patients with preeclampsia and thus diminished nitric oxide synthesis also contributes to the pathophysiological changes seen in preeclampsia.24
In preeclampsia, inhibition of this nitric oxide synthesis raises mean arterial pressure, lowers heart rate and reverses pregnancy induced refractoriness to vasopressors. Autoantibodies are thought to activate AT1 receptors and increased angiotensin II sensitivity.
Preeclamptic patients develop profound sensitivity to vasopressors, like angiotensin II, and is associated with increased morbidity for the mother and fetus.
A circulating antiangiogenic protein soluble fms-like tyrosine kinase 1 (sFLT1) elevation, precede clinical signs and symptoms of preeclampsia. Here, it was reported that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing the endothelial nitric oxide synthase (eNOS) phosphorylation and promoting free radical injury in the vasculature.
24
Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with overexpression of sFlt1. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling and reverses sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Treatment with sildenafil also improves uterine blood flow, decreases vascular resistance, and improves fetal weights in comparison with untreated sFlt-1expressing mice. Thus, sFlt-1 protein expression is inversely related to reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support that the endothelial dysfunction due to high circulating sFlt-1 may be the essential event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and it suggests that targeting sFlt-1-induced pathways can be used for treating preeclampsia and improving fetal outcomes.25
4) Prostaglandins
The prostaglandins (PGI2 and PGE) are vasodilating and platelet- disaggregating prostaglandins. They are increased during normal pregnancy and this accounts for many of the hemodynamic changes, beginning from the first trimester. In contrast to this, there is a relative increase in the vasoconstricting, platelet-aggregating prostaglandins (thromboxane A2 and PGF2 alpha) seen in preeclampsia. This disruption in the balance between these two groups of prostaglandins may also play an important role in the pathogenesis of preeclampsia.26
25
Endothelial prostacyclin (PGI2) action is mediated by phospholipase A2. Thromboxane A2 is produced by platelets, its levels are increased in preeclampsia.
Imbalance of prostaglandins, especially decreased prostacyclin: Thromboxane A2
ratio, result in vasoconstriction and hypertension in preeclampsia.
In normal pregnancy, PGI2 is more than TXA2 and there is vasodilation and no hypertension. In Preeclampsia, PGI2 is less than TXA2 and there is vasoconstriction and hypertension (Chen et al., 1993).
Endothelins (ET-I) are potent vasoconstrictors produced by human endothelium. Plasma ET-I levels are elevated in preeclampsia and they mostly arise from systemic endothelial activation. (Taylor and Roberts 1999). ET-1 has been suggested that it produces hypertension in pre-eclampsia. Recently, endothelin -1 has been implicated in the induction of both the oxidative stress and endoplasmic reticulum stress in pre-eclampsia and these are responsible for many of the clinical manifestations of this disorder. ET-1 activate many of the key signaling molecules that will lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress thereby it decreases the risk of developing preeclampsia27.
26
5.Angiogenic imbalance:
This describes excessive amounts of antiangiogenic factors in preeclampsia that are thought to be produced by worsening hypoxia at the uteroplacental interface. Numerous studies have given the evidence that there is excess of some antiangiogenic molecules released by the placenta to maternal circulation such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) and decreased levels of proangiogenic substances like vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) play an important role in the pathogenesis of preeclampsia28.
27
Two important antiangiogenic factors are detected in circulation of women who are destined to develop preeclampsia.
First one is soluble fms – like tyrosine kinase (sFlt-1) is a transmembrane receptor for VEGF (vascular endothelial growth factor). Elevated maternal sFlt-1 levels in circulation will inactivate and it antagonizes the action of VEGF and placental growth factor (PIGF) by binding and preventing their interaction with the cellular receptors. SFlt-1 levels are elevated in preeclamptic women by five times the levels in a normal pregnancy. In addition, injection of adenovirus expressing sFlt-1 into rat models resulted in preeclampsia-like symptoms, such as significant hypertension, glomerular endotheliosis, proteinuria, and fetal growth restriction. This effect of sFlt-1 is dose dependent with a strong correlation between sFlt level and disease severity. Interestingly, a study by Thadhani et al. demonstrated that there is significant reduction in protein/
creatinine ratio in preterm preeclamptic women following removal of sFlt-1 via whole blood apheresis. This further reinforces role of sFlt-1 in the pathogenesis of preeclampsia and suggests a novel therapy that may be explored further29.
Multiple studies have demonstrated the important role of PIGF and VEGF in the pathogenesis of preeclampsia. Maynard et al. demonstrated significantly reduced levels of VEGF and PlGF in the preeclamptic patient serum when compared to normotensive pregnant women. Interestingly, clinical trials for an anti-VEGF monoclonal antibody, bevacizumab used in chemotherapy, patients often suffered from the side effects of hypertension and proteinuria suggesting the
28
idea that VEGF deficiency is also a component of preeclampsia. PlGF, with its angiogenic function is also a factor in the development of preeclampsia. Maynard et al. showed that both VEGF and PlGF blockade are likely required for the development of a preeclamptic syndrome. In his model, VEGF deficiency alone does not lead to preeclamptic sequale. When recombinant human PlGF is injected in multiple animal models for preeclampsia, they demonstrated a reversal in the hypertensive component of the disease, suggesting a potential therapeutic role for PlGF in preeclampsia29.
Second one is soluble endoglin (sEng) by binding to endothelial receptors this inhibits various isoforms of transforming growth factor beta (TGF-β). sEng is a form of a cellular receptor endoglin that binds with transforming growth factor (TGF)-β1. sEng have multiple similarities with sFlt-1. It is also circulating in the maternal bloodstream and it antagonizes pro-angiogenic TGF-β1. Venkatesha et al. demonstrated a dose dependent elevation in sEng related with disease severity.
In addition, rats injected with adenovirus expressing sEng developed features of hypertension and proteinuria. Interestingly, injecting both sEng and sFlt-1 in rats developed symptoms of increased severity, including severe hypertension, nephrotic-range of proteinuria, and HELLP syndrome. This suggests that the two anti-angiogenic factors work together in the pathogenesis of preeclampsia.
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PATHOPHYSIOLOGY:
Cardiovascular system:
In preeclampsia, cardiovascular disturbances are more common. They are related to
1. Greater cardiac afterload by hypertension 2. Endothelial activation
3. Reduced cardiac preload by pathologically diminished volume expansion during pregnancy.
Cardiovascular changes of preeclampsia are based on disease severity, presence of underlying chronic disease and severity of hypertension.
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There is a high prevalence of cardiovascular and cardiopulmonary complications in preeclamptic patients. Cardiopulmonary complications are seen in 6% of severe preeclampsia, this is increasing to 12% HELLP (hemolysis, elevated liver enzymes, and low level of platelets) syndrome. Pulmonary edema is the most common cardiopulmonary complication, which occurs up to 3% of women with preeclampsia. It occurs mainly in the peripartum or postpartum stage
28. Cardiac failure and secondary maternal mortality and morbidity are strongly associated with preeclampsia, associated with comorbidities, like advanced maternal age, contributing to the strength of this association30.
In preeclampsia when assessing cardiac function consideration can be given to echocardiographic measures of myocardial function and ventricular function.
Myocardial function:
Acute cardiovascular complications are observed in 6% of severe preeclampsia patients and epidemiological studies also demonstrate that there is an association between preeclampsia and subsequent cardiovascular mortality and morbidity. Preeclampsia is associated with asymptomatic left ventricular dysfunction and left ventricular hypertrophy with increased cardiovascular risk status within few years postpartum. These findings are more commonly seen in early onset preeclampsia. There is increasing evidence supporting the concept that the history of early onset of preeclampsia should be taken into consideration to identify women who are at high cardiovascular risk even in the absence of any other concomitant risk factors31.
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Preeclampsia is associated with significant asymptomatic global left ventricular dysfunction and abnormal geometry during the acute phase of this disorder. These subclinical abnormalities are considered very important in risk stratification for nonpregnant patients. Various studies have given the fact that after one year of postpartum, there is significant asymptomatic left ventricular moderate to severe dysfunction and hypertrophy mainly seen in preterm preeclampsia (56%) as compared with term preeclampsia (14%) .The risk of developing essential hypertension within 2 years of postpartum was significantly higher in both preterm preeclamptic women and those with persistent left ventricular abnormal function or geometry. The cardiovascular complications of preeclampsia does not end with the delivery of baby and placenta. The majority of preterm or early onset preeclamptic patients have asymptomatic heart failure in postpartum, and 40% of women will develop essential hypertension within 1 to 2 years after pregnancy. Thus, women with a history of early onset preeclampsia may benefit from cardiovascular risk assessment in the one or two years after delivery. This helps to identify those who would benefit from targeted therapeutic intervention32.
Women with early-onset pre-eclampsia requiring delivery before 34 weeks are at an increased risk of developing cardiac diastolic dysfunction one year after delivery when compared to normotensive women33.
In women with preeclampsia, serial echocardiographic studies suggest diastolic dysfunction in 40 to 45 percent. (Guirguis,2015; Melchiorre, 2012).
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Ventricles do not properly relax and cannot fill properly with this dysfunction. This dysfunction may persist upto 4years after delivery. (Evans,2011; Orabona,2017).
Early-onset preeclampsia is associated with worse left ventricular diastolic function and there is higher prevalence of preclinical diastolic LV dysfunction in the fifth decade of life. This association persists after accounting for age, systolic blood pressure, smoking status, body mass index and educational level. Left ventricular diastolic dysfunction is associated with higher plasma levels of IL-6 and sICAM-1, which are found to be elevated in preeclampsia34.Diastolic dysfunction occurs due to ventricular remodeling, which is an adaptive response to maintain normal ventricular contractility inspite of increased afterload in preeclampsia.
Ventricular function:
Both normal pregnant women and preeclamptic women have normal or slight hyperdynamic ventricular function. In addition to this, aggressive hydration results in hyperdynamic ventricular function. This is accompanied by elevated pulmonary capillary wedge pressure, and patient will develop pulmonary edema inspite of normal ventricular function. This occurs due to alveolar – epithelial cell leak along with decreased oncotic pressure from the low serum albumin level.
Patients with preeclampsia showed certain adaptations such as increase in systemic blood pressure, with significant modification of left ventricular
structure and function. This is also related to the plasma levels of both atrial natriuretic peptide and brain natriuretic peptide35.
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Haemodynamic changes in pregnancy:
Pregnancy is associated with extensive anatomical and functional changes in the cardiovascular system so as to meet the demands of pregnancy. In pregnancy, there is a rapid expansion of the circulating blood volume with increase in heart rate and stroke volume associated with increase in cardiac output. Blood pressure decreases progressively until it reaches a nadir at 20–24 weeks and it increases progressively towards term. Hemodynamic adaptation can be detected from early pregnancy onwards. Generalised vasodilatation develops from the luteal phase after conception and peripheral vascular resistance fall starts after 5 weeks gestation, reaching values 34% lower than the preconceptional value at 20 weeks. As a result of this vasodilatation peripheral blood flow increases substantially, primarily in the uteroplacental, renal and cutaneous circulation.
Alterations in production or response to vasoactive substances like nitric oxide (NO), prostaglandins, angiotensin and endothelin also plays a important role in reduction of peripheral resistance in these vascular beds36.
In preeclampsia, the normal hemodynamic and vascular adaptive changes in pregnancy is disturbed. One longitudinal study regarding early hemodynamic changes of pregnancy showed that women who subsequently develop PE have increased cardiac output throughout the pregnancy. But cardiac output has been reported to be decreased or normal or increased after development of preeclampsia.
These different findings reflect the heterogeneity of preeclampsia. Late hemodynamic changes in preeclampsia are characterized by increase in blood
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pressure, reduction in plasma volume, increased peripheral vascular resistance and vasoconstriction36.
During normal pregnancy, the maternal blood volume increases markedly.
At or near term it increases about 40 to 50% above the nonpregnant levels. It starts to increase from the first trimester, expands rapidly in the second trimester and then rises at a slower rate during the third trimester to reach a plateau during the last weeks of pregnancy.
Increased blood volume results from increase in plasma volume and erythrocytes.
In pregnancy, plasma volume increases by 40 to 50% and the red cell mass increases by 30%.
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Pregnancy induced hypervolemia serves to meet the demands of the pregnant uterus with its hypertrophied vascular systems and to protect the mother and fetus from the deleterious effects of impaired venous return in the erect and supine position and to safeguard the mother from the adverse effects of blood loss occurs during parturition.
Augmentation of blood volume causes alterations in the stroke volume and cardiac output. Cardiac output during pregnancy is estimated to increase by 30 to 50% of nonpregnant state. It begins to rise around the fifth week and peaks between the middle of second and third trimesters. Cardiac output is maintained at the same level after third trimester. Changes in body position can produce substantial changes in cardiac output, its level rises in the lateral position and declines in the supine position. The early increase in cardiac output is due to augmented stroke volume that results from decreased peripheral vascular resistance. Later in pregnancy resting pulse increases and stroke volume also increases even more, probably because of increased diastolic filling from the expanded blood volume.
Heart rate also increases which peaks during the third trimester. The average increase in heart rate is about 10 to 15 beats/minute (Stein and coworkers 1999).
Systemic arterial pressure begins to fall in the first trimester and reaches a nadir in mid-pregnancy and returns to pre-pregnancy level before term. As the fall in diastolic pressure is greater than the fall in systolic pressure, pulse pressure widens. Blood pressure is the product of cardiac output and total peripheral resistance. Therefore, the reduction in blood pressure results from decline in total
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peripheral resistance which is due to vasodilatation. This is probably mediated by the presence of hormonal activity and increased levels of circulating prostaglandins in maternal circulation.
During pregnancy, there are some important hemodynamic variations occur which produces transient changes in preload and afterload of maternal heart. These changes are essential for the progression of successful pregnancy, but these changes may also impose additional load on the heart. Since, heart disease is the leading non obstetric cause of mortality during pregnancy and there risk for cardiovascular complications are also constantly increasing in pregnant women.
Because of this, identification and understanding cardiac structure and function and its changes in pregnancy have much clinical significance and is also essential for the management of cardiac patients in pregnancy37.
Despite there are many studies on maternal cardiac adaption being published, there is some controversy about the changes in left ventricular (LV) performance during pregnancy. Though it is reported that the increase in cardiac output (CO) is paralleled by reduced peripheral vascular resistance, the changes such as the enlargement of chamber size, LV wall thickness and mass are inconsistent .The myocardial systolic function parameters such as ejection fraction (EF), fractional shortening and tissue doppler velocity have been variously described as decreased, increased or remained constant . These parameters are load dependent, these variations are produced by the variations in ventricular loading conditions in pregnancy. These changes such as increase in left ventricular volume,
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LV mass and other components of myocardial deformation can be detected by echocardiographic study. These findings will help in dynamic assessment of the echocardiographic parameters during pregnancy and early detection of pregnancy- associated disorders 37.
Left ventricular mass increases during pregnancy, while the left ventricular diastolic function, which is determined by the changes in mitral valve flow velocities, increased in the first two trimesters but declines in the third trimester38. Clark and colleagues (1989) studies have contributed greatly to the understanding of cardiovascular physiology during pregnancy. Using invasive haemodynamic study methods, they reported that late pregnancy was associated with increases in stroke volume, heart rate and cardiac output with significant decrease in systemic vascular and pulmonary vascular resistance. But there was no change in intrinsic left ventricular contractility in pregnancy.
Haemodynamic alterations in preeclampsia:
In preeclampsia, the normal physiological changes of the haemodynamics of pregnancy are altered. Increase in intravascular volume which occurs in normal pregnancy is reduced or absent in patients with preeclampsia. This occurs due to generalised vasoconstriction and also by increased vascular permeability. Various cross-sectional studies in women with preeclampsia have revealed diverse hemodynamic findings like elevated cardiac output, increased vascular resistance and reduced intravascular fluid volume and reduced myocardial contractility. The
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physiological changes in left ventricular structure and function during normal pregnancy is exaggerated preeclamptic patients.39
High total vascular resistance (TVR) in preeclampsia suggests elevated afterload which is linked with reduced emptying of left ventricle. Elevated end systolic volume suggests that elevated end systolic pressure which is generated by increased afterload. The E wave velocity was found to be high in preeclamptic patients, suggests the greater transmittal pressure gradient during early passive filling and it also reflects the changes in passive myocardial compliance of hypertrophic ventricle. The higher peak A wave velocity observed in preeclampsia suggests the important role of atrial systole in filling of the hypertrophied ventricle.
The prolonged IVRT in preeclamptic subjects suggests that longer time is needed for left ventricular pressure to fall below the left atrial pressure. The E wave deceleration time is prolonged in preeclamptic subjects which is consistent with the increased passive filling time of left ventricle during early diastole. 39
Haemodynamic changes studied in women with preeclampsia using invasive cardiovascular monitoring by various investigators have shown that cardiovascular status changes from high cardiac output with low vascular resistance to low cardiac output with high vascular resistance. In addition to this, left ventricular filling pressures was found to be pathologically high which was estimated by pulmonary capillary wedge pressure.
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LEFT VENTRICULAR (LV) MECHANISM IN PREECLAMPSIA:
In preeclampsia, increased systemic vascular resistance and contracted blood volume are the characteristic findings. These alterations in hemodynamics can adversely affect the left ventricular performance making it difficult to differentiate the abnormalities that results from changes in load or from those produced by depressed myocardial contractility. To address this issue, a study was done with the contractility-sensitive, load-independent relationship between left ventricular end-systolic wall stress and rate-corrected velocity of fiber shortening in 10 nulliparous preeclamptic patients. Comparisons were made with the 10 age – matched normotensive pregnant women. Studies were performed by two- dimensionally targeted M-mode echocardiography and they calibrated carotid pulse tracings during early labor, 24 hours after delivery and 4 weeks after delivery. Patients with preeclampsia had increased blood pressure and increased total systemic resistance, during early labor and 1 day after delivery. By the end of 4 weeks of delivery,these parameters returned to normal. Before delivery and 1 day after delivery, the preeclamptic patients had lower overall left ventricular performance and increased left ventricular afterload, when compared with controls. These findings were not present 4 weeks after delivery. Despite the time- related intergroup differences in hemodynamics, left ventricular contractility was similar between preeclamptic subjects and normotensive controls at all stages of the study. The alterations seen in overall left ventricular performance of preeclamptic patients reflect an appropriate mechanical response to the increased afterload rather than the abnormality in the ventricular contractility.40
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In preeclampsia, especially in early-onset preeclampsia, the diastolic LV function is impaired and levels of biomarkers such as NT-pro-BNP and cystatin C, are also increased when compared to normotensive pregnancy. Atrial natriuretic peptide (ANP) and B- natriuretic peptide (BNP) which are secreted by cardiomyocytes are increased in response to stretch in atrial wall due to volume overload. These are vasoactive substances and that promote sodium and water excretion. Lowe and coworkers (1992) showed that plasma levels of ANP during normal pregnancy are maintained in the nonpregnant range despite the increase in plasma volume. These physiological adaptative changes may be important in the of extracellular fluid volume expansion in normal pregnancy.
Early-onset preeclampsia is associated with more severe cardiac impairment than with late-onset preeclampsia, and this is evidenced by an increased prevalence of diastolic dysfunction, concentric hypertrophy and higher levels of brain natriuretic peptide. Thus early-onset preeclampsia produces greater myocardial damage and it increases the cardiovascular morbidity risk in both peripartum and postpartum period.41
Pulmonary edema occurs in 3% of patients with preeclampsia and is one of the significant cause of maternal mortality and morbidity. Pulmonary edema may occur due to left ventricular dysfunction secondary to increased systemic vascular résistance, volume overload associated with contracted intravascular volume, reduced plasma colloid oncotic pressure or pulmonary capillary membrane injury.
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Preeclampsia is associated with significant cardiovascular morbidity both during pregnancy and also later in life. A prospective case-control study was done with 50 term preeclampsia patients and 50 normotensive pregnant women and both the groups were assessed by echocardiography and tissue Doppler analysis. They observed that global diastolic dysfunction was frequently studied in preeclamptic women when compared to controls (40% versus 14%, P = 0.007). Increased cardiac work and left ventricular mass indices in preeclamptic women suggests that the left ventricular remodeling was an adaptive response in order to maintain myocardial contractility. Approximately 20% of preeclamptic patients have more evident myocardial damage at term. Abnormalities in diastolic function usually precedes systolic dysfunction in the evolution of hypertensive cardiac diseases or myocardial ischemic changes and this has greater prognostic value in the prediction of long-term cardiovascular morbidity. 42
Diastolic dysfunction refers to abnormality in the ventricular filling during diastole. Any condition that produces impaired relaxation of left ventricle results in diastolic dysfunction.This is characterized by increased diastolic pressure of the left ventricle inspite of normal or subnormal diastolic volume. In preeclampsia, increased total peripheral resistance causes increase in afterload which makes the left ventricle become stiff thus leading to diastolic dysfunction.
When there is abnormality in left ventricular filling, blood regurgitates into left atrium and then into the lungs in backward direction leading to pulmonary edema.
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There are four patterns of diastolic dysfunction in echocardiography. The mildest form is called an abnormal relaxation pattern or grade 1 diastolic dysfunction is abnormal relaxation pattern. This is the mildest form and there will not be clinical signs and symptoms of heart failure whereas grade 2 and grade 3 patients have signs and symptoms of failure.
DIASTOLIC DYSFUNCTION GRADES:
GRADE I -impaired relaxation pattern with normal filling pressure (Ia = impaired relaxation pattern with increased filling pressure)
GRADE 2- Pseudonormal pattern GRADE 3
Reversible restrictive pattern Irreversible restrictive pattern
Pseudo-normal filling pattern is seen in grade 2 diastolic dysfunction. In this condition, the left atrial pressure rises due to progressive diastolic dysfunction.
This increased left atrial pressure increases the pressure gradient between the left ventricle and the left atrium which will act as a driving force for ventricular filling in early diastole. So the size of E wave relative to A wave will also increase and E/A ratio will be in the range of 0.8 to 1.5. There will be decrease in deceleration time (DT) and isovolumetric relaxation time. This pattern is similar to that of
“normal” diastolic function and so it is referred as “ pseudonormal‘’pattern.
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Several approaches were made to differentiate normal from pseudonormal filling pattern. Valsalva maneuver unmasks the diastolic dysfunction and alters pseudonormal filling into impaired relaxation. Other modalities like use of Tissue Doppler at the mitral annulus will guide us to estimate the filling pressure. When the average E/e’ ratio is above 14 then it is indicative of diastolic dysfunction and ratio between 8 and 12 indicate possible diastolic dysfunction.
Thus the subclinical diastolic dysfunction in patients with normal systolic function of left ventricle can be easily detected by echocardiography which cannot be detected by routine clinical examination and investigations like ECG.
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The above picture represents the E wave and A wave distribution in various grades of diastolic dysfunction.
ECHOCARDIOGRAPHY:
An echocardiogram is a noninvasive technique for imaging heart. It uses standard two-dimensional, three-dimensional, and Doppler ultrasound to produce
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images of the heart which helps in evaluating structural, functional and hemodynamic status of heart and cardiovascular system.
Echocardiography is routinely used in the diagnosis, management, and follow-up of patients with any known heart disease like congenital heart diseases, valvular heart diseases and hypertensive disorders and also other pregnancy complications on heart. It can also provide helpful information regarding the size and shape of the heart, pumping capacity of the heart and the location and extent of any tissue damage after any injury to heart. It also gives physician the information regarding other estimates of heart function, such as ejection fraction, cardiac output, systolic and diastolic function and its dysfunction during pregnancy.
It can also helps in accurate assessment of the blood flowing through the heart by using pulsed- or continuous-wave Doppler ultrasound. This also determines both normal and abnormal blood flow through the heart. Doppler technique is also used to measure tissue motion and velocity measurement, by tissue Doppler echocardiography. Echocardiography with doppler also assesses left ventricular systolic and diastolic function.
Advantages of echocardiography include that this is noninvasive, rapid, portable, readily available, does not require radiation, and in experienced hands, can provide an accurate and comprehensive assessment of LV systolic and diastolic function in pregnancy and other cardio vascular disorders of the heart like preeclampsia.
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Correct assessment of LV diastolic function is relevant in patients with both preserved LV ejection fraction (EF >50%) and depressed (EF < 50%) .Tissue Doppler (TD) imaging has been useful in demonstrating impaired LV relaxation in the cases with preserved LVEF, which causes increase in LV filling pressures and this produces dyspnea due to diastolic heart failure.
In patients with depressed LVEF, there will be impaired left ventricular relaxation and impaired left ventricular compliance. Thus in these cases, transmitral flow velocities (E and A, and E/A) and deceleration time, left atrial volume, pulmonary venous Doppler, and pulmonary artery (PA) pressures will be sufficient for the accurate assessment of LV filling pressures. Thus, the diastolic assessment by echo-Doppler can be readily achieved by incorporating many 2- dimensional and tissue Doppler imaging variables rather than relying on any single, diastolic parameter which may lead to errors.
The following parameters are most commonly used to define LV systolic function of heart:
1. Cardiac output 2. Ejection fraction 3. Fractional shortening
Cardiac output (CO): It is the amount of blood pumped by the heart per minute.
Cardiac output = stroke volume ×heart rate Average heart rate =70 beats per minute
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Average stroke volume= 70-80 ml/ beat Average cardiac output=5000ml/ minute
Cardiac output varies widely with the level of activity of body.
The above image showing the position of the cardiac probe (transducer) on the chest to acquire the parasternal long axis image. Note the index maker (red dot) on the probe should be towards right shoulder tip and the probe should be held softly and perpendicular to the chest.
