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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.

Abstract

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.

SOURCE:

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

PRE-ECLAMPSIA

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.

http://www.preeclampsia.org/health-information/about-preeclampsia?gclid=CNeVjpG537cCFUYaOgodC0QASg

VIEW VIDEO – SIX Sections, Pauses in between

http://on.aol.com/video/preeclampsia-vs–pregnancy-induced-hypertension-484063856

  • 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).

Thrombophilia

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

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145161/?report=printable

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.

http://www.mayoclinic.com/health/high-blood-pressure-in-pregnancy/MY02263

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


Posted Thursday , June 06,2013

preeclampsia

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.

http://bionews-tx.com/news/2013/06/06/texas-a-and-m-new-data-for-the-treatment-of-preeclampsia-preclinical-research-shows-plx-cells-may-be-effective-in-treating-preeclampsia/

REFERENCE

http://www.preeclampsia.org/health-information/about-preeclampsia?gclid=CNeVjpG537cCFUYaOgodC0QASg

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  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.

REFERENCES ON THE GENETICS of PRE-ECLAMPSIA in

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145161/?report=printable

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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

https://pharmaceuticalintelligence.com/2013/05/24/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

https://pharmaceuticalintelligence.com/2013/05/17/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

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

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

https://pharmaceuticalintelligence.com/2013/05/11/arterial-elasticity-in-quest-for-a-drug-stabilizer-isolated-systolic-hypertension-caused-by-arterial-stiffening-ineffectively-treated-by-vasodilatation-antihypertensives/

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

https://pharmaceuticalintelligence.com/2013/05/07/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

https://pharmaceuticalintelligence.com/2013/05/04/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

https://pharmaceuticalintelligence.com/2012/05/29/445/

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

https://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

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

https://pharmaceuticalintelligence.com/2013/02/09/an-important-marker-of-hypertension-in-young-adults/

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

https://pharmaceuticalintelligence.com/2013/02/09/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

ABSTRACT

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.

http://pediatrics.aappublications.org/content/early/2013/06/05/peds.2012-3426.abstract?sid=1755f2a0-4e03-4bc8-a563-23458d9dc988

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:

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C. Prediction of cardiovascular events and

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et al. Lifetime fruit and vegetable consumption

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Young Finns Study. Circulation. 2010;122

(24):2521–2528

 

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Young Finns Study. Int J Epidemiol. 2008;37

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Pulse sounds and measurement of diastolic

blood pressure in children. Lancet.

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et al. Analysis of cardiovascular responses

to passive head-up tilt using continuous

pulse wave analysis and impedance cardiography.

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Simultaneous non-invasive assessment of

arterial stiffness and haemodynamics—

a validation study. Clin Physiol Funct Imaging.

2003;23(1):31–36

 

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

 

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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.

2009;119(17):2408–2416

 

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

(11):795–802

 

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

Abstract

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.

http://hyper.ahajournals.org/content/early/2013/05/20/HYPERTENSIONAHA.113.00859.abstract.html?papetoc

 

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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

Abstract

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.

http://hyper.ahajournals.org/content/early/2013/05/20/HYPERTENSIONAHA.113.01039.abstract.html?papetoc

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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

 

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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

FULL NETWORK ACCESS
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.

https://play.google.com/store/apps/details?id=air.iElastance

 

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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

and

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.

 

Class

Description

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

Class

Example

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:

http://en.wikipedia.org/wiki/Statin

Clinical Considerations of Statin Therapy’s manifold effects, in

https://pharmaceuticalintelligence.com/2012/10/08/statins-nonlipid-effects-on-vascular-endothelium-through-enos-activation/

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

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

and

https://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

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.

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

and

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

and

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

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.

https://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

and

https://pharmaceuticalintelligence.com/2012/10/20/nitric-oxide-and-sepsis-hemodynamic-collapse-and-the-search-for-therapeutic-options/

and

https://pharmaceuticalintelligence.com/2012/10/17/chronic-heart-failure-personalized-medicine-two-gene-test-predicts-response-to-beta-blocker-bucindolol/
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:

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

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.

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

and

https://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

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

Affiliations

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

Contributions

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.

 http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12105.html

  • Genetic Therapy to Conductivity Disease

https://pharmaceuticalintelligence.com/2012/10/01/ngs-cardiovascular-diagnostics-long-qt-genes-sequenced-a-potential-replacement-for-molecular-pathology/

  • Regenerative Medicine for Vasculature Function Protection

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

and

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

and

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

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.”

http://www.theheart.org/article/1502067.do

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.

http://www.theheart.org/article/1093553.do

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.

http://arxiv.org/abs/1305.0727v2

http://arxiv.org/pdf/1305.0727v2.pdf

 

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

Abstract

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)).

Conclusions

  • 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

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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

https://pharmaceuticalintelligence.com/2013/05/24/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

https://pharmaceuticalintelligence.com/2013/05/17/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

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

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

https://pharmaceuticalintelligence.com/2013/05/07/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

https://pharmaceuticalintelligence.com/2013/05/04/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

 

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