Posts Tagged ‘Blood pressure’

Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study

Reporter: Aviva Lev-Ari, PhD, RN


Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives

Results From the Pharmacogenomic Evaluation of Antihypertensive Responses Study

Yan Gong, PhD, Caitrin W. McDonough, PhD, Zhiying Wang, MS, Wei Hou, PhD,Rhonda M. Cooper-DeHoff, PharmD, MS, Taimour Y. Langaee, PhD, Amber L. Beitelshees, PharmD, MPH, Arlene B. Chapman, MD, John G. Gums, PharmD, Kent R. Bailey, PhD, Eric Boerwinkle, PhD, Stephen T. Turner, MD and Julie A. Johnson, PharmD

Author Affiliations

From the Department of Pharmacotherapy and Translational Research (Y.G., C.W.M., R.M.C.-D., T.Y.L., J.G.G., J.A.J.), Department of Biostatistics, College of Medicine (W.H.), Division of Cardiovascular Medicine, College of Medicine (R.M.C.-D., J.A.J.), and Department of Community Health and Family Medicine (J.G.G.), University of Florida, Gainesville, FL; Division of Epidemiology, University of Texas at Houston, Houston, TX (Z.W., E.B.); Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD (A.L.B.); Renal Division, Emory University, Atlanta, GA (A.B.C.); and Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (S.T.T.).

Correspondence to Yan Gong, PhD, Department of Pharmacotherapy and Translational Research, University of Florida, PO Box 100486, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail gong@cop.ufl.edu.


Background—To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs.

Methods and Results—We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical Pvalues were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected α of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3×10–6 for systolic BP; P=1.6×10–6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test.

Conclusions—These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.


Circulation: Cardiovascular Genetics.2012; 5: 686-691

Published online before print October 19, 2012,

doi: 10.1161/ CIRCGENETICS.112.964080


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Reporter: Aviva Lev-Ari, PhD, RN


Preeclampsia is a disorder that occurs only during pregnancy and the postpartum period and affects both the mother and the unborn baby. Affecting at least 5-8% of all pregnancies, it is a rapidly progressive condition characterized by high blood pressure and the presence of protein in the urine. Swelling, sudden weight gain, headaches and changes in vision are important symptoms; however, some women with rapidly advancing disease report few symptoms.

Typically, preeclampsia occurs after 20 weeks gestation (in the late 2nd or 3rd trimesters or middle to late pregnancy) and up to six weeks postpartum, though in rare cases it can occur earlier than 20 weeks. Proper prenatal care is essential to diagnose and manage preeclampsia. Pregnancy Induced Hypertension (PIH) and toxemia are outdated terms for preeclampsia. HELLP syndrome and eclampsia (seizures) are other variants of preeclampsia.

Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year.


VIEW VIDEO – SIX Sections, Pauses in between


  • Preeclampsia vs. Pregnency -Induced Hypertension
  • When Preeclampsia Occur
  • Preeclampsia – Effects on Fetus Health
  • Preeclampsia – Effects on the Baby

Genetic Aspects of Pre-eclampsia

The genetics of pre-eclampsia and other hypertensive disorders of pregnancy

Human Genetics Research Group, School of Molecular and Medical Sciences, University of Nottingham, A Floor West Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK
*Corresponding author. Tel.: +44 (0) 115 8230758; Fax: +44 (0) 115 8230759. Email: Paula.Williams@nottingham.ac.uk
Epidemiological studies clearly confirm a genetic component to pre-eclampsia. Numerous candidate genes have been studied that fall into groups based on their proposed pathological mechanism, including

  • thrombophilia,
  • endothelial function,
  • vasoactive proteins,
  • oxidative stress and
  • lipid metabolism and
  • immunogenetics.
It is expected that no one gene will be identified as the sole risk factor for pre-eclampsia, as in the general population pre-eclampsia represents a complex genetic disorder. Interactions between numerous SNP either alone or with combination with predisposing environmental factors, are most likely underpin the genetic component of this disorder. We must be cautious in our approach to genetics and acknowledge that we are still in the infancy of this research. Following on from GWAS, further fine mapping studies to delineate SNP that are causal from those that are in linkage disequilibrium, followed by functional laboratory studies will be required. Only when we have a better understanding of how the environment interacts with genes will we be in a better position to target treatment for women, for example knowing that women with a certain genotype will benefit from losing weight, enabling us to yield clinical benefit.
At present no genetic test is available to predict pre-eclampsia. The lack of a predictive test can be overcome by careful monitoring and assessment of women, especially those in high-risk groups, including:

    Those at either end of the reproductive age spectrum•Obesity•Black ethnicity•Primiparity•Previous history of pre-eclampsia•Multiple pregnancy•Pre-existing medical conditions: renal disease, insulin-dependent diabetes, autoimmune disease, antiphospholipid syndrom

Genetic aspects of pre-eclampsia

Clustering of cases of pre-eclampsia within families has been recognised since the 19th century, suggesting a genetic component to the disorder.2 Deciphering the genetic involvement in pre-eclampsia is challenging, not least because the phenotype is expressed only in parous women. Furthermore, in complex disorders of pregnancy, it is necessary to consider two genotypes, that of the mother and that of the fetus, which includes genes inherited from both mother and father. Maternal and fetal genes may have independent or interactive effects on the risk of pre-eclampsia. Finally, the heterogeneous nature of the disorder, with a sliding scale of severity, has resulted in differences in the definition of pre-eclampsia used within studies (see above), often with overlap of non-proteinuric gestational hypertension.

Twin studies investigating the relative contribution of genetic versus environmental factors to pre-eclampsia risk, initially yielded disappointing results. They showed that discordance for pre-eclampsia between monozygotic twin sisters was common, suggesting that heritability caused by maternal genes was low.3 These early studies were small. More recent investigations, however, using the large Swedish Twin, Medical Birth and Multigeneration Registries have estimated the heritability of pre-eclampsia to be about 55%, with contributions from both maternal and fetal genes. A further study in monozygotic twins4 found concordance of pre-eclampsia to be as common as discordance. Evidence from the largest published twin study, which correlated the Swedish Twin Register with the Swedish Medical Register, revealed pre-eclampsia penetrance to be less than 50%, suggesting diversity within models of inheritance.5–7

Pre-eclampsia: a complex genetic disorder

For a small number of families, pre-eclampsia seems to follow Mendelian patterns of disease inheritance,8 consistent with a rare deleterious monogenic variant or mutation with high penetrance. For most of the population, however, pre-eclampsia seems to represent a complex genetic disorder, and occurs as the result of numerous common variants at different loci which, individually, have small effects but collectively contribute to an individual’s susceptibility to disease. Environmental exposures, including age and weight, also determine whether these low penetrant variants result in phenotypic manifestation of the disease. It is likely that no single cause or genetic variant will account for all cases of pre-eclampsia, although it is possible that different variants are associated with various subsets of disease (e.g. pre-eclampsia combined with intrauterine growth restriction). Complex genetic disorders affect a high proportion of the population, representing a large burden to public health. New approaches to susceptibility gene discovery have emerged to address this challenge. Unfortunately, early diagnosis would only permit closer focus on routine antenatal care, as at present no intervention other than delivery has been shown to alter the course of pre-eclampsia.

Determining susceptibility to pre-eclampsia

The need to assess both the maternal and the fetal genotype is clear. The role of the placenta in the primary pathogenesis of the disorder indisputably indicates a fetal contribution to susceptibility to the disorder.9 Reports of severe, very early-onset pre-eclampsia in cases of fetal chromosomal abnormalities such as diandric hydatifidiform moles of entirely paternal genetic origin10 are consistent with a role for paternally inherited fetal genes in the determination of clinical phenotype. This is supported by epidemiological studies reporting a higher rate of pre-eclampsia in pregnancies fathered by men who were themselves born of pre-eclamptic pregnancies.11 The occurrence of pre-eclampsia in daughters-in-law of index women9 further supports a genetic contribution from both parents. The genetic conflict hypothesis states that fetal (paternal) genes will be selected to increase the transfer of nutrients to the fetus, whereas maternal genes will be selected to limit transfer in excess of a specific maternal optimum.12 Fetal genes are predicted to raise maternal blood pressure in order to enhance the uteroplacental blood flow, whereas maternal genes act the opposite way. Endothelial dysfunction in mothers with pre-eclampsia could, therefore, be interpreted as a fetal attempt to compensate for an inadequate uteroplacental nutrient supply.

As the phenotype is apparently only expressed during pregnancy, identification of ‘susceptible’ men is impossible. Most genetic studies of pre-eclampsia have focused on maternal genotypes only. The Genetics of Pre-eclampsia consortium highlighted the need to include analysis of all contributing genotypes, and carried out transmission disequilibrium testing in maternal and fetal triads.13 Understanding the contribution of the fetal genotype will require large sample sizes, with the development of algorithms to determine the relative contribution from mother and fetus. Furthermore, the decreased incidence of pre-eclampsia in second and subsequent pregnancies hampers analysis of the contribution of the fetal genotype.

Candidate gene approach

The candidate gene approach has been widely used in pre-eclampsia, and largely focuses on the maternal genotype. In this method, a single gene is chosen as the candidate for investigation based on prior biological knowledge of the pathophysiology of pre-eclampsia. The choice is strengthened if the gene lies within a region identified by linkage studies. A case-control design is usually used, comparing the frequencies of allelic variants in women with pre-eclampsia and normotensive pregnancies. Such studies need careful definition of inclusion criteria for cases and controls, and subtle ethnic stratification of groups must be avoided. Such performance characteristics of the genotyping assays as the rate of mis-genotyping, and the quality assurance methods used, should be clearly stated, but this is rarely done. Over 70 biological candidate genes have been examined, representing pathways involved in various pathophysiological processes, including vasoactive proteins, thrombophilia and hypofibrinolysis, oxidative stress and lipid metabolism, endothelial injury and immunogenetics.14 In common with the experience in other genetically complex disorders, results from candidate gene studies have been inconsistent, and no universally accepted susceptibility gene has been identified. Although this may, in part, be attributed to variation within populations, a more important factor is the small size of most of the candidate studies, which have been underpowered to detect variants with small effects. As there are more than 20,000 genes and 10 million single nucleotide polymorphisms (SNP) available, multiple testing will inevitably result in numerous results that achieve P values of less than 0.05. The development of robust statistical techniques for the minimisation of both false positive and false negative results is an important area.15,16 Only in recent years, as susceptibility genes for other complex disorders have been reported, has the small effect size of individual genetic variants become apparent, the majority increasing the risk of disease by less than 50%. A further limitation of the candidate gene approach is its reliance on the generation of an a-priori hypothesis based on our current incomplete knowledge of the pathophysiology of the disorder. The candidate genes studied belong to different groups according to their functional properties and plausible role in the pathophysiology (Table 2).


A successful pregnancy requires the development of adequate placental circulation. It is hypothesised that thrombophilias may increase the risk of placental insufficiency because of placental micro-vascular thrombosis, macro-vascular thrombosis, or both, as well as effects on trophoblast growth and differentiation.17 Abnormalities of the clotting cascade are well documented in women with pre-eclampsia.18 The endothelial damage of pre-eclampsia is associated with an altered phenotype from anticoagulant to procoagulant and decreased endothelially mediated vasorelaxation. It is possible that this phenotype is present before pre-eclampsia in pregnancy, or it may develop as a consequence of damage initiated during placentation. Furthermore, a subset of women develop frank thrombocytopaenia, often in association with haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Association of the three most widely studied thrombophilic factors, factor V Leiden (F5), methylenetetrahydrofolate (MTHFR) and prothrombin (F2), with pre-eclampsia has been shown; however, several studies have also shown contradictory results.14 A recent meta-analysis indicated a two-fold increase in risk for pre-eclampsia associated with 1691G>A mutation in F5, but no associations were found for MTHFR or F2.19 To date, the number of studies showing no association with pre-eclampsia for these three genes is much higher than the number confirming association. Association with the inhibitor of fibrinolysis plasminogen activator factor-1 gene has also been reported; however, replication attempts have failed.20–22

Haemodynamics and endothelial function

The renin-angiotensin system (RAS) is important for regulating the cardiovascular and renal changes that occur in pregnancy. Several studies have implicated the RAS in the pathophysiology of pre-eclampsia.23 As such, genes in the RAS have been considered as plausible candidates for pre-eclampsia. Angiotensin-converting enzyme (ACE), angiotensin II type 1 and type 2 receptor (AGTR1, AGTR2), and angiotensinogen (AGT) have all been studied extensively in pre-eclampsia. Recent meta-analyses have identified the T allele of AGT M235T as increasing the risk of developing pre-eclampsia by 1.62 times and similar increases in disease risk have been found in AGT and the angiotensin-converting enzyme I/D polymorphism.24 A rare functional polymorphism in AGT, which results in replacement of leucine by phenylalanine at the site of renin cleavage, has been reported in association with severe pre-eclampsia.25

Endothelial nitric oxide synthase 3 (eNOS3), which is involved in vascular remodelling and vasodilation, has been shown to have reduced activity in pre-eclampsia26 Association studies in different ethnic populations, however, have yielded both positive and negative findings. A meta-analysis investigating the E298D polymorphism, which had initially been associated with pre-eclampsia in Colombian women, failed to find increased risk.24 Vascular endothelial growth factor (VEGF) is important for endothelial cell proliferation, migration, survival and regulation of vascular permeability. The number of studies that have investigated SNP in the genes involved in the VEGF system is small. Two polymorphisms in VEGF, 405G>C and 936C>T, were found to be associated with the severe form of pre-eclampsia in two small studies, but cannot at present be considered as major risk factors.27,28

Oxidative stress and lipid metabolism

Oxidative stress plays a central role in the pathogenesis of pre-eclampsia. Maternal perfusion of the placenta does not occur until towards the end of the first trimester,29 when a rapid increase in local oxygen tension takes place, and the probable occurrence of a period of hypoxia–reperfusion until stability is reached. This is accompanied by increased expression and activity of such antioxidants as glutathione peroxidase, catalase and the various forms of superoxide dismutase.30 If this antioxidant response were reduced, then the cascade of events leading to impaired placentation could be initiated. Evidence for reduced antioxidant activity in pre-eclampsia has recently been reviewed.31 Genes involved in the generation or inactivation of reactive oxygen species, if defective, could increase endothelial dysfunction via lipid peroxidation, which has been a candidate causative agent for the endothelial damage of pre-eclampsia for more than 20 years.32 Despite the strong correlation between oxidative stress and pre-eclampsia, only a small handful of genes have been investigated. Functional polymorphisms in the gene for microsomal epoxide hydrolase (EPHX) that catalyses the hydrolysis of certain oxides and may produce toxic intermediates that could be involved in pre-eclampsia, and glutathione S-transferase (GST), an antioxidant capable of inactivating reactive oxygen species, have shown associations. Conflicting results, however, have also been reported.33–36

Abnormal lipid profiles associated with the lipid peroxidation caused by oxidative stress are also characteristic of pre-eclampsia. Lipoprotein lipase (LPL) and apolipoprotein E (ApoE) are the two major regulators of lipid metabolism, abundantly expressed in placenta, and have therefore been proposed as possible candidate genes.37,38 A recent study using bioinformatic analysis identified altered glycosylation of circulating ApoE isoforms in pre-eclampsia.39 A deglycosylated basic ApoE isoform was increased in pre-eclampsia, and an acidic ApoE sialyated isoform was decreased. Functionally, this might increase the risk of developing placental atherotic changes. The most promising genetic variant in this context is a mis-sense mutation, Asn291Ser, in LPL which correlates with lowered LPL activity and increased dyslipidaemia in two separate studies. Again, others have failed to replicate these findings.38,40,41 The fetal genotype of these two genes has also been reported to contribute to the metabolism of the maternal lipoproteins.37

Immune system

The maternal immune response to pregnancy is crucial in determining pregnancy outcome and success. The increased incidence of pre-eclampsia in primiparous women, especially those at either end of the childbearing age range, indicates a strong association between immune factors and pre-eclampsia.42 However, the protective effect of multiparity is lost with change of partner. Advances in assisted reproductive technology are also posing new challenges to the maternal immune system. The use of donated sperm or eggs increases the risk of pre-eclampsia three-fold.43

Human leucocyte antigen

Trophoblast cells express an unusual repertoire of histocompatibility antigens, comprising human leucocyte C, E and G class antigens (HLA-C, HLA-E, HLA-E), of which only HLA-C displays marked polymorphism. The expression of HLA on the invading cytotrophoblast is important, as these interact with killer immunoglobulin, such as receptors (KIR) expressed on maternal uNKs and cytotoxic T-lymphocytes, down-regulating their cytolytic activity and stimulating the production of cytokines needed for successful placentation. Multiple highly homologous KIR genes map to chromosome 19q, probably arising from ancestral gene duplications, and the two main resulting gene clusters have been classified as haplotypes A and B. The A group codes mainly for KIR, which inhibit natural killer cells, whereas the B group has additional stimulatory genes.44 Pre-eclampsia is more frequent in women who are homozygous for the inhibitory A haplotypes (AA) than in women homozygous for the stimulatory B haplotypes (BB). The effect is strongest if the fetus is homozygous for the HLA-C2 haplotype.45 Alteration in KIR interaction on uNK cells with HLA-C on interstitial trophoblast alters the decidual immune response, resulting in impaired extravillous trophoblast invasion and deficient spiral artery remodelling, associated with pre-eclampsia.

An association of HLA-G, which displays limited polymorphism, with pre-eclampsia, has also been reported. A possible association between the presence of the HLA-G allele G*0106 in the placenta and an increased risk of pre-eclampsia has been identified in two small studies.46,47 these were underpowered, however, and further studies using larger cohorts of mothers and babies are needed to replicate these results. HLA-G variants foreign to the mother may lead to histo-incompatibility between mother and child. A maternal rejection response to the semi-allogeneic fetus may represent one of the pathways involved in the development of pre-eclampsia.

A number of pro-inflammatory cytokines have also been investigated for possible associations with pre-eclampsia. Excessive release of tumour necrosis factor alpha (TNFα) has been implicated owing to its contribution to endothelial activation, which in turn could contribute to maternal symptoms.48 Interestingly, in pregnant rats, TNF induces hypertension, a response not seen in non-pregnant rats.49 Furthermore, plasma levels of TNFα are significantly higher in women with pre-eclampsia than matched controls.50 TNFα is also involved in the production of reactive oxygen species and subsequently oxidant mediated endothelial damage. The most frequently studied variant in pre-eclampsia is the –308G>A transition in the promoter region, which is associated with increased levels of TNFα production and an increased risk for pre-eclampsia linked disorders, including type 2 diabetes, coronary artery disease and dyslipidaemia.51,52 However, a meta-analysis from 2008 combined 16 studies investigating this promoter SNP, but failed to detect a significant association to pre-eclampsia.53

Interleukin-10 (IL-10) has also been implicated in the pathogenesis of pre-eclampsia by enhancing the inflammatory response towards trophoblast cells resulting in reduced invasion and remodelling of the spiral arteries.54 Expression of IL-10 is reduced in pre-eclamptic placentae.55 Studies investigating associations of variants of the gene and pre-eclampsia, however, have yielded conflicting results.56–58 Associations have also been detected for two additional inflammatory genes, interleukin-1α (IL-1α) and the interleukin 1 receptor anatagonist (IL1Ra) in relatively small studies, but few studies have addressed the role of polymorphisms in these genes so far.59,60

Antioxidant enzymes

A large family of cytosolic glutathione-s-transferases (GST) exists, and the P class is highly expressed in the human placenta. Several relatively small case-control studies of polymorphisms in this family in relation to pre-eclampsia have failed to identify any significant effect of several GST polymorphisms studied individually. However, a cumulative effect of the number of polymorphisms in various biotransformation enzymes, including GST, which would result in decreased antioxidant capacity, has been reported.61 Intriguingly, the use of semi-quantitative polymerase chain reaction on a small data set identified using serial analysis of gene expression profiles, seems to identify a specific molecular signature for HELLP, which includes decreased expression of GST P1.62

Remarkably, few studies of possible functional polymorphisms in antioxidant enzyme systems have been reported. The 242C>T polymorphism in exon 4 of the gene for the p22phox subunit of NADPH/NADH oxidase (CYBA), which is part of the cascade of superoxide generation, has been reported as showing no evidence of an association with either pre-eclampsia or HELLP and pre-eclampsa.63 A small preliminary study of the Ala40Thr polymorphism of the superoxide dismutase 3 gene (SOD3), which has been associated with insulin resistance, reported a significant excess of the mutant allele in women with severe intrauterine growth restriction.64


High blood pressure in pregnancy: What’s your story?

By Mary M. Murry, R.N., C.N.M.

Blood pressure tends to fluctuate during pregnancy.

For example, it’s normal to experience a drop in blood pressure during the second trimester. In fact, your blood pressure might be lower than it’s ever been. During the third trimester, a gradual increase in blood pressure is common.

Sometimes, though, blood pressure changes more dramatically — or sustained high blood pressure becomes a concern.

By definition, there are various types of high blood pressure during pregnancy:

  • Chronic hypertension. If high blood pressure develops before pregnancy or during pregnancy but before 20 weeks, it’s known as chronic hypertension. High blood pressure that lasts more than 12 weeks after delivery is also considered chronic hypertension.
  • Gestational hypertension. If high blood pressure develops after 20 weeks of pregnancy, it’s known as gestational hypertension. Gestational hypertension usually goes away after delivery.
  • Preeclampsia. Sometimes chronic hypertension or gestational hypertension leads to preeclampsia. This is a serious condition characterized by high blood pressure and protein in the urine after 20 weeks of pregnancy.

All of these conditions can be dangerous for you and your baby. If your pregnancy has been normal until now, a diagnosis of high blood pressure can be especially jarring.

Depending on the circumstances, your health care provider might recommend close monitoring or, in some cases, an early delivery.

Count on your health care provider to help you understand what’s happening and what you can do to promote a healthy outcome. Above all, don’t hesitate to ask questions. Being fully informed can help you make the best decisions for you and your baby.


Texas A&M Researcher Uncovers New Data for the Treatment of Preeclampsia

Posted Thursday , June 06,2013


A Researcher From Texas A&M Has Uncovered New Data for the Treatment of Preeclampsia: Preclinical Research Shows PLX Cells May Be Effective in Treating Preeclampsia.

Preliminary research led by Brett Mitchell, PhD, an Associate Professor of Internal Medicine in the Cardiovascular Research Institute (CVRI) at Texas A&M University College of Medicine, is demonstrating that administrating placental stem cells may aid in reversing symptoms linked with preeclampsia within days after dosing with no apparent harmful effects to fetus or mother.

Preeclampsia may occur after the 20th week of pregnancy when the mother-to-be’s blood pressure has increased and there are signs of excessive protein in the urine. This condition affects somewhere between 6-8 percentage of pregnancies in the US, and can be serious, as there is a shift from protecting mother and fetus as immunologically privileged sites. This brings about vascular issues that involve the inability of blood vessels to dilate or relax.

Dr. Mitchel has been able to look at the immune cells that are responsible for the development of high blood pressure (hypertension) during pregnancy in hopes to develop new therapies that diminish the immune cells that are responsible for this action while maintaining normal immune cell function.

Mitchel and colleagues have taken mice that had preeclampsia and injected placenta-based cells (stem cells) known as PLX (Placentall eXpanded) into leg muscle.  PLX cells are used as a way of delivering drugs and in particular therapeutic proteins in response to inflammatory and ischemic events.  They tested eight groups of 2 separate animal models (preeclampsia models) and found that PLX cells were effective in treating preeclampsia.

They observed a reduction in

  • systolic pressure to normal levels within 3 days and a reduction of
  • urinary proteins within 4 days.

They also observed an

  • increase in endothelial function.  This was measured by acetylcholine-induced relaxation and was effective within 4 days. A
  • weight reduction of the spleen was also observed within 4 days.

Pregnant mice who didn’t have preeclampsia were subjected to the same protocol and it was found that muscle injection of PLX cells did not effect a normal pregnancy.  They also found that the number of pups or fetal demise in a litter were not different indicating that PLX cells caused no fetal harm.

Dr. Mitchel presented his findings at the Society for Gynecologic Investigation Summit in Jerusalem on May 30, 2013.  Mitchell suggests that the factors that were secreted from the PLX cells were able to decrease inflammation thereby restoring endothelial function.

Currently, there are no treatments available for preeclampsia, so this therapy looks promising.




  1. Pregnancy. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/hbp/issues/preg/preg.htm. Accessed March 9, 2011.
  2. Conde-Agudelo A, et al. Maternal infection and risk of preeclampsia: Systematic review and metaanalysis. American Journal of Obstetrics and Gynecology. 2008;198:7.
  3. Bodnar LM, et al. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology & Metabolism. 2007;92:3517.
  4. High blood pressure and preeclampsia. March of Dimes. http://www.marchofdimes.com/complications_preeclampsia.html. Accessed March 9, 2011.
  5. Norwitz ER, et al. Management of preeclampsia. http://www.uptodate.com/home/index.html. Accessed March 7, 2011.
  6. Leanos-Miranda A, et al. Urinary prolactin as a reliable marker for preeclampsia, its severity, and the occurrence of adverse pregnancy outcomes. Journal of Clinical Endocrinology & Metabolism. 2008;93:2492.
  7. August P, et al. Clinical features, diagnosis, and long-term prognosis of preeclampsia. http://www.uptodate.com/home/index.html. Accessed March 7, 2011.
  8. Sibai BM, et al. Hypertension. In: Gabbe SG, et al. Obstetrics: Normal and Problem Pregnancies. 5th ed. Philadelphia, Pa.: Churchill Livingstone Elsevier; 2007. http://www.mdconsult.com/das/book/body/208746819-4/0/1528/0.html. Accessed March 9, 2011.
  9. Barton JR, et al. Prediction and prevention of recurrent preeclampsia. Obstetrics & Gynecology. 2008;112:359.
  10. Bellamy L, et al. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: Systematic review and meta-analysis. British Medical Journal. 2007;335:974.
  11. Facchinetti F, et al. Migraine is a risk factor for hypertensive disorders in pregnancy: A prospective cohort study. Cephalalgia: An International Journal of Headache. 2009;29:286.
  12. Steegers EA, et al. Pre-eclampsia. The Lancet. 2010;376:631.



1. Brown M.A., Lindheimer M.D., de Swiet M. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP) Hypertens Pregnancy. 2001;20:IX–XIV. [PubMed: 12044323]
2. Chesley L.C., Annitto J.E., Cosgrove R.A. The familial factor in toxemia of pregnancy. Obstet Gynecol. 1968;32:303–311. [PubMed: 5742111]
3. Thornton J.G., Macdonald A.M. Twin mothers, pregnancy hypertension and pre-eclampsia. Br J Obstet Gynaecol. 1999;106:570–575.[PubMed: 10426615]
4. O’Shaughnessy K.M., Ferraro F., Fu B. Identification of monozygotic twins that are concordant for preeclampsia. Am J Obstet Gynecol. 2000;182:1156–1157. [PubMed: 10819852]
5. Chappell S., Morgan L. Searching for genetic clues to the causes of pre-eclampsia. Clin Sci (Lond) 2006;110:443–458. [PubMed: 16526948]
6. Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res.2004;6(Suppl. 2):S125–140. [PubMed: 15203816]
7. Salonen Ros H., Lichtenstein P., Lipworth L. Genetic effects on the liability of developing pre-eclampsia and gestational hypertension. Am J Med Genet.2000;91:256–260. [PubMed: 10766979]
8. Redman C.W., Sargent I.L. Latest advances in understanding preeclampsia. Science. 2005;308:1592–1594. [PubMed: 15947178]
9. Cooper D.W., Brennecke S.P., Wilton A.N. Genetics of pre-eclampsia. Hypertens Pregnancy. 1993;12:1–23.
10. Esplin M.S., Fausett M.B., Fraser A. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344:867–872.[PubMed: 11259719]
11. Skjaerven R., Vatten L.J., Wilcox A.J. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005;331:877. [PMCID: PMC1255793] [PubMed: 16169871]
12. Haig D. Genetic conflicts in human pregnancy. Q Rev Biol. 1993;68:495–532. [PubMed: 8115596]
13. GOPEC Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study. Am J Hum Genet. 2005;77:127–131. [PMCID: PMC1226184] [PubMed: 15889386]
14. Mutze S., Rudnik-Schoneborn S., Zerres K. Genes and the preeclampsia syndrome. J Perinat Med. 2008;36:38–58. [PubMed: 18184097]
15. Colhoun H., McKeigue P., Davey Smith G. Problems of reporting genetic associations with comlex outcomes. Lancet. 2003;361:865–872.[PubMed: 12642066]
16. Wacholder S., Chanock S., Garcia-Closas M. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96:434–442. [PubMed: 15026468]
17. Isermann B., Sood R., Pawlinski R. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med. 2003;9:331–337.[PubMed: 12579195]
18. Brenner B. Thrombophilia and pregnancy loss. Thromb Res. 2002;108:197–202. [PubMed: 12617981]
19. Lin J., August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005;105:182–192. [PubMed: 15625161]
20. Dalmaz C.A., Santos K.G., Botton M.R. Relationship between polymorphisms in thrombophilic genes and preeclampsia in a Brazilian population. Blood Cells Mol Dis. 2006;37:107–110. [PubMed: 16963292]
21. Fabbro D., D’Elia A.V., Spizzo R. Association between plasminogen activator inhibitor 1 gene polymorphisms and preeclampsia. Gynecol Obstet Invest.2003;56:17–22. [PubMed: 12867763]
22. Gerhardt A., Goecke T.W., Beckmann M.W. The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia. J Thromb Haemost. 2005;3:686–691. [PubMed: 15842353]
23. Shah N.C., Pringle S., Struthers A. Aldosterone blockade over and above ACE-inhibitors in patients with coronary artery disease but without heart failure.J Renin Angiotensin Aldosterone Syst. 2006;7:20–30. [PubMed: 17083070]
24. Medica I., Kastrin A., Peterlin B. Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol.2007;131:115–126. [PubMed: 17112651]
25. Inoue I., Rohrwasser A., Helin C. A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system.J Biol Chem. 1995;270:11430–11436. [PubMed: 7744780]
26. Brennecke S.P., Gude N.M., Di Iulio J.L. Reduction of placental nitric oxide synthase activity in pre-eclampsia. Clin Sci (Lond) 1997;93:51–55.[PubMed: 9279203]
27. Banyasz I., Bokodi G., Vannay A. Genetic polymorphisms of vascular endothelial growth factor and angiopoietin 2 in retinopathy of prematurity. Curr Eye Res. 2006;31:685–690. [PubMed: 16877277]
28. Papazoglou D., Galazios G., Koukourakis M.I. Vascular endothelial growth factor gene polymorphisms and pre-eclampsia. Mol Hum Reprod.2004;10:321–324. [PubMed: 14997002]
29. Foidart J., Hustin J., Dubois M. The human placenta becomes haemochorial at the 13th week of pregnancy. Int J Dev Biol. 1992;36:451–453.[PubMed: 1445791]
30. Jauniaux E., Watson A., Hempstock J. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000;157:2111–2122. [PMCID: PMC1885754] [PubMed: 11106583]
31. Perkins A.V. Endogenous anti-oxidants in pregnancy and preeclampsia. Aust N Z J Obstet Gynaecol. 2006;46:77–83. [PubMed: 16638026]
32. Wickens D., Wilkins M.H., Lunec J. Free radical oxidation (peroxidation)products in plasma in normal and abnormal pregnancy. Ann Clin Biochem.1981;18:158–162. [PubMed: 7283366]
33. Canto P., Canto-Cetina T., Juarez-Velazquez R. Methylenetetrahydrofolate reductase C677T and glutathione S-transferase P1 A313G are associated with a reduced risk of preeclampsia in Maya-Mestizo women. Hypertens Res. 2008;31:1015–1019. [PubMed: 18712057]
34. Gebhardt G.S., Peters W.H., Hillermann R. Maternal and fetal single nucleotide polymorphisms in the epoxide hydrolase and gluthatione S-transferase P1 genes are not associated with pre-eclampsia in the Coloured population of the Western Cape, South Africa. J Obstet Gynaecol. 2004;24:866–872.[PubMed: 16147638]
35. Laasanen J., Romppanen E.L., Hiltunen M. Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are jointly associated with preeclampsia. Eur J Hum Genet. 2002;10:569–573. [PubMed: 12173035]
36. Ohta K., Kobashi G., Hata A. Association between a variant of the glutathione S-transferase P1 gene (GSTP1) and hypertension in pregnancy in Japanese: interaction with parity, age, and genetic factors. Semin Thromb Hemost. 2003;29:653–659. [PubMed: 14719182]
37. Descamps O.S., Bruniaux M., Guilmot P.F. Lipoprotein metabolism of pregnant women is associated with both their genetic polymorphisms and those of their newborn children. J Lipid Res. 2005;46:2405–2414. [PubMed: 16106048]
38. Kim Y.J., Williamson R.A., Chen K. Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia. Hypertension. 2001;38:992–996.[PubMed: 11711487]
39. Atkinson K.R., Blumenstein M., Black M.A. An altered pattern of circulating apolipoprotein E3 isoforms is implicated in preeclampsia. J Lipid Res.2009;50:71–80. [PubMed: 18725658]
40. Hubel C.A., Roberts J.M., Ferrell R.E. Association of pre-eclampsia with common coding sequence variations in the lipoprotein lipase gene. Clin Genet.1999;56:289–296. [PubMed: 10636447]
41. Zhang C., Austin M.A., Edwards K.L. Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women. Clin Genet. 2006;69:33–39. [PubMed: 16451134]
42. Roberts J.M., Pearson G., Cutler J. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension.2003;41:437–445. [PubMed: 12623940]
43. Wang J.X., Knottnerus A.M., Schuit G. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet. 2002;359:673–674.[PubMed: 11879865]
44. Hiby S.E., Walker J.J., O’Shaughnessy K.M. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200:957–965. [PMCID: PMC2211839] [PubMed: 15477349]
45. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201–214. [PubMed: 15719024]
46. Moreau P., Contu L., Alba F. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage.Biol Reprod. 2008;79:459–467. [PubMed: 18509163]
47. Tan C.Y., Ho J.F., Chong Y.S. Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies. Mol Hum Reprod. 2008;14:317–324. [PubMed: 18353802]
48. LaMarca B.D., Ryan M.J., Gilbert J.S. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep.2007;9:480–485. [PubMed: 18367011]
49. Alexander B.T., Cockrell K.L., Massey M.B. Tumor necrosis factor-alpha-induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression. Am J Hypertens. 2002;15:170–175. [PubMed: 11863253]
50. Sharma A., Satyam A., Sharma J.B. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol. 2007;58:21–30. [PubMed: 17565544]
51. Elahi M.M., Asotra K., Matata B.M. Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta. 2009;1792:163–172. [PubMed: 19708125]
52. Saarela T., Hiltunen M., Helisalmi S. Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia. Mol Hum Reprod. 2005;11:437–440. [PubMed: 15901845]
53. Bombell S., McGuire W. Tumour necrosis factor (-308A) polymorphism in pre-eclampsia: meta-analysis of 16 case-control studies. Aust N Z J Obstet Gynaecol. 2008;48:547–551. [PubMed: 19133041]
54. Renaud S.J., Macdonald-Goodfellow S.K., Graham C.H. Coordinated regulation of human trophoblast invasiveness by macrophages and interleukin 10.Biol Reprod. 2007;76:448–454. [PubMed: 17151353]
55. Makris A., Xu B., Yu B. Placental deficiency of interleukin-10 (IL-10) in preeclampsia and its relationship to an IL10 promoter polymorphism. Placenta.2006;27:445–451. [PubMed: 16026832]
56. Daher S., Sass N., Oliveira L.G. Cytokine genotyping in preeclampsia. Am J Reprod Immunol. 2006;55:130–135. [PubMed: 16433832]
57. Goddard K.A., Tromp G., Romero R. Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes. Hum Hered. 2007;63:1–16. [PubMed: 17179726]
58. Kamali-Sarvestani E., Kiany S., Gharesi-Fard B. Association study of IL-10 and IFN-gamma gene polymorphisms in Iranian women with preeclampsia.J Reprod Immunol. 2006;72:118–126. [PubMed: 16863661]
59. Faisel F., Romppanen E.L., Hiltunen M. Polymorphism in the interleukin 1 receptor antagonist gene in women with preeclampsia. J Reprod Immunol.2003;60:61–70. [PubMed: 14568678]
60. Haggerty C.L., Ferrell R.E., Hubel C.A. Association between allelic variants in cytokine genes and preeclampsia. Am J Obstet Gynecol. 2005;193:209–215.[PubMed: 16021081]
61. Zusterzeel P.L., Peters W.H., Burton G.J. Susceptibility to pre-eclampsia is associated with multiple genetic polymorphisms in maternal biotransformation enzymes. Gynecol Obstet Invest. 2007;63:209–213. [PubMed: 17167268]
62. Buimer M., Keijser R., Jebbink J.M. Seven placental transcripts characterize HELLP-syndrome. Placenta. 2008;29:444–453. [PubMed: 18374411]
63. Raijmakers M.T., Roes E.M., Steegers E.A. The C242T-polymorphism of the NADPH/NADH oxidase gene p22phox subunit is not associated with pre-eclampsia. J Hum Hypertens. 2002;16:423–425. [PubMed: 12037698]
64. Rosta K., Molvarec A., Enzsoly A. Association of extracellular superoxide dismutase (SOD3) Ala40Thr gene polymorphism with pre-eclampsia complicated by severe fetal growth restriction. Eur J Obstet Gynecol Reprod Biol. 2009;142:134–138. [PubMed: 19108943]
65. Arngrimsson R., Sigurardo-ttir S., Frigge M.L. A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13. Hum Mol Genet. 1999;8:1799–1805. [PubMed: 10441346]
66. Laivuori H., Lahermo P., Ollikainen V. Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Am J Hum Genet.2003;72:168–177. [PMCID: PMC378622] [PubMed: 12474145]
67. Moses E.K., Lade J.A., Guo G. A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2. Am J Hum Genet. 2000;67:1581–1585. [PMCID: PMC1287935] [PubMed: 11035632]
68. Lachmeijer A.M., Arngrimsson R., Bastiaans E.J. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet. 2001;9:758–764.[PubMed: 11781687]
69. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–247.[PubMed: 7581446]
70. Zintzaras E., Kitsios G., Harrison G.A. Heterogeneity-based genome search meta-analysis for preeclampsia. Hum Genet. 2006;120:360–370.[PubMed: 16868762]
71. Akolekar R., Etchegaray A., Zhou Y. Maternal serum activin a at 11-13 weeks of gestation in hypertensive disorders of pregnancy. Fetal Diagn Ther.2009;25:320–327. [PubMed: 19776595]
72. Roten L.T., Johnson M.P., Forsmo S. Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study) Eur J Hum Genet. 2009;17:250–257. [PMCID: PMC2696227] [PubMed: 18781190]
73. Fitzpatrick E., Johnson M.P., Dyer T.D. Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia. Mol Hum Reprod.2009;15:195–204. [PMCID: PMC2647107] [PubMed: 19126782]
74. Riento K., Ridley A.J. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4:446–456. [PubMed: 12778124]
75. Kandabashi T., Shimokawa H., Miyata K. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101:1319–1323. [PubMed: 10725293]
76. Ark M., Yilmaz N., Yazici G. Rho-associated protein kinase II (rock II) expression in normal and preeclamptic human placentas. Placenta. 2005;26:81–84. [PubMed: 15664415]
77. Johnson M.P., Roten L.T., Dyer T.D. The ERAP2 gene is associated with preeclampsia in Australian and Norwegian populations. Human Genetics.2009;126(5):655–666. PMCID: PMC2783187. [PMCID: PMC2783187] [PubMed: 19578876]
78. WTCCC Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678.[PMCID: PMC2719288] [PubMed: 17554300]
79. Bezerra P.C., Leao M.D., Queiroz J.W. Family history of hypertension as an important risk factor for the development of severe preeclampsia. Acta Obstet Gynecol Scand. 2010;89:612–617. [PubMed: 20423274]
80. Hatada I., Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet. 1995;11:204–206. [PubMed: 7550351]
81. Oudejans C.B., Mulders J., Lachmeijer A.M. The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Mol Hum Reprod. 2004;10:589–598. [PubMed: 15208369]
82. Rigourd V., Chauvet C., Chelbi S.T. STOX1 overexpression in choriocarcinoma cells mimics transcriptional alterations observed in preeclamptic placentas. PLoS One. 2008;3:e3905. [PMCID: PMC2592700] [PubMed: 19079545]
83. Berends A.L., Bertoli-Avella A.M., de Groot C.J. STOX1 gene in pre-eclampsia and intrauterine growth restriction. BJOG. 2007;114:1163–1167.[PubMed: 17617193]
84. Iglesias-Platas I., Monk D., Jebbink J. STOX1 is not imprinted and is not likely to be involved in preeclampsia. Nat Genet. 2007;39:279–280. author reply 280–271. [PubMed: 17325670]
85. Kivinen K., Peterson H., Hiltunen L. Evaluation of STOX1 as a preeclampsia candidate gene in a population-wide sample. Eur J Hum Genet.2007;15:494–497. [PubMed: 17290274]
86. Yu L., Chen M., Zhao D. The H19 gene imprinting in normal pregnancy and pre-eclampsia. Placenta. 2009;30:443–447. [PubMed: 19342096]
87. Nussbaum R.L., McInnes R.R., Willard H.F. In: Genetics in medicine. 6th ed. Thompson and Thompson, editor. Saunders; Philadelphia: 2004. pp. 289–309.
88. Treloar S.A., Cooper D.W., Brennecke S.P. An Australian twin study of the genetic basis of preeclampsia and eclampsia. Am J Obstet Gynecol.2001;184:374–381. [PubMed: 11228490]
89. Ronningen K.S., Paltiel L., Meltzer H.M. The biobank of the Norwegian mother and child cohort study: a resource for the next 100 years. Eur J Epidemiol. 2006;21:619–625. [PMCID: PMC1820840] [PubMed: 17031521]
90. Kho E.M., McCowan L.M., North R.A. Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol. 2009;82:66–73. [PubMed: 19679359]

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Curator: Aviva Lev-Ari, PhD, RN

We covered the Elevated Blood Pressure and High Adult Arterial Stiffness in the following articles on this Open Access Online Scientific Journal:

Pearlman, JD and A. Lev-Ari 5/24/2013 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management


Lev-Ari, A. 5/17/2013 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging


Bernstein, HL and A. Lev-Ari 5/15/2013 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems


Pearlman, JD and A. Lev-Ari 5/11/2013 Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus


Pearlman, JD and A. Lev-Ari 5/7/2013 On Devices and On Algorithms: Arrhythmia after Cardiac Surgery Prediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset


Pearlman, JD and A. Lev-Ari 5/4/2013 Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making


Lev-Ari, A. 5/29/2012 Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes


Lev-Ari, A. 12/31/2012 Renal Sympathetic Denervation: Updates on the State of Medicine


Manuela Stoicescu, MD, PhD, 2/9/2013 An Important Marker of Hypertension in Young Adults


Manuela Stoicescu, MD, PhD, 2/9/2013 Arterial Hypertension in Young Adults: An Ignored Chronic Problem


We present below, a new study on whether elevated pediatric BP could predict high PWV in adulthood and if there is a difference in the predictive ability between the standard BP definition endorsed by the National High Blood Pressure Education Program and the recently proposed 2 simplified definitions.

Simplified Definitions of ElevatedPediatric Blood Pressure and High Adult Arterial Stiffness

  1. Heikki Aatola, MDa,
  2. Costan G. Magnussen, PhDb,c,
  3. Teemu Koivistoinen, MD, MSca,
  4. Nina Hutri-Kähönen, MD, PhDd,
  5. Markus Juonala, MD, PhDb,e,
  6. Jorma S.A. Viikari, MD, PhDe,
  7. Terho Lehtimäki, MD, PhDf,
  8. Olli T. Raitakari, MD, PhDb,g, and
  9. Mika Kähönen, MD, PhDa

+Author Affiliations

  1. aDepartments of Clinical Physiology,

  2. dPediatrics, and

  3. fClinical Chemistry, Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland;

  4. eDepartments of Medicine, and

  5. gClinical Physiology and Nuclear Medicine, and

  6. bthe Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Hospital, Turku, Finland; and

  7. cMenzies Research Institute Tasmania, University of Tasmania, Tasmania, Australia


OBJECTIVE: The ability of childhood elevated blood pressure (BP) to predict high pulse wave velocity (PWV), a surrogate marker for cardiovascular disease, in adulthood has not been reported. We studied whether elevated pediatric BP could predict high PWV in adulthood and if there is a difference in the predictive ability between the standard BP definition endorsed by the National High Blood Pressure Education Program and the recently proposed 2 simplified definitions.

METHODS: The sample comprised 1241 subjects from the Cardiovascular Risk in Young Finns Study followed-up 27 years since baseline (1980, aged 6–15 years). Arterial PWV was measured in 2007 by whole-body impedance cardiography.

RESULTS: The relative risk for high PWV was 1.5 using the simple 1 (age-specific) definition, 1.6 using the simple 2 (age- and gender-specific) definition, and 1.7 using the complex (age-, gender-, and height-specific) definition (95% confidence interval: 1.1–2.0, P = .007; 1.2–2.2, P = .001; and 1.2–2.2, P = .001, respectively). Predictions of high PWV were equivalent for the simple 1 or simple 2 versus complex definition (P = .25 and P = .68 for area under the curve comparisons, P = .13 and P = .35 for net reclassification indexes, respectively).

CONCLUSIONS: Our results support the previous finding that elevated BP tracks from childhood to adulthood and accelerates the atherosclerotic process. The simplified BP tables could be used to identify pediatric patients at increased risk of high arterial stiffness in adulthood and hence to improve the primary prevention of cardiovascular diseases.

Key Words:

  • blood pressure
  • pediatrics
  • prehypertension
  • screening
  • stiffness
  • Abbreviations:
    AUC —
    area under receiver-operating characteristic curve
    BP —
    blood pressure
    CVD —
    cardiovascular diseases
    NHBPEP —
    National High Blood Pressure Education Program
    NPV —
    negative predictive value
    NRI —
    net reclassification improvement
    PPV —
    positive predictive value
    PWV —
    pulse wave velocity
  • Accepted March 12, 2013.


Kids’ High BP Tied to Arterial Stiffness as Adults

By Todd Neale, Senior Staff Writer, MedPage Today

Published: June 10, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

High blood pressure in childhood defined in three different ways was associated with high pulse wave velocity — a surrogate marker for cardiovascular disease — 27 years later, researchers found.

The relationship remained significant whether high blood pressure was identified using a complex definition that incorporated age, sex, and height or one of two simplified definitions (relative risk 1.5 to 1.7), according to Mika Kähönen, MD, PhD, of Tampere University Hospital in Finland, and colleagues.

The predictive ability of the two simplified definitions was comparable to that of the more complex definition, the researchers reported online in Pediatrics.

In guidelines published in 2004, the National High Blood Pressure Education Program recommended screening blood pressure at all pediatric visits starting at age 3. The document provides definitions for normal, prehypertensive, and hypertensive blood pressure levels according to age, sex, and height. But including all three of those factors results in hundreds of blood pressure thresholds for patients up to age 17.

Recently, two simplified definitions have been proposed — one that relies only on age and sex and reduces the number of blood pressure thresholds to 64 and another that relies on age alone and reduces the number of thresholds to 10.

“Our results support the previous finding that elevated blood pressure tracks from childhood to adulthood and accelerates the atherosclerotic process,” they wrote. “The simplified blood pressure tables could be used to identify pediatric patients at increased risk of high arterial stiffness in adulthood and hence to improve the primary prevention of cardiovascular diseases.”

“This complex definition could at least partly explain the poor diagnosis of prehypertension and hypertension in children and adolescents reported previously,” Kähönen and colleagues wrote.

The researchers explored the relationship between high blood pressure in childhood and high pulse wave velocity, which is a measure of arterial stiffness, in adulthood, as well as whether the definition of high blood pressure mattered, using 1,241 participants from the Cardiovascular Risk in Young Finns Study.

The participants were 6- to 15-years-old (mean age 10.7) at baseline in 1980. The researchers followed them for 27 years, at which point arterial pulse wave velocity was measured using whole-body impedance cardiography.

At baseline, the percentage of participants who had high blood pressure was 53.9% according to the definition based on age, 57.8% according to the definition based on age and sex, and 43.2% according to the more complex definition recommended in the guidelines.

At the 27-year follow-up assessment, 20% of the participants had a high pulse wave velocity. Compared with those with a low pulse wave velocity, these individuals had significantly higher blood pressure values and higher rates of elevated blood pressure at baseline. The differences widened at the adult follow-up.

Elevated pediatric blood pressure was associated with a greater risk of having a high pulse wave velocity for all three definitions used in the study:

  • Age-based: RR 1.5, 95% CI 1.1-2.0
  • Age- and sex-based: RR 1.6, 95% CI 1.2-2.2
  • Age-, sex-, and height-based: RR 1.7, 95% CI 1.2-2.2

The predictive ability of the definitions were not different from one another, as illustrated by a lack of significant differences when comparing area under the receiving-operating characteristic curves and net reclassification indexes (P>0.1 for all comparisons).

“This finding is clinically meaningful because both these simplified tables could be more easily implemented as a screening tool in pediatric healthcare settings and outside of a physician’s office when the height percentile required for the complex definition may not be obtainable,” the authors wrote.

They acknowledged that their study was potentially limited in that the method for measuring pulse wave velocity is not commonly used in epidemiologic settings. In addition, there could have been bias stemming from participants dropping out during follow-up and generalizability of the findings may be limited to white European individuals.

The study was supported by the Academy of Finland, the Social Insurance Institution of Finland, the Turku University Foundation, the Medical Research Fund of Kuopio University Hospital, the Medical Research Fund of Tampere University Hospital, the Turku University Hospital Medical Fund, the Emil Aaltonen Foundation, the Juha Vainio Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Cultural Foundation, and The Tampere Tuberculosis Foundation.

The authors reported no conflicts of interest.

From the American Heart Association:


1. Berenson GS, Srinivasan SR, Bao W, Newman

WP III, Tracy RE, Wattigney WA. Association

between multiple cardiovascular risk factors

and atherosclerosis in children and

young adults. The Bogalusa Heart Study. N

Engl J Med. 1998;338(23):1650–1656


2. McGill HC Jr, McMahan CA, Zieske AW,

Malcom GT, Tracy RE, Strong JP. Effects of

nonlipid risk factors on atherosclerosis in

youth with a favorable lipoprotein profile.

Circulation. 2001;103(11):1546–1550


3. Raitakari OT, Juonala M, Kähönen M, et al.

Cardiovascular risk factors in childhood and

carotid artery intima-media thickness in

adulthood: the Cardiovascular Risk in Young

Finns Study. JAMA. 2003;290(17):2277–2283


4. Hartiala O, Magnussen CG, Kajander S,

et al. Adolescence risk factors are predictive

of coronary artery calcification at

middle age: the cardiovascular risk in

young Finns study. J Am Coll Cardiol. 2012;



5. Wang Y, Beydoun MA. The obesity epidemic

in the United States—gender, age, socioeconomic,

racial/ethnic, and geographic

characteristics: a systematic review and

meta-regression analysis. Epidemiol Rev.



6. McCrindle BW. Assessment and management

of hypertension in children and adolescents.

Nat Rev Cardiol. 2010;7(3):155–163


7. Bao W, Threefoot SA, Srinivasan SR,

Berenson GS. Essential hypertension

predicted by tracking of elevated blood

pressure from childhood to adulthood: the

Bogalusa Heart Study. Am J Hypertens.



8. Chen X, Wang Y. Tracking of blood pressure

from childhood to adulthood: a systematic

review and meta-regression analysis. Circulation.



9. Juhola J, Magnussen CG, Viikari JS, et al.

Tracking of serum lipid levels, blood pressure,

and body mass index from childhood

to adulthood: the Cardiovascular Risk in

Young Finns Study. J Pediatr. 2011;159(4):



10. National High Blood Pressure Education

Program Working Group on High Blood

Pressure in Children and Adolescents. The

fourth report on the diagnosis, evaluation,

and treatment of high blood pressure in

children and adolescents. Pediatrics. 2004;

114(suppl. 2, 4th report):555–576


11. Hansen ML, Gunn PW, Kaelber DC. Underdiagnosis

of hypertension in children and

adolescents. JAMA. 2007;298(8):874–879


12. Mitchell CK, Theriot JA, Sayat JG, Muchant

DG, Franco SM. A simplified table improves

the recognition of paediatric hypertension.

J Paediatr Child Health. 2011;47(1-2):22–26


13. Kaelber DC, Pickett F. Simple table to

identify children and adolescents needing

further evaluation of blood pressure. Pediatrics.



14. Cohn JN, Quyyumi AA, Hollenberg NK,

Jamerson KA. Surrogate markers for cardiovascular

disease: functional markers.

Circulation. 2004;109(25 suppl 1):IV31–IV46


15. Vlachopoulos C, Aznaouridis K, Stefanadis

C. Prediction of cardiovascular events and

all-cause mortality with arterial stiffness:

a systematic review and meta-analysis. J

Am Coll Cardiol. 2010;55(13):1318–1327


16. Mancia G, De Backer G, Dominiczak A, et al;

The task force for the management of arterial

hypertension of the European Society

of Hypertension; The task force for the

management of arterial hypertension of

the European Society of Cardiology. 2007

guidelines for the management of arterial

hypertension: The task force for the management

of arterial hypertension of the

european society of hypertension (ESH)

and of the European society of cardiology

(ESC). Eur Heart J. 2007;28(12):1462–1536


17. Aatola H, Hutri-Kähönen N, Juonala M, et al.

Lifetime risk factors and arterial pulse

wave velocity in adulthood: the cardiovascular

risk in young Finns study. Hypertension.



18. Aatola H, Koivistoinen T, Hutri-Kähönen N,

et al. Lifetime fruit and vegetable consumption

and arterial pulse wave velocity

in adulthood: the Cardiovascular Risk in

Young Finns Study. Circulation. 2010;122



19. Li S, Chen W, Srinivasan SR, Berenson GS.

Childhood blood pressure as a predictor of

arterial stiffness in young adults: the

Bogalusa Heart Study. Hypertension. 2004;



20. Raitakari OT, Juonala M, Rönnemaa T, et al.

Cohort profile: the cardiovascular risk in

Young Finns Study. Int J Epidemiol. 2008;37



21. Uhari M, Nuutinen M, Turtinen J, Pokka T.

Pulse sounds and measurement of diastolic

blood pressure in children. Lancet.



22. Tahvanainen A, Koskela J, Tikkakoski A,

et al. Analysis of cardiovascular responses

to passive head-up tilt using continuous

pulse wave analysis and impedance cardiography.

Scand J Clin Lab Invest. 2009;69



23. Kööbi T, Kähönen M, Iivainen T, Turjanmaa V.

Simultaneous non-invasive assessment of

arterial stiffness and haemodynamics—

a validation study. Clin Physiol Funct Imaging.



24. Koivistoinen T, Kööbi T, Jula A, et al. Pulse

wave velocity reference values in healthy

adults aged 26–75 years. Clin Physiol Funct

Imaging. 2007;27(3):191–196


25. Hlatky MA, Greenland P, Arnett DK, et al;

American Heart Association Expert Panel

on Subclinical Atherosclerotic Diseases

and Emerging Risk Factors and the Stroke

Council. Criteria for evaluation of novel

markers of cardiovascular risk: a scientific

statement from the American Heart Association

[published correction appears in

Circulation. 2009;119(25):e606]. Circulation.



26. DeLong ER, DeLong DM, Clarke-Pearson DL.

Comparing the areas under two or more

correlated receiver operating characteristic

curves: a nonparametric approach.

Biometrics. 1988;44(3):837–845


27. Pencina MJ, D’Agostino RBS Sr, D’Agostino

RB Jr, Vasan RS. Evaluating the added

predictive ability of a new marker: from

area under the ROC curve to reclassification

and beyond. Stat Med. 2008;27(2):157–

172, discussion 207–212


28. Cook NR, Ridker PM. Advances in measuring

the effect of individual predictors of

cardiovascular risk: the role of reclassification

measures. Ann Intern Med. 2009;150



29. Juonala M, Magnussen CG, Venn A, et al.

Influence of age on associations between

childhood risk factors and carotid intimamedia

thickness in adulthood: the Cardiovascular

Risk in Young Finns Study, the

Childhood Determinants of Adult Health

Study, the Bogalusa Heart Study, and the

Muscatine Study for the International Childhood

Cardiovascular Cohort (i3C) Consortium.

Circulation. 2010;122(24):2514–2520


30. Sun SS, Grave GD, Siervogel RM, Pickoff AA,

Arslanian SS, Daniels SR. Systolic blood

pressure in childhood predicts hypertension

and metabolic syndrome later in life.

Pediatrics. 2007;119(2):237–246


31. Juhola J, Oikonen M, Magnussen CG, et al.

Childhood physical, environmental, and

genetic predictors of adult hypertension:

the cardiovascular risk in young Finns

study. Circulation. 2012;126(4):402–409


32. Juonala M, Järvisalo MJ, Mäki-Torkko N,

Kähönen M, Viikari JS, Raitakari OT. Risk

factors identified in childhood and decreased

carotid artery elasticity in adulthood:

the Cardiovascular Risk in Young Finns

Study. Circulation. 2005;112(10):1486–1493


33. Zieman SJ, Melenovsky V, Kass DA. Mechanisms,

pathophysiology, and therapy of arterial

stiffness. Arterioscler Thromb Vasc

Biol. 2005;25(5):932–943


34. Greenwald SE. Ageing of the conduit

arteries. J Pathol. 2007;211(2):157–172

FUNDING: Supported by the Academy of Finland (grants 77841, 117832, 201888, 121584, and 126925); the Social Insurance Institution of Finland; the Turku University Foundation; the Medical Research Fund of Kuopio University Hospital; the Medical Research Fund of Tampere University Hospital; the Turku University Hospital Medical Fund; the Emil Aaltonen Foundation (T. Lehtimäki); the Juha Vainio Foundation; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; and The Tampere Tuberculosis Foundation.

Aatola H, et al “Simplified definitions of elevated pediatric blood pressure and high adult arterial stiffness” Pediatrics2013; DOI: 10.1542/peds.2012-3426.


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Reporter: Aviva Lev-Ari, PhD, RN



  • Original Article

HYPERTENSIONAHA.113.00859 Published online before print May 20, 2013,doi: 10.1161/​HYPERTENSIONAHA.113.00859

Serum Uric Acid Level, Longitudinal Blood Pressure, Renal Function, and Long-Term Mortality in Treated Hypertensive Patients
  1. Jesse Dawson,
  2. Panniyammakal Jeemon,
  3. Lucy Hetherington,
  4. Caitlin Judd,
  5. Claire Hastie,
  6. Christin Schulz,
  7. William Sloan,
  8. Scott Muir,
  9. Alan Jardine,
  10. Gordon McInnes,
  11. David Morrison,
  12. Anna Dominiczak,
  13. Sandosh Padmanabhan,
  14. Matthew Walters

+Author Affiliations

  1. From the Institute of Cardiovascular and Medical Sciences (J.D., P.J., L.H., C.J., C.H., C.S., S.M., A.J., G.M., A.D., S.P., M.W.), West of Scotland Cancer Surveillance Unit (W.S., D.M.), College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom.
  1. Correspondence to Matthew Walters, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, Western Infirmary, University of Glasgow, Glasgow G11 6NT, United Kingdom. E-mail matthew.walters@glasgow.ac.uk; or Sandosh Padmanabhan, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126 University Pl, University of Glasgow, Glasgow G12 8TA, United Kingdom. E-mail Sandosh.padmanabhan@glasgow.ac.uk


Uric acid may have a role in the development of hypertension and renal dysfunction. We explored the relationship among longitudinal blood pressure, renal function, and cardiovascular outcomes in a large cohort of patients with treated hypertension. We used data from the Glasgow Blood Pressure Clinic database. Patients with a baseline measure of serum uric acid and longitudinal measures of blood pressure and renal function were included. Mortality data were obtained from the General Register Office for Scotland. Generalized estimating equations were used to explore the relationship among quartiles of serum uric acid, blood pressure, and estimated glomerular filtration rate. Cox proportional hazard models were developed to assess mortality relationships. In total, 6984 patients were included. Serum uric acid level did not influence the longitudinal changes in systolic or diastolic blood pressure but was related to change in glomerular filtration rate. In comparison with patients in the first quartile of serum uric acid, the relative decrease in glomerular filtration rate in the fourth was 10.7 (95% confidence interval, 7.9–13.6 mL/min per 1.73 m2) in men and 12.2 (95% confidence interval, 9.2–15.2 mL/min per 1.73 m2) in women. All-cause and cardiovascular mortality differed across quartiles of serum uric acid in women only (P<0.001; hazard ratios for all-cause mortality 1.38 [95% confidence interval, 1.14–1.67] for the fourth quartile of serum uric acid compared with the first). Serum uric acid level was not associated with longitudinal blood pressure control in adults with treated hypertension but was related to decline in renal function and mortality in women.

Key Words:

  • Received February 19, 2013.
  • Revision received April 23, 2013.
  • Accepted April 23, 2013.



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Reporter: Aviva Lev-Ari, PhD, RN
  • Original Article

HYPERTENSIONAHA.113.01039 Published online before print May 20, 2013,doi: 10.1161/​HYPERTENSIONAHA.113.01039

Arterial Stiffness From Monitoring of Timing of Korotkoff Sounds Predicts the Occurrence of Cardiovascular Events Independently of Left Ventricular Mass in Hypertensive Patients

  1. Philippe Gosse,
  2. Antoine Cremer,
  3. Georgios Papaioannou,
  4. Sunthareth Yeim

+Author Affiliations

  1. From the Department of Cardiology and Hypertension, University Hospital of Bordeaux, Bordeaux, France.
  1. Correspondence to Philippe Gosse, Department of Cardiology and Hypertension, University Hospital of Bordeaux, Hopital Saint Andre, 1 Rue Jean Burguet, 33075 Bordeaux, France. E-mail philippe.gosse@chu-bordeaux.fr


Several studies have established that the increase in arterial stiffness (AS) is a cardiovascular risk factor but to date no studies have evaluated in hypertensive patients its prognostic value in comparison with another powerful risk factor, left ventricular mass (LVM) as measured by echocardiography. We prospectively evaluated the prognostic value of AS and LVM in patients with essential hypertension. The population studied comprised 793 patients (56% men) aged 54±14 years. For 519 patients, baseline measurements were made before any antihypertensive treatment, for 274 patients, the measurement were obtained during the follow-up period under antihypertensive treatment. AS was assessed from ambulatory monitoring of blood pressure and timing of Korottkoff sounds. Left ventricular mass was measured in 523 patients. After a mean follow-up of 97 months, 122 cardiovascular events were recorded in the whole population and 74 in the group with LVM determination. AS as continuous or discontinuous variable was independently related to cardiovascular events. The existence or not of antihypertensive treatment at the time of its measurement did not affect its prognostic value. When LVM was forced in the model, AS remained significantly related to cardiovascular events. Thus, AS has an independent prognostic value in the hypertensive, whether measured before or after the administration of antihypertensive treatment. This prognostic value persists after taking LVM into account.

Key Words:

  • Received January 10, 2013.
  • Revision received March 25, 2013.
  • Accepted April 22, 2013.


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iElastance: Calculates Ventricular Elastance, Arterial Elastance and Ventricular-Arterial Coupling using Echocardiographic derived values in a single beat determination

Reporter: Aviva Lev-Ari, PhD, RN




First iElastance release for Android!

iElastance is an application designed for calculate Ventricular Elastance, Arterial Elastance and Ventricular-Arterial Coupling using Echocardiographic derived values in a single beat determination.
This application is extremely useful to a variety of health care givers such as Cardiologists, Intensivists, Anesthesiologist and more who want to calculate ventricular arterial coupling even in the Critical Care setting and, above all, bedside.

The variables needed for the calculator to work are:

Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Stroke Volume (ml)
Ejection Fraction (0-1)
Total Ejection Time (msec)
Pre Ejection Time (msec)

Formulas are validated and extracted from the article by Chen CH et Al J Am Coll Cardiol. 2001 Dec;38(7):2028-34.

DISCLAIMER: The calculator provided is not meant to be a substitute for professional advice and is not to be used for medical diagnosis. Extensive effort has been exerted to make this software as accurate as possible; however the accuracy of information provided by this software cannot be guaranteed. Health care professionals should use clinical judjement and individualize therapy to each patient care situation.

All rights reserved – 2013 Pietro Bertini – Department of Cardiothoracic Anesthesia and Intensive Care Medicine – University Hospital of Pisa – Dr. Fabio Guarracino, Head of Department

Allows the app to create network sockets and use custom network protocols. The browser and other applications provide means to send data to the internet, so this permission is not required to send data to the internet.



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Pros and Cons of Drug Stabilizers for Arterial  Elasticity as an Alternative or Adjunct to Diuretics and Vasodilators in the Management of Hypertension.

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC


Article Curator: Aviva Lev-Ari, PhD, RN

This article presents the 2013 Thought Frontier on Hypertension and Vascular Compliance.

Conceptual development of the subject is presented in the following nine parts:

1.        Physiology of Circulation and Role of Arterial Elasticity

2.      Isolated Systolic Hypertension caused by Arterial Stiffening may be inadequately treated by Diuretics or Vasodilatation Antihypertensive Medications

3.         Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

4.         Vascular Compliance – The Potential for Novel Therapies

  • Novel Mechanism for Disease Etiology: Modulation of Nuclear and Cytoskeletal Actin Polymerization.
  • Genetic Therapy targeting Vascular Conductivity 
  • Regenerative Medicine for Vasculature Function Protection

5.        In addition to curtailing high pressures, stabilizing BP variability is a potential target for management of hypertension

6.        Mathematical Modeling: Arterial stiffening  explains much of primary hypertension

7.         Classification of Blood Pressure and Hypertensive Treatment Best Practice of Care in the US

8.         Genetic Risk for High Blood Pressure

9.         Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.

Summary By Justin D. Pearlman MD ME PhD MA FACC

1.       Physiology of Circulation and Role of Arterial Elasticity

  • Simplistically, high blood pressure stems from too much volume (salt water) for the vascular space, or conversely, too little space for the volume. Biological signals, such as endothelin, hypoxia, acidosis, nitric oxide, can modify vascular volume by constricting muscles in blood vessel walls. Less simplistically the physics of circulation are governed by numerous factors, with essentials detailed below.
  • The vascular space has two major circuits: pulmonary (lungs) and systemic (body).
  • Compliance (C)  relates change in volume (ΔV) to change in pressure (ΔP) as a measure of the strength of elasticity, where elasticity summarizes the intrinsic forces that  return to original shape after deformation: C = ΔV/ΔP . Those values can be estimated by ultrasound imaging with Doppler blood velocity estimation, by MRI, or invasively. Related properties can also be measured, such as wave propagation time or fractional flow reserve.
  • The vascular system is dynamic, with frequency components and reactive elements. The fundamental frequency is governed by the heart rate delivering a stroke volume forward into the vasculature; a heart rate of 60/minute corresponds to the frequency of 1 Hertz (1 cycle/second). The pressure rise due to the ejection of stroke volume is called the pulse pressure.
  • Numerous factors affect blood flow, including blood composition (affected by anemia or blood dilution), leakiness of vessels, elasticity, wave propagation, streamlines, viscosity, osmotic pressure (affected by protein deficiency and other factors),
  • In a static system, the driving force relates linearly flow by way of resistance (R  in units of dyn·s·cm−5): V=IR (Ohm’s law).
    • Pulmonary:\frac {80 \cdot (mean\ pulmonary\ arterial\ pressure - mean \ pulmonary \ artery \ wedge \ pressure)} {cardiac\ output}
    • Systemic:\frac {80 \cdot (mean\ arterial\ pressure - mean \ right \ atrial \ pressure)} {cardiac\ output}
  • In a dynamic, reactive system, the relation between the driving potential (pressure gradient), and current (blood flow) is governed by a differential equation. However, use of complex numbers and exponentials recovers simplicity similar to Ohm’s law:
    • Variables take the form Ae^{st}, where t is time, s is a complex parameter, and A is a complex scalar. Complex values simply mean two dimensional, e.g., magnitude (as in resistance) plus phase shift (to account for reactive components).
    • Complex version of Ohm’s law: \boldsymbol{V} = \boldsymbol{I} \cdot \boldsymbol{Z} where V and I are the complex scalars in the voltage and current respectively and Z is the complex impedance.
    • Frequency dependent “resistance” is captured by the term impedance.
  • Breathing in increases the return of blood to the heart, adding to pulse variation.
  • Dynamic elastance  (Eadyn relates volume variation (VVS) to pressure variation (PPV): Eadyn=PPV/SVV
    • PPV(%) = 100% × (PPmax − PPmin)/[(PPmax + PPmin)/2)]
      • where PPmax and PPmin are the maximum and minimum pulse pressures determined during a single  respiratory cycle
    • SVV(%) = 100% × [(SVmax − SVmin)/SVmean]
      • where SVmax and SVmin  are the maximum and minimum standard deviation of arterial pressure about the mean arterial pressure during a single respiratory cycle
  • The nervous system provides both stimulants and inhibitors (sympathetic and vagal nerves) to regulate blood vessel wall muscle tone and also heart rate. Many medications, and anesthetic agents in particular, reduce those responses to stimuli, so the vessels dilate, vascular impedance lowers, pressures drop, and autoregulation is impaired.
  • Diuretics aim to decrease volume of circulating fluid, vasodilators aim to increase the vascular space, and elasticity treatments will aim to preserve or improve the ability to accommodate changes in volume of fluid.
    • Vessel dilation near the skin promotes heat loss.
  • Vascular elasticity is impaired by atherosclerosis, menopause, and endothelial dysfunction (impaired nitric oxide signals  response, impaired endothelin response).
  • Elastance in a cyclic pressure system of systole-diastole (contraction-dilation) presents impedance as a pulsatile load on the heart. Inotropy describes the generation of pressure by cardiac contraction, lusiotropy the compliance of the heart to accept filling with minimal back pressure to the lungs. Chronic exposure to elevated vascular impedance leads to impairment of lusiotropy (diastolic failure, stiff heart) and inotropy (systolic failure, weak heart).

2.      Isolated Systolic Hypertension caused by Arterial Stiffening may be inadequately treated by Diuretics or Vasodilatation Antihypertensive Medications

3. Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

Antihypertensive agents have focused on the following approaches:

  1. The most common prescriptions, a mild diuretic, hydrochlorothiazide (HCTZ), is known to improve blood vessel compliance by reducing cell turgor, which explains why its full onset of benefit as well as its slow offset when stopped can take more than one month.
  2. Chlorthalidone  – Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for the treatment of hypertension. However, a recent study concluded: chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia.
  • Increased vascular space (vasodilation)

    • Alternatively, the pressure can be lowered by increasing the vascular space for a given vascular volume. Examples of mediators for arterial tone (degree of dilation) include nitric oxide, prostacyclin and endothelin.




Hyperpolarization mediated (Calcium channel blocker) Changes in the resting membrane potential of thecell affects the level of intracellular calciumthrough modulation of voltage sensitive calcium channelsin the plasma membrane.
cAMP mediated Adrenergic stimulation results in elevated levelsof cAMP and protein kinase A, which results inincreasing calcium removal from the cytoplasm.
cGMP mediated (Nitrovasodilator) Through stimulation of protein kinase G.Until 2002, the enzyme for this conversion wasdiscovered to be mitochondrial aldehyde dehydrogenase.Proc. Natl. Acad. Sci. USA 102 (34): 12159–12164. doi:10.1073/pnas.0503723102http://www.pnas.org/content/102/34/12159.long



Hyperpolarization mediated (Calcium channel blocker) adenosineamlodipine (Norvasc),diltiazem (Cardizem,Dilacor XR) andnifedipine (Adalat, Procardia).
cAMP mediated prostacyclin
cGMP mediated (Nitrovasodilator) nitric oxide
  • Reduced pulsatile force (beta blockers)

These work by blocking certain nerve and hormonal signals to the heart and blood vessels, thus lowering blood pressure. Frequently prescribed beta blockers include

  • metoprolol (Lopressor, Toprol XL)
  • carvedilol (Coreg)
  • nadolol (Corgard)
  • penbutolol (Levatol).
  • Metabolized nebivolol increases vascular NO production, involves endothelial ß2-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca2+]i and endothelial NO synthase–dependent NO production
  • Angiotensin-converting enzyme (ACE) inhibitors

These allow blood vessels to widen by preventing the hormone angiotensin from affecting blood vessels. Frequently prescribed ACE inhibitors include captopril (Capoten), lisinopril (Prinivil, Zestril) and ramipril (Altace).

  • Angiotensin II receptor blockers

These help blood vessels relax by blocking the action of angiotensin. Frequently prescribed angiotensin II receptor blockers include losartan (Cozaar), olmesartan (Benicar) and valsartan (Diovan).
Another very commonly prescribed drug class of medication counteracts hardening of arteries.

Atheroma lipids have enzyme systems that explicitly disassemble cholesterol esters and reconstruct them inside blood vessel walls,e.g.,  Anacetrapib, Genetic variants that improve cholesterol levels are stimulating development of additional medications.

We can propose that atheroma build up in arterial blood vessel walls constitutes a maladaptive defense against aneurysm and risk of vessel rupture from hypertension.

Arguably, HMG-CoA reductase inhibitors,  statin therapy is a second example of a medication that helps protect vascular elasticity, both by its lipid effects and its anti-inflammatory effects.

The best-selling statin is atorvastatin, marketed as Lipitor (manufactured by Pfizer) and Torvast. By 2003, atorvastatin became the best-selling pharmaceutical in history,[4] with Pfizer reporting sales of US$12.4 billion in 2008.[5] As of 2010, a number of statinsare on the market: atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin(Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex).[6] Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available.

References for Statins from:


Clinical Considerations of Statin Therapy’s manifold effects, in


Compensatory Effects in the Physiology of Circulation

Before declaring vessel elasticity a new and highly desirable treatment target, consider that it is not firmly established that hardening of arteries (loss of elasticity) is entirely maladaptive.

In parallel with any focus on increasing vascular elasticity or compliance, each of the issues discussed, below merits scrutiny and investigation.

Cardiac Circulation Dynamics

Endothelium morphology, rheological properties of intra vasculature fluid dynamics and blood viscosity provided explanation for shear stress of vessels under arterial pressure




Aging and Vasculature Diminished Elasticity

While among other reasons for Hypertension increasing prevalence with aging, arterial stiffening is one.

Yet, stiffer vessels are more efficient at transmitting pressure to distal targets. With aging, muscle mass diminishes markedly and the contribution to circulation from skeletal muscle tissue compressions combined with competent venous valves fades.






Aging and Myocardial Diminished Contractility and Ejection Fraction

With aging heart contractility diminishes. These issues can cause under perfusion of tissues, inadequate nutrient blood delivery (ischemia), lactic acidosis, tissue dysfunction and multi-organ failure. Hardened arteries may compensate. Thus, pharmacotherapy to increase Arterial Elasticity may be counterindicated for patients with mild to progressive CHF.





Our biosystems are highly interdependent, and we cannot leap to conclusions without careful thorough evidence. Increasing arterial elastance will lower vascular impedance and change the frequency components of our pulsatile perfusion system.

MOST comprehensive review of the Human Cardiac Conduction System presented to date:


Diminished contractility will increase the amount of energy needed to maintain circulation. It will change efficiency dramatically – consider the difference between periodically pushing someone sitting on a swing at the resonance frequency if the pendulum versus significantly off resonance.




Increased Arterial Elasticity – Potential Risk to Myocardium

The hypothesis that we should focus on cellular therapies to increase vascular compliance may decrease the circulation efficiency and result in worsening of cardiac right ventricular morphology and development of Dilated cardiomyopathy and hypertrophic cardiomyopathy (muscle thickening and diastolic failure), an undesirable outcome resulting from an attempt to treat the hypertension.

4. Vascular Compliance – The Potential of Noval Therapies

  • Novel Mechanism for Disease Etiology for the Cardiac Phenotype: Modulation of Nuclear and Cytoskeletal Actin Polymerization.

Lamin A/C and emerin regulate MKL1–SRF activity by modulating actin dynamics

Chin Yee Ho,

Diana E. Jaalouk,

Maria K. Vartiainen

Jan Lammerding

Nature (2013) doi:10.1038/nature12105

Published online 05 May 2013


Cornell University, Weill Institute for Cell and Molecular Biology/Department of Biomedical Engineering, Ithaca, New York 14853, USA

Chin Yee Ho &

Jan Lammerding

Brigham and Women’s Hospital/Harvard Medical School, Department of Medicine, Boston 02115, Massachusetts, USA

Chin Yee Ho,

Diana E. Jaalouk &

Jan Lammerding

Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland

Maria K. Vartiainen

Present address: American University of Beirut, Department of Biology, Beirut 1107 2020, Lebanon.

Diana E. Jaalouk


C.Y.H., D.E.J. and J.L. conceived and designed the overall project, with valuable help from M.K.V. C.Y.H. and D.E.J. performed the experiments. C.Y.H., D.E.J. and J.L. analysed data. C.Y.H. and J.L. wrote the paper.

Corresponding author Jan Lammerding

Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery–Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison–Gilford progeria syndrome1. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes1. Here we report in mice that lamin-A/C-deficient (Lmna/) and LmnaN195K/N195K mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function2. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna/ and LmnaN195K/N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmnamutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.


  • Genetic Therapy to Conductivity Disease


  • Regenerative Medicine for Vasculature Function Protection






5. Stabilizing BP Variability is the next Big Target in Hypertension Management

Hypertension caused by Arterial Stiffening is Ineffectively Treated by Diuretics and Vasodilatation Antihypertensives

Barcelona, Spain – An aging population grappling with rising rates of hypertension and other cardiometabolic risk factors should prompt an overhaul of how hypertension is diagnosed and monitored and should spur development of drugs with entirely new mechanisms of action, one expert says. Speaking here at the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome, meeting cochair Dr Reuven Zimlichman (Tel Aviv University, Israel) argued that the definitions of hypertension, as well as the risk-factor tables used to guide treatment, are no longer appropriate for a growing number of patients.

Most antihypertensives today work by producing vasodilation or decreasing blood volume and so are ineffective treatments in ISH patients. In the future, he predicts, “we will have to start looking for a totally different medication that will aim to improve or at least to stabilize arterial elasticity: medication that might affect factors that determine the stiffness of the arteries, like collagen, like fibroblasts. Those are not the aim of any group of antihypertensive medications today.”

Zimlichman believes existing databases could be used to develop algorithms that take this progression of disease into account, in order to better guide hypertension management. He also points out that new ambulatory blood-pressure-monitoring devices also measure arterial elasticity. “Unquestionably, these will improve our ability to diagnose both the status of the arteries and the changes of the arteries with time as a result of our treatment. So if we treat the patient and we see no improvement in arterial elasticity, or the patient is worse, something is wrong, something is not working—either the patient is not taking the medication, or our choice of medication is not appropriate, or the dose is insufficient, etc.”


Oslo, Norway – New research that is only just starting to be digested by the hypertension community indicates that visit-to-visit variability in blood-pressure readings will likely become another way of looking for “at-risk” hypertensive patients and in fact is likely to be more reliable as an indicator of cardiovascular risk than the currently used mean BP.

The Goal of Stabilizing BP variability 

June 29, 2010  

Discussing the importance of this issue for guidelines and clinical practice, Dr Tony Heagerty (University of Manchester, UK) told the recent European Society of Hypertension (ESH) European Meeting on Hypertension 2010: “We are poking around in the dark, offering treatment blankly across a large community, and probably treating a lot of people who don’t need to be treated, while not necessarily treating the highest-risk patients. We should stop being reassured by ‘occasional’ normal BPs. The whole game now is, can we improve the identification of our ‘at-risk’ individuals?”

Heagerty was speaking at a special plenary session on late-breaking research discussing BP variability as a risk factor. This issue has emerged following new analyses reported at the ACC meeting and published in a number of papers in the Lancet and Lancet Neurology earlier this year, which showed that variability in blood pressure is a much stronger determinant of both stroke and coronary disease outcome than average blood pressure.


Three years later, 2/1/2013, Zimlichman also argued that definitions of essential and secondary hypertension have changed very little over the past few decades and have typically only been tweaked up or down related to other CV risk factors. Diastolic hypertension has been the primary goal of treatment, and treatment goals have not adequately taken patient age into account (in whom arterial stiffening plays a larger role), and they have typically relied too heavily on threshold cutoffs, rather than the “linear progression” of risk factors and their impact on organ damage.

6. Mathematical Modeling: Arterial stiffening provides sufficient explanation for primary hypertension

Klas H. PettersenScott M. BugenhagenJavaid NaumanDaniel A. BeardStig W. Omholt

(Submitted on 3 May 2013 (v1), last revised 6 May 2013 (this version, v2))

Hypertension is one of the most common age-related chronic diseases and by predisposing individuals for heart failure, stroke and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age, and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure, arise as emergent properties of the integrated system. Results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function. The results support the view that a major target for treating chronic hypertension in the elderly is the reestablishment of a proper baroreflex response.

Klas H. Pettersen1, Scott M. Bugenhagen2, Javaid Nauman3, Daniel A. Beard2 & Stig W. Omholt3

1Department of Mathematical and Technological Sciences, Norwegian University of Life Science, Norway

2Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

3NTNU Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Trondheim, Norway

Correspondence should be addressed to: KHP (klas.pettersen@gmail.com)

Keywords: hypertension, mechanogenic, baroreceptor signaling, cardiovascular model, arterial stiffening

Author contributions: K.H.P. and S.W.O. designed the study. K.H.P. constructed the

integrated model and performed the numerical experiments with contributions from

D.A.B. and S.M.B.. J.N. extracted and compiled empirical test data from the HUNT2

Survey. S.W.O, K.H.P. and D.A.B. wrote the paper.




7. Classification of Blood Pressure and Hypertensive Treatment:

Best Practice of Care in the US

8. Genetic Risk for High Blood Pressure

Hypertension.2013; 61: 931doi: 10.1161/​HYP.0b013e31829399b2

Blood Pressure Single-Nucleotide Polymorphisms and Coronary Artery Sisease (page 995)

Blood pressure (BP) is considered a major cardiovascular risk factor that is influenced by multiple genetic and environmental factors. However, the precise genetic underpinning influencing interindividual BP variation is not well characterized; and it is unclear whether BP-associated genetic variants also predispose to clinically apparent cardiovascular disease. Such an association of BP-related variants with cardiovascular disease would strengthen the concept of BP as a causal risk factor for cardiovascular disease. In this issue of Hypertension, analyses within the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis consortium indicate that common genetic variants associated with BP in the population, indeed, contribute to the susceptibility for coronary artery disease (CAD). Lieb et al tested 30 single-nucleotide polymorphisms—that based on prior studies were known to affect BP—for their association with CAD. In total, data from 22 233 CAD cases and 64 762 controls were analyzed. The vast majority (88%) of BP-related single-nucleotide polymorphisms were also shown to increase the risk of CAD (as defined by an odds ratio for CAD >1; Figure). On average, each of the multiple BP-raising alleles was associated with a 3% (95% confidence interval, 1.8%–4.3%) risk increase for CAD.

Masked Hypertension in Diabetes Mellitus (page 964)

The first important finding in the IDACO study of masked hypertension (MH) in the population with diabetes mellitus and non–diabetes mellitus was that antihypertensive treatment converted some sustained hypertensives into sustained normotensives; this resulted in an increased cardiovascular disease risk in the treated versus untreated normotensive comparator group (Figure). Not surprisingly, normalization of blood pressure (BP) with treatment did not eliminate the lifetime cardiovascular disease burden associated with prior elevated BP nor did it correct other cardiometabolic risk factors that clustered with the hypertensive state.

The second important IDACO finding was that treatment increased the prevalence of MH by decreasing conventional BP versus daytime ambulatory BP (ABP) by a ratio of ≈3 to 2. The clinical implication of increased prevalence of MH with therapy in the population of both diabetes mellitus and non–diabetes mellitus was that these subjects did not receive sufficient antihypertensive therapy to convert MH into normalized ABP (ie, treated, normalized ABP being the gold standard for minimizing cardiovascular disease risk). Indeed, there is a transformation-continuum from sustained hypertension to MH and finally to sustained normotension with increasing antihypertensive therapy. These IDACO findings strongly suggest that many physicians mistakenly have their primary focus on normalizing in-office rather than out-of-office home BP and/or 24-hour ABP values and this results in an increased prevalence of MH. However, what constitutes optimal normalized ABP will remain empirical until established in randomized controlled trials.

Genetic Risk Score for Blood Pressure (page 987)

Elevated blood pressure (BP) is a strong, independent, and modifiable risk factor for stroke and heart disease. BP is a heritable trait, and genome-wide association studies have identified several genetic loci that are associated with systolic BP, diastolic BP, or both. Although the variants have modest effects on BP, typically 0.5 to 1.0 mm Hg, their presence may act over the entire life course and, therefore, lead to substantial increase in risk of cardiovascular disease (CVD). However, the independent impact of these variants on CVD risk has not been established in a prospective setting. Havulinna et al genotyped 32 common single-nucleotide polymorphisms in several Finnish cohorts, with up to 32 669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. Genetic risk scores were created for systolic BP and diastolic BP by multiplying the risk allele count of each single-nucleotide polymorphism by the effect size estimated in published genome-wide association studies on BP traits. The GRSs were strongly associated with baseline systolic BP, diastolic BP, and hypertension (all P<10–62). Hazard ratios for incident CVD increased roughly linearly by quintile of systolic BP or diastolic BP GRS (Figure). GRSs remained significant predictors of CVD risk after adjustment for traditional risk factors, even including BP and use of antihypertensive medication. These findings are consistent with a lifelong effect of these variants on BP and CVD risk.

Related Articles on Genetics and Blood Pressure

Genetic Predisposition to Higher Blood Pressure Increases Coronary Artery Disease Risk

  • Wolfgang Lieb,
  • Henning Jansen,
  • Christina Loley,
  • Michael J. Pencina,
  • Christopher P. Nelson,
  • Christopher Newton-Cheh,
  • Sekar Kathiresan,
  • Muredach P. Reilly,
  • Themistocles L. Assimes,
  • Eric Boerwinkle,
  • Alistair S. Hall,
  • Christian Hengstenberg,
  • Reijo Laaksonen,
  • Ruth McPherson,
  • Unnur Thorsteinsdottir,
  • Andreas Ziegler,
  • Annette Peters,
  • John R. Thompson,
  • Inke R. König,
  • Jeanette Erdmann,
  • Nilesh J. Samani,
  • Ramachandran S. Vasan,
  • andHeribert Schunkert
  • , on behalf of CARDIoGRAM

Hypertension. 2013;61:995-1001, published online before print March 11 2013,doi:10.1161/HYPERTENSIONAHA.111.00275

Masked Hypertension in Diabetes Mellitus: Treatment Implications for Clinical Practice

  • Stanley S. Franklin,
  • Lutgarde Thijs,
  • Yan Li,
  • Tine W. Hansen,
  • José Boggia,
  • Yanping Liu,
  • Kei Asayama,
  • Kristina Björklund-Bodegård,
  • Takayoshi Ohkubo,
  • Jørgen Jeppesen,
  • Christian Torp-Pedersen,
  • Eamon Dolan,
  • Tatiana Kuznetsova,
  • Katarzyna Stolarz-Skrzypek,
  • Valérie Tikhonoff,
  • Sofia Malyutina,
  • Edoardo Casiglia,
  • Yuri Nikitin,
  • Lars Lind,
  • Edgardo Sandoya,
  • Kalina Kawecka-Jaszcz,
  • Jan Filipovský,
  • Yutaka Imai,
  • Jiguang Wang,
  • Hans Ibsen,
  • Eoin O’Brien,
  • and Jan A. Staessen
  • , on behalf of the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) Investigators

Hypertension. 2013;61:964-971, published online before print March 11 2013,doi:10.1161/HYPERTENSIONAHA.111.00289

A Blood Pressure Genetic Risk Score Is a Significant Predictor of Incident Cardiovascular Events in 32 669 Individuals

  • Aki S. Havulinna,
  • Johannes Kettunen,
  • Olavi Ukkola,
  • Clive Osmond,
  • Johan G. Eriksson,
  • Y. Antero Kesäniemi,
  • Antti Jula,
  • Leena Peltonen,
  • Kimmo Kontula,
  • Veikko Salomaa,
  • and Christopher Newton-Cheh

Hypertension. 2013;61:987-994, published online before print March 18 2013,doi:10.1161/HYPERTENSIONAHA.111.00649

9. Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.

Heart doi:10.1136/heartjnl-2012-303461

  • Epidemiology
  • Original article

Estimating the effect of long-term physical activity on cardiovascular disease and mortality: evidence from the Framingham Heart Study

  1. Susan M Shortreed1,2,
  2. Anna Peeters1,3,
  3. Andrew B Forbes1

+Author Affiliations

  1. 1Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

  2. 2Biostatistics Unit, Group Health Research Institute, Seattle, Washington, USA

  3. 3Obesity and Population Health Unit, Baker IDI Heart and Diabetes Institute, Melbourne, Australia

Correspondence toDr Susan M Shortreed, Biostatistics Unit, Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101, USA; shortreed.s@ghc.org

  • Published Online First 8 March 2013


Objective In the majority of studies, the effect of physical activity (PA) on cardiovascular disease (CVD) and mortality is estimated at a single time point. The impact of long-term PA is likely to differ. Our study objective was to estimate the effect of long-term adult-life PA compared with long-term inactivity on the risk of incident CVD, all-cause mortality and CVD-attributable mortality.

Design Observational cohort study.

Setting Framingham, MA, USA.

Patients 4729 Framingham Heart Study participants who were alive and CVD-free in 1956.

Exposures PA was measured at three visits over 30 years along with a variety of risk factors for CVD. Cumulative PA was defined as long-term active versus long-term inactive.

Main outcome measures Incident CVD, all-cause mortality and CVD-attributable mortality.

Results During 40 years of follow-up there were 2594 cases of incident CVD, 1313 CVD-attributable deaths and 3521 deaths. Compared with long-term physical inactivity, the rate ratio of long-term PA was 0.95 (95% CI 0.84 to 1.07) for CVD, 0.81 (0.71 to 0.93) for all-cause mortality and 0.83 (0.72 to 0.97) for CVD-attributable mortality. Assessment of effect modification by sex suggests greater protective effect of long-term PA on CVD incidence (p value for interaction=0.004) in men (0.79 (0.66 to 0.93)) than in women (1.15 (0.97 to 1.37)).


  • Cumulative long-term PA has a protective effect on incidence of all-cause and CVD-attributable mortality compared with long-term physical inactivity.
  • In men, but not women, long-term PA also appears to have a protective effect on incidence of CVD.

Summary – PENDING

1. Kannel WB, Gordan T (1978) Evaluation of cardiovascular risk in the elderly: the Framingham study. Bull N Y Acad Med 54:573–591.
2. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D (1999) Is pulse pressure useful in predicting risk for coronary heart disease?: The Framingham Heart Study. Circulation 100:354–360.
3. Mitchell GF et al. (2010) Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum: Noninvasive Evaluation in the Framingham Heart Study. Circulation 122:1379–1386.
4. Khattar RS, Swales JD, Dore C, Senior R, Lahiri A (2001) Effect of Aging on the Prognostic Significance of Ambulatory Systolic, Diastolic, and Pulse Pressure in Essential Hypertension. Circulation 104:783–789.
5. Franklin SS et al. (1997) Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 96:308.
6. Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7:335–346.
7. Monahan KD (2007) Effect of aging on baroreflex function in humans. Am J Physiol Regul Integr Comp Physiol 293:R3–R12.
8. Zieman SJ (2005) Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness. Arterioscler Thromb Vasc Biol 25:932–943.
9. McVeigh GE, Bank AJ, Cohn JN (2007) Arterial compliance. Cardiovasc Med:1811–1831.
10. Guyton AC (1991) Blood pressure control–special role of the kidneys and body fluids. Science 252:1813–1816.
11. Smith BW, Chase JG, Nokes RI, Shaw GM, Wake G (2004) Minimal haemodynamic system model including ventricular interaction and valve dynamics. Med Eng Phys 26:131–139.
12. Smith BW, Geoffrey Chase J, Shaw GM, Nokes RI (2005) Experimentally verified minimal cardiovascular system model for rapid diagnostic assistance. Control Eng Pract 13:1183–1193.13. Bugenhagen SM, Cowley AW, Beard DA (2010) Identifying physiological origins of baroreflex dysfunction in salt-sensitive hypertension in the Dahl SS rat. Physiol Genomics 42:23–41.14. Beard DA et al. (2012) Multiscale Modeling and Data Integration in the Virtual Physiological Rat Project. Ann Biomed Eng.15. King AL (1946) Pressure-Volume Relation for Cylindrical Tubes with Elastomeric Walls: The Human Aorta. J Appl Phys 17:501.16. Dayan P, Abbott LF (2001) Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems (Computational Neuroscience) (The MIT Press). 1st Ed.17. Andresen MC, Krauhs JM, Brown AM (1978) Relationship of aortic wall and baroreceptor properties during development in normotensive and spontaneously hypertensive rats. Circ Res 43:728–738.18. Hallock P, Benson IC (1937) Studies on the elastic properties of human isolated aorta. J Clin Invest 16:595–602.19. Coffman TM (2011) Under pressure: the search for the essential mechanisms of hypertension. Nat Med 17:1402–1409.20. Proctor DN et al. (1998) Influence of age and gender on cardiac output-V O 2 relationships during submaximal cycle ergometry. J Appl Physiol 84:599–605.21. Fagard R, Thijs L, AMERY A (1993) Age and the Hemodynamic Response to Posture and Exercise. Am J Geriatr Cardiol 2:23–40.22. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB (1994) Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation 89:1648–1655.23. Holmen J et al. (2003) The Nord-Trøndelag Health Study 1995–97 (HUNT 2): objectives, contents, methods and participation. Norsk epidemiologi 13:19–32.24. Chobanian AV et al. (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560–2572.25. Cowley AW, LIARD JF, Guyton AC (1973) Role of the Baroreceptor Reflex in Daily Control of Arterial Blood Pressure and Other Variables in Dogs. Circ Res 32:564–576.26. Schreihofer AM, Sved AF (1992) Nucleus tractus solitarius and control of blood pressure in chronic sinoaortic denervated rats. Am J Physiol 263:R258–66.27. Ito S, Sved AF (1997) Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats. Am J Physiol Regul Integr Comp Physiol 273:R1657–R1662.28. Thrasher TN (2004) Baroreceptors, baroreceptor unloading, and the long-term control of blood pressure. Am J Physiol Regul Integr Comp Physiol 288:R819– R827.29. Monahan KD et al. (2001) Age-associated changes in cardiovagal baroreflex sensitivity are related to central arterial compliance. Am J Physiol Heart Circ Physiol 281:H284–H289.30. Malpas S (2009) Editorial comment: Montani versus Osborn exchange of views. Experimental Physiology 94:381–382.31. Mori T et al. (2008) High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension. Journal of the American Society of Nephrology 19:1472–1482.32. Beard DA, Mescam M (2012) Mechanisms of pressure-diuresis and pressurenatriuresis in Dahl salt-resistant and Dahl salt-sensitive rats. BMC Physiol 12:6.33. Iliescu R, Irwin ED, Georgakopoulos D, Lohmeier TE (2012) Renal Responses to Chronic Suppression of Central Sympathetic Outflow. Hypertension 60:749–756.34. Krum H et al. (2009) Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373:1275–1281.35. Mahfoud F et al. (2012) Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension. Hypertension 60:419–424.36. Vink EE, Blankestijn PJ (2012) Evidence and Consequences of the Central Role of the Kidneys in the Pathophysiology of Sympathetic Hyperactivity. Front Physio 3.37. Cowley A Jr (1992) Long-term control of arterial blood pressure. Physiol Rev 72:231–300.38. Mancia G, Ludbrook J, Ferrari A, Gregorini L, Zanchetti A (1978) Baroreceptor reflexes in human hypertension. Circ Res 43:170–177.39. Kaess BM et al. (2012) Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 308:875–881.

40. Kirkwood TBL (1977) Evolution of ageing. Nature 270:301–304.

41. Nakayama Y et al. (2001) Heart Rate-Independent Vagal Effect on End-Systolic Elastance of the Canine Left Ventricle Under Various Levels of Sympathetic Tone. Circulation 104:2277–2279.

42. Cohen A (1991) A Padé approximant to the inverse Langevin function. Rheologic Acta 30:270–273.

43. Brown AM, Saum WR, Tuley FH (1976) A comparison of aortic baroreceptor discharge in normotensive and spontaneously hypertensive rats. Circ Res 39:488–496.

44. Smith H (2011) in Texts in Applied Mathematics, Texts in Applied Mathematics. (Springer New York, New York, NY), pp 119–130.

Other related articles were published on this Open Access Online Scientific Journal including the following:

Pearlman, JD and A. Lev-Ari 5/24/2013 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management


Lev-Ari, A. 5/17/2013 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging


Bernstein, HL and A. Lev-Ari 5/15/2013 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems


Pearlman, JD and A. Lev-Ari 5/7/2013 On Devices and On Algorithms: Arrhythmia after Cardiac Surgery Prediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset


Pearlman, JD and A. Lev-Ari 5/4/2013 Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making


Larry H Bernstein, MD, FACP, 12/10/2012

Genomics & Genetics of Cardiovascular DiseaseDiagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FACP, 3/7/2013

Mitochondrial Dysfunction and Cardiac Disorders

Curator: Larry H Bernstein, MD, FACP

Aviva Lev-Ari, PhD, RN, 4/7/2013


Read Full Post »

Arterial Hypertension in Young Adults: An Ignored Chronic Problem

Author: Manuela   Stoicescu, MD, PhD

Original research

Manuela   Stoicescu, MD, PhD

Consultant Internal Medicine, Assistant Professor

Faculty of Medicine and Pharmacy, Medical Disciplines Department

University of Oradea,  Romania




Don’t ignore the young patients: being young does not necessary mean being healthy.


The objectives in this study was to analyzed the principal clinical aspects and conduct laboratory investigations with young people in group of age 18-35 years. Attracting attention to the diagnosis of hypertension in the young in the early stages of life. I choice this topic because high blood pressure in the young, in particularly, in this group age was insufficiently studied while a high frequency of cases presented every day was continuously  increasing.

Material and method:

The study was performed in the Ambulatory Specialty of the Internal Diseases Department in the County Hospital in Oradea, Romania. Study period was  1 October 2006 to 31 July 2009. Included in the study were 321 patients with hypertension exceeding 140/90 mmHg which was maintained higher after three consecutive determinations in intervals of one week to exclude the “white coat phenomenon”, an effect noted very frequent in young people, especially in young women, because a young persons have hyperactivity of simpatico nervous systemic, or the value of blood pressure was higher more than 170/110 mmHg from first determination.


1. Importance of the genetic factors in the etiologies of disease was suggests that family prevalence of hypertension in the young people and another family diseases like hyperaldosteronism, polycystic kidney and multiple endocrine neoplasias MEN2a.

2. Importance of personal pathologic antecedents demonstrated in my study that repetitive Streptococcus angina with Streptococcus β hemolytic group A originated in the first place as a cause in hypertension in the young people in context of acute streptococcal renal parenchymatous diseases.

3. Renin plasmatic level is a very important marker of high blood pressure in the young. It was high in 121 cases (37.69%). This situation suggests that hypertension in the young is hyperreninemic hypertension in many cases because a young person has a systemic hyperactivity of simpatico nervous.

4. Left ventricular hypertrophy is been detected in X-ray, ECG and echocardiography. In my studied I detected left ventricular hypertrophy in 35 patients representing 10.49%.

5. Proteinuria was represented in 96 cases (29.90%) has two meanings:

  • nephropathy complication of hypertension  or
  • acute glomerulonephritis or
  • nephritis syndrome accompaniment with hematuria 38 cases (11.83%).

6. The eye ground findings of young people with hypertension are frequently normal. In the absence of prior readings, one needs to look for evidence of target organ damage that may suggest chronicity. In my study this changes appeared for 86 cases 23.3 %, hemorrhages and exudates I rarely found in 9 cases represent 2.8% and papilla edema was presented in 2 cases even when hypertension was very severe more than 200/120 mmHg and complicate with hypertensive encephalopathy.

Conclusions: Guidelines for hypertension treatment with young patients group of ages 18-35 was developed, which I hope will help the activity of physicians in general specialties in their practice, to use for diagnosis and easy work. This is new and hypertension in the young in this group of ages was insufficiently studied.

Key words: hypertension diagnosis, young adults.


Prior to the last twenty years it was impossible to accept the idea that hypertension and atherosclerosis begin in adolescence and even earlier in childhood. Current concepts concerning the nature of hypertension in the young are changing. Earlier clinical impressions indicated that hypertension in the young was secondary and the essential hypertension occurred only rarely.

In my recent study, involving young people, of the age group of age 18-35 year old, indicated that young with high levels of blood pressure often the cause is known and often is unknown. When high BP (HBP) is found in the young the young compared with their peers, it is  likely that the HBP will continue to Adulthood. My study has indicated that the level of blood pressure in young is closely related to the occurrence of hypertension in adulthood. Thus, changing concepts suggest that essential hypertension begins in early life. Considerable information is now known about the clinical and pathologic features of hypertension in adults.

We understand clinical diagnoses, the pathophysiology and humoral background, and the consequences of end stage renal disease (ESRD). We are even beginning to consider that essential hypertension may represent more than one disease. By contrast, little is known about the early natural development of essential hypertension. For example, how can hypertension in young be defined? We cannot equate level of blood pressure with cardiovascular damage as in adults (cardiovascular, cerebral, and renal disease). Furthermore, there is little specific information that can be used to predict development of adult hypertension. As a beginning, descriptive studies of the early natural development of essential hypertension are needed. It is logical to assume that prevention would be most successful if the disease process could be understood and treated in its earliest phase.


      Don’t ignore the young adult patient. Being young does not necessary means being healthy. Key objectives in my study was to analyze the principal clinical aspects and laboratory tests performed on  young adults in the group age 18-35 year old, to advocate for the attention needed for diagnosis of hypertension in the young adults in the early stages of the disease.                                                                                                         


     The study was performed in the Ambulatory Specialty of the Internal Diseases Department at the County Hospital in Oradea, Romana. Study period was  1 October 2006 to 31 July 2009. Study participants:

  • 321 young patients,
  • group of ages 18-35, patients with high blood pressure more than 140/90 mmHg
  • after three consecutive determinations in interval one week maintain higher than 140/90 mmHg to exclude the “white coat phenomenon”, effect very frequently encountered with young adults especially with young women, because young person have a hyperactivity of sympathetic nervous system, or
  • the value of blood pressure was high more than 170/110mmHg from first determination.

The patients had a comprehensive physical examination (clinical and par clinical) and diagnosed with hypertension in different stages.

The study consideration was done after having confirmed the diagnosis of hypertension and the standardization according to the phenomenon of high blood pressure and the classification of OMS.

The patients agreed to participate after being introduced in the study after they have been explained the deontological and preserving of the confidentiality criteria.

For statistics data I has been used the EPIINFO application, 6.0 version, a program of The Center of Disease Control and Prevention- Atlanta, with the Student method (test t) and χ²


We observed that a 1/5 of the patients studied have in family antecedents of young adults hypertensive member of the family:hypertension in 70 cases (21.80%), stroke in 46 cases  (14.33%), myocardial infarction in 55 cases (17.13%), peripheral vascular disease in 23 cases ( 7.16%)  obesity 38 (11.83%), pre-eclamptic toxemia in 31 cases(9.65% ), hyperaldosteronism in 18 cases (5.60%),  polycystic kidney in 26 cases (8.09%), multiple endocrine neoplasias MEN2a in 14 cases (4.36%) Distribution of cases according to family history.  See, Table 1.

Table 1: Distribution of Cases according to Family History


No. of cases


Hypertension for parents, grandparents, aunts, uncles and cousins



Family antecedents of stroke


14.33 %

Family antecedents of myocardial infarction



Family antecedents of peripheral vascular disease



Family antecedents of obesity



Pre-eclamptic toxemia






Polycystic kidney



Multiple endocrine neoplasias MEN2a



A significant numbers of patients in my studies did not have any  antecedents of hypertension in their family history. That fact demonstrates that not only genetic factors have an important role in the etiology of the disease.ENvironmental factors count.

Significant number of  hypertensive young  patients had diseases in their personal history: Scarlatti in 27 (8.41%), repetitive angina with Streptococcus β hemolytic group A in 88 (27.41%), chronic ORAL infection focus in 35 (10.90%) chronic stomathological focus infections in 19 (5.91%), nephritis in 34(10.59%), endocrine disorders in 16 (4.98% ), physical and psychological in 22 (6.85%), head trauma in 11 (3.42%), therapy with corticosteroids secondary to another disease (for example erythematous systemic lupus) in 5 (1.55%),  therapy with AINS  drugs in 21 (6.54%), use decongestion nasal in 4 (1.24%) repetitive urinary tract infection in 28 (8.72%), syphilis in 11 (3.42%). See, Table II.

Table II: Distribution of Cases by Illnesses in  Personal History


No. of cases





Repetitive Streptococcus angina with Streptococcus β hemolytic group A



Chronic ORAL infection focus



Chronic stomathological infection focus






Endocrine disorders



Physical and psychical suprademanding



Head  trauma



Therapy with corticosteroids



Therapy with AINS



Use decongestion at nasal



Repetitive urinary tract infections






Fig.1: Principal Diseases Etiology for Young Hypertensive Patients


Table III: Laboratory Results

Hemoglobin value ↑



Hematocrit ↑



Value of glucose ↑



Cholesterol  ↑



HDL cholesterol  ↑



LDL cholesterol  ↑



Triglycerides ↑



Uric acid  ↑



Creatinina ↑



Urea ↑



Serum sodium ↑



Serum potassium↓



Urinalysis -albuminuria+






Urine culture with female +



Table IV: Laboratory Special Tests

Rennin plasmatic↑



Vanillyl Mandelic Acid testing (VMA): in urine↑



Catecholamine urine↑



Cortisol urine ↑



Cortisolemia  ↑






T3    ↑



T4   ↑



CT abdominal



RMN abdominal



Intravenous urogrography



Observations on Eye Exam and Retinopathy [The eye ground (eye ground findings)]

Clearly, the most helpful information to have when one is attempting to establish the chronicity of hypertension is past blood pressure readings. Unfortunately, these are by no means always available since routine blood pressure measurement in young adults is not yet uniformly obtained. In the absence of prior readings, one needs to look for evidence of target organ damage that may suggest chronicity. In adolescent with even severe chronic hypertension or hypertensive encephalopathy. In my study this changes appear for the optic fund may show no more than retinal arteriolar narrowing in 103 cases represent 32.09% and arterio-venous nicking in 98 cases represent 30.53%, hemorrhages and exudates I rarely found in 9 cases represent 2.8%, papilla edema may be absent except in 2 cases even when hypertension was very severe more than 200/120 mmHg with complications of encephalopathy and in 109 cases represent 33.96 was normal result of eye ground examination. See Table V and Fig. 2

Just as there may be minimal eye ground findings, there are infrequently cardiac findings that suggest chronicity.

Table V  Distribution of Cases by Eye Exam Findings




Arteriolar narrowing



Arterio-venous nicking



Exudates and hemorrhages



Papilla edema




Fig. 2: Distribution of Cases by Changes of Eye Ground Findings

The heart morphology was not clinically enlarged in many cases and the ECG and chest X-ray were usually unhelpful in detecting left ventricular hypertrophy unless hypertension has been prolonged and severe. In my studies left ventricular hypertrophy was present in 35 cases (10.49%), they are helpful in determining chronicity of hypertension and in 206 cases (64.18%) left ventricular hypertrophy was absent.  If negative suggesting nothing about the duration of hypertension. See Table VI and Fig 3

Table VI: Distribution of Cases by Changes in Chest X-Ray




Elongation and elevated of left inferior arcos






Aneurism of thoracic aorta




Fig. 3: Distribution of Cases by Changes of chest X-Ray

The echocardiography seems to be more sensitive for evaluating chamber size and wall thickness than the ECG and can be helpful. Left atria hypertrophy and left ventricular hypertrophy (Sokolow -Lyon index) and left axial deviation was possible to detect. In my studies I found 35 cases (10.49%) with LVH, 36 cases (11.21%) with LAH and 35 cases (10.49%) with left axial deviation. Secondary changes of depolarization like ST segment sub elevated and negative T wave I found in 35 cases represent 10.49%. See Table VII and Fig. 4

Table 7: Distribution of Cases by Changes in ECG




Left axial deviation> -30



Left atria hypertrophy



Left  ventricular hypertrophy

Sokolov -Lyon index(SV1+RV5/V6>35mm)



Secondary  changes of depolarization – ST segment sub elevated  and T wave negative




Fig. 4: Distribution of Cases by Changes in ECG

Table VIII:  Distribution of cases by Echocardiography of Hearth Examination




Left ventricular hypertrophy



Ejection fraction(FE) of left ventricular<55%



Aortic coarctation




Fig. 5: Distribution of cases by Changes in Echocardiography

Table IX: Distribution of Cases by Urine Analysis Results









11.83 %

Proteinuria I detect in 96 cases (29.90%) and hematuria in 38 cases (11.83%). See Fig. 6


Fig.6: Distribution of cases by Urine Analysis Results

OMS stadialization classification high blood pressure in three stages. In my study about hypertension in the young adults,  the results are as follows:

  • Stages I:  270 cases represents 84.11%,
  • Stages II:  40 cases represents 12.46%,
  • Stages III:  9 cases (2.80%) and
  • Stage IV: malign hypertension 2 cases represents 0.62%.

See, Table IX  and Fig.7

Table IX: Distribution of Cases by Stadialization

Stages I



Stages II



Stages III



Stages IV





Fig. 7: Distribution of Cases by Stadialization


1.   A 1/5 of group of patients studied have in family antecedents of young hypertensive family member with the following diseases:

  • stroke 46 cases  (14.33%),
  • myocardial infarction 55 cases (17.13%),
  • peripheral vascular disease 23 cases (7.16%),
  • obesity 38 (11.83%),
  • pre-eclamptic toxemia 31 cases (9.65%),
  • hiperaldosteronism in 18 cases (5.60%),
  • polycystic kidney 26cases (8.09%),
  • multiple endocrine diseases II 14 cases (4.36%).

These results  are in concordance with observations of Kotchen JM [1] which in a studies about young hypertensive patients concluded that family aggregation of hypertension was very frequent 20.2% (p<0,001) suggesting the importance of a genetic factor in the etiology of hypertension in the young adults.

    2.   An important number of  hypertensive young  patients were present in personal pathological antecedents: Scarlatti 27 (8.41%), repetitive angina with Streptococcus β hemolytic group A 88 (27.41%),chronic ORL infection focus 35 (10.90%) chronic stomathological focus infections 19 (5.91%), nephritis 34 (10.59%), endocrine disorders 16 (4.98% ), physical and psychical supra solicitation 22 (6.85%), head trauma 11 ( 3.42% ), therapy with corticosteroizi  from another disease (for example erithematous systemic lupus) 5 (1.55%) therapy with AINS  drugs 21 (6.54%), use decongestion nasal 4 (1.24%) repetitive urinary tract infection 28 (8.72%), syphilis 11 (3.42%)(p<0,001). Loggie JMH [2] in a studies with  hypertension in the young reported the streptococcus infection with Streptococcus β hemolytic group A was 18.2% , chronic ORAL infection focus was 8.9%, chronic stomathological focus infections was 3.98%, glomerulonephritis was 6.2% and  physical and psychical supra solicitation was 12.43% in personal pathological antecedents.

3.   Changes of retinal vascular were insufficiently studied in young adults. In my study this changes appear for the optic fund may show no more than retinal arteriolar narrowing 103 cases represent 32.09% and arterio venous nicking 98 cases represent 30.53% , hemorrhages and exudates I rarely found from 9 cases represent 2.8%, papilla edema may be absent except 2 cases even with hypertension was very severe more than 200/120mmHg and complicate with encephalopathy and 109 cases represent 33.96% was normal result of funduoscopic examination (p<0.001).

Skalina MEL et al. [3] observations: 281 hypertensive young patients 140 have changes for the optic fund arterio venous nicking 93 cases, hemorrhages found from 7 cases and exudates appear from 40 patients. 141 patients have the optic fund examination normal.

4.   The heart is not often clinically enlarged and the ECG and chest X-ray are usually unhelpful in detecting left ventricular hypertrophy unless hypertension has been prolonged and severe. In my studies left ventricular hypertrophy was present in 35 cases (10.49%), they are helpful in determining chronicity of hypertension and from 206 cases (64.174%) left ventricular hypertrophy was absent, that suggest that if negative, they tell one nothing about the duration of hypertension. The results are in concordance with observation with Laird WP and Fixler DE [4] who reports after performing chest X-ray for 210 young hypertensive, 103 have normal results, 78 have elongation and elevated of left inferior arcos and 29 present’s cardiomegaly.

5.   The echocardiogram seems to be more sensitive for evaluating chamber size and wall thickness than the ECG and can be helpful. Left atria hypertrophy and left ventricular hypertrophy (Sokolow-Lyon index) and left axial deviation it’s possible to detect. In my studies I found 35 cases (10.49%) with LVH, 36 cases (11.21%) with LAH and 35 cases (10.49%) with left axial deviation. Secondary changes of depolarization like ST segment sub elevated and negative T wave I found from 35 cases represent 10.49% (p<0,001).The results are in concordance with observation with Laird WP and Fixler DE [4], who reports than 18% from young hypertensive subject, presents left ventricular hypertrophy detected after echocardiography examination, end in concordance with observation with Schieken RM et al. [5] in Muscatine studies who reports more than 14% from young hypertensive subjects have left ventricular hypertrophy after make echocardiography examination.

6.   Proteinuria I detect in 96 cases (29.90%) and hematuria in 38 cases (11.83%).This changes appear in context of acute  glomerulonephritis and hypertension was secondary renal.

Schmider et al. [6] sustained that glomerular hyperfiltration is a early marker for nefroangiosclerosis and a sign for subclinical organ affected.

7. OMS stadialization classification high blood pressure in three stages. In my study about hypertension in young adults the results are: in stages I found 270 cases represents 84.11%, in stages II 40 cases represents 12.46%, in stages III 9 cases (2.80%) and malign hypertension 2 cases represents 0.62%.


  • 1. Importance of genetic factors in etiologies of disease is suggested that family aggregation of hypertension in young adults and another familial diseases like hyperaldosteronism, polycystic kidney and multiple endocrine diseases II.
  • 2. Importance of personal pathologic antecedents demonstrated in my study that repetitive Streptococcus angina with Streptococcus β hemolytic group A was found in the first place as a cause of hypertension in the young people in context of acute streptococcal renal parenchymatous diseases.
  • 3. Except nonspecific symptoms of high blood pressure exist specifically symptoms who suggest etiology of hypertension with young people.
  • 4. The fundoscopic findings in the young adult with hypertension are frequently normal. In the absence of prior readings, one needs to look for evidence of target organ damage that may suggest chronicity. In my study this changes appear for 86 cases 23.3 %  and hemorrhages and exudates I rarely found from 9 cases represent 2.8% and papilla edema may be absent except 2 cases even with hypertension is very severe more than 200/120mmHg and complication of encephalopathy.
  • 5. Left ventricular hypertrophy is possible to detect X-ray, ECG and echocardiography. In my studied I detected left ventricular hypertrophy from 35 patients represent 10.49%.
  • 6. Proteinuria 96 cases (29.90%) have two significance:  nephropathy complication of high blood pressure, or etiology in context or glomerulonephritis alone or accompaniment with hematuria 38 cases (11.83%) in nephritis syndrome.
  • 7. Renin plasmatic level is very important marker of high blood pressure in the young. Was high in 121 cases (37.69%).This situation suggests that hypertension in the young is hiperreninemic hypertension in many cases because young adults have hyperactivity of sympatetic nervous system.
  • 8. OMS classification evaluated stages I 270 cases (84.11%), stages II 40 cases (12.46%) in stages III 9 cases (2.80%) and malign hypertension (stages IV) 2 cases (0.62%)
  • 9. Finally I make a small guideline about hypertension with young patients group of ages 18-35, which I hope to help activity of every physician indifferent specialties in your practice, to use for diagnosis and easy work.


1. Kotchen JM “Effect of relative weight on familial blood pressure aggregations“ Am J Epidemiol.1987 105-214.

2. Loggie JMH. “The diagnostic evaluation of adolescents with hypertension.” In Hunt JC, Dreifus LS, Dustan HP et al, eds Dialogues in Hypertension Update II vol 1. Lyndhurst, NJ: Health Learning Systems 1984:43-56.

3. Skalina MEL et al.:  Annable WL, Kleigman RM, Fanaroff AA “ Hypertensive retinopathy in the adolescent“ J Adolesc. 1983:103:781-6.

4. Laird WP and Fixler DE. “Left ventricular hypertrophy in adolescents with elevated blood pressure: assessment by chest roentgenography, electrocardiography and echocardiography.” Adolescents 2001;67:255-9.

5.Schieken RM and coauthors: Clarke WR, Lauer RM, “Left ventricular hypertrophy in the young with blood pressures in the upper quin-tile of the distribution: the Muscatine study.” Hypertenesion 2004;3:669-75.

6. Schmider and coauthors: Messerli FH, Garavaglia GE, Nunez BD “Glomerular hyperfiltration indicates target organ disease in essential hypertension.” Circulation 2003; 76: III-273.


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Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 5/29, 2013

Renal Denervation Safe in Real-World Setting

By Todd Neale, Senior Staff Writer, MedPage Today

Published: May 25, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points:

PARIS — May 21-24, 2013

Out in everyday practice, renal denervation with the Symplicity device safely lowers blood pressure in patients with hypertension, preliminary results from the Global SYMPLICITY registry showed.

The Global SYMPLICITY registry is part of the clinical program evaluating the Symplicity device. It has been approved for use in Europe and elsewhere but remains restricted to investigational use in the U.S. Medtronic, which makes the Symplicity device, announced on Thursday that it has completed enrollment in Symplicity HTN-3, the pivotal U.S. trial.

The registry has a targeted enrollment of about 5,000 patients from about 200 centers worldwide; 149 sites spread throughout Canada, Mexico, South America, Europe, Africa, the Middle East, Asia, and Australia have already started collecting data.

Any patient who receives renal denervation can be included in the registry, and thus the study will include patients with hypertension and other conditions associated with increased sympathetic activity, including heart failure, insulin resistance, atrial fibrillation, sleep apnea, and chronic kidney disease.

European Society of Cardiology‘s recently published consensus paper on renal denervation, which recommended treatment in patients with a systolic blood pressure of 160 mm Hg or higher (or at least 150 mm Hg for type 2 diabetics) who were taking at least three antihypertensive medications, including a diuretic.


Expert consensus document from the European Society of Cardiology on catheter-based renal denervation


Most of the first 617 patients included the registry (60%) were treated in accordance with the European Society of Cardiology’s recently published consensus paper on renal denervation, above.

About one-fifth of the patients (22%) started with a systolic blood pressure of at least 180 mm Hg, which was the average baseline blood pressure in the Symplicity HTN-1 and HTN-2 trials.

The average starting blood pressure overall was 164/89 mm Hg, and patients were taking an average of 4.35 medications. Common comorbidities included diabetes (38.2%), renal disease (30.1%), sleep apnea (16.3%), a history of cardiac disease (49%), heart failure (9.3%), and atrial fibrillation (11.9%).

The registry data showed significant drops in blood pressure measured both in the office and with 24-hour ambulatory monitoring, although the reductions were smaller than those seen in the clinical trials.

That’s not surprising, according to Mahfoud, because out in everyday practice blood pressure is not recorded as appropriately as in a clinical trial setting and poor compliance to medication becomes more of an issue. In fact, he said, a recent study showed that 47% of patients with resistant hypertension were not adherent to their medication regimens.

Also contributing to the smaller reductions in the real-world population is the fact that the average starting blood pressure was lower than in the clinical trials, Mahfoud said, adding that it is known that renal denervation induces greater reductions in blood pressure among those with the highest readings initially.

Mahfoud reported receiving institutional grant/research support from Medtronic, St. Jude, Recor, and serving as a consultant for St. Jude, Medtronic, Boston Scientific, and Cordis. Medtronic makes the Symplicity renal denervation device.

 Primary source: European Association of Percutaneous Cardiovascular Interventions


Mahfoud F, et al “Early results following renal denervation for treatment of hypertension in a real-world population: the Global SYMPLICITY registry” EuroPCR 2013.

Adverse Events:
Of the first 617 patients included in the registry, only two had vascular complications related to access during the procedure, and none had serious events stemming from delivery of the radiofrequency energy to the renal artery; the rate of vasospasm was 9%, according to Felix Mahfoud, MD, of Saarland University Medical Center in Homburg/Saar, Germany.Through 6 months of follow-up, there were two hospitalizations for hypertensive crisis, two myocardial infarctions, one new case of end-stage renal disease from nephrotoxic overdose, and one death that was not considered to be related to the procedure, he reported at the EuroPCR meeting here.The procedure was not only safe, but also effective at lowering blood pressure, with reductions in office-based readings ranging from 13/6 mm Hg among patients with a baseline systolic blood pressure of 140 mm Hg or higher to 28/18 mm Hg among those with a baseline systolic pressure of 180 mm Hg or higher at 3 months. The findings were similar at 6 months.

“The take-home message will be hopefully … that renal denervation is a safe procedure providing blood pressure lowering in patients with high blood pressure at baseline and that that procedure might have an impact on clinical outcomes,” Mahfoud said in an interview.

Positive Effects of Renal Denervation Ablation for Hypertension in Controlled Randomized SYMPLICITY HTN-2 Trial

Renal Nerve Ablation Effects on BP Lasting

Download Complimentary Source PDF 

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: January 08, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Late-term results from a study of the safety and effectiveness of renal denervation to reduce hypertension mirrored positive results seen earlier in the randomized SYMPLICITY HTN-2 trial, researchers found.

The mean reduction in systolic blood pressure at 1 year post procedure was a significant 28.1 mmHg (P<0.001), similar to the mean 31.7 mmHg drop at 6 months (P=0.16 for the comparison), according to Murray Esler, MD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and colleagues.

Those in the control group who crossed over to the intervention at 6 months also had a significant fall in systolic blood pressure from a mean 190 to 166 mmHg (P<0.001), researchers reported in the January issue of Circulation: Journal of the American Heart Association.

The increasing prevalence of hypertension is a worldwide phenomenon, with an estimated 1.56 billion predicted to be affected in 2025, the authors noted. Yet, many of these patients cannot control their blood pressure (with control being defined as a pressure <140/90 mmHg) even when taking three or more antihypertensive medications.

Esler and colleagues cited a 2005 study that found a range of 47% to 87% of people in North America and Europe whose blood pressure is not under control (Lancet 2005; 365: 217-223).

Renal denervation has shown promise in these patients who are refractory to medication. The percutaneous procedure uses energy such as radiofrequency waves to scar the renal artery in an attempt to disrupt the sympathetic nerves, thereby affecting blood pressure.

Three-year data from the nonrandomized SYMPLICITY HTN-1 study were in line with 2- and 1-year results, showing a mean drop of 33/19 mmHg associated with the intervention.

In the current study, researchers from the multi-center randomized controlled SYMPLICITY HTN-2 trial enrolled 106 patients with essential hypertension (systolic blood pressure ≥160 mmHg, or ≥150 mmHg for diabetics). Patients were taking at least three antihypertensive medications.

The initial 1-year data from the SYMPLICITY HTN-2 trial were reported at the 2012 American College of Cardiology meeting. The primary endpoint was a change in systolic blood pressure at 6 months. Also at the 6-month mark, patients in the control group were allowed to cross over and receive the treatment; they were then followed for 6 more months.

The 6-month data were based on 101 patients (49 in the treatment group versus 51 controls). The 1-year data were based on 47 patients in the primary treatment group and 35 per-protocol controls who crossed over. The crossover patients also had to have a systolic blood pressure of ≥160 mmHg.

The significant decrease of 28.1 mmHg in systolic blood pressure in the treatment arm at 1 year was matched by significant drops in diastolic blood pressure at 6 and 12 months, as well as in the crossover group at 6 months (P<0.001 for all).

The authors reported that 84% of initial denervation patients had a decrease of at least 10 mmHg at 6 months; at 1 year, the number was 79%. In the crossover group, that rate was 63% at 6 months.

Interestingly, there was no significant difference in the changes in medication — reduced dosage or fewer drugs — between the treatment arm and controls, despite the reduction in blood pressure for the treatment arm.

“These data further substantiate the safety of renal sympathetic denervation via delivery of controlled radiofrequency energy bursts,” Esler and colleagues concluded.

They also noted that renal function remained unchanged at both 6 and 12 months. A pilot study by the Melbourne group looking specifically at patients with chronic kidney disease found renal denervation to be safe in this population.

The limitations to the current study include the lack of 24-hour blood pressure monitoring and the lack of blinding among the staff measuring blood pressure. The investigators noted that the ongoing SYMPLICITY HTN-3 trial addresses these limitations.

This study was funded by Medtronic Ardian.

Esler and three co-authors reported receiving research support from Medtronic Ardian. During the conduct of the trial, senior author Sobotka was chief medical officer of Ardian, and was a medical adviser to Medtronic.

From the American Heart Association:


Other articles on this topic on this Open Access Online Scientific Journal:

Lev-Ari, A. (2012aa). Renal Sympathetic Denervation: Updates on the State of Medicine



Lev-Ari, A. (2012U). Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics


Lev-Ari, A. (2012C). Treatment of Refractory Hypertension via Percutaneous Renal Denervation


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Reported by: Dr. Venkat S. Karra, Ph.D.

Recent study by Margareta Ring, et.al., indicates that Arterial Structure and Function in Mild Primary Hyperparathyroidism Is Not Directly Related to Parathyroid Hormone, Calcium, or Vitamin D.

They found normal arterial function, despite high PTH and Ca as well as low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors.

English: Main complications of persistent high...

The cardiovascular risk associated with low vitamin D and/or high PTH and Ca levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on the arterial structure, author said. Research findings support the importance of adequate blood pressure control in PHPT if PTX is not performed, but do not indicate vascular abnormalities motivating extended follow-up after PTX.




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